ASCO Guidelines Podcast Series

Dr. Ko Un “Clara” Park and Dr. Mylin Torres present the latest evidence-based changes to the SLNB in early-stage breast cancer guideline. They discuss the practice-changing trials that led to the updated recommendations and topics such as when SLNB can be omitted, when ALND is indicated, radiation and systemic treatment decisions after SLNB omission, and the role of SLNB in special circumstances. We discuss the importance of shared decision-making and other ongoing and future de-escalation trials that will expand knowledge in this space. Read the full guideline update, “Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer: ASCO Guideline Update” at www.asco.org/breast-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-00099       Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Ko Un "Clara" Park from Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Dr. Mylin Torres from Glenn Family Breast Center at Winship Cancer Institute of Emory University, co-chairs on “Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer: ASCO Guideline Update.” Thank you for being here today, Dr. Park and Dr. Torres. Dr. Mylin Torres: Thank you, it's a pleasure to be here. Brittany Harvey: And before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Torres and Dr. Park, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. To start us off, Dr. Torres, what is the scope and purpose of this guideline update on the use of sentinel lymph node biopsy in early-stage breast cancer? Dr. Mylin Torres: The update includes recommendations incorporating findings from trials released since our last published guideline in 2017. It includes data from nine randomized trials comparing sentinel lymph node biopsy alone versus sentinel lymph node biopsy with a completion axillary lymph node dissection. And notably, and probably the primary reason for motivating this update, are two trials comparing sentinel lymph node biopsy with no axillary surgery, all of which were published from 2016 to 2024. We believe these latter two trials are practice changing and are important for our community to know about so that it can be implemented and essentially represent a change in treatment paradigms. Brittany Harvey: It's great to hear about these practice changing trials and how that will impact these recommendation updates. So Dr. Park, I'd like to start by reviewing the key recommendations across all of these six overarching clinical questions that the guideline addressed. So first, are there patients where sentinel lymph node biopsy can be omitted? Dr. Ko Un "Clara" Park: Yes. The key change in the current management of early-stage breast cancer is the inclusion of omission of sentinel lymph node biopsy in patients with small, less than 2 cm breast cancer and a negative finding on preoperative axillary ultrasound. The patients who are eligible for omission of sentinel lymph node biopsy according to the SOUND and INSEMA trial are patients with invasive ductal carcinoma that is size smaller than 2 cm, Nottingham grades 1 and 2, hormone receptor-positive, HER2-negative in patients intending to receive adjuvant endocrine therapy, and no suspicious lymph nodes on axillary ultrasound or if they have only one suspicious lymph node, then the biopsy of that lymph node is benign and concordant according to the axillary ultrasound findings. The patients who are eligible for sentinel lymph node biopsy omission according to the SOUND and INSEMA trials were patients who are undergoing lumpectomy followed by whole breast radiation, especially in patients who are younger than 65 years of age. For patients who are 65 years or older, they also qualify for omission of sentinel lymph node biopsy in addition to consideration for radiation therapy omission according to the PRIME II and CALGB 9343 clinical trials. And so in those patients, a more shared decision-making approach with the radiation oncologist is encouraged. Brittany Harvey: Understood. I appreciate you outlining that criteria for when sentinel lymph node biopsy can be omitted and when shared decision making is appropriate as well. So then, Dr. Torres, in those patients where sentinel lymph node biopsy is omitted, how are radiation and systemic treatment decisions impacted? Dr. Mylin Torres: Thank you for that question. I think there will be a lot of consternation brought up as far as sentinel lymph node biopsy and the value it could provide in terms of knowing whether that lymph node is involved or not. But as stated, sentinel lymph node biopsy actually can be safely omitted in patients with low risk disease and therefore the reason we state this is that in both SOUND and INSEMA trial, 85% of patients who had a preoperative axillary ultrasound that did not show any signs of a suspicious lymph node also had no lymph nodes involved at the time of sentinel node biopsy. So 85% of the time the preoperative ultrasound is correct. So given the number of patients where preoperative ultrasound predicts for no sentinel node involvement, we have stated within the guideline that radiation and systemic treatment decisions should not be altered in the select patients with low risk disease where sentinel lymph node biopsy can be omitted. Those are the patients who are postmenopausal and age 50 or older who have negative findings on preoperative ultrasound with grade 1 or 2 disease, small tumors less than or equal to 2 cm, hormone receptor-positive, HER2-negative breast cancer who undergo breast conserving therapy. Now, it's important to note in both the INSEMA and SOUND trials, the vast majority of patients received whole breast radiation. In fact, within the INSEMA trial, partial breast irradiation was not allowed. The SOUND trial did allow partial breast irradiation, but in that study, 80% of patients still received whole breast treatment. Therefore, the preponderance of data does support whole breast irradiation when you go strictly by the way the SOUND and INSEMA trials were conducted. Notably, however, most of the patients in these studies had node-negative disease and had low risk features to their primary tumors and would have been eligible for partial breast irradiation by the ASTRO Guidelines for partial breast treatment. So, given the fact that 85% of patients will have node-negative disease after a preoperative ultrasound, essentially what we're saying is that partial breast irradiation may be offered in these patients where omission of sentinel node biopsy is felt to be safe, which is in these low risk patients. Additionally, regional nodal irradiation is something that is not indicated in the vast majority of patients where omission of sentinel lymph node biopsy is prescribed and recommended, and that is because very few of these patients will actually end up having pathologic N2 disease, which is four or more positive lymph nodes. If you look at the numbers from both the INSEMA and the SOUND trial, the number of patients with pathologic N2 disease who did have their axilla surgically staged, it was less than 1% in both trials. So, in these patients, regional nodal irradiation, there would be no clear indication for that more aggressive and more extensive radiation treatment. The same principles apply to systemic therapy. As the vast majority of these patients are going to have node-negative disease with a low risk primary tumor, we know that postmenopausal women, even if they're found to have one to three positive lymph nodes, a lot of the systemic cytotoxic chemotherapy decisions are driven by genomic assay score which is taken from the primary tumor. And therefore nodal information in patients who have N1 disease may not be gained in patients where omission of sentinel lymph node biopsy is indicated in these low risk patients. 14% of patients have 1 to 3 positive lymph nodes in the SOUND trial and that number is about 15% in the INSEMA trial. Really only the clinically actionable information to be gained is if a patient has four or more lymph nodes or N2 disease in this low risk patient population. So, essentially when that occurs it's less than 1% of the time in these patients with very favorable primary tumors. And therefore we thought it was acceptable to stand by a recommendation of not altering systemic therapy or radiation recommendations based on omission of sentinel nodes because the likelihood of having four more lymph nodes is so low. Dr. Ko Un "Clara" Park: I think one thing to add is the use of CDK4/6 inhibitors to that and when we look at the NATALEE criteria for ribociclib in particular, where node-negative patients were included, the bulk majority of the patients who were actually represented in the NATALEE study were stage III disease. And for stage I disease to upstage into anatomic stage III, that patient would need to have pathologic N2 disease. And as Dr. Torres stated, the rate of having pathologic N2 disease in both SOUND and INSEMA studies were less than 1%. And therefore it would be highly unlikely that these patients would be eligible just based on tumor size and characteristics for ribociclib. So we think that it is still safe to omit sentinel lymph node biopsy and they would not miss out, if you will, on the opportunity for CDK4/6 inhibitors. Brittany Harvey: Absolutely. I appreciate you describing those recommendations and then also the nuances of the evidence that's underpinning those recommendations, I think that's important for listeners. So Dr. Park, the next clinical question addresses patients with clinically node negative early stage breast cancer who have 1 or 2 sentinel lymph node metastases and who will receive breast conserving surgery with whole breast radiation therapy. For these patients, is axillary lymph node dissection needed? Dr. Ko Un "Clara" Park: No. And this is confirmed based on the ACOSOG Z0011 study that demonstrated in patients with 1 to 3 positive sentinel lymph node biopsy when the study compared completion axillary lymph node dissection to no completion axillary lymph node dissection, there was no difference. And actually, the 10-year overall survival as reported out in 2017 and at a median follow up of 9.3 years, the overall survival again for patients treated with sentinel lymph node biopsy alone versus those who were treated with axillary lymph node dissection was no different. It was 86.3% in sentinel lymph node biopsy versus 83.6% and the p-value was non-inferior at 0.02. And so we believe that it is safe for the select patients who are early stage with 1 to 2 positive lymph nodes on sentinel lymph node biopsy, undergoing whole breast radiation therapy to omit completion of axillary lymph node dissection. Brittany Harvey: Great, I appreciate you detailing what's recommended there as well. So then, to continue our discussion of axillary lymph node dissection, Dr. Torres, for patients with nodal metastases who will undergo mastectomy, is axillary lymph node dissection indicated? Dr. Mylin Torres: It's actually not and this is confirmed by two trials, the AMAROS study as well as the SENOMAC trial. And in both studies, they compared a full lymph node dissection versus sentinel lymph node biopsy alone in patients who are found to have 1 to 2 positive lymph nodes and confirmed that there was no difference in axillary recurrence rates, overall survival or disease-free survival. What was shown is that with more aggressive surgery completion axillary lymph node dissection, there were higher rates of morbidity including lymphedema, shoulder pain and paresthesias and arm numbness, decreased functioning of the arm and so there was only downside to doing a full lymph node dissection. Importantly, in both trials, if a full lymph node dissection was not done in the arm that where sentinel lymph node biopsy was done alone, all patients were prescribed post mastectomy radiation and regional nodal treatment and therefore both studies currently support the use of post mastectomy radiation and regional nodal treatment when a full lymph node dissection is not performed in these patients who are found to have N1 disease after a sentinel node biopsy. Brittany Harvey: Thank you. And then Dr. Park, for patients with early-stage breast cancer who do not have nodal metastases, can completion axillary lymph node dissection be omitted? Dr. Ko Un "Clara" Park: Yes, and this is an unchanged recommendation from the earlier ASCO Guidelines from 2017 as well as the 2021 joint guideline with Ontario Health, wherein patients with clinically node-negative early stage breast cancer, the staging of the axilla can be performed through sentinel lymph nodal biopsy and not completion axillary lymph node dissection. Brittany Harvey: Understood. So then, to wrap us up on the clinical questions here, Dr. Park, what is recommended regarding sentinel lymph node biopsy in special circumstances in populations? Dr. Ko Un "Clara" Park: One key highlight of the special populations is the use of sentinel lymph node biopsy for evaluation of the axilla in clinically node negative multicentric tumors. While there are no randomized clinical trials evaluating specifically the role of sentinel lymph nodal biopsy in multicentric tumors, in the guideline, we highlight this as one of the safe options for staging of the axilla and also for pregnant patients, these special circumstances, it is safe to perform sentinel lymph node biopsy in pregnant patients with the use of technetium - blue dye should be avoided in this population. In particular, I want to highlight where sentinel lymph node biopsy should not be used for staging of the axilla and that is in the population with inflammatory breast cancer. There are currently no studies demonstrating that sentinel lymph node biopsy is oncologically safe or accurate in patients with inflammatory breast cancer. And so, unfortunately, in this population, even after neoadjuvant systemic therapy, if they have a great response, the current guideline recommends mastectomy with axillary lymph node dissection. Brittany Harvey: Absolutely. I appreciate your viewing both where sentinel lymph node can be offered in these special circumstances in populations and where it really should not be used. So then, Dr. Torres, you talked at the beginning about how there's been these new practice changing trials that really impacted these recommendations. So in your view, what is the importance of this guideline update and how does it impact both clinicians and patients? Dr. Mylin Torres: Thank you for that question. This update and these trials that inform the update represent a significant shift in the treatment paradigm and standard of care for breast cancer patients with early-stage breast cancer. When you think about it, it seems almost counterintuitive that physicians and patients would not want to know if a lymph node is involved with cancer or not through sentinel lymph node biopsy procedure. But what these studies show is that preoperative axillary ultrasound, 85% of the time when it's negative, will correctly predict whether a sentinel lymph node is involved with cancer or not and will also be negative. So if you have imaging that's negative, your surgery is likely going to be negative. Some people might ask, what's the harm in doing a sentinel lymph node biopsy? It's important to recognize that upwards of 10% of patients, even after sentinel lymph node biopsy will develop lymphedema, chronic arm pain, shoulder immobility and arm immobility. And these can have a profound impact on quality of life. And if there is not a significant benefit to assessing lymph nodes, particularly in someone who has a preoperative axillary ultrasound that's negative, then why put a patient at risk for these morbidities that can impact them lifelong? Ideally, the adoption of omission of sentinel lymph node biopsy will lead to more multidisciplinary discussion and collaboration in the preoperative setting especially with our diagnostic physicians, radiology to assure that these patients are getting an axillary ultrasound and determine how omission of sentinel lymph node biopsy may impact the downstream treatments after surgery, particularly radiation and systemic therapy decisions, and will be adopted in real world patients, and how clinically we can develop a workflow where together we can make the best decisions for our patients in collaboration with them through shared decision making. Brittany Harvey: Absolutely. It's great to have these evidence-based updates for clinicians and patients to review and refer back to. So then finally, Dr. Park, looking to the future, what are the outstanding questions and ongoing trials regarding sentinel lymph node biopsy in early-stage breast cancer? Dr. Ko Un "Clara" Park: I think to toggle on Dr. Torres's comment about shared decision making, the emphasis on that I think will become even more evident in the future as we incorporate different types of de-escalation clinical studies. In particular, because as you saw in the SOUND and INSEMA studies, when we de-escalate one modality of the multimodality therapy, i.e., surgery, the other modalities such as radiation therapy and systemic therapy were “controlled” where we were not de-escalating multiple different modalities. However, as the audience may be familiar with, there are other types of de-escalation studies in particular radiation therapy, partial breast irradiation or omission of radiation therapy, and in those studies, the surgery is now controlled where oftentimes the patients are undergoing surgical axillary staging. And conversely when we're looking at endocrine therapy versus radiation therapy clinical trials, in those studies also the majority of the patients are undergoing surgical axillary staging. And so now as those studies demonstrate the oncologic safety of omission of a particular therapy, we will be in a position of more balancing of the data of trying to select which patients are the safe patients for omission of certain types of modality, and how do we balance whether it's surgery, radiation therapy, systemic therapy, endocrine therapy. And that's where as Dr. Torres stated, the shared decision making will become critically important. I'm a surgeon and so as a surgeon, I get to see the patients oftentimes first, especially when they have early-stage breast cancer. And so I could I guess be “selfish” and just do whatever I think is correct. But whatever the surgeon does, the decision does have consequences in the downstream decision making. And so the field really needs to, as Dr. Torres stated earlier, rethink the workflow of how early-stage breast cancer patients are brought forth and managed as a multidisciplinary team. I also think in future studies the expansion of the data to larger tumors, T3, in particular,reater than 5 cm and also how do we incorporate omission in that population will become more evident as we learn more about the oncologic safety of omitting sentinel lymph node biopsy. Dr. Mylin Torres: In addition, there are other outstanding ongoing clinical trials that are accruing patients right now. They include the BOOG 2013-08 study, SOAPET, NAUTILUS and the VENUS trials, all looking at patients with clinical T1, T2N0 disease and whether omission of sentinel lymph node biopsy is safe with various endpoints including regional recurrence, invasive disease-free survival and distant disease-free survival. I expect in addition to these studies there will be more studies ongoing even looking at the omission of sentinel lymph node biopsy in the post-neoadjuvant chemotherapy setting. And as our imaging improves in the future, there will be more studies improving other imaging modalities, probably in addition to axillary ultrasound in an attempt to accurately characterize whether lymph nodes within axilla contain cancer or not, and in that context whether omission of sentinel lymph node biopsy even in patients with larger tumors post-neoadjuvant chemotherapy may be done safely and could eventually become another shift in our treatment paradigm. Brittany Harvey: Yes. The shared decision making is key as we think about these updates to improve quality of life and we'll await data from these ongoing trials to inform future updates to this guideline. So I want to thank you both so much for your extensive work to update this guideline and thank you for your time today. Dr. Park and Dr. Torres. Dr. Mylin Torres: Thank you. Dr. Ko Un "Clara" Park: Thank you. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Irene Su and Dr. Alison Loren present the latest evidence-based recommendations on fertility preservation for people with cancer. They discuss established, emerging, and investigational methods of fertility preservation for adults and children, and the role of clinicians including discussing the risk of infertility with all patients. Dr. Su and Dr. Loren also touch on other important aspects of fertility preservation, including the logistics of referral to reproductive specialists, navigating health insurance, and costs. They also discuss ongoing research and future areas to explore, including risk stratification, implementing screening, referral, and navigation processes in lower resource settings, fertility measurements, and health care policy impacts. Read the full guideline update, “Fertility Preservation in People with Cancer: ASCO Guideline Update” at www.asco.org/survivorship-guidelines." TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/survivorship-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology,  https://ascopubs.org/doi/10.1200/JCO-24-02782   In this guideline, the terms "male" and "female" were defined based on biological sex, specifically focusing on reproductive anatomy at birth. "Male" refers to individuals born with testes, while "female" refers to those born with ovaries. The guideline, and this podcast episode, we will refer to individuals as "males" or "females" based on this definition. Brittany Harvey Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Irene Su from the University of California, San Diego, and Dr. Alison Loren from the University of Pennsylvania, co-chairs on “Fertility Preservation in People With Cancer: ASCO Guideline Update.” Thank you for being here today, Dr. Su and Dr. Loren. Dr. Irene Su: Thanks for having us. Dr. Alison Loren: Thanks for having us. Brittany Harvey: Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Su and Dr. Loren, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to jump into the content here, Dr. Loren, this is an update of a previous ASCO guideline. So what prompted this update to the 2018 guideline on fertility preservation? And what is the scope of this particular update? Dr. Alison Loren: Yeah, thanks, Brittany. So, yeah, a couple of things, actually. I would say the biggest motivation was the recognition that the field was really moving forward in several different directions. And we felt that the previous guidelines really hadn't adequately covered the need for ongoing reproductive health care in survivorship, including the fact that fertility preservation methods can be engaged in even after treatment is finished. And then also recognizing that there is increasing data supporting various novel forms of fertility preservation in both male and female patients. And we wanted to be able to educate the community about the wide array of options that are available to people with cancer, because it really has changed quite a bit even in the last six years. And then lastly, as I'm sure this audience, and you definitely know, ASCO tries to update the guidelines periodically to make sure that they're current. So it sort of is due anyhow, but I would say motivated largely by those changes in the field. Brittany Harvey: Great. I appreciate that background information. So then I'd like to dive a little bit more into those updates that you discussed. So, Dr. Su, I'd like to review the key recommendations across the main topics of this guideline. So starting with what are the recommendations regarding discussing the risk of infertility with patients undergoing cancer treatment? Dr. Irene Su: Thanks, Brittany. So for every child, adolescent, and adult of reproductive age who's been diagnosed with cancer, the recommendation remains that healthcare clinicians should discuss this possibility of infertility as early as possible before treatment starts, because that allows us, as reproductive endocrinologists and fertility specialists, to preserve the full range of options for fertility preservation for these young people. Where it's possible, I think risk stratification should be a part of the clinical infertility risk counseling and then the decision making. And then for patients and families who have an expressed interest in fertility preservation, and for those who are uncertain, the recommendation is to refer these individuals to reproductive specialists. And it turns out this is because fertility preservation treatments are medically effective for improving post-treatment fertility and counseling can ultimately reduce stress and improve quality of life, even for those who don't undergo fertility preservation. And as Dr. Loren said, a change in the guideline is specifically about continuing these discussions post-treatment yearly or when cancer treatments change because that changes their infertility risk or when pregnancy is being considered. Brittany Harvey: Absolutely. Discussing that risk of infertility at the beginning, before any treatment is initiated, and when treatment changes, is key. So then talking about the options for patients, Dr. Loren, what are the recommended fertility preservation options for males? Dr. Alison Loren: There has been a little bit of an evolution in options for male patients. The standard of care option which is always recommended is cryopreservation of sperm, or otherwise known as sperm banking. And this is something that should be offered ideally prior to initiating cancer directed therapy. The guideline does reflect the fact that we're starting to understand in a little bit more depth the impact of cancer-directed treatments on the health and quantity of sperm. And so trying to understand when, if ever, it's appropriate to collect sperm after initiation of treatment, but before completion of treatment remains an area of active research. But the current understanding of the data and the evidence is that sperm banking should be offered prior to initiating cancer-directed therapy. And all healthcare clinicians should feel empowered to discuss this option with all pubertal and post-pubertal male patients prior to receiving their treatment. We do offer a little bit more information about the ideal circumstances around sperm banking, including a minimum of three ejaculates of sufficient quality, if possible, but that any collections are better than no collections. We also talk about the fact that there is a relatively new procedure known as testicular sperm extraction, which can be offered to pubertal and post-pubertal males who can't produce a semen sample before cancer treatment begins. There remains no evidence for hormonal protection of testicular function - that has been a long-standing statement of fact and that remains the case. And then we also begin to address some of the potential risk of genetic damage in sperm that are collected soon after initiation of cancer-directed therapy. We are starting to understand that there is a degradation in the number and DNA integrity of sperm that can occur even after a single treatment. And so, really highlighting the fact that collecting samples, again, to Dr. Su's point, as early as possible and as many as possible to try to optimize biological parenthood after treatment. Brittany Harvey: Yes. Thank you for reviewing those options and what is both recommended and not recommended in this scenario. So then, following those recommendations, Dr. Su, what are the recommended fertility preservation options for female patients? Dr. Irene Su: There are a number of established and effective methods for fertility preservation for people with ovaries, and this includes freezing embryos, freezing oocytes, freezing ovarian tissue. For some patients, it may be appropriate to do ovarian transposition, which is to surgically move ovaries out of the field of radiation in a conservative gynecologic surgery, for example, preserving ovaries or preserving the uterus in people with gynecologic cancers. We do recommend that the choice between embryo and oocyte cryopreservation should be guided by patient preference and clinical considerations, their individual circumstances, including future flexibility, the success rates of embryo versus egg freezing that we detail more in the guideline, and legal considerations. And what is new in this guideline, as Dr. Loren alluded to earlier, is consideration of post-treatment fertility preservation for oocyte and embryo freezing. And this is going to be because, for some females, there's going to be a shortened but residual window of ovarian function that may not match when they are in their life ready to complete their families. And so for those individuals, there may be an indication to consider post-treatment fertility preservation. We clarify that gonadotropin releasing hormone agonists, GNRH agonists, while they shouldn't be used in the place of established fertility preservation methods, e.g., oocyte and embryo freezing, they can definitely be offered as an adjunct to females with breast cancer. Beyond breast cancer, we don't really understand the benefits and risks of GNRH agonists and feel that clinical trials in this area are highly encouraged. And also, that for patients who have oncologic emergencies that require urgent chemotherapy, these agonists can be offered because they can provide additional benefits like menstrual suppression. What's emerging is in vitro maturation of oocytes. It's feasible in specialized labs. It may take a little bit shorter time to retrieve these oocytes. There are cases of live births following IVM, in vitro maturation, that have been reported. But these processes remain inefficient compared to standard controlled ovarian stimulation. And therefore, it's really being treated as an emerging method. Finally, uterine transposition. It's experimental, but it's a novel technique for us. It's really moving the uterus out of the field of radiation surgically. We recommend that this is done under research protocols. So taken together, there are improvements in fertility preservation technology, and consideration of which of any of these methods really depends on tailoring to what is that patient's risk, what is the time that they have, what is feasible for them, and what is the effectiveness comparatively among these methods for them. Brittany Harvey: I appreciate you reviewing those recommendations and considerations of patient preferences, the clarification on GNRH agonists, and then those emerging and experimental methods as well. So then the next category of recommendations, Dr. Loren, what are the recommended fertility preservation options for children? Dr. Alison Loren: Thanks, Brittany. This remains a very challenging area. Certainly for older children and adolescents who have begun to initiate puberty changes, we support proceeding with previously outlined standard methods of either sperm or oocyte collection and cryopreservation. For younger children who are felt to be at substantial risk for harm to fertility, the really only options available to them are gonadal tissue cryopreservation, so ovarian tissue or testicular tissue cryopreservation. As Dr. Su mentioned, the ovarian tissue cryopreservation methods are quite effective and well established. There's less data in children, but we know that in adults and older adolescents that this is an effective method. Testicular cryopreservation remains experimental, and we suggest that if it is performed, that strong consideration should be given to doing this as an investigational research protocol. However, because these are the only options available to children, we understand there may be reasons why there might need to be some flexibility around this in the proper setting of informed consent and ascent when appropriate for children. Brittany Harvey: Absolutely. And so we've discussed a lot of recommendations on fertility preservation options. So, Dr. Loren, what is recommended regarding the role of clinicians in advising people about these fertility preservation options? Dr. Alison Loren: Yeah, this is a really important question, Brittany, and I think that we really hope to empower the entire oncology clinical team to bring these issues to the forefront for patients. We know from qualitative studies that oncology providers sometimes feel uncomfortable bringing these issues up because they feel inexpert in dealing with them or because it's so overwhelming. Obviously, these are usually younger patients who are not expecting a cancer diagnosis, and there can be quite a lot of distress, understandably, around the diagnosis itself and the treatment plan, and it can be sometimes overwhelming to also bring up fertility as a potential risk of therapy. We are seeing that as patients are becoming more familiar and comfortable kind of speaking up, I think, social media and lots of sort of online communities have raised this issue, that we're seeing that young people with cancer do spontaneously bring this up in their visits, which we really appreciate and encourage. But I think sometimes clinicians feel it's sometimes described as a dual crisis of both the cancer diagnosis and a risk to future fertility and it can be a really challenging conversation to initiate. I feel, and we hope that the guidelines convey, that the whole point is just to bring it up. We do not expect an oncology clinician of any kind, including social workers, nurses, to be able to outline all of the very complex options that are articulated in this guideline. And in fact, the reason that the co-chairs include myself, a hematologist oncologist, and Dr. Su, who's a reproductive specialist, is because we understand that the complex reproductive options for our patients with cancer require expert conversations. So we do not expect the oncology team to go into all the guideline options with their patients. We really just want to empower everyone on the team to bring up the issue so that we can then get them the care that they need from our colleagues in reproductive endocrinology so that they can be fully apprised of all of their options with enough time before initiation of treatment to be able to embark on whichever therapies they feel are most suited to their family planning wishes. Brittany Harvey: Absolutely. And then jumping off of that, as a reproductive endocrinologist, Dr. Su, what do you think clinicians should know as they implement these updated recommendations? Dr. Irene Su: I wholly echo what Dr. Loren has said about- this is a team effort and it's been really fun to work as a team of various specialties on this guideline, so we hope that the guideline really reflects all of the partnerships that have occurred. I think that what clinicians should know is it may be well worth spending some time in identifying a pathway for our patients. So that starts off with the oncology team. How are we going to screen? How are we going to screen with fidelity? And then from the time of screening, really anybody who has an interest or potentially is unsure about their future fertility needs, who are the reproductive specialists, male and female, that you are in the community with to refer to? What is that referral process going to be like? Is it emails? Is it a phone? Is it a best practice advisory in your electronic health record system? From our standpoint as fertility specialists, we need to spend some time implementing in this system a way to receive these referrals urgently and also be able to support insurance navigation. Because actually, what is really exciting in this field is for the purpose of equitable access, there is increasing insurance coverage, whether it is because employers feel that this is the right thing to do to offer, or 17 states and the District of Columbia also have state mandates requiring fertility preservation coverage by many insurances, as well as, for example, federal employees and active military members. So more than ever, there is a decreased cost barrier for patients and still early days, so navigating health insurance is a little bit challenging. And that is the role, in part, of navigators and fertility clinic teams to help support these patients to do that. Dr. Alison Loren: Forming these relationships and reinforcing them so early and often is really key. Because although these patients come up with some infrequency, when they occur, they're really emergencies and we want to make sure that there's a well-established path for these patients to get from their oncology clinicians to the reproductive specialists. And as Dr. Su said, whatever works best for your system - there's a lot of different ways that people have tackled these challenging referrals - but it is really important to have an expedited path and for the receiving reproductive specialist office to understand that these are urgent patients that need to be expedited and that the oncology clinician's responsibility is to make sure that that's communicated appropriately. Brittany Harvey: Definitely. Thinking in advance about those logistics of referral and navigating health insurance and cost is key to making sure that patients receive the care that they want and that they'd like to discuss with clinicians. So then, Dr. Loren, you touched on this a little bit earlier in talking about the dual crisis, but how does this guideline impact people diagnosed with cancer? Dr. Alison Loren: Well, what we're hoping is that this is sort of a refresher. I think that many or hopefully most or all oncology clinicians are aware that this is a potential concern. And so part of our hope is that, as this guideline rolls out, it'll sort of bring to the top of people's memories and action items that this is an important part of oncology care is the reproductive health care of our patients. And it's a critical component of survivorship care as well. We want to remind people that the field continues to advance and progress. In oncology, we're very aware of oncologic progress, but we may not be so aware of reproductive healthcare progress. And so letting people know, “Hey, there's all these new cool things we can do for people that open up options, even in situations where we might have thought there were no options before.” It's a reminder to refer, because we're not going to be able to keep up with all the advances in the field. But Dr. Su and her colleagues will be able to know what might be an option for patients. I want to highlight that communication piece again because our reproductive colleagues need to know what treatments are going to be given, what the urgency is, what the risks are. And so part of our responsibility as part of the team is to make sure that it's clear to both our patients and our reproductive specialist colleagues what the risks are. And Dr. Su mentioned this earlier, but one really important open question is risk stratification. We know that not all cancer treatments are created equal. There are some treatments, such as high dose alkylating agents, such as cyclophosphamide or busulfan, or high doses of radiation directly to the gonadal tissue, that are extremely high risk for causing permanent gonadal harm very immediately after exposure. And there are other therapies, particularly emerging or novel therapies, that we really just have no idea what the reproductive impact will be. And in particular, as patients are living longer, which is wonderful for our patients, how do we integrate reproductive care and family building into the management of perhaps a younger person who's on some chronic maintenance therapies, some of which we know can harm either the developing fetus or reproductive health, and some of which we really don't know at all. And so there's a very large open question around emerging therapies and how to counsel our patients. And so we hope that this guideline will also raise to the forefront the importance of addressing these questions moving forward and helping our patients to understand that we don't necessarily have all the answers either, which we hope will enrich the discussion and really have it be a good example of shared decision making between the clinical teams and the patient, so that ultimately the patients are able to make decisions that make the most sense for them and reduce the potential for decision regret in the future. Dr. Su, I know you have spent a lot of time thinking about this. Dr. Irene Su: Yeah. I really echo this notion that not all cancer treatments are going to be toxic to future reproductive function. And as clinicians, I and colleagues know that patients want to know as much when there is no effect on their fertility, because that feels reassuring in that that prevents them from having to go through the many hoops that sometimes it can be to undergo fertility preservation, as it is to know high risk, as it is to know we don't know. This is key and central, and we need more data. So, for example, we often chat about, wouldn't it be great if from the time of preclinical drug development all the way to clinical trials, that reproductive health in terms of ovarian function, testicular function, fertility potential, is measured regularly so that we are not having to look back 30, 40, 50 years later to understand what happened. And so this is one of our key research questions that we hope the field takes note of going forward. Dr. Alison Loren: This is an important point. We focus greatly, as we should, on potential harms to fertility, making sure that there's access to all the reproductive options for young people with cancer. But to Dr. Su's point, not all therapies are created equal, and there are some therapies that are somewhat lower risk or even much lower risk, including, I'm a blood cancer specialist and so certainly in the patients that I take care of, the treatments related to AML, ALL, and some lymphomas are actually fairly low risk, which is why the post-treatment fertility preservation options are so important. And particularly for patients who potentially present acutely ill with acute leukemia do not have the time or the ability to engage in fertility preservation because of their medical circumstances, it's important to have that conversation. I want to emphasize to oncology clinicians that even if you know medically that this patient is unable to undergo fertility preservation techniques at the time of diagnosis of their cancer, that it's still appropriate to talk about it and to say, “We're going to keep talking about this, this is something that we're going to raise again once you're through this initial therapy. I'm not forgetting about this. It may not be something we can engage in now, but it's a future conversation that's important in your ongoing care.” And then to think about pursuing options when possible, particularly for patients who may require a bone marrow transplant in their future, either due to higher risk disease at presentation or in the event of a relapse, we know that generally bone marrow transplants, because of the high intensity conditioning that they require for most patients who are young, that permanent gonadal insufficiency will be a fixture. And so there can be a window of time in between initial therapy and transplant where a referral might be appropriate. So my public service announcement is that it's never the wrong time to refer to a reproductive specialist. And sometimes people make assumptions about chemotherapy that, “Oh, they've already been treated, so there's nothing we can do,” and I want to make sure that people know that that's not true and that it's always appropriate to explore options. Dr. Irene Su: I think we talk a lot about how important screening and referral is and I can imagine that it's hard to actually know how to implement that. One of our other research questions to look out for is that we see a lot of tertiary care centers that have put together big teams, big resources, and that's not always feasible to scale out to all kinds of settings. And so what's emerging is: What are the key processes that have to happen and how can we adapt this screening, referral, financial navigation process from larger centers to smaller centers to less resource settings. So I guess my public service announcement is there's research in this area, there's focus in this area, so keep an eye out because there will be hopefully better tools to be able to fit in different types of settings. And more research is actually needed to be able to trial these different screening, referral, navigation processes in lower resource settings as well. Brittany Harvey: Absolutely. It's important to think about the research questions on how to improve both the delivery of fertility preservation options and the discussion of it, and it's important to recognize, as you mentioned, the different fertility risks of different cancer directed treatment options and the importance to have the conversations around this. So then just to expand on this notion a little bit, Dr. Su, we've touched on the research needed here in terms of discussing fertility options with patients and referring and then also in some of the experimental and emerging treatment options. So, what are the other outstanding research questions regarding fertility preservation for people with cancer? Dr. Irene Su: A couple others I'd like to add and then have Dr. Loren chime in in case I missed anything in all of our discussions, there's so many wants. So head to head comparisons of which method is best for which patient and what the long term outcomes are: How many kiddos? Do we complete family building? That is still missing. Being able to invest in novel methods from - there's fertoprotective agents that are being tested, potentially spermatogonial stem cell transplant. These are closer to clinical trials to really early research on ovarian, testicular, uterine biology. This is needed in order to inform downstream interventions. One of the questions that is unanswered is: After treatment starts, when is it safe to retrieve oocytes? And so this is a question because, for example, for our leukemia patients who are in the middle of treatment, when is it safe to retrieve eggs? And we don't know. And then post-treatment, for people who have a reduced window, when do you optimally have the most number of eggs or embryos that you can cryopreserve? That's unknown. But I think the question around once treatment has started, is recent exposure of anti-cancer treatments somehow mutagenic or somehow toxic to the oocytes with regard to long term offspring health? That is unanswered. I'm going to scope out a little bit and maybe policy nerd this a little bit. It's been very exciting to see advocacy, advocacy from our patients, from our clinicians on trying to improve health care policy. Like how can we use mandates to improve this delivery? But we actually don't know because actually the mandates from states that require health insurance coverage for fertility preservation, they vary. And so actually what are the key ingredients and policies that will ultimately get the most patients to the care they need? That is in question and would be really interesting. And so what is a part of this guideline which is not often seen in clinical guidelines, is a call for what we think are best practices for health insurance plans to help patients be able to access. And so this means that we recommend being specific and comprehensive in the coverage of these established fertility preservation services that have been recommended. And this means, for example, an egg freezing covering the whole process from consultation to office visits, to ultrasounds and laboratories, to medicines, to the retrieval, and then to long term storage. Because particularly for the youngest of our patients, these gametes could be frozen for a number of years and may not always be so affordable without health insurance coverage. We think that fertility preservation benefits really should be at parity, that you should not be having more cost sharing on the patient compared to other medical services that are covered. This is an inequity and where possible we should eliminate prior authorization because that timing is so short between diagnosis and needing to start anti-cancer treatment. And so prior authorization having to go through multiple layers of health insurance is really a key barrier because we all know that health insurance literacy is limited for all of us. And so whatever we can do to support our patient for the intent of these benefits would be recommended. Dr. Alison Loren: That was so well said, Dr. Su. I'll take the oncology perspective and say that from our side, really being able to understand the risks of infertility and understanding better measurements of fertility capacity, understanding where our patients are - every patient is different. These conversations are very different for a 37-year-old than they are for a 17-year-old. And so what we haven't really talked about is the fact that certainly at least female patients, as they age, their reproductive potential declines naturally. And so their infertility trajectory may be accelerated, they may have a shorter timeline or have less reserve than younger patients. And so being able to tailor our risk discussions not just based on the specific treatments, but on the reproductive age of the patient sitting in front of us and really being able to tailor those to very personalized risks would be really helpful. Because, as Dr. Su mentioned, and I think, as many people know, undergoing fertility preservation techniques can be really arduous. Even if they're covered and paid for, and all of those logistics are easy, which they seldom are, the physical drain of having to do injections, go for labs, all of the parts of those therapies can be really difficult for patients. And so being able to really understand who needs to have these interventions and who could pass, and understanding what the risks are, as I mentioned earlier, for these novel and emerging therapies would be really helpful. Another really important aspect of future research questions is we would like to encourage all clinicians, both reproductive specialists and oncology clinicians, and also our young people with cancer, to participate in clinical studies pertaining to fertility measurements and preservation. We also exhort our industry colleagues to consider including important reproductive endpoints, including biomarkers of ovarian and testicular reserve, if possible, in clinical trials. It will enhance our ability to provide counseling and support for these therapies in the future to be able to understand what the true impact of infertility, family building and health of offspring to be able to include these data in prospective databases and trials. Brittany Harvey: Definitely. And I want to thank you both for raising those really important points. So we'll look forward to this ongoing research and optimizing policies for covering fertility preservation benefits for all patients with cancer. I want to thank you both so much for your work to update this critical guideline and talk about these important needs of people with cancer. And thank you for your time today, Dr. Su and Dr. Loren. Dr. Alison Loren: Thanks so much for having us. Dr. Irene Su: You're welcome. This was really fun. Dr. Alison Loren: It was fun. And I just will add that the team at ASCO is amazing and really made this a pleasure. Dr. Irene Su: I couldn't agree more. And from the point of being a fertility specialist, being invited to be a part of this with ASCO and with all of our colleagues, it's been really amazing. And so thanks for allowing us to contribute. Brittany Harvey: Definitely. And a big thanks to the entire panel as well. And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Mellar Davis discusses the joint guideline from MASCC, ASCO, AAHPM, HPNA, and NICSO on opioid conversion in adults with cancer. He reviews the limited evidence, and the formal consensus process used to develop the guideline. He shares the key recommendations on pre-conversion assessment, how opioid conversion should be conducted, including opioid conversion ratios, and post-conversion assessment. We touch on gaps and questions in the field and the impact of these new recommendations.  Read the full guideline, “Opioid Conversion in Adults with Cancer: MASCC-ASCO-AAHPM-HPNA-NICSO Guideline” at www.asco.org/supportive-care-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/supportive-care-guidelines. Read the full text of the guideline in the Supportive Care in Cancer, https://link.springer.com/article/10.1007/s00520-025-09286-z   Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Mellar Davis from Geisinger Medical Center, lead author on “Opioid Conversion in Adults with Cancer: Multinational Association of Supportive Care and Cancer, American Society of Clinical Oncology, American Academy of Hospice and Palliative Medicine, Hospice and Palliative Nurses Association, Network Italiano Cure di Supporto and Oncologia Guideline.” Thank you for being here today, Dr. Davis. Dr. Mellar Davis: Thank you. I'm glad to be here. Brittany Harvey Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Davis, who has joined us here today, are available online with the publication of the guideline, which is linked in our show notes. So then, to dive into the content here, Dr. Davis, can you provide an overview of both the scope and purpose of this guideline on opioid conversion in people with cancer? Dr. Mellar Davis: This is an important topic in management of cancer pain and this topic came up as a result of a survey that MASCC had done, which involved 370 physicians in 53 countries. They were queried about how they change or convert one opioid to another, which is a common practice, and we found that there was quite a divergence in opioid conversion ratios. To step back a little bit, about two thirds of patients with advanced cancer have moderate to severe pain and most of the time they're managed by opioids. But about 20% or 40% require a switch either because they have an adverse reaction to it or they don't respond to it, or the combination of both. Rarely, it may be that they need a route change, perhaps because they have nausea or vomiting. So, the opioid conversion works basically because of the complexity of the new opioid receptor which has at least four exons to it as a result of that non-cross tolerance between opioids. As a result of the survey, we convened a group of specialists, 14 international specialists, to look to see if we could develop an international guideline. And we did a systematic review which involved viewing 21,000 abstracts and we came up with 140 randomized trials and 68 non-randomized trials. And after reviewing the data, we found that the data was really not strong enough to provide a guideline. As a result, ASCO, MASCC, the AAHPM, the HPNA and the Italian Group formed a supportive network that allowed us then to do a Delphi guideline based upon ASCO modified criteria for doing Delphi guidelines. And so we then involved 27 additional international experts informing the guideline to it. And this guideline is then the result of the Delphi process. It consists basically of a pre-conversion ratio recommendations, conversion ratios, which is actually a major contribution of this guideline, and then what to do after converting someone to another opioid. Our target audience was not only oncologists, but also we wanted to target nurses, pharmacists, hospitalists, primary care physicians, patients and caregivers. Brittany Harvey: I appreciate that background information, particularly on the evidence that is underpinning this and the lack of quality of evidence there, which really transformed this into a formal consensus guideline. We're glad to have all of these organizations coming together to collaborate on this guideline. So then next I'd like to review the key recommendations. So starting with, what is recommended for pre-conversion assessment? Dr. Mellar Davis: In regards to pre-conversion, physicians and clinicians need to be aware of pain phenotypes. That is, there are pains that are more opioid refractory than others, such as neuropathic pain, hence, they may be more resistant to the opioid that you're converting to. One needs to be aware of the fact that patients may not be compliant, they're either afraid of opioids not taking what was prescribed, so it's important to query patients about whether they are taking their opioid as prescribed. Occasionally, there are patients who will divert their medication for various reasons. Pain may be poorly controlled also because of dosing strategies that are poorly conceived, in other words, giving only ‘as needed' opioids for continuous cancer pain. And there are rare circumstances where an opioid actually induces pain and simply reducing the opioid actually may improve the pain. The other issue may be cancer progression. So that poorly controlled pain or rapidly increasing pain may actually be a result of progressive cancer and changing treatment obviously will be important. And you need to assess the pain severity, the quality of the pain, the radiating localizing effects, which does require not only a physical exam but also radiographic examinations. But the other thing that's very important in opioid conversions are pain scales with function. A significant number of patients don't quite understand a numerical scale which we commonly use: 0 to 10, with 10 being severe pain and 0 being no pain. They may in fact focus more on function rather than on pain severity or pain interference with daily activities or roles. Sometimes patients will say, “Oh, my pain is manageable,” or “It's tolerable,” rather than using a numerical scale. Choices of opioids may be based on cost, drug-drug interactions, organ function, personal history or substance use disorder so that one will want to choose an opioid that's safe when converting from one to another. And obviously social support and having caregivers present and understanding the strategy in managing pain will be important. Brittany Harvey: Thank you, Dr. Davis, for reviewing those pre-conversion assessment considerations and particularly the challenges around some of those. So, following this pre-conversion assessment, what are the recommendations on how opioid conversion should be conducted? Dr. Mellar Davis: Opioid conversions are basically the safe dose. People have used the term ‘equianalgesia', but the panel and the consensus group felt that that would be inappropriate. So a conversion ratio is the dose at which the majority of patients will not experience withdrawal or adverse effect. It would be the safe dose. Thereafter, the dose will need to be adjusted. So, in converting, that's only the first step in managing pain, the doses need to be adjusted to the individual thereafter. There are a significant number of conversions that are done indirectly, that is that there has not been a study that has looked at a direct conversion from one opioid to another in which one needs to convert through another opioid. We call that a ‘morphine equivalent daily dose'. So, most of the time a third opioid is used in the conversion. It allows you then to convert when there hasn't been a direct study that has looked at conversion between those two opioids, but it is less accurate and so one has to be a little bit more careful when using morphine daily equivalents. We found, and I think this is the major advantage to the guideline, is that commonly used opioids - oxycodone, morphine, hydromorphone - we did establish conversion ratios to which we found in the MASCC guideline they were widely divergent and hope that actually, internationally, they will be adopted. We also found some conversion ratios for second-line opioids. However, we felt also that an opioid like methadone, which has a unique pharmacology, should be left to experts and that experts should know at least several ways of converting from morphine usually to methadone. There is what appears to be a dose-related increased potency of methadone relative to morphine, which makes it more difficult, particularly at higher doses, to have an accurate conversion ratio. Most patients will have transient flares of pain. We came up with two suggestions. One is using a 10 or 15% of the around-the-clock dose for the breakthrough dose, but we also realized that there was a poor correlation between the around-the-clock dose and the dose used for transient flares of pain. And so the breakthrough dose really needs to be adjusted to the individual responses. There was also a mention of buprenorphine. One of the unique things about buprenorphine is that if you go from high doses of a drug like morphine to buprenorphine in a stop-start dosing strategy, you can precipitate withdrawal. And so one has to be careful and have some experience in using buprenorphine, which can be an effective analgesic. Brittany Harvey: Yes, I think that the conversion ratios that you mentioned that are in Table 3 in the full guideline are a really useful tool for clinicians in practice. And I appreciate the time that the panel and the additional consensus panel went through to develop these. I think it's also really key what you mentioned about these not being equianalgesic doses and the difficulties in some of these conversions and when people need to really look to specialists in the field. So then, following opioid conversion, what assessments are recommended post-conversion? Dr. Mellar Davis: Post-conversion, probably the cardinal recommendation is close observation for response and for toxicity. And I think that probably summarizes the important parts of post-conversion follow up. So assessment should be done 24-48 hours after conversion and patients followed closely. Assessment scales should include patient personalized goals. Now, it used to be in the past that we had this hard stop about a response being below 4 on a 0 to 10 scale, but each patient has their own personal goals. So they gauge the pain severity and their function based upon response. So a patient may function very well at “a severity of 5” and feel that that is their personal goal. So I think the other thing is to make sure that your assessment is just not rote, but it's based upon what patients really want to achieve with the opioid conversion. The average number of doses per day should be assessed in the around-the-clock dose so those should be followed closely. Adverse effects can occur and sometimes can be subtle. In other words, a mild withdrawal may produce fatigue, irritability, insomnia and depression. And clinicians may not pick up on the fact that they may be actually a bit under what patients have or they're experiencing withdrawal syndrome. It's important to look for other symptoms which may be subtle but indicating, for instance, neurotoxicity from an opioid. For instance, visual hallucinations may not be volunteered by patients. They may transiently see things but either don't associate with the opioid or are afraid to mention them. So I think it's important to directly query them, for instance, about visual hallucinations or about nightmares at night. Nausea can occur. It may be temporary, mild, and doesn't necessarily mean that one needs to stop the second opioid. It may actually resolve in several days and can be treated symptomatically. Pruritus can occur and can be significant. So close observation for the purposes of close adjustments are also necessary. As we mentioned, you want to start them on an around-the-clock of breakthrough dose, but then assess to see what their response is and if it's suboptimal then you'll need to adjust the doses based both upon the around-the-clock and the breakthrough dose or the dose that's used for breakthrough pain. Also looking at how patients are functioning, because remember that patients frequently look at pain in terms of function or interference with their roles during the day. So, if patients are able to do more things, that may, in fact, be the goal. Brittany Harvey: Thank you for reviewing all of these recommendations across pre-conversion assessment, how opioid conversion should be conducted, including conversion ratios, and what assessments are recommended after opioid conversion. I think it's really important to be watching for these adverse events and assessing for response and keeping in mind patient goals. So, along those lines, how will these guideline recommendations impact both clinicians and people with cancer? And what are the outstanding questions we're thinking about regarding opioid conversion? Dr. Mellar Davis: I think it's important to have a basic knowledge of opioid pharmacology. There's, for instance, drugs that are safer in liver disease, such as morphine, hydromorphone, which are glucuronidated. And there are opioids that are safer in renal failure, such as methadone and buprenorphine, which aren't dependent upon renal clearance. I think knowing drug-drug interactions are important to know. And sometimes, for instance, there may be multiple prescribers for a patient. The family physician's prescribing a certain medication and the oncologist is another, so being aware of what patients are on, and particularly over-the-counter medications which may influence opioid pharmacokinetics. So complementary medications, for instance, being aware of cannabis, if patients are using cannabis or other things, I think, are important in this. There are large gaps and questions and that's the last part of the guideline that we approach or that we mentioned that I think are important to know. And one is there may be ethnic differences in population in regards to clearance or cytochrome frequencies within communities or countries, which may actually alter the conversion ratios. This has not been explored to a great extent. There's opioid stigmata. So we are in the middle of an opioid crisis and so people have a great fear of addiction and they may not take an opioid for that reason, or they may have a relative who's been addicted or had a poor experience. And this may be particularly true for methadone and buprenorphine, which are excellent analgesics and are increasingly being used but may in fact have the stigmata. There are health inequalities that occur related to minority groups that may in fact not get the full benefit of opioid conversions due to access to opioids or to medical care. Age, for instance, will cause perhaps differences in responses to opioids and may in fact affect conversion ratios. And this may be particularly true for methadone, which we have not really explored to a great extent. And finally, the disease itself may influence the clearance or absorption of an opioid. So for a sick patient, the opioid conversion ratio may be distinctly different than in a healthy individual. This is particularly seen with transdermal fentanyl, which is less well absorbed in a cachectic patient, but once given IV or intravenously has a much longer half life due to alterations in the cytochrome that clears it. And so conversion ratios have frequently been reported in relatively healthy individuals with good organ function and not that frequently in older patient populations. So just remember that the conversion ratios may be different in those particular populations. Brittany Harvey: Yes. So I think a lot of these are very important things to consider and that managing cancer pain is key to quality of life for a lot of patients and it's important to consider these patient factors while offering opioid conversion. I want to thank you so much for your work to review the existing literature here, develop these consensus-based recommendations and thank you for your time today, Dr. Davis. Dr. Mellar Davis: Thank you. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Lyudmila Bazhenova joins us again to share the newest changes to the living guideline on therapy for stage IV NSCLC without driver alterations. She discusses new evidence reviewed by the panel and changes to second-line recommendations for patients with good performance status and HER2 overexpression, and what these updates mean in practice. We discuss ongoing evidence generation as we await further updates to these living guidelines. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02786     Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, co-chair on “Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3.” It's great to have you back on the show today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: It's my pleasure to be here as always. Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the entire guideline panel, including Dr. Bazhenova, who has joined us here today, are available online with the publication of the guide in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into the content here, first, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations has frequent updates to the recommendations. What prompted this latest update? Dr. Lyudmila Bazhenova: Living ASCO guidelines are created to keep up with rapidly changing evidence which affect treatment of our patients with lung cancer. As a committee, we review published literature on a specific topic at the regular intervals and determine if it alters any recommendations. This time, upon our literature review, we felt that there are new data that requires an update in the guidelines and therefore the guidelines were updated. Brittany Harvey: Great. Thank you for that updated information. So then it looks like the panel updated recommendations for second line and subsequent treatment options for patients with good performance status and HER2 overexpression. What is that updated recommendation from the panel? Dr. Lyudmila Bazhenova: Yes, this is correct. We now added an extra recommendation for patients with stage IV non-small cell lung cancer who have overexpression of the protein called HER2. HER2 overexpression with 2+/3+ level via immunohistochemistry is seen in approximately 8% to 20% of patients with lung cancer. And the data behind our recommendation comes from the DESTINY-Lung01 trial where patients with HER2 overexpression were treated with trastuzumab deruxtecan. And we saw that if patients with stage IV non-small cell lung cancer had a HER2 IHC score of 3+, overall response rate was seen at 53% and median duration of response was 6.9 months and, therefore, that in our opinion qualified for updated recommendation. We are still waiting for additional results that will be released later on another clinical trial where we see preliminary data presented at the World Conference of Lung Cancer in 2024. They looked at 36 patients also with HER2 overexpression and saw the overall response rate of almost 45%. It is important to highlight in this smaller study that a majority of the patients in the study were actually having EGFR mutation and the response rate in those patients who had an EGFR mutation was higher than the response rate in patients without EGFR mutations who just had a HER2 overexpression. So for now this is updated in the guidelines, but we will wait for additional data or formal publication of a World Lung Conference presentation and see if those recommendations need to be changed. Brittany Harvey: Understood, and I appreciate you providing the context of some of those ongoing developments as well. So then what should clinicians know as they implement this updated recommendation? Dr. Lyudmila Bazhenova: Number one, we should all start from remembering to test for HER2 via immunohistochemistry. There is a slight difference in what considers HER2 positive in lung versus breast. In lung, we use what's called the gastric scoring and the difference is the circumferential versus non circumferential staining of the membrane. And number two, immunohistochemistry is not always included in next generation sequencing panels. So when you order your next generation sequencing, I think it's important to know if your company that you're using is testing for HER2 via immunohistochemistry. And if it's not, make sure that you find a company that does or work with your local pathology department to make sure that this testing is offered. It is also important to know the difference between HER2 overexpression and HER2 exon 20 insertion mutation even though the treatment for those two abnormalities is the same, which is trastuzumab deruxtecan. But the benefit that you can cite your patients and the rigor of the literature supporting the usage of trastuzumab deruxtecan in mutation versus overexpression is different. Brittany Harvey: Yes. And as you mentioned, it's essential that, in the first place, patients are actually receiving the testing so that we know if they're eligible for these treatment options. So what additionally does this change mean for patients with stage IV non-small cell lung cancer and HER2 overexpression? Dr. Lyudmila Bazhenova: So for patients, it adds another treatment modality which is now FDA approved. So if there are patients listening to me, make sure that your physician has tested your tumor for HER2 overexpression. So I think proactive asking of your physician would be very appropriate in this situation. Brittany Harvey: Absolutely. And then earlier you mentioned an ongoing trial that the panel was looking to for the future. But what other additional trials did the panel review during this guideline update and what is the panel examining for future updates to this living guideline? Dr. Lyudmila Bazhenova: So at this point we reviewed three additional studies. The results of those studies did not make it into a change in guidelines. So we reviewed the HARMONi-2 trial.  HARMONi-2 trial so far does not have an official publication and, as per our strategy on how we come up with ASCO guidelines, we need to wait for an official publication. So this is one thing we're going to be expecting in the future. Once this is published, we will review it and decide if we need to make an additional change in recommendations. For those of you who are not aware, HARMONi-2 trial used bispecific monoclonal antibody against VEGF and PD-1 and was a phase III randomized trial comparing their investigational product which is called ivonescimab over pembrolizumab for patients with PD-L1 more than 50. And again, we are waiting for the final publication to make our recommendation. The second trial we reviewed was a LUNAR trial and the LUNAR trial looked at addition of tumor treating fields to chemotherapy or immunotherapy in patients whose cancer progressed with platinum doublet. The key point about this study is that immunotherapy was not required to be administered in a first line setting which is a current standard of care in the United States. And even though the study met their primary endpoint of overall survival, there were more benefits in patients who were immunotherapy naive in the second line. And we felt that given the potential lifestyle implication of wearing a device for 18 hours per day, and the lack of evidence in immunotherapy-pretreated population, and the absence of data in the first-line setting where we currently using immunotherapy in the United States, we felt that there is insufficient data to definitely recommend addition of tumor treating fields to systemic chemotherapy for most patients. And we are waiting for additional trials that are ongoing in this setting to formalize or change our recommendations. And we also reviewed- the final study that we reviewed was TROPION-Lung01. TROPION-Lung01 study was a phase III study in post platinum doublet setting which compared efficacy of Dato-DXd and docetaxel and trials showed improvement in progression free survival but not in overall survival. And progression free survival benefit was more pronounced in non-squamous carcinoma histology subgroup and we felt that the results do appear promising, but the strength of evidence which was based on unplanned subgroup analysis was not sufficient enough to make a change in treatment recommendation at this time. Brittany Harvey: I appreciate your transparency on why some of that data did not prompt a change to recommendations at this time. And additionally, we'll look forward to those future published results and potential incorporation of new data into future versions of this living guideline. So, I want to thank you so much for your work to rapidly and continuously update this guideline and for your time today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: It is my pleasure. Thank you so much. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the  Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  

Dr. Jyoti Patel is back on the podcast to discuss the updates to the living guideline on therapy for stage IV NSCLC with driver alterations. She shares updated recommendations in the first- and second-line settings for patients with stage IV NSCLC and classical EGFR mutations, and the impact of these updates for clinicians and patients. We also look to the future to discuss ongoing developments in the field. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02785     Brittany Harvey: Welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows including this one at asco.org/podcasts.   My name is Brittany Harvey and today I'm interviewing Dr. Jyoti Patel from Northwestern University, co-chair on “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3.” It's great to have you back on the show today, Dr. Patel. Dr. Jyoti Patel: Thanks so much. Happy to be here. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel, who has joined us here today, are available online with the publication of the guideline and in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content of this update, Dr. Patel, this clinical practice guideline for systemic therapy for patients with stage IV non small cell lung cancer with driver alterations is living, meaning that it's continuously reviewed and updated. So what data prompted this latest change to the recommendations? Dr. Jyoti Patel: Thanks so much. So it's really been an exciting time in the treatment of EGFR lung cancer, particularly this past year has required us to rethink approaches to front- and second-line therapy. In this particular update, we examined what patients in the front-line setting may be offered by their clinicians. And so we're talking about the population of classical EGFR mutations, so exon 19 and exon 21 L858R substitution. And so certainly for this population, osimertinib has a high level of evidence and should be offered to all patients at the time of diagnosis when they present with advanced disease. Our last update included a recommendation that patients could also get platinum doublet chemotherapy with osimertinib or osimertinib alone. This current recommendation also introduces another alternative therapy and that's the combination of amivantamab plus lazertinib. And so now, clinicians are faced with three really good options for their patients with EGFR exon19 deletion or L858R. Brittany Harvey: It's great to hear that there's this advance in the space, particularly for patients with these classical EGFR mutations that you mentioned. So what should clinicians know as they implement these new first-line recommendations? Dr. Jyoti Patel:  I think it's become more complex than ever. Certainly, we know again that patients should get osimertinib in the frontline setting. But we've been kind of stuck at progression-free survival that's between a year and a half and two years. And so we've really been looking at opportunities to intensify therapy. So one could certainly be with chemotherapy or switching over to amivantamab, the bispecific antibody that targets EGFR and MET plus lazertinib, an oral TKI that's very similar in structure to osimertinib. And when you're talking to a patient, it's really a conversation about balancing efficacy with toxicity. Unfortunately, as we know, there aren't that many free lunches. And so if we think about what a patient is hoping for in their therapy and how we can further personalize treatment options, really is important to look at some of the analyses for this study. So in the study of amivantamab plus lazertinib, we know that there were increased toxicities with a combination of both therapies. In fact, up to 75% of patients had over grade 3 toxicities, versus about 43% of patients with osimertinib monotherapy. And we know if we look back at FLAURA2, almost two thirds of patients with osimertinib and chemotherapy had grade 3 toxicities, compared to 27% of patients with osimertinib alone. So we certainly see an increase in toxicities. Then we have to ask ourselves, are those paper toxicities or ones that really impact patients? And we know that amivantamab, for example, causes significant cutaneous toxicities. With both of these therapies, whether it's chemotherapy or adding amivantamab, there's the burden of infusional visits and increased time in the doctor's office. Certainly with chemotherapy, there can be an increased incidence of myelosuppression. And so when we're thinking about advising our patients, certainly we need to talk about the toxicities. But one thing that we've been able to do is to look at the patients that were included in this trial. And what we really find is that in higher risk cohorts, particularly those that we know historically have done less well with standard osimertinib, so patients, for example, with CNS metastasis, for those patients with co-mutations, it may be that that additive benefit is significant. And so one example I think would be from the MARIPOSA study, again, the study of amivantamab and lazertinib versus chemotherapy. What we can say is that patients who had co-mutations, so patients with EGFR mutations as well as TP53, lazertinib and amivantamab led to a hazard ratio of 0.65 compared to osimertinib alone. So that was 18.2 months versus 12.9 months. And so this may be really important to patients. And we also see conversely that patients with wild type TP53, so those patients who didn't have the mutation, probably had equivalent survival regardless of therapy. So certainly, we need to prospectively study some of these high-risk cohorts. We've only seen progression-free survival in these studies. And so at this juncture, we can advise our patients about toxicity, the improvements in certain categories of progression-free survival, but we really still don't know how this pans out in overall survival. In many of these studies, all patients do not necessarily cross over to the study arm and so they may have lost the benefit of subsequent therapy. Brittany Harvey: Absolutely. It's very important to talk about that balance of benefits and risks and particularly those toxicities that you discussed. So I appreciate reviewing that recommendation and the considerations for clinicians for first-line therapy. This update also included a second-line treatment update. What is that update for patients with EGFR alterations? Dr. Jyoti Patel: So this is where it gets super tricky because we have a frontline option with amivantamab and now we've had an update in the second line option. So what we said is that for patients who have progressed on an EGFR TKI, and in the United States, certainly that's predominantly osimertinib, or those in other parts of the world that may have gotten an earlier generation TKI, but do not have evidence of T790M or other targetable mutations, we can offer patients chemotherapy with or without amivantamab. And so certainly we have seen that this again leads to improved survival. There have also been a number of studies looking at incorporation of PD-L1 and anti-VEGF therapies. And what we can say, I think pretty clearly is that multiple phase 3 trials have really shown no benefit of the addition of PD-1 to platinum chemotherapy. But there are some emerging bispecific antibodies that may target PD-1 as well as VEGF, or combinations of antibodies that target both of those pathways that may improve outcome. At this juncture, I think we feel that the evidence surrounding chemotherapy plus amivantamab is strongest, but there is certainly work in this space that will be of interest. Now, what happens if your patient received amivantamab and lazertinib in the frontline setting and then has progression? And so we're trying to understand resistance mechanisms and opportunities for treatment. What the panel decided to recommend, based on the available evidence, was that certainly those patients should get platinum-based chemotherapy, but there may also be a role for antivascular endothelial growth factor targeting therapy such as bevacizumab in patients in whom it would be safe. Brittany Harvey: Great. I appreciate you detailing those recommendations when it gets complicated in the second-line setting. So what should clinicians know as they implement these second-line recommendations too? Dr. Jyoti Patel: So certainly the frontline setting matters significantly. So if a patient gets osimertinib in the frontline setting, we generally suggest that patients undergo repeat testing to see if they have another targetable mutation. If they don't, then I think preferred therapy would be chemotherapy with or without amivantamab. And amivantamab leads to a significant improvement in progression-free survival and response rate at the cost of increased risk of toxicity. For patients who get FLAURA2 in the frontline setting, chemotherapy plus osimertinib, it's a little bit of an unclear space. Those patients most likely would get docetaxel with or without ramucirumab. But there are other agents that we hope to have available to our patients in the near future. For patients who receive amivantamab and osimertinib, we recommend that those patients get chemotherapy probably with anti-VEGF as demonstrated by multiple trials that have shown the improved progression-free survival with introduction of an anti-VEGF agent. And we've seen evidence of amivantamab in the third line setting, so it is likely that this question about sequencing really takes center stage in our next set of trials. When you're talking to a patient, I think again, it's absolutely important to discuss: What are their goals? How symptomatic or how fast is their progression? Are there ways in which patients may benefit from spot treatment oligoprogression such as radiation? When is the right time for introduction of amivantamab and when do we think patients need chemotherapy? Is it up front or predominantly in the second-line setting? Brittany Harvey: Definitely. And then you've just touched on the goals of treatment for individual patients. So in your view, what does this update mean for patients with stage IV non-small cell lung cancer and an EGFR alteration? Dr. Jyoti Patel: For patients, this is a time in which shared decision making really needs to take center stage. So our best patients are those patients that are best informed not only about their disease but also have a good understanding about what is important to them and their families in terms of care. And so bringing that shared understanding to the table again helps us think about this particular cancer as more of a journey rather than just a one off treatment. Therapy will hopefully be prolonged, and so it's absolutely important that we address toxicities, make therapies more tolerable, again, with the shared goal of living long and living well. Brittany Harvey: Absolutely. Those are key points to making sure that patients are living both longer and have a good quality of life during that time as well. So then, before you mentioned the possibility of future sequencing trials and other ongoing developments. What additional studies or future directions is the panel examining for future updates to this living guideline? Dr. Jyoti Patel: So certainly we're thinking about trials that look at, for example, cfDNA clearance. So are there patients that do well and can we detect that early on without having to intensify therapy on day 1 so it may be that we add chemotherapy a little bit later. I think really exciting are some of the new bispecific. The HARMONi-A trial was a trial in China of a novel bispecific, ivonescimab. And this drug targets both PD-1 and VEGF and it was combined with chemotherapy. And this trial found almost a doubling of progression-free survival with this drug in combination chemotherapy in an EGFR patient population. That study is being planned and being run in the United States to see if we have similar outcomes with a more diverse population. So certainly that's exciting. There are a number of antibody drug conjugates that are being studied in the post-chemotherapy setting as well. And I think we'll likely soon see a better understanding of what co-mutations and burden of disease really mean when we're thinking about assigning treatment. So which patients, again, need intensification of therapy and which patients may do really well on just an oral agent that they're taking at home with more tolerable toxicity than dual treatment. Brittany Harvey: Yes, we'll look forward to continued developments in these fields and seeing some of those studies come to fruition. So with that, I want to thank you for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Patel. Dr. Jyoti Patel: Thanks so much, Brittany. It's really an exciting time for lung cancer and we hope that these updates really help physicians decide the best treatments for their patients. Again, it's a rapidly evolving landscape which is fantastic, but it does become more cumbersome to stay ahead of the literature. Brittany Harvey: Definitely. And so we appreciate your time and the panel's time spent reviewing this literature and providing this much needed information to clinicians everywhere. So finally, thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the  Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Chris Holsinger shares the new guideline from ASCO on transoral robotic surgery (TORS) for patients with oropharyngeal squamous cell carcinoma. He reviews the evidence-based recommendations on baseline assessment, the role of TORS in HPV-positive and HPV-negative disease and in the salvage/recurrent setting, which patients are eligible or ineligible for TORS, and the role of adjuvant therapy. He discusses the importance of multidisciplinary collaboration and shared decision-making between patients and their clinicians. Read the full guideline, “Transoral Robotic Surgery in the Multidisciplinary Care of Patients with Oropharyngeal Squamous Cell Carcinoma: ASCO Guideline.”   TRANSCRIPT This guideline, clinical tools, and resources are available at asco.org. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology.   Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.    My name is Brittany Harvey and today I'm interviewing Dr. Chris Holsinger from Stanford University, lead author on “Transoral Robotic Surgery in the Multidisciplinary Care of Patients with Oropharyngeal Squamous Cell Carcinoma: ASCO Guideline.” Thank you for being here today, Dr. Holsinger. Dr. Chris Holsinger: Thanks, Brittany. We've been working together for years on these guidelines and what a pleasure to get to meet you at least virtually today. Brittany Harvey: Yes, it's great to have you on. And then just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Holsinger, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So let's jump into this important guideline. Dr. Holsinger, to start us off, can you provide an overview of both the scope and purpose of this guideline? Dr. Chris Holsinger: Absolutely. And again, thanks for the opportunity to be here, Brittany. I appreciate the invitation to participate in the ASCO Guidelines and to work with the great people on this paper that's now out there. I think it's a really important guideline to be published because it really talks about surgery, specifically transoral robotic surgery, a minimally invasive technique, as a new way to treat head and neck cancer. Why that's so important is that what is now known as head and neck cancer is completely different than what we saw even 25 years ago. Around the turn of the century, some really thoughtful epidemiologists working at Hopkins and UW in Seattle started to see this connection between the human papillomavirus and head and neck cancer. And since then we've seen this precipitous rise in the number of throat cancers specifically due to HPV. The results from the American Cancer Society showed last year that head neck cancer, in particular these cancers of the oropharynx, actually were one of the few cancers that still had an increasing incidence, I think it was around 2.5% per year. And other studies have shown that almost 50% of the cases we're seeing across the United States now are actually HPV-mediated throat cancers. That's bad news because we're seeing this rise in cases, but it's good news in the sense that this is a cancer that is highly curable and I think opens up a lot of different treatment avenues that we didn't have a couple of decades ago. And when patients are facing a mortality risk that's two or three times lower than the formerly HPV-negative smoking-driven cancers, it really behooves us as clinicians, as oncologists to think about treatment selection in a completely different way. And for years, the only function-sparing option, surgery certainly was not, was radiation therapy with concurrent cisplatin chemotherapy. In 2009, the FDA approved the use of surgical robotics using a transoral approach, a minimally invasive approach to resect the primary tumors and to perform neck dissection. And so now when patients walk in the door, they not only have this gold standard option in the path of radiation therapy with chemo, but also frontline surgery. And with some recent publications, especially the ECOG 3311 study, there's some really good evidence that for HPV-mediated throat cancers, we can actually de-escalate the intensity of adjuvant therapy when we start with surgery first. So who we choose that option for, which patients want that option - these are all really important new questions that we try to grapple with in these guidelines. Brittany Harvey: That background is really key for setting the stage for what we're about to talk about today. And so next I'd like to review the key recommendations across the clinical questions that the panel addressed. So you just talked about the importance of treatment selection. So to start that off, first, what is recommended for baseline assessment for patients with oropharyngeal squamous cell carcinoma who are being considered for transoral robotic surgery? Dr. Chris Holsinger: So I think here we tried in the guidelines to really standardize the workup and approach of this disease, in general, but with a strong focus on who might be a good surgical candidate. As I mentioned in the introduction, I mean, this is a disease that is very new. Our workup is in flux. And so what we tried to do, especially in items 1.2 and 1.3, is to really standardize and confirm that the tumor that we're dealing with, which oftentimes presents in a metastatic lymph node, is in fact associated with the human papillomavirus. So how biopsy is done, how high risk HPV testing is performed, whether you're doing that with an in situ hybridization, a DNA based study, or a p16 immunohistochemical study. And we try to tackle these issues first to really make sure that the patient population we're considering is actually indeed eligible for this kind of treatment de-escalation with surgery. Brittany Harvey: Understood. So it's important to consider which patients could be eligible for TORS upfront. So what is the role of TORS in patients with HPV-positive oropharyngeal squamous cell carcinoma? Dr. Chris Holsinger: Yeah, exactly. So I think first of all, surgery is ideally suited, and the robot is FDA approved for early-stage cancers - T1 and T2 cancers that are amenable to a minimally invasive approach. And we really try to emphasize, especially in our patient selection section of the guideline, who is really an ideal candidate for this. It's not just the T1 and T2 tumor. It's a tumor that is lateralized so that we can maybe consider managing the neck concurrently just on the side of the tumor, rather than doing bilateral neck dissection for most patients. Which patients might get the best functional outcome is a really critical component of this. And in fact, that actually goes back to a guideline that we didn't have time to chat about earlier, which is that we think every head neck cancer patient, whether or not they're being considered for transoral robotic surgery or frontline radiation therapy with cisplatin, every patient should have a pre-treatment assessment by a speech and swallowing expert. They're called different names across the country: speech language pathologists, speech pathologists, etc. But having a really good functional assessment of the patient's ability to swallow before treatment selection is really critical. And why that's important with frontline surgery is that there's a period of about one or two weeks after which that patient really needs intensive rehabilitation. And so for every patient being considered by TORS, we want to work really hand in hand with that speech pathologist to do pre-habilitation and then immediate post-operative rehab and then long longitudinal rehabilitation so that if radiation is needed down the road in a month, that patient just hopefully sails through this de-escalated treatment that we're offering. Brittany Harvey: Great. I appreciate you describing which patients can be considered for transoral robotic surgery. So beyond that, which patients with HPV-positive oropharyngeal squamous cell carcinoma aren't really good candidates for TORS? Dr. Chris Holsinger: We talked about that sort of ideal patient, but you know, we're not always living in an ideal world. And so I think it's important, and I'm really happy about the multidisciplinary discussions that led to these final guidelines because I think it helped engage radiation oncologists, medical oncologists, and surgeons around who's maybe not a good candidate for this because radiation therapy, with or without cisplatin chemotherapy, remains a good option for many of these patients. But I think the consensus, especially among the surgeons in this group, were that patients with tumors were more endophytic - that's the old fashioned oncology and surgical oncology term that refers to tumors that seem to not be as evident on the surface and have more of an infiltrative deep growth pattern - these are not ideal tumors. Whereas an exophytic tumor that's growing upwards, that's more readily seen on flexible endoscopy during a routine clinic assessment, or frankly, better seen on imaging, those exophytic tumors are better suited to a surgical approach because the surgeon has a better chance when he or she sees the tumor to get a good margin. When we can appreciate not just the surface mucosal margins that need to be taken, but also have a better chance to appreciate their depth. And with those infiltrative tumors, it's much harder to really understand how to get that deep margin, which in many cases is always the hardest. And so that's a long way to say that surgical decision making, patient selection is really critical when it comes to offering TORS as a multidisciplinary group. And then there are a few other things that we can quickly talk about before we move on to discussing adjuvant therapy. But I think there are some relative contraindications to patients who might have tumors arising in a palatine tonsil or tonsillar pillar, but which might grow significantly into the soft palate, such that a major palatal resection would be needed to get a good margin. For T1 and T2 tumors, we're not sure that that is an ideal candidate. And the other relative contraindication, but it's a hard and fast contraindication in my personal practice, is patients with extensive nodal disease. I think a patient who has preoperative extranodal extension, matted nodes, clinically and on MRI, you know pre-op they're going to need intensive post operative concurrent chemoradiation post-op that's maybe not the best patient for TORS, although there are some select cases where that that might make sense. But that's a quick overview of patient selection for TORS, Brittany. Hopefully, that's helpful. Brittany Harvey: That's definitely helpful. I think it's really important to consider not only who is eligible, but who isn't eligible for this de-escalation of treatment, and I appreciate you clarifying some of that. So then you've just also mentioned adjuvant therapy along with multidisciplinary discussion. So what is recommended regarding adjuvant therapy for patients who have resected HPV-positive oropharyngeal squamous cell carcinoma? Dr. Chris Holsinger: Definitely. And I think the post-operative discussion has to begin with great pre-op planning. And pre-op planning is really anchored in a really robust multidisciplinary team. So, we spoke earlier about the critical importance of getting speech language pathology involved initially, but they're part of a much larger team that includes not just a surgeon, but medical oncologist, a radiation oncologist and a dental oncologist - all of these specialties, and I could think of several others if we had time to chat further - this should also be really engaged in the care of these patients. But great decision making regarding adjuvant therapy really begins with a robust multidisciplinary consultation pre-op and we try to emphasize that in the guidelines. But just to return and answer your question very directly, I think adjuvant therapy is really the critical piece in getting that great functional outcome for a patient with HPV-mediated throat cancer. And I think traditionally patients who have a variety of different risks, based on a large study done again by the ECOG group, ECOG 3311, we showed that by stratifying patients based on their surgical pathology rather than on an estimate of disease extent, we can better stratify adjuvant therapy. And so the low risk patient is a patient with good margins and of course, good margin, we could spend another two hours discussing that. But good margins are greater than at least 1 to 3 millimeters superficially and a clear deep margin. Patients with lymph node metastases that are less than 3 cm and a single lymph node can sometimes be observed but most patients don't fall into that low risk category. Most patients fall into an intermediate risk where the margin is good and it's clear, but it might be close. That depends if you're talking about the superficial mucosal margin or the deep. But more often than not, we spend a lot of time considering the extent of lymph node involvement as it pertains to how adjuvant therapy is delivered. And I think for patients with less than 4 lymph nodes traditionally without extranodal extension, radiation therapy will suffice for adjuvant therapy after TORS. And the question of dose then comes up. Are we talking 50 Gray, the experimental arm that showed real promise in the ECOG 3311 trial, or 60 Gray or more traditional dose? And that is a topic definitely for another podcast, which we should do with a radiation oncologist online. I don't want to get into the weeds with that, but I refer you to our guidelines and Bob Ferris and Barbara Burtness' paper from JCO in 2021 for further details about that. But then for patients with positive margins with more than four lymph nodes, but especially patients with extranodal extension, the role of radiation therapy and chemotherapy is really absolutely critical. Because these patients and while they only accounted for around 20% to 30% of patients that we're seeing in this new era of TORS, they're the ones that we're really focusing on how can we do better because their overall survival is still good, it's 90%, but it's not as good as the patients we're seeing with a low and intermediate risk. So that's a brief overview there. Brittany Harvey: I appreciate that overview. And yes, we'll refer listeners to the full guideline, which is linked in the show notes of this episode to learn more about the intricacies of the radiation therapy that you mentioned. So then we've talked a lot about patients with HPV-positive disease, but what is the role of TORS in patients with HPV-negative disease? Dr. Chris Holsinger: I think TORS still has a role for these patients. Our colleague in India, Surender Dabas, has a really nice series that shows that for HPV-negative patients, this is a way for early stage cancers to potentially escalate the intensity of treatment for a disease that does worse than this new HPV-positive we're seeing in the US. So I think there's a good signal there. I think more study needs to be done and I think those studies, in fact, are underway in India and other countries. I hope that we can, as an oncology community here in the United States, also tackle this disease, which is still a significant part of the disease we face in head and neck oncology. Brittany Harvey: Yes, we'll look forward to more data coming out for HPV-negative disease. So then, the last clinical question that the guideline panel addressed: What is the role of TORS in the salvage or recurrent setting? Dr. Chris Holsinger: So we wrap up the guidelines tackling this topic. It's definitely something for the experienced TORS surgeon in consultation with that multidisciplinary team. Oftentimes, we are still seeing many patients who need salvage surgery and I think, while TORS alone could be a really effective treatment option, TORS with a microvascular reconstruction is oftentimes what is needed for these patients who, with recurrence, do often present with an RT 2, 3, 4 tumor. In my own practice, I found that using TORS as a way to minimize the superficial mucosal extent and then delivering that tumor through a traditional lateral pharyngotomy, then neck dissection and then having a microvascular flap inset done after that really provides the best possible chance for good long term function and of course control of the tumor. Here, I definitely refer the listener to some great work done out of the Royal Marsden with Vin Paleri, who we're happy to have on our TORS guideline panel for his RECUT study that really grapples in some detail with these very issues. Brittany Harvey: Excellent. And so we've covered a lot of the recommendations here that were made by the panel and you've touched a little bit about how this changes things for clinicians in practice. But what should clinicians know as they implement these new recommendations? Dr. Chris Holsinger: One thing as we close, I hope that in the future we can really start to grapple with this concept of patient selection. I think these guidelines help establish that TORS is a great oncologic option with - really the only option for treatment de-escalation in the here and now. Radiation therapy and cisplatin concurrent chemotherapy is going to be an option that is such an important choice for patients. And I think where I hope the field goes in the future is figuring out which patient wants one of these options. And I think certain patients really want that tumor taken out and others just the idea of surgery is not something that makes sense for them. How we in the context of a multidisciplinary team, really engage that patient, elicit their treatment preferences and then through considering treatment eligibility criteria that we've spelled out here for surgery and can be spelled out for chemo RT, bringing all that together in a formal shared decision making process is really where I hope the field will be going in the next few years. And hopefully these guidelines help to pave the way there. Brittany Harvey: Definitely the aspect of care by a multidisciplinary team and talking with patients to go through shared decision making is key to implementing these guidelines. So then, in that same vein, what do these recommendations mean for patients with oropharyngeal squamous cell carcinoma? Dr. Chris Holsinger: I think the central take home message for patients should be that especially if you have a T1 and T2 tumor, it's really important to have that consultation with a surgeon who knows how to do TORS and has a busy practice, but then also having an honest discussion up front about what the functional outcomes would be both with surgery and also chemo RT. And I think just knowing all those different options, that multidisciplinary treatment selection process is going to be that much more robust. And I think more right decisions will get made and we'll see less decisional regret down the road, which I think is a long term goal of our field. Brittany Harvey: Absolutely. That discussion of preferences is key. So then to wrap us up, you touched on this a little bit earlier in talking about ongoing research and data, particularly in the field of HPV-negative disease, but what are the outstanding questions regarding TORS in this patient population? Dr. Chris Holsinger: Yeah, I think that in addition to this work around shared decision making, I really hope that we'll embrace shared decision making in the context of future clinical trial. I think where we are now is you have surgeons saying, “Hey, TORS and 50 gray is a great option. Why aren't we doing that?” And then our colleagues, perhaps across the aisle, if I can use a political metaphor, are saying, “Well, where's the comparative data? Can we even do a randomized clinical trial between surgery and radiation?” Well, Christian Simon in Lausanne in Switzerland is trying to do this in a small pilot study being led by the EORTC, and I would encourage American investigators to consider something analogous. But I think how we solve this question of I think treatment choice is going to be pivotal for any such trial to ever be done. And then finally, I think, how will the changing treatment landscape around immunotherapy change this? There's some really provocative data that dates back to 1996 in a JCO paper from Ollivier Laccourreye and the University of Paris experience that showed induction chemotherapy followed by function preserving surgery in the larynx was a really powerful strategy for organ preservation, and that has never been followed up in the United States. And so especially with the upcoming presentation of KEYNOTE-689, will we be doing neoadjuvant approaches for patients and then following them by minimally invasive surgery or lower dose radiation? I think these are going to be some exciting new areas of study and I can't wait to see how this might evolve so we can refine the treatment - still get those great outcomes, but reduce those late toxicity. Brittany Harvey: Yes. We'll look forward to this ongoing research to continue to move the field forward. So, Dr. Holsinger, I want to thank you so much for your time to develop this important guideline. It's been great to have you on the podcast to discuss it today. Dr. Chris Holsinger: Well, thanks a lot Brittany. It's nice to finally meet you. Brittany Harvey: Likewise. And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Dr. Stéphanie Gaillard and Dr. Bill Tew share updates to the evidence-based guideline on neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer. They highlight recommendations across ten clinical questions, addressing initial assessment, primary cytoreductive surgery, neoadjuvant chemotherapy (NACT), tests and/or procedures that should be completed before NACT, preferred chemotherapy regimens, timing of interval cytoreductive surgery (ICS), hyperthermic intraperitoneal chemotherapy (HIPEC), post ICS-chemotherapy, maintenance therapy, and options for those without a clinical response to NACT. They highlight the evidence supporting these recommendations and emphasize the importance of this guideline for clinicians and patients. Read the full guideline update, “Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: ASCO Guideline Update” at www.asco.org/gynecologic-cancer-guidelines." TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Stéphanie Gaillard from Johns Hopkins University and Dr. Bill Tew from Memorial Sloan Kettering Cancer Center, co-chairs on “Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: ASCO Guideline Update.” Thank you for being here today, Dr. Gaillard and Dr. Tew. Dr. Bill Tew: Thank you for having us. Dr. Stéphanie Gaillard: Yeah, thank you. It's great to be here. Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Gaillard and Dr. Tew, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into the content here, first, Dr. Tew, could you describe what prompted this update to the neoadjuvant chemotherapy for ovarian cancer guideline? And what is the scope of this update? Dr. Bill Tew: Yeah. It's been almost a decade since ASCO first published its neoadjuvant chemotherapy guidelines for women with newly diagnosed ovarian cancer, and over that 10-year period, there's really been a major shift in how oncologists treat patients in the U.S. If you look at the National Cancer Database, between 2010 and 2021, the proportion of patients with advanced ovarian cancer who underwent primary surgery fell from about 70% to about 37%. And there's been a doubling in the amount of neoadjuvant chemotherapy used. So we wanted to take a look at that and really both highlight the appropriate patient populations for primary surgery versus new adjuvant chemotherapy, as well as review any studies that have been published since then. There's been, I think, about 61 trials published, nine randomized trials alone in the last 10 years. And the scope of the guideline was really not only the neoadjuvant chemotherapy and surgical questions, but also to touch upon some new treatments that have come to the forefront in newly diagnosed ovarian cancer, including heated intraperitoneal chemotherapy or HIPEC, as well as the integration of maintenance therapy, particularly bevacizumab and PARP inhibitors. Brittany Harvey: Understood. That's a large amount of new evidence to review in this Update. Then, next, Dr. Gaillard, I'd like to review the key recommendations across the 10 clinical questions that the guideline addressed. So, starting with: What is recommended regarding initial assessment for patients with newly diagnosed pelvic masses and/or upper abdominal or peritoneal disease? Dr. Stéphanie Gaillard: Sure. So in talking about the first guidelines, the first one that we addressed was how to do the initial assessment for these patients. And first, and probably most critically, it's important to recognize that these patients really should be evaluated by a gynecologic oncologist prior to initiation of any therapy, whether that means a primary cytoreductive surgery or neoadjuvant chemotherapy, because really, they are the best ones to determine the pathway that the patient should take. The initial assessment should involve a CA-125, a CT of the abdomen and pelvis with oral and IV contrast, if not contraindicated, and then also chest imaging, in which a CT is really the preferred modality. And that helps to evaluate the extent of disease and the feasibility of the surgical resection. Now, there may be some other tools that could be helpful to also refine this assessment. So, for example, a laparoscopy can really help to determine the feasibility of surgical resection as well as the extent of disease. Further imaging, such as diffusion-weighted MRI or FDG-PET scans can be helpful, as well as ultrasounds. And then also an endometrial biopsy. And that was newly added because there really has been a divergence of treatment for endometrial cancer versus ovarian cancer. And so it's really important to determine upfront where the source of the disease is coming from. Brittany Harvey: I appreciate you describing those recommendations surrounding initial assessment. So following this assessment, Dr. Tew, which patients with newly diagnosed advanced epithelial ovarian cancer should be recommended primary cytoreductive surgery? Dr. Bill Tew: The key thing here is if the GYN oncology surgeon feels that they have a high likelihood of achieving a complete cytoreduction with acceptable morbidity, the panel overwhelmingly agrees that primary cytoreduction surgery should be recommended over chemotherapy. And we know that surgery is really the cornerstone to achieving clinical remission. And our concern is that neoadjuvant chemotherapy may be overused in this fit population. Sometimes it is challenging to determine truly if a patient has a high likelihood of complete cytoreduction or what is acceptable morbidity. But an evaluation with performance status, fitness, looking at age or frailty, nutritional status, as well as a review of imaging studies to plan and determine for who is the right patient for primary surgery is key. Brittany Harvey: And then the title of this guideline, Dr. Gaillard, for which patients is neoadjuvant chemotherapy recommended? Dr. Stéphanie Gaillard: Yeah. So there's really two patient populations that we think are best suited to receive neoadjuvant chemotherapy. Those may be patients who are fit for a primary cytoreductive surgery, but they're unlikely to have a complete cytoreduction if they were to go to surgery directly. And so that's where neoadjuvant chemotherapy can be very helpful in terms of increasing the ability to obtain a complete cytoreduction. The second population is those who are newly diagnosed who have a high perioperative risk, and so they're not fit to go to surgery directly. And so it may be better to start with neoadjuvant chemotherapy and then do an interval cytoreductive surgery. Again, I just want to emphasize the importance of including a gynecologic oncologist when making these determinations for patients. Brittany Harvey: Absolutely. So then the next clinical question. Dr. Tew, for those patients with newly diagnosed stage 3 to 4 epithelial ovarian cancer, what tests and or procedures are recommended before neoadjuvant chemotherapy is delivered? Dr. Bill Tew: The key test is to confirm the proper diagnosis, and that requires histological confirmation with a core biopsy. And this was a point the panel strongly emphasized, which is a core biopsy is a much better diagnostic tool compared to cytology alone. But there will be cases, exceptional cases, where a core biopsy cannot be performed. And in those settings, cytology combined with serum CA-125 and CEA is acceptable to exclude a non-gynecologic cancer. The other reason why cord biopsy is strongly preferred is because we already need to start thinking about germline and somatic testing for BRCA1 and 2. This information is important as we start to think about maintenance strategies for our patients. And so having that information early can help tailor the first-line chemotherapy regimen. Brittany Harvey: So then you've described who should be receiving neoadjuvant chemotherapy, but Dr. Gaillard, for those who are receiving neoadjuvant chemo, what is the preferred chemotherapy regimen? And then what does the expert panel recommend regarding timing of interval cytoreductive surgery? Dr. Stéphanie Gaillard: Sure. So for neoadjuvant chemotherapy, we generally recommend a platinum taxane doublet. This is especially important for patients with high grade serous or endometrioid ovarian cancers, and that's really because this is what the studies had used in the neoadjuvant trials. We recognize, however, that sometimes there are individual patient factors, such as advanced age or frailty, or certain disease factors such as the stage or rare histology that may shift what is used in terms of chemotherapy, but the recommendation is to try to stick as much as possible to the platinum taxane doublet. And then in terms of the timing of interval cytoreductive surgery, this was something that the panel discussed quite a bit and really felt that it should be performed after four or fewer cycles of neoadjuvant chemotherapy, especially in patients who've had a response to chemotherapy or stable disease. Sometimes alternative timing of surgery can be considered based on some patient centered factors, but those really haven't been prospectively evaluated. The studies that looked at neoadjuvant chemotherapy usually did the interval cytoreductive surgery after three or four cycles of chemotherapy. Brittany Harvey: For those patients who are receiving interval cytoreductive surgery, Dr. Tew, earlier in the podcast episode, you mentioned a new therapy. What is recommended regarding hyperthermic intraperitoneal chemotherapy? Dr. Bill Tew: Yeah, or simply HIPEC as everyone refers to it. You know, HIPEC isn't really a new therapy. HIPEC is a one-time perfusion of cisplatin, which is a chemotherapy that has been a standard treatment for ovarian cancer for decades. But the chemotherapy is heated and used as a wash during the interval cytoreductive surgery. And since our last guideline, there has been a publication of a randomized trial that looked at the use of HIPEC in this setting. And in that study there was improved disease-free and overall survival among the patients that underwent HIPEC versus those that did not. So we wanted to at least emphasize this data. But we also wanted to recognize that HIPEC may not be available at all sites. It's resource-intensive. It requires a patient to be medically fit for it, particularly renal function and performance status. And so it's something that could be discussed with the patient as an option in the interval cytoreductive surgery. One other point, the use of HIPEC during primary surgery or later lines of therapy still is unknown. And the other point is this HIPEC trial came prior to the introduction of maintenance PARP inhibitors. So there's still a lot of unknowns, but it is a reasonable option to discuss with appropriate patients. Brittany Harvey: I appreciate you reviewing that data and what that updated recommendation is from the panel. So then, Dr. Gaillard, after patients have received neoadjuvant chemotherapy and interval cytoreductive surgery, what is the post ICS chemotherapy recommended? Dr. Stéphanie Gaillard: The panel recommends some post ICS chemotherapy, as you mentioned. This is typically to continue the same chemotherapy that was done as neoadjuvant chemotherapy and so preferably platinum and taxane. And typically we recommend a total of six cycles of treatment, although the exact number of cycles that is given post-surgery can be adjusted based on different patient factors and their response to treatment. Importantly, also, timing is a factor, and we recommend that postoperative chemotherapy begin within four to six weeks after surgery, if at all feasible. Brittany Harvey: Absolutely. Those timing recommendations are key as well. So then, Dr. Tew, you mentioned this briefly earlier, but what is the role of maintenance therapy? Dr. Bill Tew: Maintenance therapy could be a full podcast plus of discussion, and it's complicated, but we did want to include it in this guideline in part because the determination of whether to continue treatment after completion of surgery and platinum based therapy is key as one is delivering care in the upfront setting. So first off, when we say maintenance therapy, we are typically referring to PARP inhibitors or bevacizumab. And I would refer listeners to the “ASCO PARP Inhibitor Guideline” that was updated about two years ago, as well as look at the FDA-approved label indications. But in general, PARP inhibitors, whether it's olaparib or niraparib, single agent or olaparib with bevacizumab, are standard treatments as maintenance, particularly in those patients with a germline or somatic BRCA mutation or those with an HRD score positive. And so it's really important that we emphasize germline and somatic BRCA testing for all patients with newly diagnosed ovarian cancer so that one can prepare for the use of maintenance therapy or not. And the other point is, as far as bevacizumab, bevacizumab is typically initiated during the chemotherapy section of first-line treatment. And in the guidelines we gave specific recommendations as far as when to start bevacizumab and in what patient population. Brittany Harvey: Great. Yes. And the PARP inhibitors guideline you mentioned is available on the ASCO guidelines website and we can provide a link in the show notes for our listeners. So then, the last clinical question, Dr. Gaillard, what treatment options are available for patients without a clinical response to neoadjuvant chemotherapy? Dr. Stéphanie Gaillard: Yeah, this is a tough situation. And so it's important to remember that ovarian cancer typically does respond to chemotherapy initially. And so it's unusual to have progressive disease to neoadjuvant chemotherapy. So it's really important that if someone has progressive disease that we question whether we really have the right diagnosis. And so it's important to, I think at that point, obtain another biopsy and make sure that we know what we're really dealing with. In addition, this is where Dr. Tew mentioned getting the molecular profiling and genetic testing early in the course of disease. If that hasn't been done at this point in time, it's worth doing that in this setting so that that can also potentially help guide options for patients. And patients who are in those situations, really, the options are other chemotherapy regimens, clinical trials may be an option, or in some situations, if they have really rapidly progressing disease that isn't amenable to further therapy, then initiation of end-of-life care would be appropriate. Brittany Harvey: I appreciate you both for reviewing all of these recommendations and options for patients with advanced ovarian cancer. So then to wrap us up, in your view, what is both the importance of this guideline update and how will it impact clinicians and patients with advanced ovarian cancer? Dr. Bill Tew: Well, first off, I'm very proud of this guideline and the panel that I work with and Dr. Gaillard, my co-chair. The guideline really pulls together nicely all the evidence in a simple format for oncologists to generate a plan and determine what's the best step for patients. The treatment of ovarian cancer, newly diagnosed, is really a team approach - surgeons, medical oncologists, and sometimes even general gynecologists - and understanding the data is key, as well as the advances in maintenance therapy and HIPEC. Dr. Stéphanie Gaillard: For my part, I'd say we hope that the update really provides physicians with best practice recommendations as they navigate neoadjuvant chemotherapy decisions for their patients who are newly diagnosed with ovarian cancer. There is a lot of data out there and so we hope that we've synthesized it in a way that makes it easier to digest. And along that regard, I really wanted to give a special shout out to Christina Lacchetti, who just put in a tremendous effort in putting these guidelines together and in helping to coordinate the panel. And so we really owe a lot to her in this effort. Dr. Bill Tew: Indeed. And ASCO, as always, helps guide and build a great resource for the oncology community. Brittany Harvey: Absolutely. Yes, we hope this is a useful tool for clinicians. And I want to thank you both for the large amount of work you put in to update this evidence-based guideline. And thank you for your time today, Dr. Gaillard and Dr. Tew. Dr. Stéphanie Gaillard: Thank you. Dr. Bill Tew: Thank you for having us. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/gynecologic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Evan Yu presents the new evidence-based guideline on genetic testing for metastatic prostate cancer. He discusses who should receive germline and somatic testing with next-generation sequencing technologies, what samples are preferred for testing, and the therapeutic & prognosistc impacts of genetic testing. Dr. Yu emphasizes the need for awareness and refers to areas of active investigation and future research to improve personalized therapies for patients with metastatic prostate cancer.  Read the full guideline, “Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline” at www.asco.org/genitourinary-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02608 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Evan Yu from the University of Washington and Fred Hutchinson Cancer Center, lead author on “Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline”. Thank you for being here today, Dr. Yu. Dr. Evan Yu: Thanks for having me on. Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the entire guideline, including Dr. Yu, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, Dr. Yu, to start us off on the content of this guideline, could you first provide an overview of both the purpose and scope of this guideline? Dr. Evan Yu: Yeah, absolutely. So I think the one key thing to recognize is that prostate cancer is the highest incidence of all cancers in males. Additionally, it's the second highest cause of mortality in males, and that's about 35,000 deaths in 2024. So with that being said and done, it's a disease where we need to do better. And part of that is recognizing that we now have many targeted therapies, precision medicine type of therapies, but unlike a lot of other cancers out there, prostate cancer patients are not always getting sequencing, next generation DNA sequencing, let's say, to identify both inherited and also spontaneously develop what we call somatic mutations in their tumor. And I suspect that's partially because other cancers like breast cancer, we're so used to- in the first line, you present the patient, you throw out their estrogen receptor status, progesterone receptor status, HER2, ER/PR HER2; in lung cancer it's EGFR, ALK, ROS1, etc. In things like prostate cancer, things like BRCA2 have major important patient treatment implications and potentially family counseling and downstream cascade testing implications. But it hasn't made their way into that first-line presentation yet. And for that reason, there are some studies out there that show that testing in the community may be as low as 15% of patients with metastatic prostate cancer. We want to bring awareness to that and hopefully increase testing down the road so that we can better help our patients with metastatic prostate cancer. Brittany Harvey: Absolutely. It's important to get these targeted therapies to the patients who can benefit most. Using that context, I'd like to next review the key recommendations of this guideline across the six clinical questions that the panel addressed. So, starting with: Who should receive germline testing with next generation sequencing technologies? Dr. Evan Yu: Yeah. We think that it's common enough that everyone with metastatic prostate cancer should receive germline genetic testing. And the reason for that is there have been studies that have looked at this and have shown that 12% of men with metastatic prostate cancer have some sort of inherited germline mutation in a gene, mostly DNA repair genes. But 12% have something that is inherited and that loved ones, first degree relatives, siblings, offspring might have also inherited. Now, most of these are in the DNA repair genes, but that being said and done, there's not only treatment implications for the patient, where there are newer drugs that that patient could get treated with, but other loved ones that might have inherited these gene mutations, that these things can cause other cancers as well - not just prostate cancer, but breast cancer, endometrial cancer, ovarian cancer, pancreatic cancer. So, it's very important to test, with as high of an incidence as 12%, to test, and if you identify it in a patient, it's our job to talk to the patient about it and talk to them about the pros and cons of family counseling and talking to their loved ones and potentially having their loved ones get tested. Because if they test positive, then their doctors may want to know and may screen them very, very aggressively and differently for a whole host of other cancers. And the whole idea is you find the cancer very early and cure the patients before the cancer really takes hold and has the ability to spread so we can save a lot of lives down the road. Brittany Harvey: Absolutely. This germline testing is important not just for the patient, but has wider implications for their families as well, as you mentioned. So then, beyond those recommendations for germline testing, which patients should receive somatic testing with next-generation sequencing technologies? Dr. Evan Yu: So let's talk a little bit about somatic testing. So germline again, as we know, is inherited. The patient inherited it in every single cell in their body, then it becomes very easy, many of these are cancer predispositions for them to lose the other allele and then to have biallelic loss and then develop the cancer. Now, somatic just means it spontaneously occurred. Certainly, it's not going to occur in every cell in the body, but you can get one hit, lose one allele and then lose the other allele. And if that gene is truly carcinogenic and leading to that cancer, then that can have implications potentially for treatment as well. So we recommend that all patients with metastatic prostate cancer also undergo somatic next-generation sequencing testing. We recognize that at this point in time it's only those with metastatic castration-resistant prostate cancer or hormone-resistant prostate cancer, which is a later disease state where there are drugs that may target those mutations, for instance, like PARP inhibitors, but that early identification for a patient population that's fit and that can benefit from these therapies makes sense so that you know it's in place already and you have your treatments outlined and mapped out for the future. So we recommend it for everybody - somatic testing also for everyone with metastatic prostate cancer. Brittany Harvey: Understood. And then when patients are receiving that somatic testing, what is recommended for somatic testing? Primary tumor archival tissue? Fresh metastatic biopsy tissue? Or circulating tumor DNA testing? Dr. Evan Yu: We recommend that in the initial setting when you're first diagnosed, that archival tissue samples are fine and preferred. But circulating tumor DNA is good when there's no accessible archival tissue, or if the archival tissue, let's say, is very old and it's been sitting around for a long time, or you can't get it anymore because it's many years back when maybe a patient had a prostate needle biopsy. So if it's not accessible, then we recommend ctDNA. We believe that is preferred and also that ctDNA is recommended in a situation where you can't easily biopsy a metastatic site. Sometimes it's just not in a safe area to go after. Sometimes it's just a small lesion. So in general, we recommend tissue when available, and when we think that the tissue sample will yield clean results, if not, then we recommend doing ctDNA at that point in time. Brittany Harvey: So you have described who should get germline and somatic genomic testing. But what are the therapeutic impacts of this germline or somatic testing for single gene genetic variants? Dr. Evan Yu: We pulled this panel together and we met like every single month for like 12 months straight, and part of it was to review the literature. And as part of this literature review, we were able to pull a whole bunch of different trials. I think there was like 1713 papers we identified in the literature search. Eventually, we narrowed it down because with ASCO, we want to present the data with the highest level evidence, level 1 evidence, randomized controlled prospective data. And after reviewing 1713 papers, we narrowed it down to 14 papers. With those 14 papers, if you look at it, there are a lot of things that we think may have implications for treatment or prognosis, but we didn't feel was the highest level of evidence that we could support. So the things that have the highest level of evidence that we can support are certain DNA repair gene alterations, especially BRCA2, and treatment with PARP inhibitors because there are many PARP inhibitor prospective trials that show progression-free survival benefit and even overall survival benefit. And so that's the type of study that achieved the level of evidence that we could include. So I would say BRCA1 and BRCA2 highest level of evidence and PARP inhibitor use also is included in that. Brittany Harvey: Understood. I appreciate you reviewing those therapeutic options. So then, the last clinical question, which you just touched on briefly, but what are the prognostic impacts of germline and/or somatic testing? Dr. Evan Yu: Whenever you do testing, especially if you use panel testing, you find a lot of information. There's a lot of different mutations and some of which are VUSs (variants of unknown significance) where we don't quite know what it means yet, but we can track that, especially if it's germline. But with somatic, we find lots of things that have implications, but maybe just not treatment implications. A perfect example is p53. p53 is one of the most common tumor suppressor gene mutations on all cancers, but in prostate cancer they can occur and they can usually occur late, although there can even be germline inherited p53 alterations. There's no treatment that targets p53 right now, but we know that if you have a p53 mutation that those patients may have more aggressive disease and that prognostic information is important to give to the patient. And I think it's important for future clinical trial design and direction. So we do not recommend making treatment recommendations or changes based on these prognostic only biomarkers at this point in time. But we do recommend that, based on this, we can design intensification trials for those patients who have these poor risk biomarkers and de-intensification trials for patients who may have a good risk biomarker. So for instance, SPOP is a gene where we think these patients may have better outcomes, they might respond better to certain hormonal therapies like abiraterone. I say might because the level of evidence isn't quite there. But what I would say is that these prognostic only biomarkers, we just don't think they cut the mustard yet to be able to make treatment decisions. But we do think that they can drive counseling for the patient and potential selection and trial design for the future to say, “Okay. This is a patient population that has a more aggressive cancer. We need to be more aggressive in treating these patients.” “This patient population might have a less aggressive cancer. Maybe we can de-intensify and say side effects and quality of life may be better for the patients.” Brittany Harvey: Definitely. It's important for thinking through how to personalize care for these patients. So then you've talked about this a little bit in talking through the recommendations, but could you expand on what is the importance of this guideline and how it will impact both clinicians and patients with metastatic prostate cancer? Dr. Evan Yu: Yeah, I think the number one thing is awareness. I think the data's out there and people that are in my field, they know this. But by evidence of the fact that it's not first-line presentation lingo that everyone's talking about things like BRCA status, it means it hasn't necessarily disseminated all the way through. So it's increasing awareness of the fact that both germline and somatic alterations can occur and that these may have impacts on the patient for their treatment and their prognosis, and basically to increase testing for the future. I really think that in the future, there'll be other reasons that we may want to serially even retest and we may find that there may be mutations that develop as mechanisms of resistance that might guide therapy down the road. So we need to get people to start doing this for everyone with metastatic prostate cancer, because someday we might be doing it not just once, but over and over again. Brittany Harvey. Absolutely. We hope this guideline reaches a wide audience and that these recommendations can be put into practice. Finally, you've talked about how not all the data in the field has yet risen to the level of evidence that made it into the guidelines. So what are the outstanding questions in future research areas for both germline and somatic genomic testing for metastatic prostate cancer? Dr. Evan Yu: It was in our discussion, but it clearly- it's not common enough for there to be randomized prospective trials that would reach that level of evidence to make it in this guideline recommendation. But we all know that for any solid tumor, you can get mismatched repair deficiency, microsatellite instability leading to hypermutation or high tumor mutational burden. And that happens in maybe 3 to 5% of patients with metastatic prostate cancer as well. There is evidence and data that these patients can potentially benefit from immunotherapies like pembrolizumab. But again, it's just not common enough for there to be those randomized prospective controlled trials out there. But we mention it because we know it's FDA-approved across all the tumor types, so we felt like we have to mention it because that's something that has treatment implications for the patient. But also, I alluded to this earlier, I think an area of active investigation is the tried and true number one driver of prostate cancer, which is androgen receptor. Testosterone binds to androgen receptors, stimulates it. That's how androgen deprivation therapy works. That's how abiraterone and the amides like enzalutamide, apalutamide, darolutamide, that's how they all work. But even beyond that, we're starting to identify that maybe 15%, 20% of patients with metastatic castration resistant prostate cancer have androgen receptor mutations. And there are newer classes of therapies like androgen receptor degraders like CYP11A1 antagonist that lead to complete adrenal annihilation of other steroid hormones that might promiscuously stimulate these androgen receptor mutants. These things develop as mechanisms of resistance, and in the future, we might want to serially test- and that's an active area of investigation in the future, to say you've been treated, let's say, with androgen deprivation therapy and abiraterone for years. There are certain mutations that might develop as a resistance mechanism. We might need to serially test somebody because you didn't have that mutation earlier on, but later in the disease course you might. And then there might be a new drug X out there that we would want to use. Again, we need the data, we need the randomized prospective controlled trials, but they're happening out there. And somewhere down the road we may rewrite this guideline and have a lot more recommendations to add to it. Brittany Harvey: Yes, we'll look forward to more research in this field to better provide targeted therapies for patients with metastatic prostate cancer across the treatment paradigm. And we'll look forward to report outs from those trials that you mentioned. So I want to thank you so much for your work to develop this guideline and thank you for your time today, Dr. Yu. Dr. Evan Yu: Thank you so much. It's wonderful to be here today. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Hedy Kindler joins us on the podcast to discuss the latest update to the treatment of pleural mesothelioma guideline. She discusses the latest changes to the updated recommendations across topics including surgery, immunotherapy, chemotherapy, pathology, and germline testing. Dr. Kindler describes the impact of this guideline and the need for ongoing research in the field. Read the full guideline update, “Treatment of Pleural Mesothelioma: ASCO Guideline Update” at www.asco.org/thoracic-cancer-guidelines.   TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02425 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Hedy Kindler from the University of Chicago, lead author on “Treatment of Pleural Mesothelioma: ASCO Guideline Update.” Thank you for being here today, Dr. Kindler. Dr. Hedy Kindler: Thank you so much. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Kindler, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to jump into the content of this podcast episode, first, Dr. Kindler, can you provide an overview of the purpose and scope of this guideline update on pleural mesothelioma? Dr. Hedy Kindler: The initial ASCO practice guideline on mesothelioma, which we published in 2018, was quite comprehensive, but since that time incredible progress has been made which has truly transformed the management of this disease. So we felt it was really important to update the guideline now, focusing on four key areas: the role of surgery, new systemic treatments, pathologic insights, and germline testing. Brittany Harvey: Great. Thank you for highlighting those key areas of the guideline. And so I'd like to next review the key updated recommendations for our listeners. So starting with what are the new updates for surgery? Dr. Hedy Kindler: So surgery has always been controversial in meso, with significant geographic variation in its use. Now, it's even more controversial. Recent randomized data from the MARS 2 trial, placed in the context of other data we also reviewed in this update, suggest that surgical cytoreduction should not be routinely offered to all patients based solely on anatomic resectability. Surgery should only be offered to highly selected patients with favorable prognostic characteristics. This includes comprehensively staged patients with early-stage epithelioid tumors. Patients should preferably be treated at centers of excellence which have documented low morbidity and mortality, and this should also be done in the context of multimodality therapy and preferably within clinical trials. Brittany Harvey: Understood. I appreciate you reviewing those recommendations for who surgery should be offered to. So following those, what are the main recommendations for immunotherapy for treating pleural mesothelioma? Dr. Hedy Kindler: So for a disease in which for 16 years there was only one FDA-approved regimen, pemetrexed and platinum, the pace of recent changes in systemic therapy has been a welcome change with the FDA approval of doublet immunotherapy in October of 2020 and the approval of chemo immunotherapy just a few months ago in September of 2024. Now that we have choices, we've tried to help clinicians determine the optimal treatment regimen for the individual patient. Doublet immunotherapy with ipilimumab and nivolumab should be offered as a first-line systemic option to any mesothelioma patient. For patients with non-epithelioid histology, doublet immunotherapy is hands down the recommended regimen based on the dramatic improvement in survival from 8.8 to 18.1 months for immunotherapy compared with chemo. For patients with previously untreated epithelioid mesothelioma, either ipilimumab-nivolumab immunotherapy or platinum-pemetrexed chemotherapy are reasonable options. Therapy can be individualized based on the patient's comorbidities, acceptance of differing toxicities. and treatment goals. Chemoimmunotherapy with pembrolizumab, pemetrexed, and carboplatin is a newer treatment option for patients with newly diagnosed pleural mesothelioma. This regimen is noteworthy for its very high objective response rate of 62%. Brittany Harvey: It's great to have those new options to improve outcomes for patients. Beyond the chemoimmunotherapy recommendation that you just described, what are the highlights for chemotherapy recommendations? Dr. Hedy Kindler: So pemetrexed platinum-based chemotherapy with or without bevacizumab still plays a role in this disease and should be offered as a first-line treatment option in patients with epithelioid histology. This regimen is not recommended in patients with non-epithelioid disease unless they have medical contraindications to immunotherapy. Pemetrexed maintenance chemotherapy following pemetrexed-platinum chemotherapy is not recommended. Brittany Harvey: Thank you for reviewing those recommendations as well. So then next, what are the important changes regarding pathology? Dr. Hedy Kindler: Well, one fun fact is that we've changed the name of the disease. It's no longer malignant mesothelioma. Now it's just mesothelioma. Since the non-malignant mesothelial entities have been renamed, all mesos are now considered malignant, so there's no need to use the prefix malignant in the disease name. Mesothelioma should be reported as epithelioid, sarcomatoid, or biphasic because these subtypes have a clear prognostic and predictive value. Knowing the subtype helps us decide on whether chemotherapy or immunotherapy is the optimal treatment for a patient, so it must be reported. Additionally, within the epithelioid subtype, histologic features, including nuclear grade, some cytologic features, and architectural patterns should be reported by pathology because they have prognostic significance. Pathologists have recently identified a premalignant entity, mesothelioma in situ, which can be found in patients with long standing pleural effusions and should be considered in the differential diagnosis. In the appropriate clinical setting, additional testing, including BAP1 and MTAP IHC should be performed. Brittany Harvey: Definitely. These pathologic recommendations are important for treatment selection. So in that same vein, in the final section of the recommendations, what are the updated recommendations from the panel regarding germline testing? Dr. Hedy Kindler: This is one of our most important recommendations, that universal germline testing should be offered to all mesothelioma patients. The proportion of patients with mesothelioma who have pathogenic or likely pathogenic germline variants is similar to other diseases in which universal germline genetic testing and counseling are now the standard of care. This is most commonly observed in the tumor suppressor gene BAP1 and this not only affects cancer risk in patients and their family members, but also has key prognostic significance. For example, pleural mesothelioma patients with BAP1 germline mutations who receive platinum-based chemotherapy live significantly longer, 7.9 years compared to 2.4 years for those without these mutations. Thus, we recommend that all patients with mesothelioma should be offered universal germline genetic counseling and/or germline testing. Brittany Harvey: So there were a large amount of new and updated recommendations in this update. So in your view Dr. Kindler, what is the both importance of this update and how will it impact both clinicians and patients with pleural mesothelioma? Dr. Hedy Kindler: Even as we were researching and writing this update, new data kept emerging which we needed to include. So it's clearly a time of great progress in the management of this disease. We've comprehensively reviewed and analyzed the extensive emerging data and provided clinicians with a roadmap for how to incorporate these new advances into their management of this disease. Brittany Harvey: Absolutely, that is key for optimal patient care. So you've just mentioned emerging data and rapid evidence generation, so what future research developments are being monitored for changes in the treatment of pleural mesothelioma? Dr. Hedy Kindler: Despite these recent advances in disease management, mesothelioma continues to be a lethal cancer, and there's clearly a need to develop better treatments. This includes ongoing studies of novel immunotherapeutic agents such as bispecific antibodies, cell therapy using chimeric antigen receptors targeting mesothelioma tumor antigens, and precision medicine approaches to target tumor suppressor genes. Finally, strategies for early cancer detection and prevention are vital for individuals predisposed to develop mesothelioma due to BAP1 and other germline mutations, as well as for those who are occupationally or environmentally exposed to asbestos. Brittany Harvey: Absolutely. We'll look forward to these new updates to continue development in the field. So thank you so much for this mountain of work to update this guideline, and thank you for your time today, Dr. Kindler. Dr. Hedy Kindler: Thank you so much. It's been a pleasure. Thank you for asking me to do this. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline update, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Van Morris presents the new evidence-based guideline on systemic therapy for localized anal squamous cell carcinoma. Dr. Morris discusses the key recommendations from the Expert Panel, including recommended radiosensitizing chemotherapy agents, dosing and schedule recommendations, the role of induction chemotherapy and ongoing adjuvant chemotherapy, and considerations for special populations. He emphasizes the importance of this first guideline from ASCO on anal squamous cell carcinoma for both clinicians and patients with stage I-III anal cancer, and ongoing research the panel is looking to for the future. Read the full guideline, “Systemic Therapy for Stage I-III Anal Squamous Cell Carcinoma: ASCO Guideline” at www.asco.org/gastrointestinal-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02120 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Van Morris from MD Anderson Cancer Center, co-chair on “Systemic Therapy for Stage I-III Anal Squamous Cell Carcinoma: ASCO Guideline.” Thank you for being here today, Dr. Morris. Dr. Van Morris: Thank you for having me. On behalf of our committee who put together the guidelines, I'm really excited to be here and talk with you today. Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Morris, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to jump into the content of this guideline, Dr. Morris, can you provide an overview of both the purpose and the scope of this guideline on stage I to III anal squamous cell carcinoma? Dr. Van Morris: So anal cancer is considered a rare malignancy for patients in the United States and across the world as well. Even though it's not something we see as commonly, for example, as the adjacent colorectal cancer, this still is a cancer that is rising in incidence every year in the United States. And really, despite the presence of the preventative HPV vaccines, which we hope will ultimately prevent and eradicate this cancer, we still expect the incidence to continue to rise in the coming decades before we really start seeing numbers begin to decrease as a result of the vaccine. So this is an alarming trend for which oncologists will continue to see likely more and more cases and new diagnoses every year. So we wanted to review the most recent literature and provide oncologists up to date recommendations for how they can best take care of patients with a new diagnosis of localized anal cancer. Brittany Harvey: Absolutely. I appreciate that background and context to set the stage for this guideline. So then next I'd like to review the key recommendations of this guideline. So starting from the first clinical question, what are the recommended radiosensitizing, doublet or single chemotherapy agents for patients with stage I to III anal cancer? Dr. Van Morris: It's true that really the standard treatment for patients with localized anal cancer has not changed over the last literally half century. When the Nigro regimen was first reported back in 1974, 50 years ago, the standard of care for patients with a new diagnosis of localized anal cancer centers around concurrent chemotherapy and radiotherapy. And we looked at the various randomized control trials and the highest level of evidence which has been reported over the past decades, and really for most patients, the standard of care continues to remain doublet cytotoxic chemotherapy in combination with radiation. We reported that the most commonly, and I think most accepted, regimen here is a combination regimen of 5-FU, intravenous 5-fluorouracil with mitomycin C. And this most commonly is given on a week 1 to 5 regimen. The 5-FU, we recommended a dose of 1000 milligrams per meter squared per day on days 1 to 4 and then on days 29 to 32 of the radiation treatment. And then the mitomycin C, looking at various trials, has been given at a dose of 10 milligrams per meter squared on day 1 and day 29, or alternatively a single dose of mitomycin C at 12 milligrams per meter squared on day 1. I think that the thing that's important for clinicians and patients alike to remember is that this chemotherapy can be very toxic in patients who are undergoing a curative-intent therapy for this diagnosis of localized anal cancer. I think it's just important for oncologists to be watching closely the blood counts for the patients to make sure that the myelosuppression doesn't get too bad. And then in select cases, if that is the case, when the oncologist opts to go for the day 1 and day 29 dosing, it may be prudent, if the myelosuppression is too excessive, to consider withholding that day 29 dose. Brittany Harvey: Great. Thank you for providing those recommendations along with some of those dosing and the schedule recommendations from the expert panel. So are there any other alternate dose or schedule recommendations from the expert panel? Dr. Van Morris: Yeah, but I think that we saw with the ACT II data that was a randomized trial that was done out of the UK that compared 5-FU mitomycin with 5-FU cisplatin as two different doublet cytotoxic regimens, that overall outcomes were very similar between the two regimens in terms of curative outcomes for patients treated whether 5-FU mitomycin or 5-FU cisplatin. So certainly there is evidence supporting the use of cisplatin as a second cytotoxic agent with 5-fluorouracil. In the ACT II study that was given at a dose of 60 milligrams per meter squared on days 1 and 29 along with the 5-FU at the regimen I talked about previously. There is other lower level of evidence data suggesting that even the 5-FU and cisplatin can be given on a weekly schedule and that that can be safe. Actually, at my institution at MD Anderson, that is our standard practice pattern as well. There's also the option when we're thinking about giving pelvic radiation for patients with lower GI cancers, many oncologists in the treatment of localized rectal adenocarcinoma are accustomed to using capecitabine as a chemosensitizer in patients with localized rectal cancer. If I'm giving chemoradiation for a patient with localized anal cancer, can I substitute the intravenous 5-FU with oral capecitabine? And although the evidence is not as strong in terms of available data with regards to randomized controlled trials, there certainly is data that suggests that capecitabine may be an acceptable alternative in lieu of intravenous 5-fluorouracil that would be given at a dose of 825 milligrams per meter squared on days of radiation. But certainly, I think that that's a feasible approach as well and maybe even associated with less hematologic toxicity than intravenous 5-FU would be. Brittany Harvey: Great. It's important to understand all the options that are out there for patients with early-stage anal squamous cell carcinoma. So in addition to those chemoradiation recommendations, what is recommended from the expert panel regarding induction chemotherapy or ongoing adjuvant chemotherapy for this patient population? Dr. Van Morris: When we think about treating patients with lower GI cancers with curative intent therapies, when we think about the more common rectal adenocarcinoma, oncologists may be used to giving chemoradiation followed by subsequent cytotoxic chemotherapy. But actually when you look at the data for anal cancer, really there's not any data that strongly supports the use of either induction chemotherapy prior to chemoradiation or adjuvant post-chemoradiation chemotherapy. The RTOG 98-11 study was a trial which evaluated the role of induction 5-fluorouracil prior to chemoradiation and did not show any survival benefit or improved outcomes with the use of induction chemotherapy in a randomized control trial setting. The ACT II trial, which I referenced earlier, was a 2 x 2 design where patients were either randomized to concurrent chemoradiation with 5-FU mitomycin C or concurrent chemoradiation with 5-FU cisplatin. But then there was a second randomization after chemoradiation where half of the study participants received adjuvant cisplatin 5-fluorouracil after completion of their chemo radiation, or the other half were randomized to the standard of care, which of course would be observation. And what that trial showed was that there was no added benefit with the addition of post-chemoradiation cytotoxic chemotherapy. So we look at these data and say that in general, for the general population of patients with localized stages I to III anal cancer, there really is no supporting data suggesting benefit of either induction chemotherapy or adjuvant chemotherapy. And to that end, really it's concurrent chemoradiation remains the standard of care at this time for patients with a new diagnosis of localized anal cancer. Brittany Harvey: Absolutely. It's just as important to know what is not recommended as it is to know what is recommended for these patients. And so I thank you for explaining the evidence behind that decision from the panel as well. So then, are there any other considerations for special populations that oncologists should consider? Dr. Van Morris: I think so. I think that anal cancer is a disease where we don't see that many patients being diagnosed earlier at a younger age, especially in relation to the alarming trend of early onset colorectal cancer that we're currently seeing right now. So there may be patients who come with a new diagnosis of localized anal cancer who are an octogenarian at an advanced age or may have other significant medical comorbidities. And if that is the case, we get called about this quite frequently from outside institutions. I have an 85 year old who is coming to my clinic with this diagnosis. I don't feel comfortable giving this patient doublet cytotoxics, what options do I have? Especially given other organ dysfunction that may precede this diagnosis. And I think that in that case, there are times when it's okay safely to drop the mitomycin C and opt for single agent 5-fluorouracil as a single cytotoxic agent. So I think that that would be something that we've certainly incorporated into our practice at our institution. There's also an association between various autoimmune disorders, patients on immunosuppression, even persons living with HIV being at higher risk for this virally associated cancer. So I think that, again, if the patient is coming with baseline immunosuppression for these reasons prior to treatment, certainly kind of being in tune to the potential for hematologic toxicity. And watching these patients very closely as they're getting chemoradiation remains really important. Brittany Harvey: Definitely. So, you've just discussed some of those comorbidities and patient characteristics that are important for clinicians to consider when deciding which regimens to offer. So in addition to those, in your view, what is the importance of this guideline and how will it impact clinical practice for clinicians who are reading this guideline. Dr. Van Morris: Chemoradiation remains a very effective option and most patients will be cured with this diagnosis and with this treatment. So it's important to make sure that these patients are able to safely get through their treatment, minimizing treatment delays due to toxicities which may come about because of the treatment, and really help to carry them over the finish line so that they have the best likelihood for achieving cure. So we really hope that these data will provide oncologists with a readily available summary of the existing data that they can refer to and continue to help as many patients as possible achieve and experience a cure. Brittany Harvey: Absolutely. So then to build on that, it's great to have this first guideline from ASCO on anal squamous cell carcinoma. But how will these new recommendations affect patients with stage I to III anal cancer? Dr. Van Morris: I certainly hope it will allow patients and oncologists to know what their options are. It certainly is not a one size fits all treatment approach with regards to the options which are available. Depending on the patient, depending on the various medical conditions that may accompany them, these treatments may need to be tailored to most safely get them through their treatment. Brittany Harvey: I appreciate you describing the importance of this guideline for both clinicians and patients. So what other outstanding questions and future research do you anticipate seeing in this field? Dr. Van Morris: It's a really good question and I think that there is a lot coming on the horizon. Even though the standard treatment has really not changed over the last half century, I think it still remains true that not all patients will achieve cure with a chemoradiation treatment. So a recent trial has completed enrollment in the United States, this is the EA2165 trial led by one of our committee members, Dr. Rajdev and Dr. Eng as well, that's looking at the use of nivolumab anti PD-1 immunotherapy after completion of concurrent chemo adiation. So in that trial, patients were randomized to concurrent chemoradiation followed by either observation or six months of adjuvant anti PD-1 therapy. We're really awaiting the results of that. Hopefully if we see an improvement with the addition of nivolumab following concurrent chemoradiation, our hope would be that more patients would be able to achieve a cure. So we're certainly looking forward to the outcomes of that EA2165 study. And then I think one question that we often get from our patients in the clinics is, “What is the role of circulating tumor DNA in the management of my disease?” And really, to date there have been some series which have shown that we can assess patients or circulating tumor DNA after completion of their concurrent chemo radiation that may need to start about three months after to give time for the radiation to wear off and most accurately prognosticate that. But I think that this will be a powerful tool moving forward, hopefully, not only in the surveillance to identify patients who may be at high risk for recurrence, but ultimately to translate that into next generation clinical trials which would treat patients at higher risk for recurrence by virtue of a detectable circulating tumor DNA result. In doing so, hopefully cure even more patients with this diagnosis. Brittany Harvey: Yes, we'll look forward to these developments and hope to add more options for potential treatment and surveillance for patients with anal cancer. So, I want to thank you so much for your work to develop these guidelines and share these recommendations with us and everything that the expert panel did to put this guideline together. Thank you for your time today, Dr. Morris. Dr. Van Morris: Thank you. And thank you to ASCO for helping to keep this information out there and ready for oncologists for this rare cancer. Brittany Harvey: Absolutely. And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.    

Dr. Greg Kalemkerian reviews the latest evidence-based rapid update from the Expert Panel on systemic therapy for small cell lung cancer. He discusses the updated recommendations for patients with limited-stage SCLC based on the ADRIATIC trial, and for patients with relapsed SCLC based on the DeLLphi-301 trial. Dr. Kalemkerian shares insights on what these changes mean for clinicians and patients, and highlights new trials in progress to provide more options for patients diagnosed with SCLC. Read the full rapid update, “Systemic Therapy for Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update” at www.asco.org/thoracic-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02245   Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Greg Kalemkerian from the University of Michigan, lead author on, “Systemic Therapy for Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update”. Thank you for being here today, Dr. Kalemkerian. Dr. Greg Kalemkerian: Thank you. Thank you for the invitation. Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Kalemkerian, who has joined us here today, are available online with the publication of the update in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content of this rapid update, Dr. Kalemkerian, what prompted this update to the Systemic Therapy for Small Cell Lung Cancer Guideline, which was previously published in 2023? Dr. Greg Kalemkerian: So even though the original guideline only came out a year ago, the past year we've seen two significant advances in small cell lung cancer with two reports, one in limited stage with the addition of immunotherapy, the other in the addition of a new immunotherapeutic agent in relapsed small cell lung cancer. Brittany Harvey: It's great to have this new data in the small cell lung cancer space. So based on these new changes, what are the updated recommendations from the expert panel? Dr. Greg Kalemkerian: So the first recommendations have to do with patients with limited-stage small cell lung cancer based on the ADRIATIC trial which added consolidation durvalumab for patients who had not had progression after standard chemotherapy and radiotherapy. And this study demonstrated a significant improvement in overall survival with about a 10% improvement in both 2- and 3-year overall survival, up to a 57% overall survival at 3 years for the patients receiving consolidation durvalumab. And based on those findings, we updated the recommendation for the standard treatment for limited-stage small cell lung cancer such that it included the use of consolidation immunotherapy with durvalumab for up to two years in patients who had had no disease progression, and completion of concurrent chemoradiotherapy for limited-stage small cell lung cancer. Of course, those patients would be those who do not have contraindications to the use of immunotherapy. As a corollary to that recommendation, for patients who have poorer performance status, so performance status of 3 or 4, who had had initial treatment perhaps with sequential chemotherapy and radiotherapy, if their performance status improves with their initial treatment, then it would also be reasonable to add consolidation immunotherapy for those patients as long as their performance status maintains improvement and they have no evidence of progression. The other update of the guidelines had to do with patients with relapsed small cell lung cancer and that was based on the DeLLphi-301 trial which was a phase II study looking at the use of tarlatamab, a bispecific T cell engager, binds to both DLL3 and CD3 in order to increase the immune killing of small cell lung cancer cells. So what this study did was it treated patients who had had at least two prior regimens. So this is third-line or beyond was what the population that this study looked at. And the majority of these patients had already had some immune checkpoint therapy. They all had good performance status and it did allow patients with brain metastases to be included in the study. When we look at the patients who received the approved 10 milligram dose of the drug, the response rate was about 40%. Responses were seen in both patients with sensitive and refractory based on the time since their prior treatment and the median duration of response was 10 months, which is much better than anything we've seen before with relapsed small cell lung cancer patients, remembering that all these patients were also third-line or beyond. So based on the results of the DeLLphi-301 trial, we updated two of the recommendations regarding relapsed small cell lung cancer. In the first one, we stated that in patients with relapsed small cell lung cancer with a chemotherapy free interval of less than 90 days, single agent systemic therapy would be considered standard of care, and that the preferred agents would include topotecan, lurbinectedin, or, now, tarlatamab. We did mention as a qualifying statement that single-agent chemotherapy is preferred over multi-agent chemotherapy. And the second recommendation was that, in patients with relapsed small cell lung cancer with a chemotherapy interval longer than 90 days, the rechallenge with a platinum-based regimen or single-agent chemotherapy was considered standard and the preferred agents for single agent therapy would be topotecan, lurbinectedin, or tarlatamab being added in the recent study. Tarlatamab was approved by the FDA for use in patients with relapsed small cell lung cancer with no stipulations with regard to the treatment. Brittany Harvey: Understood. I appreciate you describing those updated recommendations along with the supporting data for both limited stage small cell lung cancer and relapsed small cell lung cancer. So then, what should clinicians know as they implement these new and updated recommendations into practice? Dr. Greg Kalemkerian: So with regard to the ADRIATIC trial or the consolidation durvalumab being added for limite- stage small cell lung cancer patients, I think the important considerations are that this was done after patients had demonstrated no progression of disease after chemotherapy and radiotherapy, so the initial treatment does not change with platinum-etoposide plus definitive radiotherapy being recommended. The addition of durvalumab is going to be potentially useful in patients generally with good performance status, so performance statuses 0 to 1, and we still have to pay attention to the patients who may have contraindications to immunotherapy, things like interstitial lung disease, autoimmune problems that do occur in patients with small cell lung cancer where they develop paraneoplastic autoimmune syndromes such as Lambert-Eaton myasthenic syndrome. Those patients with those types of preexisting conditions would not be good candidates for immunotherapy use. So still having the tailored treatment to the individual patient is what's most important. The duration of the durvalumab was up to two years and not beyond that, so following those specific guidelines for the use of durvalumab in patients with limited-stage small cell lung cancer. With regard to tarlatamab, tarlatamab is an immunotherapy treatment. So we still do have the exclusions of people who have had prior severe immune-related adverse events, people who have pneumonitis, people who have interstitial lung disease, people with autoimmune neurologic problems we can see with small cell lung cancer, these patients should not be considered good candidates for the use of tarlatamab. The study did include patients who had had treated and asymptomatic brain metastases and there is some evidence that tarlatamab can have some control of brain metastases. So that's not necessarily an exclusion. Tarlatamab does have some other specific considerations to it in that 51% of patients had some evidence of cytokine release syndrome (CRS). Only 1% of those patients had grade 3 CRS. So even though they had frequent fevers and hypotension and hypoxia, it was generally not severe. But this concern for CRS and also for neurologic complications after treatment does require that patients be admitted to the hospital for a 24-hour observation period during the first and second doses. Subsequent to that, patients can be observed for some time after the infusion in the outpatient setting. But they also need to have very clear and strict guidance for when they go home about what things to look for. Looking for fevers, looking for shortness of breath, looking for any neurologic changes. It's a good idea for them to have a caregiver with them in order to observe them during that time. Most of these complications occur during the first or second cycles, but it is a drug that is going to require significant education not only of our staff, but also of the patients in order to ensure that the drug's used safely. Brittany Harvey: Absolutely. For these new options, it's important to tailor cancer treatment to the individual patient and the factors that you mentioned and be mindful of these potential toxicities. So, it's always great to learn of new options for patients. But in your view, how will this update impact patients with small cell lung cancer? Dr. Greg Kalemkerian: Well, clearly we need longer term follow up. So, with regard to the limited-stage small cell lung cancer situation, that's a curative situation. We have been curing patients with limited-stage disease with chemotherapy and radiotherapy for several decades now, but the cure rates were relatively low with about 25%, 30% of people becoming long term survivors. Now the hope is with the durvalumab being added on, that we can increase that number. Thus far, we have three-year survival data with a three-year survival of 57% overall survival and we're hoping that that is maintained over time and that we're not just delaying recurrences, but that we're actually preventing recurrences and helping people live longer, as has been seen with non-small cell lung cancer in stage III disease with the addition of durvalumab to chemoradiotherapy. So hopefully, we will be improving the cure rate of people with limited-stage small cell lung cancer. There are several other trials with immunotherapy in this space coming down the line and we're anxiously awaiting not only long term follow up from ADRIATIC, but also initial data from studies such as KEYLYNK and ACHILLES and NRG-LU005. So all of these studies in the next few years are hopefully going to guide treatment for limited-stage small cell lung cancer and hopefully improve the long term survival outcomes. With regard to tarlatamab, unclear at this point what the long term outcomes are going to be. Is a 40% response rate substantially better than what we've seen before? Well, lurbinectedin also had about a 40% response rate in patients who had sensitive disease, but the duration of response does look longer. And there are some patients now who have been on this study that are doing very well for quite long periods of time with the drug. So, the hope here also is that we will have some small subset of patients who continue to do better for long periods of time. Whether that'll translate into a cure or not, way too early to know, clearly hoping to add another brick in the wall so that we can keep the disease at bay, at least for a longer period of time for these patients. How we will integrate tarlatamab into the regimens is a bit unclear. Whether most of us will start using it as second-line therapy or whether we will use perhaps lurbinectedin or topotecan as second-line and tarlatamab as third-line, we're all going to have to work that out based on the potential toxicities, the logistical complications of using the drug at this point in time. But I do think that it's nice to have more options to add to our armamentarium to treat this very, very challenging and difficult disease. Brittany Harvey: Definitely. So, you've just discussed the need for both longer term follow up here along with some important ongoing trials in this space. So we'll look forward to future readouts of those trials to learn more about caring for patients in small cell lung cancer. So, I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Kalemkerian. Dr. Greg Kalemkerian: Okay. Again, thank you for the invitation, Brittany, and thanks to ASCO for developing the whole guideline structure to help all of us take better care of our patients. Brittany Harvey: Absolutely. And also thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full update, go to www.asco.org/thoracic-cancer-guidelines.  You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Dr. Lyudmila Bazheova share the latest updates to the ASCO living guideline on therapy for stage IV non-small cell lung cancer with driver alterations. She discusses changes for patients with EGFR driver alterations in both the first- and second-line setting, and reviews the evidence supporting these updated recommendations, from trials such as MARIPOSA, MARIPOSA-2, CheckMate 722, and KEYNOTE-789. Stay tuned for future updates to this continuously updated guideline. Read the full update, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.2.” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02133   Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.   My name is Brittany Harvey and today I'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, lead author on “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.2.” Thank you for being here, Dr. Bazhenova. Dr. Lyudmila Bazhenova: It is my pleasure. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bazhenova, who has joined us on this episode today, are available online with the publication of the guideline update in the Journal of Clinical Oncology, which is linked in the show notes. So then, to kick us off on the content here, Dr. Bazhenova, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer with driver alterations is being updated routinely as a living guideline. So what prompted the update to the recommendations in this latest version? Dr. Lyudmila Bazhenova: Living ASCO Guidelines are developed to keep up with rapidly changing evidence which affect treatment of our patients with lung cancer. In this recently published guideline, we reviewed new evidence for patients with metastatic lung cancer harboring driver alterations. We reviewed evidence from four published studies, MARIPOSA, MARIPOSA-2, CheckMate 722 and KEYNOTE-789 that resulted in updated guidelines. Brittany Harvey: Great. And then based off those four trials that you just mentioned, what are the updated recommendations for patients with stage IV non-small cell lung cancer and an EGFR exon 19 deletion or exon 21 L858R substitution? Dr. Lyudmila Bazhenova: In the previous guideline, we detailed FLAURA 2 study which was presented and published in the past. In this guideline, we specifically highlighted a phase 3 MARIPOSA trial which took patients with untreated advanced non-small cell lung cancer which harbored classical EGFR mutations such as EGFR deletion 19 and L858R. In this study, patients were randomly assigned to receive amivantamab plus lazertinib or osimertinib or lazertinib alone. And the study showed that the primary endpoint which was progression-free survival was longer with amivantamab plus lazertinib compared to osimertinib, and numerically the progression free survival was 23.7 months with ami-lazertinib versus 16.6 months with osimertinib which was statistically significant. The challenge that we have to face when discussing that option with our patients is increased toxicity with amivantamab and lazertinib combination. For example grade 3 treatment adverse events were 75% with amivantamab and lazertinib and 43% with osimertinib. So this will require shared decision making between our patients and ourselves. We also noticed in the guidelines that there was a subgroup analysis of that study showing that the patients with a higher disease burden, central nervous metastasis or brain metastasis as well as disease which considered to be a higher risk such as commutation, for example, p53 and liver metastasis, they might benefit from intensified therapy. However, another thing that we are highlighting in the guideline is that at this point we do not know how the intensification of therapy will change overall survival of our patients. So one needs to take into account increased toxicity with that combination. Brittany Harvey: So then Dr. Bazhenova, in addition to those updates for first line therapy, what are the updated recommendations for second line therapy? Dr. Lyudmila Bazhenova: For patients who have progressive disease on osimertinib or other EGFR tyrosine kinase inhibitors, we also updated our guidelines highlighting MARIPOSA 2 study. In the MARIPOSA 2 study, patients were assigned to chemotherapy versus amivantamab plus lazertinib plus chemotherapy versus amivantamab plus chemotherapy. And both of the amivantamab arms showed superiority in progression-free survival compared to chemotherapy alone arm and therefore this becomes an additional treatment option for our patients who develop resistance to osimertinib. In addition, we also updated the results which highlight the lack of efficacy of immunotherapy in the patients who progressed on osimertinib. There were two studies that we highlighted. One of them was a CheckMate 722 which randomly assigned patients with metastatic non-small cell lung cancer whose cancer has progressed on EGFR tyrosine kinase inhibitor to receive either chemotherapy or chemotherapy plus nivolumab which is an immune checkpoint inhibitor. And the second study was KEYNOTE-789 which had a very similar study design. Again, patients who progressed on EGFR TKI also were assigned to receive chemotherapy plus pembrolizumab or chemotherapy alone and in both of those studies there was no improvement in progression-free survival when adding immunotherapy to chemotherapy. So for all your patients who are progressing on EGFR tyrosine kinase inhibitors and you're thinking if additional immunotherapy is necessary, we now have two randomized phase 3 studies telling us that immunotherapy should not be used in addition to chemotherapy for patients who develop progression on osimertinib. Brittany Harvey: Understood. I appreciate you talking about the evidence that supports these latest recommendations from the expert panel. So then you've already touched on this a little bit in mentioning shared decision making and discussing toxicity with these new therapies, but what should clinicians know as they implement these new recommendations and how do these new recommendations fit into the previous recommendations made by the panel? Dr. Lyudmila Bazhenova: Our previous recommendations did not include a MARIPOSA trial, so did not include amivantamab and lazertinib. So in our current guidelines for patients with newly diagnosed treatment-naive EGFR classical mutations, we have three options. Number one is osimertinib, number two is osimertinib plus chemotherapy based on the FLAURA study that we highlighted in the prior version of the guidelines. And the third is amivantamab plus lazertinib. At this point, we do not have any randomized head-to-head studies of those combinations with an exception of FLAURA 2 which is osimertinib plus chemo versus osimertinib. And so the decisions will have to be made on a cross-trial comparison, taking into account patient wishes if they would like to receive chemotherapy or amivantamab plus lazertinib, understanding that this combination will result in increased toxicity. Brittany Harvey: Absolutely. I appreciate you detailing those considerations. So then finally, what do these new options mean for patients with non-small cell lung cancer and an EGFR alteration? Dr. Lyudmila Bazhenova: As a patient, it is important to also be aware of what options we have and have a direct dialogue with the physician, with the treating physician, trying to understand what option will fit with each individual patient's goals, life goals, as well as toxicity concerns. Brittany Harvey: Definitely. It's always great to have more options for patients and it's also important to discuss all of those options with their clinician as well. So I want to thank you so much for your work on this update and thank you for your time today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: My pleasure. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Sepideh Gholami and Dr. Aaron Scott join us to discuss the latest evidence-based guideline from ASCO on the management of locally advanced rectal cancer. They review the recommendation highlights on topics including assessment, total neoadjuvant therapy, timing of chemotherapy, nonoperative management, and immunotherapy. Additionally, we discuss the importance of this guideline for both clinicians and patients, and the outstanding research questions in the management of locally advanced rectal cancer. Read the full guideline, “Management of Locally Advanced Rectail Cancer: ASCO Guideline” at www.asco.org/gastrointestinal-cancer-guidelines. TRANSCRIPT  This guideline, clinical tools, and resources are available at www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.01160    Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at ASCO.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Aaron Scott from the University of Arizona Cancer Center and Dr. Sepideh Gholami from Northwell Health, co-chairs on, “Management of Locally Advanced Rectal Cancer: ASCO Guideline.” Thank you for being here, Dr. Scott and Dr. Gholami. Dr. Sepideh Gholami: Thank you for having us. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Scott and Dr. Gholami, who have joined us here today, are available online with a publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to kick us off on the content of this episode, Dr. Gholami, first, what is the purpose and scope of this guideline on locally advanced rectal cancer? Dr. Sepideh Gholami: Well, I think, historically, this is the group of patients with locally advanced rectal cancer for which we've used multiple therapies to address their management. And with the advent of the total neoadjuvant approach, we really have seen tremendous changes. So the purpose really of these guidelines was to consolidate the various approaches that we've had in several clinical trials and to provide the oncology community a general management recommendation guideline to really optimize the outcomes for these patients. And I would further notice that with the specifics to like which patients are included for these, so we define patients with locally advanced rectal cancer as any of those patients with T3 or T4 tumors and/or lymph node positive disease. Brittany Harvey: Great. I appreciate you providing that background and context of this guideline. So then, next, I'd like to review the key recommendations of this guideline. So, Dr. Scott, starting with the first section of the guideline, what are the recommendations for assessment of locally advanced rectal cancer? Dr. Aaron Scott: Yeah, thank you. So really, we were charged with trying to answer, I think, several very important questions as it comes to the treatment of locally advanced rectal cancer. And the first step in doing so is to define the patient group. So, as far as the first section goes in the assessment, we were really charged with defining what locally advanced rectal cancer means. We think that this is best done with a high resolution pelvic MRI, dedicated rectal sequence prior to any treatment for risk assessment and proper staging, and the use of standardized synaptic MRI is recommended that includes relation of the primary tumor to the anal verge, sphincter complex, pelvic lymph nodes, the mesorectal fascia, otherwise known as the MRF, and includes assessment of the EMVI tumor deposits and lymph nodes. Brittany Harvey: I appreciate you reviewing those highlights for assessment of locally advanced rectal cancer. So following that, Dr. Gholami, what does the panel recommend regarding total neoadjuvant therapy and standard neoadjuvant chemotherapy for patients with proficient mismatch repair or microsatellite stable tumors? Dr. Sepideh Gholami: Yeah, thanks so much for that question, Brittany. I would say that the guidelines really provide a lot more details, but in general, the consensus was that TNT should be offered as really initial treatment for patients with low rectal locally advanced rectal cancers or those who have higher risk for local and distant metastases. Those risk factors included anyone with either T4 disease, extramural vascular invasion and/or tumor deposits identified on the MRI for any threatening of the mesorectal fascia or the intersphincteric plane. Brittany Harvey: Excellent. So then, Dr. Gholami just discussed who should be offered TNT. But Dr. Scott, what are the recommendations regarding timing of TNT? Dr. Aaron Scott: So the way I take this question, think about this question, is a lot of the work that we put toward defining whether chemoradiation plus consolidation versus induction chemotherapy is the right choice, and there are a lot of implications to consider in this situation. The panel recognizes that the decision to proceed with chemoradiation followed by chemo versus chemotherapy followed by chemoradiation often depends on logistics regarding the time to treatment start, concern for distant metastases, and desire for local control that may impact surgical decision making. When we look at the subgroup analysis for overall survival of patients treated with TNT, it doesn't seem to matter which approach you take. Either induction or consolidation doesn't seem to have an impact on overall survival. However, there are other outcomes that may be of importance. Based on the CAO/ARO/AIO-12 randomized phase II trial, both pathologic complete response rates and sphincter sparing surgery were numerically higher with consolidation chemo. That said, there was no difference in disease free survival. So if you have a patient that really wants to consider some sort of sphincter sparing surgery, or a patient has a highly symptomatic disease burden, etc., these are patients that we would recommend starting with chemoradiation followed by consolidation chemotherapy. Brittany Harvey: Understood. And so you have both mentioned radiation included in treatment regimens. So Dr. Gholami, what is recommended in the neoadjuvant setting? Short course radiation or long course chemoradiation? Dr. Sepideh Gholami: Yeah, we actually had a really long discussion about this, but I think in general the consensus was that if radiation is included in any patient's treatment plan, neoadjuvant long course chemoradiation is preferred over short course RT for patients with locally advanced rectal cancer. And really the recommendation was based on the long term results that we've seen from the RAPIDO phase 3 clinical trial, which showed a significant higher rate of five year local regional failure with a total neoadjuvant approach with short course of 10% compared to the standard chemo RT with only 6% of the local recurrence rate. So that's why they opted for the long course, if the patients can actually tolerate it. Brittany Harvey: Excellent. I appreciate reviewing the recommendation and the supporting evidence that the panel reviewed to come to those recommendations. Then following that, Dr. Scott, for those patients who have a complete clinical response after initial therapy, what is recommended regarding nonoperative management? Dr. Aaron Scott: First, I would like to just say that this is really an area that still remains somewhat controversial and needs more investigation to best select patients for this approach. This topic was not systematically reviewed for the ASCO guideline. However, the expert panel was surveyed and most agreed with the time interval used in the OPRA phase 2 trial, which assessed patients for clinical complete response within eight weeks plus or minus four weeks after completion of TNT. Expert panel members and reviewers noted that if the radiation therapy component of TNT is delivered first, then an eight week interval following subsequent chemotherapy may result in a prolonged period of no treatment and therefore a first assessment of this response in this scenario would occur on the earlier side of the recommended interval. If a near clinical complete response is noted, then reevaluation within eight weeks is recommended to assess for developing a clinical complete response. Brittany Harvey: Absolutely. That information is helpful to understand what is recommended regarding nonoperative management and clinical complete responses. Then the final clinical question, Dr. Gholami, for patients with tumors that are microsatellite instability high or mismatch repair deficient, which treatment strategy is recommended? Dr. Sepideh Gholami: Yeah, I think we really came up to summarize that in general, when there is no contraindication to immunotherapy, then patients with MSI high tumors should be really offered immunotherapy. The evidence for this recommendation was relatively low, though, just due to the small sample size of the data that's currently available. But we did want to highlight that the data is very promising, but a definitive recommendation by the committee should be validated in future larger clinical trials. Brittany Harvey: Absolutely. Well, thank you both for reviewing the highlights of these recommendations for each clinical question. Moving on, Dr. Scott, in your view, what is the importance of this guideline and how will it impact both clinicians and patients with locally advanced rectal cancer? Dr. Aaron Scott: This would be the first guideline through ASCO to spell out management options for locally advanced rectal cancer. This has largely been needed due to the increased number of phase II and III trials investigating the specific patient population that have investigated a variety of different TNT approaches and treatment combinations utilizing systemic therapy, radiation, and surgical treatment. So, in this guideline, we really set out to define what locally advanced rectal cancer is, have organized and analyzed impactful large randomized studies to address multimodality therapy, and have consolidated this information into what we consider a concise and generalizable approach to help clinicians and patients individualize their management based on specific clinical pathologic features of their cancer. Brittany Harvey: Yes, this has been a mountain of work to review all the evidence, consolidate it into a concise review of that evidence, and develop recommendations for best clinical practice for management of locally advanced rectal cancer. So then, finally, to wrap us up, Dr. Gholami, what are the outstanding questions regarding management of locally advanced rectal cancer? Dr. Sepideh Gholami: Yeah, I think I just want to reiterate, Brittany, what you mentioned, this was a tremendous amount of body work, and we really would like to thank the committee and everyone from ASCO to help us with creating these general guidelines. I think one of the outstanding questions really still remains is the use of circulating tumor DNA as a management tool for patients with rectal, locally advanced rectal cancer. And also, I think outside of what we can think of the straightforward populations to deduce from PROSPECT, be really interested to see what other patient populations, for example, could also potentially maybe avoid radiation therapy. And lastly, I think we really wanted to highlight that this guideline really focuses on the locally advanced, and it would be great to see future guidelines for early stage rectal cancer which will be forthcoming. Brittany Harvey: Definitely. We'll look forward to answering those outstanding questions and for upcoming guidelines on earlier stage rectal cancer. So, I want to thank you both so much for, as you said, the tremendous amount of work that went into these guidelines and thank you for taking the time to speak with me today, Dr. Scott and Dr. Gholami. Dr. Aaron Scott: Thank you. Dr. Sepideh Gholami: Thank you so much for having us. Appreciate it. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please read and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Megan Daly presents the latest rapid recommendation update to the ASCO management of stage III NSCLC guideline, based on data from the phase III randomized LAURA trial, presented at the 2024 ASCO Annual Meeting, and subsequently published. She discusses the results of the trial, shares the updated recommendation from the expert panel, and the impact for both clinicians and patients. We also discuss future research in the area and exciting new developments to watch out for in the field. Read the full rapid update, “Management of Stage III Non-Small Cell Lung Cancer: ASCO Rapid Guideline Update” at www.asco.org/thoracic-cancer-guidelines. TRANSCRIPT   This guideline, clinical tools, and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-01324. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Megan Daly from the University of California Davis Comprehensive Cancer Center, lead author on, “Management of Stage III Non–Small-Cell Lung Cancer: ASCO Rapid Guideline Update.” Thank you for being here today, Dr. Daly. Dr. Megan Daly: Thanks for having me, Brittany. Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Daly, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to start us off on the content of this update, first, this guideline was updated based off new evidence presented at the 2024 ASCO Annual Meeting. Dr. Daly, could you describe the trial that prompted this rapid update to the management of stage III non-small cell lung cancer guideline? Dr. Megan Daly: The trial that prompted this update is the LAURA trial. The LAURA trial was a phase III randomized trial conducted in patients with unresectable stage III non-small cell lung cancer harboring EGFR mutations, either exon 19 deletions or L858R insertions. Patients in this trial were randomized 2:1 between the third generation EGFR tyrosine kinase inhibitor osimertinib or placebo, and osimertinib or placebo were continued until progression or other reasons for discontinuation. Osimertinib was found to provide a considerable benefit in progression free survival, with a hazard ratio of 0.16. The median progression free survival for patients randomized to osimertinib was 39.1 months, and for patients on the placebo arm, it was 5.6 months. We did not yet have overall survival data from the LAURA trial. The data is not mature, but the considerable progression free survival benefit noted with osimertinib has drawn a lot of interest to this trial. Brittany Harvey: Absolutely. Thank you for describing the results of those trials and the endpoints. So then, based on this new evidence, what is the updated recommendation from the guideline expert panel? Dr. Megan Daly: The updated recommendation from the panel is that patients with unresectable stage III non-small cell lung cancer with an EGFR exon 19 deletion or exon 21 L858R mutation may be offered consolidation osimertinib after definitive chemoradiotherapy, which can be either platinum-based chemotherapy and thoracic radiation given either concurrently or sequentially. Our evidence quality is moderate and the strength of the recommendation is strong. Brittany Harvey: Great. And thank you for reviewing both the strength of the recommendation there as well as the evidence quality rating. So it's great to have this new option for patients. So what should clinicians know as they implement this new recommendation? Dr. Megan Daly: I think it's important for clinicians to know when they're counseling patients about considering osimertinib to understand that first, the LAURA trial enrolled patients who had common EGFR mutations. So exon 19 deletions or L858R mutations. Patients with other uncommon EGFR mutations were not included in the trial. It's important to know that overall survival data is not yet mature. We do not know yet whether the use of consolidation osimertinib leads to a survival benefit at this time. We only know that it leads to a progression-free survival benefit as compared to placebo. I think it's also important to know that there was increased toxicity noted on the experimental arm. Grade 3 or higher adverse events was significantly higher with the use of osimertinib. So these are all important considerations when counseling patients and considering the use of osimertinib. Brittany Harvey: Absolutely. Those are definitely key points, as you mentioned, to consider. And you've already touched on this a little bit. But how does this change impact patients living with stage III non-small cell lung cancer? Dr. Megan Daly: We do see in the LAURA trial a rather remarkable benefit for progression-free survival. The progression-free survival, as I already mentioned, increased from 5.6 months median on the control arm to 39.1 months on the experimental arm with consolidation osimertinib. So this is an exciting new option for patients with unresectable stage III non-small cell lung cancer who have one of these mutations to extend their progression-free survival by almost three years. And we hope that this progression-free survival benefit will end up translating into a considerable overall survival benefit as well. So, certainly, the overall survival data is eagerly awaited. Brittany Harvey: Definitely, this is a promising option for patients, and we look forward to future readouts of long-term data on this trial. So that's one of the outstanding questions here. But what other outstanding questions are there regarding the management of stage III non-small cell lung cancer? Dr. Megan Daly: I think what many of us question when we look at this data is whether we could extrapolate to the use of other targeted agents with other less common oncogenic driver mutations. Unfortunately, the answer is we simply don't know yet. We hope to see some ongoing data in the resectable setting. Doing randomized trials with rare oncogenic drivers in unresectable stage III lung cancer is very difficult, unfortunately, and there's always a degree of extrapolation for clinicians when trying to figure out how to best manage our patients. But for me, that's one of the biggest outstanding questions I think specifically ties into interpreting the LAURA trial and other related trials in patients with oncogenic driver mutations. I think there's still many outstanding questions about how we continue to improve outcomes for our patients with unresectable stage III non-small cell lung cancer, questions about how we optimize our radiation regimens to have the best possible local control while reducing toxicity. We still need to continue to have randomized trials looking at questions on optimizing radiation, optimizing concurrent chemotherapy, whether there are any settings where we might be able to reduce or omit chemotherapy in place of some of these newer agents. These are all outstanding questions that hopefully will be answered over the next several years. We also continue to have open questions about when patients are more appropriate for surgery and more appropriate for non-surgical options, those borderline patients with N2 nodes who may technically be surgical candidates or could potentially be downstaged with neoadjuvant therapy. So, I think there's a lot of exciting work going on in stage III right now. Brittany Harvey: Absolutely. We'll look forward to that more data that you mentioned for more optimal individualized options for these patients with stage III non-small cell lung cancer. And I want to thank you so much for your time to rapidly update this guideline based off new evidence presented and then published. And thank you for your time today, Dr. Daly. Dr. Megan Daly: Thank you, Brittany. It's great to be on here. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline update, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Ms. Charité Ricker, MS, CGC and Dr. Nadine Tung, MD, FASCO share updates from the new ASCO guideline on selection of germline genetic testing panels in patients with cancer. They discuss highlights on family history collection, when and how multigene panel germline genetic testing should be used, which genes are generally recommended for testing, and how germline genetic testing interfaces with somatic genetic testing. Ms. Ricker and Dr. Tung also note the importance of the guideline and the impact of these new recommendations on clinicians and patients with cancer. Read the full guideline, “Selection of Germline Genetic Testing Panels in Patients with Cancer: ASCO Guideline” at www.asco.org/molecular-testing-and-biomarkers-guidelines. TRANSCRIPT GDL 24E13 This guideline, clinical tools, and resources are available at www.asco.org/molecular-testing-and-biomarkers-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00662  Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts My name is Brittany Harvey, and today I'm interviewing Dr. Nadine Tung, a medical oncologist from Beth Israel Deaconess Medical Center in Boston, and Ms. Charité Ricker, a cancer genetic counselor with the Norris Comprehensive Cancer Center at the University of Southern California and Los Angeles General Medical Center, co-chairs on, “Selection of Germline Genetic Testing Panels in Patients with Cancer: ASCO Guideline.” Thank you for being here, Ms. Ricker and Dr. Tung. Dr. Nadine Tung: Pleasure.  Ms. Charité Ricker: Thank you. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Tung and Ms. Ricker, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.   So then, to start us off first, Dr. Tung, could you provide us a broad overview of both the purpose and scope of this guideline? Dr. Nadine Tung: Sure. A main impetus for creating the guideline is that oncologists are increasingly being tasked with ordering genetic testing for hereditary cancer risk for their cancer patients. More and more now, they may find themselves sending the test and then seeking guidance from genetic experts to interpret the result. And these panels range from focused tests with just a few genes to comprehensive ones that include over 100 genes. So it can be very overwhelming for an oncologist to be able to understand ordering these tests and explaining them to their patients. So, we believe that it was important to offer some guidance and direction on the use of these multigene panels. Brittany Harvey: Thank you for setting the stage for this guideline and the recommendations that come from it.   So then, Ms. Ricker, this guideline addresses four overarching clinical questions. I'd like to review the recommendations based on each of those questions for our listeners. So starting with that first question, what is the importance of family history collection in the setting of germline multigene panel testing and which elements of family history are the most important? Ms. Charité Ricker: Thanks. As a genetic counselor, this is probably one of my favorite questions. I love the opportunity we have to sit with families and really dig into family history. But family history collection can be overwhelming and a big lift sometimes in busy clinics where genetics is not the focus. So, what we tried to do was to break down the key elements of what components of family history are most relevant to informing which test to do, and also the interpretation of those test results. And I like to think about the key pieces of family history as being the who, what, and when of somebody's family cancer history. Who was diagnosed with cancer within their close relatives? And usually we're most focused on first and second degree relatives. So parents, siblings, grandparents, aunts, and uncles. But sometimes relevant history might go into third degree relatives like cousins or more distant. So the who being who has cancer on both sides of the family? And then the what: what kind of cancer was it? Or where did that cancer begin? And the when: how old was that individual at the time they were diagnosed? Often we ask patients maybe not to fixate on the exact age, but to give us a sense. So was this somebody who was diagnosed young, in their 20s or 30s or older, in their 60s or 70s? Because that at least gives us a ballpark around what might be relevant for understanding the genes that should be included on somebody's test.  When we are thinking about the purpose of this history, as Dr. Tung said, often the range of multigene panels might be from a few very focused genes to a very broad panel. Family history can help us understand if we need to step beyond the very focused genes that might be relevant for the patient's history of cancer and include other genes that might be indicated based on that family history. So I think about the role that family history has at the time of identifying which test to do and then its role when interpreting what those results mean for the patient and their family. Again, Dr. Tung touched on the fact that we are often testing very large panels. However, we still don't know everything. And so a negative genetic test result does not mean that somebody does not have additional cancer risk. And family history becomes our kind of guiding star for understanding if there is still a need to change the cancer screening and prevention management for that individual and their family members. Brittany Harvey: Absolutely. Those are key points to understanding the important role of family history for each individual patient.  So then moving to the next clinical question, Dr. Tung, what does the panel recommend regarding when and how multigene panel germline testing should be used, when germline genetic testing is indicated? Dr. Nadine Tung: Well, anytime multiple genes need to be tested, as Ms. Ricker said, because of the patient's own personal cancer history, or their family history of cancer and close relatives, it's appropriate to consider a multi-gene panel. And in truth, we rarely ever just order one gene these days. Perhaps we do if there's a known gene like a BRCA gene in the family, and a relative just wants to know if they have that. But it's not all that common. And to be clear, as Ms. Ricker is going to cover a bit later, we are recommending that the appropriate minimal panel at least include the genes relevant to the patient's own cancer and the cancers in their relatives.  But it's worth thinking about what are some of the pros and cons of ordering genes beyond that, beyond the patient's own cancer or their relatives? Well, for pros, since a patient's awareness of their family history may be incomplete, testing for a larger number of cancer risk genes does ensure that significant pathogenic variants won't be overlooked. And sometimes, even if the family history is well known, pathogenic variants in important cancer risk genes can be found even when the family history would not have prompted testing for them. But it is important for clinicians to appreciate that bigger isn't necessarily better. Some larger panels may include genes for which management of pathogenic variants is not entirely clear and that can create anxiety or unnecessary screening. And if the clinician receiving the information is not well informed about the significance of the finding, that can lead to unnecessary treatment and sometimes even unnecessary surgeries.   And I'd add one final point that clinicians must have a system for communicating reclassification of these variants, the ones with uncertain significance that we call VUS. Because as the number of genes tested increases, so does the likelihood of encountering these VUS. So I would say those are some of the main points about when to use the panel and when to think about larger or smaller panels. Brittany Harvey: Yes, I appreciate you reviewing both the pros and cons of expanding the genes included in multi-gene panel testing and the importance of variants of uncertain significance.   So then Dr. Tung just touched on this, but speaking of minimal panels and which genes should be included, Ms. Ricker, what are the recommendations on which genes are generally recommended for germline genetic testing? Ms. Charité Ricker: I think this is one of the harder questions that our group took on as we were working on this guideline. I don't think there is a one size fits all and one easy answer to this question. However, we chose to approach it by selecting the more common solid tumors that oncologists see in their clinics and the ones where the role of genetic testing is most well defined, as well as some very rare tumors where they're kind of easy. So we know that all individuals with certain types of cancers, even though they are rare, should merit genetic testing regardless of age of diagnosis, family history.  And so as we approached it, and I really appreciate ASCO's support in helping us develop some tools and tables that hopefully will be important aids for clinicians who are trying to make these decisions, we took the approach of, as Dr. Tung mentioned, selecting kind of a minimal set of recommended genes where most individuals who are informed in this area would agree that if nothing else was done, these genes should be done, but then also acknowledged that there is an expanding understanding about the impact of certain genes on cancer risk, and so then also provided a kind of a next level if somebody wanted to be more expansive, what we would recommend less strongly, but would be reasonable to consider. Then I think the other last piece that the committee felt was important to acknowledge is that given how common, in comparison to some of these genetic conditions that we work with, pathogenic variants in BRCA1 and BRCA2 can be, and also the important clinical impact of those genes along with the genes associated with Lynch syndrome, we felt that those were important to think about in the setting of all cancer patients. So if you're approaching a panel and thinking about what genes to include, looking at that kind of minimally recommended based on the patient's personal and family history, maybe the next level, which might include some additional genes that we have included in kind of the less strongly recommended category for those tumor types. And then consideration of the BRCA1 and 2 genes and genes associated with lynch syndrome, if they weren't already encapsulated by your other personal and family history considerations. Brittany Harvey: Definitely. This was a big lift for the panel to tackle, and the tools and tables that you mentioned are all available online with the publication in the Journal of Clinical Oncology. So listeners who are looking for more specifics on that can definitely refer to those tools and tables there.  Dr. Tung, the last clinical question: which patient should be offered germline genetic testing, who will have or who have previously had somatic genetic testing? Dr. Nadine Tung: Identifying which genes identified through the tumor testing should trigger germline testing is really important for assessing our patients' future risk of cancer and their relatives. So during the development of our guidelines, the ASCO expert panel became aware that the ESMO Precision Medicine Working group had updated their recommendations for this topic, namely germline testing in response to tumor test findings. And these recommendations were based on the Memorial Sloan Kettering IMPACT registry, which consists of nearly 50,000 tumors and paired germline testing. Given the sheer volume of that data and the methods that ESMO used, our group decided to use that as a framework to develop our recommendations. The ASCO guideline provides a list of genes that, if found in the tumor, a pathogenic variant in those genes may prompt germline testing.  And we offered or proposed two different approaches. The first approach, which is broad and perhaps simplest, involves doing germline testing if a pathogenic variant is found in any of the genes listed. But then we offer a conservative approach to test the germline for all highly actionable genes, like BRCA1 and 2, or lynch genes that are found in a tumor, but for less actionable genes, testing the germline only if the pathogenic variant is found in a tumor relevant to that gene. So, for example, ATM, if found in breast cancer or pancreatic cancer, would trigger germline testing with this approach, but not if found in lung cancer, whereas with the permissive first approach, you would simply test the germline if any pathogenic variant is found in any of the genes on the list. This latter, more conservative approach, while less sensitive for identifying every germline pathogenic variant, increases the likelihood that a pathogenic variant found in the tumor will actually be germline. That approach considers the limited resources available, such as genetic counselors, and respects trying not to overwhelm a system already stressed. Brittany Harvey: Thank you for reviewing both of those approaches and to you both for discussing all of the recommendations included in this guideline.   Finally, to wrap us up, in your view, Ms. Ricker, what is the importance of this guideline and how will it impact both clinicians and patients with cancer? Ms. Charité Ricker: I hope that this guideline can open the door for more expansive and appropriate utilization of germline genetic testing. For me, I think about, from both the clinical and patient side, for example, all ovarian cancer patients have had a recommendation for germline genetic testing for many years. Nonetheless, data from multiple research studies has shown us that ovarian cancer patients still are not being tested universally, and this has important implications for their treatment plans and for their family members. And so even in the setting where genetic testing, if I can use the phrase, has been simple in that it didn't require family history, it didn't require even a specific age criteria, it was just broad, testing is not utilized as much as it should be, and then you step into the world of more complex decision making around genetic testing for other tumor types. And so we hope that this provides a framework to simplify that decision making process for providers to increase appropriate utilization.   And then from the patient perspective, I also think about the lack of access of genetic testing in underrepresented communities and minoritized patient populations where there's many barriers that patients face in accessing genetic services. And so if we can help reduce the barriers for this piece of the genetic testing process, my hope is that that opens up better avenues for access to testing, not just for patients with certain tumor types, but for all patients from all communities and backgrounds. Brittany Harvey: Yes, those are key points. We hope that this guideline helps all patients access the appropriate testing to better inform their cancer prevention and treatment.  So I want to thank you both so much for your work on this comprehensive guideline on germline genetic testing and all of the work that you put into it. And thank you for your time today. Ms. Ricker and Dr. Tung,  Dr. Nadine Tung: Thank you. Ms. Charité Ricker: It was a pleasure to be here. Thank you. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/molecular-testing-and-biomarkers-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Jyoti Patel discusses the latest update to the stage IV NSCLC with driver alterations living guideline, specifically for patients with EGFR or ROS1 alterations. She shares the latest recommendations based on recently published evidence, such as the FLAURA2, MARIPOSA-2, and TRIDENT-1 trials. Dr. Patel talks about how to choose between these new options and the impact for patients living with stage IV NSCLC, as well as novel drugs the panel is monitoring for future guideline updates. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.1” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00762  Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Jyoti Patel from Northwestern University, co-chair on, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.1.”  Thank you for being here today, Dr. Patel. Dr. Jyoti Patel: Thanks so much.   Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then to dive into the content of why we're here today, Dr. Patel, this living clinical practice guideline for systemic therapy for patients with stage four non-small cell lung cancer with driver alterations is being updated on a regular basis. So what prompted the update to the recommendations in this latest update?  Dr. Jyoti Patel: This recent update, I think, absolutely reflects how quickly the science is changing. The landscape of treatment options for patients with advanced non-small cell lung cancer is evolving so rapidly, and guidelines from even six months ago don't address some of the newest approvals and newest data and the newest clinical scenarios that we're presented with when we see patients. I think it's harder because before there was usually a single answer, and now there are a number of scenarios, and we hope that the guideline addresses this. Brittany Harvey: Absolutely. The panel's had a lot of data to review as you keep this guideline up to date.  So then this latest update addresses updates to both EGFR and ROS1 alterations. So starting with EGFR, what are the updated recommendations for patients with stage four non-small cell lung cancer and an EGFR exon 19 deletion or exon 21 L858R substitution?  Dr. Jyoti Patel: So for patients with classical driver mutations in EGFR, our recommendation remains that patients should be offered osimertinib. We now also have data to support intensification of therapy with osimertinib and chemotherapy. The FLAURA2 trial was a global randomized study in which patients with classical mutations were assigned to receive either osimertinib or osimertinib with doublet chemotherapy. The trial showed that progression free survival was longer with osimertinib plus chemotherapy with a hazard ratio that was pretty profound, 0.62. In patients who had CNS metastasis as well as patients with L858R mutations, this benefit remained and was perhaps even greater. Now the study remains immature in terms of OS. What we can say is that chemotherapy adds toxicity, so the inconvenience of 13 weekly infusions, expected toxicities from chemotherapy of myelosuppression and fatigue. I think this- we'll continue to watch as the study matures to really see the OS benefit, but certainly intensification in the frontline setting is an option for patients.  The other major update was for second and subsequent line therapy for these patients with EGFR mutations. Another important trial, a study called MARIPOSA-2, was published in the interim, and this was for patients who had received osimertinib in the frontline setting. Patients were randomized to one of three arms. The two arms that are most relevant for us to discuss are chemotherapy with amivantamab or chemotherapy alone. Chemotherapy with amivantamab was associated with an improvement in progression free survival with a hazard ratio of 0.48 as well as improvements in response rate with almost a doubling of response rate to the mid 60%. There was certainly an increase in AEs associated with amivantamab, primarily rash and lower extremity edema and importantly infusion reaction. Based on this data, though in the superior PFS and response rate, we've said that patients after osimertinib should be offered chemotherapy plus amivantamab. Patients may opt for chemotherapy alone because of the toxicity profile, but this recent update is reflective of that data. Brittany Harvey: Excellent. Thank you for reviewing those updated recommendations and the supporting evidence behind those recommendations. I think that's important to the nuance and the toxicity associated with these new recommendations as well.   So then, following those recommendations, what are the updated recommendations for patients with stage four non-small cell lung cancer and a ROS1 rearrangement? Dr. Jyoti Patel: ROS1 fusions have been noted in a small but important subset of patients. We now reflect multiple new options for patients. Traditionally, crizotinib was the primary drug that was recommended, but we now have two very active drugs, repotrectinib, and entrectinib, that have both been FDA approved. Repotrectinib was approved based on a study called the TRIDENT-1 trial. In this study, patients who were treatment naive, who had not received a prior TKI, had a response rate of 79% and a long duration of response over 34 months. For patients who had received prior TKIs, so primarily crizotinib, the response rate was lower at 38%. But again, very clinically meaningful. Repotrectinib has known CNS activity, so it would be the favored drug over crizotinib, which doesn't have CNS penetration. The decision between entrectinib and repotrectinib is one, I think, based on toxicity. Repotrectinib can cause things like dizziness and hypotension. Entrectinib can cause weight gain, and also has CNS effects. Brittany Harvey: Appreciate you reviewing those recommendations as well.  So then you've already talked a little bit about this in terms of deciding between some of the options. But in your view, what should clinicians know as they implement these new recommendations, and how do these new recommendations fit into the previous recommendations? Dr. Jyoti Patel: So there's an onslaught of new data, and certainly many of us want to remain at the front of our fields and prescribe the newest drug, our most effective drug, to all of our patients. But for the person living with cancer and in the practice of medicine, I think it's much more nuanced than that. For example, for a patient with an EGFR mutation exon deletion 19, the expectation is that osimertinib will have a deep and durable response. Certainly a patient will eventually have progression. I think the decision about intensification of therapy and chemotherapy on the onset really has to do with how much the patient is willing to deal with the inconvenience of ongoing chemotherapy, the uncertainty about what comes next after progression on chemotherapy. It may be, though, that a patient may very much fear progressive disease, and so that inconvenience is lessened because anxiety around feeling like they're doing everything for their cancer is diminished by intensification of therapy. Others who may have a large volume of disease or profoundly symptomatic, or who have L858R or brain metastasis it may make sense to give chemotherapy again, we're improving the time until progression significantly by combination therapy. Brittany Harvey: Definitely those nuances are important as we think about which options that patients should receive, along with shared decision making as well.  So then what do these new options mean for patients with EGFR or ROS1 alterations? Dr. Jyoti Patel: It's fantastic for patients that there are multiple options. It's also really hard for patients that there are multiple options, because then again, we have to really clarify aims of therapy, identify what's really important in patient experience and the lived importance of treatment delivery and the burden of treatment delivery. Now more than ever, oncologists have to know what's new and exciting. But patients have to be willing to ask and participate in the shared decision making - understanding their cancer and understanding that their options are absolutely important. As patients start making their decisions, we have the data just in terms of trial outcomes. I think we're now trying to understand the burden of treatment for patients. And so that piece of communicating financial toxicity, long term cumulative lower grade toxicity is going to be more important than ever. Brittany Harvey: Absolutely. It's great to have these new options, and those elements of communication are key to ensuring that patients meet their goals of care.  So then finally, as this is a living guideline, what ongoing research is the panel monitoring for future updates to these recommendations for patients with stage four non-small cell lung cancer with driver alterations? Dr. Jyoti Patel: It's certainly been an exciting time, and that's primarily because we've been able to build on years of foundational science and we have new drugs. Patients have been willing to volunteer to go on clinical trials and to think about what treatment options may be best. Now, the work really comes on seeing the longer term outcomes from these trials. So looking at these trials for overall survival, we want to also better identify which patients will benefit the most from these treatments and so that might be additional biomarker analysis. So it may be that we can identify patients that may need intensification of therapy based on tumor factors as well as patient factors as well in those patients in whom we can de-escalate treatment. I think there are a number of new compounds that are in the pipeline. So fourth generation EGFR TKIs are certainly interesting. They may be able to overcome resistance for a subset of patients who progress on osimertinib. We also think about novel drugs such as antibody drug conjugates and how they'll fit into our paradigm with osimertinib or after carboplatin-based doublets. Brittany Harvey: Definitely. We'll look forward to both longer term readouts from the current trials and new trials in this field to look at additional options for patients.  So I want to thank you so much for your time today, Dr. Patel, and thank you for all of your work to keep this living guideline up to date. Dr. Jyoti Patel: Great. Thanks so much, Brittany. It really is an exciting time for people who treat lung cancer and for patients who have lung cancer. We certainly have a long way to go, but certainly the rapid uptake of these guidelines reflect the progress that's being made.  Brittany Harvey: Absolutely. And just a final thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines.  You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Bradley Hunter, MD, MPH and Ms. Amy Evers, BSN, RN, OCN, MBA join us on the latest episode of the ASCO Guidelines Podcast to share key points and insights on the updated ASCO-ONS antineoplastic therapy administration safety standards for adult and pediatric oncology standards. They highlight key updates across the four standards domains: (1) creating a safe environment, (2) patient consent and patient education, (3) ordering, preparing, dispensing, and administering oral and parenteral antineoplastic therapies in a health care facility, organization, or in the home, and (4) monitoring during and after antineoplastic therapy is administered, including adherence, toxicity, and complications. They also comment on the importance of these standards to provide a framework for optimal safe and effective care for all patients. Read the standards, “Antineoplastic Therapy Administration Safety Standards for Adult and Pediatric Oncology: ASCO-ONS Standards” at www.asco.org/standards. TRANSCRIPT These standards, clinical tools, and resources are available at www.asco.org/standards. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the JCO Oncology Practice, https://ascopubs.org/doi/10.1200/OP.24.00216 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Bradley Hunter from Intermountain Health and Amy Evers from the University of Pennsylvania, authors on “Antineoplastic Therapy Administration Safety Standards for Adult and Pediatric Oncology: American Society of Clinical Oncology – Oncology Nursing Society Standards.” Thank you both for being here. Dr. Bradley Hunter: Yeah, thanks. Good to be with you. Amy Evers: Thank you. Brittany Harvey: Now, before we discuss these standards, I'd like to note that ASCO takes great care in the development of its guidance products and ensuring that the ASCO Conflict of Interest Policy is followed for all standards. The disclosures of potential conflicts of interest for the expert panel are available online with the publication of the standards in the JCO Oncology Practice, which is linked in the show notes.  So then to start us off, Dr. Hunter, what prompted an update to the ASCO-ONS standards? And what is the scope of this update? Dr. Bradley Hunter: The last guidelines were published in 2016. And just thinking about in the world of oncology, so much has changed since that time. There are a lot of therapies that have become commonplace now that were really not used too much before, including oral genomically determined targeted therapies, immunomodulatory agents, CAR T cell therapy, bispecific antibodies, etc. So there's really been a need to just talk about how do we navigate those therapies and how do we create systems of care in which they are delivered safely. Additionally, the sites of care have changed. I think all of us, eight years ago, wouldn't have imagined a global pandemic, and how that would have changed the way that we needed to deliver oncology care. So there's been a huge influx of telehealth, including tele-oncology centers, where the oncologist and the patient may never even meet face to face, but just by video. And so it relies on a team approach for that sort of an outreach setting. Intermountain Health spans seven states, there are so many sites like this that we have and I know that we are not unique. This is an issue and a global thing now. Additionally, patients are even getting chemo in their own homes, so that has changed and we need to figure out how to address that so that everyone could be able to have that site of care so they can get there and they can get their therapy in a safe manner.  So, these varied care settings present a challenge to us as oncology providers to ensure that a standard of quality of care is maintained, and that the therapies can be given to patients no matter where they live and that we maximize benefit while minimizing risk to the patient. So I mean, just thinking where we are now, I can't imagine where we're going to be eight years from now or the next time these guidelines are updated. Brittany Harvey: Absolutely. Thank you for setting the stage and the impetus for this update. It sounds like a lot has changed in the last few years to impact these standards.  So then I'd like to review the key points of the standards and the key updates for our listeners. There are four domains of standards. Starting with domain one, Amy, what are the key points of the standards for creating a safe environment for all routes of antineoplastic therapy? Amy Evers: So domain one is all about who can write chemotherapy orders, who can prepare chemotherapy and then who can administer that chemotherapy and then what their competencies are both initial and then ongoing. So looking at the existing standards, we did end up making a few updates mainly on how providers discuss and document pregnancy status and fertility preservation with patients. And I think this is really timely given that we're seeing a big uptick in younger patients that are being diagnosed with cancers that were typically considered “old person diseases”. And I think we can and we should do better in ensuring that patients who want to preserve their ability to have a family one day can do so before they start treatment.  The update also included the addition of an assessment for social determinants of health, calling out financial and logistical constraints that patients may face as part of their cancer journey, which I think is extremely important making sure that we have equitable access to care regardless of a patient's background, their financial status, everybody's receiving the highest quality of care they can in their community.  And the last change that we made was to highlight an accurate measurement of height and weight using metric units, which is important when we're calculating the doses of drugs for some of these very high risk medications.  Brittany Harvey: Excellent. Thank you for reviewing those important points for our listeners.  So following those standards, for domain two, Dr. Hunter, what are the key standards for patient consent and patient education? Dr. Bradley Hunter: In domain two, we're really seeking to figure out what policies around treatment planning, patient consent and patient's education are shown to result in fewer medical errors and reduce preventable harm? But one of the big things we've found is having a really detailed understanding of exactly what a patient is taking in terms of medications, including over the counters and supplements and herbal remedies, really helps reduce medical errors. You know, some of the research and literature we came across suggest that upwards of 80% of the time when you see a patient's medication there are discrepancies between what's on that list and what patients are actually taking. So being able to sit down as part of a consent discussion and ongoing care and talk about everything that a patient's taking is really important.  My background, I am a bone marrow transplant, stem cell transplant and cellular therapist. Just this last weekend I was on the inpatient service and a patient had brought in food from home which we completely are supportive of. The patient brought in a bunch of superfood shakes that she had bought at Costco and then some CBD tea and she asked us if it was okay if she could take those. And as we reviewed them and what was in all of those shakes and then what was in the CBD tea, there were major interactions between those supplements or those herbal remedies, and then what was in the medications we were giving in the hospital, so it was important. And she told us - it wasn't like I sat down and and was the shining example here, but it was helpful that we were able to take her global picture of what she was taking from a medication standpoint and be able to make sure that we were treating her in a safe manner and making sure that we weren't inadvertently causing harm.  So, those are some of the things that we talked about. So, at every patient visit, and especially the first time you meet a patient you're going to start therapy to be able to go over all of the different substances that patients are taking to make sure that they're safe.  Brittany Harvey: Thank you so much for reviewing those key standards and key updates and that example of how important it is to review all of medications and herbal supplements that patients are taking to ensure safe care for our patients.  So then following that, Amy, for domain three, what are the key points regarding ordering, preparing, dispensing and administering oral and parenteral antineoplastic therapy in a healthcare facility organization or in the home? Amy Evers: So, domain three, actually, it was the domain that had probably the biggest discussion and fruitful debate between the panel members, but I think that we had some really great discussions and I think we had brought some really good changes and updates to the standards here. So domain three is where all of the verification standards live. So this is for practices who would either have been through the QOPI certification process or have been QOPI certified. This is where the surveyor actually will observe in real time how the clinical orders are reviewed by staff, how the drugs are prepared by pharmacy, and then how the drugs are checked one final time at the chair side or bedside immediately prior to administration.  So as I mentioned earlier, antineoplastic therapies are being given more frequently in the home or in settings where there may not be two clinical staff members present. In this post-COVID world, we're finding patients can be treated safely in the home, but the standards didn't really reflect kind of these changes in where patients are receiving treatment. And often, more and more practices are relying on technology to supplement the verification process both either in the pharmacy setting where there may be a centralized pharmacist verifying the drug mixing process for multiple sites, or in the actual home setting where a nurse can connect virtually with another clinician to verify a drug immediately or administration. So the standards were updated to include these workflows. And I think it's becoming more and more commonplace, but how do we do this in a safe and effective way where we're ensuring that all of these same safe handling processes are completed, regardless of where the patient may be seeking treatment?  So previous versions of the standards had three verifications. The first was before the actual preparation of the drug that someone other than the provider who wrote the order is verifying the order for all of the correct elements. The second verification is what usually happens in the pharmacy, upon preparation, what's being checked by the pharmacist or pharmacy technician who's preparing the drug. And then a third verification is done at, generally, the chair side where they're doing one final check of the orders to the drug to the patient.  So with this update, we actually broke out that third verification into a fourth verification. So the third verification is that check with the drug in the order by the administering and then a second verifier. And then the fourth verification is actually the one where the patient's involved in the verification. So there are two clinicians making that final double check with the patient immediately upon preparation, which I think is important and is reflective of this change that we're seeing more drugs being administered in the home setting. The chair side or bedside final verification was also expanded to include a visual inspection of the administration tubing, this is sometimes referred to as tracing the lines, which ensures that the drug is being accurately infused, that there aren't any loose connections, that the clamps are open etc. And I think this is something that most nurses do in their normal clinical practice, but I think adding this as an actual check in the verification process, is really important. And I know personally, I was really happy to see this added in as a formal check. Dr. Bradley Hunter: Yes, thanks, Amy. One other new standard within domain three is regarding immunomodulatory or immune effector cell therapies that have the risk of cytokine release syndrome and how we build a framework to try to mitigate those toxicities. We really wanted to try to make a set of standards that would apply whether or not you're at a coronary care center, like Penn or whether you were at a center, like within Intermountain Health, it's a small rural outreach center that you're trying to be able to get patients to care. So really, the main thing within dealing with therapies that have the risk of cytokine release syndrome is really just building a framework that there's a management policy that's present from the institution, and that it's up to date, it's following what we know will work for these therapies in order to mitigate their toxicity, and then also making sure that adequate antidote therapy, whether for example, for cytokine release syndrome, it could be tocilizumab or anakinra or other therapies, and that order sets are present to be able to follow along with the policy guidelines to guide clinicians wherever they are practicing to help mitigate cytokine release syndrome, neurologic toxicity, ICANS, or other sorts of therapies that are associated with these novel agents.  Brittany Harvey: So for or the last domain, domain four, what are the key points for monitoring during and after antineoplastic therapy is administered, including adherence, toxicity, and complications? Amy Evers: So domain four is pretty straightforward. It discusses the importance of assessing adherence and toxicities related to antineoplastic treatments. There wasn't a whole lot of updates here. We did include having emerging treatment plans or equipment in the home and the healthcare setting. But what I really think is important and we need to underscore both with patients and clinicians, particularly as we've seen this rise in oral chemotherapy agents, is that a lot of times patients forget that this is the same chemotherapy that they're getting in the infusion suite. They're just taking it in a pill form. And I think patients forget that their adherence is just as important in taking that pill regularly and as prescribed. Financial toxicity is a real problem for most of our patients. Some of these drugs cost hundreds if not thousands of dollars for one treatment plan. As clinicians we've all heard stories of these patients who try to extend their prescription so they'll take a pill every other day instead of daily as prescribed, which really doesn't let the drug do what it's supposed to do. So I think when we talk about adherence, it's not just asking a patient whether they've taken their drug, it's about whether or not oral therapy is even appropriate for that particular patient. Do they have memory problems? Do they have metastatic disease to the brain where they may not be able to follow a complicated oral regimen? Do they have arthritis where opening a pill container is difficult? So having these conversations before a drug is even prescribed and making sure that it's the right route of administration for a patient is just as important as ensuring that they're maintaining their adherence to that drug.  And oftentimes, the toxicities of these oral drugs are worse than what's actually being administered in some of the infusion clinics, and so making sure that we're checking in on these patients regularly to ensure that they're not having any toxicities that aren't being managed appropriately. Or if there may be toxicities that would require a dose reduction, or perhaps switching to a different drug entirely. So, even though it's a pretty simple and straightforward domain, I think it's really important that we're educating our clinicians and our patients about the importance of adherence.  Dr. Bradley Hunter: I completely agree with what Amy said. She said it so well. I just want to echo back a couple of things that she said. Historically, we use the word non-compliant, which I think kind of sounds terrible to describe the patient's adherence to medication. I think part of this domain is recognizing that there is an entire environment that has to do with the patient that influences the way they're able to take their medication whether that's financial toxicity; we were talking to two people in our clinic who are professional financial toxicologists, and their entire job description is to help people get drugs for less so that they can actually take the side effects. If a patient feels terrible at that time, they're not going to take it. So, understanding these barriers and really understanding the patient's entire picture, when you're figuring out how is the treatment plan going to match up with their reality, I think is super important.  When it comes to site of care, we just want to make sure also that whether you're getting chemo at home or you're getting chemo in the clinic down the street, or in a coronary care center, that there is a policy in place to respond to an emergency, but also the equipment available in all of those sites of care that you can respond. And that's another aspect that we wanted to make sure we hit in the domain as there's been so many changes in how patients get care in the last eight years. Brittany Harvey: Absolutely. Recognizing the barriers and factors that impact the ability of an individual to receive the right therapy is crucial. And I want to thank you both for reviewing all of the standards and updates through all four domains.  So then following that, in your view, how will these updated standards impact clinicians? Dr. Bradley Hunter: It's our hope that these standards will guide the development of treatment infrastructure and help clinicians avoid error prone environments. We hope they're going to guide training efforts and that they will help clinicians ensure that they have relevant and accurate information about their patients and are able to respond appropriately when emergencies or even urgencies arise. Because of COVID, there's been such high staff turnover. And in the midst of all of this change, it's difficult to maintain a culture of safety when you've lost a lot of institutional knowledge of how to deal with that. And so, really trying to help bring people together again to have an infrastructure in place that makes training as seamless as possible and deal with the historical high staff turnover we've had.  So we're again, hopeful that we're helping to create a framework that cancer centers, treatment centers can use, whether they are a coronary care center in a large academic space, or whether they're in a rural tele-oncology space to be able to use the standards to create a space and a place and experience for cancer patients in which they're kept safe and we're maximizing the benefit of their chemotherapy, their antineoplastic agents, and also minimizing the risk just to optimize benefits for the patient.  Brittany Harvey: Definitely. Those are key points to provide a framework for clinicians.  So then along those same lines, finally, what does this update mean for patients receiving antineoplastic therapy?  Amy Evers: So while these standards are not necessarily patient facing, what I hope that this update will do, or actually not do, is that a patient shouldn't recognize any change in how they are cared for, regardless of what setting that they're receiving treatment. So whether it's at home, whether it's an ambulatory infusion center or in the hospital, they're still going to receive that same level of high quality care while they're receiving treatment. And I think that that's the most important thing that they should take away from this. Brittany Harvey: Absolutely.  So I want to thank you both so much for all of your work on these standards to ensure patients receive optimal safe and effective care. And I want to thank you both so much for your time today.  Amy Evers: Thank you so much.   Dr. Bradley Hunter: Yeah, thank you. It's really great to talk about this stuff.  Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the complete standards go to www.asco.org/standards. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Rachel Freedman and Dr. Sharon Giordano share the latest rapid guideline update from ASCO on the adjuvant use of the CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer. They share details on the impetus for the update, supporting evidence, and considerations of benefits and harms for individuals. Additionally, Drs. Freedman and Giordano discuss what these options mean for clinicians and patients, and outstanding questions regarding optimal adjuvant chemotherapy and targeted therapy for patients with early breast cancer. Read the full rapid update, “Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer – CDK4/6 Inhibitors: ASCO Rapid Guideline Update” at www.asco.org/breast-cancer-guidelines." TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00886  Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Rachel Freedman from Dana Farber Cancer Institute and Dr. Sharon Giordano from MD Anderson Cancer Center, co-chairs on “Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer – CDK 4/6 Inhibitors: ASCO Rapid Guideline Update.” Thank you for being here, Dr. Freedman and Dr. Giordano. Dr. Rachel Freedman: Hi. It's great to be here, thank you. Dr. Sharon Giordano: Yeah, thank you for having us. Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Freedman and Dr. Giordano, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content here. First, Dr. Freedman, what prompted this update to the “Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer Guideline”, which was previously updated in 2021? Dr. Rachel Freedman: Yeah, at that time, we published guidelines which were part of an amendment to the previously published 2020 early breast cancer guidelines to include consideration of adjuvant CDK4/6 inhibitor use, because the first data for adjuvant abemaciclib became available from the monarchE trial, and because the FDA had acted to grant approval for the use of abemaciclib in those with node positive disease and a Ki-67 score of at least 20%. Our recommendation at that time was to apply abemaciclib in the greater context of the intention-to-treat population included on the monarchE study. But since that time, the FDA in 2023 expanded its approval for adjuvant abemaciclib for a broader population, removing that Ki-67 requirement that was a part of their initial approval. With this change, the recently published longer term data from the monarchE study and the recently published data from the NATALEE trial and adjuvant ribociclib study, we felt that it was time to update our guidelines to be more relevant to the most current data available. Brittany Harvey: I appreciate you providing that background information on the impetus for this latest update. So then, Dr. Giordano, based on this new data, what are the updated recommendations in the latest version of this guideline? Dr. Sharon Giordano: So we really have two updated recommendations and then two qualifying statements that go with the new recommendations. So the first recommendation focuses on the use of adjuvant abemaciclib, which, as Rachel noted, was included in our previous guideline. So this recommendation is that abemaciclib for two years plus endocrine therapy for five or more years may be offered to patients who meet the criteria of the intent-to-treat analysis in the monarchE study. These are patients with resected, hormone receptor-positive, HER2-negative, node-positive breast cancer at high risk of recurrence. The way the study defined the high risk of recurrence was having either four or more lymph nodes involved, axillary lymph nodes involved, or having one to three lymph nodes, plus other high risk features, which included having a grade three tumor the size of 5 cm or greater, or having a Ki-67 of more than 20%. And so, although the FDA has dropped the requirement for the Ki-67 testing, and the language is quite broad now, the panel recommends the use of abemaciclib, really in that subgroup of patients that would have been eligible for the original monarchE study. That's the first recommendation, kind of a long one, but that was the update. The second recommendation focuses on the use of adjuvant ribociclib, and this is based on the data from the phase three NATALEE trial that was recently published. This recommendation is that ribociclib for three years plus endocrine therapy, may be offered to patients with stage two or three breast cancer who would have met criteria for study entry and have a high risk of recurrence. I would note with this one, I think it's important to remember that the ribociclib that's used in the adjuvant setting is a different dosing. So it's 400 milligrams daily, three weeks on, one week off, as compared to the 600 milligrams we're using in the metastatic setting. That was the second new recommendation. As I previously mentioned, however, there were two qualifying statements. The first qualifying statement was really the panel wanted to make, because they felt that CDK4/6 therapy in the adjuvant setting may not provide meaningful clinical benefit to every single patient who would have been eligible for these two trials. The concern was especially around lower risk patients. So the early stage two breast cancer patients who were included in the NATALEE trial, and in that situation, the panel felt for some patients, the risks may outweigh the benefits. The challenge here really was that there was not a great way to pick a very specific subgroup of patient that would benefit or wouldn't benefit. So based on that, the panel really recommended taking a broad approach and considering the benefits of therapy, the risks, the costs, and of course, patient preference when making the decision about whether or not to offer these drugs in the adjuvant setting. Then the second qualifying statement was really around how to pick between the two drugs. What the panel stated was that for patients that met the criteria for both studies, they could have been in either monarchE or NATALEE, for those patients, that abemaciclib has longer follow up, has a deepening benefit over time, it's more convenient because it's two years versus three years, and it has FDA approval. So for patients, again, that would have met criteria for either study, the panel favored using abemaciclib, except if patients had some contraindication or intolerance. That is the update, both the recommendations and the qualifying statements in this updated guideline. Brittany Harvey: Understood. Thank you for reviewing both of those recommendations and the nuances between choosing between some of those options as detailed in the qualifying statements. So then, Dr. Freedman, I think Dr. Giordano has talked about this already a little bit, but what should clinicians know as they implement these new recommendations into practice? Dr. Rachel Freedman: Yeah, in the guidelines, as Sharon said, we've really tried to offer recommendations that balance the available efficacy data along with the toxicity data and even some mention of cost consideration, although we purposely can't address that in the guideline. And we just feel that all of these need to be considered in combination for the individual patient. And just like you heard, our panel felt that for those meeting criteria for both the monarchE and NATALEE trials, given all the reasons that Sharon explained, that abemaciclib may be the preferred agent for now, but we all look forward to the evolving data in this space. It's great to have another evidence-based option with ribociclib at this time, but we really acknowledge that longer term follow up will evolve these recommendations further. Brittany Harvey: Absolutely. As you mentioned, it's great to have another option in this space. So then, in your view, Dr. Giordano, how will these recommendations impact patients with early breast cancer? Dr. Sharon Giordano: I think that, overall, this is really good news for patients who are at high risk because there's now two new available therapies that they can use to help prevent recurrence. I will note, as we mentioned before, though, they do come with a price, both the cost of the drug and the additional side effects of having two or three years of an additional drug that they're taking. But having said that, I think it's always good to have new options for therapy, and we can discuss these options with the individual patients, weigh the risks and the benefits, and ultimately, we hope with longer follow up, it would be great to see if these drugs would actually improve overall survival, which is ultimately our biggest goal. Brittany Harvey: Definitely, those are key for shared decision making between patients and their clinicians. Then finally, looking forward, Dr. Freedman, what are the outstanding questions regarding the optimal adjuvant chemotherapy and targeted therapy for early breast cancer? Dr. Rachel Freedman: Well, there are a lot of outstanding questions with regard to chemotherapy. We have a lot of questions. We still have insufficient data to specify which subgroups, who may have a higher degree of nodal involvement, or what we call anatomical risk, but perhaps a favorable biology or genomics. And we don't know which subgroups still need chemotherapy. And I think this is a group many of us are struggling with in the clinic, is what to do when you have high anatomical risk, but a well behaving cancer, so to speak. And I think that's a burning question for many of us. I still think we have room to improve our adjuvant regimens and figuring out who needs more and who needs less therapy when we are going to move forward with chemotherapy. And we also, with regard to CDK4/6 inhibition, have a lot of ongoing questions. There are a lot of patients who may not benefit from CDK4/6 inhibition as much as others, and the broader population on the NATALEE trial allows us to explore this a little bit, but we're cautious about interpretation of subgroups. But the lowest risk patients on the NATALEE trial may be a group of patients that it's really important to think about when it comes to balancing that toxicity and efficacy risk, as opposed to that higher risk patient where you're sure you want to move ahead. And I think we really await the survival data from both NATALEE and monarchE, neither of which have shown a statistically significant survival advantage to date. We really need ongoing follow up of these studies, and we look forward to learning more in the years to come. Dr. Sharon Giordano: Yeah, I completely agree. It's very well said. I mean, I think one of the biggest challenges, as Rachel said, it's really hard to figure out which subset of patients are truly going to benefit and have the benefit of the drug outweigh the side effects. I hope as we get longer follow up on the studies and additional data come out, we're able to get more information so that we can really give the best therapies to the patients that need it, but also spare patients who don't need it from the additional side effects. Brittany Harvey: Absolutely. We'll await the longer term follow up of these trials and then future updates to these guidelines. So I want to thank you so much for your work to rapidly update this breast cancer guideline. And thank you so much for your time today, Dr. Giordano and Dr. Freedman. Dr. Rachel Freedman: Thanks so much. Dr. Sharon Giordano: Yeah, thank you very much, our pleasure. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full rapid recommendation update, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Karen Mustian joins us to share the latest update to the management of fatigue in adult survivors of cancer guideline from the American Society of Clinical Oncology and the Society for Integrative Oncology. Dr. Mustian highlights the recommendations across the continuum of care, including recommendations for patients with cancer-related fatigue during active treatment, after treatment, and for patients with advanced cancer or at the end of life. She also discusses interventions that are not recommended for treating cancer-related fatigue. The episode wraps up discussing the importance of this guideline for clinicians and patients, and a call for more research both on interventions and on dissemination and implementation to improve symptom management for cancer-related fatigue. Read the full guideline update, “Management of Fatigue in Adult Survivors of Cancer: ASCO-SIO Guideline Update” at www.asco.org/survivorship-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/survivorship-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00541   Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.   My name is Brittany Harvey, and today I'm interviewing Dr. Karen Mustian from the University of Rochester School of Medicine and Wilmot Cancer Institute in New York, co-chair on “Management of Fatigue in Adult Survivors of Cancer: American Society of Clinical Oncology –Society for Integrative Oncology Guideline.” Thank you for being here, Dr. Mustian. Dr. Karen Mustian: Thank you for having me, Brittany. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Mustian, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to dive into the content of this episode, Dr. Mustian, what is the purpose and scope of this updated guideline on fatigue in adult survivors of cancer? Dr. Karen Mustian: Cancer-related fatigue is one of the most common and debilitating consequences that patients experience when they go through treatment, and it can actually interfere with their ability to complete treatment and their recovery along the way. And it's not the same as a typical fatigue that you might experience from physical activity, let's say, where you can come back in and rest for a little while or take a nap or sleep, and you wake up refreshed and not feeling fatigued anymore. This type of fatigue actually needs special attention and needs to be treated with therapies.   So, this particular guideline is developed in a manner to help clinicians when patients present with fatigue, especially moderate to severe fatigue, that can be very debilitating, help patients decide what kinds of treatments they can use to reduce this fatigue. It's really important that this fatigue be reduced for a number of reasons. But some of the reasons we think of as being really critical are so that they can actually get their full treatment as prescribed, and then when finished with treatment, so they can actually resume their normal daily activities. They can keep working, they can keep engaging with their families, they can resume all those wonderful normal life activities that we hope for and that their prognosis will be a good one. Brittany Harvey: Absolutely. It's critical to address cancer-related fatigue for all adults with cancer.  Then, this guideline covers three distinct patient populations and provides recommendations for each. Starting with the first section, what are the key recommendations for patients with cancer-related fatigue during active treatment? Dr. Karen Mustian: Well, one of the things I want to mention about this guideline before I answer that question is this guideline encompasses the entire cancer trajectory. In previous guidelines for treating fatigue, we really focused on how to work with patients once they had completed their primary treatments for their cancer. This time, we're able, because the research and the literature have advanced more, to really now address what we should be doing to help patients with their fatigue while they're receiving active treatment. This can be primary treatment and/or maintenance therapies, but then also once they're done with treatment and they are in the recovery stage. And then also the third area is how should we help patients with advanced cancers with their fatigue that they are experiencing?  And I believe that you just asked me how we should be working with patients really during active treatment. This guideline, when we reviewed the literature, there's really good evidence to suggest that for people undergoing cancer treatment, clinicians should recommend exercise, cognitive-behavioral therapy, mindfulness-based programs, and Tai Chi or Qigong as first-line therapy to reduce the severity of fatigue that patients can experience during treatment. We also found that the literature suggests that psychoeducation and American ginseng may also be recommended in adults undergoing cancer treatment. Brittany Harvey: Understood. Thank you for providing those key recommendations for patients with cancer-related fatigue during active treatment.  Then, following those recommendations, at the next point in the cancer trajectory, what does the expert panel recommend for patients with cancer-related fatigue after treatment? Dr. Karen Mustian: Well, for survivors after treatment, the literature is also strong in that clinicians should be recommending also exercise, again, cognitive-behavioral therapy, and mindfulness-based interventions and programs. There's also a good amount of data to suggest that we should be recommending yoga, acupressure, and moxibustion for cancer-related fatigue after completion of treatment. Brittany Harvey: I appreciate you reviewing those recommendations as well.  Then that final third population that you previously mentioned, what are the key points for the management of cancer-related fatigue for patients with advanced cancer or at the end of life? Dr. Karen Mustian: For patients at the end of life, we should be offering those individuals cognitive-behavioral therapy and corticosteroids. Brittany Harvey: Thank you for reviewing all of those recommendations for patients with cancer-related fatigue during active treatment, after their treatment, and for patients with advanced cancer.  Are there additional recommendations that were made by the expert panel that we should know about treating cancer-related fatigue? Recommendations for things that we should not be doing to treat cancer-related fatigue? Dr. Karen Mustian: One of the things that's also characteristically different about this particular guideline update for ASCO is that this time we actually have research to suggest that there are some interventions that historically may have been used, but the research is actually suggesting that they should not be recommended at this time. The guidelines now state that clinicians should not recommend L-carnitine or antidepressants, wakefulness agents, or routinely recommend psychostimulants to manage symptoms of cancer-related fatigue. One of the things that this really highlights is the recommendation to pull back on the use of pharmaceutical products as a first-line therapy for treating fatigue and to really look at behavioral interventions which are showing the strongest evidence in the research in terms of effectiveness, both during treatment, after treatment, and for our patients with advanced cancer, and to really promote these behavioral interventions for patients rather than just reaching right for that pharmaceutical product.  There are still instances where pharmaceuticals may be really important for patients, such as if someone tries behavioral therapies and they fail, for example, or if someone has fatigue that is just absolutely so severe that they cannot even give a good effort or attempt to trying something like exercise or cognitive-behavioral therapy or mindfulness-based programs. You know, even considering that most of the cognitive-behavioral therapy and mindfulness-based programs don't require physical activity, they're very low intensity types of behavior change. And that's really a big area where these guidelines also differ in the update from previous guidelines.  Brittany Harvey: Absolutely. I appreciate you reviewing those so that we know what strategies and treatments also should not be used and how we need to tailor our interventions to specific patients and their needs.  So then, in your view, Dr. Mustian, what is the importance of this guideline and how will it impact both clinicians and patients with cancer-related fatigue? Dr. Karen Mustian: I've seen a lot of ASCO guidelines and helped with a lot of ASCO guidelines, and one of the things that I think is really great about this particular guideline for cancer-related fatigue is, I'll reiterate, this is one of the most prevalent, debilitating toxicities experienced by virtually all cancer patients at some point during their time being treated or in recovery. And I'm really pleased to see that the research has come far enough that we now actually have interventions that we can recommend strongly, and then we also have other interventions that we recommend that the evidence is still growing for.  What's also nice about this, and what's really going to be impactful for patients, as I just said, is that the recommendations are not focused on pharmaceuticals. Patients already take a lot of pharmaceutical products, we have to worry about polypharmacy and all the side effects associated with that, especially in our elderly populations. This guideline gives clinicians and patients not just one or two, but several behavioral interventions that they can use that, if used in the correct way, as stated in the guidelines, stand an excellent chance of reducing the amount of fatigue that they experience. So, it really is going to change the landscape of care for patients. It's also going to change the landscape of what clinicians have to offer in their toolkit for treating patients. And I know that oftentimes we think it's easy for a physician to recommend a pharmaceutical product. But I also know that a lot of oncologists love being able to recommend lifestyle interventions to really help their patients with side effects and toxicities. And that's exactly what this guideline is offering. And I think it's just going to provide a wonderful place for a clinician and patients to come together to have conversations about what the guidelines say is effective, and to allow them to have a conversation surrounding choice. Which one seems to be the best fit? Which one would a patient actually like to try? Which of these lifestyle interventions does the patient think they have the best chance of succeeding with both in terms of accessing it in their community, adhering to it, being able to do it so that they can actually derive the benefits that we expect to see. That's really one of the key components of the efficacy of these interventions as well, is what really is going to determine, ultimately, how well these interventions work is working together to pick the one that the patient feels that they can actually do and accomplish in order to receive the benefits. It really is going to change the landscape of how we work with symptom management surrounding fatigue. Brittany Harvey: Yes. As you mentioned, it's great to have these multiple evidence-based recommendations to have a real impact for patients. You also just noted that evidence is still growing in some areas. So what future research is needed regarding the management of cancer-related fatigue in adult survivors of cancer?  Dr. Karen Mustian: I think oftentimes when we see a guideline come out, many times people say, “Well, we have the answers now, so we don't need to fund any more research in that area.” Or maybe it becomes less of a priority. For all that we do have these treatments to recommend now, we're still really very in the early stages of being able to identify, characterize and accurately provide therapies and treatments for cancer-related fatigue. When I look back at the history of nausea and vomiting and where we've come in the decades of research that has ensued since the first initial findings on that. I think fatigue is still very much in its early years.   Some of the things that we still don't necessarily know when it comes to these kinds of interventions, and I can tell you we struggled with in the guideline committee, is what is the actual dose of some of these behavioral interventions? I think when we prescribe a medicine, we think, “Oh, you need this particular dosage of this particular agent. You take it this many times a day, this many times a week for x number of weeks, and there you go.” With behavioral interventions, it's a little more complex. And so really getting down to the nitty-gritty of defining exactly what type of exercise, the intensity of that exercise, exactly how many minutes a day, exactly how many minutes a week do you have to do? We weren't really able to get our recommendations refined to that degree, and I think future research that really wants to be in service of clinicians and patients should work towards defining specific prescriptions of these interventions.   Exercise, I just gave that example, but it's the similar kind of approach for cognitive-behavioral therapy. What are the specific components that need to be included? What does the ratio of focus on those different components need to look like? Also, the same with Tai Chi, Qigong moxibustion, acupressure that we mentioned - really refining those specific prescriptions, I think, is something that we need research on, and that will take us to the next step, where we have patients doing enough that they get the effect that they want, but not wasting their time, effort, energy, and finances doing too much that they don't need to do in order to achieve the benefit that we hope for.   For some of the recommendations that are not strong, we still need large, definitive, randomized clinical trials on those interventions. So, for example, we talk about that we may recommend psychoeducation and American Ginseng for patients undergoing cancer treatment. We need more research in that area in order to be able to really say whether or not we should be offering that for patients undergoing treatment. And specifically, those large, definitive, phase III randomized clinical trials, talking about trials that also could be done across multiple centers where we can have more generalizable populations, different kinds of communities where those interventions are being delivered, rural dwelling communities, for example. And then, of course, there's always the need for newer and better interventions. Some of these interventions have very decent effect sizes in terms of their outcome, but it would be wonderful to actually find an intervention that completely mitigated cancer-related fatigue, and it was completely gone, never to return. I think we're still in some ways waiting for that intervention to be developed. And I also would say, even though we're not recommending pharmaceuticals quite a lot in this guideline, they're not our first-line therapy, there's still always the opportunity to identify molecular targets that really could help with remediating cancer-related fatigue. So there's still a plethora of research to be done out there and things that we don't know.   And then lastly, and very much importantly, we need to do research and dissemination and implementation. Behavioral interventions are really challenging to deliver. So unlike a doctor recommending a pharmaceutical product where they can write a prescription, and then the patient gets the prescription from the pharmacy and they have what they need, supposedly understanding how to prescribe these interventions for patients, or even understanding how to refer them to places in communities where they can actually get a credible practitioner that is using an evidence-based approach that is known for being one of the types of yoga or exercise, or mindfulness-based stress reduction or CBT, that will actually have a positive influence on fatigue is also challenging. And so we need that dissemination and implementation research  - that I do believe is going to be also really key in the next decade at changing the landscape of what this toxicity looks like in the patient experience of cancer. Brittany Harvey: Definitely, these all will be key to understanding the best options for all patients, and we'll look forward to continued research in these areas to fuel future guideline updates and improve management of cancer-related fatigue in all adults with cancer.  So, I want to thank you so much for your work developing this guideline, and thank you for your time today, Dr. Mustian. Dr. Karen Mustian: Oh, it's such a pleasure. I did not develop this guideline alone. I definitely want to say thank you to all my colleagues who worked very diligently and very hard on digesting the research and making these recommendations. They are representative from institutions all across the United States. A very wonderful expert panel. Thank all of them very much and give them the credit that they are due for all their hard work. And thank ASCO for supporting these efforts for clinicians and patients. And Brittany, thank you very much for having me. Brittany Harvey: Absolutely. A big thank you to the whole panel.   And thank you also to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Debra Lundquist, PhD, RN and Dr. Arun Ghoshal, MD, MBBS discuss the new update to the palliative care for patients with cancer guideline developed by an interdisciplinary Expert Panel. They share the key updated recommendations on the most effective palliative care interventions, how these recommendations relate to other supportive care services, interventions for family caregivers, care partners, and communities, referrals to specialist palliative care services, and specific strategies for the integration of palliative care for patients with hematologic malignancies and those on early phase clinical trials. Dr. Lunquist and Dr. Ghoshal also discuss the contextual factors that affect equity at the intersection of palliative and oncology care, the impact of this guideline refresh for clinicians and patients, and future innovations in the field of palliative care. Read the full guideline update, “Palliative Care for Patients with Cancer: ASCO Guideline Update” at www.asco.org/supportive-care-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00542 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.    My name is Brittany Harvey, and today I'm interviewing Dr. Arun Ghoshal from Princess Margaret Cancer Center and Dr. Debra Lundquist from Massachusetts General Hospital, authors on, “Palliative Care for Patients with Cancer: ASCO Guideline Update.” Thank you for being here, Dr. Ghoshal and Dr. Lundquist. Dr. Ghoshal: Thanks, Brittany. Thank you for having us here. Dr. Lundquist: Yes, it's a pleasure. Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Lundquist and Dr. Ghoshal, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to start us off, Dr. Lundquist, what prompted this guideline update, and what is the scope of the current update for palliative care for patients with cancer? Dr. Lundquist: Sure. So the goal of this refresh is really to provide oncology professionals with current recommendations regarding palliative care and assess which of the 2016 recommendations remain valid. The scope did increase to also include hematologic malignancies and participants of early phase clinical trials. In addition, this was an opportunity to reflect more recent evidence around the understanding of linguistic, geographic, ethical, and contextual factors that affect equity at the intersection of palliative and oncology care. This update also increased discussion about the inclusion of palliative care, as I mentioned earlier, for the enrollment of patients in clinical trials. And also, in terms of the equity piece, there is also a companion manuscript with the guidelines that focused on the health equity in the oncology palliative care setting. Brittany Harvey: Excellent. Thank you for setting the stage for this update, Dr. Lundquist.   So then next, I'd like to review the key updated recommendations for our listeners. So starting with clinical question one, Dr. Ghoshal, what are the key recommendations regarding the most effective interventions to provide palliative care to patients with cancer? Dr. Ghoshal: As we know, healthcare providers should proactively engage in the early integration of specialized, interdisciplinary palliative care teams for patients diagnosed with advanced solid tumors, and as mentioned, not only solid but also hematological malignancies. The most important thing is that palliative care should be offered not only for inpatients but also for outpatients, and oftentimes, when we talk about early palliative care, it is in concurrence with active cancer treatment. So if you want to talk about the core components of such an effective palliative care practice that would encompass establishing a nurturing rapport and relationships with patients and their family caregivers to foster trust and open communication. And obviously, it will encompass symptoms, distress, and functional limitations comprehensively, including but not only limited to pain, dyspnea, fatigue, sleep disturbances, mood disorders, nausea, and constipation.   Another important part is providing education and facilitating discussions to enhance patients' understanding of their illness and prognosis. That means we need to play an active part in clarifying the treatment goals through a shared decision-making process that aligns the patient's values and preferences with their physicians. And apart from that, in this revised guideline, the key evidence about question number one, which is from 2016, and updated to the present is mainly based on three trials with a low risk of bias. These three studies actually demonstrated that early referral to specialized palliative care of patients with advanced cancer led to improvement in the quality of life and also mood, which was a secondary outcome in that study and the higher likelihood of discussing or documenting end-of-life care preferences. I know that the link to the full documents are in the show notes, and I would encourage the listeners to refer to the supplement to the paper that is coming out in the Journal of Clinical Oncology for understanding and getting a detailed insight into the studies which are included in these recommendations. Brittany Harvey: Absolutely. Early integration of all those aspects of palliative care that you just detailed are imperative. And as you just mentioned, the listeners can find a link to the full guideline in the show notes of this episode to refer back to the more detailed aspects of the guideline.  So following those recommendations, Dr. Lundquist, what does the expert panel recommend regarding how palliative care services should relate in practice to other supportive care services? Dr. Lundquist: The panel examined the role of the use of additional supportive care services that focus on services including nurse navigation, lay navigation, community and home health care, as well as geriatric oncology, psycho-oncology, pain services, and telehealth services. And findings supported that models of delivering palliative care with the use of other services as well can really improve the patient experience. And one of the ways of doing that, more utilization of standardized assessments of symptoms, certainly, but also encompassing the multidimensions of distress, spirituality, and psychosocial factors. And then emphasizing discussions around prognostic and treatment options to really get a better sense about the patients' understanding of their prognostic awareness, which may also lead to more improved communications around advanced care planning.  And the studies around this guideline supported that most pragmatic approaches to ensuring that patients benefit from palliative care is really through the involvement of this interdisciplinary team and looking from a broad lens, looking at all their potential palliative care needs that may need to be met. But certainly, referral to a specialized interdisciplinary palliative care team is also very important. But it really is where that step before is really looking at the whole experience of the patient and where they are in their cancer trajectory.   Brittany Harvey: Excellent. Yes, incorporating all of those additional supportive care services really benefit patients.   So then beyond these recommendations for patients with cancer, Dr. Ghoshal, what are the recommendations for interventions that are helpful for family caregivers, care partners, and communities? Dr. Ghoshal: This is a very pertinent question for palliative care practitioners. So, interesting to note that the panel found that there is limited data that exist on how best to support the caregivers of patients with advanced cancer, and especially so in under-resourced settings. And also, most of the evidence that came from the literature is from data which was collected in studies before the COVID-19 pandemic. So the previous guideline stressed the option of phone interventions for those in rural or under-resourced areas. But as we know, with the growth of telehealth and telemedicine related to the pandemic, especially after the pandemic, more people are used to such interventions, more people probably could access and feel comfortable with virtual care. So telehealth, app-based support, and virtual care options, which are probably available and largely familiar to many people, could potentially allow increased access to support services. Talking about these support services, the focus that has been mostly seen in literature are about education and training programs to empower the caregivers of these patients with advanced cancer, psychosocial support services for emotional well-being of the carer as we know that it can be pretty tough for someone to deal with cancer and also for their caregivers. Also sometimes practical assistance with daily tasks, if possible, to ease the burden of caregiving. Sometimes importance is there on respite care to provide temporary relief for these caregivers. Community supports can play a big role for sharing the resources. Social connections can also play an important part when it's available. And also very important and we all know that advance care planning discussions to ensure patients' wishes are known to their caregivers. And of course, we must keep this in our mind that cultural sensitivity in caregiving practices is very important to accommodate people from diverse backgrounds. So mostly these are interventions, as mentioned in the guideline, which are aimed at supporting caregivers in their role to alleviate their stress, and to improve the overall caregiving experience for both caregivers and patients with cancer. Brittany Harvey: Thank you for reviewing the recommendations for support services for both caregivers and care partners in addition to patients with cancer.  So then Dr. Lundquist, you previously mentioned referral to specialist palliative care services. Who does the expert panel recommend should be offered or referred to palliative care services, and when should those referrals occur?  Dr. Debra Lundquist: And as the panel looked at referral to palliative care services, we looked at essentially patients with advanced solid tumors or hematologic malignancies, particularly, those patients with cancer who have unaddressed physical needs, psychosocial needs, and spiritual distress, and as we just heard, the importance of including the caregivers in care and offering palliative care. And the caregivers may include family members, chosen family, friends of individuals who have advanced cancer. And then also looking at including patients that we'll talk a little bit later about the patients that are on phase one clinical trials as well and why they might be another population to be considering.  But certainly, as we've mentioned a little bit already, early in the course of the advanced cancer diagnosis is a very important time to initiate the palliative care. The panel recommends not waiting for the discontinuation of antineoplastic therapy or treatments around the cancer diagnosis, but rather focusing on the specific palliative needs of the individual and really thinking more about it occurring when the patient is getting their active treatment as well in a way to better support them while they potentially may be experiencing side effects from their treatments, from their disease, and thinking about this earlier in the disease continuum.  Ideally, clinicians and organizations really need to prioritize the assessment of these dimensions of the patient experience for earlier recognition of their needs at the time of diagnosis of their advanced cancer, but to also really be thinking about while the patients are still receiving active treatment, to really be identifying and determining what other palliative care needs may need to be addressed.  Brittany Harvey: Definitely, those are key considerations for clinicians, and I thank you for defining what early referral means in these circumstances.  So, you both mentioned that this guideline expanded to patients with hematologic malignancies. Dr. Ghoshal, what strategies are recommended for the integration of palliative care into the care of patients with hematologic malignancies?  Dr. Arun Ghoshal: The updated review this time identified three publications. Actually, two of those publications are randomized controlled trials including patients with hematologic malignancies, especially those with acute myelogenous leukemia and those receiving hematopoietic stem cell transplantation. It is important because the trajectory of illness for hematologic cancers and solid tumors can be a bit different. Patients with hematologic malignancies, despite newer therapies offering long-term survival, often face significant side effects. Compared to the solid tumor patients, those with hematologic cancers experience higher hospitalization rates, frequent intensive care unit admissions, and unfortunately, the rates of in-hospital deaths are also more in these patients. And as a result of that, the typical length of stay in hospice is shorter for these patients. Regardless of prognosis, the recommendations state that proactive palliative care should begin at diagnosis and continue throughout the illness trajectory and survivorship of these patients with hematologic cancers.   Historically, integrating specialist palliative care has been infrequent in this group of patients due to misconceptions, and obviously, limitations. However, the latest evidence that we're talking about supports the benefits of palliative care for patients with hematological cancers, especially, improving their quality of life and psychological outcomes. However, given the paucity of studies in this domain, further research is needed to expand the recommendations beyond the studied population. Brittany Harvey: Thank you for highlighting the specific needs and recommendations for this patient population.   So then, Dr. Lundquist, for the final clinical question, you've already touched on this a little bit. But what is the role of palliative care for patients with cancer participating in early phase cancer clinical trials?  Dr. Debra Lundquist: As I mentioned earlier, the panel this year included this patient population in the refresh of the guidelines. And the early phase clinical trial population is a population of patients who present functionally well, however, most present with advanced disease and have frequently received multiple lines of therapy prior to coming to the clinical trial. They may experience a distinct set of symptoms and concerns with unique supportive and palliative care needs. When we looked at the literature, there is a growing body of research around this, although it is still quite small at this time. Certainly an area for future research.   Patients who are participating on early phase clinical trials come to the trial and they may be struggling to cope with the uncertainty regarding their future, as well as symptoms they may be experiencing and really not knowing what that clinical trial experience is going to look like. So the panel, as we were looking through the literature, it's becoming more clear that this is a patient population who may have existing physical and psychosocial concerns who would possibly benefit from earlier identification of their palliative care needs as well as intervention with palliative care support coming on to the clinical trial. With the research being limited, the focus on better understanding their palliative care needs is an area for the future that we really may want to be considering more in terms of improving the patient experience. This is a patient population who, I think, in terms of ongoing research, we're starting to see the benefits and looking at their unique dimensions of their care as they come onto the trial. But then providing  the opportunity to enhance their experience and also better identify their distinct supportive care needs may, in fact, enhance their quality of life while they're on the early phase clinical trial. Brittany Harvey: I appreciate you both reviewing all of this updated and expanded recommendations from the expert panel.  In your view, Dr. Ghoshal, what is the importance of this update and how will it impact both clinicians and patients?  Dr. Arun Ghoshal:  So 2015 to 2023, the time and the duration that the update took into consideration, you won't believe, we got 52 randomized control trials on the subject, and one systematic review, which is the evidentiary basis for the guideline recommendations. So the ASCO guideline update on palliative care for patients with cancer underscores the importance of a comprehensive, patient-centered approach to care that prioritizes symptom management, communication, and support for not only patients but also their families. It distinguishes itself through its rigorous methodology, the expert consensus from a wide array of people who take part in these updates, and also, there is a special section for all the recommendations as far as clinical relevance is considered. The updates are very timely and also comprehensive for sure. So all of these features make it a valuable resource for clinicians who want to seek guidance on providing optimal palliative care to patients with cancer.   I believe that the uptake, as far as possible, by institutions and physicians, factoring physicians all around the world, these guidelines would benefit the patients by providing evidence-based recommendations that improve symptom management, enhance care communication, and shared decision making, ultimately ensuring timely access to palliative and supportive care services. The uptake will support the caregivers and hopefully will help a long way in optimizing the end-of-life care for these patients suffering from cancer.  Brittany Harvey: Definitely, we hope that these updated guidelines are a useful resource for clinicians, as you pointed out, to provide better end-of-life care for all patients with cancer.   So, you both touched a little bit on the limited evidence and some future research opportunities. So finally, to wrap us up, Dr. Lundquist, what are the outstanding questions and future research needed on palliative care in patients with cancer? Dr. Debra Lundquist: As we've been hearing about in our conversation today, the findings and the benefits of palliative care, they're well known. We know the difference palliative care makes in the life of patients that are experiencing or living with advanced cancer as well as their caregivers and their families. But certainly, more studies are needed to explore more innovative and other models of care. Because we also need to acknowledge that as much as we want every single person to have the opportunity to get palliative care, the workforce is not going to support that. So this is an important time to think about innovative, potentially scalable, and compelling strategies to address the unmet needs of patients in order to deliver palliative care. Innovative approaches are needed, particularly, to overcome the shortage of the workforce in order to better support the unique needs of our patient population. So as we're thinking forward, novel application of interventions to address unmet needs tailored to the unique needs of patients across the disease trajectory, and that may include collaborative care models, telehealth, additional training and resources, for example, nurses; advanced practice providers. But as we're doing that, we really need to be thinking about how we're going to design, develop, and test these interventions in order for them to be scaled appropriately. And then how do we implement and disseminate across different settings, rural, urban, different locations, in order to best meet the needs of this patient population.       Brittany Harvey: Absolutely. Those are important questions for us all to consider moving forward, and we'll look forward to future research in these areas to continue to provide optimal palliative care to all patients.  So I want to thank you both so much for all of your work on this guideline update, and thank you for taking the time to share the important nuances of this guideline with our listeners today, Dr. Lundquist and Dr. Ghoshal.  Dr. Arun Ghoshal: It's been a pleasure being here.  Dr. Debra Lundquist: Thank you very much, Brittany. It was a wonderful opportunity. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Douglas Peterson presents the latest evidence-based guideline from ISOO, MASCC, and ASCO on the prevention and management of osteoradionecrosis (ORN) in patients with head and neck cancer treated with radiation therapy. He covers topics such as recommended initial workup, best practices for prevention of ORN of the head and neck before and after radiation therapy, nonsurgical and surgical management of ORN, and management of adverse events associated with ORN. Dr. Peterson also comments on the importance of this guideline and what researchers should address moving forward. Read the full guideline, “Prevention and Management of Osteoradionecrosis in Patients with Head and Neck Cancer Treated with Radiation Therapy: ISOO-MASCC-ASCO Guideline” at www.asco.org/head-neck-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/head-neck-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02750.   Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts, bringing you timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all our shows, including this one, at asco.org/podcasts.   My name is Brittany Harvey and today, I'm interviewing Dr. Douglas Peterson from UConn Health, lead author on “Prevention and Management of Osteoradionecrosis in Patients with Head and Neck Cancer Treated with Radiation Therapy: International Society of Oral Oncology, Multinational Association for Supportive Care in Cancer, American Society of Clinical Oncology Guideline.” Thank you for being here, Dr. Peterson. Dr. Douglas Peterson: Thank you, Brittany. My pleasure to be here. Brittany Harvey: Before we discuss the guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensures that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Peterson, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to dive into the topic we're here to discuss, Dr. Peterson, could you first provide an overview of the scope and purpose of this joint ISOO-MASCC-ASCO guideline? Dr. Douglas Peterson: I'll be pleased to do so, Brittany. Again, thank you for the opportunity to represent the panel in this guideline. The panel has strived to present a guideline that brings consistency in clinical practice regarding prevention and management of osteoradionecrosis of the jaw (ORN) based on the highest quality contemporary science. Given the mechanistic and clinical complexity of ORN, we also stress the importance of interprofessional oncology care of these patients. The team includes, but is not limited to, clinicians representing radiation oncology, head and neck surgery, medical oncology, otolaryngology, dental medicine, oral medicine, oral oncology, oral and maxillofacial surgery, and patient advocacy organizations. So it really is a collective enterprise that we bring to bear in the guideline.  In some cases, the panel has been fortunate to be able to utilize a high quality evidence base in the literature upon which we could build strong recommendations. In selected other cases, however, we utilized informal consensus given the low evidence quality in the field. The recommendations presented have been carefully framed in this context, with the goal of providing state-of-the-science guidelines in clinical decision making and management of ORN. I'd also like to point out that the guideline brings linkage to other guidelines published by ASCO and other major oncology organizations, regarding management of symptoms and other supportive care needs associated with ORN. These companion guidelines include addressing pain, dysphagia, oral care, trismus, and psychosocial impact and survivorship, to name a few. I'd also like to say that combining the expertise of ISOO, MASCC, and ASCO has provided an important opportunity to produce this guideline. This has been a comprehensive effort by many experts. In addition to the outstanding input from the panel, I am also personally so very grateful for the expert input from ASCO's Evidence-Based Medicine Committee, as well as endorsements from other key organizations, including the American Head and Neck Society, the American Society for Radiation Oncology, and the American Academy of Oral Medicine as endorsees of the guideline. Finally in addition, Dr. Nofisat Ismaila's leadership as ASCO staff has been absolutely invaluable as well.  Brittany Harvey: Excellent. I appreciate you providing that background on the development of this evidence-based guideline, which was developed by a multi-organizational and multidisciplinary panel.   So to dive into the key recommendations of this guideline, this guideline addresses six clinical questions. So, starting with question one, what key points would you like to highlight regarding how ORN is characterized, graded, and reported, and what is the recommended initial workup for patients?  Dr. Douglas Peterson: Osteoradionecrosis of the jaw of the mandible and maxilla should be characterized in the view of the panel as a radiographic, lytic, or mixed sclerotic lesion of bone, and/or visibly exposed bone, and/or, importantly, bone probed through a periodontal pocket or fistula. In the latter case, the clinical appearance of exposed bone may be extremely subtle. ORN is occurring within an anatomical site previously exposed to a therapeutic dose of head and neck radiation therapy. So we have a combined radiographic/clinical approach characterizing the lesion in the context of the patient having received previously a therapeutic dose of head/neck radiation therapy. We do recommend that clinicians evaluate ORN based on the most contemporary staging system, the ClinRad system, which is cited in the publication itself. We also advocate for the use of the ClinRad staging system not only in clinical assessment of patients, but also in clinical trials moving forward. We'll touch a little bit later on future research opportunities as well.  Finally, the initial evaluation of ORN should include a clinical intraoral examination, and again, the appearance of exposed bone may be extremely subtle, and/or a formal radiographic examination. The guideline delineates the various types of radiographic examinations that we recommend.  Brittany Harvey: Understood. Thank you for reviewing those recommendations regarding reporting and characterization of ORN, as well as the workup.   The next section of the guideline, it focuses on best practices to prevent ORN of the head and neck prior to radiation therapy. What are the key recommendations of that section?  Dr. Douglas Peterson: As with other adverse events in oncology patients, prevention is key. Prevention of ORN does require interprofessional management. The guideline lists several key recommendations along these lines. Now, an important caveat in what the guideline presents is that the target coverage of the tumor should not be compromised in order to avoid radiation dose to bone. So that's a very important caveat. Now having said that, focused effort should be made to reduce the mean dose to the jaw and the volume of bone receiving above 50 Gy whenever possible. So it's really a balance between maximizing target coverage of the tumor while limiting exposure to normal bone. In addition, a dental assessment by a dentist and dental specialist, if possible, is strongly advised prior to therapeutic-intent radiation therapy. The purpose of this assessment by the dental team is to identify and remove teeth which will place the patient at risk of developing ORN during the patient's lifetime, and to comprehensively educate the patient about the lifelong risk of ORN. Dental extraction in advance of radiation is often a consideration to these patients, and if clinically indicated, should occur at least two weeks prior to the commencement of radiation therapy. Now having said that, in the setting of a rapidly progressive tumor, extraction should be deferred and not cause delay in the initiation of radiation therapy. Brittany Harvey: So you just touched on key points of prevention prior to radiation therapy. Following those recommendations, what does the expert panel recommend regarding best practices to prevent ORN after radiation therapy? Dr. Douglas Peterson: This can be a challenging clinical issue. So the panel recommends that before finalizing dental treatment plans that may include extractions in patients with a history of head and neck radiation therapy, a review of the radiation therapy plan should be performed with particular attention focused on dose to the mandible and maxilla. For teeth in areas of high-risk for ORN, alternatives to dental extraction may be possible, for example, root canal or endodontic procedures, crowns, or dental restorations, or dental filling should be offered unless the patient has recurrent infections, intractable pain, or other symptoms that cannot be alleviated without extraction. So it really becomes a combined clinical decision making effort between the dental team and oncology team.  One controversial area has been hyperbaric oxygen being administered prior to dental extractions in patients who have received head and neck radiation therapy previously. The panel does not recommend routine use of prophylactic HBO prior to dental extractions in these patients who have received prior head and neck radiation therapy. However, the evidence base here is limited with low quality and we offer a weak strength of recommendation. It is a controversial area, so we did also include a qualifying statement that prophylactic HBO may be offered to patients undergoing invasive dental procedures at oral sites where a substantial volume of the mandible and/or maxilla receive at least 50 Gy. This is an area of controversy. We can talk about this in the future research directions, but clearly, new high quality research related to the role of HBO in the management of these patients is needed.  Brittany Harvey: Definitely. Thank you for touching on those points and that area of controversy. We can definitely touch on that a bit later as we talk about future research in this field.  As you mentioned, Dr. Peterson, this guideline addresses both prevention and management. So, in moving into the management of ORN, how should ORN be managed nonsurgically?  Dr. Douglas Peterson: The guideline relative to nonsurgical management of ORN is focused on the use of pentoxifylline. Now this maybe used in, and this is important, in cancer-free patients with mild, moderate, and severe cases of ORN. But pentoxifylline, the guideline also notes, is most likely to have a beneficial effect if the treatment is combined with tocopherol, antibiotics, and prednisolone as well. So there's clinical judgment involved in the nonsurgical management of ORN, centered with pentoxifylline in combination with tocopherol, antibiotics, and prednisolone. Brittany Harvey: Understood. And then expanding on the management of ORN, what are the key points for surgical management of ORN? Dr. Douglas Peterson: The panel offered several recommendations for which the strength of the recommendations was strong. Just to cite a few, in partial thickness ORN as defined by the ClinRad stage one and two that we talked about earlier, surgical management can start with transoral minor interventions which can lead to resolution over time. It may take time. It may take weeks or even a few months. Now this minimally invasive surgery may include debridement, sequestrectomy, alveolectomy, and/or soft tissue flap closure. Furthermore, small defects, clinically, for example, less than 2.5 cm in length, may heal spontaneously with local topical measures such as we described. It is recommended that larger defects, larger than 2.5 cm, in general be covered with vascularized tissue.  Brittany Harvey: Appreciate you reviewing those recommendations regarding surgical management of ORN. So to wrap up our discussion of the recommendations with the final clinical question, what is recommended for assessment and management of adverse events associated with ORN?  Dr. Douglas Peterson: This is a really important area as well in addition to prevention and management of ORN per se. The panel recommends that patients should be assessed by their healthcare providers for the presence of adverse events at the time of ORN diagnosis and periodically thereafter until the adverse event resolves based on patient status including any interventions or the adverse events that are clinically indicated. The panel and its literature evaluation learned that there is a relative lack of data specifically directed to the management of adverse events associated with ORN. However, this is such an important area that we wanted to address it head on. And so the management we recommend should be informed by pertinent available other guidelines that had been developed for analogous symptoms and/or disease states. The guideline provides links to these companion guidelines developed by ASCO as well as by MASCC and ISOO, the European Society of Medical Oncology, and NCCN. And so in the guideline we provide links on management of adverse events as produced by these other organizations. Table 3 presents a summary of the guidelines that address symptoms and supportive care needs associated with ORN.  Brittany Harvey: Thank you for reviewing all of these recommendations. It's clear that the panel put a lot of work and thought into these recommendations and provided needed guidance in areas with limited evidence. We'll have links available in the show notes for listeners to be able to go and read these recommendations for themselves and refer to the tables that you mentioned.  So in your view, Dr. Peterson, what is the importance of this guideline and how will it impact clinicians and patients with head and neck cancer? Dr. Douglas Peterson: As we talked about throughout this podcast, the guideline is designed to synthesize the contemporary science regarding ORN and translate that into recommendations for clinical practice in both prevention and management. As noted in the guideline, oncologists plus other interprofessional healthcare providers have been directly involved in the creation of the guideline, that interprofessional theme, which we believe is so essential given the mechanistic and clinical complexity of ORN.  Now, in addition to the expertise of the panel, the pending widespread distribution of the guideline represents an additional important opportunity for extending the impact across clinical oncology. So in addition to the publication in the Journal of Clinical Oncology, dissemination by MASCC and ISOO as well as our endorsees, the American Head and Neck Society, the American Society for Radiation Oncology, and the American Academy of Oral Medicine will also be key in broadening the impact and hopefully the utilization of the guideline. And members of these organizations may very well be involved in the management of these patients as well.  And then finally, the guideline is also designed to stimulate future research based on current gaps of the knowledge and we touched on some of those gaps, for example, with HBO for which new high quality research is needed.   Brittany Harvey: Absolutely. It's great to have so many partners in this guideline and we hope that this guideline will have a large impact for patients with head and neck cancer to improve their quality of life.   So then your final comment leads nicely into my last question and that we've already talked a little bit about some of the future research opportunities that this guideline highlights. So, to wrap us up, Dr. Peterson, what are the outstanding questions regarding osteoradionecrosis of the jaw secondary to head and neck radiation therapy in patients with cancer?  Dr. Douglas Peterson: There are several key areas that the panel identified as we went through a rigorous review of the highest quality literature. Some of the key areas to address moving forward include: prospective studies are needed to evaluate the clinical presentation, trajectory, and response to treatment of ORN-related symptoms and function impairment, in other words, the adverse event side of the story. In addition, social determinants of health, quality of life, and psychosocial impact of ORN warrant further investigation in head and neck cancer survivors as well. In addition, new research including randomized controlled trials and prospective multicenter trials regarding the systemic and surgical treatment of ORN is also warranted, and we touched on, for example, hyperbaric oxygen. Hyperbaric oxygen has been a long standing management strategy of ORN. However, the trials to date are of limited quality in relation to supporting its use. So high quality new research related to the role of HBO in these patients is needed.   And the expert panel also encourages creation of predictive tools, a priori tools, directed to development, grading, and staging of ORN. These could include, for example, bone turnover markers and genetic markers to name two. And finally, the research opportunities that are presented in the guidelines such as what I briefly summarized today should ideally be addressed in large prospective multicenter observational studies of risk, outcomes, and financial cost of ORN or the various treatment strategies that are highlighted in the guideline.    Brittany Harvey: Excellent. Well, we'll look forward to research that addresses those outstanding questions and I want to thank you so much for your all your work on this guideline and for taking the time to share the highlights of this guideline with me today, Dr. Peterson.  Dr. Douglas Peterson: Thank you. My privilege to do so, Brittany. Brittany Harvey: And thank you to all our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app in the Apple App Store or the Google Play Store. If you have enjoyed what you heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Raymond Chan and Dr. Larissa Nekhlyudov share the newest standards and practice recommendations from MASCC and ASCO on survivorship care for people with advanced or metastatic cancer. They discuss highlights of the standards across seven domains: person-centered care, coordinated and integrated care, evidence-based and comprehensive care, evaluated and communicated care, accessible and equitable care, sustainable and resourced care, and research and data-driven care. Drs. Nekhlyudov and Chan also comment on the impact of these standards for clinicians and for patients with advanced and metastatic cancer and the goal of providing high-quality evidence-base survivorship care for all patients. Read the standards, “Survivorship Care for People Affected by Advanced or Metastatic Cancer: MASCC-ASCO Standards and Practice Recommendations” at www.asco.org/standards. TRANSCRIPT These standards, recommendations, and resources are available at https://asco.org/standards. Read the full text of the standards and review authors' disclosures of potential conflicts of interest in the JCO Oncology Practice, https://ascopubs.org/doi/10.1200/OP.23.00716.  Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.   My name is Brittany Harvey, and today I'm interviewing Dr. Larissa Nekhlyudov from Brigham and Women's Hospital and Harvard Medical School, and Dr. Raymond Chan from Flinders University, authors on, “Survivorship Care for People Affected by Advanced or Metastatic Cancer: Multinational Association for Supportive Care in Cancer (MASCC) and American Society of Clinical Oncology (ASCO) Standards and Practice Recommendations”. Thank you for being here, Dr. Nekhlyudov and Dr. Chan. Dr. Raymond Chan: Thank you for having us. Dr. Larissa Nekhlyudov: Great to be here. Brittany Harvey: Then, before we discuss these standards, I'd like to note that ASCO takes great care in the development of its guidance products and ensuring that the ASCO conflict of interest policy is followed through each panel. The disclosures of potential conflicts of interest for the expert panel, including the guests on this episode today, are available online with the publication of the standards in the JCO Oncology Practice, which is linked in the show notes.  So then, to dive into the content of the standards and recommendations. First, Dr. Chan, could you provide both an overview of the scope and purpose of these joint MASCC-ASCO standards and practice recommendations? Dr. Raymond Chan: Thank you, Brittany. First of all, as outlined and introduced by yourself, I would like to acknowledge that this is a great collaboration between the Multinational Association for Supportive Care in Cancer and ASCO. And if you may indulge me for a minute, I would like to give you a little bit of background of how this all started. It was in 2019 when I came across an article written by Ms. Terry Langbaum and Dr. Thomas Smith, who wrote a piece in the New England Journal of Medicine outlining the insufficient work and research done to advance care for people with incurable, long-term, metastatic cancer survivorship. And both Terry and Tom were living with metastatic cancer, and with their lived experience, they provided a new level of meaning to our work. And subsequently, in honor of Terry Langbaum, who is a renowned and esteemed hospital administrator who worked in cancer care, Dr. Thomas Smith and myself created the Terry Langbaum Cancer Survivorship Fellowship and appointed Dr. Nicholas Hart to complete this work.   Within this work, we aim to develop international standards and practice recommendations to guide care for people living with treatable but incurable, metastatic, and advanced cancer. In this work, we conducted an extensive systematic review involving 81 studies, 17 guidelines, and framework documents, gathering the wisdom and consensus from 77 experts from 33 countries around the globe. Together, we reached consensus on 45 recommendations that we hope will be helpful for the clinical care community in improving care, experiences, and outcomes for people living with metastatic cancer. Brittany Harvey: Excellent. Thank you for providing this essential background information and describing the impetus for this project.  Then, as you discussed, Dr. Chan, these standards and recommendations have over 45 recommendations within them. So I'd like to review each of those key points from each section. This document provides these standards and practice recommendations across seven domains. So to start with that first domain, Dr. Chan, what are the key points you'd like to highlight regarding person-centered care?  Dr. Raymond Chan: Sure, Brittany. Now, without repeating what is in the document because I hope that this podcast can lead you to that document and for you to read it in detail, it is really around a comprehensive set of principles that experts felt were important to ensure that patients themselves participate in the care as much as possible. It is around respecting their agency and making sure that their clinical and psychosocial care needs associated with their metastatic cancer diagnosis are considered and addressed.  Brittany Harvey: Absolutely. Thank you for providing those key points regarding person-centered care. So, moving into that next section, coordinated and integrative care, what points would you like to highlight there? Dr. Raymond Chan: Thank you, Brittany, for the question. The standards and recommendations within this section are really around articulating the coordination, navigation, and the multidisciplinary care team approach requirements for this population. In particular for people living with metastatic or advanced cancer, it is not a given that they will be able to access survivorship care services or palliative care services. And a lot of the time, we know that care access is around the resource setting. And a lot of the time, palliative care services may not necessarily be able to cover people living with relatively longer prognosis, such as this population, the longer term metastatic and advanced cancer population. Another point is around transition and the shared care arrangement between the oncology team, survivorship care clinicians where available, and the palliative care team. Once again, these recommendations really articulate the importance of a well-coordinated, integrated approach for these patients. Brittany Harvey: Absolutely. Those points that you just highlighted are important for care for the whole patient.  So then, next, Dr. Nekhlyudov, I'd like to turn to you for the next couple of sections. Could you review what the highlights are for the next section: evidence-based and comprehensive care? Dr. Larissa Nekhlyudov: Yes. Thank you, Brittany. This standard emphasizes that people affected by advanced or metastatic cancer receive the most up-to-date, evidence-based, comprehensive, multidisciplinary, and interprofessional survivorship care and receive it in programs that continuously evolve their approach as guided by evidence. So as such, it is important that these survivorship programs are informed by ongoing professional development, including educational programs for healthcare professionals, that also includes active contributions by those affected by advanced or metastatic cancer. The other piece is that people affected by advanced and metastatic cancer should receive comprehensive care that encourages and supports informed decision-making in order to promote health, manage disease, and reduce stress. Brittany Harvey: Definitely, those are very important points regarding care of the patient.  So then, moving into the fourth domain, Dr. Nekhlyudov, what are the key points for evaluated and communicated care? Dr. Larissa Nekhlyudov: So the famous line is, "What can't be measured can't be improved." And so it is important that clinicians routinely and systematically evaluate and monitor supportive care needs and provide appropriate referrals to relevant survivorship care services and healthcare professionals. In order to do that, we need to establish multidirectional communication systems that take into account communication with patients and communication across healthcare professionals involved in their care. Effective communication, of course, needs to be timely, it needs to be clear, effective, respectful, and appropriate. We all know that communication is challenging across cancer care, but it may be particularly so in this specific patient population. For example, in communicating with patients, cancer care clinicians may be comfortable communicating with those with early-stage cancers or patients with early- stage cancers. And may also have had training to communicate with those patients nearing the end of life. But as we already mentioned, those affected by advanced or metastatic cancer may have different needs and as such, it is important that there is additional training for clinicians to address survivorship care needs among these individuals and their caregivers.  And then, in addition to patient-clinician communication, to enable timely communication and collaboration between multiple healthcare providers who may be involved in caring for these patients, enhanced and secure communication strategies are needed. And as with everything else, it's important that healthcare settings engage in service evaluations and quality improvement activities to continue to examine what works, what does not, and make changes that are needed. Brittany Harvey: It is important that these patients with metastatic or advanced cancer have their unique needs met by providing care and appropriate communication to them.  So then, into the next section. Dr. Nekhlyudov, I believe Dr. Chan mentioned this briefly already in talking about being able to access care as part of integrative care. But what is recommended regarding accessible and equitable care? Dr. Larissa Nekhlyudov: Right. Absolutely. I mean, as with any healthcare or cancer care, the standard emphasizes that cancer survivorship care for all people affected by advanced or metastatic cancer is not only comprehensive but also accessible. So affordable, acceptable, available, appropriate, and equitable. And the key is that it does not vary based on someone's personal, cultural, or religious factors. It is important that health workforce diversity and cultural awareness training with the development and provision of culturally and linguistically appropriate resources, that these can help healthcare professionals better understand and cater to the unique needs of the cancer survivor and the caregiver populations. We also need to develop metrics to assess the evaluation  and improvement and make sure that supportive care options are innovative, inclusive, and targeted towards eliminating disparities.  Some of the work that Dr. Chan has otherwise led is looking at provision of telehealth and virtual care for cancer survivors. So particularly for this patient population, it is important to examine the potential benefits of virtual healthcare so that these patients who may have a lot of different needs, physical challenges, mental health challenges, caregivers, that we don't necessarily bring them to the healthcare setting and can potentially provide them the care that they need. And the last thing that I would like to point out with respect to this is that people affected by advanced or metastatic cancer may face additional challenges particularly returning to work in some capacity and should be supported by advocacy groups, or consumer groups as they are often called internationally, that advocate for accessible and equitable care and then work with specific personnel to access employment, financial and legal assistance that they may need.  Brittany Harvey: Those are important for providing both inclusive and individualized care to every patient who a clinician may see.  So then following those points, what is recommended and what are the key points you'd like to highlight regarding sustainable and resourced care? Dr. Larissa Nekhlyudov: Thanks, Brittany. This is a really important point, and not to take away from any of the other standards, but in order for us to provide ongoing high quality cancer survivorship care for people affected by advanced and metastatic cancer, we need to have a sustainable and adequately resourced approach to do so. So, these standards acknowledge that not all countries or healthcare systems have access to sufficient resources. As such, supportive care may need to utilize a step-care or resource stratified approach that offers the least resource-intensive care that aligns with the needs of the patient, but then also takes into account resources that are available, but really the care should not stop there.  Survivorship care interventions and models of care should be cost-effective yet clinically relevant and meaningful and need to have the adequate financial investment by the healthcare systems. So healthcare settings providing survivorship care for those affected by advanced and metastatic cancer have to be properly resourced in order to provide high quality ongoing care. And this includes intentional planning for support services, and  where healthcare settings provide these programs with adequate level of human resources, equipment, facilities, and leadership who value support, facilitate, and appropriately invest in such care. And as we mentioned before, it's always important to continue to evaluate what is being provided, what is being offered, sort of what are the return on investment metrics in order to continue to evolve the programs to serve the needs of the population.  Brittany Harvey: Understood. I appreciate you providing highlights across these past couple of domains. So then to turn to the last domain, Dr. Chan, what is recommended regarding research and data-driven care? Dr. Raymond Chan: So the panel actively advocated for cancer registries to enable population-wide surveillance of the incidence and prevalence of people with advanced or metastatic cancer. Knowing the number of people with advanced or metastatic cancer is extremely important for care planning. We also advocated for the active involvement of people affected by advanced or metastatic cancer to participate in the co-design of research so that we can make sure that our research better meets the needs or end-users and enhance the rigor, relevance, reach, and impact of survivorship research.  The last point I would like to highlight is that a number of survivorship trials out there only limit the population or the focus of the trial being on early stage disease, people treated with curative intent. And within this standards and principles, we advocated for research trials to explicitly include people affected by advanced or metastatic cancer in the clinical trials and trying to address also the barriers that impede people from enrolling or participating at all levels.  Brittany Harvey: Thank you both for reviewing these key points, standards, and practice recommendations across these seven domains.   These standards and recommendations cut really across all aspects of care for people impacted by advanced and metastatic cancer. Dr. Nekhlyudov, in your view, what is the importance of these standards and how they will impact clinicians? Dr. Larissa Nekhlyudov: Thank you for that question, Brittany. The MASCC-ASCO standards were developed, as we already mentioned, to promote the provision of high-quality, evidence-based survivorship care for people with advanced or metastatic cancer emphasizing the need for care that is person-centered, coordinated and integrated, evidence-based and comprehensive, evaluated, and communicated, accessible and equitable, sustainable and resourced, as well as research and data-driven. For clinicians, these standards and practice recommendations provide a critical resource in order to facilitate tailored and effective care for people living with advanced or metastatic cancer across disciplines and settings.  As we know, and much of it is due to the efforts of ASCO, cancer care is always changing resulting in changing prognoses. As such, people diagnosed with cancer in the past that had poor prognosis are now living and are living longer. And so diagnoses that fall into this specific category of patients that we're discussing here today will continue to evolve. And likewise, advanced cancer is less clearly defined for other cancer such as hematologic or CNS malignancies, but these survivors may face similar issues and challenges.   So overall, applying these standards will help provide survivorship care to these patients. And the important piece is that what we hoped to achieve with these standards is that when we consider survivorship care, we are not only applying it to those who have early stage disease. We're not applying it only to those whose disease has been “cured.” We're not applying it to those who have been deemed disease-free or those who have completed treatments. We really need to make sure that clinicians understand the challenges experienced by often disregarded or forgotten population of cancer survivors and yet acknowledge the ever changing landscape of cancer survivors and appropriately apply these survivorship standards for people affected by advanced or metastatic cancer. And I think as Ray would probably say as well, we should focus on including rather than excluding people with cancer, all cancers, from survivorship services and programs.  Brittany Harvey: Definitely. This is an important population with often unrecognized or unmet needs, and the goal of these standards, as you've mentioned, is to provide a better quality survivorship care for patients with advanced and metastatic cancer.   So that leads nicely into my final question for you, Dr. Chan. In your view, how do these standards and recommendations impact people affected by advanced or metastatic cancer? Dr. Raymond Chan: As we continue to promulgate these standards of recommendations, I believe that patients will benefit from these standards in three ways.  First, as clinicians, researchers, and service planners continue to improve care as per outlining the standards, patients are going to indirectly benefit from it. It is meant to lead to better care, better experiences, and better outcomes.  Secondly, it is around the expectations of care. Many of us here would know that if we don't expect that care, it is unlikely that we would go and try to access it. And so it is extremely important that patients know what to expect. So now that I have been diagnosed with advanced or metastatic cancer, what does good care look like? So in the past, there are a number of pallaiative care standards whereby people are thinking, “Do I need palliative care? What does good palliative care look like?” Their set of standards. And now, these standards would enable patients to develop that expectation around what good care looks like.  Thirdly is around the patients, the family units, and their navigators or their care networks to advocate for themselves, to advocate for the patient, to be able to access that care from the care team. So we hope that as we continue to promulgate these standards, that benefit would be translated into the real world for people affected by advanced or metastatic cancer. Brittany Harvey: Excellent. We definitely hope that this improves care for all patients impacted by advanced and metastatic cancer.   So, I want to thank you both so much for this important work to develop these recommendations and standards. And thank you for taking the time to speak with me today, Dr. Nekhlyudov and Dr. Chan.   Dr. Larissa Nekhlyudov: Thank you. Great to be here.   Dr. Raymond Chan: Thank you.   Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full standards and practice recommendations, go to www.asco.org/standards. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. John Gordan discusses the newest evidence-based guideline update from ASCO on systemic therapy for advanced hepatocellular carcinoma (HCC). He shares the updated recommendations for first-, second-, and third-line therapy for patients with Child-Pugh Class A liver disease, guidance for patients with Child-Pugh Class B liver disease. Dr. Gordan also touches on the importance of this guideline for both clinicians and patients and the outstanding questions regarding treatment options for HCC. Read the full guideline, “Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update” at www.asco.org/gastrointestinal-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02745   Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.  My name is Brittany Harvey, and today I'm interviewing Dr. John Gordon from the University of California, San Francisco, lead author on "Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update." Thank you for being here, Dr. Gordon. Dr. John Gordon: Of course, happy to be here. Brittany Harvey: Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Gordon, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.   So, to jump into the content of this episode, first, Dr. Gordon, what prompted this update to the Systemic Therapy for Advanced Hepatocellular Carcinoma Guideline, which was last published in 2020?  Dr. John Gordon: So, both the initial guideline in 2020 and then the update now were driven by advances in the standard of care. The original 2020 guideline was actually held for a little bit so that we could incorporate the availability of atezolizumab plus bevacizumab, which just reported back and then received FDA approval during 2020. We were happy to be able to provide what was a very timely update to clinicians about being able to use that new regimen that had really changed the face of therapeutics for advanced HCC. The update was driven again by a shift in therapeutics, specifically it was the presence of much more evidence for the use of combination CTLA-4, PD-1 or PD-L1 immunotherapy strategies. The primary thing was the availability of durvalumab plus tremelimumab, which was studied in the so-called HIMALAYA phase III trial. The key shift in this guideline was being able to incorporate those data as a second first-line option. Furthermore, when the 2020 guideline was released, data were just becoming available about the combination of ipilimumab and nivolumab, and were not covered in any great detail. So we wanted to be able to be sure to incorporate both of those regimens, which we thought were quite significant in the current therapy for advanced HCC. Brittany Harvey: Appreciate you providing that background on the evidence informing both the original guideline and this update. Next, I'd like to review the key recommendations of this update. So, starting with, what is recommended for first-line therapy? Dr. John Gordon: The current recommendation in the first-line setting is to offer patients either atezolizumab plus bevacizumab, sometimes called atezo-bev or durvalumab plus tremelimumab. But, at this time, those two regimens we're not able to distinguish between them based on the primary evidence available. But there are a few distinctions in the studies and the patients that physicians may wish to consider. In particular, because atezo plus bev contains an immune therapy and then an anti vascular agent, for patients who are not eligible for antivascular agents or for whom an antivascular therapy might be of higher risk, for example, people with a history of esophageal varices or people with peripheral arterial disease, we would encourage physicians to preferentially consider durva plus treme.  Similarly, for patients where reactivation of an autoimmune disorder is a particular concern, staying away from the more potent immune combination is also advised. But again, the data themselves support the consideration of both, and it's really up to the provider, their multidisciplinary team, and then communication with the patient to determine what is optimal for that patient.   In addition, in the frontline setting, it is advised that for those patients who are unable to receive atezo plus bev or durva plus treme, sorafenib and lenvatinib, the traditional tyrosine kinase inhibitors that were more commonly used prior to 2020, may also be considered in the frontline setting. Furthermore, for some patients, it's also reasonable to consider the use of durvalumab alone, which is the PD-L1 inhibitor component of the durva-treme combination.  Brittany Harvey: Understood. It's helpful to understand which regimens are optimal for which patient population and options that are available for shared decision making between patients and their clinicians.  So then, following those recommendations for first-line treatment, what is recommended for second-line therapy? Dr. John Gordon: One of the things I want to be clear about the second-line recommendations is that these are largely driven by expert opinion rather than primary research studying the use of these agents after either atezo plus bev or durva plus treme. So, if you look at the history of HCC drug development, five or ten years ago, when we were confined to the use of sorafenib in the frontline setting, many studies explicitly studied the second and later-line population. But in the current era, where new frontline therapies have supplanted those agents, it becomes a little bit harder to provide a truly evidence-based answer. As a result, the recommendation is, frankly, to consider all of the options of FDA-approved agents and just as was the case of the frontline setting, to balance what might be patient-specific characteristics, both in terms of comorbidities and also ability to adhere with these regimens, which are not the easiest. All of those things should be considered when opting for a second-line agent.  Just to be slightly more explicit about it, for those patients who've received frontline atezo-bev, the considerations would be either transitioning to a tyrosine kinase inhibitor, most classically sorafenib, lenvatinib, or cabozantinib, or in principle, ramucirumab, the biologic antivascular agent, or a CTLA-4 and PD-1 or PD-L1 combination, such as durva-treme or nivolumab plus ipilimumab. Conversely, for those patients who might have received durva-treme in the frontline setting, it's reasonable to consider either a TKI or atezo plus bev. Brittany Harvey: Absolutely. Thank you for reviewing both those recommendations and the level of evidence behind those. I think it's important that even in areas where the expert panel didn't have a lot of evidence to go off of, there are still recommendations available for clinicians that are based on expert opinion.  So then, following those second-line therapy options that you just described, what recommendations did the expert panel make for third-line therapy? Dr. John Gordon: So, regarding the recommendation for third-line therapy, one of the things that we did want to make clear as a panel is that third-line therapy is a reasonable consideration in a subset of HCC patients. Quite often, five or ten years ago, it was very seldom that a patient might be considered for frontline therapy because of the burden of toxicity and/or disease progression during the first two lines. But now, for patients with intact liver function and good performance status, I think it's very reasonable to consider the same list of agents that might have been considered for second line. And again, I think the general guidance here is if you've already given your patient both atezo-bev and some kind of CTLA-4 and PD-1 combination, it's probably best to use a non-overlapping regimen, something like a TKI. If, in the frontline setting, you followed atezo-bev by TKI or durva-treme by TKI, then it would be reasonable to look at the immune therapy combination that the patient hadn't received yet. Unfortunately, again, at this point, this is all at the level of expert guidance and personal experience. But just thinking about the mechanistic rationale behind these different combinations, and which ones your patient has had the opportunity to benefit from yet, is probably the best guidance that we can give as you move into the later line. Brittany Harvey: Definitely. Thank you for reviewing that guidance as well.  So then, these recommendations that you've already described refer to patients with Child-Pugh Class A liver disease. What is recommended in the guideline for patients with Child-Pugh Class B advanced hepatocellular carcinoma? Dr. John Gordon: Thanks. I think that's another important question, and it's a part of the field that's still evolving. So this is in some ways similar to the situation for third line therapy. The level one evidence that we have and the clinical trials that were done were almost exclusively done in the context of Child-Pugh A liver function. But we know well that many patients with hepatocellular carcinoma have some degree of impairment to their liver function, making them Child-Pugh Class B or beyond. Similar to third line therapy, we do believe that it's appropriate to cautiously consider systemic therapy for these patients, particularly a better compensated patient with Child-Pugh Class B liver function may be considered. The same systemic therapy options that are considered for patients with Child-Pugh Class A may be considered here, even to the level of considering atezo-bev or durva plus treme. I will also acknowledge, though, that when considering the liver function, bleeding risk, portal hypertension, and all of the other issues that may be at play, it may end up being safer for clinicians to consider monotherapy with an agent like durvalumab or using a TKI, by simple virtue of the fact that if complications ensue, treatment can be interrupted and the therapeutic will leave the patient's system relatively promptly. The key take home here is please do consider systemic therapy in this population, but also consider it with caution, with an understanding that the underlying hepatic dysfunction also plays a role in considering and affecting the outcome. Brittany Harvey: Thank you for reviewing those recommendations for patients with Child-Pugh Class B advanced HCC and all of these recommendations, which are based off of expert review of the evidence and consensus of the entire expert panel.  So then, Dr. Gordon, in your view, what is the importance of this guideline update, and how will it impact both clinicians and patients with hepatocellular carcinoma? Dr. John Gordon: I think the impact of this guideline update was really to open the field and really just make clear that the use of CTLA 4-containing combinations was appropriate for patients with HCC because those data were not available at the time of the last guideline and to try to provide some insight about where and when to incorporate them. We really think that these agents have the potential to significantly impact outcomes for patients with HCC, and so we wanted to be clear that these can be considered therapeutically even after frontline use of a PD-L1 inhibitor like atezolizumab. And so I think the key objective of this guideline is really to be enabling and really to make it clear that within the now somewhat surprisingly broad range of approved agents that we have for HCC, these options are on the table and may be used in succession, depending on patient-specific tolerance and their clinical course.  Brittany Harvey: Absolutely. So then you've specifically mentioned that both the original guideline and the guideline update were developed to provide timely guidance from recently published randomized clinical trials. So what are the outstanding questions still regarding treatment options for advanced hepatocellular carcinoma?  Dr. John Gordon: I think those questions are really reflected in one of the things which is challenging about these guidelines, which is that it's a very kind of open set of guidelines. We provide clinicians with a range of options, but we're really not in a position to provide much evidence-based guidance around treatment selection beyond the sort of careful avoidance of contraindications. I think that there will continue to be drug development for HCC. I think there are more potent immune therapies that are currently in use for other tumors that are being studied here, and I think we do hope to see new agents in future guidelines as well. But I really feel like the key question is going to be starting to stratify patients for who's going to be most likely to benefit from exposure to an antivascular agent, who's going to be more likely to benefit from exposure to a more potent immunotherapy so that we can give our patients the best medicine for them in the first setting, and that we're less in the position of having to sample the available options to see which one might work for our patient. And I think that's going to require significant effort, particularly, honestly, in academic medicine, as these medicines start to get used, to develop the kinds of data that will enable identification of biomarkers and mechanisms of response, as well as identification of efficacy, which has been this sort of key limiting step in HCC therapeutics for the last 10 years. Now that we've got so many effective agents, we would like to see them be more effective, but nevertheless, it's been huge strides forward. Then the question is, who gets what when?  I think the other place of interesting development right now is the integration of locoregional therapies like embolization procedures, either chemoembolization or radioembolization, as well as stereotactic body radiotherapy with systemic therapy. My suspicion is that it's going to take a little bit more time before the use of these is really well understood and how they might fit into the current standards of care. But we're starting to see some large studies tackling this question. I think that we will see impact of the combinations of systemic therapy and local regional therapy in guidelines to come in parallel to a better understanding of which treatment is right for which patient. Brittany Harvey: We'll look forward to all of the future developments in the care of patients with advanced hepatocellular carcinoma, and look forward to inclusion of all of the things that you just mentioned into guidelines in the future.  So I want to thank you, Dr. Gordon, for all of your work that you've done to update these guidelines and for taking the time to speak with me today.  Dr. John Gordon: Absolutely. And I actually just want to express what a great experience I've had working with the ASCO Guidelines team. I think that this is very challenging work, and I really appreciate the professionalism and commitment that they bring to it. I think it has a huge impact, and I'm glad to be part of it. Brittany Harvey: Absolutely. And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Lisa Law and Dr. Randy Taplitz share the latest evidence-based recommendations from ASCO on vaccines in adults with cancer. They discuss recommended routine preventative vaccinations, additional vaccinations and revaccinations for adults undergoing HSCT, CD19 CAR-T treatment, or B cell-depleting therapy, guidance for adults with cancer traveling outside the U.S., and recommendations for vaccination of household and close contacts of adults with cancer. Dr. Law and Dr. Taplitz also share their insights on the guideline, including the importance of this guideline for adults with cancer and their clinicians, future advances in research, and current unmet needs. Read the full guideline, “Vaccination of Adults with Cancer: ASCO Guideline” at www.asco.org/supportive-care-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00032       The ASCO Specialty Societies Advancing Adult Immunization (SSAAI) Project is supported by the Centers for Disease Control and Prevention (CDC) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award to the Council of Medical Specialty Societies (CMSS) (with 100 percent funded by CDC/HHS). The contents are those of the authors and do not necessarily represent the official views of nor endorsement, by CDC/HHS or the U.S. Government. Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.  My name is Brittany Harvey, and today, I am interviewing Dr. Lisa Law from Kaiser Permanente and Dr. Randy Taplitz from City of Hope Comprehensive Cancer Center, authors on “Vaccination of Adults with Cancer: ASCO Guideline.” Thank you for being here, Dr. Law and Dr. Taplitz. Dr. Lisa Law: Thank you. Dr. Taplitz: Thank you, Brittany. Brittany Harvey: Before we discuss this guideline, I'd like to take note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Taplitz and Dr. Law, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to dive into the content, here first, Dr. Taplitz, can you provide a general overview of both the scope and purpose of this guideline on vaccination of adults with cancer? Dr. Randy Taplitz: Yes, so people with cancer often experience a compromised immune system due to a variety of factors. This includes chronic inflammation, impaired or decreased function of the hematopoietic system, and treatments that compromise their immune function. Because of this, people with cancer are at a higher risk for infection, including with vaccine-preventable diseases. Also, response to vaccines in patients with cancer may well be affected by this underlying immune status, and their anticancer therapy, as well as the severity of the underlying malignancy. The purpose of vaccination in this group of patients is to prevent infection or to attenuate the severity of the disease when infection cannot be fully prevented.   This ASCO review builds on a 2013 guideline by the Infectious Diseases Society of America, or IDSA, and uses what's called a systematic literature review of 102 publications between 2013 and 2023. This includes 24 systematic reviews, 14 randomized clinical trials, and 64 non-randomized studies. The largest body of evidence in these studies, not surprisingly, addresses COVID vaccines on the efficacy and safety of vaccines used by adults with cancer or their household contacts. ASCO convened an expert panel to review this evidence and formulate recommendations for vaccinations in this population. Brittany Harvey: Understood. I appreciate that context, Dr. Taplitz. So then, next, Dr. Law, I'd like to review the key recommendations of this guideline. The guideline addresses four overarching clinical questions. So starting with the first question, what are the recommended routine preventative vaccinations for adults with cancer? Dr. Lisa Law: Thank you, Brittany. Before I start, I just want to wholeheartedly thank the first author of this paper, Dr. Mini Kamboj, Dr. Elise Kohn from the NCI, as well as the ASCO staff in putting this publication and guideline together. It is a very, very important guideline, and I echo everything Dr. Taplitz just said.  So going back to your question, what are the recommended routine preventative vaccines for adults with cancer? As per this guideline, there are about 7 to 8 based on patient age and risk. Namely, they are: seasonal flu, RSV for those aged 60 or above, COVID-19, Tdap, Hepatitis B, Shingrix, Pneumococcal vaccine, and the HPV vaccine. These vaccines should ideally be given two to four weeks before therapy. However, non-live vaccines can be given anytime during or after chemo, immunotherapy, hormonal treatment, radiation, or surgery. Brittany Harvey: Excellent. Thank you for reviewing those vaccinations and the timing of them as well. So then, following those recommendations, Dr. Taplitz, what additional vaccinations and revaccinations are recommended for adults undergoing hematopoietic stem cell transplantation, CD19 CAR-T treatment, or B-cell depleting therapy?  Dr. Randy Taplitz: Many studies have shown that stem cell transplant recipients essentially lose immunity from childhood immunizations, and we know that these individuals are very vulnerable to infection, particularly in the first year after transplant. Revaccination is critical to help restore their immunity. The optimal timing of vaccination is based on our understanding of adequate immune reconstitution with B and T-cell recovery so that the individual can mount a response to the vaccine. We know that a lot of factors influence this immune reconstitution, including the age of the stem cell transplant recipient, the source of the donor, the time from transplant, graft-versus-host disease prophylaxis, the treatment and severity of graft-versus-host disease, and the vaccine type and antigens used.   There are a number of bodies throughout the world, IDSA as I mentioned, CDC, American Society for Transplant and Cellular Therapy, European Society for Blood and Marrow Transplant, and European Conference for Infections and Leukemia. All of these bodies have guidelines that approach vaccination in stem cell transplants. However, variation does exist in the use of a variety of things including whether to use immune predictors to help guide vaccination, and there is really not consensus on whether this immune predictor guided vaccination is more likely to produce a protective immune response versus a standardized schedule. In addition, the duration of protection is incompletely understood.  The bottom line in these guidelines is that they recommend complete revaccination starting for most vaccines at 6 to 12 months after stem cell transplant, in order to restore vaccine-induced immunity. And I just want to go through a few of the particulars. For COVID-19, which is a three-dose series in the primary series, influenza - generally high-dose influenza - and pneumococcal vaccine, PCV20 in general, ultimately four doses, can be administered, starting as early as three months after transplant. Although there is really not much data to guide the use of the recombinant zoster vaccine in allogeneic stem cell transplant, the vaccine can be administered after the end of antiviral prophylaxis, which in general is 12 to 18 months after allogeneic and 3 to 12 months after autologous stem cell transplant. Some of the other vaccines, such as hepatitis B, Tdap, meningococcal vaccines, and HPV revaccination in those less than 45 are also recommended.   I want to also spend the moment talking about the two recently licensed RSV vaccines, which were essentially studied in less compromised hosts and really without any immunogenicity data in stem cell transplant, and thus, there is no recommendation in this guideline for the use of these vaccines after transplant. Live vaccines, such as MMR and varicella – varicella would be in varicella-seronegative patients without a prior history of varicella – should be delayed for at least two years and only given in the absence of active graft-versus-host disease or immunosuppression.  Moving briefly to CAR T, which is an immunotherapy that involves adoptive cell therapy, given the available data and after a review by the group, it was recommended that adults with hematopoietic malignancies receiving CAR T therapy directed against B-cell antigens should receive influenza and COVID-19 vaccines either two weeks before lymphodepletion or no sooner than three months after the completion of therapy. Administration of non-live vaccines preferably should occur before CAR T treatment or at least 6 to 12 months after, following the same timing as what we recommend for stem cell transplant. There is really little data to guide the safety and timing of administration of live vaccines after CAR T therapy.   In terms of adults receiving B-cell depleting therapy, they are generally unable for time to mount an effective humoral response but may have at least partially intact cellular immune responses. They are encouraged to be revaccinated for COVID-19 no sooner than six months after completion of B-cell depleting therapy, and they should receive influenza vaccine approximately four weeks from the most recent treatment dose for patients on chronic therapy. For other non-seasonal immunizations, vaccines ideally should be given two to four weeks before commencing anti-CD20 therapy or delayed until 6 to 12 months after completion, except for the recombinant zoster vaccine, which can be given one month after the most recent dose of B-cell depleting therapy. Brittany Harvey: I appreciate you reviewing each of those vaccinations and when they should be given, and reviewing the available data – albeit, limited data – in these situations.  So beyond these routine preventative vaccinations and revaccinations that you've both just described, Dr. Law, what additional vaccinations does the expert panel recommend for adults with cancer traveling outside the United States? Dr. Lisa Law: Good question. As per these ASCO guidelines, adults with solid or blood cancer traveling outside of the United States should follow the CDC standard recommendations for their destination. For the 2024 CDC Yellow Book, travel vaccines, in general, should be delayed until three months from the last chemotherapy or, and for those with solid tumors, ideally when the disease is in remission. Of note, hepatitis A, typhoid, inactivated polio, Hep B, rabies, meningococcal vaccine, and Japanese encephalitis vaccines are considered to be safe. In all cases of travel, patients should be counseled by their healthcare provider about the travel timing, with the additional attention to the regional seasonality of infections, for instance, influenza is more common in late summer in Australia, and also with attention to any outbreaks that may be occurring globally at the time of travel. Brittany Harvey: Absolutely. Those are key points for clinicians to discuss with their patients as they consider upcoming travel.  So then, the final clinical question that the panel addressed, Dr. Taplitz, what vaccinations does the panel recommend for household and close contacts of adults with cancer?  Dr. Randy Taplitz: Thank you. Yes, it is recommended that all household members and close contacts, when possible, be up to date on their vaccinations. And the only further thing I would say is that there are some special considerations for the use of live vaccines in household contacts, particularly in stem cell transplant recipients. Contacts of people who receive stem cell transplants should preferably receive inactivated influenza vaccines. As was mentioned, MMR and varicella vaccines are both safe to administer to close contacts. Vaccine strain transmission to immunocompromised hosts has not been associated with MMR use in family members.   Eleven cases of the varicella vaccine strain transmission are described in the published literature, but none occurred in compromised hosts. Because the vaccine strain can cause severe and fatal varicella in profoundly immunocompromised people, precautions are advised to avoid close contact with a person with a vaccine-induced rash. For household contact travelers, MMR and yellow fever vaccines are considered safe. Oral cholera should be avoided. For smallpox vaccines, the second-generation ACAM2000 has rarely been associated with vaccinia transmission and should be avoided because of this. But the live replication-deficient MVA-based JYNNEOS vaccine is felt to be safe for household contacts of immunocompromised individuals. Brittany Harvey: I appreciate you reviewing the importance of vaccination for household and close contacts, and some of those precautions that individuals should take. I appreciate you both for reviewing all of these recommendations.  So then in your view, Dr. Law, what is the importance of this guideline, and how will it impact both clinicians and adults with cancer? Dr. Lisa Law: In my opinion, this is a very important guideline that is long overdue in the oncology community and will have a huge impact on both clinicians and adults with cancer. Over the years, I have often been asked by my colleagues and patients, “Can I have the flu vaccine, and if so, when?” So this guideline really is going to be helpful. More importantly, our cancer patients are living much longer. They may have years of quality of life even with third or fourth line of treatment, especially, for instance, like CAR T for myeloma and lymphoma. However, we know that with additional treatment, that carries a substantial risk of infection complication among these immunocompromised patients. So it is of paramount importance to inform our patients and colleagues to be proactive in advocating preventive therapy ahead of time, meaning trying to get the patients appropriately vaccinated as early as possible to generate immunity.  Another case in point is the Shingrix vaccine. I used to see lots of shingles, but ever since we have the recombinant Shingrix, I have fewer encounters. And this is huge because post-herpetic neuralgia robs a patient's quality of life. So, again, it is very important to recommend appropriate vaccines for our cancer patients.  Brittany Harvey: Absolutely. It is key to ensure patients receive these preventative vaccines, and we hope that this guideline puts an emphasis on that for clinicians and patients.  So finally, to wrap us up, Dr. Taplitz, what are the current gaps in knowledge regarding the vaccination of people with cancer? Dr. Randy Taplitz: There are a number of really important gaps in knowledge and really critical unmet needs that require research and other dedicated efforts. Among these are, and I think paramount, are really the participation of people with cancer with varied types of immunocompromise in vaccine trials. Where vaccine trials are only for cancer patients, obviously is ideal, testing vaccines in the appropriate population. But when that's not feasible, pre-existing cancer should not preclude eligibility, and inclusion of cohorts of people receiving anticancer treatment should be incorporated prospectively. So that's really critical because the quality of our guidelines is based upon the data. We use the data for developing guidelines and gathering more data in the particular patient population is really, really critical.  Secondly, work for creating more immunogenic vaccines and research to understand the immune response to vaccines after immuno-depleting therapies, particularly with newer therapies such as CAR T and newer B cell therapies, bispecific antibodies, etc. is really critical. We need to really understand the immune response and have the most potent vaccines available to these people who may have impaired immune responses.  Switching gears a little bit, we really need mechanisms to promote institutional commitment to integrate and sustain immunization best practices for people with cancer. This will largely be through multidisciplinary, team-based approaches, protocol-based vaccination standing orders, and leveraging data sharing so that we can all be on the same page with giving vaccines to these individuals. We also need education and evidence-based decision-making tools, emphasizing preventive care through immunization, the availability of educational resources to clinicians and patients to address commonly asked questions and also misconceptions about vaccination, that's absolutely critical.  And finally, I think we need to develop strategies for addressing unique challenges and factors contributing to vaccine hesitancy during cancer therapy. We need to focus on patient and clinician communication, and very importantly, we need to consider health equity considerations in the development and approach to vaccines in these compromised patients. Brittany Harvey: Definitely, we'll look forward to research and advances in these areas that you've just described to support these guidelines and increase vaccine uptake.  So I want to thank you both so much for your work on this important guideline, and thank you for your time today, Dr. Law and Dr. Taplitz. Dr. Lisa Law: Thank you.  Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Ilana Braun and Dr. Eric Roeland join us on the ASCO Guidelines podcast to discuss the latest evidence-based recommendations on cannabis and cannabinoids in adults with cancer. They discuss nonjudgmental patient-clinician communication, the relatively narrow cancer-related indications for which there is actionable clinical evidence for cannabis and/or cannabinoids, and key information for adults with cancer and their clinicians. Dr. Braun and Dr. Roeland also review the limited evidence regarding cannabis and cannabinoid use in adults with cancer and the outstanding questions and importance of research in this area. Read the full guideline, “Cannabis and Cannabinoids in Adults with Cancer: ASCO Guideline” at www.asco.org/supportive-care-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology,  Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcast hosts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all of the shows, including this one, at asco.org/podcasts.  My name is Brittany Harvey, and today, I'm interviewing Dr. Ilana Braun from Dana-Farber Cancer Institute, and Dr. Eric Roeland from Oregon Health & Science University, co-chairs on “Cannabis and Cannabinoids in Adults with Cancer: ASCO Guideline.”   Thank you both for being here Dr. Braun and Dr. Roeland. Dr. Ilana Braun: Thanks so much for having us, Brittany. Dr. Eric Roeland: Thanks, Brittany. Brittany Harvey: Then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensures that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Braun and Dr. Roeland, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. Then to jump into the content of this guideline, first, Dr. Roeland, could you give us an overview of both the scope and purpose of this guideline?  Dr. Eric Roeland: Sure, Brittany. I think it's important for everyone to recognize just how common the issue of cannabis or cannabinoid use is amongst people living with cancer. And I think clinicians in academia as well as through community sites, we are asked about the use of cannabis on a daily basis. And so our target audience is really to focus on clinicians providing care to adults with cancer, but also the health systems in which we work because this is a very complex issue, as well as the people living with cancer and their caregivers, as well as researchers dedicated to this field. Brittany Harvey: So as you mentioned, this is a complex issue, and I'd like to review the key recommendations of this guideline. This guideline provides recommendations across three clinical questions that the expert panel targeted. So, starting with the first question, what is recommended for patient-clinician communication regarding cannabis or cannabinoids?  Dr. Ilana Braun: Given the high prevalence of medicating with cannabis or cannabinoids that Eric references, somewhere in the neighborhood of 20% to over 40% of adults with cancer consume cannabis products, ASCO's guideline offers the following common-sense, good practice statement: In the clinic, providers should routinely and non-judgmentally inquire about cannabis consumption or consideration of cannabis, and either guide care or direct adults with cancer to appropriate resources. In other words, the guideline works to fully destigmatize this conversation. The guideline goes on to offer suggestions for taking a cannabinoid and cannabis history. This includes the goals of use, how the products are sourced, what formulations are being used (including the ratios of active ingredients like THC and CBD), the inactive ingredients (for instance coconut oil), whether it is herbal or synthetic, and whether the product is pharmaceutical grade or non-pharmaceutical grade. And then other questions like routes of administration, dosing schedules, perceived benefits and risks, and whether the products are being used adjunctively or as a replacement for standard treatments. It is also probably important to query potential contraindications, such as a history of cannabis use disorder or psychosis.  Brittany Harvey: Thank you for reviewing those good practice statements. Those are key for non-judgmental communication and taking an accurate and complete history.  So following those statements, the expert panel next addressed the question: Does use of cannabis and/or cannabinoids by adults improve cancer-directed treatment? What recommendations did the expert panel provide for this section? Dr. Eric Roeland: When we think about the use of cannabis or cannabinoids in treating the underlying cancer, it's incredibly important to recognize the excitement that patients and clinicians have around the potential promise. Much of this data is generated from preclinical models. However, when we're engaging patients consuming cannabis or cannabinoids to augment their cancer-directed treatment, we could find no evidence to support its use. And so we do not recommend that patients be using it to augment treatment, nor do we recommend that patients should be using it instead of their cancer-directed therapy. And I think this is a major challenge for multiple oncologists, where their patients may be using these with a goal of treating their cancer, and then present with very advanced cancer and/or multiple poorly controlled symptoms. Dr. Ilana Braun: And I think that there are some areas of particular concern. For instance, there were two oncologic cohort studies that suggest that cannabis, which we know is an immune modulator, may actually worsen immunotherapy outcomes. These outcomes included median time to progression and overall survival. There are obvious limitations of preliminary observational data, and we now need to gather prospective, gold-standard data. But for the time being, the guideline recommends that clinicians should advise against adults receiving immunotherapy from medicating or considering medicating with cannabis and cannabinoids. And then I think there are some additional reasons for concern. First of all, this type of therapy tends to be very expensive and not covered by insurance and there are some risks for drug-drug interactions, in terms of pharmacodynamic ones, Cannabis may exacerbate neuropsychiatric side effects of opioids and even benzodiazepines. In terms of pharmacokinetic drug-drug interactions, it's not a particularly risky substance, but there are three to be wary of in particular: warfarin, buprenorphine, and tacrolimus all have high-risk interactions with cannabinoid products.  Brittany Harvey: I appreciate you both for reviewing these recommendations and evidence regarding the use of cannabis and/or cannabinoids regarding cancer-directed treatment.   So then the last clinical question, Dr. Braun, what is recommended regarding use of cannabis and/or cannabinoids in managing cancer treatment-related toxicities and/or symptoms? Dr. Ilana Braun: The first thing to make clear is that high-quality clinical evidence evaluating the utility of cannabis and cannabinoids for adults with cancer is limited as Eric has said. The evidence that does exist weakly supports a practice of using cannabis and cannabinoids to address refractory chemotherapy-induced nausea and vomiting when standard treatments have failed. For other potential oncologic indications, like management of cancer-related pain, there is weak, negative, conflicting, or no evidence. But that being said, a 2017 monograph published by the National Academies of Science, Engineering, and Medicine concluded that there is substantial evidence that cannabis is an effective treatment for chronic non-cancer pain, and I'm sad to say, that chronic non-cancer pain happens too in adults with cancer. Brittany Harvey: Thank you for reviewing those recommendations as well.  So you've both touched on this a little bit in that patients are often asking clinicians for recommendations regarding cannabis and/or cannabinoids, but in your view, what is the importance of this guideline, and what should clinicians know as they discuss these recommendations with their patients? Dr. Eric Roeland: Probably one of the most important points is for clinicians to ask and to be open and to create a space where our patients are telling us about what they're using. I think we've all had patients that we've been surprised that have been using cannabis or cannabinoids in conjunction with other medications that may increase the risk of unwanted side effects or risks, including sedation or falls. I also find it challenging that many patients are receiving recommendations for the use of cannabis or cannabinoids directly from friends or family instead of through their medical providers. Therefore, I think one of the very first things is to just make sure that you're asking about it and then inquiring what the goal of their use is.  When we talk about the use of cannabis, we also need to recognize the difference between the available data that can guide us in evidence-based recommendations, as well as the enthusiasm and available access that patients have to cannabis that has really outpaced our ability to research it. So it's important to recognize these tensions that we're living with in clinic day-to-day. Brittany Harvey: Absolutely. Those points are key for clinicians as they discuss this complex issue with their patients.  Following that, how will these guideline recommendations affect adults with cancer? Dr. Ilana Braun: One really important takeaway from these guidelines is that they clearly state that cannabis and cannabinoids are medicinal, and for a medical community to clearly articulate this point is notable. I suspect they will provide encouragement, legitimacy, confidence, and even a script to oncology clinicians who were previously reticent to inquire, document, and provide clinical recommendations around non-pharmaceutical cannabis and cannabinoids. It may have a similar effect even at the institutional level in terms of supporting these practices. At the same time, I suspect they will encourage those who are recommending oncologic use of cannabinoids and cannabis for myriad cancer-related indications to adopt a more circumscribed approach. The reason I say this is that the cancer-related indications for which there is actionable clinical evidence at this time are quite narrow. So all this to say, I believe these guidelines will lead to greater transparency around cannabis decision-making in the clinic, as Eric mentions, but also lead to a possible narrowing of indications for which cannabis is clinically recommended.  Dr. Eric Roeland: Another major role of the use of these guidelines in clinical care is informing clinicians and patients about cannabis. Cannabis has been used by humans as a plant for thousands of years, and although it's a very complex plant with hundreds of parts, the two parts that researchers have studied most are delta nine-tetrahydrocannabinol, or THC, and cannabidiol, or CBD. In rough terms, THC can cause a high feeling, while CBD typically does not. And there are multiple types of products that have different ratios of THC and CBD. So it's critical for people to understand what those ratios are, how many milligrams of those things there are, as well as what are the programs within your region to measure or quantify what's actually in the products you're consuming. If a person with cancer medicates with cannabis, most oncologists would prefer that they use it by mouth, such as an edible, rather than inhaling or smoking cannabis given concerns about potential impact on lung function. One challenge when consuming cannabis by mouth is that it can take up to two hours to have its full effect. So patients should be very careful not to take too much or to stack their doses, which can cause sedation, confusion, and even increase the risk of falls. Whereas when patients are consuming cannabis by breathing in a smoke or vapor, they typically feel the effects almost right away, which is why patients sometimes prefer smoking or vaping as their preferred route of administration. Brittany Harvey: Understood. Definitely. We hope these guidelines provide key information and clarity for both adults with cancer and their clinicians.  So then, finally, you've both mentioned that there is limited evidence regarding cannabis and cannabinoid use in adults with cancer. So what are some of the outstanding questions regarding cannabis and cannabinoids in cancer care? Dr. Eric Roeland: Thanks, Brittany. I think the questions also align with priorities for future research, and we need to recognize that the lack of evidence aligns with some of the challenges of funding research in this space. However, ongoing future research priorities include what is the nature of healthcare disparities pertaining to medical cannabis use by adults with cancer, and what are effective means to address these disparities? We also wonder, what are the optimal strategies to maximize communication in the oncology clinic regarding medical cannabis and/or cannabinoid use? And when we're thinking about cannabis and/or cannabinoids for cancer treatment specifically, we still need to know do cannabis and/or cannabinoids possess clinically meaningful anticancer activity in humans. We also need to understand what are the drug-drug interactions with our standard-of-care cancer treatments, including cytotoxic chemotherapy, targeted therapy, immunotherapy, radiation, and combinations of all the above. We also are wondering what the effect of cannabis and/or cannabinoids on outcomes in adults with cancer receiving some of our newer therapies, including antibody-drug conjugates and some of our newer vaccine therapies.  Dr. Ilana Braun: I might add that collating the existing research as the guideline did is a very good first step and should serve to highlight where the gaps in knowledge lie. This guideline discusses some of the unique challenges to conducting cannabis and cannabinoid research, including limitations in funding source and study drug, red tape procedures, and issues around legalization. I believe it will take a group of highly determined and creative researchers to move the needle forward in this area, but we must. Brittany Harvey: Definitely. Thank you both so much for all of your work developing this guideline and creating these evidence-based recommendations. And thank you for taking the time to come on the podcast today and teach us all a little bit more about cannabis and cannabinoids in cancer care. And thank you for your time, Dr. Braun and Dr. Roeland.   Dr. Ilana Braun: Thanks so much, Brittany. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Angela DeMichele, Dr. Lynn Henry, and Dr. Harold Burstein present the latest breast cancer rapid recommendation update impacting two ASCO guidelines. This update focuses on the new option, capivasertib plus fulvestrant, for patients with hormone receptor-positive, HER2-negative metastatic breast cancer with activating PIK3CA or AKT1 mutations or inactivating alterations in PTEN based on data from the recent CAPItello-291 trial. They discuss the updated recommendations on lines of endocrine treatment and selecting between the options for patients with activating PIK3CA mutations. Additionally, we discuss implications for clinicians and patients, and what ongoing research is occurring in the field. Read the latest update, “Endocrine and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer – Capivasertib-Fulvestrant: ASCO Rapid Guideline Update“ at www.asco.org/breast-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00248 Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.   My name is Brittany Harvey, and today I am interviewing Dr. Harold Burstein from Dana-Farber Cancer Institute, Dr. Angela DeMichele from the University of Pennsylvania, and Dr. Lynn Henry from the University of Michigan, co-chairs on “Endocrine and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: Capivasertib–Fulvestrant: ASCO Rapid Guideline Update.” Thank you for being here, Dr. Burstein, Dr. DeMichele, and Dr. Henry. Dr. Harold Burstein: We're happy to be here.  Brittany Harvey: And before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests on this episode today, are available online with the publication of the guideline update in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to kick us off, Dr. Burstein, could you first describe what prompted this rapid update, which provides updated recommendations for two ASCO guidelines: the biomarkers for systemic therapy in metastatic breast cancer guideline, and the endocrine treatment and targeted therapy for hormone receptor-positive, HER2-negative metastatic breast cancer guideline? Dr. Harold Burstein: Thanks, Brittany. Well, this team has been working, as you mentioned, actually, on two guidelines, which are clearly evolving in parallel and kind of converging, actually, when you look at data, as we'll be talking about in the next few minutes. The particular catalyst here was a large randomized clinical trial which looked at a new targeted therapy in the space of estrogen receptor-positive, HER2-negative breast cancer. That drug is capivasertib. And the trial was the so-called CAPItello study. In that trial, patients who were receiving second-line therapy with fulvestrant were randomized to that treatment alone, or that plus capivasertib. So the data from that study were the first strong signal that we needed to update the guideline because they were important clinical data.   The other strong signal was that the drug was tested in a cohort of patients who had a specific set of mutations in their cancers. And that included PIK3CA mutations, a class of mutations for which we already had a targeted drug. But it also included some new potential targets, including mutations in the AKT gene itself, capivasertib is an AKT inhibitor, as well as loss of PTEN protein functionality, which potentially sensitizes tumors to the targeted action of this drug as well. So while we had a couple of guidelines catching up on the endocrine therapy space, which is increasingly looking like a targeted therapy space, it was clear that this major study, which had clinical and diagnostic implications, would sort of push them together and served as the impetus for updating both guidelines at the same time. Brittany Harvey: Understood. I appreciate that background information.   So then, Dr. DeMichele, based on this updated data that Dr. Burstein just described, what is the updated recommendation from the guideline panel regarding lines of endocrine treatment? Dr. Angela DeMichele: Well, I think this is where the biomarker evolution that Dr. Burstein just referred to really comes in because now we have the opportunity to perform genomic testing in patients who have ER-positive, HER2-negative metastatic breast cancer, on either the tumor or commonly from the blood. And we can now start to tailor treatment to the specific genomic abnormalities that that patient's tumor contains. So now our guideline really marries both the genomic abnormality with the therapeutic option. First-line treatment remains endocrine therapy plus a CDK 4/6 inhibitor. But things then really start to diverge once we enter second and third-line therapy because at that point, we now have the option to test for several genomic markers: ESR1 mutations, PIK3CA mutations, AKT1 mutations, and PTEN inactivation. And based on whether the tumor has one or any of those mutations, we can then select the therapy based on that.  So in the case of capivasertib, as you just heard, that is a therapy for patients whose tumors have PIK3CA mutations or activating mutations in AKT1 or loss of PTEN. But other patients who don't have one of those mutations may, in the second line, go on to another drug. For example, if they have an ESR1 mutation, they then may be eligible to take elacestrant. Patients who have no targetable mutations still have a targeted option in that they can use everolimus. And in all of these settings, the endocrine therapy partner for this line of therapy is typically fulvestrant. So now we're really starting to tailor therapy in the second- and third-line based on genomic changes. Brittany Harvey: Excellent. That information is helpful for choosing optimal therapy tailored to the individual patients, as you just described.  So then, Dr. Henry, what guidance does the expert panel provide regarding choosing a PIK3CA targeted option? Dr. Lynn Henry: Thank you. So for patients whose tumors are found to have an activating mutation in PIK3CA, we now have two drug options: either alpelisib or capivasertib in combination with fulvestrant. And the problem is, these drugs have not been compared head-to-head. We can't say that one is clearly better than the other, either in terms of efficacy or in terms of side effect profile. What we do have is information from two separate trials in which they were each tested against placebo. The efficacy appears to be fairly similar based on the data that we have. It does appear that the side effect profiles may be slightly different. And so, when you have a patient sitting in front of you and you're trying to decide how best to treat her, you really have to think about, what symptoms does my patient already have? What is she more or less likely to tolerate? So what we do know is that it appears that the rates of grade 3 diarrhea and rash were slightly higher with capivasertib. It looks like hyperglycemia was higher with alpelisib, as was treatment discontinuation. So really you have to make an individualized decision when you have a patient sitting in front of you about which drug you'd like to try. Of course, if someone doesn't tolerate one drug, you can always switch to the other one.  Brittany Harvey: I appreciate that analysis and to provide guidance without a head-to-head trial and to specifically provide options based on an individual patient's profile.   So then, Dr. DeMichele, what should clinicians know as they implement these new recommendations?  Dr. Angela DeMichele: Well, first of all, I think most clinicians now are becoming more familiar with the procedures required for doing genomic testing. But this is something that now has become the standard of care. And so, it is incumbent upon all of us who treat these patients to understand what the options for genomic testing are for that patient, which companies offer this testing, how to send a sample, and how to interpret the report that comes back. So, I think this has really added a level of complexity to the therapy for patients. I also think that one can't simply apply an algorithm to a patient. We have to really treat the whole patient and we have to take into consideration, as Dr. Henry said, the toxicities of these agents and the cost which is also a major issue. So I think that while it is more complex, really that doctor-patient relationship is so important in communicating what these genomic tests mean for a patient and for their options, and also important for the clinician to really understand what the different therapeutic agents might mean for a patient, and really try to pick the agent that's best for that patient. Using genomic testing is just one of several different features that they'll consider. Brittany Harvey: Absolutely. It's key to obtain the data needed to select appropriate patients and to recognize the complexity.   So then, Dr. Henry, in your view, how will this update impact patients with metastatic breast cancer? Dr. Lynn Henry: Yes, so as we've discussed, I think this is really exciting. Over the last few years, we have had quite a number of new medications that have become available for patients and have been FDA-approved. And so this is yet the latest in a series. For those patients whose tumors have a PIK3CA mutation, as we discussed, there are now two options. So you have a choice depending on which one is better covered by insurance, by which one you may tolerate better. But I think the other thing is now, although it's a smaller subset of patients, there are patients out there whose tumors have mutations in AKT1 or alterations in PTEN, and so there's an entirely new endocrine therapy-based option available for them that wasn't available before. So I think that thinking about the new data that are out there, the new drugs that are out there, really is exciting because there are new options available and hopefully there are more to come as well.    Brittany Harvey: Absolutely. It's great to have these new options.  So, finally, Dr. Burstein, Dr. Henry just mentioned what's to come. Could you touch on what some of the outstanding questions are regarding endocrine therapy for patients with metastatic breast cancer?  Dr. Harold Burstein: A couple of things to say. First, ER-positive metastatic breast cancer is the most common kind of metastatic breast cancer, roughly three quarters of metastatic cases of breast cancer will be hormone receptor-positive cancers. So this is a very big public health issue around the world, actually, breast cancer being the number one most commonly diagnosed cancer of women around the world. So minor or major improvements in treatment for advanced ER-positive breast cancer really have a tremendous impact.  The second thing is it's been remarkable to see the progress in the past decade. We've gone from simply targeting the hormonal access itself with medicines like tamoxifen or aromatase inhibitors or an injectable selective estrogen receptor degrader like fulvestrant to incorporating targeted therapies at the same time. And this whole class of drugs called CDK4/6 inhibitors has emerged which we use in either first- or in second-line therapy. Those drugs have transformed our standard of care, improved survival for patients with advanced ER-positive disease, now with median survival nearly 50% longer than what we had seen in the past.  And if you've heard, we have a wealth of opportunities. We can target PIK3CA, we can target ESR1 mutations. Other drugs emerging in the space include PROTACs which is another way of degrading the estrogen receptor. And so there's going to be more progress in the years to come.   So one of the biggest challenges has been to try and understand, is there really an optimal way to use these drugs, or can we be smarter about the particular sequence of all these particular things that are happening.  So one example of this was a recent study that is on a drug, not as yet FDA-approved, called inavolisib, which is a PIK3CA targeted drug used in first line in combination with a CDK4/6 inhibitor and endocrine therapy. And that study, for a high-risk group of women with ER-positive metastatic disease, actually showed a dramatic improvement in overall survival, asking the question if combining some of these targeted therapies together might yet further improve outcomes.  And as you've heard from the diagnostic space, one of the other interesting things is that tumors evolve over time. And so acquisition of the estrogen receptor mutations, ESR1 mutations, which are typically not found early in the course of advanced breast cancer but otherwise later, now have targeted treatments. So there's a whole bunch of stuff going on all at the same time, including multiple ways of targeting things, serial testing to look for acquisition of ESR1 mutations and new pathways to explore. It's an embarrassment of riches in some respects because it has meant it's actually really hard to write a guideline as you've heard, which says, “Do this first, do this second, and do this third.” I suppose that's a good problem to have under the circumstances, but it's going to require really thoughtful clinical trials and careful analysis to help guide specific lines of treatment recommendations like that.  Brittany Harvey: Excellent. We'll look forward to these exciting, continuing developments for patients with metastatic breast cancer. And I want to thank you all so much for your work to develop this rapid recommendation update for these two guidelines. And thank you for taking the time on this podcast today. Dr. Harold Burstein: Thanks. Dr. Lynn Henry: Thank you so much.  Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Natash Leighl and Dr. Jyoti Patel are back on the podcast to discuss the update to the living guideline on stage IV NSCLC with driver alterations. This guideline includes recommendations for first-, second-, and subsequent-line therapy for patients with driver alterations including: EGFR, ALK, ROS1, BRAFV600E, MET exon skipping mutation, RET rearrangement, NTRK rearrangement, HER2, and KRAS G12C. They highlight the key changes to the recommendations, addition of recent trials, the importance of biomarker testing, and the impact of this guideline for clinicians and patients living with advanced NSCLC. Stay tuned for future updates to this continuously updated guideline. Read the full update, “Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02744.    Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.    My name is Brittany Harvey, and today I am interviewing Dr. Jyoti Patel and Dr. Natasha Leighl, co-chairs on “Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3.” Thank you for being here, Dr. Patel and Dr. Leighl.  And before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel and Dr. Leighl, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So, to start us off on this living clinical practice guideline, Dr. Leighl, this guideline for systemic therapy for patients with stage four non-small cell lung cancer with driver alterations is being routinely updated. What new data was reviewed in this full update to the living guideline? Dr. Natasha Leighl: Thanks so much, Brittany. So, we looked through the literature for publications between February and the end of October 2023, and also any novel agents that were approved, in particular by the United States FDA, to really incorporate this update in the current guidelines. In particular, we had updates in EGFR-driven tumors, BRAF and RET-driven tumors. And we also worked very hard to make this more digestible. In particular, it was turning into a bit of a laundry list of all of the things that we had ever recommended. So we really wanted to shorten things, pare them down, and really make them helpful and very, very current for the treatment of people with lung cancer in 2023 and 2024. Brittany Harvey: Excellent. Thank you for providing that overview of the evidence reviewed and the key updates that we will address in this guideline. So then I would like to talk about some of those key updated recommendations from the expert panel. You mentioned both EGFR, BRAF, and RET. So starting with patients with stage IV non-small cell lung cancer with EGFR alterations, Dr. Leighl, what are the key changes to those recommendations? Dr. Natasha Leighl: So, as I said, we really started to get quite a long list of things we recommended, including drugs that, to be honest, we no longer think are what we should lead with first-line. So we updated the recommendation to recommend first-line osimertinib in patients with sensitizing mutations. We were also able to capture in this update for patients with EGFR exon 20 insertion mutant lung cancer, the data from the randomized PAPILLON trial, recommending amivantamab plus chemotherapy for progression-free survival benefit. Not yet an overall survival benefit, but we will see how these data mature.  The other thing that we did was we moved all of the- I don't want to call them "legacy agents" because, in many countries, these are still very important. But older agents such as gefitinib, approaches such as gefitinib plus chemotherapy, and drugs like dacomitinib and other agents where we truly believe as an international panel that we would prefer a third-generation kinase inhibitor like osimertinib. We moved all of those to our discussion, just to recognize that, around the world, not everybody may have access. And we also specified that things are different in different countries. So, for example, in China, there are other third-generation kinase inhibitors with randomized data to support their use. And those are approved and used in China. And also, for example, in Korea, there are other agents that are used. So, we have really tried to be both inclusive and yet keep things simple at the same time. And hopefully, we have succeeded.  One of the challenges was that, with all of the updates that we made, we did not have all of the publications out yet at the end of October to make recommendations about moving beyond osimertinib in the first-line setting. So, please stay tuned for the next guideline update, where we're going to tackle whether we should give osimertinib alone or combination therapy. Brittany Harvey: Excellent. Thank you for providing those updates and clarifications for those patients with non-small cell lung cancer and an EGFR alteration. And we will look forward to the guideline panel's review of that evidence and future updates as well. So then, Dr. Leighl, you had previously mentioned that additional recommendations were updated, such as those for patients with BRAF alterations and RET alterations. So, Dr. Patel, what are the other key updated recommendations from the expert panel? Dr. Jyoti Patel: Thanks so much, Brittany. So certainly, I think we have seen many of these trials mature over time, which has been fantastic. I think one remarkable achievement was the reporting of a phase III selpercatinib trial. This was a trial in the front-line setting, in which patients who were RET-positive were randomized to selpercatinib versus carboplatin-based chemotherapy. And the selpercatinib significantly outperformed platinum-based chemotherapy, and I think really demonstrated a significant improvement in progression-free survival. So, based on that phase III trial, the recommendation for selpercatinib was elevated. Many of these agents that are used in clinical practice are approved initially on smaller phase I or phase II trials. And so, seeing the maturity of these phase III trials gives clinicians and patients greater certainty that these agents are really effective. And so, the evidence was increased for that, and that's now a preferred agent over another TKI, pralsetinib, in which there is only phase II data. So, certainly, those kinds of real things that we can explain to patients are important in these guidelines.  Another thing that we were able to update was another doublet for BRAF V600E non-small cell lung cancer. So, the combination of the two TKIs, encorafenib and binimetinib, was also included in the guidelines.  One thing that we tried to help was really identifying the best therapy post-progression on these first-generation TKIs. And again, there is a paucity of data, but often we went back to carboplatin-based doublets, and there is some data regarding whether or not patients with driver alterations should get immunotherapy in the second-line setting. And so, certainly, I think we have a number of randomized studies for patients with classical EGFR mutations, and our recommendation is generally avoidance of immunotherapy for these patients and treating many of these patients with carboplatin and pemetrexed when appropriate. I do not think we have the data for a lot of other subsets of patients. So, again, stay tuned as these data evolve. Brittany Harvey: Thank you for reviewing those updated recommendations and the supporting evidence. I think it's helpful for our listeners to understand the level of evidence behind these recommendations as well.  So then, Dr. Leighl, what should clinicians know as they implement these new and updated recommendations? Dr. Natasha Leighl: It's really important, first of all, to make sure that you have the information that you need to get your patients to these great new treatments as part of the shared decision-making process. So your patients need biomarker testing. You need to get that as quickly as you can. As Dr. Patel has highlighted, you really want to get that before they start their first-line therapy, if at all possible. We also really tried to bring out in this guideline that when things are delayed, I mean, this is the real world that we live in, just to be very cautious of immunotherapy with chemotherapy for that first cycle. That obviously, again, is a discussion with your patient, but this concept that the approach of a cycle of chemotherapy while you wait for the next-generation sequencing testing. And then if the patient does not have a driver alteration, adding any other therapy as appropriate is okay. It's something that people do. We believe it's important as we talk about the balance between benefits and harms. And so I think that's in there for clinicians, and I hope that they and patients can really benefit from that to avoid toxicity and also to really improve the ability to get molecular testing results first line.  Also, I think it's really important that when people read the wording of the guidelines, that this really follows GRADE, which is a type of system that we use to develop our recommendations. And so things like "may" do not mean that you shouldn't do it. So sometimes we'll hear back from clinicians and say, "Well, you said that they may use alectinib or lorlatinib, for example, with ALK, and I can only get coverage for one or the other." And so I think it's really important that clinicians and patients recognize that all of the things that we do recommend, even if we do use the word "may" or the recommendation is more conditional, we do think that these agents should be available for patients and clinicians, and that they go through this shared decision-making process together.  And so I think that's something that clinicians, we hope, can help take forward as they advocate for their patients to get access to these different and new and emerging treatments that have clearly shown benefit. Even when we say patients and clinicians may use this or that, there may be excellent reasons for using something newer, that's emerged, perhaps for toxicity benefits or benefits in terms of efficacy, even though we can't compare directly. And so we really want clinicians and patients to be empowered to access these new compounds and these new exciting agents that are in our guidelines. Brittany Harvey: Absolutely. Thank you for reviewing those key points. And, yes, that's a great comment that the level of obligation in the recommendations may be based on the evidence quality, but that doesn't mean that clinicians and patients shouldn't have access to all of the recommended treatment options to offer patients based off their individual patient and clinical characteristics.  So then, Dr. Patel, in your view, how will these changes affect patients with non-small cell lung cancer, with driver alterations?  Dr. Jyoti Patel: A lot of this echoes the points made by Dr. Leighl. I think there are opportunities for patients to assess toxicity or what it means for intensification of therapy. So, particularly for EGFR patients, for example, we have data that chemotherapy with osimertinib can improve progression-free survival, or the incorporation of a bispecific antibody, amivantamab, can improve progression-free survival over the TKI alone. It certainly comes with increased toxicity. And so how we weigh this in the absence of a known survival benefit at this juncture is one that, again, really gives patients the opportunity to prioritize what's important for them. And so I think this guideline affects patients and that we have multiple options, we help with the weight of the evidence so they may be able to better discern what treatment makes sense for them. Brittany Harvey: Understood. Yes, this guideline provides lots of options for different patients based off their driver alterations. So it's helpful to have that information for shared decision-making with their clinicians.  So then finally, to wrap us up, Dr. Leighl, what current research is the living guideline expert panel monitoring for updates to the guideline recommendations? Dr. Natasha Leighl: This process of the living guidelines has really been to help us stay on top of the amazing and incredibly rapid progress that we're making in lung cancer and other cancers. And even with this process, where we're trying to stay up-to-the-minute, there have already been some changes in the literature between the start of November and now. And so we're already working on some additional commentary and options for the first-line treatment of patients with EGFR-mutant lung cancer. Also, the subsequent treatment of patients with EGFR-mutant lung cancer, depending on what they've had before. Also, a great new study in patients with ROS1 fusion-driven lung cancer. And so these are some of the things that we're looking at.   Also, a bit more discussion about the importance of molecular testing. In our companion article, the Journal of Oncology Practice, along with Dr. Patel, we're going to be talking a bit more about new ways to genotype, for example, using both liquid biopsy and tumor tissue at the same time, and some of the support for that and how it gets us with our patients to the answers that they need faster.  Brittany Harvey: Absolutely. The pace of research in non-small cell lung cancer has moved quite quickly. So we definitely appreciate the panel's efforts to review all of this evidence on a continuous basis and take the time to develop these guideline recommendations for both clinicians and patients with non-small cell lung cancer.  So I want to thank you so much for your work to update these guidelines, and thank you for your time today, Dr. Patel and Dr. Leighl. Dr. Natasha Leighl: Thanks so much. It's a real pleasure to be here. Dr. Jyoti Patel: Thank you.  Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Jyoti Patel and Dr. Natasha Leighl discuss the latest full update to the stage IV NSCLC without driver alterations living guideline. This guideline addresses first-, second-, and subsequent-line therapy for patients according to their histology (squamous cell and nonsquamous cell carcinomas) and PD-L1 expression. They discuss the streamlined recommendations, incorporation of recent evidence, and the highlights for implementation of these recommendations in the treatment of advanced non-small lung cancer. Dr. Patel and Dr. Leighl also point out ongoing trials that will inform this continuously updated guideline as we look ahead.  Read the full update, “Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.3” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02746.    Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts  delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all of our shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Jyoti Patel and Dr. Natasha Leighl, co-chairs on “Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.3.” Thank you for being here, Dr. Patel and Dr. Leighl. Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel and Dr. Leighl, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So, to start us off on the content of this episode, Dr. Patel, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations is being updated on a regular basis. Could you provide some background information on the process for these living guidelines? Dr. Jyoti Patel: The ASCO Living Guideline offers continually updated recommendations based on review of systemic randomized controlled trials. We bring a panel of experts together that includes representatives from Ontario Health as well as ASCO patient representatives. We review phase III studies and other published studies between the times from July 2022 and October 2023 for this most updated guideline. We think about the size of the populations that are being tested, what kind of interventions we have, the outcomes. We certainly look at PFS, as well as OS, but also toxicity, and overall response rates. We prioritize randomized trials and really look for studies that have large sample sizes. We exclude studies that were only meeting abstracts and really look at those that are published in peer-reviewed journals.  When we weigh the evidence, we really think about a number of factors. So what is the strength of the evidence, what's the sample size, and how we can make recommendations for our patients based on the totality of the data. Certainly, because this is such a rapidly evolving field, one of the things we are looking at is how to update in real-time these guidelines. So for this coming year, for example, these guidelines are published and we look forward to quarterly updates and, again, incorporate the latest evidence. Brittany Harvey: Great. Thank you for that explanation on the background and how these living guidelines are developed.  So, Dr. Leighl, could you describe what the key changes are from the expert panel? Dr. Natasha Leighl: So what we try to do in the guidelines for this latest publication, was really try and streamline the way we set up a format to make it much easier for people to use. In terms of new recommendations, we made sure to include more recent studies of additional PD-1 or PD-L1 inhibitors, for example, cemiplimab in combination with chemotherapy, or the combination of durvalumab and tremelimumab with chemotherapy, both of these in unselected patients, so with any PD-L1 expression, of course, this continues with pembrolizumab with or without chemotherapy, atezolizumab with chemotherapy combinations, and, of course,  nivolumab and ipilimumab with and without chemotherapy. And so it really is just an update on all of the potential options. In the discussion, we've really tried to go through some of the nuances in the trials just to help when you're discussing with patients or discussing with your oncologists, how to figure out which of these is best for you. Brittany Harvey: Excellent. It's helpful to have all of the recommendations listed out together so that clinicians and patients know all of the available options available to them.  So then, Dr. Patel, what should clinicians know as they implement these changes into their clinical practice? Dr. Jyoti Patel: I think it's important to stress that our decision-making in the treatment of advanced non-small cell lung cancer is really reliant on adequate biomarker testing. And so the way we approach this is our assumption that all appropriate patients undergo molecular testing and have PD-L1 testing to help us get the best therapies. And the other assumption is that patients and physicians are engaging in a dialogue to better assess patient preferences to have a better understanding of performance status, for example, as we think about allocating therapy. One thing that we've been able to do is to take the evidence and break it up by histology as well as PD-L1 expression for patients who don't have driver alterations. Based upon that, think about the toxicity data with, for example, dual immunotherapy versus chemo-immunotherapy for subsets of patients, and so hopefully get some guidance to clinicians as they are going through this process. The other part of the guideline was to, once again, look at second-line and subsequent therapies. So, again, for patients who get immunotherapy alone, the recommendation is that patients get a carboplatin-based doublet in the second-line setting. We still do not know if patients should get immunotherapy after that initial exposure, that is the subject of ongoing randomized studies. We also have stronger evidence than ever that docetaxel is an appropriate second-line agent, but there are other options there, so docetaxel and ramucirumab, as well as other single-agent chemotherapies. Brittany Harvey: Understood. Those are key points for informed and shared decision-making and are helpful for clinicians to know.  So then, Dr. Leighl, in your view, how will these guideline recommendations impact patients with non-small cell lung cancer without driver alterations? Dr. Natasha Leighl: Thanks. So, we're really hoping that with all of the focus in the first-line setting, that more patients will receive immunotherapy with or without chemotherapy in the first-line setting to really bring it forward and really make sure that patients can start benefiting as soon as possible. As Dr. Patel said, one of the challenges, of course, is to understand who might benefit most with a chemotherapy-free approach and have treatments in sequence versus who really needs everything together. And so, we've really tried in the discussion to try and help with that discussion both from a provider and patient perspective. So, we want more people to get immunotherapy to help improve their outcomes and also to potentially get it earlier. I think the other thing, and Dr. Patel has brought this up, but when we looked at what happens after first-line therapy, we really have very limited recommendations. And so it's our real hope that this will spur the community on to do even more studies to help us figure out what's next and how do we really improve outcomes for our patients after all of these great first-line options have stopped working. Brittany Harvey: Absolutely. I appreciate you touching on those key points for improved outcomes for patients with non-small cell lung cancer.   Finally, Dr. Patel, you have mentioned some ongoing randomized clinical trials and so has Dr. Leighl. So, what are the ongoing developments that the living guideline expert panel is monitoring for future updates? Dr. Jyoti Patel: We will continue to update guidelines based on available literature, but certainly, there are a number of trials that we should be reading out in the next year or so, looking at combinations of immunotherapy in the second-line setting. Certainly comparing novel agents to docetaxel in the second-line settings, and things like antibody-drug conjugates. So certaintly that's evidence that we hope to incorporate this evidence within the guideline with the idea that  we can really help clinicians and patients recognize or at least identify the best options for treatment for them.  Brittany Harvey: Definitely. Well, we'll look forward to the expert panel's review and interpretation of this evidence as those trials read out. And appreciate all of your work on this guideline update and we'll hear more as these guidelines are continuously updated. Thank you so much for your time today, Dr. Patel and Dr. Leighl.  Dr. Jyoti Patel: Thank you. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Banu Arun and Dr. Sana Al Sukhun share recommendations from the newest ASCO resource-stratified guideline on systemic treatment for patients with metastatic breast cancer. They describe the importance of this new guideline, the four-tier resource setting approach, key recommendations, and implementation considerations. Recommendations are discussed for systemic therapy for HER2-positive, triple-negative, and hormone receptor-positive metastatic breast cancer, across Basic, Limited, and Enhanced resource settings. Drs. Arun and Al Sukhun highlight the importance of this guideline for clinicians and patients in regions with limited resources to optimize cancer care. Read the full guideline “Systemic Treatment of Patients with Metastatic Breast Cancer: ASCO Resource-Stratified Guideline” at www.asco.org/resource-stratified-guidelines." TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/resource-stratified-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the JCO Global Oncology, https://ascopubs.org/doi/10.1200/GO.23.00285  Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Banu Arun from the University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Sana Al Sukhun from Al Hayat Oncology Practice in Amman, Jordan, co-chairs on “Systemic Treatment of Patients with Metastatic Breast Cancer: ASCO Resource-Stratified Guideline.”  Thank you for being here, Dr. Arun and Dr. Al Sukhun. Dr. Banu Arun: Thank you for having us.  Dr. Sana Al Sukhun: Thank you. Pleasure to join you. Brittany Harvey: And before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including the guests who have joined us today on this episode, are available online with the publication of the guideline in the JCO Global Oncology, which is linked in the show notes.   Then, to jump into the content of this guideline, Dr. Al Sukhun, can you first provide an overview of the scope and the purpose of this guideline?  Dr. Sana Al Sukhun: Sure. And again, thank you, Brittany. Pleasure to join you. This guideline is really interesting and very important. It addresses the care and treatment of the most common cancer worldwide, particularly metastatic breast cancer, taking into consideration different availability of resources, particularly in countries with limited resources. As you know, most of us are aware of the importance of clinical practice guidelines improving outcomes for patients in medicine, not only in oncology, but most of those guidelines are developed in countries that are highly resourced. So their applicability in countries of limited resources that lack infrastructure and resources is definitely limited because they cannot really adopt and adapt to those guidelines, which makes resource adapted or resource stratified guidelines quite important and helpful. First, to clinicians caring for patients so that they can properly allocate resources, prioritize how to use therapy for patients, but also even policymakers to allocate resources and plan graduated implementation of science to improve outcomes for their patients according to the progressive availability of resources.  So we're talking about breast cancer, the most common cancer worldwide. And not only is it the most common cancer worldwide, but also more than two-thirds of new cases are diagnosed in countries of limited resources. Unfortunately, they also carry the burden of more than 70% of the mortality attributed to breast cancer. Another challenge is that the median age for the patients affected with breast cancer in countries of limited resources is indeed at least a decade younger than Western societies, which adds to the burden, not only the social, but also the economic burden of cancer. And unfortunately, presentation in these countries is mostly locally advanced, metastatic breast cancer, therefore comes the focus on helping our colleagues in countries of limited resources to care for patients according to the resources available, not only in countries of limited resources, even colleagues practicing in less fortunate areas within countries that are highly resourced. Brittany Harvey: Excellent. Thank you for providing that background information for this guideline.  So then you've just described how many countries and areas have different resources. So, Dr. Arun, could you describe the four-tier resource setting approach that this expert panel used? Dr. Banu Arun: Yeah, Brittany, that's a good question. I think it's important to know where we started and what infrastructure we used. So for developing resource stratified guidelines, ASCO has adopted its framework from the four-tier resource setting approach, which was actually developed by the Breast Health Global Initiative, and we employed modifications to that framework based on the disease control priorities. What this framework emphasizes is also that variations can be present not only between countries, but actually within countries with disparities, for example, differences between rural and urban areas within one country.   So the four settings are obviously basic, limited, enhanced, and maximal settings. The basic setting includes core resources or fundamental services that are really absolutely necessary for any public health, primary health care system to function at all. These include services that are typically applied in a single clinical interaction. For example, vaccination is feasible for highest need populations.   The next tier would be the limited setting. That includes countries or settings with second-tier resources or services that are intended to produce major improvements in outcomes, such as incidences and cost effectiveness. Unlike the basic setting, it can involve single or multiple interactions with providers or healthcare services. Then the third tier is the enhanced setting, where the services are optional but important, and these services should ideally produce further improvements in outcome and increase the number of quality of options and also individual choices, maybe countries having the ability to track patients and links to registries.  And then the last one is of course, the maximal setting that includes high-level, state-of-art resources and services that are available in some high-resource countries. Brittany Harvey: Thank you for describing that framework and the approach that the panel used. So then I'd like to move on and talk about the key high-level recommendations of this guideline for systemic therapy for metastatic breast cancer across those three lower tiered resource settings - the basic, limited, and enhanced resource settings. So, Dr. Al Sukhun, could you start with the recommendations across these settings focusing on HER2-positive breast cancer?  Dr. Sana Al Sukhun: Sure. You know, HER2-positive metastatic breast cancer is one of the most aggressive subtypes of breast cancer. However, its outcome has been transformed with the introduction of HER2-targeted therapy. So, apart from patients who suffer from congestive heart failure or limited compromised ejection fraction, which can be evaluated on a case-by-case basis, patients are candidates for HER2 targeted therapy. When we made the recommendations according to the availability of resources, we started in a gradual approach. So, in a maximal setting, you treat patients with HER2-positive metastatic breast cancer in the frontline setting using the combination of trastuzumab, pertuzumab, and taxanes or endocrine therapy if patients have limited disease burden, or if they have the recurrence after a long disease-free interval. Usually, the combination of trastuzumab and pertuzumab with taxane is used. But then again, clinicians can use navelbine, considering good data from the HERNATA trial about its efficacy as compared to taxanes and even also, we recommended platinum therapy according to availability.   However, if pertuzumab is not available, you go to the next level where we recommend offering, again, chemotherapy, be it taxane, navelbine, platinum, with trastuzumab, or even without trastuzumab if trastuzumab is not available. So, something to keep in mind, chemotherapy is not without efficacy in this aggressive subtype. It is not as good as when you use the combination with HER2-targeted therapy, but it still works. Patients and clinicians in this era of biologic therapy immunotherapy tend to think only pricey medications are the ones that can be used for treatment and improving outcome. However, definitely adding help with targeted therapy is great whenever it's available. But if it's not available, chemotherapy still could be used in a sequential manner. We listed all possible chemotherapeutic options starting with taxanes, navelbine, platinums, even CMF, capecitabine.   When it comes to second-line therapy, including those patients who relapse within 12 months of adjuvant therapy, the optimal line of treatment would be trastuzumab deruxtecan. However, if it's not available, we recommend to be offered with successive or progressive preference, if it's not available, T-DM1 could be used. If it's not available, capecitabine and lapatinib could be used. If it's not available, trastuzumab with chemotherapy could be used. If it's not available, we go back to the sequential use of chemotherapy, including adriamycin, taxanes, platinums, capecitabine, or even CMF.  Brittany Harvey: I appreciate you reviewing those recommendations for HER2-positive breast cancer.  So then, moving along, Dr. Arun, what are the recommendations for patients with metastatic triple-negative breast cancer? Dr. Banu Arun: Thank you, Brittany. Triple-negative breast cancer, of course, is one of the serious subgroups of breast cancer. About 10 to 15% of patients have triple-negative breast cancer. What I will do is I will divide it into the three-tier settings as well as first-, second-, and third-line therapies.  For patients with triple-negative PD-L-negative metastatic breast cancer in the limited settings and even enhanced settings, single-agent chemotherapy rather than combination chemotherapy should be recommended as the first-line. However, if patients are symptomatic or have immediate life-threatening disease, combination chemotherapy can be offered.  For patients with triple-negative breast cancer that are PD-L1 positive, they may be offered in addition to chemotherapy, an immune checkpoint inhibitor, as first-line therapy, most probably in enhanced settings and in basic and limited, of course, chemotherapy. When you move on to the second-line for metastatic breast cancer in patients with or without previous PD-L1 checkpoint inhibitors, clinicians can offer palliative or best supportive care in the basic setting. In the limited setting, chemotherapy with anthracyclines, taxanes, platinums are options. And in the enhanced setting if sacituzumab govitecan is not available, chemotherapy would be an option. Now, when we move on to the third-line setting for triple-negative breast cancer, clinicians can actually offer chemotherapy and/or palliative care, depending really on the status of the patient. Brittany Harvey: Excellent. Thank you for providing those recommendations for triple-negative breast cancer. As you mentioned, it's one of the rarer forms of breast cancer. So then, Dr. Al Sukhun, I'd like to move into the last section of patients, actually the most common, but hormone receptor-positive breast cancer. What are those recommendations?  Dr. Sana Al Sukhun: Thank you, Brittany. As you mentioned, it's the most common subtype worldwide. The rule of the thumb is sequential hormonal therapy, depending on availability. So, whatever you have hormonal therapy, sequential hormonal therapy unless pending visceral crisis or symptomatic disease, it's recommended that you offer sequential single-agent chemotherapy, unless it's a real visceral crisis, where we recommend combination chemotherapy. That's a classic in all our guidelines.  When considering frontline hormonal therapy, again, I will start from the maximal level and gradually recommend according to availability. So in enhanced levels in many countries now, we have generic CDK4/6 inhibitors, which increase their availability. So we do recommend hormonal therapy with CDK4/6 inhibitors. Upon progression or when they are not available, on progression, you move to the second line of hormonal therapy. If you have liquid biopsy, check for PIK3CA mutation. Sometimes you do have the liquid biopsy, but you do not have alpelisib to offer to your patients with hormonal therapy, then it's okay, you still can move to second-line fulvestrant with everolimus. Sequentially, you can move forward to fulvestrant by itself if you do not have everolimus. And even you can sequence tamoxifen until your patient stops responding to hormonal therapy then you can offer sequential single-agent chemotherapy.  Brittany Harvey: Thank you, Dr. Al Sukhun for providing those recommendations.  So then, Dr. Arun, what should clinicians do when we do not have access to receptor assessment? What is recommended for best practices for management of those patients? Dr. Banu Arun: So, Brittany, that's an important question. There are some basic settings where unfortunately, immunohistochemistry for ER/PR HER2neu determination is not available. Our group really recommends in these cases that clinicians may presume hormonal receptor positivity and offer tamoxifen in most cases. It is expected that IHC would be available in limited and, of course, enhanced settings. Brittany Harvey: Great. Thank you for providing that information.  So further, what else should clinicians know as they implement these recommendations, Dr. Arun?  Dr. Banu Arun: It's very important that we, all healthcare provider clinicians, really know the data. I think reading the guidelines or knowing about first and second line therapies is obviously important, but the devil is in the details. And I think knowing the publications and subgroup analyses, if needed, because every patient is different and sometimes the recommendations cannot go by the books. You really need to do an assessment of the patient and see in which setting you are and then make the most of the guidelines that are recommended. It's to guide. The name is guidelines. It's to guide. And ultimately, it's the clinician's responsibility to find the best available therapy for the patient. And sometimes that includes no treatment and supportive care. Dr. Sana Al Sukhun: Totally agree with Dr. Arun. They are there to support the clinician decision. After all, the clinician is the one who sees the patient, who can evaluate the patient from all aspects — social aspect, physical aspect, the tumor aspect. So it's not just about the tumor, it's about the patient and the environment where the clinician is treating the patient. However, I believe there is support to the clinician not only in treating the patient, but also on addressing priorities for research to improve outcomes for patients in different resource settings. There is also support for the clinicians to help them advocate for improving care for patients in a strategic way, where they prioritize resource allocation. So they are there to support the clinician at all levels, not only when treating patients, but when advocating for patients, when helping patients to make decisions, when they're discussing with their health officials and policymakers.   Brittany Harvey: Absolutely. Those are excellent points that you both made about individualizing patient care for the specific person in front of you. So then, finally, Dr. Al Sukhun, how will these guideline recommendations impact patients with metastatic breast cancer globally?  Dr. Sana Al Sukhun: The ultimate goal for anything we do, including guidelines, is to improve outcomes for patients worldwide. They are there to support clinician decisions, empower clinicians to optimize care for their patients, to advocate for improving outcomes for patients by strategically allocating resources according to the most impactful strategy. They help clinicians to identify areas for research that are needed according to the resources available to them. They are there to guide policymakers, again, also implementing strategies to implement science that could improve outcomes in an efficient way for their societies. So hopefully, all these, with our research, with our advocacy, with our health policy, with our treatment decisions, hopefully all these will improve outcomes for breast cancer patients and ultimately reduce mortality, particularly in less fortunate, limited resource settings for patients everywhere. Brittany Harvey: Absolutely. We hope that these guidelines improve outcomes and quality of life for patients worldwide.  So I want to thank you both so much for your work to develop this guideline. There's certainly a large amount of recommendations, so I encourage our listeners to read the full guideline, which is linked in the show notes. And I want to thank you so much for your time today, Dr. Al Sukhun and Dr. Arun. Dr. Sana Al Sukhun: Thank you for having us. Dr. Banu Arun: Thank you, Brittany. Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/resource-stratified-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Isabelle Bedrosian and Dr. Mark Robson discuss the new guideline from ASCO and SSO on germline testing in patients with breast cancer. They discuss the framework for which patients should be offered BRCA1/2 testing, and what additional moderate- and high-penetrance genes may be considered for inclusion in germline testing. They highlight key aspects of personal and family history, recommendations surrounding counseling for genetic testing, and the impact for patients and their families. They close the conversation with a discussion of gaps in the research. Read the full guideline, Germline Testing in Patients with Breast Cancer: ASCO-SSO Guideline TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02225 Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.  My name is Brittany Harvey, and today I'm interviewing Dr. Isabelle Bedrosian from the University of Texas MD Anderson and Dr. Mark Robson from Memorial Sloan Kettering Cancer Center, co-chairs on “Germline Testing in Patients with Breast Cancer: American Society of Clinical Oncology – Society of Surgical Oncology Guideline.”  Thank you for being here, Dr. Bedrosian and Dr. Robson. Dr. Mark Robson: My pleasure. Dr. Isabelle Bedrosian: Thank you, Brittany. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bedrosian and Dr. Robson, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to jump into the content of this particular guideline, Dr. Bedrosian, could you give us a general overview of both the scope and the purpose of this guideline? Dr. Isabelle Bedrosian: Yeah, sure. So, in the last decade or so, the whole area of clinical cancer genetics has become incredibly complicated, driven, I think, predominantly by the development of extended gene testing. And in the midst of this complexity, our goal here was to try to give providers a framework through which they can think about the application of germline testing within their patient population. And really, this framework was to help them think through how testing can best be applied to patients that were both newly diagnosed with breast cancer or had a history of breast cancer, and also to help them think through the scope of that testing as well, be it BRCA testing or testing in a more extended fashion that may help inform longer-term decisions such as risk management. Brittany Harvey: Absolutely. We appreciate your efforts to provide recommendations in this framework in this complicated space.  So then, I'd like to review the key recommendations of this guideline developed by the expert panel. So first, Dr. Robson, who should be offered BRCA1/2 testing? Dr. Mark Robson: Thank you. I think this is perhaps one of the most important things that comes out of the guideline is that we, and the group, are now recommending that anyone who is either newly diagnosed with breast cancer at or before the age of 65, or if they're over 65 and have suggestive personal or family history criteria, or alternatively, if they are eligible for PARP inhibitor therapy, that they all be offered BRCA1 or BRCA2 testing. And the same would hold for women who had a personal history of breast cancer but were not currently under active treatment if their diagnosis had been made at or before 65 or older than that, with certain criteria then they should be offered testing. This is a much simpler way to look at things than the rather complicated existing criteria, which are perhaps a bit both difficult to remember and unfortunately inadequately sensitive in a setting where there is such critical, both therapeutic and risk management implications to the identification of a BRCA mutation. Dr. Isabelle Bedrosian: Yeah, I would just also add there's one other, albeit a much smaller group of women for whom BRCA testing could be considered, and those are women who develop a second primary breast cancer. That's another group that I think we can think about offering BRCA1/2 testing to. Brittany Harvey: Understood. I appreciate you both reviewing those recommendations for BRCA1/2 testing.  So, Dr. Bedrosian, which additional genes does the panel recommend including in germline testing? Dr. Isabelle Bedrosian: Yeah. So, in this area, outside of BRCA genes, Brittany, I think the panel didn't make any definitive recommendations or any specific genes that should be tested for. I think the panel felt that the decision to test for additional high penetrance genes and also for some moderate penetrance genes should be guided by the specifics of the individual case, whether the identification of germline mutations makes sense in the context of the patient's personal history and family history. So, in other words, is there a worrisome pattern in the family that might warrant more in-depth testing beyond BRCA, and also considerations around the implications of those test results. Would it change the management for the patient themselves? Either in the treatment of the index malignancy, which, in the case of most of these non-BRCA genes, there really is not changes to the management of the breast cancer that would be offered based on the finding of non-BRCA germline mutations. But potentially, the finding of a non-BRCA germline mutation in a breast cancer patient might help better understand risks of second malignancies that would then be addressed. And certainly for families as well of the patients, identifying those that are carriers could offer opportunities for risk assessment, risk mitigation. Dr. Mark Robson: I totally agree with Dr. Bedrosian. One thing I think it's important to understand is that most commercial testing done in the United States now does involve panels of genes. And the group certainly did not intend to suggest that that practice not continue. So, I think if somebody has a history of breast cancer, I think the panel felt that it would at least be reasonable to test for breast cancer susceptibility genes. However, this issue of do you test for all of the high penetrance genes when the family history doesn't suggest it, was certainly something we left open and we did not want to imply that it was obligatory to test for a large number or large panel of genes that weren't related to the patient's personal and family history. So, in other words, didn't want to imply that it was obligatory to do an extremely large panel just as a target of opportunity, if you will. Dr. Isabelle Bedrosian: I think really a key part of these guidelines was that we wanted to afford the oncologist flexibility. It's very difficult beyond BRCA to be prescriptive. There are so many considerations about testing, and those considerations will be applied differently in every patient context. So, we really wanted to let providers know that while they have to think about these other genes, and oftentimes there'll be good reason to do these other genes as part of the overall germline testing, again, that it's not obligatory to do so. It's not a fixed set that needs to be tested for. And really, the understanding of the patient's personal history, family history, therapeutic goals, and risk assessment goals should be used to determine kind of the ultimate scope of the testing. Brittany Harvey: It sounds like these decisions will be individualized, based on patient characteristics and with working between both patients and their clinicians. So that leads into my next question. But, Dr. Robson, how should patients with breast cancer considering genetic testing be counseled? Dr. Mark Robson: With this recognition and emphasis on the therapeutic implications for patients with breast cancer, both surgical and potentially systemic using PARP inhibitors, the approach has gradually moved away from the concept of testing for personal utility, in other words, just wanting to know, and more towards the idea of this being a clinically useful test that's to some extent necessary for the appropriate management of a fair number of patients. And so the counseling is usually- the pre-test counseling is perhaps more educational than we have used in the past, rather than this extensive discussion of whether or not somebody wants to know. Obviously, it's always the patient's ultimate decision whether or not to be tested, and we have to give them the same elements of education that we would have given back in the day. But it can be delivered in a more didactic type of context rather than necessarily the back and forth that takes place with formal genetic counseling.  Now, for patients who have complicated or extensive family histories or who have histories that may suggest predispositions other than those for breast cancer, the type of thing that Dr. Bedrosian was talking about earlier, they could certainly benefit, again, from a more formal evaluation by a provider experienced in cancer genetics to help select what the scope of the testing should be, for instance, and also to help interpret those results. And certainly anybody who had a pathogenic variant or a likely pathogenic variant identified should be considered for meeting with somebody who's experienced in clinical cancer genetics both to interpret and also to help with family expansion when appropriate.  Brittany Harvey: Excellent. Thank you for reviewing those recommendations from the expert panel. So, Dr. Robson just touched on this a little bit, but Dr. Bedrosian, how will these guideline recommendations affect patients with breast cancer and their families? Dr. Isabelle Bedrosian: Yeah, so from a patient perspective, I think there are two ways that these recommendations can impact care. For those women that are identified as germline carriers, specifically with BRCA, it will open the door for receipt of PARP inhibitors, which are currently recommended for patients that are high-risk primary cancer or those with metastatic disease. The other ways that patients will be affected by a germline testing is really in this idea of second cancer risks. Some of these germline mutations are well established to carry risks of either second primary breast cancer or non-breast malignancies. And understanding those risks will allow the patients and their providers to create management strategies, be they surgical or with more intensified screening that will help them mitigate the effects of that germline-driven risk.  And I think similarly for the families of patients, the ones the proband has identified, I think that family now has a very real opportunity to better understand their cancer risks and again be able to more effectively manage those risks through either surgical or non-surgical means. And it would really underscore the family component of this. I think oftentimes oncologists are very much focused on the patient and admittedly so that is the person that has the most immediate needs. But I think there's a real opportunity to extend efforts at prevention and early detection by identifying the at-risk family members and allowing them the opportunity to access care that mitigates their cancer risks and hopefully will improve survival outcomes in so doing. So, I think the opportunities for families here to understand risks of germline testing is a really important one to underscore from these recommendations. Dr. Mark Robson: Just to expand a little bit on what Dr. Bedrosian was saying, I think this is a very important place for collaboration between the oncology community and the clinical cancer genetics providers because the oncologist is pretty occupied taking care of all of their cancer patients, and the approach to people who are unaffected is a little bit different. People who are unaffected perhaps do need a little bit more pretest counseling to understand the pros and cons of choosing to be tested for the familial mutation. And certainly that idea of family expansion is something that's well known to clinical cancer genetics providers and that's really very much something that they can help the primary oncologists do. Brittany Harvey: Absolutely, these recommendations have impacts beyond just the individual patient, but also for their families as well.  So then, finally, Dr. Robson, what are the outstanding questions regarding germline testing in breast cancer? Dr. Mark Robson: Oh, there are so many. Where should I start? I think over the years we've become, as a community, pretty comfortable managing individuals who have BRCA1 or BRCA2 mutations. There are certainly some questions left, but there's a lot of familiarity with that. I think the challenges expand into these what we call moderate penetrance genes and how to guide people with alterations in those genes. Because except for PALB2, which is relatively uncommon, many of the other genes don't really have the same implications for therapy because it's not clear that they confer PARP sensitivity. It's not at all clear that they have high risks of contralateral breast cancer. And even in the unaffected setting, we know that there's a wide distribution of risk for people who carry these alterations. And some individuals with these alterations probably are not at increased risk at all because they have protective factors. So the management of breast cancer susceptibility genes beyond BRCA1 and BRCA2 is still very much in evolution. They can't be handled exactly the same way as a woman with a BRCA carrier.   And then, of course, this issue of how much should we test and what do we do with some of the alterations that we find, if you will, out of context, what are the implications for that and what's the most appropriate management? Those still remain very much open questions. So I think there's still plenty of work to do. Dr. Isabelle Bedrosian: Yeah, I agree. I think one of the enormous challenges has been the disconnect between how rapidly our technology has advanced and can sequence alterations, and our ability to really understand the biologic and clinical implications, which really is a time-dependent issue. We need to see over time how patients do for us to understand the implications of some of these germline findings. So that disconnect is a very difficult one to bridge, particularly, I think, for surgical oncologists because they are oftentimes referred patients who don't have a cancer history, necessarily, or have a distant history, and really the concern is “I'm at risk and I would like to reduce my risk.” And it becomes very difficult to counsel patients as to the benefits of risk reduction when we don't have such a great handle on the degree to which they are actually at risk. So that really is a significant gap, I think, for surgeons in particular to have to contend with. Brittany Harvey: Definitely. We'll look forward to answering some of those questions as we learn more and get more data to address those gaps.  So I want to thank you both so much for your work to develop this framework for genetic testing in breast cancer, and thank you so much for your time today, Dr. Robson and Dr. Bedrosian. Dr. Isabelle Bedrosian: Thank you, Brittany.  Dr. Mark Robson: Thank you for having us. Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Dr. Rohan Garje reviews the latest rapid recommendation update for the ASCO guideline on systemic therapy in men with metastatic castration-resistant prostate cancer (mCRPC). He reviews what prompted the guideline update and the latest recommendation from the expert panel. Dr. Garje also discusses future updates to the guideline that are currently underway, and outstanding questions regarding systemic therapy for mCRPC. Read the latest update, “Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Rapid Recommendation Update” at www.asco.org/genitourinary-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02128  Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Rohan Garje from Miami Cancer Institute Baptist Health South Florida, lead author on “Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Rapid Recommendation Update.  Thank you for being here today, Dr. Garje. Dr. Rohan Garje: Thank you so much for having me, Brittany. Brittany Harvey: And then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Garje, who has joined us on this episode today, are available online with the publication of the update in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to dive into the content of this rapid update, first, Dr. Garje, what prompted this rapid update to the guideline on Systemic Therapy for Metastatic Castration Resistant Prostate Cancer? Dr. Rohan Garje: So, last year, when we did a rapid update on ASCO prostate cancer guidelines, we recommended the addition of 177Lutetium-PSMA-617, also called as PLUVICTO, as a treatment choice for patients who have PSMA-positive metastatic castrate-resistant prostate cancer. After that approval, the primary imaging modality at the time of this initial drug approval was based on gallium-68, which was used in that clinical trial, which was VISION. Since then, we have access to a couple of new radiotracers, one of them being piflufolastat, also called as PYLARIFY, and the newer one called flotuflastat F-18, which is also called as POSLUMA, as additional imaging agents to detect PSMA-positive lesions. So, our expert panel group, along with my co-chairs, we thought to add these additional choices for patient selection because this provides the treating physicians additional options because there really are nuances involved in these imaging agents. So this helps broaden the access to  177Lutetium-PSMA-617 for patients. Brittany Harvey: Excellent. I appreciate you providing that background that the panel was reviewing.   So then, based on this updated information, what is the updated recommendation from the expert panel? Dr. Rohan Garje: So, for the new recommendation, the guideline expert panel recommends use of one of these three radio tracers, that is Ga-68PSMA-11, or piflufolastat F-18, or flotufolastat F-18 as one of the radiotracer choices to screen for PSMA-positive lesions on a PSMA scan, and potentially select the patients for PSMA 177lutetium. This way, we can use one of these three agents rather than previously recommended, as per FDA approval of gallium 68. Now, the reason behind these additional agents, as I was just alluding in my initial comment, is each institution may have access to one of these agents. For example, if a patient had a testing done by piflofolastat or flotufolastat, if they are PSMA-positive, it has shown PSMA-positive lesions as per VISION criteria, we do not suggest the patients to undergo gallium-68 assisted imaging again to have selection for PSMA lutetium therapy. This is unnecessary imaging. We have evidence now, based on the studies which were done with PYLARIFY, which is the piflofolastat, or the flotufolastat, which is POSLUMA, that they are equally good in detecting PSMA-positive lesions. This way we can avoid additional imagings for patients who are being screened for lutetium therapy. Brittany Harvey: Understood. Thank you for reviewing the expansion of this recommendation to avoid additional or unnecessary screening.  So then, Dr. Garje, the article mentions complete updates to the metastatic castration-resistant prostate cancer guideline are underway. At a high level, could you review what new evidence the panel will look at to update their evidence-based recommendations? Dr. Rohan Garje: There have been a lot of developments in the last year, at least, in the treatment strategies for patients with metastatic castration-resistant prostate cancer. Earlier this year, we have seen three big updates about the first-line metastatic CRPC setting, where the combination of PARP inhibitors and androgen receptor pathway inhibitors were tested. For example, in the TALAPRO-2 study talazoparib and enzalutamide, and in the MAGNITUDE study, it was niraparib along with abiraterone. And in the PROpel study, the combination of olaparib and abiraterone was studied. Now, all these combinations have recently received FDA approval with specific nuances with regards to folks who have biomarker positive disease, specifically BRCA1 and BRCA2 mutations. So it is very important to refine this information so that it is utilized by practicing oncologists so that it is widely adapted in their day to day practice. Now, in addition, we also are focusing on addressing the need for utilizing biomarkers. The biggest thing for us to offer a biomarker driven therapy is to do biomarker testing. So we are focusing on making sure patients with advanced prostate cancer get biomarker testing so that we can identify who are the patients who get selected. So this particular guideline update is addressing those needs.  And then most recently at the recent ESMO meeting, we also noted the positive data from a study called PSMAfore, which evaluated PSMA 177lutetium prior to chemotherapy. This study showed positive data based on progression free survival benefit. So we will review additional data from that and see if a guideline update can be done based on this. So it is very exciting. Now, obviously, we are also waiting on survival data on all the studies. So we are closely monitoring all the updates on these studies so that we can provide more rational guidance based on not only progression-free survival benefit in a specific cohort and also to see if it helps with overall survival improvement. Brittany Harvey: Absolutely. We'll look forward to the panel's review of this evidence and then future updates to this full guideline.  So then, finally, Dr. Garje, you've alluded to awaiting some data. So could you expand on what are some of the outstanding questions regarding systemic therapy for metastatic castration-resistant prostate cancer? Dr. Rohan Garje: I would put that in two boxes. Number one, sequencing. So we are excited that we have a broad spectrum of options; androgen receptor pathway inhibitors, chemotherapy options, radium-223. We have lutetium based options and then biomarker selected patients with PARP inhibitor combinations and select patients with benefit for checkpoint inhibitors. Now, the biggest question we need to answer is how to sequence them, which drug or which combination strategy is ideal for one particular patient. Now, obviously, when we do not have clinical trials which have addressed sequencing, we as an expert panel would want to come up with some mechanism of consensus to identify what treatment sequence would work best for patients. So that is an important question this guideline panel wants to address where we can give some generic information as a consensus, based on the experience of the panel to give guidance for practicing physicians the best sequencing.  Now, second thing, very equally important, is biomarkers. This particular guideline update is also focusing on making sure biomarker testing is universal. There has been a lot of evidence that biomarker testing happens very late in the course of the disease, which precludes a lot of patients from these combination strategies. So this particular guideline also is focusing on what biomarkers to be tested and at what time frame, so that they can be optimally utilized for the patient treatment so that the patients will have the best cancer outcomes. Brittany Harvey: Definitely, those are important questions for personalized care for people with prostate cancer.   I want to thank you so much for your work on this rapid update and your ongoing work on the updates to the full guideline, Dr. Garje, and thank you for your time today. Dr. Rohan Garje: Sure, thank you so much. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline update, go to www.asco.org/genitourinary-cancer-guidelines.  You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  

Dr. Greg Kalemkerian joins us on the ASCO Guideline Podcast to discuss the newest ASCO – Ontario Health (Cancer Care Ontario) Guideline on systemic therapy for small-cell lung cancer (SCLC). He reviews the evidence-based recommendations from the panel, including guidance on systemic therapy options for resected, limited-stage, extensive-stage, and relapsed SCLC, and NSCLC with an EGFR mutation that has transformed to SCLC, recommendations for older adults with poor performance status, the role of biomarkers, and the use of myeloid supportive agents. Dr. Kalemkerian also highlights future research for systemic therapy options for SCLC, and the impact of guidelines on both clinicians and patients with SCLC. Read the full guideline, “Systemic Therapy for SCLC: ASCO-OH (CCO) Guideline” at www.asco.org/thoracic-cancer-guidelines." TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01435  Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.   My name is Brittany Harvey, and today I'm interviewing Dr. Greg Kalemkerian from the University of Michigan, co-chair on “Systemic Therapy for SCLC: American Society of Clinical Oncology – Ontario Health Guideline.” Thank you for being here, Dr. Kalemkerian.  Dr. Greg Kalemkerian: Thank you. Brittany Harvey: Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Kalemkerian, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to move into what we're here today to discuss, Dr. Kalemkerian, can you provide an overview of both the scope and the purpose of this guideline? Dr. Greg Kalemkerian: So, the guideline is meant to update the systemic treatment for small-cell lung cancer. There have been several changes in the last couple of years. For the first time in quite a few decades, we actually have some newer drugs that have demonstrated benefits in this disease. So we're really focusing on the systemic therapy. And ASCO does endorse the ASTRO guidelines for the radiotherapy involved in patients with small-cell lung cancer. Brittany Harvey: Great. That's great to hear that there's new systemic therapy options for patients with small-cell lung cancer.  So then I'd like to review the key recommendations of this guideline. This guideline reviews eight clinical questions in total, so we can go through the key points of the recommendations for each question. So let's start with what is recommended for adjuvant systemic therapy in patients with resected small-cell lung cancer? Dr. Greg Kalemkerian: So, to start with, only fewer than 5% of people have what would be considered resectable small-cell lung cancer, and that's stage I small-cell lung cancer. So tumors less than 5 cm in size without any lymph node involvement, either hilar or mediastinal lymph node involvement. So purely the very early stages, which are rare in small-cell. And if patients undergo surgical resection for such tumors, the recommendation afterward is to provide adjuvant chemotherapy with four cycles of either cis-or carboplatin plus etoposide in order to try and improve longer-term survival for those patients.  The other part of the recommendation is we do recommend that treatment be started within eight weeks of surgery. There is little data on timing in small-cell lung cancer, but that's derived from extrapolating from non-small cell lung cancer as well. Brittany Harvey: Understood. I appreciate you reviewing those recommendations for resectable small-cell lung cancer.  So then, moving along, what does the panel recommend for patients with limited-stage small-cell lung cancer? Dr. Greg Kalemkerian: So, the treatment with limited-stage small cell lung cancer unfortunately has not changed in quite some time. We recommend that patients receive four cycles of either cisplatinum or carboplatin and etoposide concurrently with radiotherapy. Preferably the radiotherapy should be given early and concurrently with the chemotherapy, though we do not recommend that people wait for the radiation to get started in order to start the chemotherapy. So we do recommend that the chemotherapy get started as soon as possible and then the radiation can be added in on the second cycle of chemotherapy. Brittany Harvey: Then to follow that up, what is recommended for patients with extensive stage small-cell lung cancer? Dr. Greg Kalemkerian: So, extensive stage small-cell lung cancer now is probably the most straightforward of the portions of this. Based on the data from two trials thus far, the IMpower 133 trial and the CASPIAN trial, we now recommend chemotherapy with immunotherapy. The chemotherapy should be cisplatinor carboplatin plus etoposide along with concurrently either atezolizumab or durvalumab as the immunotherapy for four cycles of the combined chemo-immunotherapy followed by maintenance with the immunotherapy drug of choice. With regard to the choice of either cisplatin or carboplatin, meta-analysis has demonstrated that there is no significant difference between the two and our belief is that carboplatin is likely the more reasonable drug in the palliative treatment situation based on its better non-hematologic toxicities. Brittany Harvey: Appreciate you sharing those recommendations and some of the rationale behind those.  So then moving along, what options are available for patients with relapsed small-cell lung cancer? Dr. Greg Kalemkerian: So relapsed small-cell lung cancer gets a little more potentially complicated. One of the main drivers of outcome in patients with relapsed small cell lung cancer is the time since they completed their initial chemotherapy. Patients who have had a longer time since chemotherapy do better and have better responses to subsequent therapy. For patients who relapse with a short interval within 90 days or three months of completion of prior chemotherapy, our recommendation is that they be treated with single-agent chemotherapy. There are two drugs that are currently FDA approved for use in relapsed small cell lung cancer, topotecan and lurbinectedin, and either one of those is the preferred agent as a single-agent treatment in this scenario. For people with a longer chemotherapy-free interval, so beyond the 90 days or three months, one could either use combination chemotherapy, so reinitiation or re-induction with the regimen such as carboplatin and etoposide, or one could use single-agent chemotherapy with the preferred agents being topotecan or lurbinectedin again. The use of combination chemotherapy has been shown to improve response rates in this situation over topotecan alone. However, we have not been able to demonstrate that there is a significant improvement in overall survival. So one has to look at the individual patient and make some judgment on whether you think that the added potential toxicity of combination chemotherapy is beneficial for that individual.  For people who have progression of disease while they are on maintenance therapy with immunotherapy for extensive stage small-cell lung cancer, we do not recommend continuation of the immunotherapy. So if people progress while they're on the immunotherapy, even if they're nine months out on that, then treatment with second-line chemotherapy, either with the combination agent or with single agents, would be what we would recommend, and not continuing the immunotherapy. If patients had previously been treated for limited-stage small-cell lung cancer where immunotherapy is not part of the initial treatment at this time, and they relapse, say, six months or nine months out from their initial chemotherapy and radiation therapy treatment, then it would be reasonable to perhaps initiate carboplatin etoposide and one of the immunotherapy agents as appropriate treatment, because that patient is immunotherapy naive.  However, the single-agent immunotherapy does not have a role in the treatment of patients with relapsed small-cell lung cancer.  Brittany Harvey: Understood. It sounds like some of the treatment options are individualized to the specific patient then.  So the next question also addresses specific groups of patients. So what did the panel recommend for older adults with small cell lung cancer or for those with poor performance status? Dr. Greg Kalemkerian: Approximately half of people who have small-cell lung cancer are over the age of 70 years old, so it is a disease of older smokers. Many of these people have comorbidities that can limit our ability to use standard treatments. Many of these individuals also have poor performance status because the disease is an aggressive disease that causes a lot of problems for people. So the issue of older individuals and people of poor performance status is something that we run into on a regular basis in treating people with small-cell lung cancer.  For patients with limited-stage small-cell lung cancer who are older and have a performance status of 0 to 2, it is very reasonable to utilize standard treatment with standard chemo and radiotherapy with curative intent. For people with limited-stage small-cell lung cancer who have a performance status of 3 or 4, and this would include people who might be in an ICU with an obstructive airway, then it is reasonable to initiate chemotherapy in order to try and shrink the cancer down and improve their situation. Small-cell lung cancer is a disease that is very sensitive to chemotherapy initial treatment, so many of these people will have shrinkage of tumor and improvement of their symptoms. If the poor performance status is due to the small-cell lung cancer, it has potential to get better. So we do recommend for people at limited-stage small-cell lung cancer and a poor performance status that is felt to be due to the disease, the cancer, then it is reasonable to initiate treatment with chemotherapy. And depending on the person's response and recovery and improvement in their performance status, then one could add radiotherapy later on or do it sequentially with the definitive radiotherapy for the limited-stage small-cell lung cancer.  For older individuals with extensive stage small cell lung cancer who have a performance status of 0-2, it is very reasonable to utilize the standard chemotherapy and immunotherapy as we outlined previously in treating that. For individuals who have a poorer performance status, so performance status 3 or 4, one really needs to individualize the situation. If the poor performance status is due to the cancer, then again, it would be reasonable to attempt chemotherapy in an effort to try and shrink the cancer. There is no data on the use of chemo plus immunotherapy in this patient population. But the use of standard chemotherapy, obviously, in the older individuals preferring carboplatin over cisplatinum with etoposide would be a reasonable option, taking into account abnormalities in organ function that may require dose adjustments or reductions. Because small-cell lung cancer is a disease that is quite sensitive and responds well to  chemotherapy, then one can individualize in those situations for patients with poor performance status to see if they can improve their overall situation and have some period of time of optimized quality of life. Clearly, it is a very individualized decision-making whether or not to treat these patients. That requires clearly the patient's input as well, as a primary driver of what is done.  Brittany Harvey: Absolutely. That nuance is helpful for patient-clinician shared decision-making, depending on the factors that you mentioned.  So then, switching to the next topic that the expert panel addressed, what does the panel recommend for patients with non-small cell lung cancer with an EGFR mutation that has then transformed to small-cell lung cancer?  Dr. Greg Kalemkerian: The EGFR mutant non-small cell lung cancer transformation to small-cell lung cancer is relatively rare. I think in the real world, this probably is occurring in 2%-3% of people with EGFR mutant non-small cell lung cancer, but we do see it. Now, these patients are initially being treated with EGFR inhibitor therapy for their mutant non-small cell lung cancer and then they develop a more aggressive progression of disease. It is important to note that when people progress in that situation, it is important to get a biopsy in order to see whether or not transformation has occurred and whether or not there are any other new driver mutations that might be targetable. If the patient has a small cell lung cancer transformation, then the recommendation is to treat them as we treat patients with small cell lung cancer with chemotherapy consisting of platinum and etoposide for four to six cycles, as we usually do. It does not appear that there is a role for immunotherapy in this situation, though we clearly have a paucity of data on these patients. So we do not yet have any trials that have looked at the management of this population. We do have several series that have presented these individuals and what their outcomes are with treatment. And their outcomes are very similar to people with de novo small-cell lung cancer. So not a very good situation, but we do recommend that they be treated with standard chemotherapy, platinum plus etoposide.  Another question that arises is do you continue with the targeted therapy with the EGFR inhibitor. And the honest answer is we don't know. We don't have data on that. We do know from case reports, the series, and from personal experiences, that some people, in fact, I think many people, if not most of these individuals, have a mix of both EGFR mutant adenocarcinoma and small-cell lung cancer at the time that they transform. So not every tumor in their body is transforming, so that EGFR mutant tumor is still present in their body. So even though the small-cell lung cancer component, because it's progressing, is clearly not responsive to the EGFR inhibitor any longer, the adenocarcinoma component most likely is still sensitive to the EGFR inhibitor. So it is not unreasonable to continue with the EGFR-targeted therapy along with the small cell lung cancer-directed chemotherapy. Even though we don't have any strong data supporting one way or the other. Brittany Harvey: I appreciate that guidance, even with the dearth of data in this relatively rare scenario.  So then we've talked a bit about individualized treatment, and often in that conversation, biomarkers come up. So what does the guideline say regarding the role of biomarkers for patients with small-cell lung cancer? Dr. Greg Kalemkerian: This is pretty straightforward. Thus far, in people with de novo small-cell lung cancer - so we're not talking about the transformed patients from EGFR mutant, we're talking about people who present with small-cell lung cancer - we have no evidence that molecular diagnostic testing would help guide treatment or improve patient outcomes at this time. So we do not support obtaining molecular diagnostic testing for the routine care of patients with de novo small-cell lung cancer. I would love to talk for the next half hour about what's coming down the pipeline in small-cell lung cancer with regard to identifying subsets of patients and trying to identify the vulnerabilities within those subsets of patients that may lead to better-targeted therapy based on molecular diagnostics, but in the current environment, there is no role for molecular diagnostics.  Brittany Harvey: Understood. We'll look for that in future guideline updates instead, then.  So then the last clinical question that the guideline addressed - what myeloid supportive options may be offered for patients with small cell lung cancer? Dr. Greg Kalemkerian: So this has to be couched initially with whether or not one thinks that myeloid suppressive agents are necessary in the treatment of patients with small-cell lung cancer. So in extensive-stage disease with the use of chemotherapy, say, carboplatin and etoposide, the majority of patients likely don't require myeloid supportive agents. However, if one believes that the patient, because of their own individual characteristics, or in a patient who has already developed myelosuppressive problems, then one could either utilize trilaciclib, which was FDA-approved a couple of years ago and was shown to improve the blood counts in people with small cell lung cancer treatment, or one could utilize G-CSF. So either trilaciclib or G-CSF could be utilized to support the patient's bone marrow. In patients who have limited-stage disease, for many years, we have recommended against using G-CSF in combination with chemotherapy and radiotherapy due to concerns for increasing toxicities, including thrombocytopenia. Recent data suggests that this may not necessarily be a hard and fast rule and that if one feels that the patient requires or would benefit from some myeloid support, then G-CSF may be offered to patients undergoing chemotherapy and radiotherapy. I do not think that the standard patient that we see who is starting on treatment requires such support, but some subsets of patients or patients who have already proven that they're getting into trouble with their counts, G-CSF could be utilized in this situation.  So with regard to this recommendation, overall, it's that for patients with extensive stage disease, trilaciclib or G-CSF could be used if one feels they're necessary. And for limited-stage small cell lung cancer, G-CSF could be utilized if you feel it's necessary.  Brittany Harvey: Thank you for reviewing those options and all of these recommendations. The panel was certainly hard at work reviewing the evidence and developing these recommendations.  In your view, Dr. Kalemkerian, what is the importance of this guideline for both clinicians and for patients with small-cell lung cancer? Dr. Greg Kalemkerian: Well, I think it's not just small-cell lung cancer, but when you look at guidelines overall, I think they are very important to have evidence-based guidelines as well as expert consensus-based guidelines because, quite honestly, the field is moving very quickly, the field of oncology. Now, small-cell lung cancer hasn't moved as quickly as we would like compared to other aspects of oncology, but it's very hard for the clinician who is trying to care for patients with lots of different tumor types to keep up with all of the flood of literature, the flood of new FDA approvals that are coming out every week. So I do think that utilizing the guidelines is important in order to see what the standard approach might be.  Now, I also have to couch that with saying that guidelines are never enough. We have to look at the individual sitting across the exam table from us. We have to personalize the treatment to that individual. I will say that in my own practice, there are very few people who walk in the door who are the optimal patient, who are the person who has outstanding physical function. And in lung cancer, that's even more true because patients tend to be older smokers, and they have a lot of comorbidities and other things that you have to personalize therapy towards in them. So the guidelines are a very good starting point in order to know what the optimal treatment might be and then to adjust that accordingly to the person sitting in the room with you.  Brittany Harvey: Definitely, we hope guidelines are a place that clinicians can turn to for evidence-based recommendations and succinct recommendations, but individualized patient and clinician decision-making is paramount to each of our guidelines.   So then, Dr. Kalemkerian, we've already talked about this a little bit when you mentioned molecular testing advances down the road. So maybe I'll ask what are the most pressing, unanswered questions about systemic therapy for small-cell lung cancer? Dr. Greg Kalemkerian: Yeah, so one of them I'll come back to limited-stage small-cell lung cancer. So, obviously, in the extensive stage, we've now incorporated immunotherapy. And yet I didn't talk about immunotherapy in the limited-stage setting, and neither do the guidelines because thus far we don't have any data on the use of immunotherapy in limited-stage small-cell lung cancer. We are expecting data to be coming down the line within the next year hopefully, definitely, within the next two years, because a number of trials that are either ongoing or have recently been completed looking at incorporating immune checkpoint inhibitors into the treatment of limited-stage small-cell either concurrently with chemoradiation or as consolidation after chemoradiotherapy. So that data is anxiously anticipated. And we're hoping that that might move the needle a little bit further in limited-stage small-cell lung cancer and hopefully improve that long-term survival or cure rate that we see in that disease.  Other avenues coming down the line – many of us have made a career of doing negative trials in small-cell lung cancer, myself included, and a lot of that has had to do with trying to target therapies to specific molecular abnormalities, and none of those have really panned out thus far. But coming down the line, as we start to molecularly subtype lung cancers, and the best molecular subtyping that we have thus far is not based on mutational analysis, but more based on expression, gene expression analysis, expression of particular transcriptional factors within different subsets of small cell lung cancer, we're now starting to see some vulnerabilities. So one of these subsets in the small cell lung cancer array has a high expression of DLL3, which is part of the Notch pathway, and we can target that. We haven't figured out how to target it as far as its activity goes, but we can target it as a homing device in order to get either drugs delivered by use of antibody-drug conjugates, or to use a BiTE—a T-cell engaging type molecule—that targets both DLL3and T cells in order to try and amplify that immune response in small cell lung cancers. So recently a compound called tarlatamab had data presented at ASCO and also published in JCO that shows some response, about 20-25% response, in people with relapse small cell lung cancer. These were heavily pretreated patients. So that's moving the needle a bit in favor of a specific targeted therapy. And we're hoping that will lead to further avenues to look at the vulnerabilities of different subsets and be able to develop newer targeted treatments for these diseases, trying to amplify that immunotherapy response as well.  Small cell lung cancer is a little bit of an outlier in that it does not respond well to immunotherapy compared to other tumors. Not what we expected based on the high tumor mutational burden and the aggressiveness of the disease. But we know that it does not express a lot of PD-L1. We know that it doesn't have MHC class I molecules. So there are a number of reasons why it doesn't respond, and there is work going on to try and amplify that immune response as well. So I think those three things: the use of immunotherapy in limited-stage, the development of targeted therapies based on subsets, and trying to amplify that immune response are the things that I look forward to in the next few years. Brittany Harvey: That's great to hear. We'll await the data to provide answers to those outstanding questions.  So I want to thank you so much for your work to develop these evidence-based guidelines, and thank you for sharing your perspective with me today, Dr. Kalemkerian.  Dr. Greg Kalemkerian: Thank you, Brittany. And thanks to ASCO for getting these guidelines together and getting the outstanding group of people we had to work on it and getting them out in a timely manner so they can help our patients. Brittany Harvey: And also, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines.  You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Eric Singer highlights the recent rapid recommendation update from ASCO on the management of metastatic renal cell cancer (ccRCC), based on the review of evidence from the phase III COSMIC 313 trial. Dr. Singer reviews the discussion from the Expert Panel and emphasizes clinicians should continue to follow the previously issued recommendations for the management of metastatic ccRCC. He also mentions future directions, ongoing clinical trials, and outstanding questions for these evidence-based guidelines. Read the latest update, “Management of Metastatic Renal Clear Cell Cancer: ASCO Guideline Rapid Recommendation Update” at www.asco.org/genitourinary-cancer-guidelines.  

Dr. Jaydira Del Rivero and Dr. Kimberly Perez discuss the latest ASCO guideline featuring evidence-based recommendations on systemic therapy for well-differentiated grade 1 to grade 3 metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). They discuss the recommendations, insights from the guideline expert panel, impact for clinicians and patients, and outstanding questions in the field. Read the full guideline update, "Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline” at www.asco.org/gastrointestinal-cancer-guidelines.

Dr. Michael Atkins and Dr. Vernon Sondak highlight the latest updates to the systemic therapy for melanoma recommendations in this newest guideline. The discussion covers neoadjuvant and adjuvant therapy for resected cutaneous melanoma, options for unresectable and/or metastatic cutaneous melanoma, and therapies for noncutaneous melanoma. They review the importance of this guideline and the most pressing outstanding questions to help inform better treatment strategies for patients with melanoma. Read the full guideline update, "Systemic Therapy for Melanoma: ASCO Guideline Update" at www.asco.org/melanoma-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/melanoma-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO. 23.01136 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Michael Atkins from Georgetown Lombardi Comprehensive Cancer Center, and Dr. Vernon Sondak from H. Lee Moffitt Cancer Center and Research Institute, authors on “Systemic Therapy for Melanoma: ASCO Guideline Update.”   Thank you for being here today, Dr. Atkins and Dr. Sondak. Dr. Vernon Sondak: Happy to be here. Dr. Michael Atkins: Yeah, it's a pleasure. Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Sondak and Dr. Atkins, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content here, Dr. Sondak, what prompted this full update to the Systemic Therapy for Melanoma Guideline, which was initially published in 2018? Dr. Vernon Sondak: Well, the last 10 years or so have seen enormous advances in the management of metastatic melanoma and localized melanoma with systemic therapy, and the last few years haven't slowed up at all. So since 2018, we've seen new approvals, we've seen key pivotal trials that have shown some amazing results that we'll talk about, and all of these things together weighed into the decision to update the systemic therapy guidelines. Brittany Harvey: Great. Thank you for that background on what prompted the update. So then, this guideline provides updated recommendations across four clinical questions. I'd like to review the key updated recommendations for our listeners. So first, Dr. Sondak, what has changed in the updated recommendations regarding neoadjuvant therapy for adults with resectable cutaneous melanoma? Dr. Vernon Sondak: Neoadjuvant therapy is one of the most rapidly evolving and exciting parts of the management of melanoma with systemic therapy. The updated guidelines now include neoadjuvant pembrolizumab as a new recommendation for patients with resectable stage IIIB to IV cutaneous melanoma. This is based on the SWOG S1801 clinical trial, which was a very simple and yet incredibly influential clinical trial. It took patients with resectable metastatic melanoma, either metastatic to the lymph nodes or beyond, as long as it could be removed surgically, and randomized all of the patients to either get surgery, followed by a year of adjuvant pembrolizumab, which is very standard, or the same exact surgery and the same total amount of pembrolizumab, but with three of the doses given before surgery. So that simplicity, that ability to just compare the effect of neoadjuvant or preoperative pembrolizumab to entirely postoperative adjuvant pembrolizumab, made this trial a really pure assessment of the value of neoadjuvant pembrolizumab.  Impressively, this study showed a significant improvement in event-free survival for patients who got those three doses of pembrolizumab upfront. What's event-free survival? That includes relapse-free survival, but also the kinds of events that you can see happening with neoadjuvant therapy, such as progression of the disease prior to surgery that makes the patient unresectable. And the bottom line is that there was really the same number of issues with neoadjuvant pembrolizumab as with surgery, followed by adjuvant therapy, but there were many fewer recurrences among the patients who got neoadjuvant pembrolizumab. So that's why this was put into the guidelines. Brittany Harvey: Excellent. I appreciate you reviewing the evidence behind those recommendations and what's new for neoadjuvant therapy. So then, Dr. Atkins, moving into adjuvant therapy, for patients with resected cutaneous melanoma, what is new in the recommendations regarding adjuvant systemic therapy options? Dr. Michael Atkins: Sure. In the prior version, adjuvant therapy was recommended for patients with stage IIIB, IIIC, and for some patients with stage IV resected to NED. And those were based on studies with adjuvant pembrolizumab, adjuvant ipilimumab, and adjuvant nivolumab compared to ipilimumab. But what's happened since then is some really important adjuvant studies have been carried out in patients with stage IIB, IIC, and IIIA disease who are at slightly lower risk of recurrence, but still have substantial risk of recurrence, and make up a large percentage of the patients who eventually develop stage IV disease. And in these studies, one with pembrolizumab compared to placebo, there was about a 40% to 50% reduction in relapse-free survival observed, leading to the FDA approval of pembrolizumab in that setting. And then recently we saw the results of a similar study involving nivolumab that showed maybe even a slightly better reduction in the risk of relapse in that same patient population. Ultimately, this will lead to FDA approval as well. And we felt it was important to put in the guidelines the results of these studies so that people can have informed discussions with their patients about whether they want to receive this therapy going forward. It's important to point out that we don't have good data yet on overall survival. We just have data on relapse-free survival. So we don't, for sure, know that treating patients early, rather than waiting until a subset of them relapse and treating those late leads to an improved overall survival. That's an important discussion to have with patients to provide them with this option. In addition, we saw the results of the IMMUNED trial, which looked at nivo-ipi or nivo monotherapy versus placebo or observation in patients with stage IV disease that had been completely resected. And we saw dramatic improvement for the nivo-ipi combination compared to nivo or observation in those patients with stage IV NED. And we felt that, therefore, this was also an important patient population where we should offer guidance Brittany Harvey: Absolutely. That shared patient-clinician decision-making is paramount. And then you've both reviewed the options for resected cutaneous melanoma. But Dr. Atkins, what is new regarding systemic therapy options for patients with unresectable and/or metastatic cutaneous melanoma? Dr. Michael Atkins: Yes. For patients with unresectable metastatic cutaneous melanoma, there was a new drug combination that was approved combining nivolumab with relatlimab, which is an anti-lag-3 antibody that showed benefit compared to nivolumab monotherapy across almost all subgroups. In particular, the benefit was similar regardless of BRAF mutation status, regardless of elevated LDH, and regardless of patient stage. That led to FDA approval, and this is now an available treatment option, which is associated with less toxicity and similar efficacy to the standard of care nivo-ipi. In addition, although nivolumab-ipilimumab had been approved and was in our last recommendation for patients with BRAF-mutated melanoma, we didn't really know whether they should receive BRAF/MEK inhibitors, which were also approved, versus nivolumab-ipilimumab as their initial therapy. And so in the past few years, we saw the results of the DREAMseq trial, which randomized patients with BRAF-mutant melanoma to either nivolumab-ipilimumab, followed by BRAF-MEK inhibitor progression, versus the converse sequence. And we saw that at two years, the starting with a nivolumab-ipilimumab had a 20% improvement in two-year overall survival. This prompted the NCCN to change their guidelines to list nivolumab-ipilimumab or other immunotherapies as a preferred frontline therapy. And we thought that this data was important enough and somewhat validated by a randomized phase II trial, the SECOMBIT, which had a lot smaller numbers to encourage us to change the guidelines. Other minor things that we did were to take T-VEC and no longer recommend that as an option for patients with BRAF-wild type disease who had progressed on anti-PD-1 therapy and that ipilimumab and ipilimumab-containing regimens were no longer recommended for patients with BRAF-mutated disease after progression on other immunotherapy. We felt that those patients probably are best served to get BRAF/MEK inhibitors. Brittany Harvey: It's good to have clarity on some of those sequencing options for patients and also on which treatments are working better for patients in these subpopulations. So then, Dr. Sondak, the last set of recommendations. What has changed regarding options available for patients with noncutaneous melanoma?  Dr. Vernon Sondak: There's no question that our patients with noncutaneous melanomas, such as uveal melanoma or mucosal melanoma, have many fewer options and haven't benefited as much from the revolution in treatment that we've seen with our cutaneous melanoma patients, but there have been definite improvements and progress. The full update incorporates new recommendations for uveal melanoma that were published in 2022 as a rapid recommendation update, specifically a new drug called tebentafusp, which is restricted to HLA-A*02:01-positive patients. It's HLA-type restricted, but it is active in patients with metastatic uveal melanoma. And so the new guideline is that previously untreated patients with metastatic uveal melanoma who are HLA-A*02:01-positive should be offered tebentafusp as a treatment option. So that means all our patients with metastatic uveal melanoma should get HLA typed, so they know if they're a person who is eligible for this treatment and it should be considered early on in the treatment paradigm. Brittany Harvey: Well, thank you both for reviewing the updates to these evidence-based recommendations. There's a lot that's new in this field.  So then, Dr. Atkins, what is the importance of this guideline? And in your view, how will it impact clinicians, and also how will these guideline recommendations affect patients? Dr. Michael Atkins: Sure. Well, we have new treatments such as relatlimab and tebentafusp that are available and should be offered to appropriate patients, and new data on how to optimally apply previously approved treatments such as nivolumab-ipilimumab in patients with BRAF-mutated or resected stage IV melanoma, pembrolizumab use in the neoadjuvant setting, and nivo and pembro in earlier stage disease. And with this new information out there and included in the guidelines, hopefully, this will allow practitioners to give the best possible treatments to their patients, and patients to receive treatments which will improve their outcomes. Brittany Harvey: Absolutely. It's great to have new data to better inform treatment options for patients with melanoma.   So then, finally, Dr. Sondak, what are some of the most pressing outstanding questions regarding systemic therapy for patients with melanoma that may need to be addressed in a future guideline update? Dr. Vernon Sondak: Every advance brings up new questions. In neoadjuvant therapy, we have single-agent pembrolizumab with strong data from the randomized trial I spoke about. We anticipate more data about combination immunotherapy, specifically low-dose ipilimumab and nivolumab in the setting of neoadjuvant therapy. There are some trials going on with that. The best neoadjuvant treatment, the best sequence, how long should we treat, and even should we change the surgery based on the results of neoadjuvant therapy, not just the surgery, but the postoperative adjuvant therapy? Those are all questions that are key in the neoadjuvant side.  In the adjuvant therapy side, we have much more clarity now about BRAF versus immunotherapy in unresectable disease, but we still don't know always what's the best adjuvant therapy for our BRAF-mutated patients. That's an area we hope will eventually get more clarity, but I think it's going to take a while for that.   And finally, we'll learn more about the optimum sequencing of patients with metastatic disease, but especially for the patients who've already failed adjuvant or neoadjuvant therapy. So much of the data that Dr. Atkins and I talked about in metastatic disease, whether cutaneous or noncutaneous, involved previously untreated patients. But so many of our metastatic disease patients today have come to us already with some form of treatment in the adjuvant or neoadjuvant setting. We still have a lot of work to do to define the best treatment strategies for those patients.  Brittany Harvey: Definitely. Well, we'll look forward to learning more as new data comes out and as some of that research comes to fruition. So I want to thank you so much for your work to update this guideline and thank you for your time today, Dr. Sondak and Dr. Atkins. Dr. Vernon Sondak: Thank you. Dr. Michael Atkins: You're very welcome. Thanks a lot. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/melanoma-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Julia Rowland shares the newest evidence-based recommendations from SIO and ASCO on integrative therapies for managing anxiety and depression symptoms in adults with cancer. Listen in to hear recommended options, such as acupuncture, aromatherapy, hypnosis, mindfulness, music therapy, relaxation, reflexology, Tai Chi and/or Qigong, and yoga. Dr. Rowland also discusses therapies the panel investigated but found insufficient evidence to support a recommendation for use in treating anxiety and depression. We also review how this guideline complements the recent ASCO guideline on conventional therapies for managing anxiety and depression, and the impact for patients and clinicians. Read the full guideline, "Integrative Oncology Care of Symptoms of Anxiety and Depression in Adults with Cancer: SIO-ASCO Guideline" at www.asco.org/survivorship-guidelines TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/survivorship-guidelines. Read the full text of the update and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00857    Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.  My name is Brittany Harvey and today I'm interviewing Dr. Julia Rowland from the Smith Center for Healing in the Arts, Co-chair on “Integrative Oncology Care of Anxiety and Depressive Symptoms in Adult Patients with Cancer: Society for Integrative Oncology – American Society of Clinical Oncology Guideline.”  Thank you for being here, Dr. Rowland.   Dr. Julia Rowland: Lovely to be here, Brittany. Thanks for this opportunity.  Brittany Harvey: We're glad to have you on.  Then before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including the guest on this episode, are available in line with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then I'd like to jump into the content of this guideline. So Dr. Rowland, what is the purpose of this joint SIO and ASCO guideline?  Dr. Julia Rowland: The purpose of the joint guideline, Brittany, published in the Journal of Clinical Oncology is to provide evidence-based recommendations to healthcare providers on integrative approaches to managing anxiety and depression symptoms in their adult cancer patients. By integrative approaches, we mean such interventions as yoga, relaxation, hypnosis, mindfulness, acupuncture, music therapy in treating anxiety and depression. Many of these therapies are already being used by people with cancer both during and after their treatment, with rates increasing over time. While use of integrative interventions can serve to improve quality of life, reduce stress, and provide individuals with a sense of control over their health, and they're often reported by patients as doing just that, it's important to note that for the purpose of this guideline, we examine specifically the ability of these interventions to significantly reduce symptoms of anxiety and depression. Brittany Harvey: Great. And then, as you just mentioned, this guideline covers both anxiety and depression. So then I'd like to review the recommendations made by the expert panel and we'll go in order of those. So starting with those recommendations for anxiety, what integrative therapies are recommended for managing symptoms of anxiety experienced after diagnosis or during active treatment?  Dr. Julia Rowland: The strongest recommendations in the guideline are for the use of mindfulness-based interventions, which include mindfulness-based stress reduction, meditation, and mindful movement. These interventions were recommended across the board to treat both anxiety and depression symptoms in patients in active treatment, and those post-treatment due to the strong evidence to show their benefits to patients. Yoga was also recommended for patients with breast cancer to treat both anxiety and depression symptoms, although the strength of the evidence was moderate. Data was less compelling for its use during or after treatment in other cancers, likely due to the lack of small numbers of non-breast cancer survivors included in study samples. There was also evidence for the use of relaxation, music therapy, and reflexology for treating anxiety symptoms during active treatment, and that the use of hypnosis and aromatherapy using inhalation were of modest to some benefit during diagnostic or treatment procedures. Brittany Harvey: Understood. Thank you for reviewing those recommendations. And you already mentioned a few items that are helpful and recommended for adults with cancer experiencing anxiety post-treatment, but which additional integrative therapies are recommended for this patient population?  Dr. Julia Rowland: In addition to mindfulness-based interventions and yoga, acupuncture, Tai Chi, and/or Qigong, and reflexology are recommended for treating anxiety symptoms post-treatment.  Brittany Harvey: Excellent. Thank you for that summary of recommendations. So then, moving into the recommendations on depression, what does the expert panel recommend for adults with cancer experiencing symptoms of depression?  Dr. Julia Rowland: For depression symptoms during treatment, the panel recommended mindfulness-based interventions, yoga, music therapy, relaxation, and reflexology, while post-treatment mindfulness-based interventions, yoga, and Tai Chi or Qigong were recommended.  Brittany Harvey: Excellent. Thank you for reviewing all the recommendations that the panel put forward. So this guideline reviewed a large breadth of integrative therapies. Are there any therapies that the panel reviewed but couldn't make a recommendation for, for this particular guideline?  Dr. Julia Rowland: Thank you for asking that question because as people listen to this podcast, they may realize that there are some therapies that may be widely used by their population or in their center or clinic, including such things as natural products and supplements, melatonin, healing touch, massage, light therapy, to name a few. Where the panel found in its review of the literature of over 110 studies or systematic reviews, there was insufficient evidence for the vast majority of these to make any conclusive recommendation. It just means we have a lot more work to do in assessing the efficacy of these, especially in treating anxiety and depression.  One intervention stands out in particular that's widely used and that's expressive writing. While this may be very helpful for improving quality of life or making sense of the cancer experience and providing an outlet for self-expression, the data does not support its use for treating anxiety and depression. It may be because it's too brief an intervention for conditions that have more depth and permanence. It doesn't mean you can't use it for other purposes, but the panel did not recommend its use for treating anxiety and depression. Brittany Harvey: Understood. That makes sense that there are some integrative therapies that work across different parts of the treatment spectrum and that there are some areas in which we just don't have the evidence yet. So, thank you for reviewing all of those recommendations.  So then, how does this guideline complement the recently published ASCO Guideline on the Management of Anxiety and Depression in Adult Survivors of Cancer?  Dr. Julia Rowland: That's a terrific question. The recently published ASCO Guideline on Management of Anxiety and Depression in Adult Cancer Survivors represents an update of our original 2014 guideline. The ASCO guideline provided recommendations regarding the use of conventional therapies, psychological, behavioral, and psychopharmacologic interventions for managing anxiety and depression. The current SIO and ASCO guidelines sought to expand upon and essentially complement these recommendations by identifying those integrative therapies that might also be effective in the management of anxiety and depression in adults treated for cancer. Further, the SIO and ASCO guidelines attempted to determine when, in the course of care, during diagnosis and active treatment and/or post-treatment, these interventions worked best. Both sets of recommendations strongly endorse the benefits of mind-body interventions in addressing both anxiety and depression, specifically mindfulness-based interventions in this SIO and ASCO guideline and cognitive, behavioral, behavioral activation, and mindfulness-based stress management programs in the ASCO guideline. Brittany Harvey: It's great to have these complementary guidelines available at the same time for a complete approach to managing anxiety and depression during treatment and post-treatment. So then, in your view, Dr. Rowland, what is the importance of this guideline and how will it impact clinicians and patients with symptoms of anxiety and/or depression? Dr. Julia Rowland: Brittany, cancer takes a significant psychological toll on affected individuals. Research has shown that cancer survivors have a significantly elevated risk of developing mental health disorders compared with the general population. Despite this, their psychological symptoms are often under-recognized and undertreated. As the number of cancer survivors continues to grow, so does the challenge to healthcare providers of meeting their mental health needs. Anxiety and depression symptoms have long been associated with lower quality of life and higher mortality in people with cancer. Treating symptoms of anxiety and depression using evidence-based, integrative therapies has the potential to not only improve patients' quality of life and help them better manage their care but may also improve length of life.  With the publication of this guideline, we now know which therapies could have the biggest impact. An added benefit of incorporating, or at least considering, integrative therapies to manage anxiety and depression are that they have few, if any, side effects, can be readily modified to accommodate individuals with multiple comorbidities, are well received by the majority of patients, and can be received in a variety of settings, including at home and online. Brittany Harvey: Those are key points that you just made. These recommendations are key for improving quality of life for patients, and it's great to have options for patients, including, as you mentioned, at home.   So then finally, what are the outstanding questions for the use of integrative approaches in managing anxiety and depression in patients with cancer? Dr. Julia Rowland: As I look at these new guidelines, both the SIO and ASCO, as well as the renewed ASCO guidelines, perhaps the biggest question raised is how to increase the use of recommended care. And I think there are three parts to this challenge. One critical first part is raising awareness about these guidelines, which it's hoped this podcast will help us achieve. A second, equally critical step, however, is identifying available treatment resources. While most treatment clinics and centers have access to mental health resources in a number of settings, this may be quite limited. Further, it's not clear how many such programs include integrative programs and services.  In addition to the questions about availability, lack of familiarity with some of these therapeutic modalities may leave clinicians reluctant to refer their patients for such care and raise questions for them about how to assess the training and qualifications of integrative care providers and the rigor of the therapy they provide. An important recommendation made by both ASCO and the SIO and ASCO Anxiety and Depression Management Guideline panels is that oncology clinicians should conduct a landscape analysis of who is and what types of programs are available to provide the recommended therapies to their patients. Arguably, not knowing where to refer a patient suffering from anxiety and depression is the most significant area to that patient's receipt of optimal care. The landscape review should include in-house or affiliated mental health providers, integrative program leads if present, local professionals, and organizations offering this care, as well as access to community-wide and national groups providing integrative care remotely via online and telephone. Asking patients themselves who they have seen and found helpful in improving their emotional well-being can also broaden resource lists generated.   A third challenge is how best to identify and refer those patients most in need. Recommendations regarding screening and assessment of anxiety and depression were not within the scope of the SIO and ASCO guidelines. However, in the two published ASCO Guidelines on use of conventional interventions for managing anxiety and depression, both the 2014 original and the updated 2023 revised, the expert panels emphasize the critical need to routinely screen for both anxiety and depression using standardized measures such as the GAD-7 and the PHQ-9.  ASCO's QOPI or Quality Oncology Practice Initiative already includes screening for emotional distress early in the course of care as a key practice standard. Other appropriate times for screening include changes in disease or treatment status, transition to palliative and end-of-life care, and when clinically indicated. Screening is the critical and necessary first step to identification and referral for appropriate and timely care of cancer patients and survivors suffering from anxiety and depression. Figuring out how to do this well and systematically should be a priority for reducing the burden of cancer nationally. Brittany Harvey: Absolutely. As you mentioned, screening is critical for identifying patients experiencing anxiety and depression, and I appreciate you reviewing those implementation barriers and how clinicians and practices can work to reduce these barriers and increase the uptake of these recommendations. We'll have some of those resources linked in the guideline also on the ASCO website and in the show notes of this episode.  So I want to thank you so much for your insights on this guideline and for your time today, Dr. Rowland. Dr. Julia Rowland: My pleasure, Brittany. I hope the word gets out and we'll see more uptake of these affected therapies and in broader use. Thank you.  Brittany Harvey: Definitely. That's the goal of all of these guidelines.  I also want to thank all of our listeners for tuning into the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/survivorship-guidelines.  You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of medical conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Navneet Singh joins us again, this time to discuss the rapid recommendation update for stage III non-small cell lung cancer, incorporating updated data presented at the 2023 ASCO Annual Meeting. He discusses the new trials that prompted the guideline update and updated recommendations on adjuvant osimertinib for patients with EGFR exon 19 deletion or exon 21 L858R mutation, and the option of neoadjuvant chemoimmunotherapy for patients with stage III NSCLC. Read the update, "Management of Stage III Non-Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update" at www.asco.org/thoracic-cancer-guidelines TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01261 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.  My name is Brittany Harvey, and today I'm interviewing Dr. Navneet Singh from the Postgraduate Institute of Medical Education and Research in Chandigarh, India, Co-chair on “Management of Stage III Non-Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update.”  Thank you for being here, Dr. Singh. Dr. Navneet Singh: Thank you for having me. Brittany Harvey: Then, before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Singh, who is joining us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to dive into the content of this guideline, first, Dr. Singh, what prompted this rapid update to the ASCO management of stage III non-small cell lung cancer, which was initially published in 2021? Dr. Navneet Singh: There have been a number of studies that have involved patients with stage III non-small cell lung cancer since the publication of the stage III NSCLC management guidelines. Of note, three trials deserve special recognition and have actually formed the basis for this rapid update. These include the ADAURA trial for use of osimertinib as adjuvant treatment for completely resected stages Ib to IIIa NSCLC and harboring a sensitizing EGFR mutation. The other two trials have explored the use of PD-1 immune checkpoint inhibitor therapy in combination with chemotherapy as neoadjuvant treatment of potentially resectable stages I to III NSCLC. And these are the CheckMate 816 trial with nivolumab and the KEYNOTE-671 trial with pembrolizumab. Brittany Harvey: Great, thank you for that background. So then, based off these three new trials that you just mentioned, what are the updated recommendations issued in this rapid recommendation update? Dr. Navneet Singh: The first updated recommendation is based on the overall survival benefit observed in the ADAURA trial. And this recommendation is that patients with dissected stage III NSCLC and harboring an EGFR exon 19 deletion or an exon 21 L858R mutation should be offered adjuvant osimertinib after platinum-based chemotherapy. The second important update is that in the absence of contraindications, patients with stage III non-small cell lung cancer who are planned for surgical resection should receive a neoadjuvant combination of a platinum doublet chemotherapy, and immunotherapy. Now, both of these are based on high-quality evidence and have a strong strength of recommendation. Brittany Harvey: Understood. I appreciate you reviewing both the level of evidence and the strength of the recommendation for those as well. So then, what should clinicians know as these new recommendations are implemented? Dr. Navneet Singh: Now, it's very important for clinicians involved in the management of lung cancer to realize the importance of biomarker testing, something that was initially believed to have relevance only for metastatic disease. But now, with the availability of data indicating the benefit of immunotherapy and targeted therapy not just in metastatic disease but also in early-stage as well as locally advanced disease, clinicians need to ensure that biomarker testing, especially EGFR mutation and PD-L1 expression by approved and validated methods is performed in all patients with stages I to  III non-small cell lung cancer. This is important to decide and select patients for the appropriate biological therapy, which is either targeted therapy or immunotherapy that can be used in conjunction with or following chemotherapy. I need to clarify here that the spectrum of biomarker testing that is recommended for metastatic disease is much larger than what is currently being advocated for early or locally advanced NSCLC. Brittany Harvey: Great, and I appreciate that clarification. So then you've just described what this guideline means for clinicians, but how does this rapid update impact patients diagnosed with stage III non-small cell lung cancer? Dr. Navneet Singh: Well, for patients with stage III non-small cell lung cancer, all the three trials that form the basis for this rapid update indicate very encouraging developments. The neoadjuvant chemo-immunotherapy approach is now the standard of care for potentially resectable stage III disease, as this combination has been shown to be superior to chemotherapy alone in terms of higher probability of achieving a complete or major pathological tumor response, as well as improving recurrence or event-free survival following surgical resection. Similarly, adjuvant osimertinib for resected stage III NSCLC patients having a sensitizing EGFR mutation has been shown to significantly improve overall survival compared to placebo. It is important to highlight here that osimertinib treatment in stage III NSCLC should be initiated following the completion of adjuvant chemotherapy. Brittany Harvey: Understood. So then this panel works to rapidly update this guideline, turning it around after the ASCO Annual Meeting. But what are the ongoing research developments that the panel is monitoring for future guideline updates? Dr. Navneet Singh: Well, the expert panel is eagerly awaiting overall survival data from the neoadjuvant chemo-immunotherapy trials. We have several unanswered questions which ongoing research will attempt to answer. And some of these questions include number one, whether adjuvant immunotherapy is beneficial for patients who have already received neoadjuvant chemo-immunotherapy, and if so, what is the optimal duration for the same? Second, is the three-year adjuvant osimertinib duration appropriate? Can lesser duration of treatment suffice for a subgroup of patients? And if so, it would lead to a reduction in both treatment costs as well as a reduction in potential treatment-related adverse effects. On the other hand, other patients in whom stopping at three years may not be warranted, and should patients with exon 19 deletion be treated differently from those with exon 21 L858R mutation? Third, does a similar adjuvant targeted therapy approach be warranted for ALK-rearranged NSCLC that has been surgically resected? And fourth, are there specific subgroups of patients undergoing neoadjuvant treatment in whom immunotherapy as a neoadjuvant treatment may not be effective? Examples are those with EGFR mutations or ALK rearrangements, or even those with no PD-L1 expression. Brittany Harvey: Absolutely. We'll look forward to finding the answer to those questions for future guideline updates. So I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Singh. Dr. Navneet Singh: Pleasure. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store.  If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Supriya Mohile , Dr. William Dale, and Dr. Heidi Klepin discuss the updated guideline on the practical assessment and management of age-associated vulnerabilities in older patients undergoing systemic cancer therapy. They highlight recent evidence that prompted the guideline update, and share the updated evidence-based recommendations from the panel, focusing on geriatric assessment-guided management. Dr. Mohile also reviews what the expert panel recommends should be included within a geriatric assessment, and Dr. Dale highlights the Practical Geriatric Assessment tool, aimed at helping clinicians implement a geriatric assessment. Dr. Klepin comments on the impact for both older adults with cancer and their clinicians, and reviews outstanding questions and challenges in the field. Read the full guideline, "Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy: ASCO Guideline Update" at www.asco.org/supportive-care-guidelines TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the update and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00933. See also the Practical Geriatric Assessment tool and associated videos (How to do a Geriatric Assessment, What to do with the Results of a Geriatric Assessment) mentioned in the podcast episode. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.  My name is Brittany Harvey, and today I'm interviewing Dr. William Dale from City of Hope National Medical Center, Dr. Heidi Klepin from Wake Forest Baptist Comprehensive Cancer Center, and Dr. Supriya Mohile from University of Rochester Medical Center—co-chairs on “Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy: ASCO Guideline Update.”  Thank you for being here, Dr. Dale, Dr. Klepin, and Dr. Mohile. Dr. William Dale: Nice to see you. Thanks for having us. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensures that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests joining us on this podcast episode today, are available online with the publication of the guideline in the Journal of Clinical Oncology linked in the show notes.  Diving into the content of this guideline first, Dr. Dale and Dr. Mohile, can you speak to what prompted an update of this ASCO guideline on the practical assessment and management of age-associated vulnerabilities in older patients undergoing systemic cancer therapy, which was previously published in 2018? Dr. William Dale: Sure. Yes. In 2018, that was the very first guideline for older adults that ASCO had created, and that was based on work that had been done up to that time, focused on chemotherapy toxicities. And to summarize what was put out at that time, the evidence was thought to be strong enough for doing geriatric assessments. And these are specialized assessments across a number of domains, including functional impairments, cognitive losses, social impairments, etc. But to do these kinds of geriatric assessments with validated tools; that a certain selection of these domains to cover everything that was relevant; to conduct non-cancer prognostication so that for decision-making purposes, if someone were to have their cancer cured, what would be their prognosis, and help make decisions about giving chemotherapy and what doses; and then to enact geriatric assessment-guided target interventions was the fourth recommendation. And so that's where we were in 2018.  In 2020 at ASCO, there was an oral session that had four randomized controlled trials that enrolled older adults. And in that was kind of the signal that there was more coming. And in 2021, two big trials that are practice-changing were published. One led by Dr. Mohile in Lancet that we call the GAP70+ study, and another one was published in JAMA Oncology. And they essentially showed the same thing, which was that GA-guided interventions could change the primary outcome, which was to reduce chemotherapy toxicity up to 20%, and also to affect a number of other outcomes. That, along with a number of other trials that have since come out and are included in the upcoming guidelines, and made it a high priority to update these guidelines. So that's where we got from there to here. And I think it's worth saying a few words about these new trials, particularly the GAP and GAIN studies. So the GAIN study included patients who were 65 and older who were starting systemic chemotherapy and looked at the likelihood of having chemotherapy toxicity as described and looked at a number of other outcomes. Most importantly, it showed that chemotherapy toxicity could be reduced with these interventions based on the geriatric assessment from about 60% to about 50%. It also showed that the likelihood of completing advanced directives would go up by around 25%. And importantly, there was no impact after all of the use of the geriatric assessments on mortality. So patients were living just as long, but they were having less toxicity and they were having more goal-concordant care. And at almost the same time, the GAP study came out, which I would hand over to Dr. Mohile to describe. Dr. Supriya Mohile: Thank you, Dr. Dale. I agree that it was time for an update, and I'm glad ASCO partnered with us to do this. I'll also just mention that Dr. Dale, Dr. Klepin, and I lead the Cancer and Aging Research Group, and many of the original predictive models that showed that geriatric assessment could help us identify patients at highest risk for toxicity were designed by Cancer and Aging Research Group investigators. And that's what informed the first guideline. I'll mention Dr. Arti Hurria, who unfortunately passed away a few years ago, and she led some of the first large studies that developed these predictive models. We built on that data in both GAP and GAIN studies to show that the geriatric assessment—when you assess and provide management—can reduce chemotherapy toxicity.   Like GAIN, GAP70+ implemented a geriatric assessment intervention that both assessed and provided management to older adults. There were some key differences. In GAP70+, the patients had advanced cancer, whereas, in the GAIN study, it was a more generalizable population of patients with both curative intent and advanced cancer. And in the GAP70+ study, we enrolled patients who already had geriatric assessment domain impairments, meaning that these patients were more vulnerable because of those aging-related conditions. We were trying to enroll patients who are traditionally excluded from therapeutic clinical trials. The GAP70+ study was done in oncology offices by Community Oncology practices.  So this was what I think was really interesting, in that geriatricians were not involved in implementing the geriatric assessment in this study. Oncologists received the assessment information from their team, and they're the ones that implemented the recommendations. We found in GAP70+ that not only chemotherapy toxicity was reduced, that we were able to reduce the prevalence of falls and reduce the incidence of polypharmacy, which are important geriatric outcomes for older adults. We included patients who were receiving chemotherapy, but also patients who are receiving high-risk targeted agents in GAP70+, which also leads us to believe that these interventions are important for patients who are receiving treatments other than chemotherapy.  So we believe these two trials, plus others, really inspired the ASCO guidelines. Brittany Harvey: Absolutely. I appreciate you both for providing that context and background and some of the new evidence that's informed this latest update. So then I'd like to move into some of the updated recommendations of the guideline. So, Dr. Mohile, what is the updated recommendation from the panel regarding the role of geriatric assessment in older adults with cancer? Dr. Supriya Mohile: So the first guideline really focused on the assessment piece, what should be assessed, and why, which we still incorporate in this new guideline. This guideline extends now because of the randomized controlled trials into management. And when we think about geriatric assessment, we think about two pillars of management. One is how geriatric assessment influences cancer decisions, that includes what treatments to provide, what dose to provide. And then the second is how geriatric assessment can influence management recommendations that are supportive care based that address some of the geriatric assessment domain impairments.  I'll just give you an example of both. So when we see patients with advanced cancer who have geriatric assessment domain impairments who are presenting for treatment, often the doses of chemotherapy may be overtreatment because those doses were developed in therapeutic clinical trials in younger, more fit patients. And in our geriatrics world, we often think about going slow and starting low, and we may do a first cycle that's dose reduced a touch, to kind of see how the patient does physiologically with that first cycle. There are therapeutic clinical trials like FOCUS2 in patients with metastatic colon cancer that show the benefits of being careful with dosing in the first cycle.  So, in GAP70+, the oncologists who received information from the assessment were more likely to reduce the dose of the treatment in the first cycle which led to less toxicity but did not lead to a difference in survival, so do not compromise survival. And I think this is because we don't know the right doses for patients who have significant aging-related impairments. So that's one example of decision-making.  As examples for geriatric management recommendations that are supportive care, this can be done in almost like an algorithmic approach. So, if a patient has an impairment on a physical function test, then through the geriatrics literature we know of management recommendations that can improve outcomes like physical therapy, home safety evaluations, balance, training, fall prevention information. And if we implement those supportive care recommendations through that patient who's at risk for falls, we may prevent falls and we were able to show that in addition in GAP70+ as well as other trials showed benefits in some of those outcomes.  And so those are the two pieces that I think are newer with this guideline than with the previous guideline. We know more about how those management recommendations can improve outcomes.    Brittany Harvey: Understood. Yes. It's helpful to understand those examples of how integrating this geriatric assessment can help improve the management of care for these patients. So then you've mentioned some of the geriatric assessment domain impairments. So, Dr. Mohile, what does the guideline recommend should be included within a geriatric assessment? Dr. Supriya Mohile: This was a really great question for us to rise and think about, as part of this guideline and as a panel, we went back and forth with all of the authors to try to think about what is the most streamlined number of domains that should be assessed? What are the highest priority domains that, if you could only do a few things in a busy oncology clinic, which are the ones that oncologists should have to do because without doing them, they won't have relevant information to inform treatment decisions or to improve the outcomes of their patients?  And so when we think about geriatric assessment, there has been literature to show that almost all of the domains we do are important in identifying patients who are at risk of poor outcomes. These include physical function, cognitive function, emotional health, comorbidities, polypharmacy, nutritional status, and social support. That sounds like a lot, but we do many of those assessments sort of naturally in oncology clinics. There are just a few that are not done as standard. For example, it is not standard for oncologists to assess cognition using a validated screening test for cognition. And we know that recognizing patients who may have cognitive impairment is really important in identifying vulnerabilities and providing support systems in place so patients who are receiving treatment can go through treatment safely.   Other things, like just doing a formalized nutritional assessment, really bringing in the caregiver, are done not in a standard way. And so what the geriatric assessment allows is for us to assess each of those domains in a standard way. When we're communicating to our colleagues and tumor boards, we can describe vulnerabilities in a standard way. And we're moving now past the eyeball test, which is different for different clinicians, and having more objective ways of describing health status to be able to have a common language across studies and in clinical care. Brittany Harvey: That's helpful to understand moving past the less formal approach to geriatric assessment and making it more standardized.  So then, Dr. Dale, this guideline offers a specific tool, the Practical Geriatric Assessment, as an option for clinicians conducting a geriatric assessment. What is this tool and where can clinicians access it? Dr. William Dale: Very good question. Just to set the context a bit, after hearing about all the evidence that we've just described. We did do some work as a task force through ASCO and through some work that Dr. Klepin and her colleague have done to understand now that the guidelines in 2018 had come out, they weren't really being used. So when we asked, about 25% of people would say they were using them very much, even though we saw in these large studies that we did, that those who were using the guidelines were changing their practice significantly in the ways that Dr. Mohile mentioned. And this was among a large group of community oncologists.  So we have been breaking down the geriatric assessment into the most concise, most straightforward, and easiest-to-use version of the geriatric assessment, maintaining its validity and maintaining the number of domains. We really tried to make it simple. So the Practical Geriatric Assessment is not the only tool, but it is a tool that accomplishes this practical charge to make it accessible to community oncologists while also being valid. So those domains that Dr. Mohile mentioned physical function, functional status, nutrition, social support, psychological considerations, comorbidities are all in the Practical Geriatric Assessment.   But what we've done is boil it down to here's a very specific tool that we think is valid but easily applied. Here are the very specific thresholds that tell you when a deficit has been identified and then gives recommended actions to be taken, whether it's in decision-making or in other interventions like a referral to somebody, perhaps physical therapy, or a cognitive specialist, all of which come from the GAP. So this tool is designed to be very straightforward and practical, but still cover all the relevant domains. And it will be made available through both the ASCO website and through the Cancer and Aging Research Group website so that people can access it easily. Brittany Harvey: That sounds like a real challenge that the ASCO working group took on to create a comprehensive yet practical tool for clinicians to use. We'll also provide some links for people to access this in the show notes of this podcast episode.   So then I want to move on. Dr. Klepin, in your view, how will this guideline update impact both clinicians and older adults with cancer?  Dr. Heidi Klepin: Yes. Thank you. As was mentioned, for clinicians, the guidelines provide an overview of new evidence and concrete recommendations to address the challenge experienced every day in practice, that of providing personalized care in the context of age-related conditions to maximize benefits and minimize the risk for older adults with cancer. The evidence summary will educate clinicians on key outcomes that can be positively impacted by use of geriatric assessment, including decreasing treatment toxicity, enhancing decision-making, and improving communication and patient-caregiver satisfaction.  And this information on outcomes is really critical to informing the use of geriatric assessment in practice. We hope that the evidence-based recommendations with the provision of the practical geriatric assessment and the associated trigger table to guide management strategies will empower clinicians to incorporate geriatric assessment into their workflow by helping them overcome some of those known barriers that Dr. Dale mentioned, such as lack of time and uncertainty about which measures to use and what to do with the information once you have it. So, we anticipate that providing clear recommendations and accompanying readily available materials to support the implementation that clinicians in both community and academic practices will be able to use the geriatric assessment and incorporate it into routine care. For patients, we anticipate that the guideline recommendations would translate into increased use and access to this type of assessment as part of their routine oncology care. So, we hope that our patients will actually be able to access this regardless of whether they're receiving care at a specialized academic center versus a community oncology clinic. So, by doing this, we would extend the proven benefits of geriatric assessment, including lower rates of side effects, experiencing fewer hospitalizations, and improving satisfaction to older adults regardless of where they receive treatment.   And we feel like this is critically important, since currently, most older adults receive cancer care in community oncology clinics without access, as was mentioned, to any geriatric specialty care. So, as more older adults have the opportunity to participate in this type of assessment as part of routine care in their oncology clinics, they'll be able to discuss the results of the assessment with their healthcare providers, which can help them make better-informed decisions and engage, I think, more completely in what we would consider patient-centered decision making. And ultimately, we would hope that the guidelines would provide an evidence-based and practical strategy for improving the quality of care received by older adults with cancer.   Dr. Dale, would you be interested in commenting a little bit more on the patient perspective informed by our patient partners on the guideline panel? Dr. William Dale: Yeah. Thank you, Dr. Klepin. Very well said. Yeah, our guideline panel, just to fill out the picture of that, included our patient partners, along with a wide diversity of perspectives. We had experts in geriatric oncology, but we had community oncologists who take care of cancer patients. We have people from across the country. We had different backgrounds and different levels of experience. But to focus on the patients for a group that we've worked with for some time called SCOREboard, and they were some of the strongest voices on this.  Whenever people said, “Well, do we really need to require this?” The patient partners were insistent that this be included as a requirement as much as possible for what happens. I think one of the most important roles they've played is as advocates for this. If I can, when the community oncologists are having some concerns about how hard this would be or how difficult it might be, the patient partners have been the first to say, we need to find a way to do it and insist that we empower the patients to ask for it. So, one of the hopes for all of these guidelines is also that it get disseminated to patients who can self-advocate as they go forward and have tools that will be made available for them to use in this self-advocacy. Brittany Harvey: Definitely, that self-advocacy is important and the geriatric assessment is critical for optimal care for older adults.  So, then we've talked a lot about the new evidence regarding geriatric assessment and also making it easier for clinicians to implement the geriatric assessment, but Dr. Klepin, what are the outstanding questions and challenges regarding geriatric assessment in older adults with cancer?  Dr. Heidi Klepin: Thanks. So, while there's strong evidence and clear rationale to incorporate geriatric assessment into routine clinical care, there are outstanding questions and challenges that we have to consider. First and foremost, still remains a challenge of implementation. As mentioned, we hope that the Practical Geriatric Assessment, the detailed recommendations, and the associated educational materials on what to do with the geriatric assessment information will help overcome implementation barriers for many. But we recognize that more work needs to be done to both train providers to facilitate behavior change as well as to tackle clinic and healthcare system barriers to routine use.  And along these lines, we also recognize that it's important to educate patients and caregivers about the role of geriatric assessment and its value in order to optimize uptake in community clinics. We want all of our patients to be as enthused and recognize the importance of the geriatric assessment, as our colleagues on the recommendation panel did. Another consideration is the challenge of tailoring use of geriatric assessment to specific disease and treatment settings. And more research is underway testing geriatric assessment and management strategies in varied disease settings, as well as with varied treatment types and intensities.  And finally, I would suggest that another challenge is the lack of routine incorporation of geriatric assessment measures into cancer clinical trials. And this will really be necessary to interpret clinical trial data for older adults optimally and to reinforce the value of routine geriatric assessment in clinical care. Brittany Harvey: Absolutely. These are key points for moving forward and looking forward to additional research in this area and maybe future guideline updates down the line.  So, I want to thank you all so much for your work on updating this guideline and for your time today. Dr. Dale, Dr. Klepin, and Dr. Mohile.  Dr. Heidi Klepin: Thank you for having us.  Dr. William Dale: Yeah, thanks for having us here. We're delighted to be talking about this.  Dr. Supriya Mohile: Thank you.  And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store.  If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Charles Loprinzi shares the latest update to the management of cancer cachexia guideline. Dr. Loprinzi discusses the evidence that prompted the rapid update to the guideline and reviews the new evidence-based recommendations, including the addition of low-dose olanzapine as a treatment option for patients with advanced cancer to improve weight gain and appetite. Dr. Loprinzi reviews the limitations of the update, and outstanding research questions in the domain of cancer-associated cachexia. Read the latest update, "Cancer Cachexia: ASCO Guideline Rapid Recommendation Update" at www.asco.org/supportive-care-guidelines TRANSCRIPTThis guideline, clinical tools, and resources are available at http://www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01280  Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Charles Loprinzi from Mayo Clinic, Co-Chair on “Cancer Cachexia: ASCO Guideline Rapid Recommendation Update.” Thank you for being here today, Dr. Loprinzi.  Dr. Charles Loprinzi: It's a pleasure to participate. Brittany Harvey: Then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Loprinzi who has joined us here today, are available in line with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.   Then, to get into the content of this rapid recommendation update, first, Dr. Loprinzi, what prompted this rapid update to the ASCO management of cancer cachexia guideline, which was previously published in 2020? Dr. Charles Loprinzi: The impetus for the updated guideline was a recent JCO publication regarding the results of a randomized controlled trial looking at olanzapine. This prompted the expert panel to revisit this topic. The trial, conducted in India, involved 124 patients with stomach, hepatopancreatobiliary, or lung cancers as they initiated chemotherapy. Weight gain greater than 5% occurred in 60% of patients in the olanzapine arm versus 9% of the patients in the placebo arm with a p-value of 0.001 or less. Substantially improved appetite was seen in 43% versus 13%, with placebo also a p-value of less than 0.001. Grade 3 or greater chemotherapy toxicity was less common with olanzapine 12% versus 37%, with placebo with a p-value of 0.002. No substantial olanzapine-associated toxicity was apparent. There was one evidence of this with olanzapine versus two for placebo. So that was the reason for going ahead with this update. Brittany Harvey: I appreciate that background information. So then, based on this updated study on olanzapine, what are the updated recommendations from the expert panel for treating cancer cachexia? Dr. Charles Loprinzi: So, let me start to address this question by reviewing what the 2020 ASCO guidelines published said regarding the management of cancer cachexia in adults with advanced cancer. It concluded that evidence was insufficient to strongly endorse any pharmacologic agent for established anorexia/cachexia. Nonetheless, the guideline recommendation supported that clinicians could offer a short-term trial of a progesterone analog such as megestrol acetate or a corticosteroid such as dexamethasone to patients experiencing weight loss and/or appetite stimulation. These drugs stimulated appetite and caused weight gain, but they did not improve quality of life, they did not improve survival, and there was toxicity associated with these agents and therefore it was not strongly recommended.  The expert panel thoroughly discussed a potential role for olanzapine because of a couple of trials suggesting it was beneficial but concluded that the evidence was insufficient for a recommendation. Now, there was evidence from two randomized trials that supported olanzapine was an effective alternative for treating cancer-associated anorexia/cachexia. Thus, olanzapine was considered promising, but the data were not conclusive enough to support a guideline treatment recommendation. The new JCO publication was the impetus for making this guideline change. Brittany Harvey: Understood. So then, based off this new change to the recommendations, what is the breadth of these recommendations and what do these options mean for patients with advanced cancer?  Dr. Charles Loprinzi: The updated guidelines recommended that for adults with advanced cancer, clinicians could offer low-dose olanzapine once daily to improve appetite and cause weight gain. It was noted that the majority of the evidence for this recommendation came from patients with lung or GI cancers, and the largest study enrolled patients who were receiving cytotoxic chemotherapy concurrently. Having said this, there's evidence from the other two randomized trials noted above that olanzapine is helpful in patients with a wide variety of cancers and regardless of whether patients were receiving concomitant chemotherapy.   Of note, extensive data support that olanzapine leads to significant appetite stimulation and weight gain in patients without cancer who were taking olanzapine for psychiatric reasons. This was known from a long time ago in patients in that situation, who don't necessarily want to gain weight, would gain 10-20-30-40 pounds, get prediabetes, and get diabetic sort of troubles. The guideline update continues to support that clinicians may offer a short-term trial of a progesterone analog or a corticosteroid to those experiencing weight loss and/or appetite when there's a good reason for not using olanzapine.  Brittany Harvey: Understood. I appreciate you reviewing those two updated recommendations from the guideline panel.  So then you've talked about this a little bit already in describing the study details, but what is exciting about olanzapine in this setting and what should clinicians know as they implement these updated recommendations?  Dr. Charles Loprinzi: It's exciting that olanzapine is now the best-studied established treatment available for patients suffering from cancer-associated anorexia/cachexia in different oncologic situations, for prevention and/or for treatment of cancer-associated or cancer treatment-associated nausea and/or vomiting, and for treatment of cancer-associated anorexia/cachexia. Varying daily doses of olanzapine have been used, ranging from 2.5 to 10 milligrams per day. Data support that it is quite appropriate to use the 2.5-milligram per day dose for the initial treatment of cancer-associated appetite and/or weight loss. For patients who do not appear to benefit and have no apparent olanzapine toxicity, it seems reasonable to me to try a higher dose. Another thing to note is that olanzapine is a generic drug which is relatively inexpensive. While this drug has been noted to cause sedation, such sedation is usually short-lived despite drug continuation. Brittany Harvey: So then, it's great to hear that recent data have caused an update to these guidelines. But in your perspective, Dr. Loprinzi, what are the most pressing outstanding questions regarding the management of cancer cachexia? Dr. Charles Loprinzi: My goodness, you're putting pressure on me. I've been involved with a large number of cancer anorexia/cachexia trials for the better part of four decades, which did not support as strong an ASCO guideline recommendation as we now have with olanzapine. Noting that I was involved with one of the trials that supported that olanzapine was helpful for treating cancer-associated anorexia/cachexia. This is one of the trials. It was a short trial. We were mainly looking at nausea and vomiting treatment for advanced cancer, but we saw a marked increase in appetite in over just a day or two of using olanzapine. Having said this, there's always room for improvement, and a number of drugs are under development for treatment of cancer-associated anorexia/cachexia.   Recent discussions regarding the topic of olanzapine for treating cancer-associated anorexia/cachexia noted that the primary endpoint of the current trial was weight gain and that this was felt to be a more objective endpoint than appetite would be. As noted in the earlier part of the discussion, substantial improvement was seen both in weight gain and appetite, both with p-values of less than 0.001. My own opinion is that appetite improvement is as important, if not more important than is weight gain in the study population. Given that the trial was double-blinded and placebo-controlled, appropriate questionnaires regarding appetite should be able to be considered as an objective evaluation of a subjective symptom in the same way that appropriate questionnaires regarding a patient's pain can be considered an objective evaluation of a subjective symptom. For some of these subjective symptoms, you just don't have other good ways we can figure these things out by a blood test or something like this. So it's what the patient says which is most important.  Brittany Harvey: Absolutely. Incorporating how the patient feels is key to achieving better outcomes for patients.  So I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Loprinzi. Dr. Charles Loprinzi: You're welcome. Pleasure to participate. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Navneet Singh highlights the latest evidence-based recommendation updates from the ASCO living guideline on stage IV non-small cell lung cancer with driver alterations. This update focuses on new second-line options for patients with advanced NSCLC and an EGFR exon 20 insertion, including amivantamab and mobocertinib. Dr. Singh also discusses updated results from CodeBreaK 200 and the option of second-line therapy with sotorasib for patients with advanced NSCLC and a KRAS-G12C mutation. Read the update, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.2” and view all recommendations at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01055  Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.   My name is Brittany Harvey, and today I am joined by Dr. Navneet Singh from the Postgraduate Institute of Medical Education and Research in Chandigarh, India, co-chair on “Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations: ASCO Living Guideline, Version 2023.2.” Thank you for being here, Dr. Singh.  Dr. Navneet Singh: Thank you for having me, Brittany. Brittany Harvey: Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the Guideline panel, including Dr. Singh, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to dive into this living clinical practice guideline, Dr. Singh, this living guideline for systemic therapy for stage IV non-small cell lung cancer with driver alterations is being routinely updated. What new studies were reviewed by the panel to prompt an update to the recommendations in this version? Dr. Navneet Singh: So for this 2023 version 2 update, three trials were included. These include two studies which involved patients with exon 20 insertion mutations, who had received prior platinum-based chemotherapy and subsequently were treated with either amivantamab in the CHRYSALIS trial or with mobocertinib in the EXCLAIM trial. The third trial which formed the basis for this update was one which involved patients with KRAS G12C mutation who had previously received systemic therapy and subsequently were treated with sotorasib. And this was the CodeBreaK 200 trial. Brittany Harvey: Understood. So then, based on these three new trials that you've just mentioned, what are the updated recommendations from the expert panel for patients with advanced non-small cell lung cancer? Dr. Navneet Singh: For patients with advanced NSCLC with an EGFR exon 20 insertion mutation and an ECOG performance status of 0 to 2 who have received prior platinum-based chemotherapy, clinicians may offer amivantamab or mobocertinib as monotherapy. It is important to mention here that in the absence of head-to-head comparison of amivantamab or mobocertinib with each other or with other standard second-line therapies, no recommendation for sequencing can be made and therefore treatment should be individualized. Now, use of either of the two drugs is based on low-quality evidence and has a weak strength of recommendation. And the updates for treating KRAS G12C-mutated NSCLC is largely similar; that patients who have received prior systemic therapy may be offered sotorasib.  Brittany Harvey: Thank you for reviewing those updated recommendations. So what should clinicians know as they implement these new recommendations and how do they interface with the existing recommendations? Dr. Navneet Singh: It is important for clinicians involved in the management of EGFR mutant lung cancer to realize that exon 20 insertions are the third most common group of EGFR mutations and comprise approximately 5% of all EGFR mutations. Now, historically, the EGFR targeted drugs which have been the first, second, or third generation tyrosine kinase inhibitors have largely shown efficacy for the two common types of EGFR mutations, namely the exon 19 deletions and the exon 21 L858R point mutation. Exon 20 insertion mutations thus did not have any effective targeted therapy so far. But now, both of these drugs, amivantamab and mobocertinib, have shown very promising results for pretreated patients with this molecular aberration and therefore may be used in view of standard second line therapy. Similarly, in the case of KRAS G12C mutation, before this, there was no effective targeted therapy, but now sotorasib, based on the CodeBreaK 200 trial, appears to be a very valid option in view of standard second-line therapy.  Brittany Harvey: Excellent. So then, what do these new treatment options mean for patients with stage IV non-small cell lung cancer and an exon 20 insertion or a KRAS G12C mutation?  Dr. Navneet Singh: For patients with stage IV NSCLC and harboring an EGFR exon 20 insertion, the availability of two specific targeted drugs will improve the treatment options available following standard first-line therapy. Furthermore, ongoing trials for these agents in the treatment-naive setting may eventually lead to a scenario wherein such patients may be treated upfront with targeted therapy rather than chemotherapy or chemoimmunotherapy, analogous to how patients with the common EGFR mutations are treated. The ultimate aim of precision medicine is to offer the most effective treatment based on biomarker expression and targeted therapies in comparison to chemotherapy because these lead to better treatment outcomes and lesser side effects. Brittany Harvey: Absolutely. The goal of better outcomes with less side effects is what we're looking to achieve here. So then, finally, as this is a living guideline, what emerging therapies or targets is the panel monitoring for future guideline updates? Dr. Navneet Singh: As was already said, the expert panel eagerly awaits data from ongoing trials which are assessing the efficacy of drugs targeting the EGFR exon 20 insertion mutations, namely amivantamab and mobocertinib as first-line therapy, as also the drugs which target the KRAS G12C mutations which is sotorasib and adagrasib in the treatment-naïve setting. Ultimately, the optimal sequencing of therapies needs to be established in advanced and metastatic non-small cell lung cancer for several of the oncogenic driver alterations other than classical EGFR mutations and ALK and ROS-1 rearrangements. These include the EGFR exon 20 insertions and other uncommon EGFR mutations, the BRAF V600E, KRAS G12C, the HER2, and the MET exon 14 skipping mutations as well as the RET and NTRK fusions.  Brittany Harvey: It sounds like the living guideline expert panel will be busy moving forward then. So I want to thank you so much for your work to update this living guideline and thank you for your time today, Dr. Singh.  Dr. Navneet Singh:  Thank you so much, it was a pleasure being here. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Antonio Wolff and Dr. Kim Allison discuss the latest ASCO-CAP guideline update on HER2 testing in breast cancer. This guideline update affirms previous recommendations, and provides commentary based on data from the DESTINY-Breast04 trial. Dr. Wolff and Dr. Allison review the questions from the oncology and pathology community raised by these results, and provide commentary on patients with HER2 IHC 1+ and 2+ and ISH-negative metastatic breast cancer. Read the guideline update, "Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-CAP Guideline Update" at www.asco.org/breast-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.22.02864   Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.  My name is Brittany Harvey, and today I am interviewing Dr. Antonio Wolff from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and Dr. Kim Allison from Stanford University School of Medicine, co-chairs on ‘Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-CAP Guideline Update'. Thank you for being here, Dr. Wolff and Dr. Allison. Dr. Antonio Wolff: Thank you. Dr. Kim Allison: Thanks for having us.  Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in developing its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the full guideline panel, including our guests on this episode today, are available online with the publication of the guideline and the Journal of Clinical Oncology, linked in the show notes.  So now jumping into the content, to start us off, Dr. Wolff, what prompted the update expert panel to revisit the 2018 ASCO-CAP recommendations on HER2 testing and breast cancer, and what is the scope of this update? Dr. Antonio Wolff: Thank you, Brittany. We appreciate the opportunity of being with you today, and it's great to be here with my colleague, Dr. Kim Allison, as well.   What triggered this informatory update was the release from data in trial DESTINY-Breast04, which tested the antibody-drug conjugate trastuzumab deruxtecan in patients who in the past would have been considered to have HER2-negative disease. This ADC, trastuzumab deruxtecan, has a topoisomerase inhibitor payload that is linked to the antibody trastuzumab. And in the past, from all the previous data we had, trastuzumab alone, or in combination with chemotherapy, or as part of another antibody-drug conjugate T-DM1 was essentially active in patients with HER2-positive disease, which is traditionally defined as having overexpression of the HER2 protein, which almost by default is a result of gene amplification of the HER2 gene.  And what data from initial studies appear to suggest is that patients who would not be traditionally considered HER2-overexpressed or HER2-amplified were potentially benefiting or having evidence of clinical activity against this disease in the study of metastatic disease. And this was a randomized clinical trial for patients with metastatic breast cancer whose tumors were centrally determined to have IHC 1+ or IHC 2+ expression and would not have been called HER2-positive, would not have been called HER2-overexpressed. And for the tumors that were HER2 2+, they also had to have absence of gene amplification by an in-situ hybridization assay.  And what was very interesting is that there was a meaningful, clinically significant improvement in survival for that patient population. And that has some clinicians to begin asking whether there is a different subset of patients who would have in the past been called as having HER2-negative disease that now could potentially be a candidate for this drug. And is there a difference between these patients and patients who, in the past, would have been called as HER2-negative on the basis of IHC 0? And so what complicated things for us a little bit is that patients with IHC 0 were not eligible for this trial. And what is left unanswered by this clinical trial is whether all patients who don't have HER2 protein overexpression or HER2 gene amplification would potentially have benefited from this drug. Kim? Dr. Kim Allison: Yeah, agree. I think the main impetus for the update was the exciting results from the DESTINY-Breast04 trial and the questions then that the pathology community and the oncology community had about whether this should change HER2 testing guidelines. Brittany Harvey: I appreciate that background on what prompted the panel to revisit this guideline. So then, Dr. Allison, how did the panel come to the conclusion that the previous recommendations are current and valid? Dr. Kim Allison: Right. So, as Antonio mentioned, the whole reason HER2 testing was first initiated was HER2-targeted therapies that showed response in the overexpressed or amplified tested population. And so guidelines have really been fine-tuned and crafted around distinguishing the HER2-positive for over-expression and amplification from negative. And this trial really questioned that in that maybe we can target lower levels of the HER2 protein, but this assay really wasn't designed for that. So we looked at the data from the trial and some of the limited other data that's out there and really came to the conclusion that, look, everyone in DESTINY-Breast04 benefited. The whole population benefited, whether you were 1+ or 2+. And because 0s were excluded from the trial, we don't know if they benefited.  So we thought it was premature to create a new category, a new result category, and change our current reporting to a HER2-low category, mainly because we don't know that there's a new predictive threshold for response to treatment. So essentially, what we've got is a trial that showed great benefit but didn't create a new biomarker that is predictive or prognostic. Instead, it repurposed this older test as a trial entry criteria. And so now we're kind of stuck with 1+ or 2+ ISH negative as their trial entry criteria that gives you eligibility for trastuzumab deruxtecan. So essentially, we reaffirmed our prior recommendations with acknowledgment that what these categories: positive, equivocal, and negative, refer to is for protein overexpression or gene amplification and that we should continue to use the same scoring criteria, 1+, 2+, 0, and interpretation as were used in DESTINY-Breast04 for their clinical trial criteria. But awareness is important.  Dr. Antonio Wolff: Yeah, the other thing that I would add, Brittany, I think we need to go back to what was the purpose of HER2 testing back in 1998 when we identified the survival benefit from trastuzumab in metastatic disease. And then, in 2005, when we had evidence of adjuvant benefit in improving disease-free and then overall survival for patients with early-stage disease. And the immunochemistry assays at that time were developed to differentiate between patients who had HER2 overexpressing disease or HER2 gene amplified disease versus not. At that moment, it was clearly identified that patients were considered as having HER2-positive disease that defined a biological entity, a tumor subtype, a group of patients who had worse prognoses in the absence of therapy. But then when they were treated with, for instance, chemotherapy with anthracyclines at that time, but then with HER2 targeted therapies with antibodies, these patients that otherwise would have a poor prognosis now were having an improved outcome.  HER2 was a marker of poor prognosis but also a marker of a good chance of deriving clinical benefit, so there was a predictive benefit. And everything else, IHC 0, 1 or 2+, ISH-negative, there has been no evidence that targeting the HER2 pathway was clinically important. Or even more meaningful, there was no evidence that these patients have– within the subset of patients that don't have HER2 positive or overexpressing disease - there has been no evidence that those patients have a different outcome based on low levels of expression of HER2. A couple of years ago, in terms of trastuzumab, the NSABP reported findings in the data from NSABP B-47 where the antibody trastuzumab was added to chemotherapy to patients who were considered to have low levels of IHC expression, and in that case, was IHC 1+ or IHC 2+ gene non-amplified. And that settled the issue for sure, that there was absolutely no benefit in the adjuvant setting from the addition of trastuzumab. So we know that there's something different going on here. We know that if you now combine trastuzumab with a specific payload, in this case, the drug deruxtecan, which is a topoisomerase inhibitor, we are potentially targeting the HER2 protein. But these are tumors that are not considered HER2 addicted. These are not tumors whose biology is dependent on the HER2 pathway, so this is simply a better drug delivery.  And in this sense, data and evidence from Michael Press, a pathologist at USC that has done some seminal work with HER2 and HER2 testing, he once proposed that the vast majority of breast cancers have some level of HER2 present. And a lot of what is considered IHC 0 is an artifact related to suppression of the detection of the HER2 protein. So there's a chance that the tumors that are truly HER2 negative or HER2 0 are going to be a very small proportion. And IHC assays were never optimized to measure very low levels of HER2. They just don't have the dynamic range for that. And then, from a clinical standpoint, there is no evidence that different levels of HER2 when, in the absence of overexpression, identify groups of patients that have disease that have a different biologic behavior.  And I think, as Dr. Allison just mentioned, we don't have any evidence from the DESTINY-Breast04 trial that there is a differential benefit between IHC 1+ versus IHC 2+, ISH-negative. Those patients appear to equally benefit from therapy. Brittany Harvey: Understood. That context is helpful in understanding this updated guideline. So then you've both mentioned the category of patients who are HER2 IHC 1+ and 2+, and ISH-negative. So, Dr. Allison, this article includes a special commentary on those patients, those with HER2 IHC 1+ or 2+, and ISH-negative metastatic breast cancer. What are the essential points of this commentary?  Dr. Kim Allison: Yeah. So some of them we've brought up already that this test for HER2 IHC wasn't really designed to detect the low levels of protein expression that may be present in some breast cancers, including the all-important issue that the IHC 0s may not be truly null for HER2, that we may just not be sensitive enough to detect it, or there may be fixation and ischemia, time issues that are very subtle and create a false negative result, essentially by IHC that, and that in addition to not being necessarily predictive or prognostic, the 0 versus 1+ threshold, which really is a threshold that hasn't been tested yet.  But since eligibility for trastuzumab deruxtecan essentially now hinges around that 0 versus 1+ threshold, since these were clinical trial entry criteria, what can pathologists do to make best practice efforts to distinguish 0 from 1+? Because we felt like we should make some helpful recommendations, at least since this does appear to be a current status point that pathologists are going to be struggling with in practice. So the points we come up with in that commentary are to follow best practices, like making sure you're using the standardized ASCO-CAP Guidelines criteria. Making sure you pay attention to pre-analytic conditions of the tissue sample and that you're using controls with a range of protein expression, including 1+, to help ensure you've got an assay that's really looking at the right limit of detection since that has shifted somewhat in this instance.  And then for interpretation side, for pathologists to be sure to look on high power, so discriminating at 40x when you're trying to score a 0 versus 1+ stain since that's now relevant, you're going to need to go on high power and really distinguish from those two. And then, consider a second pathologist review in borderline or challenging cases or perhaps using additional tools. There's some additional tools online. There are learning sets that are out there to help with that distinction. Dr. Antonio Wolff: What I would add to that is that I think, and Kim, I'm thinking of the pathologist now getting phone calls from oncologists saying, “Hey, Doctor Pathologist, you report this cancer as being IHC 0, and are you sure that this is truly IHC 0?” And I think we need to be careful not to put pathologists in an unfair situation. And I think we also need to be careful based on our behavior as oncologists that we could almost cause the extinction of the diagnosis of IHC 0 if pathologists feel somehow compelled to “try to help the oncologists” and potentially call a tumor that they would otherwise have called IHC 0, that they call that tumor IHC 1+.  And I think the reason for being cautious, as Kim mentioned, is these assays were not optimized for the ability to truly distinguish between IHC 0 and 1+. And we do not know if tumors that are IHC 0 clinically behave differently from tumors IHC 1+. Right now, that does not appear to be the case. And I think to a degree, we are being forced, based on the decision by the study sponsors to launch a study that excluded patients of IHC 0. We are left, I often say, twisting ourselves into pretzels, trying to come up with a way to discriminate between IHC 0 and 1+ simply because of the eligibility of the clinical trial and now the resulting FDA label for the study.  Because it is plausible that what if patients who had tumors that were IHC 0 had been included in this clinical trial? And what if we had determined that those patients also benefited from this new exciting antibody-drug conjugate? In that case, we would not be talking about creating new categories of HER2 low versus HER2 “ultra-low” and HER2 0, HER2 null. Because essentially, we would have identified a new clinical use for this exciting antibody-drug conjugate for patients who have tumors that are HER2 not overexpressed and HER2 not amplified. So, in fact, it is entirely plausible that the population of patients that could benefit from this antibody may go well above the original intent of DESTINY-Breast04. We just don't have the evidence at this point to say that those patients who would be called IHC 0 don't benefit. It's just that they were not included in the clinical trial. Brittany Harvey: Well, your points there from both of you lead nicely into my next question, in that you've talked a little bit about how this impacts both oncologists and pathologists. So, Dr. Wolff, what does this guideline and commentary mean for both clinicians and patients with breast cancer? Dr. Antonio Wolff: So I think what I would try to reassure oncologists, pathologists, and also patients and their caregivers and loved ones, over the last 20 years, I think we have seen a meaningful improvement in the quality of HER2 testing. And I think pathologists and oncologists recognize that breast cancer biomarkers, in general, in the past, were used purely for prognostic reasons or to complement anatomic pathology from a diagnostic standpoint. But now, many of these assays, especially ER and HER2, are used as the sole determinant of therapy selection in a binary fashion. If you are positive for ER, you can be a candidate for ER-targeted therapy. If you're positive for HER2, you may be a candidate for HER2-targeted therapy. And I think even though the current generation of IHCs were not equipped to make a differentiation between very low levels of HER2 expression from potentially no levels of HER2 expression, with all the limitations we just said, I think pathologists are today doing a very good job. They understand the importance of the work they do in helping us clinicians take care of patients in the clinic. As I often joke, pathologists are wearing the stethoscope with us. So I think we need to be kind to pathologists and not put them under the microscope, if you will, pun intended, or putting a lot of pressure on them. And I think I tend to trust the quality of the work they do.  I think there are two things that I would like to see happening. Number one, I would love to see the study sponsor allowing investigators to use a new generation of assays that are more quantitative to be able to back on DESTINY-Breast04 and test specimens of the patients that were triggered on the trial and see if there is a differential benefit in the observed outcomes of patients treated with trastuzumab deruxtecan according to levels of HER2, but that can be measured using a truly quantitative assay. And there are a lot of new assays out there. And I think the sponsors, they do have an obligation to all the patients who are participating in the trial to allow those things to happen. And the second piece is obviously to develop assays that are more quantitative than a traditional IHC. And Kim, along these lines, a question that often comes up is what to do with patients who may have had a previous test that was IHC 0. And what should we, I guess, recommend to clinicians that they do with this situation? Dr. Kim Allison: Yeah, I think this is a common question, and because of the unreliability of a 0 versus 1+ result, and we do see them change when you look at metastatic, or core versus primary surgical excision, 0 versus 1+ results shift around much more so than you'd expect if this was a true biologic difference. So I would look at a spectrum of samples across the metastatic progression. So if any of them are not 0, I think that's a result worth looking at. And considering that either there's heterogeneity there potentially or the 0s were false negatives and not consistent over time, so I would test the metastatic sample again. If you have a new sample, if that's 0, I would still consider treating based on a prior 1+ result or a different sample that's metastatic.  Dr. Antonio Wolff: Yeah, the one thing that I haven't done yet is actually for patients who have had– Let's say, that I have a primary term that was IHC 0, and then, they had, unfortunately, metastatic disease, and the diagnostic tissue that confirmed that they had metastatic disease also tested IHC 0. And now they are– unfortunately, disease has progressed after first or second-line therapy, be it anti-estrogen if they had ER-positive disease or chemotherapy if they had ER-negative disease. What I have not done is to request a new biopsy exclusively for the purpose of doing another HER2 test because in case the tumor had changed expression from 0 to 1+. Because what we don't know because of the variability, etc., Dr. Allison was just describing whether that change is real or not.  Again, it's really unfortunate that patients who were IHC 0 were not allowed for this study. There are other studies taking place right now looking at tumors that are more than IHC 0 and less than IHC 1+; that's DESTINY-Breast06. And those patients are being called by the study sponsor as “ultra-low”. Although I am not a pathologist, but I have no idea how a pathologist can truly try using immunohistochemistry today; really reliably differentiate between it's not 0, it's not 1+, it's in between. I am just concerned that I think we may be asking or putting pathologists in a hard spot, asking them to do something with an assay that was not designed to perform that way.  Dr. Kim Allison: Even if we could get the interpretation perfect, to have digital tools to help us with interpretation, I think at that low level, IHC is just really sensitive to pre-analytics and analytic factors that are subtle. Even having a slide that's been sitting unstained for a week or so might change a 1+ to a 0 result. So it really is sensitive, maybe too sensitive, to those kinds of factors.  Brittany Harvey: Absolutely. Well, thank you both for those insights on what's facing clinicians and patients and the commonly asked questions today.  So then we've spent a lot of time talking about what's happened recently in this field. But, Dr. Allison, what are the ongoing developments and outstanding questions you're all facing regarding HER2 testing and breast cancer? Dr. Kim Allison: Yeah. I mean, I think we've covered some of those. Is IHC 0 truly 0? Would it be responsive to T-DXd or other antibody-drug conjugates targeting HER2? And so if that is relevant, then there's a lot of work looking at maybe more sensitive or quantitative assays that are really designed to detect those lower levels of expression, unlike the current assays. And then digital image analysis to standardize interpretation if they are leading to differences. And then new standards to help us calibrate.  Brittany Harvey: Great. Well, I want to thank you both so much for all of your work to review and update this guideline on HER2 testing in breast cancer. And thank you for your time today, Dr. Wolff and Dr. Allison.  Dr. Kim Allison: Thanks for having us. Dr. Antonio Wolff: Our pleasure. It's fun. Thank you.  Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline update, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Angie DeMichele and Dr. Lynn Henry present the latest rapid recommendation impacting two ASCO guidelines. This update focuses on testing for ESR1 mutations in patients with hormone receptor-positive, HER2-negative metastatic breast cancer, and presents treatment recommendations for patients with a detectable ESR1 mutation. Dr. DeMichele and Dr. Henry review the recent data from the EMERALD trial, discuss it's implications for practice, and ongoing developments they're monitoring for more effective therapeutic options. Read the latest update, "Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update at www.asco.org/breast-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the update and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.2300638  Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.  My name is Brittany Harvey, and today I'm interviewing Dr. Angie DeMichele from University of Pennsylvania, and Dr. Lynn Henry from the University of Michigan, authors on ‘Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update'.  Thank you for being here, Dr. DeMichele and Dr. Henry. Dr. Angie DeMichele: It's a pleasure.  Dr. Lynn Henry: Thank you.  Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests on this podcast episode today, are available online with a publication of the rapid recommendation update in the Journal of Clinical Oncology, which is linked in the show notes.  So then, getting into the content of this rapid recommendation first, Dr. Henry, what prompted this rapid update, which provides updated recommendations for two ASCO guidelines? First, the ‘Biomarkers for Systemic Therapy and Metastatic Breast Cancer Guideline', last published in 2022, and the ‘Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer Guideline', which was last updated in 2021. Dr. Lynn Henry: Thank you, Brittany. There's been a lot of exciting news for the treatment of metastatic breast cancer in the last few years. This particular update reflects the results of the phase III EMERALD trial. This trial compared the new oral selective estrogen receptor degrader, elacestrant, to standard-of-care endocrine therapy with either fulvestrant or an aromatase inhibitor in patients with hormone receptor-positive, HER2-negative metastatic breast cancer that had previously progressed during treatment with a CDK4/6 inhibitor in combination with endocrine therapy. Compared to standard-of-care, in this trial, they showed improved progression-free survival in both the overall study population as well as specifically in the patients who had a detectable ESR1 mutation in their circulating tumor DNA. These findings were published in the Journal of Clinical Oncology in 2022, and the drug was subsequently approved by the US Food and Drug Administration in January 2023. Therefore, we felt that it was important to update the guidelines to reflect the results of this trial and the new drug approval.  Brittany Harvey: Excellent. Thank you for describing the results of that trial and the new approval.  So then, based on this data, Dr. DeMichele, what is the updated recommendation from the guideline expert panel for testing for ESR1 mutations?  Dr. Angie DeMichele: So, the guideline panel has now recommended that ESR1 mutation testing occur for any patient who develops a recurrence or progression on endocrine therapy. And this is specifically in reference to the development of ESR1 mutations that can occur after a patient has been exposed to aromatase inhibitors. The guideline itself recommends that this testing be done on either tumor or blood, but blood is preferable because there is increased sensitivity using ctDNA testing over tumor testing. So this was an important component of the change in the recommendation because it's linked to the approval of elacestrant as a therapy. Patients are only eligible to receive elacestrant if they harbor an ESR1 mutation. Brittany Harvey: Understood. I appreciate that explanation.   So then, Dr. Henry, following that recommendation for testing, what is the new recommendation for treatment for patients with a detectable ESR1 mutation? Dr. Lynn Henry: Yes. So patients who have a detectable ESR1 mutation and who have previously received treatment with endocrine therapy in combination with the CDK4/6 inhibitor for advanced breast cancer now have multiple treatment options. The newest option is this new drug, elacestrant, which is given 345 milligrams orally daily. There are still the other options that we already knew about, which include a different endocrine therapy alone, such as fulvestrant or an aromatase inhibitor, or possibly an endocrine therapy in combination with a targeted agent, such as alpelisib or everolimus. And those decisions really need to be based on what other mutations are present in the patient's cancer.  Importantly, at this time, there are no safety or efficacy data to support using elacestrant in combination with targeted agents. Therefore, to date, it has only been approved to be used as monotherapy. But really, this is an exciting new potential option for treatment for patients whose tumors have a detectable ESR1 mutation. Brittany Harvey: Yes, this is an exciting option, and I appreciate you describing how this fits in with the existing treatment paradigm for these patients.   So then, Dr. DeMichele, as these new recommendations are implemented, what should clinicians know? Dr. Angie DeMichele: I think this is a really important new step in breast cancer in testing for ESR1 mutations. We've not previously had a medication that required the existence of an ESR1 mutation for patients to be eligible for therapy. So obtaining ESR1 mutation testing may be new for some clinicians. As I stated earlier, this can be done either on a tumor biopsy or on blood testing using the Guardant360 ctDNA test, which is the test that was used in the clinical trial. And it was stated that the ctDNA test is more sensitive than the tumor test. But what's really important here is that the testing occur at the time that the clinician is considering switching therapies, because it's important to find that ESR1 mutation prior to starting the next therapy. ESR1 mutations don't typically exist in a tumor at the time it's diagnosed. They only emerge over time after patients have been exposed to different endocrine therapies, particularly aromatase inhibitors. It's also possible that at the time of a recurrence after aromatase inhibitor therapy or progression on an aromatase inhibitor, there will not be any detectable ESR1 mutation. However, with subsequent therapy, an ESR1 mutation can occur. So a patient may need serial testing over time to determine whether an ESR1 mutation has developed.  Brittany Harvey: Understood. Those are important clinical implications.  So then, Dr. Henry, Dr. DeMichele just described some of the testing implications for patients. But in your view, how does this rapid update impact patients with hormone receptor-positive, HER2-negative metastatic breast cancer? Dr. Lynn Henry: So as Dr. DeMichele mentioned, this update specifically highlights approval of a new drug, oral SERD elacestrant. This is an exciting new option for treatment of patients whose tumors have an ESR1 mutation. So previous data have demonstrated that cancers with ESR1 mutations do not respond as well to previously available standard-of-care treatments such as aromatase inhibitors. It's nice to have a drug that may be a better option than some of the previously existing treatments for hormone receptor-positive, HER2-negative metastatic breast cancer. Brittany Harvey: Definitely. That's great to hear.  So then, finally, Dr. DeMichele, are there ongoing research developments that the panel is monitoring for future updates to these guidelines? Dr. Angie DeMichele: We certainly are monitoring additional research developments, Brittany. Specifically, there are numerous other selective estrogen receptor degraders that are being tested, and these also may ultimately require ESR1 mutation testing and detection for therapies. So we'll be monitoring the results of those clinical trials. We'll also be watching for additional trials that help us understand how to best utilize elacestrant and whether it can be combined with other therapies. And then, finally, I think we have to think about how to place this in the context of other types of molecular changes that we may detect in metastatic breast cancer, such as PIK3CA mutations and others. And as we move forward, I anticipate that we will have additional therapies that are specifically targeted to molecular changes in the tumor. And I think this is a really exciting development because this is a major step forward toward precision medicine, where we're really tailoring the therapy to the specific biology of the patient's tumor and actually responding to the ways in which the tumor is evolving over time and in response to treatment. So as tumors become increasingly resistant to therapies, we can actually take advantage of those resistance mechanisms to develop therapies that will be more effective. Brittany Harvey: Yes, we'll look forward to those new therapies and research developments and then updated guidelines in the future.  So I want to thank you both so much for your work on this rapid recommendation update and for your time today, Dr. DeMichele and Dr. Henry.  Dr. Angie DeMichele: Thank you.  Dr. Lynn Henry: Thank you very much.  Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guidelines, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.  The purpose of this Podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Nigel Key and Dr. Anna Falanga join us for a conversation on the updated ASCO VTE prophylaxis and treatment in patients with cancer guideline. They discuss recent evidence assessing apixaban for VTE treatment in patients with cancer and evaluating direct factor Xa inhibitors for extended postoperative prophylaxis. Based on this new evidence, they present updated evidence-based recommendations from the guideline expert panel. Dr. Key and Dr. Falanga also discuss outstanding questions regarding VTE prophylaxis and treatment in patients with cancer. Read the full guideline update, “Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer: ASCO Guideline Update” at www.asco.org/supportive-care-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00294.  Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at ASCO.org/podcasts.  My name is Brittany Harvey, and today I'm interviewing Dr. Nigel Key from University of North Carolina, and Dr. Anna Falanga from University of Milan Bicocca, co-chairs on ‘Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer: ASCO Guideline Update'.  Thank you for being here, Dr. Key, and Dr. Falanga.  Dr. Nigel Key: Thank you.  Dr. Falanga: Thank you. Brittany Harvey: Then, before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests on this episode, are available online with the publication of the guideline in the Journal of Clinical Oncology, linked in the show notes.  So then, jumping into this guideline update, Dr. Key, what prompted an update to the ‘ASCO VTE Guideline', which was last updated in 2019?  Dr. Nigel Key: Okay, well, thank you, Brittany, for that question. Well, first of all, ASCO has been providing this guideline since 2007 with iterations and full reviews of the data, the last complete one being in 2019. This update was really triggered by ASCO's signals approach, which relies on experts in the field suggesting an update to the guidelines based on recent publications that may be practice-changing. So, in this case, the signals were really a randomized control trial assessing apixaban for VTE treatment, venous thromboembolism treatment, in patients with cancer called the CARAVAGGIO trial, and we'll discuss that a little bit later. There were also a couple of randomized control trials which evaluated direct factor Xa inhibitors for extended postoperative prophylaxis, and these were new areas subsequent to the 2019 guidelines. So, a systematic review was carried out in the relevant topics for randomized control trials published between November 1, 2018, and June 6, 2022. And what you'll hear today is the result of that process.  Brittany Harvey: Great. And then you just described that guideline recommendations were updated both for prophylaxis and for treatment. So then, Dr. Falanga, what is the updated recommendation for perioperative VTE prophylaxis? Dr. Falanga: Thank you for this question. For this update, actually, there were two randomized trials addressing the extended thromboprophylaxis in cancer patients. This is an important question, and direct oral anticoagulants had never been included in the previous guidelines. So this new data indicating safety and in some way efficacy of these drugs were important to be in some way included. Actually, the two trials, one tested laparoscopic surgery in patients with colorectal cancer, so major surgery in colorectal cancer and tested the drug rivaroxaban against the placebo after one week of low molecular weight heparin. And the other trial tested in a different type of cancer, gynecological cancer surgery, apixaban versus a placebo after a short course with low molecular weight heparin.  So the two trials are very different, and the recommendation, after all, is weak. But the panel felt it was important to split the previous recommendation 3.5 into three recommendations. The 3.6 specifies which are the cancer patients that really need extended prophylaxis, or the recommendation addresses this population in particular at high risk, which means patients with laparoscopic or laparotomic abdominal pelvic surgery for cancer who have high risk characteristics, including restricted mobility, obesity, previous history of thrombosis, and other additional risk factors. So the recommendation is limited to this population. As I said, there is a weak recommendation because the two trials differ in the type of surgery, the type of the number of patients, the timing of prophylaxis, and one tested rivaroxaban and one tested apixaban. But in any case, the recommendation now reads that prophylaxis with these two direct oral anticoagulants may be offered in addition to the previous recommendation with the low molecular weight heparin for this indication, although the low molecular weight heparin indication remains a strong recommendation where these other two drugs are added. But still other research is needed to strengthen this recommendation. Brittany Harvey: Understood. Thank you for describing where there is evidence and where future research is needed to strengthen those recommendations and the qualifying statements for who is appropriate to receive this VTE prophylaxis. So then, Dr. Key, what did the expert panel update regarding treatment of patients with cancer with established VTE to prevent recurrence?  Dr. Nigel Key: Yes. First of all, I want to make it very clear that this particular recommendation deals, as you say, with patients with established venous thromboembolism. This is quite distinct from recommendations regarding primary prophylaxis in ambulatory patients, which is dealt with in a separate recommendation. That's number two in the 2019 guideline, and those have not been updated. But in terms of treatment of established venous thrombosis, there were three randomized control trials considered. They essentially all addressed the possible role of apixaban, which had not been included in the 2019 guideline. In this revised recommendation, the data looked at both the initial treatment of patients presenting with venous thrombosis as well as extended treatment, which what we know at present, really extends out to six months in terms of using non-vitamin K antagonists, preferably for extended prophylaxis.  So, in 4.1, the CARAVAGGIO trial that I mentioned earlier was a very large trial involving almost 1200 patients with cancer who had symptomatic or incidental acute proximal DVT or pulmonary embolism. And these patients were randomized to six months of treatment with either apixaban or dalteparin. And, in a nutshell, apixaban was non-inferior to dalteparin for the primary outcome of a recurrent VTE during the six month trial period. There was also a similar rate of major bleeding, 3.8 versus 4% in the two arms. So this was strong evidence that initial treatment could include apixaban in addition to what was already in the recommendations. And for those choosing to treat with heparin for initial five to ten days, as before, the recommendation is for low molecular heparin over unfractionated heparin.  So, the second part of this took into account the CARAVAGGIO trial, which I've already mentioned the result of, as well as two smaller trials. They had a VTE trial which had almost 300 patients, and again compared apixaban to dalteparin. And then there was a third smaller study comparing apixaban to lovenox in about 100 patients. But, essentially, the net outcome of the systematic review was that the recommendations 4.1 and 4.2 for, respectively, initial and extended treatment of established VTE, gave high quality evidence with a strong recommendation to include apixaban both for initial treatment and for extended treatment. Brittany Harvey: Understood. So then you've both discussed this a bit by describing the randomized trials supporting these recommendations. But Dr. Falanga, what should clinicians know as they implement these updated recommendations?  Dr. Anna Falanga: Well, clinicians should know that there are more options to offer to their patients for long-term treatment of VTE, as Dr. Key said, up to six months. This is an important expansion of the spectrum of choices for a more personalized treatment on the basis of the patient's characteristics and the drug characteristics. So this is very important to know. Also, for the postoperative prophylaxis, this update is relevant because of the recommendation. Although we are open to the perspective of using new drugs based on oral intake as an alternative to low molecular weight heparin, and knowing this drug appears to be safe in the specific setting where they were tested in the trial is important. Brittany Harvey: Definitely, it's great to have more options for patients. So then in your view, Dr. Key, how will these guideline recommendations impact patients with cancer?  Dr. Nigel Key: Well, I think that with more information that Dr. Falanga just presented, essentially we're looking at two different situations here, both the extended thrombosis prophylaxis after surgery and the choice of agent does need to be individualized with a discussion with a physician. There are still remaining concerns about increased bleeding with direct Xa inhibitors in patients with GI and GU malignancy, for example. So this needs to be taken into account, patients' creatinine values and so on, and what other drugs there are in terms of interactions with direct Xa inhibitors. So I think what you're looking at though is the ability to be confident for that patient that oral agents are, for the most part, as safe and effective as low molecular weight heparins. And hopefully, this will be something that is seen as a positive and maybe somewhat liberating effect for patients.  Brittany Harvey: That's great to hear.  So then finally, Dr. Falanga, you've already mentioned a few areas in which more research would be helpful to strengthen the recommendations. But are there other outstanding questions regarding VTE prophylaxis and treatment in patients with cancer?  Dr. Anna Falanga: Yes, there is a lot of work to be done ahead for prophylaxis. As we already mentioned, it's important to improve the evidence for direct oral anticoagulant safety and efficacy for extended, postoperative prophylaxis. In the medical setting, we have open questions about how to improve the management of patients with VTE beyond six months; we don't know for the treatment of VTE beyond six months, and identify better what are the best drugs and the best strategies to be utilized in this interval.  Then I think that we need to understand, in collaboration with cardiologists and neurologists, whether arterial thrombosis associated with the cancer may need a different treatment compared to subjects without cancer, and understand how to manage anticoagulant together with antiplatelet drugs in these patients who are often thrombocytopenic.  Finally, it is, of course, important to test new drugs for VTE treatment with potentially reduced bleeding risk, such as the new inhibitors of factor XI and factor XII. I think these are the major points that we need to address in the near future possibly.  Brittany Harvey: Absolutely. Well, we'll look forward to future updates of this ASCO guideline to discuss that research as it comes along.  So I want to thank you both so much for your work to update this guideline and thank you for your time today, Dr. Falanga and Dr. Key.  Dr. Anna Falanga: Thanks a lot. Bye bye.  Dr. Nigel Key: Thank you. You're very welcome. Bye bye.  Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  

Dr. Barbara Andersen delves into the newly updated guideline for management of anxiety and depression in adult survivors of cancer in this ASCO Guidelines podcast episode. This guideline affirms prior guidance regarding screening and assessment of anxiety and depression, and updates evidence-based recommendations for management of both anxiety and depression. Dr. Andersen reviews the principles of the recommended stepped-care model, along with recommended treatments, including options such as cognitive behavior therapy, cognitive therapy, behavioral activation, structured physical activity and exercise, and mindfulness-based stress reduction. Challenges regarding managing anxiety and depression in adult survivors of cancer are also discussed. Read the full guideline update, “Management of Anxiety and Depression in Adult Survivors of Cancer: ASCO Guideline Update” at www.asco.org/survivorship-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/survivorship-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00293. Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.  My name is Brittany Harvey, and today I'm interviewing Dr. Barbara Andersen from the Ohio State University, lead author on “Management of Anxiety and Depression in Adult Survivors of Cancer: ASCO Guideline Update.”  Thank you for being here, Dr. Andersen.  Dr. Barbara Andersen: Thank you. Thank you for the invitation. Brittany Harvey: And then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Andersen on this episode, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to jump into the content of this guideline, Dr. Andersen, what prompted an update to this guideline, and what is the scope of this updated version of the guideline?  Dr. Barbara Andersen: Well, as your listeners probably know, guidelines are routinely updated, primarily due to new accumulated evidence that suggests a change in diagnostic or treatment procedures. The first guideline from ASCO was in 2014. They made this important first step, which alone made that an important advance. The prior scope was on assessment, that is, which measures at what time points were important for assessing patients' depressive or anxiety symptoms. We then provided treatment pathways thereafter, noting currently available evidence for treatment. But a systematic review of the literature wasn't done at that time. So what this guide does is first affirm the prior recommendations regarding the measures to use for assessment, the PHQ-9 and the GAD-7. But the departure for these guidelines is based on a systematic review of the intervention and treatment literature, and from that review, we recommend particular treatments. Brittany Harvey: Understood. So, focusing on that intervention and treatment aspect of this updated guideline, I'd like to review the key recommendations starting with, what are the key general management principles for people with cancer and anxiety and/or depression?  Dr. Barbara Andersen: Well, one key principle is that of education. Your listeners probably are familiar with the fact that many hospitals or centers provide patient-tailored cancer treatment-related information, treatment information on surgery, chemotherapy, immunotherapy, and other topics. But we recommend that general first-level materials on coping with stress, anxiety about treatment, and depression be routinely provided as well. What that does is for individuals with elevated symptoms, it validates what they're experiencing and normalizes the patient experience. So we hope that all patients with cancer and any patient-identified caregiver, family member should be offered the information. We have so many ways we can give information to patients these days. Verbally, material, whatever mode is easy for you and the patient, but please choose one to give information to patients.  Another characteristic of the guideline is our recommendation that treatment follow the principle of stepped care. So what this means is you match the assessment of the severity, level of depression or anxiety, and you match that data to the selection of treatment contexts. This is most clearly seen in the recommendation that group treatment formats be used for those with moderate severity of symptoms versus individual or face-to-face therapy for those with severe symptoms. And this is the case for both anxiety and depressive disorders. This is a principle that's cost-effective and tailors the treatment recommendations. Another principle that we offer is when making a referral of a patient for further evaluation or psychological care; we plead with you to make every effort to reduce the barriers and facilitate patient follow-through. We say it's essential because low motivation, for example, is a symptom of depression. And that low motivation and low mood can conspire to reduce the likelihood that patients will pursue treatment. So just keep that in mind when referring patients.  Brittany Harvey: Absolutely. Those are key points for general management across anxiety and depression symptoms. So, moving beyond those principles, what are the recommendations from the expert panel for treatment and care options for patients with depressive symptoms?  Dr. Barbara Andersen: For depressive symptoms, we recommend cognitive behavior therapy or cognitive therapy, behavioral activation, psychosocial interventions using empirically supported components, and moderate structured physical activity and exercise. All of those are efficacious, empirically supported treatments for moderate depressive symptoms. And it might be easiest to offer group therapy for individuals with these problems.  Brittany Harvey: Great. Thank you for reviewing those recommendations for patients with depressive symptoms.  So, in addition, what does the expert panel recommend for treatment and care options for patients with anxiety symptoms?  Dr. Barbara Andersen: Many of the same treatments are used. Cognitive therapy, cognitive behavior therapy are the most efficacious treatments out there for cancer patients or individuals without cancer coping with anxiety symptoms or depressive symptoms. Again, behavioral activation would be useful. Mindfulness-based stress reduction has garnered significant support in the recent years, as well as interpersonal therapy.  Brittany Harvey: Understood. So thank you so much for going through each of those recommendations.  But in your view, Dr. Andersen, what is the importance of this guideline, and how will it impact both clinicians and patients with cancer and symptoms of anxiety and/or depression?  Dr. Barbara Andersen: An important element to this guideline is it names the specific empirically supported standard therapies for treatment of anxiety and depression. There's a departure, though, from our prior guideline, and in this one, pharmacotherapy is not recommended as a first-line treatment, neither alone nor in combination. It's simply not supported by the evidence. However, clinicians might consider pharmacotherapy when there's low or no availability of mental health resources. Perhaps a patient might have responded well to pharmacotherapy in the past, and patients with severe neurovegetative, or agitated symptoms of depression, those patients, as well as patients with psychotic or catatonic features, would be ones for which pharmacotherapy might be appropriate.  Brittany Harvey: Understood. And then you've just mentioned that sometimes there is no or low availability of mental health resources, so that leads to my next question. But what are the both outstanding research questions and challenges regarding managing anxiety and depression in adult survivors of cancer?  Dr. Barbara Andersen: The largest challenge is that we're in the midst of a mental healthcare crisis, and COVID has made that abundantly clear. There are problems with access to psychological care due in part to workforce problems, maybe organizational ones, but there is a shortage of mental health professionals, and that, in turn, limits referral networks from managing depression and anxiety. So that's one significant issue that is in place right now.  Since the 2014 guideline, screening is a care aim that has been disseminated, but the principles and procedures remain to be fully implemented. I was just looking at a 2022 article in the Journal of Oncology Practice. It was a study examining screening for lung and ovarian cancer patients, two very important groups because the frequency of depressive and anxiety symptoms is perhaps highest of any other groups. So they looked at more than 20 CoC-accredited facilities that studied the electronic records to see if there was screening for the patients. And the troubling finding, from my perspective, was that there was no screening for 45% of the patients in this study. So we know that there are disparities in the use of screening and its management. Those disparities exist across race, ethnicity, cancer type, stage, and facilities. And so, that remains a challenge for many sites, including CoC hospitals, to achieve a rigorous screening program. Having said that, I want to say what some might disagree with, but from my standpoint, it's a myth that screening takes a long time. The measures that we recommend probably would take a patient maybe five, maybe ten minutes to complete. But what's time-consuming or what's troublesome in many places is the infrastructure is not in place to do the screening and interpret it in an efficient manner. The other perspective on screening is that it is the effort thereafter, which is, in fact, time and resource intense - that is, finding referral sources, making referrals. But that's the most important step because when that's not done, when patients continue with symptoms, it really incurs the greatest cost for the patients. Brittany Harvey: Absolutely. Screening and then further management of anxiety and depressive symptoms is key for maintaining quality of life.  So I want to thank you so much, Dr. Andersen, for coming on today and sharing your insights and also for all your work you did to update this guideline.  Dr. Barbara Andersen: Thank you so much. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast.  To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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