Podcasts about folfox

Play Episode Listen Later Feb 6, 2025 21:13

Dr. Shaalan Beg and Dr. David Wang discuss key abstracts in GI cancers from the 2025 ASCO Gastrointestinal Cancers Symposium, including major advances in CRC, neoadjuvant approaches in esophageal cancer, and innovative studies on ctDNA. TRANSCRIPT Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg. I'm a medical oncologist and an adjunct associate professor at UT Southwestern Medical Center in Dallas. Today, we're bringing you some key highlights from the 2025 ASCO Gastrointestinal Cancers Symposium, and I'm delighted to be joined by the chair of GI25, Dr. David Wang. Dr. Wang is a GI medical oncologist at the University of Michigan. Our full disclosures are available in the transcript of this episode. Dr. Wang, thanks for coming on the podcast today. Dr. David Wang: Well, thank you. It's a pleasure to be here. Dr. Shaalan Beg: GI25 featured major therapeutic advances across the spectrum of GI malignancies, and it was exciting to hear about innovations and novel approaches that are shaping the future of our field. Before we start talking about specific abstracts, could you share some of your key highlights from the meeting? Dr. David Wang: Sure. Our theme this year was “Breaking Boundaries to Enhance Patient Centered Care.” Past years' themes have focused more on precision oncology, but we wanted to broaden our focus on patients and to be more holistic, which kind of led us into some of the Intersection [sessions] that we had. Each day started with a different Intersection. The first one was “Emerging Therapies in GI Cancers”, where invited speakers talked about bispecific antibody drug conjugates, theranostics, CAR T and other cell-based therapies. The second day was on “Personalized Risk Assessment for GI Cancers,” and this included looking at polygenic risk scores for colorectal cancer, microRNAs and liquid biopsies such as exosomes and pancreatic cancer and non-endoscopic screening modalities in esophageal cancer. And on our final day, we wanted to talk about “Integrative Oncology and Integrative Medicine,” looking at evidence-based uses of acupuncture and supplements in patients who are receiving treatment for cancer, mindfulness-based practices and exercise. And of course, we had a fantastic keynote talk by Dr. Pamela Kunz from the Yale School of Medicine titled, “Disrupting Gastrointestinal Oncology: Shattering Barriers with Inclusive Science.” She highlighted the intersection of science, patient care, and health and gender equity. And I would encourage your podcast listeners to access the lecture in ASCO's Meeting Library if they haven't yet had a chance to hear Dr. Kunz's wonderful lecture. We were really happy this year because the attendance hit a new record. We had over 5,000 people attend either in person or virtually from their home or office, and we had almost 1,000 abstracts submitted to the meeting, so these were either record or near record numbers. We offered a lot of different networking opportunities throughout the meeting, and attending found these to be incredibly rewarding and important and this will continue to be an area of emphasis in future meetings. Dr. Shaalan Beg: Let's take a deeper dive into the exciting studies presented at GI25. The late breaking abstract LBA143 was CheckMate-8HW. This was the first results of NIVO + IPI versus NIVO monotherapy for MSI-high metastatic colorectal cancer. What are your thoughts about this study? Dr. David Wang: Yeah, so we know that colorectal cancer patients with MSI-high tumors don't necessarily respond well to chemotherapy. And we were fortunate because last year CheckMate-8HW actually looked at two different arms – so this was NIVO + IPI compared to standard of care chemotherapy and showed its very significant improvement in median progression-free survival. And that was actually published in the New England Journal of Medicine back in November of 2024. This year's presentation actually focused now on NIVO + IPI versus NIVO monotherapy. And as you know IPI+NIVO can be quite toxic. So this was an important analysis to be done. So we know that NIVO is definitely more easily tolerated. So what was interesting was that the 2-year and 3-year progression-free survival not surprisingly favored IPI+NIVO and this was statistically significant. And the overall response rate was also better with IPI+NIVO versus NIVO alone. I know we're always concerned about toxicities and there were higher grade 3 and 4 toxicity incidences in the combination arm versus the monotherapy arm, but overall, only about 28 additional events in several hundred patients treated. So I think that's well-tolerated. Our discussant Dr. Wells Messersmith actually said that, with this new data, he would consider doing combination immunotherapy in any patient that presented in the front line with MSI-high or deficient mismatch repair colorectal cancer that was metastatic. Dr. Shaalan Beg: One of the focuses for directing first-line therapy for colorectal cancer has been right and left sided colon cancer because we know these are two different cancers with their own unique molecular subtypes. We heard on Abstract 17, the DEEPER trial, the final analysis of modified FOLFOXIRI plus cetuximab versus bevacizumab for RAS wild-type and left sided metastatic colorectal cancer. How do you summarize the findings of this study and what should our readers be aware of? Dr. David Wang: Interestingly, this was a phase 2 study and the emphasis of the abstract was actually a subgroup analysis of those patients with RAS wild-type and BRAF wild-type as well as left sided cancers. So, I think the entire study enrolled 359 patients, but the analysis that was discussed at the meeting really focused on 178 patients that fit that characteristic. Very similar to what we've seen in prior studies, left-sided tumors have better response to cetuximab versus bevacizumab. And if you flip it so that you now are looking at right sided tumors, targeting EGFR is actually detrimental. The depth of response was better with cetuximab in these left sided RAS and BRAF mutant tumors. And so the lead author actually suggested that this could be a new first-line standard of care. And the question is, is there a benefit of doing this triple agent regimen with modified FOLFIRINOX? We know there's a lot more toxicity with that. Not clear that there's a benefit for that over FOLFOX, maybe in younger patients that could tolerate it. When our discussant, again Dr. Wells Messersmith, spoke about this, he said that, in his practice he would, again, favor cetuximab over bevacizumab in combination with chemo, these left-sided RAS and BRAF wild-type tumors, but that he would actually prefer a doublet versus a triplet chemo regimen, and that is consistent with the current NCCN guidelines. Dr. Shaalan Beg: Another area where colorectal cancer has been a wonderful model to study new technology has been in the area of circulating tumor DNA (ctDNA). And the BESPOKE CRC trial is looking to see if ctDNA can inform adjuvant treatment decisions for stage II and III colorectal cancer. And in Abstract 15, we heard final results of the BESPOKE CRC sub-cohort. What were the findings there? Dr. David Wang: BESPOKE CRC is another one of these important ctDNA studies. It was an observational study, not a randomized trial, but it did provide a lot of different insights to us. We know that there were over 1,700 patients enrolled, and so it was reported that this is the largest ctDNA study in colorectal cancer performed in the United States. And they were able to analyze over 1,100 patients. Some of the key findings were that postoperative adjuvant therapy management decisions actually changed in 1 out of 6 patients, so that's pretty significant. In terms of surveillance, we know that patients who have ctDNA positivity, this is prognostic of recurrence. In terms of patients who have positive ctDNA post-surgery, it looked like, at least in this observational study, the majority of patients who received any benefit were those who had positive ctDNA. So adjuvant therapy, even in stage II and stage III patients seemed to only benefit those patients who have positive ctDNA. I think that does raise the question, and this also was brought up in the discussion, which is “Can we de-escalate adjuvant therapy in terms of patients who are ctDNA-negative post-op?” And Dr. Richard Kim from Moffitt felt that we are not yet there. Obviously, we need randomized control trials where we are taking ctDNA results and then randomizing patients to receive adjuvant or non-adjuvant to really know the difference. Other questions that come up with use of ctDNA include: What do you do with these patients who turn positive? This study for BESPOKE actually followed patients out to two years after surgery. So what you do with a positive ctDNA result wasn't really clear. It seems to suggest that once you turn positive, patients go on to more intensive surveillance. You know, again as an observation, patients who did turn positive were able to go to metastasis-directed therapy much more quickly. And again, this was supposedly to improve their curative intent therapy. And I think the other question that has been brought up all the time is, is this really cost effective? Patients want to know, and we want to give patients that information, but I think we're still stuck with what to do with a positive ctDNA level in a patient that's on surveillance because no randomized control studies have actually suggested that we need to start systemic therapy right away. Dr. Shaalan Beg: Yeah. And I guess in terms of practice informing or practice changing, these results may not give us a clear answer. But because a lot of patients are asking for these tests, it does give us some real world experiences on what to expect in terms of conversion of these positive into negative and the outcome so we can have a shared decision making with our patients in the clinic and then come up with a determination on whether ctDNA for molecular residual disease is something which would be worthwhile for the care of our patient. But more to come, I guess, in coming years to answer different problems around this challenge. Dr. David Wang: Yes, I agree. Dr. Shaalan Beg: The BREAKWATER trial looked at the use of encorafenib, cetuximab and chemotherapy for BRAF V600E-mutant metastatic colorectal cancer. We've covered this combination for a second- third-line treatment in metastatic colorectal cancer previously. Abstract 16 from GI25 was evaluating the use of this regimen in the first-line space. Everyone was looking forward to these results, and what did the investigators present? Dr. David Wang: I think this is, as you mentioned, a nice follow up to later lines of therapy where Dr. Kopetz from MD Anderson pioneered use of encorafenib, cetuximab and binimetinib in the BEACON trial. Everybody was kind of curious what would happen now if you use encorafenib plus cetuximab plus chemotherapy in the first-line setting. And so this is an interim analysis that was pre-planned in the phase 3 open label BREAKWATER trial. And even though there were three arms, and so the three arms were encorafenib plus cetuximab, encorafenib plus cetuximab plus FOLFOX, or standard of care chemo, only two arms were presented in the abstract. So basically looking at encorafenib plus cetuximab and FOLFOX-6 versus standard of care therapy, and the overall response rate was statistically significant with a 60.9% overall response rate encorafenib plus cetuximab plus chemo arm versus standard of care chemo was only 40%. The interim overall survival also was different. It was 92% versus 87% at 6 months and 79% versus 66% at 12 months, again favoring the chemotherapy plus encorafenib plus cetuximab. In terms of the statistics, the p was 0.0004. However, the pre-plan analysis required the p-value to be 1x10 to the -8. And so even though this looks really good, it hasn't quite met its pre-specified significance level. The good thing is that this is only interim analysis and the study is ongoing with future analysis planned. So the real question is: Does it matter when we actually use this regimen? We know that the regimen's approved in the second third-line setting. What about in the first line? And there was some preclinical data that the discussant reviewed that shows that patients actually benefit if this is done in the first-line setting. For example, there was some preclinical data showing that even FOLFIRI, for example, can upregulate RAS, which would make tumors more resistant to this combination. This was thought to be practice-changing in a patient that has B600E showing up treatment naive that we should probably consider this regimen. And actually this did receive accelerated FDA approval about a month ago. Dr. Shaalan Beg: Yeah, and for what it's worth, I put up a Twitter poll asking my Twitter followers on how the BREAKWATER trial results will change their approach for newly diagnosed BRAF mutated colorectal cancer. We got 112 responses; 72% said that they will incorporate encorafenib, cetuximab, FOLFOX for their frontline BRAF mutated patients. But 23% said that they would like to wait for overall survival results. Dr. David Wang: Wow, that's interesting. They really want that 1x10 to the -8. Dr. Shaalan Beg: I guess so. All right. Let's change gears and talk about esophageal cancer. LBA329 was the SCIENCE study which presented preliminary results from a randomized phase 3 trial comparing sintilimab and chemoradiotherapy plus sintilimab versus chemoradiotherapy for neoadjuvant resectable locally advanced squamous esophageal cancer. Where are we in this space? Dr. David Wang: Okay. So, yeah, this was an interesting trial. Again, just to set the context, esophageal squamous cell carcinoma is more prevalent in Asia. And the study sites as well as the patients were mostly from Asia. So this was again a phase 3 trial with interim results. They only rolled 146 out of the planned 420 for this interim analysis. And yeah, they're using immune checkpoint inhibitor that we don't use in the United States, sintilimab, combined with their two standards of neoadjuvant therapy, either chemotherapy, which is more common in Asia, or or chemoradiation, which is more common in the US and Western Europe, versus chemoradiation. And so they actually had two primary endpoints, but only were reporting one. So their two primary endpoints were pathCR and the other one was event-free survival. The event-free survival, again, was not reported at the meeting. What they found was that in terms of pathCR rate, if you take the two arms that are really informative about that, chemoradiation plus sintilimab versus chemoradiation alone, the pathCR rate was 60% versus 47%. We know that chemo alone doesn't induce as much of a pathCR rate, and that was 13%. So it was found that the delta in terms of pathCR between the chemoradiation arms, one with sintilimab and one without, was significant. And this actually confirms data again from Asia, like for the ESCORT-NEO trial where it used another immune checkpoint inhibitor pembrolizumab in addition to neoadjuvant chemo. So as our discussant for this abstract said, yes, we know that radiation combined with chemotherapy improves pathCR rates, but we have recent data from the ESOPEC trial, we don't know that that necessarily will translate to overall survival. So again, waiting for additional enrollments and longer term follow up before incorporating this into clinical care here. Dr. Shaalan Beg: So David, how do the results of the SCIENCE trial compare with our practice in the United States and ongoing studies asking questions for neoadjuvant therapy for esophageal carcinoma in the United States? Dr. David Wang: I think obviously immune checkpoint inhibitor in the new adjuvant setting is important. Jennifer Eads at UPenn is running that EA2174 which is looking at chemoradiation plus or minus nivolumab, and then in non-pathCR responders randomized to adjuvant nivolumab per CheckMate 577 or nivolumab with intensification adding ipilimumab. We know that the ESOPEC trial just came out, and was published actually during the meeting, and that really focuses on adenocarcinomas. So adenocarcinomas of the GE junction, distal esophagus, now, we would probably treat very similarly to gastric using perioperative FLOT. However, the standard in the US for esophageal squamous cell carcinoma remains neoadjuvant chemoradiation. We know that squamous cell carcinomas are more exquisitely sensitive to radiotherapy. And then obviously in those patients who don't achieve a pathologic complete response, the expectation would be that they would go on to receive nivolumab per CheckMate 577. Again, the thought is that these tumors are more sensitive to immunotherapy given their higher incidences of mutational changes. And so again, this kind of goes along with the positive results seen in the SCIENCE trial that we just discussed with sintilimab but also EFFECT-neo with pembrolizumab. Obviously, we await the results of Jennifer's trial. Dr. Shaalan Beg: And the last abstract I was hoping we could get your perspective on was Abstract 652, which is a Phase 3 study of everolimus plus lanreotide versus everolimus monotherapy for unresectable or recurrent gastroenteropancreatic neuroendocrine tumors, the STARTER-NET trial. What were the results of this study? Dr. David Wang: So, I just want to give a shout out because we did have a session at this year's GI ASCO that looked at more rare tumors. So appendiceal tumors, neuroendocrine tumors, those kinds of things. So again, I would encourage your listeners to listen to that session if they have interest in that. Another type of rare tumor was adenosquamous tumors. But in terms of the STARTER-NET trial, this was again an interim analysis of his phase 3trial and it was looking at combining everolimus plus lanreotide versus everolimus. So we know that in pancreatic-gastric neuroendocrine tumors, if you have low Ki-67, a well differentiated tumor, that the standard of care really is a somatostatin analog, and sometimes if they're more aggressive, we kind of consider molecular targeted therapy with everolimus. This was asking the question of whether we should do the combination on the frontline. And what was interesting is in this study, the patients were actually more of a poor prognostic set. So they had Ki-67 up to 20% or these were patients that actually had multiple liver lesions. And what they found was a median for progression free survival was improved with a combination out to 29.7 months versus 11.5 months with the somatostatin analog alone, and that the overall response rate was 23% versus 8.3%, again, favoring the combination. If you looked at subgroup analysis, it was actually those patients who had Ki-67 greater than 10%, so the more aggressive tumors, or those with diffuse liver lesions that had the most benefit. So I think that would be the patient population I would consider this new combination with using would be those patients again with poorer prognosis neuroendocrine tumor phenotype. Dr. Shaalan Beg: Thank you very much, Dr. Wang, for sharing your insights with us today and your great work to build a robust GI Cancers Symposium this year. Dr. David Wang: Well, thank you. I mean that really is a cooperative effort. We appreciate all the members of the GI25 Program Committee as well as the ASCO staff that just made it an outstanding meeting. Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Disclaimer: 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. Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Dr. David Wang Follow ASCO on social media:  @ASCO on Twitter  @ASCO on BlueSky ASCO on Facebook  ASCO on LinkedIn  Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. David Wang: Honoraria: Novartis Consulting or Advisory Role: Novartis, Cardinal Health, Bristol-Myers Squibb, BeiGene, Eisai

GI ASCO 2025 Highlights - BREAKWATER, CheckMate-8HW, ALASCCA, STARTER-NET

Oncology Brothers

Play Episode Listen Later Feb 3, 2025 20:47

Welcome to another episode of the Oncology Brothers podcast! In this episode, Drs. Rahul and Rohit Gosain are joined by Dr. Alok Khorana, a GI medical oncologist from the Cleveland Clinic, to discuss the latest highlights from the GI ASCO 2025 conference. We dive into four key studies that are practice-informing and potentially practice-changing: 1. BREAKWATER: We explore the implications of using Encorafenib and Cetuximab in combination with FOLFOX for patients with BRAF V600E mutations, which are associated with poor prognosis. 2. CheckMate-8HW: This study investigates whether dual checkpoint inhibition is more effective than single-agent immunotherapy for MSI-high patients, revealing promising results in progression-free survival. 3. Aspirin in Adjuvant Settings: We discuss the role of low-dose aspirin in reducing recurrence rates for patients with PI3K alterations, highlighting its potential as a practice-changing intervention. 4. STARTER-NET: Finally, we review the findings from the study on Everolimus combined with Lanreotide for neuroendocrine tumors, noting the lack of overall survival benefit. Tune in for an insightful discussion on these important topics in oncology, and learn how these findings could impact treatment strategies in your practice. Don't forget to like, subscribe, and check out our other episodes for more conference highlights and treatment discussions! YouTube: https://youtu.be/YOToz3hKYTg Follow us on social media: •⁠ ⁠X/Twitter: https://twitter.com/oncbrothers •⁠ ⁠Instagram: https://www.instagram.com/oncbrothers #OncologyBrothers #GIASCO2025 #ColorectalCancer #Immunotherapy #NeuroendocrineTumors #CancerResearch #Podcast

gi drs starter cleveland clinic rahul checkmate aspirin asco msi breakwater pi3k braf v600e cetuximab everolimus folfox

The Risks and Benefits of Taking a Break From Cancer Treatment

Play Episode Listen Later Aug 1, 2024 18:47

Dr. Shaalan Beg and Dr. Arjun Gupta discuss the rationale behind treatment breaks and assess the pros and cons based on feedback and data from patients with advanced-stage gastrointestinal cancers. TRANSCRIPT Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center in Dallas and senior advisor for clinical research at the National Cancer Institute. I'll be your guest host for the podcast today. On today's episode, we'll be discussing treatment holidays in GI cancers. Treatment holidays, also known as drug holidays, are increasingly being discussed in clinical practice and involve voluntarily halting treatment for a duration determined by a health care provider if believed to be beneficial for a patient's well-being. We'll address the rationale behind treatment holidays and explore their potential risks and benefits. Joining me for this discussion is Dr. Arjun Gupta, a GI medical oncologist and health services researcher at the University of Minnesota. Dr. Gupta's research on treatment-related time toxicity has explored the benefits of taking a break from treatment. Our full disclosures are available in the transcript of this episode. Arjun, it's great to have you on the podcast today. Dr. Arjun Gupta: Thanks, Shaalan. It's a joy to be here. Dr. Shaalan Beg: Your research at the intersection of oncology, supportive care, and care delivery is extremely interesting and important in today's day and age. And you've done extensive work on the concept of time toxicity in cancer treatment. So as we think about these discussions in the clinic on treatment holidays and we talk about risks and benefits, I was hoping that you could help explain the concept of time toxicity in cancer treatment and what our listeners should remember from this. Dr. Arjun Gupta: Sure. So time toxicity is simply the time commitments that cancer care imposes on people with cancer and their loved ones, and the burden that comes along with these commitments. When we specifically think about time toxicity associated with a particular cancer treatment, such as chemotherapy, it's the time costs of pursuing, receiving, and recovering from cancer treatment. Now, we have to acknowledge that much of cancer care is essential. We need blood tests to monitor organ function, we need chemo to shrink tumors, and we need a caring oncologist to break bad news. But we have to remember that oncology care is delivered in an imperfect world. Appointments that should take 10 minutes can take 5 hours. People can have uncoordinated appointments, so they're coming to the clinic 3, 4, 5 times a week. And this affects, of course, not only the patient themselves but also their informal care partners and the entire network around them. And this cancer care can completely consume people's lives, leaving no time for rest, recovery, or pursuing joyful activities. We interviewed patients and care partners in some qualitative work, and this was specifically people with advanced-stage gastrointestinal cancers. And we asked them what cancer care was like, and some of the words will shock you. People said things like, “It's like being on a leash.” “My life is like being on an extended COVID lockdown.” “Cancer is a full-time job.” A very experienced oncologist said, “It's like being on call. You may or not get called into the hospital, but you need to always be available.” And so this concept of time toxicity really applies to all people with cancer, but perhaps most so for people with advanced-stage, incurable cancer, when time is limited and when treatment regimens are perhaps not offering massive survival benefits. And in some cases, the time costs of pursuing the treatment can even overtake the very marginal survival benefit offered by the treatment. Dr. Shaalan Beg: This is particularly relevant for gastrointestinal cancers that, even in the world of advanced cancers, are highly burdensome in terms of their symptoms and the concept of being on call, whether you're a patient or a caregiver, and the burden that it has, I think will resonate with a lot of us, that it's always in the back of our mind on what if X, Y or Z were to happen? In the FOCUS4-N trial, a randomized trial from the UK, investigators assessed whether taking a treatment holiday for maintenance therapy for metastatic colorectal cancer would have a detrimental effect on progression free survival, overall survival, tolerability and toxicity. It looks like the study found that these decisions regarding maintenance therapy should be individualized, but there were not major differences in outcome. Can you comment on this and what applications that has for us in the clinic? Dr. Arjun Gupta: Sure. But before diving into the FOCUS4-N clinical trial, I just wanted to share a story from the clinic yesterday. It happened in my clinic yesterday, but I'm sure it happens to thousands of patients across the world every single day. So it was the first visit for a patient with stage 4 colon cancer, and they had polymetastatic disease with disease in the lungs and the liver, no actionable biomarkers, and so very likely to be incurable. And so we discussed the usual port and palliative care appointments and chemotherapy backbone, and doing this every 2 weeks, and then doing scans after 4 to 6 doses of chemo to see how the cancer has responded. And then the patient looks up and asks that question, “Okay. So when does this end? When are we done? Do I need to do this forever and the rest of my life?” These are just such innocent and hopeful questions, because the truth is, there is no established end date. But I shared this story that right off the bat, people are looking for breaks. They've not even started chemo, they've not experienced physical or financial or time toxicity, but just psychologically, being on chemo long-term or forever is a very, very hard adjustment. And so it's in this context that we should look at the FOCUS4-N clinical trial, which was a sub- study of a larger umbrella trial investigating whether continuing on maintenance chemo with oral capecitabine versus taking a treatment break from chemo affected the progression-free survival in people with metastatic colorectal cancer who had disease control after 4 to 6 months of upfront chemotherapy. So they randomized approximately 250 people. These people had largely been treated with FOLFOX or FOLFIRI. Most did not receive a biologic, and approximately half had partial response and half had stable disease. And then they did scans on these patients every two months or so. And the primary endpoint was progression free survival. The median PFS was approximately 4 months in the capecitabine arm and 2 months in the no treatment arm. Of course, as expected, side effects were higher in the capecitabine arm. But impressively, the overall survival was not different between these two arms. So what we're seeing here is that after this period of 4 to 6 months of intensive chemo, if we take a chemo break versus we get some oral chemotherapy, it may affect how quickly the cancer grows on scans, but it maybe does not affect how long patients live. Now, how do these data apply for an individual patient? Now, these are incredibly nuanced and personal decisions and patients can and should choose what aligns best with their values. In some work done by Dr. Mike Brundage and colleagues in Canada, they asked 100 people with advanced cancer to consider hypothetical scenarios where a new treatment did not increase the overall survival, but potentially increased the progression free survival at the cost of some physical and other toxicities. And then they asked patients if and what PFS thresholds they would accept for this treatment. And around half of patients said no matter how big the PFS is, we do not want to accept the treatment because it causes some toxicity if I'm not going to live longer. Around a quarter of patients said that if the drug elongated progression free survival by three to six months, I would take it, because that's valuable to me even if I don't live longer. But surprisingly, 1 in 6 patients said that they would accept a treatment with no PFS benefit and no overall survival benefit, even at the cost of side effects. And there was a spectrum of reasons for these preferences that they maybe had the battle narrative that “I want to be a fighter, and I don't want to have any regrets,” just showing how complex people's attitudes and values can be. So the point is that continuing on maintenance treatment versus not doing it is not wrong. The point is we often don't even have these data to offer treatment breaks to patients so that they can make decisions that align with their goals. So I think that's the biggest takeaway from the FOCUS4-N trial for me is that we have some hard data now to guide patients [FOCUS4-N Editorial]. Now, strictly speaking, when I'm talking to a patient about these data, doing oral capecitabine in 3-week cycles may not feel like much. It's perhaps a visit every 3 weeks for blood work and for meeting someone from the oncology team. There are no IV drugs given. If one does well, this might literally be one visit every 3 weeks. But we have to consider that things rarely go as smoothly as we plan them to. For someone living 100 miles away and having diarrhea and needing IV fluids, they may require 3 to 4 clinic visits for labs and monitoring. In the FOCUS4-N trial, 50% of patients on capecitabine had at least one treatment delay, denoting some toxicity. In a different but similar CAIRO3 clinical trial that tested capecitabine and bevacizumab, 10% of patients had to discontinue treatment due to toxicity. And so it's important to remember that what might seem a simple and low burden to us may be very burdensome to patients. In some work that we've done ourselves [published in The Oncologist], even a single simple appointment to a clinic, such as a lab test, often ends up taking patients hours and hours. So I think it's all of this that we have to consider when we present these data to patients. Dr. Shaalan Beg: You've talked about the FOCUS4-N trial, you mentioned the CAIRO3 study as well. How do you see this playing in the clinic? Somebody may be looking to attend a child's wedding or a notable birthday or a trip with the family, and you have the data from these trials supporting you. What are the patient factors in terms of their disease factors, patient factors that you think of when you recommend such a treatment break to a patient? Or, let me flip that over. Who would be a patient that you would be uncomfortable offering a treatment break for with metastatic colorectal cancer? Dr. Arjun Gupta: Yes, I think disease characteristics are a crucial consideration when we consider who we're even offering these treatment breaks to. I think, number one, is the overall disease burden, and if there's any critical visceral disease and how that's responded and how much it's responded to the upfront chemotherapy induction. I think patients where we're worried about having several sites of bulky disease, some that have not responded as well, I think we have to be very, very careful considering complete chemotherapy breaks. In the FOCUS4-N trial, in subgroup analysis, patients who had stable disease tended to not benefit as much from the chemotherapy break, perhaps indicating that it's really people whose disease is responding, who are doing well, who don't have as much disease burden, who may be better served by these treatment breaks. Dr. Shaalan Beg: Fantastic. I think that provides very good direction for our listeners on how they can apply the results of these trials in their clinic. So we've talked about treatment breaks as a way to give people their time back and to reduce time toxicity. What are other treatment strategies that you have seen deployed to reduce the burden of receiving cancer treatments in general? Dr. Arjun Gupta: You specifically asked about treatment strategies, so I'll start with that before moving to more broad interventions. We actually interviewed patients and care partners to ask them this question, and one of the things that they said was having prospective information from their oncology care team just about what my expected burden was going to be. So I think people recognize that they need oncology care and the clinicians are trying to help them and it's a broken system, but just knowing that 1 in 4 days will be spent with health care contact or not, or you will spend two hours arguing on the phone with a payer, for example, preparing and supporting people for these burdens is very important. There are obviously some alternative treatment schedules. Certain chemotherapies can be given less frequently now. So if you look at cetuximab in GI cancers, for example, when the initial trials were done, it was given every week, but now we more and more use it every two weeks. And it might not seem like much, but it can open up an entire week for a patient when they can think that I don't need to go in this week at all. So these are just some minor adjustments that we can make in the clinic. But patients often highlight things that may perhaps not be in the direct control of the oncologist, but in the direct control of us as an oncology community. And perhaps the most frequently cited suggestion was having more care coordination and navigation services. So patients really requested more flexibility in the site of care: “Can I come closer to home?'' In the timing of their care, ‘'Can I come in at 2:00 PM after I get childcare instead of coming in at 9:00 AM?” They really requested cluster scheduling or having appointments on the same day, if possible, instead of taking up Monday, Tuesday, Wednesday, Thursday, coming in so many times. And all of this could potentially be achieved by having a designated care coordinator, someone working directly with the patient and their care partner. And then some patients also highlighted the benefits of telemedicine and home-based care, where they were able to be home more. But we have to also recognize that those things are not universally good and often can increase burdens on the patients and care partners. Also, I wanted to highlight some feedback we received from oncology clinicians. We asked a variety of oncology clinicians, including nurses, APPs, physicians, schedulers, and social workers, what they thought were the causes of patients' time burden. You'll be surprised to hear that when they started talking about patients' time burdens, they slowly started to talk about their own time burdens. And they said, ‘‘We really want to help people, but we're just doing prior authorization and spending hours on the electronic medical record. And please fix my own time toxicity, and I will fix the patients' time toxicity,” which I thought was very profound because I think everybody who goes into medicine goes into it for the right reasons, and we end up not providing perfect care, not because of us, but because of the system. I take this as a very, very positive sign and as a hope for change. Dr. Shaalan Beg: What inspired you to focus on this topic and your research? Dr. Arjun Gupta: So I personally just hate waiting at the doctor's office. But yes, it's also been wise mentors, including you, Shaalan, during residency and fellowship, who always told me to keep my ear to the ground and listen to patients. And in full disclosure, time toxicity, and what we've done with it recently, it's nothing new. It's been around for decades. And I think our research group has just sort of named it and shamed it, and now more and more people are starting to think about it. But I can point to two specific instances that I think of. One was when I was starting fellowship in 2018, I read a piece by Dr. Karen Daily in the Journal of Clinical Oncology, where she quoted Henry Thoreau and said, “The price of anything is the amount of life, or time, that you exchange for it.” And it really struck a chord with me, entering the oncology discipline and seeing what people with cancer go through. And then the second instance is, I remember my granddad, who was perhaps the most formative person in my life. We were very, very close. And when I was about to enter medical school, he was undergoing chemotherapy for lymphoma. The image that's imprinted in my head is of him putting ketchup on gulab jamun. And I can see Shaalan salivating. But for the listeners who may not know, gulab jamun is an Indian sweet made out of milk, flour, sugar, ghee, molded into balls, deep fried and then served in sugar syrup. And my granddad could not taste anything. He could not taste gulab jamun. All he could taste was ketchup. And so he would put ketchup on everything. And at his oncologist visits when I would accompany him, they would discuss the good news about the cancer shrinking and there being a response, and he was happy, but he could just not taste his gulab jamuns. And it made me realize very early on that the tumor is not the only target. Dr. Shaalan Beg: What a wonderful story. I think those are really hard to measure, quantify, and when patients do bring those stories into the clinic, I think you realize that you have a very special connection with those patients as well, and it does help us as clinicians give personalized advice. So thanks for sharing. Arjun, thanks for sharing your valuable insights with us on the ASCO Daily News Podcast today. Dr. Arjun Gupta: Thanks so much for having me, Shaalan. Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find links to the studies discussed today in the transcript of the episode. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: 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. Find out more about today's speakers: Dr. Arjun Gupta @guptaarjun90 Dr. Gupta's Research on Time Toxicity: · The Time Toxicity of Cancer Treatment, JCO · Consuming Patients' Days: Time Spent on Ambulatory Appointments by People With Cancer, The Oncologist · Evaluating the Time Toxicity of Cancer Treatment in the CCTG CO.17 Trial, JCO OP · Patients' considerations of time toxicity when assessing cancer treatments with marginal benefit, The Oncologist · Health Care Contact Days Experienced by Decedents With Advanced GI Cancer, JCO OP · Health Care Contact Days Among Older Cancer Survivors, JCO OP Dr. Shaalan Beg @ShaalanBeg Follow ASCO on social media:   @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn  Disclosures:  Dr. Arjun Gupta: Employment (An Immediate Family Member): Genentech/Roche Dr. Shaalan Beg:   Consulting or Advisory Role: Ispen, Cancer Commons, Foundation Medicine, Genmab/Seagen   Speakers' Bureau: Sirtex   Research Funding (An Immediate Family Member): ImmuneSensor Therapeutics   Research Funding (Institution): Bristol-Myers Squibb, Tolero Pharmaceuticals, Delfi Diagnostics, Merck, Merck Serono, AstraZeneca/MedImmune

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Gastroesophageal Cancer | Year in Review: Novel Treatments and Strategies in Gastroesophageal Cancer

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Play Episode Listen Later May 3, 2024 59:47

Featuring perspectives from Prof Eric Van Cutsem, including the following topics: Immune Checkpoint Inhibitors in Localized Gastroesophageal (GE) Cancers Introduction (0:00) Case: A man in his mid 50s with localized, poorly differentiated signet ring, mismatch repair-deficient advanced gastric adenocarcinoma — Sunnie Kim, MD (3:39) HER2-Positive GE Cancers Case: A man in his early 70s with HER2-positive gastroesophageal junction (GEJ) adenocarcinoma and disease progression on FOLFOX/trastuzumab (PD-L1 CPS 0) — Dr Kim (19:22) First-Line Treatment of Metastatic Gastric and GEJ Adenocarcinoma Case: A man in his early 40s who presents with metastatic GEJ adenocarcinoma (CLDN18.2-positive, PD-L1 CPS 2) in visceral crisis from lung metastases — Dr Kim (38:53) Case: A man in his mid 60s with metastatic GEJ adenocarcinoma (PD-L1 CPS 20) — Dr Kim (50:50) CME information and select publications

Gastroesophageal Cancer | Year in Review: Novel Treatments and Strategies in Gastroesophageal Cancer (Companion Faculty Lecture)

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Play Episode Listen Later May 3, 2024 63:30

Featuring a slide presentation and related discussion from Dr Sunnie Kim, including the following topics: Year in Review: Novel Treatments and Strategies in Gastroesophageal Cancer — Dr Kim (0:00) Case: A man in his mid 50s with poorly differentiated mismatch repair-deficient advanced gastric cancer receives first-line nivolumab/ipilimumab (49:22) Case: A man in his early 70s with HER2-positive gastroesophageal junction (GEJ) adenocarcinoma who experienced disease progression on FOLFOX/trastuzumab receives trastuzumab deruxtecan (54:48) Case: A man in his mid 60s with Stage IV, PD-L1-positive GEJ adenocarcinoma (58:11) Case: A man in his early 40s with metastatic CLDN18.2-positive gastric/GEJ adenocarcinoma receives zolbetuximab (1:01:10) CME information and select publications

Episode 100: Colorectal Cancer Series, Pt. 2 - Adjuvant Therapy in Stage III Colon Cancer

The Fellow on Call

Play Episode Listen Later Apr 24, 2024

This week, we kick off our discussion of adjuvant systemic treatment in colon cancer, beginning with Stage III colon cancer. We will review the evidence basis for adjuvant therapy as well as the two main chemotherapy regimens including duration and side effects. Content: - Why do we need adjuvant therapy in stage III colon cancer? - What is FOLFOX? What is CAPOX? When do we use what?- What is the optimal duration of therapy? - What are the characteristics deemed high risk? - Can we discontinue oxaliplatin early? - What is the role of oxaliplatin in older patients? ** Want to review the show notes for this episode and others? Check out our website: https://www.thefellowoncall.com/our-episodesLove what you hear? Tell a friend and leave a review on our podcast streaming platforms!Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google Podcast

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How ctDNA Is Advancing Care for Patients With GI Cancers

Play Episode Listen Later Apr 4, 2024 17:21

Drs. Shaalan Beg and Aparna Parikh discuss the role of ctDNA as a powerful prognostic biomarker for GI cancers, along with its impact on risk stratification and the detection of recurrence. They highlight key studies in ctDNA that were featured at the 2024 ASCO GI Cancers Symposium, including COBRA, GALAXY, and BESPOKE in CRC, as well as the promise of ctDNA testing in the preoperative detection of iCCA. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Shaalan Beg, your guest host for the ASCO Daily News Podcast today. I am an adjunct associate professor at UT Southwestern's Harold Simmons Comprehensive Cancer Center in Dallas. On today's episode, we will be discussing the emergence of circulating tumor DNA (ctDNA) technology in GI cancers. I am delighted to be joined by Dr. Aparna Parikh, an assistant professor of medicine at Harvard University and the director for colorectal medical oncology at the Massachusetts General Hospital Cancer Center, where she also serves as the medical director of the Young Adult Colorectal Cancer Center. Dr. Parikh will share her insights on key research on this hot topic in GI oncology that was featured at the recent ASCO Gastrointestinal Cancers Symposium. Our full disclosures are available in the transcripts of this episode, and disclosures related to all episodes of the podcast are available at asco.org/DNpod. Dr. Parikh, it's great to have you on the podcast today. Dr. Aparna Parikh: Thanks so much, Dr. Beg. Dr. Shaalan Beg: In recent years, it has become evident that liquid biopsy and other emerging ctDNA technologies are changing how we treat GI cancers, and colorectal cancer (CRC) is in the forefront of this space. Before we dive into key studies, can you briefly highlight for our listeners how ctDNA is advancing the field and how it can influence the care that we deliver to our patients in the future? Dr. Aparna Parikh: Absolutely, ctDNA is certainly a hot topic. What we have learned over the years is that ctDNA has emerged across many solid tumor types as one of the most powerful, if not the most powerful, prognostic biomarker we have to date. ctDNA has improved risk stratification. We have learned a lot about the role in what is called minimal or molecular residual disease in patients with early-stage disease, and ctDNA being a biomarker of recurrence for those patients, with ctDNA, we have a better understanding of tumoral heterogeneity, both spatially and temporally, getting a better glimpse of what is happening in a given patient with multiple metastases, as well as genomic evolution of tumors over time. So certainly many, many roles and areas where ctDNA is emerging. Dr. Shaalan Beg: This was a hot topic at the 2024 ASCO GI Cancers Symposium, and we're going to take a deep dive into some of the abstracts that were presented. Let's start with the COBRA study, which is the NRG-GI005. That was Abstract 5 at the ASCO GI Cancers Symposium, and the GALAXY study, which was Abstract 6 at the symposium. So, the COBRA study reported results of ctDNA as a predictive biomarker in adjuvant chemotherapy for people with colon cancer. At a high level, it was a negative study, but there are some important lessons for us to learn. Similarly, in the GALAXY study, investigators from Japan presented an updated analysis on the correlation of ctDNA dynamics with outcomes in colorectal cancer with minimal residual disease. How do you synthesize all this information and help the listeners understand our current state for ctDNA applications in colorectal cancer? Dr. Aparna Parikh: Yeah. Let's take the COBRA study first. Let's talk a little bit about the design of COBRA. COBRA was intended to look at patients that were resected, stage 2 colorectal cancer patients, or colon cancer patients who were 2A. These are patients where the treating physician would, at the outset, decide that there was no adjuvant chemotherapy indicated. These are patients where active surveillance would be entirely appropriate as the standard of care. Patients were randomized to arm 1, which was active surveillance, or randomized to arm 2, which was assay-directed therapy. If there were ctDNA positive in arm 2, then they were given chemotherapy, FOLFOX or CAPOX. And if they were “ctDNA not detected,” then they would also go on to active surveillance. And so, the plan was that nearly 1,500 patients are to be recruited, and at the time of this data cut, they had around 630-some patients. The primary objective was to look at the clearance rates of ctDNA between the ctDNA-positive cohorts, remember, the chemotherapy and the active surveillance cohorts at 6 months. They had around a 5% detection rate of ctDNA patients. Ultimately, that was around 16 patients. The reason that the study shut down was that what they found was that in the surveillance arm, the arm that was not getting any treatment, they had a ctDNA clearance of 43% versus 11% in the chemotherapy arm. They had an interim analysis to look at the clearance rate between the 2 arms, and what was surprising to the investigators and the community was what was happening in terms of clearance. Why do we have a 43% clearance rate in patients that were not getting anything? And so, because of that, the study was shut down as it did not meet its prespecified interim look at clearance in those 2 arms. Many things came up in terms of learnings from COBRA. Number one was the characteristics of the assay. And so, you take an assay in a low-risk patient population that has a fixed specificity, and when your baseline prevalence of recurrence is so low, for example, in low-risk stage 2 patients, your composite predictive value is very susceptible to small changes in that specificity. And so, your PPV is going to be a lot lower in a low-risk patient population than a higher-risk patient population. The COBRA study used an older version of a tumor-uninformed assay, so it definitely called into question some characteristics of the assay. Is one-time-point clearance sufficient, and is that the right endpoint? We have seen now, including the GALAXY study that we'll talk about here, previously reported just spontaneous clearance happening in 5%, 10% of patients. The question with that spontaneous clearance is: Was it actually clearance, or was chemotherapy just perhaps in a low ctDNA shedding state? Are you just suppressing the ctDNA below the level of limited detection? And then in this study, the clearance draw was actually done in the chemotherapy arm right before the last cycle of chemotherapy, again to that point of, are you just suppressing the ctDNA with chemotherapy? There is also stochastic sampling error that can happen in patients with very low residual tumor volume. So, I think this is a disappointing study in the sense that it is still a really important question. There are still 2A patients that recur, but maybe [this was] not the right test, or maybe single-time-point testing wasn't enough. And so, lots of lessons to be learned from this study in terms of test and design, but hopefully more to come. I think certainly stage 2 patients remain an area where I think, hopefully, ctDNA still plays a factor for those patients. Dr. Shaalan Beg: And how was the patient population for the GALAXY study? That was Abstract 6, compared to the COBRA study. Could you summarize those findings for us? Dr. Aparna Parikh: Yeah, so GALAXY was part of a large study in Japan that includes an observational cohort plus therapeutic cohorts as well. And so, GALAXY was just further reporting of the observational cohort. So unlike COBRA, which is a low-risk, stage 2 study that was actually asking that interventional question: Can you use it to guide therapy? The GALAXY and the updated GALAXY just continues to show more clinical validity data rather than clinical utility data. And it was nearly 3,000 patients, pan stages. Again, the lion's share were stage 2 and 3 patients, but there were also stage 1 and stage 4 patients as well. And what they showed was that ctDNA is undoubtedly prognostic. They showed very consistent Kaplan-Meier curves, which we've seen time and time again, where if you're ctDNA-positive, you don't do as well. What they showed was, not surprisingly, with longer-term follow-up – this is 24-month follow up, so longer-term follow up than was published in their paper last year – was that when you test at one time point, so landmark testing, the sensitivity of detecting recurrence was around 48%, and that fell from the publication last year which was around 58%, 59%, which is not surprising as you follow more people. I think single time point testing soon after surgery may miss those late recurrences, but it's still prognostic and showed a specificity of around 94%. They also continued to show that if you continued to test with serial testing, your sensitivity improves, but what was really interesting and new, what they presented this time, was a clearance analysis. And showing, again, comparable to COBRA, in many ways, in the sense that clearance can be a little bit finicky, especially at one time point, is what they showed is that patients who had sustained clearance, and these are patients that had at least two time points with their ctDNA remained to be negative, they did very well. But if you had transient clearance, and again, the definition was a little bit broad, at least having one negative and then one positive, those patients ultimately, at 24 months, the curves came together with the no clearance curve. So initially, they did better than the people that didn't have any clearance. But if you transiently cleared at two years, the curves came back together. And what was interesting is that in those patients that sort of transiently clear by 9 to 12 months, 80% of those are actually having a rapid return of ctDNA. And so this begs the question of was chemotherapy just suppressing that ctDNA or maybe if you have a better test you could have actually improved it. These were some of the updated, interesting learnings from GALAXY, which remains incredibly prognostic. And then the concept of clearance, which I think we have to look into a little bit more as a field, and understanding that maybe just one time point clearance isn't sufficient. Dr. Shaalan Beg: Yeah, and one of the most important applications for ctDNA can be its ability to inform adjuvant chemotherapy. Its ability to not only identify more people who may benefit from chemotherapy, but maybe even identify people who don't need chemotherapy. And along those lines, Abstract 9, the BESPOKE study, looked to understand the role of ctDNA-based detection of molecular residual disease to inform adjuvant therapy for stage 2 and 3 colorectal cancer. And they presented interim data at the GI ASCO this year. What were your takeaways from this study? Dr. Aparna Parikh: Exactly. Beyond the prognostic implications, I think what was really interesting was that there was the initial data looking at the benefit of adjuvant chemotherapy. So, what they did was they said, “Okay. We're going to take the MRD-positive patients and look at the benefit of adjuvant chemotherapy and then the benefit of adjuvant chemotherapy in the MRD-negative patients.” And again, remember, this is a prospective observational study, so it's not looking at negative and positive to guide therapy, but it's just looking prospectively and observationally at how those patients are doing. But what they showed again is that indeed, in the adjuvant chemotherapy group, the benefit of adjuvant chemotherapy again with the follow-up to date on the study was different in the MRD-positive patients. First of all, I guess taking a step back, the DFS in the ctDNA-negative patients at 2 years was very good. So negative patients had over 98% 2-year DFS in both the adjuvant chemotherapy and observational group. And there was no real difference between adjuvant or not. But in the positive patients, not surprisingly, the DFS was worse. But what was reassuring to see is that you can make an impact with adjuvant chemotherapy in the positive patients. And the difference in DFS between the positive and negative patients, with adjuvant or not, was 42% versus 12.5%, in the observational patients. So, it is benefitting the patients who are positive so it does give us more data that, again, at least in the positive patients, you may be able to reverse the recurrences there with adjuvant chemotherapy. And maybe if you're negative, eventually, we'll get to a point of de-escalation of care. Again, keeping in mind the kinds of sensitivity limitations as well. Dr. Shaalan Beg: Wonderful. And one of the other malignancies in the GI space where precision therapies and molecular biomarkers are making a huge difference are intrahepatic cholangiocarcinoma. Genomic profiling using ctDNA is increasingly being used in this population to inform precision oncology approaches and determine mechanisms of resistance to targeted therapies as well. In Abstract 528, investigators looked at the role of preoperative ctDNA testing for resectable intrahepatic cholangiocarcinoma. What are your thoughts on that study? Dr. Aparna Parikh: Yeah, it's such an important area, as you mentioned, in the metastatic space – FGFR, IDH1, all these alterations that are emerging in intrahepatic cholangios. This was a very small study, it was preoperative, and so the tumor was intact, and around 14 patients. They used a tumor-informed approach just for detection and quantification of ctDNA. So this was not a study that was looking at a next-generation sequencing approach where you're going to actually be able to detect the alterations, but it's actually looking for the detection and quantification of ctDNA rather than genomic characterizations. And patients had about a month or so where they had their baseline blood detected. And I think what was reassuring to say was that ctDNA was actually detected in all the patients with the primary tumor intact, except for one patient who was a very low-risk stage 1A patient. There was some correlation, against a small number of patients, between the concentration of ctDNA in patients that had the lower stage and then the higher stage groups. Small numbers were actually hard to characterize and correlate with recurrence or mortality, but at least, some correlation with pathologic tumor size, they were able to because it was a bespoke panel and you're sampling the tissue and then looking in the blood, IDH1 and 2 were mutations that were tracked based on the genomic profiling and a couple of the patients were able to have their IDH mutations tracked. So it gives us a sense, a little bit, that ctDNA, we know has a lot of variable shedding across disease states and tumor locations, but gives us some promise that it is reliably detected with the tumor-informed approach, at least preoperatively in cholangios. So may again open some more opportunities for MRD testing in cholangiocarcinoma as well. Dr. Shaalan Beg: Thank you. That's a wonderful review of ctDNA applications in gastrointestinal cancers from the 2024 ASCO GI Cancers Symposium. Thank you, Dr. Parikh, for sharing your valuable insights with us on the podcast today. Dr. Aparna Parikh: Thank you so much for having me. Dr. Shaalan Beg: Thank you to our listeners for your time today. You'll find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: 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. Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Aparna Parikh @aparna1024 Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Aparna Parikh: Consulting or Advisory Role (An Immediate Family Member): PMV Consulting or Advisory Role: Checkmate Pharmaceuticals, Guardant Health, Foundation Medicine, Abbvie, Value Analytics Labs, Bayer, Taiho Oncology, Delcath, Seagen, CVS, SAGA Diagnostics, Scarce, Illumina, UpToDate, Takeda, AstraZeneca, Takeda, Pfizer, Kahr, Xilio Therapeutics, Sirtex Research Funding: PMV Pharma, Erasca, Inc, Syndax Research Funding (Institution): Bristol-Myers Squibb, Genentech, Guardant Health, Array, Eli Lilly, Novartis Pharmaceuticals UK Ltd., PureTech, Mirati Therapeutics, Daiichi Sankyo, Karkinos Other Relationship: C2i Genomics, Xgenomes, Parithera, Cadex

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Gastroesophageal Cancer | Meet The Professor: Optimizing the Management of Gastroesophageal Cancers — Part 3 of a 3-Part Series

Play Episode Listen Later Dec 6, 2023 61:55

Featuring perspectives from Dr Samuel J Klempner, including the following topics: Introduction (0:00) Case: An 80-year-old woman with newly diagnosed metastatic microsatellite-stable (MSS), HER2-negative lower esophageal adenocarcinoma; PD-L1 CPS 60 — Warren S Brenner, MD (13:36) Case: A 61-year-old man with newly diagnosed HER2-negative gastroesophageal junction adenocarcinoma and worsening dysphagia with significant pain and nausea — Priya Rudolph, MD, PhD (19:05) Case: A 69-year-old man with chest pain and progressive dysphagia who is diagnosed with HER2-negative adenocarcinoma of the distal esophagus with locoregional lymph node involvement — Matthew R Strickland, MD (23:22) Case: A 55-year-old man and Iraq War veteran with MSS, HER2-positive recurrent esophageal cancer after first-line FOLFOX/trastuzumab/pembrolizumab and maintenance 5-FU/trastuzumab/pembrolizumab — Zanetta S Lamar, MD (29:52) Case: A 63-year-old man with newly diagnosed clinical Stage I lower esophageal cancer who undergoes esophagectomy; pathology reveals Stage IVA disease — Farshid Dayyani, MD, PhD (34:41) Investigator Survey (40:25) CME information and select publications

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Gastroesophageal Cancer | Meet The Professor: Optimizing the Management of Gastroesophageal Cancers — Part 2 of a 3-Part Series

Oncology for the Inquisitive Mind

Play Episode Listen Later Nov 15, 2023 62:51

Featuring perspectives from Prof Van Cutsem, including the following topics: Introduction (0:00) Case: A woman in her early 50s who has undergone the neoadjuvant CROSS regimen and received surgery experiences local recurrence of PD-L1-negative gastroesophageal junction (GEJ) adenocarcinoma while receiving adjuvant nivolumab — Priya Rudolph, MD, PhD (15:56) Case: A man in his late 60s with localized Siewert Class III GEJ adenocarcinoma receives perioperative fluorouracil/leucovorin/oxaliplatin/docetaxel — Lai (Amber) Xu, MD, PhD (26:16) Case: A woman in her early 90s who has undergone radiation therapy for esophageal squamous cell carcinoma now experiences local recurrence; PD-L1 combined positive score (CPS) is 71 — G Richard Polkinghorn, MD (36:33) Case: A man in his late 60s with HER2-negative GEJ adenocarcinoma develops HER2-positive oligometastases — Matthew R Strickland, MD (42:17) Case: A woman in her early 70s with metastatic HER2-positive gastroesophageal cancer who received first-line FOLFOX/trastuzumab now experiences disease progression; PD-L1 CPS is 10 — Henna Malik, MD (47:53) Investigator Survey (52:26) CME information and select publications

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75. ESMO 2023 - Colorectal Cancer (Part 1)

Play Episode Listen Later Oct 31, 2023 22:44

Colorectal cancer remains the bread and butter of many an oncologist, but its commonality belies its complexity. In early and advanced disease alike, there remain many permutations, considerations and controversies regarding optimal treatment. What is the best way to treat potentially-resectable colorectal cancer with liver metastases (CRLM)? Is there a way to increase the responsiveness to immunotherapy in patients with proficient mismatch repair (pMMR)? And are we moving to a brighter future where patients with deficient MMR colorectal cancer could avoid surgical management through the miracle of immunotherapy? Ultimately, no one study is going to answer these questions, but with ESMO 2023, we may be starting to peel back the layers of this onion.Studies discussed in today's episode (subscription may be required)Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX in RAS wild-type patients with initially unresectable colorectal liver metastases: The TRICE randomized clinical trial https://esmocongress.esmo.org/esmo/esmo2023/en-GB/presentation/638067Neoadjuvant nivolumab plus relatlimab (anti-LAG3) in locally advanced MMR-deficient colon cancers: The NICHE-3 study https://esmocongress.esmo.org/esmo/esmo2023/en-GB/presentation/639575A phase II clinical trial of sintilimab plus chidamide combined with or without bevacizumab in patients with MSS/pMMR metastatic colorectal cancer https://esmocongress.esmo.org/esmo/esmo2023/en-GB/presentation/638079For more episodes, resources and blog posts, visit www.inquisitiveonc.comPlease find us on Twitter @InquisitiveOnc!If you want us to look at a specific trial or subject, email us at inquisitiveonc@gmail.comArt courtesy of Taryn SilverMusic courtesy of Music Unlimited: https://pixabay.com/users/music_unlimited-27600023/Disclaimer: This podcast is for educational purposes only. If you are unwell, seek medical advice. Hosted on Acast. See acast.com/privacy for more information.

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Peter Attia: Our conversation about his hit book OUTLIVE, Medicine 3.0, promoting healthspan, GLP-1 drugs and more

Ground Truths

Play Episode Listen Later Oct 19, 2023 43:03

In July, I reviewed Peter's Outlive book here in Ground Truths and hoped I'd be able to interview him about my concerns. Here's that conversation, recorded October 16th. I hope you'll find it informative and stimulating!The AI generated transcript (unedited) below with links to the audio recordingEric Topol (00:01):Peter, it's really great to see you. I haven't been chance to visit since early 2020, and you introduced me to Topo Chico as a great way to get carbonated water. Are you still into those?Peter Attia (00:15):Very much so, yeah. Although I have a different drink today because, well, I don't know why I grabbed for different drinks.Eric Topol (00:22):Yeah, well it's kind of amazing. Distinct from the rest of the waters, fizzy waters. At any rate, since that time, that memorable visit we had, you published an incredible book Outlive, and I think it sold more than a million, well over a million copies, which is amazing. So congratulations.Peter Attia (00:41):Thank you so much.Eric Topol (00:42):It's a great book. And you may have written my review, which I really thought it offers just a great information resource and it must've taken so many years to put it all together.Peter Attia (00:54):Yeah, I think it probably took seven years in total.Eric Topol (00:57):Well, I think it was well worth, and I think it's helping a lot of people. And in fact, I first became aware of it just because these patients were coming into me and saying, well, that's not what Dr. Attia says, or What do you think of Dr. Attia's book ? So that's prompted me to give it a really close read, and I learned a lot from all your work. I thought what we'd start off with, I think you framed it really well with this Medicine, 1.0, 2.0, 3.0 and the shift to the right. So maybe you could explain the concept on that. Sure.Peter Attia (01:34):So Medicine 1.0 is kind of a placeholder for a time before there really was medicine, or at least before, there was sort of a scientific method and an understanding of science and the natural world around us. But of course, from a timescale perspective, it's what dominated all of our civilization. So humans have been around for 250,000 years and until very, very, very recently on that timescale, we didn't really have the tools intellectually to understand science. So we couldn't understand cause and effect. We didn't have a scientific method, let alone capacity to do experiments. And so most of what we did as far as medicine was based on things that we look back at today and think are completely ridiculous. Illness was brought on by the gods or bad humors or things like that. And really then when we start to think about medicine in the way we think about it today, we're really thinking about Medicine 2.0.(02:33):And this is something that was obviously a many, many year transition. Technically I would argue it took place over hundreds of years, beginning with Francis Bacon in the late 17th century or the mid 17th century, but really accelerating in the latter part of the 19th century with germ theory. So we can think about lister, I wrote a little bit about them, and ultimately really a more concrete set of tools including physical tools such as the light microscope, ssid, Muer G writes very elegantly about the importance of the light microscope in the understanding of the cell. And of course a big part of understanding the cell was understanding bacteria, their role in disease. And then we have the advent of antimicrobial agents. So it's this sort of collective set of tools that allow us to basically double without exaggeration human lifespan in a matter of three generations.(03:31):So this is kind of a remarkable trajectory. I think it would be surprising for most people to learn, however, that in this doubling of human lifespan about, well, I would say virtually all of it has come through the reduction of and or elimination of infectious diseases and communicable diseases. And none of that has really come, or very little of that has come by addressing chronic diseases. And so as we've now lived longer by not dying due to the sort of usual infant mortality and infectious disease route, we're instead dying of these chronic diseases. And I think Medicine 2.0 has been largely unsuccessful in that arena with perhaps one exception and that exception is vaccination. So vaccination is in some ways a medicine 3.0 tool because it's a tool of prevention, meaning you treat before a person is sick, whereas most of the success of medicine 2.0 is treat once the patient is ill.(04:39):And that tool doesn't work for cancer, for dementia, and for atherosclerosis for those diseases, you actually have to treat if you will, long before the patient is sick to prevent or at least delay the onset of. So in some ways that is one of the most important pillars of Medicine 3.0, there are several others. So another very important pillar of it is an equal if not greater focus on health span over lifespan where the description and definition of health span are much more rigorous. So the Medicine 2.0 definition of health span is the period of time in which you are free of disability and disease. I kind of reject that definition is not very helpful because I'm as free of disability and disease today at 50 as I was when I was 20, I'm clearly not in as good a shape, I'm not as strong, I'm not as cardio respiratory fit, I'm not as cognitively sharp. So my health span has already declined. But by focusing on metrics of health span in a very detailed way, we're going to get a lot of lifespan benefits for free. And then there's the component of personalizing medicine. So again, it's a term that is rather glib, but it is kind of true. And so we think of evidence-based medicine as the foundation of medicine 2.0, and I think that evidence-informed medicine needs to be the pinnacle or the pillar of medicine 3.0 for reasons I'm sure we'll discuss.Eric Topol (06:10):Yeah. So I buy into the medicine 3.0 concept because we've never fulfilled the fantasy or dream of prevention really as you get to. And the four horsemen that you laid out so well, cancer, neurodegenerative disease, cardiovascular and metabolic dysfunction, all play into that, that we could actually prevent these. One of the questions on that was you shifted to the right better health span, but do you then fall off the cliff that is you have this great health span and you don't have the chronic disease, or do you wind up just basically delaying the chronicity? What are your thoughts about that?Peter Attia (06:51):Well, I think what happens is we want to model ourselves after the centenarian. So centenarians on average are living two decades if not a little bit more than the average person, so slightly more than two decades beyond the average person. And interestingly, they kind of die of the same diseases as the rest of us do. They just have a much more compressed period of morbidity, and they have this phase shift in time for the first brush with disease X. So they're going to die pretty quickly of cancer when cancer sets in, they just get cancer 20 years later. On average, their first brush with cardiovascular disease is also 20 to 25 years later. So if you think about cardiovascular disease in non centenarians, 50% of men, as you probably know, and maybe the audience doesn't, but 50% of men who are going to have a major adverse cardiac event will have it before the age of 65 and 33% of women who will have a major adverse cardiac event in their life will have, so before the age of 65 when we're talking about centenarians, they're into their eighties and nineties when they're having their first major adverse cardiac event.(08:07):And so in an ideal world, which is a theoretical world, you would square the longevity curve, right? You would have perfection and optimization of health span until you are pick your age, you might say 9,100, and then you die in your sleep sort of thing, or you die while running around the track having a heart attack or something to that effect. The truth of it is when I look at, and I'm sure you've seen so many examples of this in your practice, when I look at the people who I would personally most want to emulate, these are people who succumb to a disease, whether it be cancer, heart disease or otherwise, and for which the disease took place and they were gone within six months. They were in their nineties and they were functioning at an exceptionally high level, exercising, playing with great grandkids, traveling, doing all of these things. And then they were diagnosed with pancreatic cancer. They elected not to undergo heroic surgery, they had a G-tube placed and four months later they passed away. And I think we look at that and we say, boy, that's a much better outcome than spending 15 years in a gradual state of decline from the age of 65 to 80, which is the more common finding.Eric Topol (09:24):Yeah. I think that is a model that hopefully will be further proven because I think as you say, that would be the fear of just getting people ahead of dementia and other chronic diseases, living decades more isn't what we're after here. And I think we're totally concordant on that.Peter Attia (09:44):And there's no evidence that it can be done truthfully. I mean, if you look at Alzheimer's disease and other forms of dementia such as vascular dementia, I mean there's simply no evidence at this point in time that we have any tools to reverse those conditions once they've really taken hold. And I think that largely explains why the pharmacologic industry has failed. I mean, I'm not being histrionic when I say that. I mean it. It's been an abject failure to suggest anything otherwise. And again, that suggests that if we're going to do anything about the rising incidences of dementia, it's got to be at identifying the highest risk patients and taking the most significant preventive steps with respect to their metabolic health, exercise, sleep, even aspects of stress management and mental and emotional health. I mean, all of these things factor in, but the time to act on them is long before mild cognitive impairment or M C I sets in.Eric Topol (10:45):Absolutely. One of the things that you hit on so eloquently overall, the whole book is really an aite approach, but the insulin resistance as a critical condition, which is thematic as to getting early to these. And by the way, all four of these major areas are the common threads get to that. And so you have used continuous glucose monitoring. I don't know if you still do and you have centered on this and you're aware that in the medical community there's like a pre-diabetes is a myth, shouldn't be recognized. It's scare mongering. I mean, which is crazy. Can you sort out this because it does seem like insulin resistance and we're going to get into the Glip one drugs is a big deal that's being largely ignored.Peter Attia (11:43):Yeah, it's very interesting. I'm not sure where that's coming from because I actually think the data are quite unambiguous that even beyond or outside of the threshold of type two diabetes, which is currently defined by the hemoglobin A1C historically about 15 years ago and prior, it was defined by the oral glucose tolerance test, but let's just use the modern day definition. So a line was drawn in the sand that said if your hemoglobin A one C is 6.5% or higher, which for most people, but clearly not all people corresponds to an average blood glucose of 140 milligrams per deciliter or higher, you now have this condition called type two diabetes. And presumably anybody with an IQ above about 60 recognizes that indeed your risk of cardiovascular disease, cancer, Alzheimer's disease in addition to your risk of kidney disease and a whole bunch of other things goes up dramatically as a response to that.(12:41):In fact, your all cause mortality is up 40% when you have type two diabetes. Okay, let's put all that aside and assume anybody with half a brain agrees with that. Where I'm not sure I understand any disagreement is if you look at the data for what is the all cause mortality of people with hemoglobin A one C below 6.5, it points to a monotonic decrease in risk as you go down from 6.5 to five. In other words, having an average blood glucose of 100 milligrams per deciliter is better than having an average blood glucose of 110, which is better than 120, which is better than 130. And this is according to all cause mortality data. It's also true that we have better outcomes for people who have, and this is harder to demonstrate, but I think if you look at the type one diabetes data, you see that you have better outcomes with fewer spikes in glucose.(13:45):So in other words, it's not just the average of blood glucose, but it's managing the shape of the glycemic curve. So where I've seen people push back is they will acknowledge if confronted with those data, they'll acknowledge it, but they'll say that, Hey, those data are based on hemoglobin A one C and not C G M, to which I'll say, yeah, that's true. Those data were not captured with C G M. But to me it's a relatively minor leap to say if we know these things based on hemoglobin A one C to be true, it's very likely that they're going to be true based on capturing more accurate data with the continuous glucose monitor. So Eric, I'm not really sure what the hesitation is. If the hesitation is that we don't want payers to cover the cost of C G M for non-diabetics, frankly that's a policy question. I won't wait until that, right? I mean, again, my patients, most of them spend at least 30 days with a C G M non-diabetic patients and they pay out of pocket. So really it's not costing the system anything. And it's really not that expensive relative to the cost of missing out on that information. And for many patients, it becomes a tool that they'll use for more than 30 daysEric Topol (15:00):And they learn certain foods to avoid because of significant spikes and other things likePeter Attia (15:05):That. It's not just the food, although that's the most obvious thing that one learns. But I think what most people find more interesting, and certainly I did and I started wearing A C G M in 2015, what most people learn is the effective sleep, the effective exercise, and the effective stress and how much those things change glucose control. So I was just talking with a patient last week and they were saying, and it's sort of funny because they're telling me this, and of course I already know the answer, but I love hearing them come to this conclusion rather than me telling them. And the patient was saying, wait, what a difference it's making. If I have a bad night of sleep versus a good night of sleep with a really good night of sleep, I can get away with eating X, Y, and Z, and my glucose numbers are well within the parameters we've set for optimal. And if I sleep two hours less, I get home too late, I wake up, something goes wrong, all of that goes out the window.Eric Topol (16:07):Peter Attia (16:07):My Glucose is high overnight, I wake up with high glucose and my glucose tolerance is minimized. And I know for me personally, that was a huge insight that leads me to be very thoughtful about food choices with and without all of the other variables in my life in order.Eric Topol (16:23):Yeah, I think that's actually a project we're working on right now, the multimodal AI interactions between stress, sleep foods and all these things that change glucose spikes. And some people, of course, as you know, they don't spike to anything. And then of course many others, perhaps some majority have some or even very significant spikes. Now, one of the other things I learned, which is not the accepted recommendation, is about protein. You wrote about how one gram of protein per body weight or 130 grams or more. That's one thing I just want to commend you about there is that the medical community doesn't pay enough attention to nutrition. You obviously have zoomed in on this quite a bit, but tell us a little bit more about the protein story. Well,Peter Attia (17:18):I mean I think unfortunately the R D A, the recommended dietary allowance is sort of addressing the wrong question, right? It's a relevant question, it's just not a relevant question today. It was a relevant question in an era of food scarcity, right? So when we think back to the 1940s and the 1950s or during the war when food was not as abundant as it is today, and one was really thinking, what is the minimum effective dose? What's the minimum amount of protein I would need to survive? Yeah, then I think you're closer to that one gram per kilogram of body weight. But if you look at the data more carefully and you ask the question, okay, imagine we're coming from a world that's not resource constrained, which it clearly isn't today. We have unlimited access to energy. It's never been cheaper by energy, I mean food, then the question is, well, what's the optimal amount?(18:19):And you see that the answer is somewhere between 1.4 and two grams per kilo of body weight. So it's potentially twice as much as we've historically told people. And that you might say, well, Peter, that's a really big range, 1.4 to two. How do you anchor in on where it needs to be? And again, I think this is where medicine 3.0 can lend a hand, right? And it depends on a lot of things. It depends on your activity level, it depends on how much you're breaking down muscle on a daily basis, how active you are also depends on how old you are. So the older you get, the more anabolic resistance you have, meaning the more difficult it is to assimilate amino acids in muscle protein synthesis and therefore the more of them you need. It also depends on the quality of those amino acids.(19:07):So if a person is eating a vegetarian diet and they have to get all of their amino acids from plants, they're going to have a harder time reaching the thresholds for leucine, lysine, methionine, which would be some of the most important amino acids, and they're probably going to have to eat more total protein to hit their numbers. So all of these things factor in, and I would say the final thing that we look at is the overall balance of energy in the patient. So you heard me talk about, you probably read that I distinguished between people who are overn, nourished, undernourished, adequately muscled and under muscled. And that creates kind of a two by two that allows you to think about what do we need to do with energy restriction? And if a person is adequately muscled and undernourished, which by the way is a reasonable subset of the population, then you can be a little bit more forgiving on allowing yourself to be at the lower end of that protein intake because the goal is first and foremost to reduce total energy intake. Conversely, if a person is underused and maybe even adequately nourished, you're going to push them to higher levels of protein intake. So it's clearly an art more than it is a science, but the science is the piece that says muscle mass matters tremendously. Frailty is an enormous contributor not just to mortality, but much more importantly to morbidity in an aging population. And therefore everything must be done to minimize frailty and sarcopenia.Eric Topol (20:37):Well, you convinced me that was compelling in the book and I hope my protein intake on the basis of your work there. The other thing, of course, before I get into some questions on the grounds is about you exercise, you're an exercise fanatic. I don't know, are you still exercising three or four hours a day?Peter Attia (21:00):No, I probably average two hours a day.Eric Topol (21:02):That's pretty good. Okay. A little more than the average, I guess though, right?Peter Attia (21:07):Probably yes.Eric Topol (21:08):But it's great that you can do it and that you're committed to it. Now, one of the drugs that is out there as to potentially improving longevity, which has an every animal species tested is rapamycin, which you've acknowledged of course could be trouble because of immune suppression, but it's a candidate drug even we're trying to look at it potentially for long, covid has a lot of good for mitochondrial function as well as potentially for people with activated immune systems. But what do you think about, I guess you take rapamycin and advocate for patients? I do. Yeah.Peter Attia (21:50):I mean, probably 5% of our patients take it. So I wouldn't say that we certainly don't use it in the way we would use, say, lipid lowering drugs where we have a very strong position that's much more clear. But look, rapamycin is a drug I've been studying for probably 10 years now, maybe a little over 10 years actually. And look, I think it's, as you said, it's the most successful molecule that's ever been tested from a Jira protective perspective in the field of science and medicine. So there is no other molecule that has so repeatedly demonstrated a survival advantage across all species. And these are, again, it's important to understand this is all species that span a billion years of evolution. So if you go back and look at the effective mTOR inhibition on yeast, on worms, on flies, and of course more recently on all types of mammals and also important models of mammals. So not just like the B six mouse, but some of the more representative mouse models, of course, Matt Kalin is now testing this in companion dogs. We've got some small primate studies. All of these things are basically showing the exact same effect.(23:14):Couple that with the fact that we have human data using rapa logs, dosed intermittently. So this is a very different dosing schedule than what is used for the immunosuppressive doses, for example, in transplant patients. And we see the opposite now. We see immune enhancement. And that's why in the book I make a point of saying we've historically thought of rapamycin as an immune inhibitor. We're probably better off thinking of it as an immune modulator. So it can be an inhibitor, but it can be an enhancer. And probably one of the most interesting near-term applications for rapamycin might be indeed B-cell enhancement in elderly patients, which is the population. It's already been studied in The 2014 paper with Q Stein led by Joan Manic, demonstrated that just a six or eight week course of intermittent rapamycin followed by a washout was enough to boost immune response to a flu vaccine. So these are very interesting studies, and of course it's unfortunate we're never going to get a hard outcome study of rapamycin in humans because it would take too long and it's never going to bePeter Attia (24:27):Done. So I think the best we're going to get are better and better animal models that more closely approximate humans, for example, in the probably companion dogs would be as good as it's going to get there. The readout of that study will be 2026. And then the best thing we'll expect to see in humans are biomarker studies. Now, the promise today, we don't have really good biomarkers. Rich Miller at the University of Michigan has done some incredible work here identifying a subset of biomarkers from the I T P mice. I would love to see that work replicated in humans and first begin with, Hey, are we even able to measure these well in humans and are we able to perturb them predictably without too much biologic noise? And if we can do those things, then it starts to get very interesting. But Eric, that's my belief as to how we will bridge the gap between where we are now, which is clearly rapamycin works for every creature to where what would be very interesting to know is does it therefore work in humans?Eric Topol (25:28):That'sPeter Attia (25:28):Not a guarantee.Eric Topol (25:29):Yeah, interesting how that plays out because it has real potential. And also, of course, as you well know, it's about a dose story too. It's low doses versus higher doses. And your point about immunomodulation is really important. The next thing I want to ask you about was the total body M R I. As you know, that's become, there's many more startup companies are advocating these and that you could get total body MRIs to prevent. That's something I know you're supportive of, but also obviously there's concerns about rabbit hole incidental findings. What are your thoughts about that?Peter Attia (26:09):Yeah, I mean, I'll take a step back from minute and talk more broadly just about cancer screening because of course, whole body M R I is simply one tool one would use for cancer screening. And this is an area where I've had a real pendulum swing in the last six or seven years. So I think in my training, I trained in surgery, and so going back 15, 20 years, my view was that cancer, aggressive cancer screening was really only giving us lead time bias. And I really wasn't convinced that it was saving lives. But the truth of it is, I didn't really look closely enough at the data. And I think if you look at the data more closely, what you'll realize is that it really does matter how many cancer cells you have in the body when you treat a patient.(26:57):And I think that the burden of disease matters. And I really think that that was the big change in my perspective and the best evidence for this, and I cite two examples in the book, which I think are two of the largest examples, is when you contrast the effect of treating patients with metastatic cancer versus treating patients in the adjuvant setting for the same cancer with the same drug. So just for the listeners to make sense of that, adjuvant therapy is what you give a patient after you've surgically removed the existing tumor and you give it because there are still cells in the body. So when a patient has a colorectal cancer and the surgeon removes the piece of the colon with the cancer and the piece of the lymph nodes that are attached to it, and there's cancer there, but the CT scan demonstrates that at least grossly to the eye, there's no other cancer. So the liver, the lungs, the bones, everything is clean. What do you do with that patient? Well, you know that if you don't treat that patient, 60, 70, 80% of those patients cancer will come back.(28:12):But we know that if you give those patients the FOLFOX regimen and comparable regimens with comparable drugs, at least half of them will be cured. So that's pretty interesting. Now what happens in the case where you go and you take the colon out and now the patient has metastatic disease all over their body? Well, it turns out you're going to give them the exact same chemotherapy, but how many of those patients will survive? Zero. Zero of those patients will survive tragically, every one of those patients will die from their disease today. And so what that tells us, and by the way, we could do the same exercise with breast cancer. So you can take the most common cancers, and it's always the same situation even when you're using the same drugs. We have far better success treating adjuvant in the adjuvant setting than we do in the metastatic setting.(29:06):And I've discussed this with many oncologists, and they all sort of point back to the same argument, which is the more cancer cells you have, the higher the probability that some of those cells are going to find escape mechanisms to the drugs, they're simply going to be able to mutate their way out of the drug. And therefore, when you're treating a billion cells, which is maybe what you're treating in the adjuvant setting, you have a better chance at squashing the cancer than when you're treating tens of billions or hundreds of billions of cells in the metastatic setting. So with all of that said, if the important tool to not succumbing to cancer is reducing the probability of getting cancer, which it clearly is, and we could talk about what are the important steps there beyond the obvious, not smoking. I would say the second most important thing is if you do get cancer, and unfortunately I still believe that you can do everything and still get cancer, there's so much we just don't understand about this disease in a way that we understand so much more about cardiovascular disease.(30:12):But when it comes to cancer, I think Bert Vogelstein was absolutely correct when he said, bad luck just plays an enormous role. And of course, I'm paraphrasing, but that's a very controversial paper he wrote many years ago that I believe is correct. So we have to be able to find it early. Okay, so with all that said, what are the tools we have to detect cancer early? Let's put aside all of them and just talk about the M R I because we can talk about colonoscopy, we can talk about liquid biopsies, which you might want to talk about. But when it comes to the M R I, why has it taken hold as a pan screen of choice? I think there's a couple of reasons, but the most important is it's not invasive and it has no radiation, so there's no physical harm from the test, and that's not true for a lot of other screens, right? A CT scan comes with an enormous amount of radiation. If you're going to do whole body, a whole body CT scan is probably even today, 25 to 30 milli verts, which would be an unacceptable amount of radiation for screening.(31:13):And of course, there are certain types of screening that are very important, but they come with risk like colonoscopy and M r I wouldn't displace that, but we take a slightly more measured approach to it, whereas anybody can go and get this M R I if they're willing to pay. I don't know what the going rate is today. It's one to $2,000 probably for a whole body M R I and obviously that's out of pocket. So let's get to your question now, which is what are the advantages of doing this? What are the blind spots of doing this and what are the down spots? Well, I'll tell you, this is what I say to every one of my patients. Every one of my patients, here's a 10 minute soliloquy that I give on sensitivity, specificity, positive predictive value, negative predictive value, and pretest probability. In fact, I've made a video out of it that I usually have them watch first and then we talk about it so that they really, really get it.(32:01):But what I want everybody to understand is every screening test has an intrinsic sensitivity and specificity, and then your pretest probability is what determines the positive and predictive value. And I say, here's the deal with M R I. It's a very, very high sensitivity test. One of the highest sensitivity tests we have, meaning if you have one of the cancers, it's capable of detecting, so not luminal cancer in an early stage, but if you have one of the cancers that's capable of detecting, it's very likely to detect it. Conversely, it has one of the lowest specificities of any test we can. What that means in English is it's very bad at distinguishing between cancer and non-cancer in terms it's going to cause us a lot of false positives. So then I show them, here is your pretest probability of having cancer, and we have a little model, and I plug in the sensitivity and the specificity. And by the way, we can improve the specificity greatly using diffusion weighted imaging with background subtraction. So I actually don't advocate for off the shelf M R I scanning because they don't use D W I with background subtraction, and therefore the specificity is very low.Peter Attia (33:19):We can really increase the specificity. It's still lower than you would like using diffusion weighted imaging with background subtraction. By the way, that's what makes, for example, multiparametric, M R I for the prostate, such a valuable tool. And then I say, look, the bottom line is that the positive predictive value of this test is still 10 to 20%. That means in English, if there is a positive finding, it is much more likely to not be cancer than to be cancer. And we are going to be on a little bit of a goose chase going after it. And where MRIs are especially weak, is in glandular tissue. This is their Achilles heel. And so is there a likelihood we're going to see a thyroid nodule that is totally irrelevant? Yes. And I say in our experience, I would say one in four patients who undergoes a whole body, M R I, maybe one in five ends up needing to do a follow-up study, like a thyroid ultrasound just to chase something down. Or at a minimum they need to do another scan a year later to follow something that is almost assuredly, nothing like an adrenal adenoma, but just to make sure it's not growing.(34:34):And based on that, Eric, about 10 to 20% of my patients just elect not to do it. They're like, that's not for me. And I say, great, know thyself. If it's for you, I want you to go in eyes wide open. And if it's not for you, I want you to know that you're not doing it and why you're not doing it. But I think that the reality of it is, and where you and I probably share a concern is I think it's very dangerous for patients to go into this without an advocate. And I think, so what I don't fancy is the idea of patients who just go into this without a physician who's there to be able to do with them, what we can do with our patients, which is help them make a very informed decision and just as importantly, walk them through the morass of follow-up should an INCIDENTALOMA show up.Eric Topol (35:30):Yeah, I think the way you prep the patients who go for it is so critical because I have so many patients I know you have who have had to go through all these extra tests, biopsies and whatnot, and came at everything negative, but the anxiety they went through was profound. So that's great. How have you positioned it and maybe in the future, the multi cancer early detection test is, whether it's through methylation or through fragmentation or whatever will be the first test, and then the M r I would be, where is it and what's going on? Because as you pointed out, apley, the number of cells and pre spread is so critical. And once it's already visible on a scan, it's a lot bigger than what you might be able to pick up through the cell-free plasma tumor, D n A. So one last thing I want to ask you about. You didn't write much on the Glip one drugs gyro, and we govi, and they're obviously, I don't know if I've ever seen a drug class like this, Peter, ever. And obviously right now it's not diabetes, it's obesity. But where do you think this is headed? Because as you probably saw, there were people even with early type one diabetes where it got rid of their insulin requirement, small series, but still very intriguing, thin people, right? Where do you see this headed?Peter Attia (37:03):Yeah, I don't think I wrote at all about this in the book truthfully, although I've written and done many podcasts on it since 2020, or probably since 21 was the first time I did a podcast on it. And so I've been following it very closely. And I think like any doctor, I'm constantly being inundated by patient requests to go on it. And it's mostly to manage weight. I mean, there's nobody that's coming to me saying, I'm not happy with my insulin resistance. Please put me on, I want to lose 10 pounds. Please put me on manjaro. By the way, I'm sure you've seen this, but there's now a triple receptor, right? So there's now GLP one, G I P, and then glucagon. And that phase two looked even more dramatic than the phase two and phase three of both tze peptide and semaglutide. It's almost become a Saturday night live skid at this point where at some point there'll be a quad receptor drug that will reduce your weight to zero.(38:08):You'll violate the relativity, you'll violate the principle of conservation of mass at some point. So I won't lie, I do have a couple of concerns, Eric. So we've had a number of patients on these drugs, and in all of our patients, we monitor overnight heart rate and H R V, we do it because it's so easy to do. Every one of our patients has some wearable, they're always wearing a whoop or a Fitbit or something like that. And without exception, every single patient who is on one of these drugs we have yet to see an exception, has an increase in their overnight heart rate of eight to 12 beats per minute.Eric Topol (38:50):I hadn't heard that. I hadn't seen it know about the GI side effects, but hadn't seen the cardiovascular.Peter Attia (38:57):And it goes away when you're off drug,Peter Attia (39:00):Takes a while. It takes a couple of weeks to go away depending on how long you've been on the drug, but your heart rate will return to normal off drug. And I haven't looked in a few months, but I haven't seen an explanation as for why that's the case. But it gives me pause because I can't think of a physiologic scenario that would increase your resting heart rate by 10 beats per minute as a positive thing. Now that doesn't mean it's not a good idea for some people. So in other words, there's clearly benefits to this drug in some populations. But I guess my reaction is if you're a person who just needs to lose 10 pounds, I'm not convinced that the risk is worth it relative to the reward.Eric Topol (39:48):Well, and to your point, there is not just the fact that you're getting this onward effect, at least we would deduce it's untoward, but that these people who are losing more than 10 pounds, losing 50 60, there's no way to get off these drugs that have been mapped out, whatever the effects are. And one I thought you would really zoom in on knowing at least what you've written about is the muscle mass, the fact that there's NIA and bone density loss from these drugs, and especially in people that are taking it long-term. Are you concerned about that?Peter Attia (40:23):We absolutely are. And we don't put patients on them without a DEXA scan, so that if for nothing else, we can demonstrate to them at some point when enough is enough, we're not seeing, and I'm not saying it's not possible, but I'm just saying you probably have to be much more deliberate about it. We're not seeing what I would consider an ideal loss of body weight either. So an ideal loss of body weight is generally regarded as less than 25% of the loss is lean mass, right? So if a person loses 50 pounds less than 12 and a half of those pounds should be lean mass, that would be really, really ideal. When we see people lose 40 pounds, i e 10, of which 10 or less should be lean, we'll easily see it be 50 50.(41:15):That's a very, very common finding. So that person paradoxically, is increasing their percent body fat as they're losing weight. Assuming they started out at 35 or 40% body fat, they're actually getting slightly higher in fat percent. So again, I still think that they're unbalanced. People are getting metabolically healthier when they do this in the short run, but I'd love to see better data. I don't know why I'm not jumping up and down with joy. I know that the rest of the world is so I don't know why I'm not trying to be contrarian about it, but I do have my reservations about their pan use.Eric Topol (42:01):I share those, especially since we don't have a way to get people off if people could and maintain their weight or that. I think because these side effects are notable and even perhaps more than is generally recognized as you're bringing up, the concern here is without a exit ramp, we got a lot of potential lurking trouble there. Well, this has been terrific to review a lot of the create work you did in the book. Some of my questions that I came to when I read it saying, what did you say about this or that? But overall, it's just a great resource for people. It's an inspiration for people to take better care of their health. Maybe they don't want to get into every bit of the things that you've written about, but you certainly covered the bases really well as well as anyone ever has. So it's great work. Peter, thanks so much for joining today.Peter Attia (42:58):Thanks very much for having me, Eric, and thanks for taking the time to read the book and comment on it. Get full access to Ground Truths at erictopol.substack.com/subscribe

Colorectal Cancer | Practical Perspectives: Investigators Discuss Current Management and Actual Cases of Relapsed/Refractory Metastatic Colorectal Cancer

Play Episode Listen Later Oct 6, 2023 65:24

Featuring perspectives from Dr Kristen K Ciombor and Dr J Randolph Hecht, including the following topics: Introduction (0:00) Case: A woman in her early 80s with KRAS-mutated, HER2-positive metastatic colorectal adenocarcinoma — Zanetta S Lamar, MD (14:29) Case: A man in his late 70s with metastatic KRAS G12C-mutated rectal adenocarcinoma treated with third-line sotorasib/panitumumab — Georges Azzi, MD (26:03) Cases: A man in his late 50s with KRAS-mutated metastatic colon cancer and very slow disease progression on second-line FOLFIRI/bevacizumab, and a man in his mid 40s with KRAS wild-type metastatic colon cancer and disease progression on third-line treatment — Priya Rudolph, MD, PhD, and Ina J Patel, DO (30:41) Case: A man in his early 80s with right-sided microsatellite-stable (MSS), KRAS G12D-mutated metastatic colorectal cancer (mCRC), tumor mutational burden 10 mut/Mb, currently receiving third-line TAS-102 — Warren S Brenner, MD (37:11) Case: A man in his late 70s with microsatellite instability-high, BRAF V600E-mutated recurrent cecal adenocarcinoma — Nikesh Jasani, MD (50:09) Cases: A woman in her late 50s with MSS BRAF V600E-mutated mCRC with brain and bone metastases who experiences a good response to dose-reduced FOLFOX after disease progression on first-line encorafenib/cetuximab, and a woman in her mid 60s with RAS wild-type, BRAF V600E-mutated, MSS mCRC, now receiving encorafenib/cetuximab after disease progression on FOLFOX/bevacizumab — Farshid Dayyani, MD, PhD, and Dr Azzi (59:05) CME information and select publications

phd management current md practical perspectives investigators mb ras cme tas colorectal cancer metastatic her2 refractory kras mss relapsed mcrc azzi braf v600e folfox folfiri j randolph hecht

How Oncologists Are Confronting the Cancer Drug Shortage

Caris Molecular Minute Podcast Series

Play Episode Listen Later Aug 10, 2023 25:17

Drs. Vamsi Velcheti, Taofeek Owonikoko, and Janakiraman Subramanian discuss their experiences navigating the cancer drug shortage in the United States, the impact on patients and clinical trial enrollment, lessons learned, and proactive strategies to mitigate future crises. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic oncology at the Perlmutter Cancer Center at NYU Langone. On today's episode, we'll be discussing the impact of the shortage of cancer chemotherapy drugs across the United States. This has been affecting several thousands of patients with adult and pediatric cancers and hampering enrollment in clinical trials. Among the shortages are very commonly used drugs like cisplatin, carboplatin, methotrexate, and fludarabine. Some of these shortages have persisted since the time of the pandemic in 2020. So today, to discuss this really troubling scenario, I have two outstanding colleagues, Dr. Janakiraman Subramanian, the director of thoracic oncology at Inova Schar Cancer Institute in Virginia, and Dr. Taofeek Owonikoko, a professor of medicine and the chief of the Division of Hematology and Oncology at the University of Pittsburgh Hillman Cancer Center in Pittsburgh. Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available at asco.org/DNpod. So, a recent survey by the NCCN found that 90% of the nation's largest cancer centers have experienced a shortage in carboplatin, and 70% of the centers have reported a shortage in cisplatin. These are platinum-based chemotherapies we use frequently in patients with cancer, and these are often curative intent treatments for several cancers, and these are used in several tumor types, both solid tumors and hematologic malignancies. So, the scale of the problem is immense. Dr. Owonikoko, I'd like to hear your take on this situation and how are you dealing with this at the UPMC Cancer Center. Dr. Taofeek Owonikoko: Yeah, thank you, Dr. Velcheti, and happy to be part of this panel. As you rightly surmised, the chemotherapy drug shortage is what we've all experienced across the length and breadth of the United States. Our cancer center here in Pittsburgh is not an exception. We've had to be proactive as well as think outside the box to be able to manage the challenge. Just like every other cancer center across the country, maybe to varying degrees, we've had to look at patients in need of chemotherapy with these standard-of-care agents such as cisplatin or carboplatin, and to some degree docetaxel, during this past episode of drug shortage that we all went through. And while we did not have to, fortunately, cancel any patient treatment, we all went through it with bated breath; not sure of where the next batch of chemotherapy drugs will come through, but I would say in the past couple of weeks, we've actually seen some improvement in drug availability. But before then, we've had to have contingency plans where, on a weekly basis, we review our patient list and the drug regimens that they're going to need, and must make sure that we have enough drug on hand for those patients. And in situations where we thought we might not have enough drug; we also had a plan to use alternative regimens. We were proactive in having guiding principles that are consistent with ASCO's recommendations in terms of quality care delivery for cancer patients. So, I'm sure that this is more or less the same approach adopted by other leading cancer centers across the country. Dr. Vamsi Velcheti: Thank you, Dr. Owonikoko. And Dr. Subramanian, you're in a community setting, a large cancer center that serves a lot of patients in the state of Virginia. So, what is the scale of the problem at your institution and how are you handling it? Dr. Janakiraman Subramanian: First of all, Dr. Velcheti, thanks for having me here on this panel. And as you rightly said, this is a significant problem, and it is across the country like Dr. Owonikoko said. And as medical oncologists, we are not always thinking of drug shortages. Our focus is on taking care of our patients. So, this is one more issue that we need to keep in mind now as we manage our patients with cancer. When this shortage started, the biggest problem, as you know, was when we became aware of this was primarily in cisplatin and we had some of our patients who were getting curative treatment and we had to make a decision - can they get cisplatin or can they get carboplatin. And one of the things we did was to have an ethics committee that will review each patient that is being planned to receive cisplatin-based chemotherapy and come to a decision on how best we can support them. The template for some of this was based upon some of the triage mechanisms we used during COVID, as well as the ASCO guideline document for managing this chemotherapy shortage, which was one of the blueprints we used. And they have reviewed all cases, all patients that are being planned for cisplatin or carboplatin for that matter, and we come to a decision based on that. And we also have another committee that constantly monitors drug availability on a weekly basis and tries to forecast where the next problem would be as we take care of our patients. And particularly as a lung cancer doctor, we've had situations where we had to use carboplatin instead of cisplatin and even we also have carboplatin shortage. And so, the committee usually approves two cycles at a time, but thankfully so far we have not had a situation where we could not offer our patients the chemotherapy treatment. But we are very carefully monitoring the situation, hoping that this will improve. The other aspect of the shortage has been in 5FU. A lot of our GI colleagues; I treat esophageal cancer patients as well, where we've had to forego the bolus 5FU and have a 10% reduction on all 5FU infusions. And we've been using some of that dose reduction to ensure that we can have 5FU available for all our patients. And that's how we've been trying to manage this shortage situation here at Inova Schar. Dr. Vamsi Velcheti: Dr. Subramanian and Dr. Owonikoko, we are oncologists, we are treating patients, and the toughest part really is telling a patient that we don't have access to certain drugs and we have to switch treatments to perhaps another treatment regimen that may be suboptimal. And it's always a very anxiety-provoking discussion, and especially for patients with metastatic cancer, they're already under a lot of stress and it's a really difficult conversation. How do you handle that, Dr. Owonikoko? Dr. Taofeek Owonikoko: That's a conversation we all hope we don't have to have. And fortunately, with this current crisis, I've actually not had such misfortune of having to inform a patient that we don't have drugs to treat them or that we have to switch to something inferior. But conceptually, it's possible that could have happened and that would have been very difficult. But the one thing that we did, though, as part of our mitigation strategy was actually to inform the patient ahead of time because the way we handled this was to look at our inventory on a week-by-week basis. And if there are patients where we felt maybe they will be coming in towards the end of the week and we may not have enough drugs for them, to let them know the possibility exists that we might have to switch them to something different. While we did not have to do that for any patient, yes, there are patients that we had to give that heads up to, to say, “We're having this shortage. We're doing everything we can to make sure it's available. But just in case it's not available…” I think what is most important for most patients is to be aware of that decision ahead of time, to be able to process it, and to be transparent. The other challenge that we face was, if you have to choose between patients, what should be your guiding principles as to who gets the drug and who doesn't get it? I think it's very easy for all of us to say, “Oh, if it's curative intent, we do it. If it's not curative intent, we don't do it.” It's a little more complicated than that because if we put the equity hat on, curative intent doesn't actually mean that that life is more valuable than somebody who cannot be cured. And this is where really, I think having people with expertise in ethics of care delivery and disaster management will be very important for us to proactively anticipate that, should this become a recurrent problem in the future that we actually have a well-vetted approach, just like we did during COVID where you have to ration resources that we have those people with expertise to help us as oncologists because not all of us, at least personally I can speak for myself, that is not my area of expertise and comfort. Dr. Vamsi Velcheti: Excellent points. Dr. Subramanian, anything to add? Dr. Janakiraman Subramanian: Oh, absolutely. I echo what Dr. Owonikoko said. These are conversations that we would like to hopefully never have with our patients. But this is a crisis that we are facing now. And personally, I can tell you two situations where we ran into this problem. But overall, though, we never had to stop a treatment or cancel a treatment for our patient. In the first situation, we had a young man with a rare germ cell tumor in the hospital for whom cisplatin was key. He was already in the ICU and sometimes the treatment start dates are not perfect, unlike what we do in the outpatient setting, depending on how well he's doing or the treatment start dates might move by a day or so. So we basically had to hold a certain dose of cisplatin for him. This brings the next question, which is how do we decide who gets cisplatin versus who can go for an alternative option? And I think Dr. Owonikoko made a great point where, just because it is a curative disease does not mean their life is more valuable. This is where I think trying to make that decision at an individual level, as an individual treating physician can be extremely hard. And that's why at our institution we have this ethics committee where we have oncologists, pharmacists, and ethicists that review these chemotherapy orders, particularly for cisplatin, and try to use some guiding principles that we learned from COVID as well as ASCO's guidance to decide how we assign our resources. That's one option, one way we have done it. And then in another situation that was faced by one of my GI oncology colleagues was a patient that was originally planned to go on a clinical trial where the chemotherapy backbone was FOLFOX and because we had the 5FU shortage, we could not offer that patient clinical trial enrollment. And that was a tough conversation where they had to tell them that they could not go on a clinical trial that they were looking forward to. And this then brings the next question, which is by foregoing the bolus 5FU and by the 10% reduction in the infusional 5FU, are we providing them inferior treatment? And it's a conversation that's had at a very individual level. I don't envy my colleague who had to have that conversation. It's a challenge and we try to do our best to communicate to our patients that we are trying to provide care without trying to compromise the effectiveness of treatment for them. Dr. Vamsi Velcheti: Thank you so much both of you. And we had the same issues here at NYU in New York City as well. It appears, you know, the degree of shortage and the drugs that are in shortage has been somewhat different at different locations across the United States. But the theme has been that we are having to ration treatments for our patients. And of course, there are some tumor types where there's really no adequate substitution, for example, GU cancers. I mean, you can't really not give them cisplatin. A lot of these are situations which have curative intent and young patients. So, it's really troubling. And I think one of the things that really came out of this is there's been a lot of push from professional societies that actually ASCO has been spearheading and some intense discussions with CMS and legislators to kind of provide more long-term fix for these things. And I think all of us have to be more engaged in those discussions with our professional societies like ASCO to kind of help promote awareness. So if you kind of think about it, these drugs are not that expensive. These are generic drugs that we've all been using for such a long time. And the fact that we can't provide these drugs for various reasons is kind of really concerning. We spend so much money on research and more expensive drugs and not being able to manufacture these drugs within the country and kind of having to rely on complex supply chains is troubling, and I hope the situation improves very soon. So, I know both of you are at large cancer centers that enroll patients on clinical trials. Of course, these drugs, especially carboplatin, for lung cancer, especially, are like core treatments that are used in managing cancer patients with lung cancer. So how is this affecting your clinical trial accrual? Are you prioritizing patients on clinical trials for these drugs? Have you had to make any decisions to hold clinical trial accrual for certain trials? Kind of curious to hear. Dr. Taofeek Owonikoko: Yeah, so I can maybe weigh in a little bit on that in terms of what we've had to do for patients receiving treatment as standard of care versus those going on clinical trials. As we all recognize that when a patient goes on a clinical trial, even if they are going to receive a standard-of-care regimen as part of that trial, it still has to be administered in line with the protocol. So, during the extreme period of shortage anxiety, we actually had consideration for perhaps not putting patients on trial if we're not sure that they will be able to continue to receive the protocol-mandated treatment, whether it's a control intervention or the experimental intervention. The good thing to come out of this is at least here at UPMC, we actually did not have any instance where we had to deny a patient clinical trial participation. But there were anxious periods when we already had patients enrolled and they were scheduled to receive a platinum-containing regimen and we were not sure whether or not we were going to have adequate supply of the drug for them while on trial. I think this really raises an important consideration going forward as we come out of this current shortage. I don't by any stretch of the imagination assume that this is going to be the last one we experience, but I think the lessons learned here, we have to also carry that forward both in the design of the trial as well as in the regulatory environment surrounding clinical trial conduct, to say, should another incidence of drug shortage are to happen, how do we actually operationalize that with respect to patients on trial, whether starting or already on trial? I think it's much more challenging when the patient is already on the trial, they've already started. It's less challenging if you just have to make a decision about somebody starting newly on the trial. But equally important is that by not allowing new patients to go on trial is denying something that potentially could be of benefit to them, albeit it is still a trial, it's not an established treatment option yet. Dr. Janakiraman Subramanian : I completely agree with Dr. Owonikoko. Those were very key points and issues that we face as well. In terms of my patients with lung cancer, we haven't had a problem in getting them on clinical trials. Even though we have had carboplatin shortage patients who are already on treatment, they were able to get the carboplatin. For new patients, we were still able to provide them carboplatin as well. The biggest problem for clinical trials has been primarily with my GI colleagues who have to use 5FU. And there, as I said before, we are unable to give bolus 5FU and there is a 10% reduction of the infusional 5FU. So, we can't have any of these patients go on clinical trials. And as a result, anything that has to do with 5FU has come to a screeching halt in terms of clinical trials for our patients. And I think I echo the point of Dr. Owonikoko that by no means this is the last drug shortage we're going to be dealing with and we are here today discussing this, also because this shortage has not ended. It's been ongoing. It's one of the longest drug shortages in my memory as a medical oncologist, and that's concerning. We still see that there is some improvement, but we haven't gotten past it yet. And therefore, as we develop clinical trials and we need to have methods to address drug shortages and how we manage patient enrollment as well as how do we manage existing patients who are already on a clinical trial and, if possible, what might be their options in that situation. We may not have all the answers, but it is definitely an issue that we need to think about in the future as we develop and implement newer clinical trials for our patients. Dr. Vamsi Velcheti: I completely agree and great points, both of you. And we've had the same issues with clinical trials at NYU Langone as well due to the shortage. It's been a challenge, and I think this is a problem that's so complex because of supply chain issues and the way the drugs are priced and incentives for manufacturing these drugs in the United States are not lucrative enough to actually onshore a lot of the production of these drugs. I think at the end of the day, I think we have to come up with some creative, innovative, reimbursement structures for these generic chemotherapy drugs. I think this would require a very complex economic solution that perhaps ASCO and other organizations should kind of really foster an environment of innovation to kind of help facilitate onshoring some of the manufacturing of these key drugs within the United States. I think ASCO is already trying to do that, trying to collaborate with all the stakeholders to kind of address this problem is very critical, and I think all of us have to be engaged in some of the advocacy efforts that are ongoing to kind of address these drug shortages. And this is not a short-term problem. So, Dr. Owonikoko and Dr. Subramanian, any final thoughts before we wrap up the podcast today? Dr. Janakiraman Subramanian: So, Vamsi, you mentioned the whole complex supply chain and the fact that we rely primarily on overseas manufacturers to get these drugs that are off-patent but still a key backbone of our cancer treatment. I think those are all key issues that policymakers and leaders in the field have to keep in mind. As an institution at Inova, one of the key mechanisms that have helped us to sort of stay ahead of the shortage was to have this inventory management team that monitors the inventory out there. And in fact, the inventory management team does have access to what the inventory is in some of their main suppliers in terms of the drugs. And they also have an idea of how many patients are going through treatment, what is the weekly usage of a specific drug like carboplatin. And they try to forecast what is coming down the road and try to prepare for it. And as we try to look for solutions, maybe a forecasting mechanism in a larger scale like either spearheaded by ASCO or by policymakers level that can, for the overall country, try to see where some of the inventory is for some of these critical drugs and try to prepare for it ahead of time, rather than wait till we hit the shortage and then try to find alternative suppliers to get the drug, which obviously doesn't happen quick enough. It takes months or even longer to catch up and get the inventory back to the level where we can comfortably take care of our patients. I think that is something we should be advocating for that as well as the professional societies should take a handle on that and see if they can support something like that as well as letting the institutions know ahead of time what's coming might be very helpful. Dr. Vamsi Velcheti: Yeah, very good point, Janakiraman, and I think that's a key takeaway here. I think we have to learn from other industries and try to– I mean this is not unique to healthcare by any means. I mean these chronic shortages due to supply chain issues, inventory management, there might be some learnings from other industries here that we probably should also focus on inventory management and improve supply chain logistics. Dr. Owonikoko, any closing thoughts? Dr. Taofeek Owonikoko: Yeah, I agree as well with all the points made by Dr. Subramanian and yourself. This is a chronic problem that requires a long-term strategy. I think it's both an economic problem as well as a regulatory problem. As we all know, part of the reason why we went through this current crisis is the regulatory decision by the FDA regarding safety of one of the manufacturers. So being proactive in terms of how these audits are conducted and giving people lead time I think will help avoid similar situations in the future. It's an economic problem. There's a reason why a lot of the big pharma companies are not producing these drugs. And if the cost of production is such that the amount of money you get paid is enough to cover your price, I think there is an economic issue there to be addressed. That is unfortunately not within the scope of what any one of us can do individually, but as advocates in terms of the structure of incentivizing new drug versus old drug, some of these newer drugs are quite expensive, but oftentimes they are used along with standard drugs that are not as expensive. So, where do we strike that balance where we do not stifle innovation but at the same time, we don't create a perverse incentive system where everybody just wants to come up with the newest, most expensive drug and nobody is interested in really producing the backbone chemotherapy and other agents that will make those new drugs work well. So, I think we have to pay attention. We have to advocate for our patients through our different institutions and organizations, and I hope that society as a whole that we've learned a lot of lessons from this crisis and that will help us craft some long-term strategies. Dr. Vamsi Velcheti: Thank you both Dr. Owonikoko and Dr. Subramanian for your time today to speak with me and our listeners and for sharing your insights with us on the ASCO Daily News podcast. Dr. Taofeek Owonikoko: Thank you. Dr. Janakiraman Subramanian: Thank you. Dr. Vamsi Velcheti: And thank you to our listeners for your time today. If you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you so much. Disclaimer: 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. ASCO Resources Related to Drug Shortages are available here. Follow today's speakers:   Dr. Vamsidhar Velcheti   @VamsiVelcheti   Dr. Janakiraman Subramanian @RamSubraMD Dr. Taofeek Owonikoko @teekayowo Follow ASCO on social media:    @ASCO on X (formerly Twitter)   ASCO on Facebook   ASCO on LinkedIn     Disclosures:    Dr. Vamsidhar Velcheti:   Honoraria: ITeos Therapeutics   Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus   Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   Dr. Janakiraman Subramanian: Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Daichi, G1 Therapeutics, Jazz Pharmaceuticals, Janssen Oncology, Lilly, Blueprint Medicines, Axcess, BeiGene, Cardinal Health, Takeda, OncoCyte Speakers' Bureau: AstraZeneca, Boehringer Ingelheim, G1 Therapeutics, Jazz Pharmaceuticals, Janssen Oncology Research Funding (Inst.): G1 Therapeutics, Tesaro/GSK, Novartis, Genentech, Novocure, Merck Dr. Taofeek Owonikoko: Stocks and Other Ownership Interests: Cambium Oncology, GenCart, Coherus Biosciences Consulting or Advisory Role: Novartis, Celgene, Abbvie, Eisai, GI Therapeutics, Takeda, Bristol-Myers Squibb, MedImmune, BerGenBio, Lilly, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, Xcovery, Bayer, Merck, Jazz Pharmaceuticals, Zentalis, Wells Fargo, Ipsen, Roche/Genentech, Janssen, Exelixis, BeiGene, Triptych Health Partners, Daichi, Coherus Biosciences Speakers Bureau: Abbvie Research Funding (Inst.): Novartis, Astellas Pharma, Bayer, Regeneron, AstraZenece/MedImmune, Abbvie, G1Therapeutics, Bristol-Myers Squibb, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, Merck, Oncorus, Ispen, GlaxoSmithKline, Calithera Biosciences, Eisai, WindMIL, Turning Point Therapeutics, Roche/Genentech, Mersana, Meryx, Boehringer Ingelheim Patents, Royalties, Other Intellectual Property (Inst.): Overcoming Acquired Resistance to Chemotherapy Treatments Through Suppression of STAT3 Selective Chemotherapy Treatments and Diagnostic Methods Related Thereto DR4 Modulation and Its Implications in EGFR-Target Cancer Therapy Ref: 18089 PROV (CSP) United States Patent Application No. 62/670,210 June 26, 2018 (Co-Inventor) Soluble FAS ligand as a biomarker of recurrence in thyroid cancer; provisional patent 61/727,519 (Inventor) Other Relationship: Roche/Genentech, EMD Serono, Novartis Uncompensated Relationships: Reflexion Medical

covid-19 united states university new york city speaker cancer pittsburgh consulting drug fda pfizer nyu stocks confronting gi icu shortage drs gu inventor astrazeneca wells fargo bayer cms oncology merck inova patents health policy janssen novartis royalties gsk asco oncologists genentech amgen disclosures glaxosmithkline fujifilm abbvie hematology bristol myers squibb takeda upmc regeneron subramanian boehringer ingelheim cardinal health its implications nyu langone ipsen drug shortages eisai celgene nccn jazz pharmaceuticals co inventor incyte emd serono daichi foundation medicine united therapeutics medimmune pharmamar blueprint medicines folfox roche genentech stat3 elevation oncology janssen oncology transcript dr 5fu g1 therapeutics owonikoko astrazeneca medimmune turning point therapeutics genoptix taofeek owonikoko

Interview with Dr. Salma Jabbour: An In-depth Look at the PROSPECT Trial

Play Episode Listen Later Aug 9, 2023 21:16

Caris Precision Oncology Alliance™ Chairman, Dr. Chadi Nabhan, sits down with Dr. Salma Jabbour, Clinical Chief, Radiation Oncology and Vice Chair of Clinical Research & Faculty Development at RWJUH/Rutgers Cancer Institute. Together they discuss a plenary presentation that was given at ASCO 2023 on rectal cancer titled, the PROSPECT (Preoperative Radiation or Selective Preoperative Radiation and Evaluation before Chemotherapy and TME) trial. The PROSPECT trial attempts to challenge the current treatment paradigm by individualizing treatment through the use of radiotherapy selectively rather than reflexively. This is a randomized phase III trial of neoadjuvant chemoradiation versus neoadjuvant FOLFOX chemotherapy with selective use of chemoradiation, followed by total mesorectal excision (TME) for the treatment of locally advanced rectal cancer (LARC). For more information, please visit: www.CarisLifeSciences.com/POA-Intro/

trial depth evaluation prospect vice chair chemotherapy clinical research asco radiation oncology faculty development l'arc tme jabbour clinical chief folfox chadi nabhan

Chemotherapy Sequencing In Colorectal Cancer

university cancer pros covering prospect napoli internal medicine asco adjunct associate professor hcc texas southwestern medical center tme folfox folfirinox

Play Episode Listen Later Jul 20, 2023 13:36

A Landmark of OncoPharm from 2004: FOLFIRI --> FOLFOX or FOLFOX --> FOLFIRI. Some interesting dosing to discuss in this study. Link: https://pubmed.ncbi.nlm.nih.gov/?term=37379692

landmark chemotherapy sequencing colorectal cancer folfox folfiri

GI Cancer ASCO 2023 Highlights with Dr. Muhammad Shaalan Beg

Oncology Brothers

Play Episode Listen Later Jun 29, 2023 24:04

Discussing GI (Gastrointestinal) Cancer ASCO 2023 Highlights, focusing on practice-changing studies with Dr. Muhammad Shaalan Beg, Co-Leader Gastrointestinal Oncology, Adjunct Associate Professor of Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center. Covering three important studies: - PROSPECT: ph III trial of neoad chemoRT vs neoadj FOLFOX chemo with selective use of chemoRT, followed by total mesorectal excision (TME) for treatment of locally advanced rectal cancer (LARC) - NORPACT-1: Short-course neoadj FOLFIRINOX vs upfront surgery for resectable pancreatic head cancer - NAPOLI 3: ph III trial in mets pancreatic ductal adenocarcinoma pts, liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) vs nab-paclitaxel + gemcitabine - IMbrave050: Efficacy, safety and patient-reported outcomes (PROs) from the phase III IMbrave050 trial of adj atezo + bev vs active surveillance in pts with HCC

Novel Therapies in GI Oncology at ASCO23

Play Episode Listen Later Jun 28, 2023 18:30

Drs. Shaalan Beg and Shiraj Sen discuss notable advances in GI cancers featured at the 2023 ASCO Annual Meeting, including the PROSPECT and PRODIGE-23 trials in rectal adenocarcinoma, the MORPHEUS study in uHCC, and the NORPACT-1 trial in pancreatic head cancer. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host for the podcast today. I'm the vice president of oncology at Science 37, and I'm an adjunct associate professor at UT Southwestern Medical Center. My guest today is Dr. Shiraj Sen. He is a GI medical oncologist and the director for clinical research at NEXT Oncology in Dallas. Today, we'll be discussing practice-changing studies and other key advances in GI cancers that were featured at the 2023 ASCO Annual Meeting. You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available on our transcripts at asco.org/DNpod. Shiraj, it's great to have you on the podcast today. Dr. Shiraj Sen: Thanks so much for having me today, Shaalan. Dr. Shaalan Beg: We saw exciting new data and great progress in GI oncology at the ASCO Annual Meeting. I was hoping we could talk about LBA2. This was the PROSPECT study that was presented during the Plenary Session. It's a randomized, phase 3 trial of neoadjuvant chemoradiation versus neoadjuvant FOLFOX chemo, followed by the selective use of chemoradiation, followed by TME or total mesorectal excision for the treatment of locally advanced rectal cancer. This is the Alliance N1048 trial. What are your thoughts on this study? Dr. Shiraj Sen: Thanks, Shaalan. It was great to see another GI study presented in a Plenary Session, and I thought this was a great trial that really took us back to thinking about why we do chemoradiation as well as chemotherapy perioperatively in locally advanced rectal cancer. And asking the important question of is there a select patient set or subset where we might be able to safely omit the chemoradiation piece. To me, the impressive part was this study enrolled from 2012 to 2018. In 2012, when this treatment really started enrolling, the standard of care was long-course chemoradiation for five and a half weeks, followed by surgery, followed by adjuvant chemotherapy with FOLFOX or CAPOX. During this time, a lot of the practices of these patients have shifted from that to giving total neoadjuvant therapy, where we bunch the chemotherapy and chemotherapy upfront prior to the patient undergoing surgery. And this study really asked us to take a look at both practices and ask the question of which one is better and is it possible to de-escalate care for patients who get upfront chemotherapy and omit the chemoradiation and still have similar outcomes. I thought it was very interesting that this was done in a non-inferiority-type manner, and we can talk more about that in a few minutes as well. But taking that all into context, the fact that in this study, that the non-inferiority endpoints were met for both disease-free survival as well as overall survival in the patients who were able to omit chemoradiation, I think in the big picture sense told us that there truly might be a patient subset where—this is in patients with T2 node-negative disease or T3 node-negative or T3 node-positive disease—where we might be able to safely exclude the chemoradiation and still have similarly effective outcomes for these patients. Dr. Shaalan Beg: Those are great points, especially when we have started to think about colon cancer and rectal cancer as many different diseases based on their location. And we know that in some instances their biology can be different as well. Can you talk a little bit about who those patients are that were enrolled on this trial? Because when I think about the German rectal study that led to us using neoadjuvant chemoradiation, the data was really around pelvic control of disease and sphincter preservation. So how did the patients who enrolled in this trial relate to the typical person with rectal cancer who walks through your doors? Dr. Shiraj Sen: Yeah, great point. I think we should point out the inclusion-exclusion criteria for this study. These patients were only those who were, again, T2 node-positive or T3 node-positive or negative, patients for whom chemoradiation would be indicated in the setting, and patients for whom they'd be good candidates for sphincter-sparing surgeries. So, tumors that are quite up high. These are not for individuals who have tumors requiring an APR. These are not for patients who have clinical T4 tumors. And this is not applied, again, to those high-risk patients who have 4 or more pelvic lymph nodes that are 1 cm in size or larger in the short access. And so, patients who need essentially an APR and the high-risk T4 tumors who are, I think, better suited by something like we'll talk about later in the PRODIGE study. I think one last point that might be worth making here on the PROSPECT trial is that it was a non-inferiority trial. And in my opinion, this was really a great use of a non-inferiority study. I believe that when there's a new treatment under consideration used in a non-inferiority study, it should be because that therapy or modality of treatment is safer, more cost-effective, or could help increase access to care without compromising efficacy, and ideally maybe more than one of the above. And in this case, I think really all of those checkboxes are met. In urban settings where we work, we think about access to radiation being quite plentiful, but when we get to more rural areas, or parts of the world where they may not have access to radiation like we may, I think this data can help drive care for a number of patients there. It can certainly be more cost-effective as it allows the omission of radiation. And certainly, from some of the PRO data that they presented, it certainly can be felt to be safer and help omit some toxicities as well. Dr. Shaalan Beg: Yeah, you mentioned a total neoadjuvant therapy and we seem to be entering this space in rectal cancer where the decision on which modalities an individual person will need for the management of their disease and what sequence they will need is all up for debate, whether that's chemotherapy or radiation, long-form, short-form radiation. And we also heard some results at earlier ASCO meetings around the omission of surgery in people who've had complete clinical responses as well. And you mentioned total neoadjuvant therapy and at ASCO this year we heard the results from LBA3504, which is a PRODIGE-23 trial. The investigators reported 7-year results of this phase 3 study from the UNICANCER group in France. This study is really pushing the envelope. What are your key takeaways here? Dr. Shiraj Sen: Great point. I think this study, especially when taken in conjunction with the PROSPECT trial, highlights the fact that these patients really can have heterogeneous diseases and ones that really require careful consideration and discussion at multidisciplinary tumor boards. Unlike the patient population in the PROSPECT trial, the PRODIGE study did treat patients with higher-risk disease. So these were patients with clinical T3, T4 tumors and so higher risk, and asked the question now with more mature 7-year follow-up of, when compared to receiving the standard of care at the time, which was a chemoradiation followed by TME, followed by adjuvant FOLFOX for 12 cycles or the capecitabine, does TNT giving again now modified full FOLFIRINOX for six cycles followed by chemoradiation followed by TME and then adjuvant FOLFOX, do the improvements in both disease-free survival, overall survival, and metastatic relapse rate, do they hold up, and/or are there any differences in local control? And again, here they demonstrate that even with longer-term follow-up, that the improvements in OFS, DFS, and metastatic relapse rate, really do hold up even with longer-term follow-up. And so, for these patients with higher risk disease, it does seem that giving induction chemotherapy with modified FOLFIRINOX before chemoradiotherapy really might be kind of best practices. The safety profile, even with longer-term follow-up was unchanged. There was not any increase in local recurrences. And again, looking at quality of life metrics there seemed to be similar or maybe improved quality of life for patients who receive the TNT approach. And now again, I think the next step is, as the presenter mentioned, investigating this even in a more tailored fashion, as was done with the PROSPECT study. Dr. Shaalan Beg: Let's change gears and talk about liver cancer. Abstract 4010 showed the results of the MORPHEUS-liver study. This was a phase 1b/2 randomized trial of tiragolumab in combination with atezolizumab and bevacizumab for people with unresectable locally advanced or metastatic hepatocellular cancer. It's really exciting to see innovations with immune therapy changing how we've managed hepatocellular cancer in the last few years. And here, we're seeing an addition of a third agent to an already approved regimen of atezolizumab and bevacizumab. I was really curious to hear what your take-home message is from this study. Dr. Shiraj Sen: Yeah, this was another very interesting abstract that was presented at ASCO this year. It's hard to believe that it was only 3 years ago that we first got the approval of atezo plus bev, and that it took more than a decade to really have us as a field improve on outcomes for patients with liver cancer above and beyond giving sorafenib. And here we are just 3 years later, already launching new phase 3 studies from these sorts of early-phase adaptive signal-seeking studies. The investigators as a whole should be commended for the speed at which new drug development has really progressed in liver cancers after, again, quite a lull we had in the pre-I/O days. It's encouraging to see that in just 3 years that there's another phase 3 study now being launched in HCC on the heels of this data combining the atezo-bev backbone to the anti-TIGIT molecule tiragolumab. Now, I know there was a lot of discussion and some criticism of this study and what the real effects of adding tiragolumab to atezo-bev might be because of the underperformance of the control arm. In this study, the atezo-bev control arm, it should be noted that was only 18 patients, had a response rate of only 11%. And of course, with longer-term follow-up of the IMbrave150 study, we know that with the atezo-bev, we expect a response rate of about 30%. And so how a real-world population of individuals receiving atezo-bev would compare to those receiving tiro-atezo-bev has been discussed. But I think the only real way to answer that question would be with a large, randomized phase III study. And it's encouraging to see that one is being launched to ask that question. Dr. Shaalan Beg: Absolutely. Let's change gears and talk about pancreatic cancer. LBA4005 explored short-course neoadjuvant FOLFIRINOX versus upfront surgery for people with resectable pancreatic head adenocarcinoma in the NORPACT-1 study. This is a multicenter randomized phase 2 trial and we're starting to see the reporting of clinical trials evaluating the sequencing of systemic therapies for resectable disease. We've heard studies for neoadjuvant therapy for borderline resectable as well as resectable trials in previous meetings. But there's a lot of discussion around the NORPACT-1 trial which may be causing some people to pause on our current understanding of treatment sequencing for resectable disease. I'm curious to hear what your take homes are. Dr. Shiraj Sen: Thanks. Yes, I thought this was a very interesting study as well. Depending on which institution one practices in, in recent years, many have shifted their practice for individuals with resectable pancreatic cancer from administering full FOLFIRINOX or adjuvant therapy only after surgery to giving it in the neoadjuvant setting based on, again, a number of smaller studies, some that are single institution. This is one of the first studies that in a randomized fashion has asked the question in just resectable pancreatic cancer. So we're not talking about borderline resectable or other patients. But in resectable pancreatic cancer, whether there are differences now comes if patients receive surgery first, followed by FOLFIRINOX-only adjuvant setting or essentially getting perioperative FOLFIRINOX and so neoadjuvant, followed by surgery, followed by, as tolerated, four cycles of adjuvant FOLFIRINOX. And I was a little surprised by some of the results and to me some of these data were a little intriguing. Specifically, I think if we take a deeper look like the discussant had after the presentation, there are, I think, some unanswered questions. Specifically, half the patients were randomized to receive neoadjuvant FOLFIRINOX and half of them received upfront surgery. But in the group of individuals who received neoadjuvant FOLFIRINOX, it looked like only half of them completed neoadjuvant chemotherapy. And some answers into kind of why that was, and what it was about those patients then who were in the neoadjuvant arm, is one thing that comes to mind. Secondly, what I thought was interesting was this study was that it was designed very well to try to take out as much heterogeneity as possible. However, in both arms, there was actually quite a substantial number of individuals who ended up receiving gemcitabine-based chemotherapy. And that's even in the patients who received neoadjuvant FOLFIRINOX, and individuals who received neoadjuvant FOLFIRINOX, only 25% post-op went on to receive adjuvant FOLFIRINOX. And 75% almost received gemcitabine-based therapy. And again, why so many patients received off-protocol adjuvant therapy is something that kind of struck me. I think the third and final thing that really struck me was, in the patients that received neoadjuvant FOLFIRINOX, there was a higher rate of R0 resections. 56% of patients had an R0 resection compared to those who got upfront surgery, where there was only a 39% rate and similarly kind of higher levels of N0 resection. And yet, despite all of this, again, the authors did show quite clearly that there were not any significant improvements in outcomes for patients that received neoadjuvant therapy, but kind of how improved surgical endpoints do not translate to overall survival and overall endpoints; I think there are still some questions there. However, I do agree overall that despite these limitations with the conclusions of the author, that at this time at least, it's not clear; the results don't support the widespread use of neoadjuvant FOLFIRINOX as a standard of care for resectable pancreatic cancer. Fortunately, there are studies ongoing, like the Alliance [for Clinical Trials in Oncology] study and the PREOPANC-3 study that hopefully will kind of help settle this verdict. Dr. Shaalan Beg: Yeah, it's a stark reminder that we need better treatments. I think we've been shifting the sequencing of these treatments and slicing them in as many ways as we can. And the core challenge is in finding better systemic therapies that have been found to be effective in advanced stage as well as in curative stages like this. And one of the points that bothered me about this trial was the drop-off that they saw at the beginning when the biliary system was being drained, or they were getting biopsies because folks who went for surgery upfront didn't always require those procedures. They didn't require histologic diagnosis either. But as is standard practice, before we give systemic therapy, we require psychologic confirmation. And that may have introduced a delay of a couple of days or a couple of weeks, which could have resulted in some imbalances in how survival is measured and how folks were doing. Because, as you know, a lot of times people diagnosed with this disease can be fairly sick, and a matter of a couple of days or weeks can make a big difference in terms of treatment with those. I'm really excited to wait and hear how the Alliance study and the PREOPANC follow-up trials pan out and as a very important cautionary note for everyone, both the folks who have adopted neoadjuvant therapy and those that have not followed the data. And kudos to the investigators for completing that trial. Dr. Shiraj Sen: Yeah, I fully agree. I'm glad to see that these trials are being run. I think we should not take anything away from the fact that these are very challenging trials to run. I think we certainly owe a big kudos to the patients who enroll in these studies who have resectable disease, but they're still willing to go through the process of an extra consent form, an extra kind of screening process, additional testing required to go into a clinical trial. And it's only because of them that we're able to run these studies and, as a field, get some answers on how to best take care of our patients. Dr. Shaalan Beg: Shiraj, thank you so much for coming to the podcast today and sharing your valuable insights on the ASCO Daily News Podcast. Dr. Shiraj Sen: Thank you so much for having me, and to all of the ASCO staff for having this podcast. Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Disclaimer: 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. Find out more about today's speakers:  Dr. Shaalan Beg @ShaalanBeg Dr. Shiraj Sen @ShirajSenMDPhD   Follow ASCO on social media:  @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures:   Dr. Shaalan Beg:  Consulting or Advisory Role:  Ispen, Cancer Commons, Foundation Medicine, Genmab/Seagen  Speakers' Bureau: Sirtex  Research Funding (An Immediate Family Member): ImmuneSensor Therapeutics  Research Funding (Institution): Bristol-Myers Squibb, Tolero Pharmaceuticals, Delfi Diagnostics, Merck, Merck Serono, AstraZeneca/MedImmune    Dr. Shiraj Sen: Employment: Roche/Genentech Stock and Other Ownership Interests: Roche/Genentech Research Funding (Institution): ABM Therapeutics, Zentalis Pharmaceuticals, Parthenon Therapeutics, Pyxis Oncology, Georgiamune Inc.  

science france german alliance depending gi prospect drs tnt io abstract oncology clinical trials merck dfs t2 morpheus t3 t4 asco hcc ut southwestern medical center prodige ofs tme r0 plenary session novel therapies asco annual meeting foundation medicine folfox folfirinox tigit merck serono capox astrazeneca medimmune

Meet The Professor: Optimizing the Management of Colorectal Cancer — Part 3 of a 3-Part Series

Journal of Clinical Oncology (JCO) Podcast

Play Episode Listen Later Jun 8, 2023 58:27

Featuring perspectives from Dr Michael J Overman, including the following topics: Introduction (0:00) Case: A woman in her mid 40s with microsatellite instability-high (MSI-H) colorectal adenocarcinoma metastatic to the brain receives pembrolizumab; KRAS G13D and somatic BRCA exon 11 mutations — Warren S Brenner, MD (16:27) Case: A woman in her late 50s with MSI-H Stage IIIB adenocarcinoma of the colon, BRAF V600E mutation — Eric H Lee, MD, PhD (23:20) Case: A woman in her early 70s with past medical history of diverticulitis and partial colectomy diagnosed with T1, microsatellite stable (MSS) cecal colon adenocarcinoma, minimum residual disease-negative after resection — Farshid Dayyani, MD, PhD (32:37) Case: A woman in her late 60s with past medical history of hypothyroidism has mass in right lung consistent with colorectal adenocarcinoma but no evidence of primary or other distant disease — Swati Vishwanathan, MD (42:58) Case: A woman in her mid 60s with multiregimen-relapsed RAS wild-type, HER2-positive metastatic rectal cancer, now receiving trastuzumab/tucatinib — Sunil Gandhi, MD (46:51) Case: A man in his mid 60s with MSS metastatic cecal adenocarcinoma and progressive disease on FOLFIRINOX/bevacizumab and capecitabine/bevacizumab maintenance — Dr Brenner (50:13) Case: A woman in her mid 60s with metastatic BRAF V600E-mutant colorectal adenocarcinoma, with circulating tumor DNA positivity after FOLFOX, heated intraperitoneal chemotherapy and colectomy/debulking surgery — Jeremy Lorber, MD (54:31) CME information and select publications

phd professor management dna md optimizing ras brenner cme colorectal cancer t1 brca her2 mss braf v600e folfox msi h folfirinox michael j overman

PROSPECT Trial (Alliance N1048): PROs During and After Treatment for Locally Advanced Rectal Cancer

Play Episode Listen Later Jun 4, 2023 28:27

Host Dr. Shannon Westin interviews guests Dr. Ethan Basch and Dr Deborah Schrag on their JCO simultaneous publication paper at ASCO's 2023 annual meeting: "Patient-reported outcomes during and after treatment for locally advanced rectal cancer (Alliance N1048). TRANSCRIPT The Disclosure for guests on this podcast can be found in the show notes Dr. Shannon Westin: Hello, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on articles that are published in the Journal of Clinical Oncology. It is your host, Shannon Weston, GYN Oncologist and Social Media Editor for the JCO. And I'm so thrilled to bring you our first podcast that will be a simultaneous podcast JCO publication and ASCO presentation at ASCO 2023, dropping on June 4, 2023. And it is an exciting one. We'll be discussing “Patient-reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer: The PROSPECT Trial Alliance N1048” (10.1200/JCO.23.00903) And let me introduce both of these amazing people that are going to be with us today. First is Dr. Deborah Schrag. She's the chair in the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York City, New York. Welcome. Dr. Deborah Schrag: Thank you. Dr. Shannon Westin: And then I'm also accompanied by Dr. Ethan Basch, the Chief of the Division of Oncology and Physician in Chief at NC Cancer Hospital at the University of North Carolina, Chapel Hill, North Carolina, my alma mater. So welcome. Dr. Ethan Basch: Thanks, Shannon. Nice to be here. Dr. Shannon Westin: And this is a good one. I was really intrigued by this work and I can't wait to talk about this with the audience, and I think that you're going to get a lot of excitement around this. So let's dive right in. I think we should start, first, let's speak a little bit about the role of patient-reported outcomes, assessing patient experience, especially as it relates to the evaluation of new therapies. Dr. Ethan Basch: Yeah, I'm happy to take that question, and thanks for asking it. All of us who practice oncology or accrue to trials recognize that patients receiving cancer treatment are highly symptomatic, either from their disease or from the sequelae of treatment. And as such, assessing and managing symptoms is really a cornerstone of what we do as oncology providers or investigators. But unfortunately, there's now abundant evidence that we as clinicians or investigators miss many of the symptoms and side effects that our patients experience, in fact, up to half of them. And so over the years, there have been a number of strategies developed to try to bridge this gap to fill in the pieces. And patient-reported outcomes is the one that has emerged to fill this gap, by informing us about the experiences of our patients. And without patient-reported outcomes and trials, we really have an incomplete understanding of the properties of products, the experiences of patients. And so when we are trying to do a risk-benefit assessment, for example, from data in a clinical trial, if we don't have patient-reported outcomes, we actually have an inadequate assessment of what was happening on the ground in that trial, particularly when it comes to adverse event assessment. Dr. Shannon Westin: I think it's been great how we've been able to start incorporating these more. But before we go too far down that line, this study was particularly done in rectal cancer and we have a very diverse audience. And so just to level set, can one of you speak a little bit about the current standard of care for locally advanced rectal cancer? Dr. Deborah Schrag: So, rectal cancer has a nasty tendency to come back in the pelvis. And Shannon, you're an OBGYN, so you know how miserable that can be. These are called locally recurrent cancers and they are just miserable. They cause a great deal of symptoms and a great deal of suffering. And back in the 1970s and '80s, a strategy to treat pelvic or local recurrence of rectal cancer was developed and that strategy was radiation. And it used to be that 10%, 20%, even 30% of patients who had rectal cancer surgery would have a cancer come back. And these were people who couldn't sit down, constant pain, leaking, trouble urinating, trouble moving their bowels. Radiation was a tremendous innovation. Radiation has been part of the management of locally advanced rectal cancer since 1990. Since 2004, we've given that radiation before surgery in the neoadjuvant setting. So this has been the predominant way that we treat these cancers really for the last two decades. We give about five and a half weeks of chemotherapy and radiation. Patients then have surgery, recover from the surgery, and many, not all, go on to receive some postoperative chemotherapy. It depends a little bit on what's found at surgery. But those three phases, the chemoradiation phase first, followed by surgery, followed by chemotherapy has been the prevailing care standard. When we launched this trial, we wondered whether we could improve upon that and whether we could capitalize on some of the innovations and discoveries, and advances that have taken place in the past couple of decades. Development of better surgical technique, better chemotherapy, better imaging. And that was really what this trial was about. But the key thing is really what Dr. Basch said at the outset. We cure these patients. More and more often, we cure these patients. And so we want people to live not just long, but well. And so we really have to pay close attention to the symptoms. And the only way we could do that was by actually asking patients to tell us what their symptoms were, both during the acute phase of treatment as well as longer-term as they were followed up and recovered. Dr. Shannon Westin: Thank you so much. So I think this is a great time for us to just talk very briefly about the overarching PROSPECT trial. What were the two arms and how did it impact standard of care? Dr. Deborah Schrag: Essentially, the two groups in PROSPECT were a chemo first and radiation only if you need it group, that was the experimental group. And the standard control group was the chemotherapy and radiation for everybody. So the chemo and radiation therapy group involved our typical 5040 centigrade worth of pelvic radiation given over five and a half weeks. So Monday to Friday for five and a half weeks with some sensitizing fluoropyrimidine chemotherapy, and physicians and patients could choose whether that was given as oral capecitabine or as intravenous 5-FU, they work just the same, followed by surgery. So that's the standard group. The experimental group received six cycles of a very common chemotherapy regimen used in gastrointestinal cancer, FOLFOX, and gave that regimen six times two weeks apart, followed by restaging with a pelvic MRI and examination by the surgeon. If patients were responding and the tumor had decreased in size by at least 20%, patients could go straight to the operating room. But if patients were poor responders to chemotherapy, they had a second chance, if you will, to get the chemoradiation. We call that group the chemo first with selective chemoradiation group. That was the intervention. And we followed patients and our outcome was disease-free survival. And we have about five years of follow-up in our patients. So this is a very mature study. Dr. Shannon Westin: And what happened? What were the results? Tell us, how did this impact standard of care? Dr. Deborah Schrag: So the upshot is it was designed as a non-inferiority trial and it met the prespecified non-inferiority hypothesis. The exact point estimates were that at five years, essentially 80.4% and 78.6% of participants were alive and disease-free in each group. So that's really almost exactly the same at five years. And the results for overall survival and for local recurrence were also nearly identical. Dr. Shannon Westin: So congratulations. Why don't you now, if you could, walk us through how you assess the patient experience on this particular trial? So specifically looking at the endpoints that you assessed and also the time points that you chose. Dr. Ethan Basch: Thanks for the question. I'll take that. So in this trial, particularly because it was a non-inferiority trial being conducted in a curative context, we really wanted to get a sense of the adverse effects, the side effects of the treatment that are most salient in this population. And so to do that, we used two different approaches. The first was that we selected 14 symptomatic adverse events from the patient version of the CTCAE, also known as the PRO-CTCAE. The patient version of the CTCAE was developed about ten years ago. The purpose of it is to enable the patient voice to be brought into clinical trials around those side effects for which patients are in the best position to answer. But this was really the first large randomized trial into which the PRO-CTCAE was integrated. So this is really a landmark for that tool which is maintained by the NCI. Dr. Deborah Schrag: The PRO-CTCAE was developed by Dr. Basch, and I was his partner. So I'm going to say that Dr. Basch shepherded this tool. This was his brainchild, this was his project, this was his labor of love. He had this vision that we could do better in oncology by engaging patients in reporting their own symptoms and way back in the mid-aughts when both he and I had less gray hair. He worked really hard to develop this system. Its precursor was developed at Memorial Sloan Kettering when Dr. Basch and I worked there in the aughts, and it was tested and found to make a difference, it was very well received by patients. The NCI was persuaded that Ethan was on to something and issued a contract, a large contract, which engaged, I believe it was eight cancer centers around the country. And it took a huge amount of work. This system was developed with a way to get the right words so that patients would understand, so that we have things like construct validity, content validity, so that it would work in Alaska and Maine and Hawaii and New Mexico. The system has now been translated into over 30 languages, but this has really been a career-defining endeavor and labor led by Dr. Basch. He's had wonderful assistance from Amylou Dueck, amazing statistician who's helped, and I've been a good partner to him as well, and many others along the way. But this is really the culmination of a vision that it took more than a decade, almost two decades to realize. And I would just say to any junior investigators out there with a good idea, sometimes you have to be patient and just keep at it, as Dr. Basch has. And now we're starting to see that PRO-CTCAE is becoming standard. It's integrated in many trials. He didn't start a company. It's freely available. The NCI has it. It's NCI intellectual property. Again, available around the world. I'm just very proud of my colleague and academic partner. Dr. Shannon Westin: It's a great, inspiring story, and I love how you spelled out the timeline because it's so true. Sometimes the best ideas do take a long time to get to fruition, so I love that story. Dr. Ethan Basch: The truth of the matter is that this idea of patients reporting their own adverse events was really hatched in conversations that Deb and I had together more than 20 years ago at a coffee shop on the Upper East Side. And I think the observation at that time was that we use the CTCAE for clinical investigators to evaluate patients' adverse events on trials. But that doesn't really make sense for highly subjective phenomena like nausea or fatigue. I mean, the only way an investigator can know about a patient's fatigue is if the patient themselves reports it. And it was our empiric observation in the many clinical trials that we had been involved with that it just seemed like that stuff was being underreported, and so then we subsequently unmasked that, in fact, is the case. In looking at multiple instances perspective, we found that, indeed, there's a massive underreporting of patients' symptomatic side effects in clinical trials. This has been a partnership that Deb and I have had with other colleagues, again, for more than two decades. And so it is really gratifying in the PROSPECT trial to see this coming to fruition. I think the other piece of this, though, as long as we're handing out compliments or accolades, is that Deb has been working for more than a decade on the PROSPECT trial because of a belief that over-treatment or that treatment could be peeled away to improve the experience of patients. And I think the reason why Deb has had an interest in employing the PRO-CTCAE in this trial is because I think it's been her belief that what it's really about is the patient experience, especially in the non-inferiority setting. What's more important than what patients report themselves? And so Deb has championed this and made this happen. And it's no coincidence that Deb's PROSPECT trial is the first major trial the PRO-CTCAE was in, it's because she's a champion for the patient experience and the patient voice. So right back at you, Deb. I would say the Pro CTCAE now is embedded in hundreds of clinical trials throughout the industry. I mean, it's really been widely proliferated. It's gratifying, and it shows the power of an idea. I'd say the PROSPECT trial is really the alpha for this approach. Dr. Deborah Schrag: I just would like to inspire physicians. I know there are doctors out there and investigators out there who have different ideas that are not mainstream or they want to take risks, and not everything is going to work out. And some kooky ideas are just that. They're kooky or different, and they're not going to work, but sometimes you've just got to hang in there. Dr. Ethan Basch: I think it does show the power of an idea, or certainly the power of an idea that Deb Schrag is involved with, which is always one to bet on, for sure. Dr. Shannon Westin: I would like to get some advice here because we build in these types of PROs, we always are worried about how much burden is too much. How many things can the patients be asked to do and we don't want to put too much burden? You all had a really nice participation rate. I think it was like 83%. Any tips that you have for keeping patients engaged and encouraging participation and kind of walking that balance between how much is too much? Like, we want to get all the data we want to get, but how do we meet that balance? Dr. Ethan Basch: So as Deb alluded to, we've come really far in 20 years, and the idea of engaging patients directly through connected health technologies, it's in the zeitgeist now. I mean, it's just a given. I mean, we're all connected in so many ways. And even patients who formerly have been so hard to reach generally can be reached with one interface or another. So in this trial, we used a strategy that I would really advocate for. So first we had an electronic PRO platform that could be accessed through the web or through a handheld device. But there was also what we call an automated telephone system or an IVR system, an interactive voice response system like what the airlines use when you get the electronic voice and you can use the push buttons or speak into it. And so we gave patients a choice of using either of those, the idea being to meet people where they are. And then for those patients who did not report at the expected times, a CRA actually called them to recapture the information that was missed. And so by using this kind of strategy, we had a very high adherence rate and very little missing data. Just as a couple of quick asides, in this and other studies, we found that the patients who choose the telephone-type interfaces tend to be more rural. They have lower health literacy, lower SES, lower educational attainment. And so you really need to think about that with any technology like this one because there is a risk that this digital divide will increase disparities or representation in how we capture data or administer care. So the way that we did in this trial, I think kind of got it right in many ways and I think as an exemplar for other studies. Dr. Shannon Westin: Thank you for that. That's I think hopefully helpful for all the young investigators in the audience that are designing these types of trials. On that same note, around the population, what about the population that participated in this trial? Again, as a GYN Oncologist, I'm always intrigued by our different areas of solid tumors. Do you think this trial is pretty representative of the population and specifically the group that participated in the PRO outcomes? Dr. Deborah Schrag: So the first part of your question I will answer second. The patients who reported are highly representative of the total population. So I don't think there's any issue there. If you look at what's called Table 1 for the trial overall and Table 1 for the patients who participated in PRO reporting, the characteristics, and attributes are the same. So the results generalized. So that's very good. The bigger issue was upstream with the participants who went in the trial. And I think the biggest place where we need to make improvements is to recruit populations of patients to clinical trials who are more representative of the United States of America. And we did not achieve that. We tried in this trial, but we did not succeed. So we have unacceptably low participation from African Americans. And the racial and ethnic diversity in the clinical trial does not reflect the racial and ethnic diversity in the United States or more importantly, of patients who get rectal cancer. This is for all kinds of reasons, people are marginalized, we've got structural racism that persists. We've got issues related to mistrust. And I would just say we need to do a hell of a lot better. We didn't fail here because we're bad or because we didn't try. It's a challenging, pernicious, and persistent problem, but it is an important one and it's an important deficit. Dr. Shannon Westin: 100%. Yeah, I think across the United States this is an issue, globally as well, but especially I think we have an opportunity within our recruitment within the United States to really provide that diversity. So I think we're all familiar with the NCI and the push to have those plans, but yeah, I don't think no one would think you didn't try hard enough. I think it's definitely something that we are systemically dealing with. Dr. Deborah Schrag: Yeah, getting cancer treatment is hard. Getting cancer treatment when you're living with a lot of challenges, for example, poverty or single parenting or living in a marginalized community or with poor transportation access, or food insecurity is even harder, if not impossible. And because of the way these cooperative group trials are funded, we didn't provide any support for transportation or food or any of the other things. This was a publicly sponsored trial and I think it is worth us having a very serious conversation about what we need to do to subsidize and support trial participants to ensure that we do have more representative participation. We fell short here. Dr. Shannon Westin: Can you walk us through a little bit of the PRO findings during that, the new adjuvant chemo versus the chemoradiation group? What did you conclude? Dr. Deborah Schrag: We've got an OBGYN interviewing us here. The genesis of this trial for me personally, colorectal cancer is occurring more and more in young patients, and you can't carry a pregnancy to term once you've had pelvic radiation and it usually tips you into early menopause. And this is a real concern when we have 35-year-old women with rectal cancer. Dr. Ethan Basch: So Deb already noted the non-inferiority results in the study, and I think in the setting of a non-inferiority result, the PRO findings become of interest. And in fact, the PRO results in the two arms are quite different from each other. The two key periods when we evaluated PROs were first during neoadjuvant therapy and then in the period following surgery, one-year post-surgery, and then 18 months post-surgery. So during neoadjuvant therapy, we evaluated PROs in the two groups, which again were chemotherapy alone with selected use of radiation, which in the end, very few patients required, versus the prior standard of chemoradiotherapy. What we found was during active neoadjuvant treatment, almost all symptoms were worse with the investigation arm with chemotherapy alone, in fact, eleven of the symptoms were worse. Now, this is not a big surprise because it's FOLFOX therapy and these are the symptomatic adverse events that we would expect to see being worse during FOLFOX chemotherapy. However, diarrhea was better with FOLFOX than it was with the standard of chemoradiation. And I think that, again, intuitively, is what we might expect. What becomes interesting is the period 12 and 18 months after the surgery. And what we found in that in those time points was that the symptoms were either the same between groups but for three key symptomatic adverse events, they were significantly worse with chemoradiation therapy. And those specifically were neuropathy, fatigue, and sexual function. And Deb made a point earlier about one of the reasons that she conceived of the trial being concerned about sexual function or the ability to carry a pregnancy in young patients who undergo chemoradiation. And in fact, we see, perhaps not that surprising that sexual function is significantly better with the chemotherapy alone arm and that's durable. I think there's a question mark about sensory neuropathy. We saw that neuropathy was better in the FOLFOX arm and the chemotherapy arm at both 12 and 18 months. And one could see that as a little bit of a head-scratcher because we might expect to see that neuropathy would be worse in a FOLFOX arm because of the exposure to oxaliplatin as opposed to radiation. I think that that will warrant some further evaluation. But the empiric finding is that the late effects are in fact significantly worse in the chemoradiation arm for those three areas. Dr. Shannon Westin: Yeah, I was intrigued by the neuropathy because that's why in my experience, we don't use a ton of FOLFOX, but occasionally we'll treat our patients with mucinous ovarian cancer, and I feel like the neuropathy is a really difficult strategy. But I'm especially interested in those long-term adverse events after radiation. We do a ton of radiation for patients with cervical cancer and other of our cancers and I was really intrigued by this opportunity to potentially lose some of those long-term side effects. Any thoughts as to why there really wasn't a difference in that overall health-related quality of life at all these time points? Dr. Ethan Basch: Yeah, it's a great question. So in this study, we did use an overall quality of life or health-related quality of metric and it was no different at any time point between the two arms. I think it's a limitation of the tool that was used. The tool that was used when this study was designed, it's called the EQ-5D. It's used in a lot of health economic evaluations for cost-effectiveness analyses in Europe, in clinical trials. So it gets dropped into a lot of studies but it really is not sensitive to the nuances of symptoms like we see in this trial. It asks about overall global physical function, anxiety, depression, but it really doesn't get into the weeds of neuropathy or sexual function, some of the domains that really were most important here. So I think some of this is that the tool just wasn't sensitive enough to pick up that nuance. On the other hand, I think it's reassuring that a very high-level global health-related quality-of-life tool was no different. It suggests that big, big picture, there's not a huge difference in the overall functioning of people between these two potential treatment approaches. But when you get into the more detail, we do see the differences in those individual symptoms. Dr. Shannon Westin: And then I guess the bottom line, how are we going to use these results to inform what we do for this patient population? Dr. Ethan Basch: Yeah, I think it's nuanced. I think that goal of collecting this kind of information, like any information on trials, is that when one of us walks into the room with a patient, we sit down to make a choice when there are different options is to say what are the pluses and minuses of each. So for a patient who's really concerned about those short-term acute toxicities like nausea and fatigue during neoadjuvant treatment, then they might want to go with the standard of chemoradiation. But if they're really concerned about bowel function, or if they're really concerned about long-term sexual function or to some extent neuropathy, then probably the better choice for them would be FOLFOX alone, chemotherapy alone, the investigational approach. But really it's more information for that shared decision-making. It's a little more nuanced, it's a little bit more for us to think about in those conversations with our patients, but it really helps patients ultimately to make an informed decision so they can know what to expect. Dr. Shannon Westin: Well, I just want to say congratulations. I know you've convinced me, and I bet you've convinced everyone listening that we need to be incorporating the PRO-CTCAE in all of our upcoming large practice-changing trials. So congratulations on your work, not only in this trial but with that measure as a whole. It's really exciting. Dr. Ethan Basch: Thanks so much. The evidence really does suggest that without employing a tool like the PRO-CTCAE or another PRO tool in a trial to understand the symptomatic adverse events from the patients directly, we will have an incomplete understanding of what's going on in that trial. And it's really to the detriment of us as investigators or to drug developers not to include these kinds of tools because we really won't understand the impact on the ultimate end users of the treatments which are the patients. Dr. Shannon Westin: Well, thank you so much, and thank you to our listeners. We have been hearing about the simultaneous publication of JCO and presentation at ASCO 2023 of the Alliance N1048 Trial: Patient-reported outcomes during and after treatment for locally advanced rectal cancer from the PROSPECT trial. I'm so grateful for all of you who've listened. Please check out our other podcasts on the website and wherever you get your podcasts and otherwise. Hopefully, we'll see you around ASCO 2023. 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. Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bios: Ethan Basch is the Chief of the Division of Oncology and Physician in Chief at NC Cancer Hospital at the University of North Carolina. Deborah Schrag is the chair in the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York City, New York. Article: Patient-reported outcomes during and after treatment for locally advanced rectal cancer (Alliance N1048)

ctDNA for Recurrence Prediction in Esophagogastric Cancers

JCO Precision Oncology Conversations

Play Episode Listen Later Apr 19, 2023 29:24

JCO PO author Dr. Brandon Huffman shares insights into his JCO PO article, “Analysis of Circulating Tumor DNA to Predict Risk of Recurrence in Patients With Esophageal and Gastric Cancers” and discusses the article's findings of ctDNA levels in the preoperative, postoperative, and surveillance settings in patients with EGC. Host Dr. Rafeh Naqash and Dr. Huffman discuss ctDNA assessments, treatment paradigms and interventions, and tumor-informed assays. TRANSCRIPT Dr. Abdul Rafeh Naqash: Hello, and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, social media editor for JCO Precision Oncology, and I'm also an Assistant Professor in Medical Oncology at the OU Stephenson Cancer Center. Today, I am excited to be joined by Dr. Brandon Huffman. Dr. Huffman is a gastrointestinal medical oncologist, and he's also an instructor in medicine at the Dana-Farber Cancer Institute at the Harvard Medical School. He's the lead author on today's JCO Precision article, "Analysis of Circulating Tumor DNA to Predict Risk of Recurrence in Patients with Esophageal and Gastric Cancers." Our guest's disclosures will be linked in the transcript. Dr. Huffman, welcome to our podcast and thanks for joining us today. Dr. Brandon Huffman: Of course. Thanks for having me. Dr. Abdul Rafeh Naqash: For the sake of this discussion, we'll refer to each other using our first names. So, Brandon, exciting to have you today. We're going to talk about this very interesting topic on circulating tumor DNA and how your team used the ctDNA assessment in patients with esophageal and gastric cancers. For the sake of the listeners, could we start by asking you what are the current treatment paradigms for early-stage esophagogastric cancers? Since you practice this on a daily basis, what is the current approach, briefly, which will play into how this study looked at ctDNA in the context of early-stage esophagogastric cancers? Dr. Brandon Huffman: Yes, definitely. Thanks first for having me. Thanks for highlighting our work, and I'm really excited to talk with you about our manuscript and research today. To answer your question about how to treat localized esophagogastric cancer, it's a little bit more specific depending on where in the esophagus, GE junction or stomach where the tumors arise. For instance, we treat esophageal and upper gastroesophageal junction cancers with, often, chemoradiation, neoadjuvantly, and that is followed by surgery. And if there's a pathologic incomplete response, then many patients will get Adjuvant Nivolumab, a PD-one inhibitor, whereas the lower the tumor is in the upper GI tract, most often, perioperative chemotherapy is used for the lower GEJ and gastric cancers. Dr. Abdul Rafeh Naqash: Thank you so much. And I know, I think to some extent, if I remember correctly, immunotherapy has been incorporated into this paradigm. Is that a fair assessment? Dr. Brandon Huffman: That's exactly right. So, excitingly, we treat patients with neoadjuvant chemo or chemoradiation, and surgery is really the crux of the treatment paradigm for esophagogastric cancers in general. However, recently the CheckMate 577 clinical trial for the use of adjuvant Navolumab showed an improvement in disease-free survival in patients who had an incomplete path response. They used one year of Nivolumab compared to placebo. So it has recently become a standard of care where I practice, and I feel like a common practice around the country. Dr. Abdul Rafeh Naqash: Thank you so much. Now, going to the premise of this paper where you and your team basically looked at circulating tumor DNA as a prognostic marker in these patients that had early-stage esophagogastric cancers, was there a specific reason why you wanted to look at the early stage? What was the rationale for evaluating this biomarker in this patient population? Dr. Brandon Huffman: So, esophageal and gastric cancers affect a large number of patients every year. And unfortunately, despite our best efforts with curative intent therapy, over 50% recur within three years. So we know that there are pre surgical risk factors such as a larger bulky primary tumor or lymph node-positive disease that increase the risk for progression or recurrence after surgery. And we know, in addition, in other GI malignancies and other malignancies such as colorectal cancer, for instance, that the presence of circulating tumor DNA after surgical resection of localized tumors is associated with an increased risk of recurrence. So this has actually led to clinical trials investigating whether or not ctDNA can be integrated into the decision-making for adjuvant colorectal cancer treatment, such as ongoing trials such as the BESPOKE trial, COBRA, DYNAMIC trials that have recently been reported. The use of ctDNA is being used in other malignancies. And to give you a little bit of background, this project started when I was seeing patients with Dr. Sam Klempner at Mass General during my fellowship, where I was in the combined Dana-Farber/Mass General program. And he and others had begun collecting serial plasma samples on every patient we saw with esophagus, gastroesophageal junction and gastric cancers to assess for the presence or absence of ctDNA. And we used the tumor-informed ctDNA assay from Signatera, which, for those who aren't familiar, this is a ctDNA platform where a panel is built from the results of whole exome sequencing on the patient's FFPE tumor. The panel includes 16 patient-specific somatic single nucleotide variants for each patient, and it's new for each patient. Once that panel is built, the cell free DNA is tested from a plasma sample. And if there are two or more of the tumor-specific variants present, then they're considered ctDNA positive. So some of those colorectal cancer trials that I mentioned before are using this assay, and we wanted to investigate whether or not this high-risk population could be further assessed for risk of recurrence. Dr. Abdul Rafeh Naqash: Excellent. Thank you so much. And I know that a lot of these ctDNA based assessments have made inroads into the GI malignancy space, lesser in the other tumor types. I think we are all trying to catch up to what you guys are doing in the early-stage colon cancer space or the early-stage esophagogastric cancer space. So it's definitely very a interesting avenue to assess minimal residual or molecular residual disease. Now, going back to the methodology, I found it very interesting, and I think it's very important for listeners especially to understand the context of ctDNA assessments because I think a majority of oncologists are used to the liquid biopsy aspect. But this is not necessarily the liquid biopsy. It's somewhat different. So what I've understood, and I'd like to ask you to explain in the context of tumor-informed and tumor uninformed assays, what are the assays that are available, and how do they differ in terms of serial monitoring? And why is this ctDNA-based assessment somewhat different or more patient-customizable than our regular liquid biopsy assays, which are also blood based but not tumor-informed? Dr. Brandon Huffman: That is the question of the hour. And many different research projects are ongoing to try and identify which one is better, if one is better. I know that there are some commercial assays, for instance, that are not tumor-informed. They take a blood sample and then test for cell free DNA. The risk behind that is it's testing for common genetic mutations from a next-generation sequencing panel platform. And it may also detect CHIP variants or clonal hematopoiesis of indeterminate potential variants that aren't related to the underlying solid tumor malignancy. So a tumor-informed assay, for instance, such as the one that we used in this study, uses the patient's tumor and sequences it with whole exome sequencing and identifies very specific variants within the tumor that are only present within the tumor because they compare it also with a normal blood sample from the patient at the same time. And so they pick tumor-informed specific variants that then they test for on their assay. And that increases the sensitivity of the ctDNA assay so that you can really try to understand, is this cell free DNA that we are detecting related to the tumor or can we ignore it potentially? I don't know if we can necessarily ignore it in all honesty because it could affect- there's a lot of ongoing work that is looking at the risk of CHIP. But overall, this is specific for the primary tumor that we were investigating. Dr. Abdul Rafeh Naqash: I definitely agree with you there. I think the important point, as you mentioned, is that using the whole exome approach, in the blood and the tumor, you're able to eliminate the CHIP variants or the germline variants that may not be contributing. And that way you're able to specifically look at certain genetic alterations that eventually, I think using PCR-based approaches, you identify the same and quantify the same in the blood serially. And that's how this tumor-informed assay is somewhat unique and different. Now, going to the crux of this study, could you tell us a little about the patient population? I think you stratified patients. You had a pre-operative cohort, you had an MRD cohort, you had a surveillance cohort, and you had a cohort where you assessed ctDNA positivity at any time point. So, several different cohorts, and you assess recurrence-free survival in those cohorts. Could you tell us a little bit more about how you evaluated these cohorts? What were the selection criteria, and how many patient samples did you have for these different cohorts? Dr. Brandon Huffman: Absolutely. So, we aimed to determine the feasibility of testing ctDNA in patients with gastroesophageal cancer. And so, there were several clinicians from over 70 institutions across the United States who began prospectively collecting serial plasma samples for the presence or absence of the tumor-informed ctDNA. And they included patients from stages one through stage four, gastroesophageal cancer specifically, they included patients who were stages one through four with gastroesophageal cancer. They were collected at the discretion of the ordering clinicians and then incorporated into their routine clinical care as they saw fit. Within this dataset, we have a subset, a large number of patients that is unique to this dataset, specifically in that we have clinical outcomes, treatment, and follow-up data for the patients that were reported on the main findings in the paper. So, overall, we collected and analyzed over 900 plasma samples in almost 300 patients with gastroesophageal cancer, esophageal, gastroesophageal junction and gastric cancers. And in many of the analyses, we lumped them all together. But then we also wanted to separate it out because, as I mentioned before, the treatment paradigm does differ amongst a more proximal esophageal tumor compared to a distal gastric cancer. So, we focused a majority of our analyses on the detection of ctDNA and localized disease, which included 212 patients with stages one through three gastroesophageal cancer. And I would say we had three major findings. Most of the patients who were tested beforehand, which was a small subset, as I mentioned, this was pragmatic at the discretion of the ordering clinician, but most of the patients who were tested beforehand had positive preoperative ctDNA present. Of the patients who were tested for postoperative ctDNA at any time point, and then specifically within the different subsets of populations that we talked about, postoperative ctDNA was associated with at least a tenfold increased risk of recurrence in all subsets. And ctDNA detection postoperatively was independently associated with recurrence when controlling for age, sex, tumor location, and microsatellite status. So, a few of the populations that we wanted to test for, one in particular was the molecular residual disease, or MRD window. We labeled this MRD window as the time from surgical resection until 16 weeks. So, if patients were ctDNA positive within that window, we counted that in the primary outcome. And the reason that we chose the MRD window, in addition to this time point of 16 weeks - I should say that the 16 weeks is without any therapy postoperatively, so they have not been treated with any chemo or immunotherapy in this window. We thought that this MRD window was an interesting research topic because the CheckMate 577 Adjuvant Nivolumab clinical trial identified that 16 weeks was the window in which patients could be enrolled up until that timepoint to receive adjuvant nivolumab. So, we're thinking from a future project standpoint, a future clinical trial, perhaps, that if we have identified that patients who are ctDNA positive within this timepoint window, is there an increased risk for recurrence? Because if there is, then perhaps nivolumab intervention will decrease that risk or something that is escalated further. And that's a question that we don't have the answer for, a question that our data can't answer adequately. But it's an interesting one that I see the future questions that can be answered from these data. Dr. Abdul Rafeh Naqash: Thank you so much. And I agree with you there that this is a very intriguing approach of finding out whether treatment escalation has to be done based on ctDNA positivity, but also, conversely, treatment de-escalation, which there is a lot of emphasis being laid on, especially in the early phase trial in lung cancer, especially in the early setting when targeted therapies or immunotherapies are approved for one to three years, depending on what kind of therapy you're looking at. In those individuals that perhaps have negative ctDNA after one year, maybe therapy de-escalation would be a reasonable approach. So, definitely more interesting clinical trial ideas in this space focusing on ctDNA assessments. Now, one of the questions that comes to my mind is, when you use ctDNA-based assessments, initially, the patient gets biopsied, and it usually takes four to six weeks for ctDNA-based assessments to come back--I'm talking about tumor-informed assay results to come back, in my personal experience. So, could that potentially, or in your practice, how do you mitigate those delays? If you're trying to schedule a patient for surgery, for example, does that cause any delays in any care because you're trying to get the assessment done, or does your workflow proceed as planned and then you get the results and then subsequently you perhaps make a decision based on their ctDNA assessment? Dr. Brandon Huffman: At the present time, we are trying to gather more data to understand what we should do with the results that we're receiving. And I think the starting point of collecting serially to just understand the process is helpful. One of the questions we wanted to know that we weren't able to answer with this dataset was: is there lead time? In many cases, ctDNA detection can occur even a year prior to radiographic recurrence. In our case, because this was a pragmatic, clinically at the discretion of the investigators when they decided to test patients for ctDNA, there is heterogeneity among those who are ctDNA positive, and when they get their radiographic imaging, maybe they were moved up. I know in our practice with Dr. Klempner, when I was seeing these patients with him, it was a flag for us to order scans earlier in a patient that we might not have historically ordered so that we could then see, is there something intervenable? Maybe there was a positive lymph node on PET imaging that we could radiate or that wasn't included in the neoadjuvant radiation, for instance. So, we could not predict the lead time from positivity to radiographic recurrence, but I think that that's the hope is that we detected micrometastatic disease, my hope is that we can intervene in the future. But these data aren't able to quite answer that question perfectly. Dr. Abdul Rafeh Naqash: Sure. And there's definitely caveats to doing this in a pragmatic manner based on investigator assessments. Now, another question I was thinking of is, when you do do these ctDNA based assessments, and since these are tumor-informed, meaning you biopsy the tumor initially, you identify certain single nucleotide variants and those are the ones that you basically barcode and do PCR assessments using blood. We've learned time and again that tumors can change based on the kind of therapy that you give the patient. So, if your tumor is seeing FOLFOX nivolumab, or all the other novel therapies that you guys give in the setting, is there a chance that the tumor changes over time and you may not be able to capture those newer single-nucleotide variants that are coming up? It's just a provocative question, but I wanted to see what your thoughts are on that. Dr. Brandon Huffman: It's a great question. I don't entirely know the answer. I'll just be forthright about that. I do think that when designing these assays, they try to choose the more clonal rather than subclonal variants. And so the hope is that, despite the heterogeneity that we know occurs in esophagogastric cancers, we can eliminate that possibility. But you're right, there's no perfect way of knowing that. Dr. Abdul Rafeh Naqash: I really appreciate you using that word subclonal versus clonal. I think that perhaps makes a difference there. But again, more to do in this field to understand how the tumor evolves and whether it's the clonal mutation, subclonal mutation that needs to be followed. But definitely a lot of interesting work in this space that's ongoing, and, like you mentioned, there are ongoing trials, and both in the neoadjuvant adjuvant space, this field is definitely moving fast in the right direction. I briefly want you to highlight that one patient case study example that you had. And this was a patient with oligometastatic disease recurrence where you used the ctDNA assessment. And I do some of this in my daily practice, and I really found it useful to have this sort of a patient case example that elaborates in the bigger picture of how this kind of assessment works in a real-life scenario. So it's not just data, it's a patient's trajectory over the course of time where the treating physician was able to use this assay. Could you tell us a little bit more about this individual example here? Dr. Brandon Huffman: Yeah, absolutely. So this was a 56-year-old man that we saw in clinic with stage three esophageal adenocarcinoma, and was treated with the standard neoadjuvant cross chemoradiation, had an R0 resection with residual disease with a significant treatment effect. And there were lymph nodes that were positive on surgical resection with 39 lymph nodes removed. The patient recovered well and was followed with the standard of care radiographic and clinical surveillance. We also were looking for ctDNA, and what we noted was that there were, often you find these undulating pulmonary nodules that come and go, and they may or may not be infectious, and maybe there's one that's sub-centimeter that slowly grows, and what we found was that at about five months post-surgery, there was a positive ctDNA MRD, and we repeated it at short interval and noted a rising value, which this assay will give you a quantitative value. Once we did that, we ordered imaging and saw a nine-millimeter pulmonary nodule and ultimately biopsied it. It was there in the right upper lobe, and it was positive for metastatic adenocarcinoma. So we treated the patient with the standard FOLFOX plus Nivolumab and actually did SBRT, stereotactic body radiotherapy, to the lung metastasis. And his ctDNA became undetectable. So because FOLFOX is toxic, we transitioned to a maintenance of Nivolumab and he was on maintenance therapy for several months and had no radiographic evidence of disease and remained ctDNA negative for twelve months. So we biopsied the right upper lobe lung lesion. It was positive for metastatic adenocarcinoma, and then after a multidisciplinary discussion, we treated him with SBRT and then FOLFOX and Nivolumab and then dropped down to Nivolumab maintenance once his ctDNA was undetectable. That highlights the fact that this was an isolated recurrence, which we continued to monitor, and then he had another site of disease a few months later, and we did SBRT to that area while he maintained on just Nivolumab, and the ctDNA came down as well. So I think, although it doesn't prove anything necessarily, other than demonstrating there is a correlation with the newly diagnosed metastatic disease, it does note that you can use this in dynamic ways, and if it really helps patients live longer, although this is anecdotal--who knows? If we hadn't done SBRT to that area, it was 9 mm. We could have waited until it grew, but then maybe some subclonal, more aggressive metastasis could have really put this patient in a much tougher situation. So it's an interesting case example, and there are several others that we could have put in here that are pretty similar. Dr. Abdul Rafeh Naqash: Thank you so much for highlighting that case. I couldn't agree more that there is a certain aspect to the ctDNA assessment, where in individuals like the example that you've highlighted here, this can provide lead time potentially and help with earlier management of perhaps more like oligometastatic disease rather than diffuse disease burden. And in that context, one of the questions that I was going to ask you, based on your data, was there any correlation of tumor burden preoperatively and ctDNA positivity after surgery that you guys were able to identify or thinking of identifying? Dr. Brandon Huffman: Unfortunately, with our data set, we weren't able to look at that assessment of comparing the overall tumor burden to the quantitative value. But it's an interesting one because we know that in other malignancies, for instance, if there is a correlation of overall disease burden, it also depends on the tumor type, but we also know that perhaps patients will respond differently to chemo or immunotherapy if they have a lower tumor burden, if they have a lower ctDNA value, potentially. I think that's an interesting question for a future project. Dr. Abdul Rafeh Naqash: Thank you so much, Brandon. We do like to talk a little bit about the person behind the work. So tell us a little bit more about yourself, your training, your interests, and some little advice for other early-career investigators who might be looking into a similar space and hopefully get inspired by the kind of work that you've done or are planning to do. Dr. Brandon Huffman: Sure. So, as I mentioned, when I started this project, I was in fellowship. I was seeing patients with Dr. Sam Klempner at Mass General, where I saw patients with him for a year, and as part of my clinical training in the Dana-Farber/Mass General HemOnc Fellowship. Since that time, I have graduated fellowship. I'm a GI Medical Oncologist at Dana-Farber Cancer Institute, and in the GI division, I see patients with all GI malignancies, and I focus on the development of clinical trials in upper GI malignancies, along with investigating the use of circulating tumor DNA as a biomarker, hopefully, we can understand whether it's a predictive biomarker that we can intervene upon in the future. I think the greatest advice that I received and that I will give to all future trainees; I'm not sure that I'm qualified to tell this to all the junior investigators, but here it is: Find yourself a mentor who really cares and invests in you and your ideas. I have that with Sam, and this project was an incredible part of my development as a junior investigator. I've asked really interesting questions. There are more questions that can be answered from this data set, and I'm excited for the opportunity. Dr. Abdul Rafeh Naqash: Thank you so much, Brandon. Thanks for taking the time to speak with us today and thank you for choosing JCO Precision Oncology as a destination for your work. Hopefully, we'll see more of this subsequently in the years to come. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating, a review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts 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. Guest Bio Dr. Brandon Huffman, MD, is a gastrointestinal medical oncologist and Instructor in Medicine at Dana-Farber Cancer Institute and Harvard Medical School. Guest Disclosures Brandon M. Huffman Stock and Other Ownership Interests: Doximity

Episode 350 – My Aluminum Anniversary

The Real Estate Sessions

Play Episode Listen Later Apr 18, 2023 7:56

Many resources show aluminum as the ten-year anniversary gift. Some say it's tin, but I'll go with aluminum. I recorded this episode on April 12, 2023, 10 years from the day of my final therapy treatment in my colon cancer journey. Some of you know my disdain for the term "chemotherapy." I chose therapy instead.Once you know which protocol your oncologist has determined is best for you (FOLFOX for me), the next logical step is to check out the calendar on your phone and determine the date of your final treatment.Setting goals and waypoints made sense to Cindy and I. 12 treatments break down into four quarters, three treatments each quarter. Getting to halftime made sense as a reasonable waypoint. Reaching the final quarter was a great feeling.But there is no more incredible feeling than wrapping up the final session. Knowing there would not be another 5-hour infusion appointment with multiple trips dragging the IV tree to the bathroom. Even though the staff at Ironwood Cancer Center was fantastic, knowing this would be the last time you saw them was important. They knew that as well.So, this will be the last episode of my journey. Thank you to all the folks that publicly and privately commented about how sharing my story has helped. I love hearing that. While I am always available to answer questions or chat with a newly diagnosed colorectal cancer patient, I'm done using this forum for that purpose. I will continue to post a March episode to remind everyone about getting screened. March is Colorectal Cancer Awareness Month, for gosh sake.See you next week with another episode, and thanks again.RATE & SUBSCRIBE At Ratethispodcast.com/REsessionsOn Apple PodcastsOn Google PodcastsOn Stitcher

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Colorectal Cancer | Meet The Professor: Optimizing the Management of Colorectal Cancer — Part 2 of a 3-Part Series

Play Episode Listen Later Apr 7, 2023 60:01

Featuring perspectives from Dr John Strickler, including the following topics: • Introduction: ASCO Guidelines for the Treatment of Metastatic Colorectal Cancer (0:00) • Case: A woman in her mid 70s with metastatic colon cancer — Sunil Gandhi, MD (11:14) • Case: A man in his late 70s with T3N0 MSS adenocarcinoma of the colon who is ctDNA-negative after colectomy and would like to avoid chemotherapy — Georges Azzi, MD (22:01) • Case: A woman in her early 80s with mismatch repair-proficient Stage IIIC high-risk adenocarcinoma of the colon with neuroendocrine features after adjuvant FOLFOX — Gigi Chen, MD (25:39) • Case: A man in his late 40s with a HER2-amplified ascending colon adenocarcinoma and liver metastases who undergoes perioperative FOLFOXIRI and liver resection — Swati Vishwanathan, MD (32:54) • Case: A man in his late 50s with metastatic adenocarcinoma of the colon and disease progression after multiple lines of chemotherapy — Priya Rudolph, MD, PhD (44:31) • Case: A man in his late 70s with metastatic rectal adenocarcinoma, high tumor mutational burden and multiple genetic alterations by liquid biopsy, including KRAS G12C — Shaachi Gupta, MD, MPH (48:31) • Case: A man in his early 60s with rectal cancer, synchronous liver metastases and lung oligometastases after perioperative FOLFOX and resection of the primary and liver metastases — Dr Gupta (55:36) CME information and select publications

phd professor management md treatments optimizing mph gupta cme colorectal cancer her2 ctdna folfox

Gastroesophageal Cancers | Cases from the Community: Investigators Discuss Available Research Guiding the Care of Patients with Gastroesophageal Cancers

Play Episode Listen Later Mar 7, 2023 87:33

Featuring perspectives from Dr Yelena Janjigian, Prof Florian Lordick and Dr Zev Wainberg, moderated by Dr Samuel Klempner, including the following topics: • Optimizing the Selection of Therapy for Newly Diagnosed Advanced Gastric or Gastroesophageal Junction (GEJ) Cancer — Dr Klempner o Introduction (0:00) o Case: A man in his mid 50s with HER2-negative gastroesophageal adenocarcinoma (PD-L1 100%) — Victoria Giffi, MD (1:15) o Cases: A woman in her early 80s with a history of Stage 0 chronic lymphocytic leukemia, now with unresectable gastric adenocarcinoma, develops Coombs-positive hemolytic anemia after 2 cycles of FOLFOX and nivolumab and a man in his early 60s with localized adenocarcinoma of the GEJ receives the CROSS regimen but is found at surgery to have metastatic disease and tumor NGS demonstrates an ARID1A mutation — Matthew R Strickland, MD and Priya Rudolph, MD, PhD (8:05) o Faculty presentation: Dr Klempner (14:05) • Current Considerations in the Treatment of HER2-Positive Advanced Gastric/GEJ Adenocarcinoma — Dr Janjigian o Case: A woman in her early 30s with newly diagnosed metastatic HER2-amplified signet cell gastric adenocarcinoma — Farshid Dayyani, MD, PhD (22:36) o Cases: A man in his mid 80s with newly diagnosed HER2-positive gastroesophageal cancer metastatic to the liver and lung, tumor 3+ by IHC for HER2 with a PD-L1 of 10 and a woman in her mid 70s with HER2-positive esophageal adenocarcinoma and brain metastases after stereotactic radiosurgery — Warren S Brenner, MD and Dr Strickland (31:43) o Faculty presentation: Dr Janjigian • Selection and Sequencing of Therapy for Relapsed/Refractory Gastric/GEJ Cancer; Novel Investigational Approaches — Prof Lordick o Cases: A woman in her mid 70s with Lynch syndrome and a history of Stage III colon cancer presents with poorly differentiated GEJ carcinoma with liver and lung metastases and a man in his early 60s presents with a 70-lb weight loss and locally advanced high-grade neuroendocrine carcinoma of the distal esophagus — Namrata I Peswani, MD and Ranju Gupta, MD (46:19) o Case: A man in his early 60s with metastatic gastric adenocarcinoma (PD-L1 CPS 0) with clinical and radiographic progression of disease after 4 cycles of FOLFOX — Dr Strickland (52:31) o Faculty presentation: Prof Lordick (55:26) • Current Approaches to the Management of Esophageal Cancer — Dr Wainberg o Cases: A man in his late 50s with dysphagia, weight loss and a lower esophageal adenocarcinoma (T3N3) and a man in his mid 70s with dysphagia is found to have a lower esophageal adenocarcinoma with regional adenopathy and pulmonary nodules (CPS 40 by SP263) — Gurveen Kaur, MD and Liudmila N Schafer, MD (1:03:56) o Case: A woman in her early 60s with a known germline BRCA2 mutation and a history of Hodgkin lymphoma, breast and anaplastic thyroid cancers now has localized squamous cell esophageal cancer — Dr Brenner (1:11:56) o Faculty presentation: Dr Wainberg (1:17:49) CME information and select publications

Colorectal Cancer | Cases from the Community: Investigators Discuss Available Research Guiding the Care of Patients with Colorectal Cancer

Play Episode Listen Later Feb 22, 2023 119:06

Featuring perspectives from Drs Tanios Bekaii-Saab, Scott Kopetz, and John Strickler and Prof Eric Van Cutsem, moderated by Dr Kristen Ciombor, including the following topics: • Integration of Therapies Targeting BRAF and HER2 in Metastatic Colorectal Cancer (mCRC) — Dr Strickler o Introduction (0:00) o Case: A man in his early 40s presenting with microsatellite-stable (MSS) rectal cancer and liver metastases — Victoria Giffi, MD (2:04) o Cases: A man in his late 70s with HER2-amplified colon cancer and extensive liver metastases and a man in his late 50s with KRAS G12S-mutant HER2-amplified colon cancer and lung metastases — Ranju Gupta, MD and Shaachi Gupta, MD, MPH (9:12) o Faculty presentation (16:39) • Optimizing the Use of Immune Checkpoint Inhibitors in the Management of mCRC — Dr Ciombor o Case: A man in his mid 50s with BRAF V600E-mutant, KRAS/NRAS wild-type metastatic colon cancer with disease progression on FOLFOXIRI/bevacizumab — Lai (Amber) Xu, MD, PhD (26:13) o Case: A man in his late 60s with localized unresectable microsatellite instability-high carcinoma of the cecum — Farshid Dayyani, MD, PhD (32:02) o Faculty presentation (41:11) • Evidence-Based Selection and Sequencing of Therapy for Patients with mCRC — Prof Van Cutsem o Case: A man in his late 70s with metastatic rectal cancer and newly diagnosed PMS2-positive Lynch syndrome — Liudmila N Schafer, MD (51:39) o Case: A man in his mid 50s with pan-RAS wild-type metastatic rectal cancer treated with FOLFOX/cetuximab — Warren S Brenner, MD (56:55) o Faculty presentation (1:03:36) • Promising Agents and Strategies for Patients with mCRC — Dr Bekaii-Saab o Case: A woman in her early 50s with KRAS and BRAF wild-type, HER2-negative T3N1 rectal cancer with liver and lung oligometastases who underwent multiple ablations and stereotactic body radiation therapy and is currently receiving FOLFIRI/panitumumab – MSS, mismatch repair-proficient, PD-L1 0% — Jennifer L Dallas, MD (1:13:13) o Case: A woman in her early 60s with metastatic KRAS G12C-mutant cancer of the sigmoid colon — Philip L Brooks, MD (1:18:43) o Faculty presentation (1:22:32) • The Changing Management Paradigm for Localized CRC — Dr Kopetz o Case: A man in his early 70s with 2 synchronous T3N0 cancers of the splenic flexure and cecum who is found to have circulating tumor DNA after resection — Dr Brenner (1:35:56) o Case: A man in his early 80s with a Stage II obstructing cancer of the right colon — Namrata I Peswani, MD (1:46:12) o Faculty presentation (1:47:58) CME information and select publications

SWOG 1815, PARADIGM, and Other Advances at GI23

ASCO Guidelines Podcast Series

Play Episode Listen Later Feb 2, 2023 19:59

Dr. Rachna Shroff, chair-elect of the 2023 ASCO GI Cancers Symposium, and guest host Dr. Shaalan Beg discuss new research presented at GI23, including new data from SWOG 1815 in biliary tract cancers, advances in biomarker studies in mCRC such as the PARADIGM trial, and promising updates in ctDNA technology. She also highlights the exciting potential of AI in oncology. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center and vice president of Oncology at Science 37. Today we'll be discussing key abstracts and other highlights from the 2023 ASCO Gastrointestinal Cancer Symposium, which celebrated 20 years of transformative care in GI cancers. I'm delighted to welcome Dr. Rachna Shroff, the chair-elect of this milestone meeting. Dr. Shroff is the interim division chief of Hematology Oncology at the University of Arizona Cancer Center. She also serves as the associate dean for Clinical and Translational Research and is the chief of GI Medical Oncology. Our full disclosures are available in the transcript of this episode, and disclosures related to all episodes of the podcast are available on our transcripts at ASCO.org/podcasts. Dr. Shroff, it's great to have you back on the ASCO Daily News podcast. Dr. Rachna Shroff: Thank you so much for having me. I'm so excited to be here. Dr. Shaalan Beg: The ASCO GI Cancers Symposium has been heralded as one of the biggest conferences in the GI cancer space and has occupied this space for the past two decades. Some would say that this year's conference was probably the best GI Cancers Symposium to date. Can you comment on the 20th anniversary milestone and the impact of the symposium on GI cancers? Dr. Rachna Shroff: Absolutely, and that's so great to hear that that's the feedback that you've heard. I have to say GI ASCO is absolutely my favorite meeting of the year, so that is my full disclosure. But I think that this was a tremendous meeting, and I think it was so beautiful that it was also coinciding with the 20th anniversary. It meant so much to us to have Dr. Margaret Tempero open the meeting because she really was the impetus for creating a GI cancer-focused meeting that really brought together multidisciplinary expertise. And so to us, that is what this 20th anniversary represented—20 years of multiple different specialties coming together to discuss how to improve cancer care for patients with gastrointestinal malignancies. And it has been a transformative meeting to see the impact of research presented at this meeting and how it has been implemented over the course of 20 years. And I completely agree that this year in and of itself had some incredible pivotal data that there is no doubt will be practice-changing, and that is absolutely the purpose. I also think that the beauty of this meeting is the networking opportunities for all of us to come out of our individual silos, come together, and discuss cross-cutting care across the spectrum of GI malignancies. And I think that this meeting really did that quite well. Dr. Shaalan Beg: There were many practice-changing studies that made headlines this year, and for me, one of the most anticipated studies was a trial that you led for cholangiocarcinoma and much-anticipated results. The study finished enrollment at a record pace. Can you share your key findings of cholangiocarcinoma? And I'd really like to hear your perspective on cholangiocarcinoma studies. Dr. Rachna Shroff: Yes, it was actually a really big year in the hepatobiliary space, and I was proud to present SWOG 1815, LBA 490, which was the pivotal randomized phase 3 trial looking at gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin. This was a study that was opened across the entire NCTN and based on a single-arm phase 2 trial that had shown some promising early efficacy of the triplet chemotherapy regimen. As you mentioned, this study accrued 441 patients in two years. And it's really a testament to the fact that the cooperative group mechanism can and should be asking important questions in large, randomized studies and that it is even possible to do in what are historically thought of as, quote-unquote, “rare tumors.” The study was a randomization of two to one to the triplet chemotherapy versus the standard of care for newly diagnosed biliary tract cancer patients. And the primary endpoint was median overall survival. And while the median OS of the triplet regimen was numerically improved at 14 months compared to 12.7 months, this did not meet statistical significance. Other efficacy endpoints, including median progression-free survival and overall response rate, were also numerically improved but not statistically significant, with an overall response rate of 31% with the triplet regimen versus 22%. There were some prespecified stratification factors, including disease site and disease stage, and there may be some interesting signals that bear out of that in terms of perhaps gallbladder cancer and locally advanced patients may be benefiting from the triplet regimen a little bit more, but these are small numbers, and we would really need to explore that in a more rigorous prospective manner. The toxicities were, not surprisingly, there, especially hematologic toxicities. I will say for those of us that use this regimen in practice, we use it a little bit differently than what was done in SWOG 1815, but you can't deny that there were significantly higher grade 3-5 toxicities with anemia neutropenia and thrombocytopenia, though the treatment discontinuation rate did not differ. I think the next steps are really going to be the ongoing biomarker analyses. The study had archival tissue and prospective blood collection and we know that in the space of cholangiocarcinomas and biliary cancers, molecular complexities absolutely play a role in how patients do and how they respond to therapies. So that's going to be an important next step, I think, for this study. Dr. Shaalan Beg: Speaking of biomarkers and an impact on GI cancers, the other malignancy where biomarkers are having a much greater impact than other GI cancers is colon cancer. Another year where we continue to see advances in our understanding of molecularly targeted treatments for colon cancer. What caught your eye? Dr. Rachna Shroff: Well, there were a lot of really interesting studies happening in this space and as a biliary person, one of the first things I got excited about was seeing Abstract 139 that looked at pemigatinib, which is the drug we are very familiar with in cholangiocarcinoma. This was a single-arm phase two study looking at the use of the FGFR inhibitor pemigatinib in metastatic colorectal cancer patients who had FGFR alterations. And so this was a study that was opened through the ACCRU mechanism. It was multicenter with assignment two-stage design and it was specifically for patients with FGF and FGFR-altered metastatic colorectal cancer who had progressed on standard therapies. There was a prespecified interim analysis for futility after 12 evaluable patients and so 14 patients were enrolled in the first stage of the study and evaluated for the primary endpoint of objective response. What was seen and the study was subsequently stopped is that there was really not much efficacy, there was no evidence of safety signals, but this did not seem to be a very active drug in patients with FGFR alterations with no objective response noted. So, the study was stopped with the recognition that perhaps the FGFR translocation or fusion patient population may be something to explore since they did not look at that in this study. The other kind of study that I think is really important was important work of Dr. Raghav and colleagues through SWOG. This was SWOG 1613 Abstract 140. This was the first real study that was investigating targeting HER-2 overexpressed and amplified metastatic colorectal cancer who had RAS wild-type tumors. And it was based on, obviously, some early signals of the effectiveness of HER-2 targeting in metastatic colorectal cancer. And this was a large study looking at pertuzumab and trastuzumab in these patients. They were compared to cetuximab and irinotecan, and the initial plan was for a much larger study. Unfortunately, accrual was really slow so the study was really kind of reformatted and a total of 54 patients were randomized, 26 to the trastuzumab arm and 28 to the CetIri or cetuximab and irinotecan arm. What was seen was that you can absolutely use HER-2 targeting therapies with trastuzumab and pertuzumab in these patients. It was safe and there were some obvious signs of efficacy in terms of overall response rate with an overall response rate of 31% compared to the CetIri arm. Crossover was allowed from the CetIri arm to trastuzumab and pertuzumab. So just that's important to keep in mind when they start to follow out the survival data. But unfortunately, because this study did not accrue, it was stopped early and it's really hard to understand in terms of power calculations the impact of trastuzumab pertuzumab. Of course, we can't talk about this without recognizing that the FDA approval based on the MOUNTAINEER study for tucatinib and trastuzumab came through during GI ASCO. So clearly HER-2 targeting is here to stay in colorectal cancer. Dr. Shaalan Beg: So technology is advancing every year and it's important that we are aware of these advances and how they impact our patients. Probably one of the most exciting technologies in oncology in general is the evolution of ctDNA. And it's been amazing to watch that field unfold as we understand how to use circulating biomarkers for early detection of cancer, for minimal residual disease detection, even as a biomarker of response. What caught your eye when it comes to the use of ctDNA in GI cancers, and how do you see this space develop in the next couple of years? Dr. Rachna Shroff: I completely agree. I think the technology of ctDNA is so incredibly exciting and as somebody who does not actively see and treat colorectal cancer, I'm a little bit envious of my colleagues in that space because the strides that have been made in terms of understanding the utility of ctDNA, especially in colorectal cancer, has just been tremendous and even for the last two to three years. One perfect example of integrating that sort of technology into treatment paradigms is the PARADIGM trial, Abstract 11, which was looking at the concept of hyperselection of patients with RAS wild-type metastatic colorectal cancer who were on the PARADIGM trial which basically looked at frontline FOLFOX with panitumumab versus bevacizumab in patients with RAS wild type left-sided metastatic colorectal cancer. So, you know, the initial data from PARADIGM had demonstrated a longer median overall survival 37.9 months versus 34.3 months, but very smartly, the investigators had also collected baseline plasma ctDNA in the biomarker component of this study and used a custom panel that looked at gene alterations for hyperselection and that included KRAS, NRAS, PTEN, and extracellular domain EGFR mutations HER-2 and MET amplifications, as well as some fusions like ALK, RET, and NTRK. And so out of the 802 patients in the full set, 91% - 733 patients - actually had pretreatment samples for ctDNA, which is really in and of itself, I think, tremendous. And when you break it down, about 28% had at least one gene alteration, and that was across each of those different genes that they were looking at. In the 72% of patients who were defined as hyperselected without any gene alterations, the OS was actually longer with panitumumab versus bev, and that actually was independent of sidedness with hazard ratios that kind of ranged from 0.76 to 0.82. And OS was similar or inferior with panitumumab versus bevacizumab again, regardless of sidedness in patients with any of these gene alterations. And so I think it's a really interesting concept that you can use ctDNA to define negative hyperselection rather than looking at left sided and right sided to really help select patients with frontline therapy in terms of using panitumumab versus bevacizumab. And with the speed with which ctDNA can be obtained, this actually seems like something that could be implemented into clinical practice, which is, I think, really the important component of that. There were a number of other really interesting abstracts. Abstract 5, presented by Dr. Cohen and colleagues, really looked at the kinetics of circulating cell-free DNA and how that kind of relates to minimal residual disease detection rates. And this was in patients with resected stages one through three colorectal cancer. And so, this was a retrospective study, so we have to keep that in mind. And it was multi-institutional in really over 16,000 patients with stages 1 through 3 colorectal cancer. But the complete dataset had about 417 patients and basically the patients' circulating cell-free DNA levels, the total cfDNA, were compared to the ctDNA MRD positivity rates and they looked at very specific time points after surgery. What the authors generally found was that the postoperative cfDNA correlated well with ctDNA positivity and that there was really the ability to see plasma cfDNA levels kind of track and follow with the very specific MRD windows that were being looked at, which really, again, just kind of talks about leveraging this technology in terms of real-world and real-time application and better understanding and informing us of minimal residual disease post what is thought to be curative resection. The last one that I thought was really interesting in relation to ctDNA was actually looking at anal cancer and following ctDNA in patients who were treated with definitive chemoradiation. This was a study that was looking at 31 patients with anal squamous cell carcinoma who were treated with definitive chemo radiation and underwent ctDNA response. The majority of these patients had stage 3 disease and the majority of them received the standard 5-FU Mitomycin with radiation. The patients had ctDNA testing performed in 25 of these patients at baseline and then a smaller number over the course of time, some during chemoradiation. And then they looked again at 30 days post chemoradiation. And at baseline, 88% of patients had detectable ctDNA with those with stage three disease having numerically higher baseline ctDNA levels. And basically what they found was that over the course of treatment, ctDNA levels decreased among the patients with detectable ctDNA. And then ctDNA that tested during chemo radiation showed a drop in decline and were going into molecular remission at a time point in which it was subsequently confirmed that they had a clinical complete response. So, the suggestion here is that the time to molecular ctDNA remission was significantly shorter than being able to see that clinical complete response, which suggests that using surveillance ctDNA monitoring could be an earlier response assessment for patients with anal squamous cell carcinoma who are undergoing definitive therapy. Now, obviously this needs to be confirmed in a larger manner, but again, really suggests that we could be understanding how we're doing with treatment in more of a real-time fashion, which I just think is incredible for those of us who are making sure that we are doing and taking the right approaches for these patients. Dr. Shaalan Beg: One of the major transformative announcements that took place only a couple of months before the GI Cancer Symposium was the announcement of ChatGPT. And we heard a lot of discussion on how it can be used for improving cancer care, improving drug development, and in general, artificial intelligence and machine learning. We've been hearing these buzzwords for such a long time, to the point that a lot of people are probably just filtering it out and then this tool comes up and it makes it real. And we're seeing different people apply these technologies in different ways. But there is tremendous potential in how this technology can improve clinical trials, drug development, and early diagnosis. And luckily, we had already secured a keynote speaker, Dr. Matthew Lundgren from Nuance Communications, and he was invited to talk about artificial intelligence, machine learning, and how it applies to cancer care. I'm really curious to hear what your highlights were from his address and how you see this impacting your day-to-day, or just the ecosystem of which we're all part of. Dr. Rachna Shroff: Yeah, I will say that his keynote was really one of the highlights of the entire meeting for me. And that is coming from somebody who doesn't really know– I know who I'm speaking to, but somebody who does not truly understand the way AI is moving. And so, I was joking with him that it was like AI 101. And I really, really appreciated the way he was able to kind of speak to a crowd that he doesn't normally speak to and help us really understand the way in which artificial intelligence can be integrated into healthcare, and specifically oncology. To me, I think what were the most salient takeaways from his address was really about how this is just a rapidly evolving field and we need to be a little bit ahead of the eight ball when it comes to thinking how we can smartly leverage artificial intelligence like you mentioned, to improve our clinical research efforts, to improve access, and to improve fully integrating AI into our EMR, so that we can really leverage that technology and ensure that we are capturing every potential patient for a clinical trial and be smarter about how we're even approaching things. I mean, I loved him talking about the prior authorizations and that sort of thing, and the ways in which we can decrease the burden on health care providers and really let us focus on the areas that we need to focus on. The one thing that I thought was a really important point, though, and I think a number of people asked him, was about how using this technology has the potential to create more gaps and disparities and how can we be smart to ensure that we don't broaden those gaps. And I think that is a really important point that we all need to think about because we know that especially when we think through clinical trials, there's already underrepresentation of certain populations and certain geographic regions. And so, I think that was a really important takeaway for me is how can we make sure that we work and partner with those who are creating these technologies to ensure that we aren't taking two steps forward and four steps back. Dr. Shaalan Beg: It really calls into question how we define productivity and what our value in the entire delivery system really is. And I think from people who are in middle school or high school to people who are in college and even folks who are in the field as you and I are, it's forcing us to rethink what we bring to the table in a way that we've never been challenged to ask that question ever before. Dr. Rachna Shroff: Absolutely. Dr. Shaalan Beg: So, thank you very much, Dr. Shroff. This was wonderful. Thank you for sharing your insights with us today. And we thank you and Dr. George Chang, the chair of the ASCO GI Cancers Symposium, and everyone who worked so hard to develop a robust program this year. Dr. Rachna Shroff: Thank you. It was so wonderful to be able to speak about it. And thank you to all of the attendees for making it such a memorable meeting. Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. Disclaimer: 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. Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Rachna Shroff @rachnatshroff Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Rachna Shroff: Consulting or Advisory Role: Exelixis, Merck, QED Therapeutics, Incyte, Astra Zeneca, Taiho Pharmaceutical, Boehringer Ingelheim, SERVIER, Genentech, Basilea Research Funding: Pieris Pharmaceuticals, Taiho Pharmaceutical, Merck, Exelixis, QED Therapeutics, Rafael Pharmaceuticals, Bristol-Myers Squibb, Bayer, Immunovaccine, Seagen, Novocure, Nucana, Loxo/Lilly, Faeth Therapeutics

university ai science dna chatgpt os consulting fda crossover clinical gi advances paradigm astrazeneca bayer abstract oncology merck ras ret precision medicine emr asco colorectal cancer mountaineer genentech mrd bristol myers squibb boehringer ingelheim egfr kras raghav translational research alk hematology oncology ut southwestern shroff nuance communications lba pten seagen servier fgf ctdna incyte mcrc fgfr nras medimmune swog cfdna folfox merck serono transcript dr array biopharma disclosures dr qed therapeutics astrazeneca medimmune

Research Highlights from ESMO Congress 2022, with David Ilson, MD, PhD, FASCO, Sumanta Pal, MD, FASCO, and Tian Zhang, MD

Cancer.Net Podcasts

Play Episode Listen Later Nov 10, 2022 28:34

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. 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. Guests' statements on this 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. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In this podcast, Cancer.Net Editorial Board members discuss new research in gastrointestinal and genitourinary cancers presented at this year's ESMO Congress, held September 9-13 in Paris, France. First, Dr. David Ilson discusses treatment advances in liver, colorectal, and gastric, or stomach, cancers. Dr. Ilson is an attending physician and member at Memorial Sloan Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College. You can view Dr. Ilson's disclosures at Cancer.Net. Dr. Ilson: Hi, I'm Dr. David Ilson from Memorial Sloan Kettering Cancer Center in New York. I'm a GI medical oncologist, and it's my pleasure today to review some important presentations in GI cancers from the recent ESMO meeting in Paris from 2022. I have no relevant relationships to disclose for this discussion. So, important presentations were made in hepatocellular cancer, in colorectal cancer, and gastric and other cancers, and I'm going to highlight some of the key presentations from the meeting. One of the most anxiously awaited presentations was one in hepatocellular or liver cancer. For patients that have advanced disease who are not candidates for surgery or local treatments, standard therapy now, it used to be lenvatinib and sorafenib, and that's now been replaced by the combination of an immunotherapy drug, atezolizumab combined with the drug bevacizumab. That's the new standard of care. And recently, we had a promising data for another immunotherapy combination using the drug durvalumab combined with tremelimumab. So what we saw this year was another important global study looking at the first-line use of immunotherapy in hepatocellular cancer. This trial took 794 patients with advanced hepatocellular cancer and assigned them to a standard treatment with a drug called lenvatinib. Lenvatinib and sorafenib were the old standard treatments for hepatocellular cancer. And lenvatinib alone was compared to a combination of lenvatinib and pembrolizumab, an immunotherapy drug. The primary endpoint was to see whether adding immunotherapy to lenvatinib improved survival. And this was a negative trial. It did not show an improvement in survival for adding pembrolizumab to lenvatinib over lenvatinib alone, and there was really no significant difference in the time that patients were on treatment. The response was slightly higher with the addition of pembrolizumab to lenvatinib, but again there was no survival difference. So this combination will not move forward. And again, as I said earlier, the new standard first-line treatment is atezolizumab plus bevacizumab. In colorectal cancer, probably one of the most exciting presentations was the use of immunotherapy treatments in locally advanced colon cancer. There is an important subset of colorectal cancer that has what's called an MSI-high status. MSI-high colon cancers are very responsive to immunotherapy drugs, and there has been a lot of interest in patients with localized colorectal cancer using immunotherapy drugs prior to surgery rather than conventional chemotherapy or radiation. So this important trial looked at 112 patients with localized colorectal cancer. Most of the patients were stage 3, and they all were documented to have this MSI-high status, which indicated a higher chance of response to immunotherapy. And patients received a brief course of immunotherapy, 2 doses of the drug nivolumab combined with 1 dose of ipilimumab over only 6 weeks followed by surgery. What they showed in these 112 patients who went to surgery, there was almost 100% response to this treatment. In fact, almost two-thirds of patients had no cancer found at surgery, even only after several weeks of immunotherapy. And in the 112 patients treated, there have been no recurrences in any of these patients. So it's quite remarkable that immunotherapy could induce a complete remission in two-thirds of patients, and that was only after a few weeks of exposure of the drug. So I think we're going to see more interest in using immunotherapy treatments as a potential pre-surgical treatment for colon cancer. And we could argue with such a high rate of complete remission, if we gave immunotherapy longer, maybe we could consider nonsurgical management, to just keep treating the patients with immunotherapy. This is actually the case that's now been seen in rectal cancer, a recent study presented from my institution where they treated patients with rectal cancer with immunotherapy, and we also achieved 100% remission, and none of the patients in this small study required surgery. So I think this important study, which is called the NICHE-2 trial, indicates a high degree of effectiveness of immunotherapy in MSI-high colon cancers. And certainly, it raises interest in using this as a preoperative treatment and potentially could lead to some patients getting treatment with immunotherapy alone without surgery. Then I'm going to comment a little bit about advanced metastatic colon cancer. Another important presentation was studying a new drug called fruquintinib. Fruquintinib is an oral drug that targets the VEGF pathway, which is an angiogenesis pathway in colon cancer. Standard treatment for colon cancer when it's stage 4 disease is now use of chemotherapy, like FOLFOX and FOLFIRI, drugs like bevacizumab, cetuximab, and panitumumab. And in more chemotherapy-resistant cancers, we use drugs like regorafenib and TAS-102. So this trial looked at a large group of patients, over 690 patients who had received all conventional treatments. They had progressive disease on all conventional treatments, including the late-line drugs regorafenib and TAS-102. And this was a placebo-controlled trial in which patients either received the drug fruquintinib or they received placebo plus supportive care. It was reasonable to offer a placebo in this trial because there really was no other standard treatment option for these patients. The primary endpoint of overall survival was improved with fruquintinib. Survival was improved with a reduction in the risk of death by about 30% and improvement in time on treatment. Very few patients responded to fruquintinib, so this was largely a drug that stabilized the cancer, but it did lead to modest improvements in time on treatment and modest improvements in survival. So this drug may potentially be evaluated as a new treatment option in very chemotherapy-resistant colorectal cancer. I just want to mention briefly another new class of agents for which we had data presented at the ESMO meeting. These are drugs that inhibit a mutation in their cancer called KRAS G12C. There are promising drugs that target this pathway. And there were 2 drugs that were followed up on at ESMO, one was a drug called sotorasib and another drug was adagrasib. These are drugs that target KRAS G12C mutations in colon cancer. And both of the trials that were presented used these drugs combined with drugs that target the EGFR pathways, so either panitumumab or cetuximab, and very encouraging responses were seen on these trials. The trial that looked at the combination of adagrasib plus cetuximab achieved a response in about 46% of patients, which is very encouraging. The trial that studied sotorasib, combined sotorasib with panitumumab, and they observed a 30% response, and some of these responses were durable. So the take-home message is that these drugs, adagrasib and sotorasib, are promising new agents to target KRAS G12C mutations in patients with advanced colon cancer and indicate that we may get even a higher degree of activity when we add EGFR-targeted drugs including panitumumab or cetuximab to these agents. So the other area that I want to comment on is gastric cancer. Recently, in the United States, we had a regulatory approval for the drug trastuzumab deruxtecan in patients who have HER2-positive gastric cancer that's advanced and is being treated with chemotherapy alone, HER-2-positive patients who had received previous trastuzumab or Herceptin. So trastuzumab deruxtecan is a promising drug used in patients that develop resistance to trastuzumab. So there was an update of the trial called Gastric-DESTINY02, which was a phase 2 trial of trastuzumab deruxtecan in Wwestern patients as a second-line treatment for patients with HER2-positive gastric cancer, and the updated analysis again showed a promising response in 40% of patients. The response duration was about 8 months, and patients achieved a survival of a year or more. So this updated presentation really reinforced that this is an active drug for patients with HER2-positive gastric cancer whose disease progresses on previous treatment with trastuzumab. So this was a very exciting ESMO meeting. There were a lot of other studies and important presentations, but I've tried to highlight today what I think are the most important as we move forward in trying to identify new treatments for patients. ASCO: Thank you, Dr. Ilson. Next, Dr. Sumanta (Monty) Pal and Dr. Tian Zhang discuss new research in kidney, bladder, and prostate cancers. Dr. Pal is the co-director of City of Hope's Kidney Cancer Program and is the head of the kidney and bladder cancer disease team at the institution. Dr. Zhang is an Associate Professor of Internal Medicine at UT Southwestern Medical Center and is a medical oncologist at the Harold C. Simmons Comprehensive Cancer Center. You can view disclosures for Dr. Pal and Dr. Zhang at Cancer.Net. Dr. Pal: Welcome to this Cancer.Net podcast. My name is Monty Pal. I'm a medical oncologist in the City of Hope in Los Angeles. I'm thrilled to be here today with my dear friend and colleague, Dr. Tian Zhang from UT Southwestern. Tian, mind giving us a quick intro? Dr. Zhang: Hi, Monty. Great to be here with you today. Tian Zhang at UT Southwestern in Dallas, Texas, where I'm a GU medical oncologist. I'm really excited to talk through the ESMO trials with you today. Dr. Pal: A little bit of housekeeping first. Let's go ahead and get some of our disclosures out of the way. I get travel support from CRISPR Therapeutics and from Ipsen. Tian, how about you? Dr. Zhang: Sure. I've received honoraria from Exelixis, BMS, Genentech, AstraZeneca, and Janssen, all relevant to our discussion today. Dr. Pal: Very good, very good. Well, thank you so much for joining us today. We've got a lot to talk about in about 15 minutes. The first thing that I wanted to chat about is adjuvant therapy. First of all, before we dive into the weeds here, can you just kind of tell our audience what adjuvant therapy is in broad strokes? Dr. Zhang: In kidney cancer, we think a lot about how we might prevent disease recurrence after surgery. So adjuvant treatment refers to systemic treatment that's given after a big surgery. And so in kidney cancer, that's usually after nephrectomy or removal of the kidney. Dr. Pal: Excellent, excellent. You beat me to the punchline. We are going to focus on kidney cancer, no doubt. This year at the European Society of Medical Oncology, or ESMO, meeting, which was held in early September, we actually had some really key studies presented in this space, one of which I'll disclose that I led. Studies I would say were maybe a little bit disheartening there, but nonetheless, I do think we can learn a lot from them. One of these trials was called PROSPER. This was a really interesting study that actually didn't just look at adjuvant therapy but actually looked at treatment before surgery, which we called neoadjuvant therapy. Tian, can you kind of walk us through the design of that trial really quickly? Dr. Zhang: This was a trial done in the ECOG Cooperative Group, and patients were randomized to receiving either nivolumab, which is an immune checkpoint inhibitor, before surgery, followed by a year of nivolumab after surgery, or to surgery and observation with ongoing scans. So it was really trying to look at a perioperative approach of using nivolumab. Dr. Pal: So how about this? Maybe we'll kind of discuss some of these results in amalgam, but maybe let's go through these trial designs first. The second trial that was highlighted this year at ESMO was called IMmotion010. That's one thing that I just love about these studies. They all have very clever names. I don't know what an IMmotion is, but tell us about IMmotion010 and what that trial design looked like. Dr. Zhang: Sure. So IMmotion010, again, also was an adjuvant trial for resected intermediate- and high-risk kidney cancers, randomized folks to either atezolizumab for a year or placebo for a year. And so this is in the context of having had resected kidney cancers and following folks for the treatment results, and the primary endpoint there was disease-free survival. Dr. Pal: Okay. So we've got an immune therapy called nivolumab and the PROSPER trial that was looked at before and after surgery. We've got atezolizumab, a different checkpoint inhibitor that was looked at following surgery. Tell us about the third trial. This is the last study in the space called CheckMate 914. What did that trial look at? Dr. Zhang: That one, again, also a phase 3 adjuvant trial, enrolling folks after surgery that had high-risk kidney cancer and randomized to either the combination of nivolumab with ipilimumab, both checkpoint inhibitors versus placebo. And again, this treated patients for about 6 months and also primary endpoint of disease-free survival. Dr. Pal: Now, whenever we do these studies, we always define them as being positive or negative, and that's really not meant to sort of cast any aspersions on how well the study was done or any really sentiments around the trial itself. It's really objective, and it's based on whether or not a study hits what we define ahead of the trial as being called a primary endpoint. So we actually, in these studies, looked at a primary endpoint of something called recurrence-free survival. And so that's really the proportion of patients who actually are living on without any sort of recurrence of their kidney cancer. I think it might be easy enough to sort of describe whether or not these trials hit that endpoint were positive or negative. What was the final report here on these trials, Tian? Dr. Zhang: Well, Monty, I think all 3 of these trials were, quote-unquote, "negative," and we all had high hopes for all 3 of these trials. And certainly, many, many patients participated, and we will learn eventually a lot from these trials. But none of these 3 met their prespecified primary endpoint of recurrence-free survival endpoint. Dr. Pal: So this is a little bit tricky because we did have these 3 negative studies presented at ESMO this year, but there was 1 positive trial that's adjuvant or postoperative space presented previously and then now published, actually, in the New England Journal of Medicine with an FDA approval to boot. Can you tell us about that, Tian? Dr. Zhang: Well, that one was called KEYNOTE-564 and randomized patients to either a year of pembrolizumab or placebo. And so you're absolutely right. It did show an improvement in disease-free survival comparing pembrolizumab with placebo. And so pembrolizumab is approved in this adjuvant setting after nephrectomy. Dr. Pal: And so this can be kind of a tough space because I can imagine our listeners are hearing this saying, "OK. Well, at ESMO, we've got 3 negative trials looking at postoperative therapy, and we've got 1 positive trial looking at pembrolizumab in the space." So what's one to do in this setting? What are you telling patients these days about whether or not to use adjuvant treatment for kidney cancer? Dr. Zhang: Yeah. I think it's a conversation that patients have with their oncologist after surgery, and it really depends on their own risk factors, their clinical and pathologic features at the time of resection. It depends a lot on patient preferences and their own priorities and things such as their tolerance for toxicity or how often they're coming into the treatment center. And I do think this is a time point where they have a shared decision-making that we can help our patients understand the totality of the data and then decide if a year of pembrolizumab is worthwhile or if they'd rather continue with surveillance after surgery. Dr. Pal: I totally agree with you, and I love that term “shared decision-making,” because it's never one of those situations where I walk into the clinic room and say, "Here's what you're going to do." And it's also never the situation where the patient walks into the clinic room and says, "Here's what I want." It's always this really sort of mutual process, isn't it, where you sort of look at a patient's clinical state. You look at some of the features under the microscope, but then it comes down to really, really lengthy and personal discussions around what that patient wants to get out of treatment. So I think that's very well said, Tian. I'm going to move to actually a different setting, which is termed “metastatic disease.” So we've talked about localized kidney cancer, where the disease is sort of confined to the kidney for the most part. We talked about what we do after we remove visible evidence of disease. But there is, unfortunately, a number of patients where we can't necessarily remove all the disease burden. So we lean more heavily on what we call systemic treatments. These are treatments that enter into the bloodstream either by mouth or through the veins. And in kidney cancer, just to give you a really, really brief synopsis, there's been this huge evolution over time. When I started in the field, it was really the advent of using a single oral therapy for kidney cancer. And over the next five 5 years, we sort of saw this evolution towards using doublet therapies, which is a mix of pills and IVs or maybe IVs alone. And more recently, there's been a lot of excitement. You can probably see where this is going, right? We've looked at 1 drug, and it works. We've looked at 2 drugs, and they seem to work. Logic would perhaps suggest that maybe you could get away with using 3 drugs in concert. So, Tian, this year at ESMO, there was a really important trial called COSMIC-313 that looked at 3 drugs versus 2 drugs. Can you tell us a little bit more about the design of the study? Dr. Zhang: COSMIC-313, the large phase 3 study, which randomized more than 850 patients to either the triplet, as you're speaking of, the cabozantinib, nivolumab, and ipilimumab versus nivolumab and ipilimumab with placebo standing in for cabozantinib. And so this was a very large trial, looking particularly at progression-free survival, comparing the triplet versus the immunotherapy doublet. Dr. Pal: And then tell us about the results of this because I have to tell you. I mean, I spent a lot of time looking over this, and I struggled with the end results a little bit. We talked about the primary endpoint of studies when we were discussing adjuvant therapy. And one of the things we'd mentioned is that you decide on this beforehand. And the primary endpoint in this trial was actually the delay in cancer growth. And as you pointed out, the study met that endpoint. But how do you interpret the results overall? How are you incorporating triplet therapy now? Dr. Zhang: Sure. I think it did certainly meet the progression-free survival primary endpoint. The median was not reached for the triplet versus 11.3 months for the doublet. And so importantly, I think it was a, quote-unquote, "positive trial." But how are we using this? Well, we have not seen the overall survival data of these patients. And so when you're thinking about combining all 3 drugs in the frontline setting, I think it's really important to think about what might come after and whether these folks truly live longer with using all 3 upfront versus a sequential approach. So I think the jury is still out. It certainly met its primary endpoint, and it's quite promising. But I'm still waiting for the overall survival data to really inform or change my practice. Dr. Pal: I've got to agree with you there. One of the things that we always discussed in clinic is whether or not a particular treatment strategy is going to increase longevity. It comes up in every conversation, I would say, whenever we're thinking about approaching a new line of treatment. And I wish I could say definitively that this triplet strategy improves longevity, but to be totally fair, that data just doesn't exist yet. So it's a really difficult conversation. I agree with you. Maybe a little pause before we start incorporating triplets. So I've got to say, it was certainly a big year for kidney cancer, one of my fellows put this table together, and it really showed that this year amongst the past maybe 10 years in kidney cancer, we had more big phase 3 trials being reported as more than any year previously. But there are also some pretty key developments in other diseases that you and I treat, Tian, and one of those is bladder cancer. And a trial that I think was really quite important has the name EV-103. Tough name to remember, but it actually looked at a disease space that I think can be a bit of a challenge for us, and that's the patient who is presenting in the clinic has actually advanced bladder cancers spread to other parts of the body and is quite ill and perhaps can't receive conventional aggressive chemotherapy with a drug called cisplatin. So what did this proportion of EV-103 that was presented show us? Dr. Zhang: Well, people hear about Cohort K thrown around, and so this trial actually has had multiple cohorts. And this particular cohort came out of some really exciting data from their dose escalation studies, and also Cohort A, where patients were treated with an antibody drug conjugate, this enfortumab vedotin, or EV, with an immune checkpoint inhibitor called pembrolizumab. And in the early cohort of 40 patients, they saw a pretty high objective response rate. That means the rate of patients where tumors were shrinking. And so that was about 70% of those 40 patients had objective responses. And so they designed this Cohort K to randomize patients to either enfortumab vedotin with pembrolizumab or enfortumab vedotin on its own, which has been approved in refractory metastatic urothelial cancer but particularly for first-line cisplatin-ineligible patient population. And so they randomized about 150 patients in the setting and looked at objective responses, and I agree with you. Certainly, very promising in terms of having objective response rate of about 65% and compared with enfortumab vedotin on its own, which came in around 45%. It does seem that this combination has more activity than the monotherapy. Dr. Pal: Yeah. That's a great summary. And to the patients out there listening, when we talk about responses, we're talking about pretty deep responses here, meaning 30% or more reductions in the size of tumors. And Tian mentions that you've got 65% to 70% of patients with these responses. It really does entail a sizable reduction, not just a small decrease in the volume of tumors. And I'm telling you, just from having been in the scene for 15 years now, I mean, it's just remarkable sort of progress that we're making. We're going to wrap up by talking about prostate cancer, and just to really describe some overarching results. So there's a setting in prostate cancer that I always find to be a bit of a challenge, and these are patients who have had surgery for their prostate cancer. So extensively no visible spread of their disease, but they start having their PSA creep up afterwards. And there was a trial that sort of addressed that. Tian, can you give us the sort of quick and dirty summary of the study? Dr. Zhang: Sure. So we call this PSA recurrence or biochemical recurrence setting. And this trial was led by Dr. Rahul Aggarwal in the Alliance Cooperative Group. But everyone who had biochemical recurrence were randomized to receiving androgen deprivation therapy alone, which is usually our standard of care; a combination of that androgen deprivation therapy with apalutamide, which is an androgen receptor blocker; or the combination of a triplet of the androgen deprivation therapy, the apalutamide, and then an abiraterone acetate, which is a blocker of steroid synthesis in the adrenal glands. And so this trial enrolled ultimately about 500 patients and randomized them 1 to 1 to 1 to these 3 cohorts. And interestingly, the combinations of either the androgen receptor, androgen deprivation therapy with apalutamide or the triplet with combined abiraterone acetate all prolonged PSA progression-free survival compared to androgen deprivation therapy alone. So I think it was a really well-done study in the cooperative groups and helps answer some questions around intensifying treatment in that biochemical recurrent space. Dr. Pal: Yeah. These cooperative groups studies, each one of them are so critical. These are just funded by our federal government, and they really offer us a chance to really ask pure questions, so really, really important study design. And maybe in 30 seconds, let's go over this last study over here. I don't want to keep our listeners on for too long, but there was a study called PROpel. Again, you got to love these study names. So this PROpel study looked at advanced prostate cancer. So again, this is prostate cancer where the disease has spread from the prostate to other organ systems. This is potentially a new paradigm for the disease. Before, we used to just basically give everybody hormone therapy in this setting. We've doubled down and given patients more advanced hormonal therapy with drugs like abiraterone that you alluded to, but now there's this potential to use targeted treatments. And maybe you can tell us a little bit about how that's been incorporated in PROpel, Tian. Dr. Zhang: Sure. Well, PROpel randomized patients to a combination of abiraterone with olaparib, which is what we call PARP inhibitor, and it blocks DNA damage repair, basically, in cancer cells. And olaparib has been approved as a single agent in more refractory, metastatic, castration-resistant prostate cancer. And so this trial randomized folks with a combination in sort of earlier lines of castration-resistant disease to either that combination or abiraterone with placebo. We saw earlier this year, actually, that the primary endpoint was improved for all comers, but I don't know if we saw some more subgroup analysis of patients with BRCA alterations and also with homologous recombination repair alterations. And I think that's very important, the fact that we saw more of an improvement in those subpopulations than those patients without the BRCA alterations or the homologous recombination repair mutations. Dr. Pal: Excellent. Excellent summary. I think that's about all that we've got time for today. New paradigms in prostate cancer and bladder cancer potentially and a massive amount of new data in kidney cancer to things going forward with clinical practice from ESMO 2022. Tian, thanks so much for joining me today, and I hope everyone listening enjoyed this as well. Dr. Zhang: Thanks, Monty. Take care. ASCO: Thank you, Dr. Pal and Dr. Zhang. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

Treatment of Metastatic Colorectal Cancer Guideline

Play Episode Listen Later Oct 17, 2022 21:12

An interview with Dr. Van Morris from The University of Texas MD Anderson Cancer Center in Houston, TX and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, TN, co-chairs on "Treatment of Metastatic Colorectal Cancer: ASCO Guideline." Dr. Morris and Dr. Eng review the evidence-based recommendations from the guideline, focusing on areas of uncertainty in the treatment of metastatic colorectal cancer, and highlighting the importance of multidisciplinary collaboration and shared decision-making between patients and clinicians. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines. TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. 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 The University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, Tennessee - co-chairs on, 'Treatment of Metastatic Colorectal Cancer, ASCO Guideline.' Thank you for being here, Dr. Morris, and Dr. Eng. Dr. Cathy Eng: Thank you. Dr. Van Morris: Thank you. Brittany Harvey: First. 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 full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Morris, do you have any relevant disclosures that are directly related to the guideline topic? Dr. Van Morris: Not personally, but I do have research support to my institution from Pfizer and Bristol Myers Squibb who have products that I'll be discussing on this podcast. Brittany Harvey: Thank you, Dr. Morris. And Dr. Eng, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Cathy Eng: Also, not personally associated with any honorarium specific to this topic. Brittany Harvey: Great. Thank you both. So then, let's talk about the content of this guideline. So first, Dr. Morris, can you provide an overview of the scope of this guideline? Dr. Van Morris: Sure. So colorectal cancer is the second-leading cause of cancer-related death in the United States. And especially in the time of the recent COVID-19 pandemic with people less likely to go for screening colonoscopies, there's great concern that more and more patients will be presenting at the time of their initial diagnosis with later-stage, more advanced colorectal cancer. So with that said, research is moving very quickly for the benefit of patients with colorectal cancer, and we were interested in assembling a multidisciplinary team that consisted of medical oncologists, surgical oncologists, radiation oncologists, pathologists, and radiologists as well, to help us make guidelines that really summarize the most relevant up-to-date practices, based on rigorous literature review for treatment recommendations for advanced metastatic colorectal cancer. Brittany Harvey: Great. And then as you just mentioned, this guideline provides recommendations, and a lot of those focus on areas of uncertainty in the treatment of metastatic colorectal cancer. And I'd like to review those key recommendations that you mentioned for our listeners. So, Dr. Eng, starting with - for patients with previously untreated, initially unresectable metastatic colorectal cancer, who are candidates for chemotherapy plus bevacizumab, is doublet or triplet cytotoxic chemotherapy recommended? Dr. Cathy Eng: For treatment-naive patients, bevacizumab has been approved, and we do agree that it's a very reasonable treatment option with doublet or triplet therapy for our patient population. Obviously, these are guidelines, and it's extremely important to keep in mind that as a provider, you need to discuss the potential side effects with the patient. With bevacizumab, you know, standard concerns must be discussed with the patient, especially in regards to wound healing, if they've had recent surgery or any potential risk factors for a recent cardiac event from a recent thrombosis. So, those things obviously, would preclude the patient from initiating treatment with bevacizumab. But currently, doublet therapy or triplet therapy could be a potential option for patients. Brittany Harvey: Great. And yes, as you mentioned, shared decision-making is paramount to these decisions. So then following that recommendation, Dr. Morris, which patients should be offered pembrolizumab in the first-line setting? Dr. Van Morris: Yeah. So, I think that this represents really one of the exciting advances in the treatment of metastatic colorectal cancer over the past several years. We have great data now that suggests for patients with microsatellite instability-high metastatic colorectal cancer, especially who have not had any prior treatment, we would recommend use of immune checkpoint blockade therapies, really coming from the seminal KEYNOTE-177 trial. This was a phase III international trial that looked at patients with advanced unresectable or metastatic colorectal cancer. And patients were either randomized to pembrolizumab monotherapy, or cytotoxic chemotherapy with FOLFOX, with or without bevacizumab. And this trial did meet its primary endpoint and showed an improvement in progression-free survival, with use of pembrolizumab as a single agent relative to cytotoxic chemotherapy. And based on this trial and the clear benefit that we see in patients with pembrolizumab, the FDA has approved this as an option for patients with MSI-high untreated metastatic colorectal cancer. There are other trials which have looked at use of immunotherapy; the CheckMate 142 trial looked at combination PD-1 CTLA-4 therapy as a single-arm study. And, you know, there's another trial, the CheckMate 8HW, which is looking at one versus two immunotherapy agents in this setting as well. But really, as it stands for now, patients with MSI-high untreated metastatic colorectal cancer are the ones who benefit from the use of immunotherapy. One of the questions that we often get in talking with other clinical oncologists is the FDA approval for pembrolizumab in any cancer type for a TMB, tumor mutation burden, greater than 10. And, we talked about this with our panel in this context, and we don't see that patients with microsatellite-stable metastatic colorectal cancer, who have a tumor mutation burden over 10 benefit from use of immunotherapy. There is one exception to this for patients who harbor pathogenic POLE or POLD1 mutations, these patients oftentimes do experience sustained clinical benefit with immunotherapy. But in general, patients with microsatellite-stable metastatic colorectal cancer, who don't have POLE/POLD1 mutations, we don't favor use of immunotherapy in that context at this point in time. Brittany Harvey: Great. Thank you for reviewing that recommendation and the data behind who benefits and who doesn't benefit from immunotherapy in this setting. So then following that, the next question that this guideline addressed is for treatment-naive RAS-wild type metastatic colorectal cancer. So, for these patients, Dr. Eng, is anti-EGFR therapy recommended for patients with right or left sided primary tumors? Dr. Cathy Eng: That is such an important question, and thank you for asking this. We know based upon pivotal data from CALGB/SWOG 80405, that right-sided tumors treatment-naive, even if they're RAS-wild type, these patients should not receive anti-EGFR therapy. But also, we've learned from 80405, FIRE-3, and PEAK, which was a phase two study, that there appeared to be some benefit versus anti-VEGF therapy for left-sided tumors based upon studies that have been conducted. So, at this year's ASCO, actually, the PARADIGM trial was specifically a phase III trial, more focused on left-sided tumors. It was amended twice before it decided to focus on the left-sided patient population. And it was a phase III study where patients were randomized to FOLFOX plus panitumumab versus FOLFOX and bevacizumab. And the primary endpoint was overall survival. And we added this data to our guidelines. This data just came out, hot off the presses in June, at this year's ASCO. And the primary endpoint was fulfilled. And basically, it prospectively demonstrated that the data from the other three trials, based upon a pooled analysis, suggested left-sided tumors fare better with anti-EGFR therapy. And in fact, the PARADIGM trial basically validated those findings. Obviously, the PARADIGM trial just recently presented, we have not seen the final publication, we do not know much about the maintenance setting, but specifically, when thinking about anti-EGFR therapy, it is very reasonable to consider it in a left-sided tumor, all RAS-wild type patient population. I would like to mention though, and we do highlight this also in the guidelines, which is critically important, is that there was another study, which is a phase III trial called, TRIPLETE, that was presented as well, looking at FOLFOXIRI plus panitumumab versus basically, standard treatment. And what it noted is that there is no additional benefit for FOLFOXIRI plus panitumumab in left-sided tumors in regards to response or progression-free survival, there was no additional benefit. So, FOLFOX plus panitumumab seems very reasonable, FOLFOXIRI plus panitumumab is not necessarily needed in left-sided tumors. Brittany Harvey: Great. Thank you for that explanation, and also for the work of the panel to rapidly include this new information recently presented at ASCO. So then following those recommendations, Dr. Morris, what recommendation did the panel make for patients with previously-treated metastatic colorectal cancer with a BRAF V600E mutation? Dr. Van Morris: Yeah. So, this recommendation was made essentially based on one randomized phase III clinical trial, which reported out about three years ago now, the BEACON trial. This is looking at patients with BRAF V600E mutated metastatic colorectal cancer, which we know accounts for probably eight to 10% of all patients with advanced colorectal cancer, and when found, really harbors a poor prognosis relative to BRAF-wild type counterparts. So, the BEACON trial was a trial that looked at patients with previously-treated metastatic colorectal cancer, who have BRAF mutations, either kind of standard of care cytotoxic chemotherapy, or a BRAF/EGFR combination with encorafenib and cetuximab or alternatively, a BRAF/EGFR/MEK combination. That trial showed that improvement in survival outcomes with a BRAF/EGFR-targeted approach, as well as the BRAF/MEK/EGFR. However, because there was no difference in survival with the addition of the MEK inhibitor, the FDA subsequently approved encorafenib and cetuximab as the recommended treatment for patients with BRAF V600E previously-treated metastatic colorectal cancer. Because the MEK combination with binimetinib was not recommended by the FDA, you know, we did not include that analysis in our guidelines for ASCO. But as it stands right now, we do strongly encourage all clinicians to check for their BRAF V600E mutation status in their patients with metastatic colorectal cancer, with the goal of getting them to a targeted therapy approach over their treatment course. Brittany Harvey: Great. Thank you for providing that information. So, following that, Dr. Eng, what are the recommendations for patients with colorectal peritoneal metastases? Dr. Cathy Eng: The current recommendations for colorectal cancer with peritoneal disease, really, there's no strong evidence to support the role of heated intraperitoneal chemotherapy. We now know based upon the literature from one of the largest studies to date, the PRODIGE data, demonstrating that there may be some potential benefit from cytoreductive surgery for the patients in regards to overall survival. But these patients are at high risk for bowel obstruction, potentially for perforation, and obviously, quality of life is an issue. So, these patients should always be discussed in a multidisciplinary tumor board whenever possible, and hopefully, to meet with a surgeon that is more experienced, specifically, in treating peritoneal disease, because these patients do require a lot of multidisciplinary care and discussion. So currently, based upon the existing data, we don't recommend heated intraperitoneal chemotherapy, but there may be a role for cytoreductive surgery. Brittany Harvey: Thank you, Dr. Eng for going over those recommendations. So then following that, Dr. Morris, for patients with unresectable liver-limited metastatic colorectal cancer, which liver-directed therapies are recommended? Dr. Van Morris: So, this is I think a really good question and one that just like the prior question with regards to peritoneal surgery, is one that we felt was a challenging one, but a common one that we wanted to address. And specifically, I think this is an example of where level of evidence comes into the strength of recommendation. So, for patients with unresectable liver-limited metastatic colorectal cancer, we looked at the questions of, "What is the role of SBRT - stereotactic body radiotherapy, and what is the role of SIRT, which is selective internal radiotherapy?" And for both of these, we felt that the level of evidence was weak, and I think that it's very important to make note of that in assessing the recommendations. But to start with, for SBRT, we looked at one meta-analysis for patients with oligometastatic colorectal cancer, and also analyzed 18 non-randomized control trials in this setting. Most of the patients in these studies had one to five liver metastases, with the majority having one or two liver metastases. From the meta-analysis, we saw kind of a one-year local control rate of around 67%, a two-year control rate of 59%. So, based on those and recognizing the limitations of non-randomized trials and making recommendations, the panel did feel that it was reasonable to consider use of SBRT for oligometastatic colorectal cancer. The SABR-COMET trial is one that had looked at the role of radiotherapy for treatment of oligometastatic colorectal cancer, and I just want to make the point as well, that we did not include that in our analysis or recommendations at this point in time, because this really didn't include a lot of patients with colorectal cancer that we felt warranted inclusion. Now, with regards to SIRT, we looked at kind of one meta-analysis and three randomized control trials for patients with mostly liver-limited metastatic colorectal cancer. All patients had liver disease, but there were about 40% of the patients we looked at in the meta-analysis, had extra hepatic disease as well. In the frontline setting, there really was no difference in progression-free survival or overall survival with the use of SIRT. And more recently, we've seen in a second-line trial, it was called the EPOCH trial, reported several years ago, this looked at patients with previously-treated metastatic colorectal cancer in the second-line setting. Patients were randomized to either chemotherapy with, or without transarterial radioembolization with Y90. While there was an improvement in overall response rate, there was no meaningful improvement in overall survival with the use of SIRT. But there were significant increases in grade 3 or grade 4 toxicities when SIRT was added to chemotherapy. So, kind of given this, we didn't feel at this point in time that SIRT should be recommended for patients with metastatic colorectal cancer. Although, again, I do want to highlight that really these discussions should be happening at high-volume centers, kind of with a multidisciplinary group of clinicians. Brittany Harvey: Definitely. And thank you for highlighting that multidisciplinary collaboration. And the last section of recommendations, Dr. Eng, what is recommended for patients with metastatic colorectal cancer, and potentially-curable oligometastatic liver metastases? Dr. Cathy Eng: So, another controversial topic. And once again, this is why we decided to include this as part of the guidelines, because this is a common scenario where patients are potentially curable, following liver resection for oligometastatic disease. We cannot highlight enough the importance of multidisciplinary discussion. Prior data has not been strong regarding specific guidelines following liver resection. We do recommend that based upon the existing data, there is no level one evidence to say, you should go one way or another following metastatic resection, and whether or not adjuvant therapy is warranted in that setting. But we do recommend multidisciplinary management and engagement and discussion. So, although it's not definitive, it basically suggests that there is a role for resection. It does provide improved five year survival relative to systemic chemotherapy, if the patient is potentially resectable, but does require multidisciplinary discussion. And it is a shared decision-making process. Brittany Harvey: Great. Thank you. And I appreciate you highlighting the importance of shared decision-making throughout this guideline. So then, Dr. Morris, what is the importance of this guideline in your opinion, and how will it impact clinical practice? Dr. Van Morris: Yeah. So, I think that we understand that management of metastatic colorectal cancer is extremely complex given the various molecular annotations and the multimodality therapies which are possible for our patients. So, we tried to limit the guidelines here to include what we feel are the most recent updates, but also kind of the most clinically-relevant multidisciplinary questions that get asked for treatment of metastatic colorectal cancer. We also recognize that things are changing quickly. And for example, we didn't decide to include at this point in time, management of HER2 neu amplified metastatic colorectal cancer, although we are seeing more and more data coming out, suggesting targeted therapies. So, I think it's important for clinicians to realize that these are guidelines which are ever-changing, given the updates with new therapies available for our patients. And the other thing I think that's very good about these guidelines is that, even though we may be making recommendations about controversial topics in the management of metastatic colorectal cancer - specifically, I think the use of HIPEC with cytoreductive surgery, locally-directed therapies to the liver, and the role of perioperative chemotherapy and metastasectomy - I think it's important for oncologists to realize that these recommendations come with varying strengths of level of evidence and that we as oncologists should be considering the level of evidence that's out there when making recommendations that affect our patients as well. So, we really wanted to support these guidelines and recommendations and empower clinicians to know and understand the quality of evidence that exists in the management of patients with metastatic colorectal cancer. Brittany Harvey: Excellent. And yes, those are key points on the level of evidence and the strength of recommendations throughout the guideline. And then finally, Dr. Eng, you've talked a bit about shared decision-making and the importance of this guideline for patients. So, how will these guideline recommendations affect patients with metastatic colorectal cancer? Dr. Cathy Eng: The reason that we created these guidelines is to help patients, their caregivers, and providers, learn of the most recent developments in colorectal cancer, and the best approach based upon the information that we have personally reviewed with our multidisciplinary team of faculty members that participated in this exercise. We really just want to make sure that patients do get optimal care. And we hope that these guidelines also will help provide a foundation for some of the clinical trials that may be under development, or for other clinical trials that are being considered. So, we really just want to provide the most up-to-date information to all individuals that are interested in colorectal cancer so we can help guide their care better. Brittany Harvey: So, I want to thank you both so much for your work on these guidelines, and all of the time it's spent developing these recommendations, and thank you for your time today, Dr. Morris, and Dr. Eng. Dr. Van Morris: Thank you. Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. 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 iTunes 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.

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GI CONNECT Update from ESMO 2022 Ep 2: upper GI cancer highlights

COR2ED Medical Education

Play Episode Listen Later Sep 27, 2022 21:28

COR2ED Medical Education: This second GI CONNECT podcast episode, covers the highlights on gastroesophageal cancer from ESMO 2022. Dr Sam Klempner (Massachusetts General Hospital, Boston, USA) and Dr Yelena Janjigian (Memorial Sloan Kettering Cancer Center, New York, USA) discuss a number of key posters and oral presentations from the meeting and their implications for clinical practice. The experts start by covering a number of first line studies. First of all, they discuss a study from Dr. Janjigian’s research group which investigated regorafenib with nivolumab and FOLFOX in HER2 negative oesophagastric cancer. They then discuss LEAP-015 which investigated first-line lenvatinib plus pembrolizumab plus chemotherapy in advanced/metastatic gastroesophageal adenocarcinoma (GEA). Dr. Klempner then covers one of his posters from ESMO 2022 on the DisTinGuish trial which looked at DKN-01 and tislelizumab plus chemotherapy as first-line investigational therapy in GEA. Later they discuss MOONLIGHT which investigated FOLFOX plus nivolumab and ipilimumab versus FOLFOX induction followed by nivolumab and ipilimumab in patients with previously untreated advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Later in the podcast, they cover a number of second line studies, including the PRODIGE 59 - DURIGAST trial which evaluated FOLFIRI plus durvalumab and FOLFIRI plus durvalumab plus tremelimumab in second line treatment of patients with advanced gastric or GEJ adenocarcinoma. Finally they discuss DESTINY-Gastric02 which followed on from DESTINY-Gastric01 in Asian patients and was undertaken to evaluate T-DXd in Western patients with HER2+ unresectable/metastatic gastric/GEJ cancer who progressed on or after trastuzumab-containing regimen.

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Physical Activity Improves Survival in Colorectal Cancer

Journal of Clinical Oncology (JCO) Podcast

Play Episode Listen Later Sep 12, 2022 18:03

Dr. Westin and Dr. Justin C. Brown discuss how physical activity can improve disease-free and overall survival in colorectal cancer and its potential application across all cancer types. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Westin: Hello, everybody, and welcome to another episode of JCO After Hours, the podcast where we get in depth on recent manuscripts published in the Journal of Clinical Oncology. And it is my great pleasure today to tell you we're going to be talking about a really important manuscript: “Physical Activity in Stage III Colon Cancer: CALGB/SWOG 80702 Alliance Study.” And this was published in the JCO on August 9th, 2022. All participants in the podcast have no conflicts of interest. And I am very excited to welcome the first author on this important paper, Dr. Justin C. Brown. He is the Director of the Cancer Metabolism Program and Assistant Professor in Cancer Energetics at the Pennington Biomedical Research Center at Louisiana State University. Welcome, Dr. Brown. Thank you for being here. Dr. Justin C. Brown: Thanks so much for having me. Dr. Westin: So, this is some really important work, and I think we're starting to see more and more really objective data around the importance of physical activities. But before we get too far down the road, I do want to level set because this was a study in colon cancer. So, just because we have a really mixed audience, give us a quick bit of information about the standard treatment for colon cancer and where we are with survival outcomes. Dr. Justin C. Brown: Yeah. So, for most patients with early colon cancer, they'll get upfront surgery. And then a subset of patients who have high-risk features for recurrence, or have positive lymph nodes or tumor deposits, will get three or six months of chemotherapy. And outcomes have improved over time for this population, but there is still a lot of heterogeneity, in that, some patients do better than others. And you know, a lot of patients ask as they finish therapy or as they're starting therapy, "Are there things I can do that potentially could improve my outcomes?" And so, we think that this data will provide physicians with a lot of really important information regarding the benefits of physical activity during chemotherapy, as well as after therapy, for patients with stage three colon cancer. Dr. Westin: Okay, that's great. And so, again, continuing on that level-setting piece, before this study, what did we know about the impact of physical activity on outcomes in colon cancer? Dr. Justin C. Brown: So, we knew that there was some association between physical activity during chemotherapy and after chemotherapy with disease-free survival and overall survival. There have been studies that have linked those two things. There was some uncertainty about, what is the best exercise or physical activity prescription? And so, a lot of the current recommendations before this study basically said encourage patients to avoid sedentary behavior, encourage them to be as active as they can be, because some activity provides benefits over no activity. But for the patient who really wanted the specifics of how much should I be doing, when should I be doing it, what types of activities should I be doing, should I avoid certain things, the evidence was really absent. And so, what this study provides is a lot of important clarity for both physicians and patients about the types of activities that can maximize their disease-free survival and overall survival. Dr. Westin: I think that's so important because you're exactly right. We all have those patients that you give them a vague, and they're like, "No, I need instructions. I need to know how much time. I need to know what I'm doing." And it can be really frustrating because—I know personally, I'm like, "Well, this is what I do.” And I'm like, is that enough? I have no idea. So, this is really important work. And before we get into the specifics of the work, can you just give our listeners a little information? Do we know anything else about physical activity in other cancer types? Like, beyond colon cancer, is this something that's broad-based across everybody? Dr. Justin C. Brown: Yeah. So, there is emerging observational evidence that physical activity after diagnosis of early breast cancer, of early prostate cancer, is associated with improved disease outcomes, so disease-free survival, overall survival; that's observational data. We do have randomized clinical trial data on other quality of life endpoints and biologic endpoints in a variety of tumor types. And we know that patients who engage in physical activity or exercise during and after treatment tend to have better quality of life, they have less fatigue, they have improved physical functioning, they have reduced inflammation, improved insulin sensitivity. So, there's a variety of short, medium and potential long-term benefits to being physically active after your diagnosis of cancer. Dr. Westin: Perfect. And how did you end up here? What made you interested in this work? Dr. Justin C. Brown: So, my story dates back all the way to 2002. So, my father died from metastatic colorectal cancer. Dr. Westin: I'm sorry. Dr. Justin C. Brown: No, no, it's okay. I mean, if that didn't happen, I wouldn't be here today. And so, he is with me every day. And, when he asked his physician, "Is there anything I can do to improve my long-term outcome?" This was 2002 before we knew how patient lifestyle factors really improved or impacted disease outcomes. And so, my whole life's mission has been focused on trying to empower cancer survivors, so people from the point of diagnosis on, with information about how the choices they make outside of the oncology clinic have a profound impact on how they feel, function, and survive. And so this has come full circle for me because now I'm able to generate evidence that hopefully will inform clinical practice about how patients who are exactly like my dad and wanted to know what they could do to improve their outcomes, we now have the data that we can provide more precise recommendations about what patients might consider doing to improve their long-term disease outcomes. Dr. Westin: Great. Wow. It's so inspiring, and again, I am sorry for your loss. But I'm glad that you're really transitioning it into positive things. So, let's help everybody understand first just the overall design of the trial that you utilized, the CALGB/SWOG 80702 clinical trial. Dr. Justin C. Brown: Yeah. So this trial was a two-by-two factorial trial, and it randomized patients to three years of Celecoxib; the anti-inflammatory drug, or three years of placebo. And that was the primary analysis. The primary hypothesis was that Celecoxib would improve disease-free survival versus placebo. And that paper was published by my mentor, Jeff Meyerhardt, in JAMA last year. And that analysis showed that Celecoxib did not improve disease-free survival over placebo. The other factor of the two-by-two design was a randomization to three months of FOLFOX therapy, 5- fluorouracil and oxaliplatin, or three months of FOLFOX. And that analysis contributed to an international pooled consortium called the IDEA Consortium. And that analysis was published in 2018 in New England Journal of Medicine, and the follow-up overall survival analysis was published in Lancet Oncology in 2020. And that showed that while overall, three months of FOLFOX was not inferior to six months, there were some lower-risk patients that achieved good disease control with a shorter regimen of chemotherapy. And so, that has changed practice, and now there are certain lower-risk patients that are getting treated with three months of FOLFOX chemotherapy instead of six months. But patients with high-risk features still continue to get six months of therapy. That was the primary questions that that study was designed to answer: the Celecoxib versus placebo and then the contribution to the international pooling project to answer the question of three versus six months of postoperative therapy. Dr. Westin: Well, that's a really clever design. And then I love how you have an additional question built in here. So, why don't you explain how you incorporated your exercise objectives and also what this nested cohort design is? Dr. Justin C. Brown: Yeah. So, this is a unique opportunity to leverage an ongoing clinical trial to conduct an observational study. So, what we did is, about midway through chemotherapy, we asked patients if they wanted to participate in a lifestyle substudy. And if they chose to participate in the lifestyle substudy, they were asked questions about their physical activity and their dietary patterns and how much they weighed. And we measured those things midway through chemotherapy, and then we also measured them again about six months after patients finished their chemotherapy. And so, what this allowed us to do is to leverage all of the amazing resources that were put into place in the randomized clinical trial—that is, a homogenous patient sample, uniform treatments—and systematically ascertain disease outcomes to answer a question in an observational setting—that is, "Does physical activity relate to disease-free survival and overall survival?" So that is the nested cohort within the larger randomized clinical trial. Dr. Westin: Okay, perfect. And then just tell us how you measured the physical activity and the questionnaire that you utilized. Dr. Justin C. Brown: Yeah. So physical activity was measured by a self-reported questionnaire, and the questionnaire is included as a supplement to the JCO paper. So, if people are interested in using this questionnaire, it is available. And it asks 10 different types of physical activities, and it asks the frequency with which those activities are done in the past two months. And using the answers that the patients provided, we were able to calculate which patients were more physically active versus those that were less physically active. And we were also able to understand were the activities that they participated in more vigorous or less vigorous. So, it provided us with a lot of important details regarding the types of physical activities that patients reported during and after chemotherapy. Dr. Westin: Great. That's so interesting. And then, of course, we know diet is important, right? So, you did assess diet as well in this group. You want to give us a little bit of detail on that? Dr. Justin C. Brown: Yeah. So, we measured diet with what's called a Food Frequency Questionnaire, and it asks a series of questions regarding habitual dietary intake. And we know that people who are more physically active tend to be more mindful about what they eat. And so, that's an important confounding variable in trying to understand the relationship between physical activity and disease-free survival. So, we measured diet using that questionnaire. At the same time, we measured physical activity during and after chemotherapy. And that was included in our analysis so that we can attribute the association that we observed to the physical activity per se. Dr. Westin: Okay. And how often did you assess these time points? I'm sorry if I missed it. Dr. Justin C. Brown: So, we measured physical activity and diet two times. We measured it midway through chemotherapy, and then about six months after patients finished their chemotherapy. Because we know that activity, as well as diet, changes from when patients are being actively treated to after they finish their systemic therapy. Dr. Westin: Okay. Perfect. Great. All right, so let's hear it. What were your primary findings? Dr. Justin C. Brown: So, the benefit for the simple messaging is that any activity is better than no activity. That is, if patients need to know the bottom line, my advice is that they find an activity that they like to do and they do it for the rest of their life. For patients who want a little bit more precision, we can think about physical activity on a spectrum of intensity. So the examples I would give a patient is we can do walking, we can do jogging, and we can do running. And jogging is more intense than walking, and running is more intense than jogging. And so, if you decide to do more intense activities, you don't have to do them as much in a week. If you choose to do walking, you need to do more walking than if you choose to do running. And so, this will help to clarify what types of activities are beneficial. So, some people might choose to play tennis, which is a vigorous activity, one day a week. And that would provide them—from our analysis, that provides them with a disease-free survival and overall survival benefit. If a patient says, "My joints are too old and too achy that I can't play tennis, but I can walk around my neighborhood," then we know that those patients may need to do a little bit more activity, maybe a 20 to 30 minutes a day, three to five days a week, in order to achieve a meaningful disease-free survival benefit. So, this helps us to understand with a little bit more precision what we should be advising patients. And if patients say, "I can't do this” or “I prefer to do that," that helps us to have evidence-based recommendations about what is likely to be beneficial and worthwhile to improve their long-term disease outcomes. Dr. Westin: It's so awesome. And I think it's so great to have just very clear guidelines that we can give our patients. I know I've said it already during this podcast, but every time I—because I think we all get so frustrated with these vague recommendations, like, "Okay, drink water, eat healthy." You know, really, I want bullet points of what I can do. Now, we talked a little bit about some of the findings in other cancer types that were already existing. So, can we extrapolate your findings to other cancer types? Dr. Justin C. Brown: I think there is a reasonable expectation that our findings can probably generalize to early-stage breast cancer and maybe to prostate cancer. And the reason I say this is because these are tumor sites where there is existing evidence that being more physically active is associated with improved long-term disease outcomes. Now, the specific magnitude of benefit, I'm not sure if that will generalize. But I do think that this study provides a framework to start thinking about how we can understand the specific characteristics of physical activity that might be more or less important in terms of maximizing long-term disease outcomes. Dr. Westin: That is perfect. So, tell me, what are your next steps with this work? Dr. Justin C. Brown: So, one of the findings that this study reported was that patients who were more physically active during their chemotherapy were more likely to receive more of their planned chemotherapy. They had a higher chemotherapy RDI. So, some of us on this paper have been very fortunate that we received funding from the National Cancer Institute to launch a Bayesian Adaptive Trial of exercise, aerobic exercise, during chemotherapy, and the primary study endpoint is chemotherapy relative dose intensity. So, what we're going to be able to do is to understand, in a randomized clinical trial setting, does different doses of aerobic exercise have a causal effect on improving chemotherapy RDI? Because one of the hypothesized mechanisms through which we think physical activity may improve disease-free survival and overall survival is it enhances a patient's ability to tolerate systemic therapy. And so, we have the funding. We are in the process of planning that study. It should begin later this year, and that will provide us with concrete randomized evidence to understand if exercise during chemotherapy for colon cancer has a causal effect and can improve adherence to systemic therapy. Dr. Westin: That's outstanding. And can our listeners potentially participate in that? Are you looking for sites? Dr. Justin C. Brown: So this study will be launched at Pennington Biomedical Research Center, where I am, in Baton Rouge. This study will also take place at Kaiser Permanente, Northern California, so if there are people on the West Coast listening, as well as at Dana-Farber Cancer Institute in Boston. And so, we are part of a larger consortium of four studies that are trying to understand the benefits of both exercise as well as nutrition and their role in impacting how patients feel, function, and tolerate anti-cancer therapy in a variety of cancer sites. And we are focused on colon cancer, specifically. Dr. Westin: Well, that's great. I hope our listeners will get involved. And those of our listeners that are survivors, you heard some very clear data on what you can do to help impact your overall survival, as well as quality of life. So, I hope you'll implement that. Thank you again so much for being here, Dr. Brown. The time just flew by. And again, for the listeners, this was the JCO manuscript published August 9th, 2022, “Physical Activity in Stage III Colon Cancer: The CALGB/SWOG 80702 Trial.” And until next time, we'll see you at JCO After Hours. Take care. 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.

Gastroesophageal Cancers | Meet The Professor: Optimizing the Management of Gastroesophageal Cancers — Part 5

protect rt krish radiotherapy pgy simul protons esophageal cancer folfox

Play Episode Listen Later Sep 7, 2022 61:57

Featuring perspectives from Dr John Strickler, including the following topics: Introduction (0:00) Case: A man in his early 60s with gastroesophageal junction (GEJ) adenocarcinoma who responds to neoadjuvant chemoradiation therapy but declines surgery and develops progressive disease (HER2 1+, PD-L1 2%) — Minesh Dinubhai Patel, MD (13:54) Case: A frail woman in her late 80s with unresectable gastric cancer who chooses to receive systemic therapy (PD-L1 0%, HER2 negative, MSS) — Matthew R Strickland, MD (18:20) Case: A man in his mid 60s with T3N1M mixed gastric adenocarcinoma who responds well to neoadjuvant FLOT and has minimal residual disease at surgery — Ranju Gupta, MD (23:01) Case: A man in his early 60s with a history of prostate cancer who is now diagnosed with T2N1M0, HER2-positive GEJ adenocarcinoma — Dr Strickland (29:23) Case: A man in his early 30s with metastatic HER2-positive gastric adenocarcinoma who is responding well to FOLFOX, trastuzumab and nivolumab — Priya Rudolph, MD, PhD (33:00) Case: A man in his early 60s with metastatic HER2-positive esophageal cancer and a germline CHEK2 mutation who experiences disease progression on chemotherapy, pembrolizumab, trastuzumab and later T-DXd (PD-L1 12%) — Warren S Brenner, MD (46:34) Case: A man in his mid 70s with symptomatic anemia who is diagnosed with metastatic esophageal adenocarcinoma (PD-L1 8%, MSS, HER2 1+) — Dr Strickland (55:44) Case: A woman in her early 60s with squamous cell esophageal carcinoma metastatic to bone (PD-L1 TPS 10%) — Dr Strickland (58:46) CME information and select publications

phd professor management cancer md optimizing strickland cme her2 mss flot pd l1 gastroesophageal folfox

“See You on Twitter!”: Esophageal Cancer Radiotherapy With Krish and Yasamin

The Accelerators Podcast

Play Episode Listen Later Aug 26, 2022 44:40

We're back!The Season 2 premier of Rad Onc's favorite podcast was inspired by Simul's Twitter poll on neoadjuvant radiotherapy dosing for esophageal cancer! Are you team 4140 or 5040... or something else?In this episode, the Accelerators (Dr. Anna Laucis, Matt Spraker, and Simul Parikh) host Mayo Clinic Radiation Oncology GI specialist Dr. Krishan Jethwa and PGY-3 resident Dr. Yasamin Sharifzadeh for a conversation about the poll. We discuss dose selection and chemotherapy regimens for esophageal treatment as well as open-mindedness in adopting therapeutic strategies. Later, we discuss whether radiotherapy dose-escalation may offer patients benefits, the value of proton therapy for this disease, and... wait for it... carbon ions! Here are some studies discussed during the show: Protect-1402 (FOLFOX and RT) and an associated treatment planning studyECOG-ACRIN 2174 (ImmunoRT)PRODIGE 26 (Dose Escalation) ESO-Shanghi 12 (Dose Escalation)NRG GI-006 (Protons, phase 3)MDACC Trial (Protons, phase 2B)Podcast art generously donated by Dr. Danielle Cunningham. Intro and Outro music generously donated by Emmy-award winning artist Lucas Cantor Santiago.

Novel Therapies in GI Oncology at ASCO22

Play Episode Listen Later Jun 27, 2022 15:31

Dr. Rachna Shroff, of the University of Arizona Cancer Center, tells guest host, Dr. Shaalan Beg, of UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and Science 37, about advances in precision medicine for pancreatic cancer featured at the 2022 ASCO Annual Meeting. She also highlights compelling new data from the FOLFOX, FOENIX-CCA2, and HERB trials in hepatocellular carcinoma, cholangiocarcinoma, and biliary tract cancer. TRANSCRIPT Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News podcast. I'm Dr. Shaalan Beg, your guest host of the ASCO Daily News podcast today. I'm an adjunct associate professor at UT Southwestern Simmons Comprehensive Cancer Center and vice president of oncology at Science 37. I'm delighted to welcome Dr. Rachna Shroff, the associate dean for clinical and translational research and the chief of gastrointestinal (GI) medical oncology at the University of Arizona Cancer Center where she's also the interim chief of Hematology-Oncology. Dr. Shroff is also the chair-elect for the Gastrointestinal Cancer Symposium. Today we'll be discussing key abstracts in GI cancer that were featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the show notes and disclosures of all our guests on the podcast can be found on our transcripts at asco.org/podcasts. Dr. Shroff, thank you for being on the podcast today. Dr. Rachna Shroff: Thank you so much for having me. Dr. Shaalan Beg: Let's begin by reviewing what is new in the realm of precision medicine in GI cancers. One of the diseases where precision medicine has not made adequate inroads is pancreatic cancer. One of the most common mutations in pancreas cancer is KRAS, but there haven't been a lot of treatments that can target the most common forms of KRAS. What did we hear at ASCO22 regarding precision medicine and pancreatic cancer? Dr. Rachna Shroff: I agree, I think that the area of precision oncology is, unfortunately, lagging behind a little bit in pancreatic cancer. But I think as we have gotten better and better with our comprehensive genomic profiling, we are identifying subsets of patients within pancreas cancer who are potentially amenable to targeted therapies. You already mentioned KRAS mutations, and we obviously have a number of inhibitors in development in that space, though, we are still missing that key G12D mutation that we see in pancreas cancer. But what I think was really interesting that came out of ASCO22, was a lot of interest and emphasis on better understanding the KRAS wild-type patients in pancreatic cancer. Now, this is obviously a smaller subset of patients, given that the majority of patients have KRAS mutations. But there was a really interesting abstract, LBA4011, that looked at patients with locally advanced or metastatic pancreatic cancer, who were KRAS wild-type. They actually received gemcitabine in combination with a monoclonal antibody targeting EGFR and nimotuzumab. This was a study that was done entirely in Asia. It involved 92 Chinese patients that were randomly assigned to receive the combination of nimotuzumab with gemcitabine. What was interesting in this study is that the patients were found in the full analysis set to have a significantly longer median overall survival of 10.9 months versus 8.5 months with a hazard ratio of 0.5. So, that of course was intriguing and provocative for sure. Similarly, the other endpoints were also somewhat intriguing in terms of improvements in the median progression-free survival (PFS), etc. And specifically, patients without biliary obstruction had a longer PFS, which was an interesting finding as well. The nimotuzumab overall was pretty well tolerated and not any sort of surprising treatment-related adverse events (TRAEs) were noted. And so, this is definitely a drug that, I think, piques our interest in terms of being able to target patients with KRAS wild-type pancreatic cancer. I think that questions, however, that remain, and I think require further study is really understanding what this drug could do in combination with the chemotherapy combinations that we use more frequently in metastatic pancreatic cancers such as gemcitabine and paclitaxel or 5FU-based regimens like FOLFIRINOX. I think given that it is a relatively well-tolerated drug, it would be a very reasonable thing to investigate this drug further in the KRAS wild-type population with the kind of modern-day chemotherapy regimens that we use. And I think, of course, we all know that it is useful to be able to look at these types of drugs in a more global population. And so, a larger patient set I think would be very useful as well, but at least it tells us that there is a way to think about our KRAS wild-type patients with pancreas cancer and that perhaps we really need to understand and identify those patients' potential for precision oncology. Dr. Shaalan Beg: One of the GI cancers that has been a hotbed for precision medicine is cholangiocarcinoma, a disease that's very close to your heart. What updates did we hear at ASCO22 regarding cholangiocarcinoma and precision medicine? Dr. Rachna Shroff: This space of targeted therapy and cholangiocarcinoma has been incredibly exciting for the last few years and I think drug development has been rapid-fire in that space. The oldest, if you will, target that we've been thinking about for some time is the FGFR2 fusion patient population. And in Abstract 4009 by Dr. Goyal and colleagues, we saw the results of the FOENIX-CCA 2 trial which was looking at an oral FGFR inhibitor (futibatinib) in patients with intrahepatic cholangiocarcinoma, who harbor FGFR2 fusions and gene rearrangements. We had initially seen some of this data presented a few years back, but this was the updated data set. It was a single-arm phase 2 study that involved patients with advanced intrahepatic cholangiocarcinoma who had identified FGFR2 gene fusions, and they received futibatinib daily until progression. This was a traditional single-arm phase 2 study with a primary endpoint of overall response rate. At the final data cut, with a median follow-up of 25 months, there's actually a confirmed overall response rate of 41.7%. And I think that what was really exciting about this is this is a refractory patient population. So, in patients who have refractory cholangiocarcinoma, the other drugs, the non-targeted therapy drugs that we think through, really have response rates more in the single-digit to 10% range and so to have a confirmed overall response (OR) over 40% is truly exciting. The duration of the response was also exciting. This is not just a drug that works briefly, it has a duration of response of 9.5 months. And the mature median overall survival was 20 months. And in a disease which we talk about with the ABC-02 data of GemCis, a median OS in advanced disease of 11.7 months. This is really, really exciting for patients who harbor this fusion or gene rearrangement. We know that that's seen in about 10 to 15% of patients. So, again, we're dealing with a smaller subset, but it clearly demonstrates the need to identify FGFR2 gene fusions, so that we can offer these types of targeted therapies. This was not the first FGFR inhibitor that we have seen data on and in fact, we have 2 drugs already U.S. Food and Drug Administration (FDA) approved. And so, when we look at the common treatment-related adverse events that were identified with the futibatinib, there are really class effects related to FGFR inhibition like hyperphosphatemia, alopecia, dry mouth, nothing that really stood out or that was concerning. And so, I think this final analysis for the FOENIX study really just reaffirms the utility of futibatinib in patients with FGFR2 gene fusions, and the mature OS data, the duration of response, all of this really aligns with the need to identify patients with this alteration so that we can, post-gemcitabine based therapies, offer this targeted therapy or an FGFR inhibitor in general to these patients. I think the other really exciting abstract in the glandular carcinoma or biliary tract cancer space was Abstract 4006. This was the updated data from the HERB trial, which was an investigator-initiated multicenter phase 2 trial looking at trastuzumab deruxtecan (T-DXd) in patients who have HER2 expressing unresectable or recurrent biliary tract cancer. Trastuzumab deruxtecan, I'm sure everybody has been hearing about because it has been incredibly effective in HER2 alterations across a myriad of different disease sites. And so, not wanting to be left out, biliary tract cancers were investigated in this study with patients who had HER2 expression, so, that was HER2-positive IHC3+ or IHC2+/ISH+, and they also looked at HER2-low expressing patients, and [whose disease] were refractory or intolerant to gemcitabine-based therapy with the primary endpoint of overall response rate. So, in the HERB trial, a total of 32 patients were enrolled. 24 of them were HER2-positive and 8 were HER2-low and they all received trastuzumab deruxtecan. When you look at the efficacy data, the confirmed overall response rate in the patients with HER2-positive was 36.4%, which again, as I said, in a refractory patient population is certainly very exciting data. And the overall disease control median, PFS, and median OS were all pretty encouraging in terms of efficacy. What was also kind of intriguing was that there was some efficacy seen even in the patients who are HER2-low. Now, this is, in my opinion, a slightly less exciting amount of efficacy, but still important to note that the overall response rate in HER2-low was 12.5% with a median PFS that was also somewhat exciting at 4.2 months. And so, there is a potential clearly for targeting patients with HER2-high or HER2-positive with trastuzumab deruxtecan, and I think in the patients who are HER2-low, we need to better understand the potential utility. The common treatment-related adverse events that we see were the typical things that we've heard about with trastuzumab deruxtecan, but I think the one thing that was really worth noting was 8 patients or 25% of patients had interstitial lung disease (ILD), which we know is an important identified safety concern for patients who receive trastuzumab deruxtecan, and I think that's a pretty sizable number of 25%, so, I think that's going to really require a little bit more fleshing out for us to understand the safety for these patients. One question that a lot of us have had is whether these are patients who have received gemcitabine, which we know can also cause pneumonitis. And so, I don't know if we're seeing a higher percentage of ILD because of, 'priming' with prior gemcitabine. But regardless, I think this is just proof of principle that again, we need to identify patients with biliary tract cancers that have HER2-positivity because we now have a number of drugs including potentially trastuzamab deruxtecan to target [their disease] with after gemcitabine-based treatments Dr. Shaalan Beg: Absolutely. Any new biomarkers to keep on the radar for our listeners? Dr. Rachna Shroff: I think there are a lot of really exciting targets. One that was talked about and that we saw data on at ASCO [Annual Meeting] was from Abstract 4048, which looked at claudin [18]. Claudin is basically a transmembrane protein that kind of helps maintain the tight junctions between cells. In gastric cancer, in particular, we look at claudin 18 isoform 2, and there are 18.1 and 18.2 gene expressions that have been identified in gastric cancer. So, there was a very comprehensive abstract that was presented of over 1,900 samples that underwent comprehensive profiling by next-generation sequencing. And the patients were identified with claudin 18.1, and 18.2, high versus low. Claudin 18.2 expression was actually detected in 97% of the samples. It's slightly lower with claudin 18.1 at 63%. It's important to note that the primary tumors had higher expression levels than the metastatic tumors, so those were really the tumors in which they did a deeper dive. And in the process of doing this deeper dive, they did a really interesting kind of better understanding of the immune microenvironment and the immune profile in the samples that had claudin expression. And what was identified is that there was an inverse relationship basically between claudin 18.1 and 18.2 expression and correlation with PD-L1 positivity, tumor mutational burden (TMB)-high, M1 macrophages expression, NK cell presence, CD4 positive T-cells, myeloid dendritic cells. And so, there's clearly something between the presence of this claudin expression and the effect it has on the immune microenvironment. I think that's very relevant to keep in mind because as we all know, there's a whole space of drug development focused right now on anti-claudin 18.2 monoclonal antibodies, as well as a target for antibody-drug conjugates (ADC) and cellular therapies with CAR T-cell therapies being developed specifically against claudin 18. And so, understanding the immune microenvironment and the interaction between the claudin expression will be really important as we continue to charge forward in that space. Dr. Shaalan Beg: Absolutely. Very, very exciting. Sticking with the liver pancreas theme, what other studies piqued your interest with regards to hepatocellular carcinoma (HCC)? Dr. Rachna Shroff: It's a really exciting time in HCC. I mean, we actually have drugs that are working in the advanced space. And so, now there's a lot of interest in shifting to looking at preoperative neoadjuvant, and adjuvant approaches and what we can do to improve disease-free survival and overall survival in patients who are able to undergo prior resection. So, Abstract 4013 looked specifically at the efficacy and safety of adjuvant hepatic arterial infusion chemotherapy with FOLFOX. And this was a randomized open-label phase 3 trial. It actually included a total of 315 patients between 5 different centers and patients were randomly assigned to receive either 1 to 2 cycles of adjuvant HAIC FOLFOX (Hepatic Arterial Infusion Chemotherapy FOLFOX) versus just follow up, the control group had no adjuvant treatment, and the primary endpoint was disease-free survival here and in the intention to treat population, there was a significantly improved median disease-free survival at 27 months versus 11 months in the patients who were on the control arm. And there was a protocol analysis, there were a number of other efficacy endpoints including disease-free survival rates at 1, 2, and 3 years. And everything kind of leaned towards and or suggested an improvement with the utility of HAI FOLFOX in patients who undergo complete resection. It should be noted that this included patients specifically who had microvascular invasion on their resection. And so, these are patients who are at higher risk for recurrence as we know. This to me suggests that there could be a role for adjuvant treatment in patients who undergo complete resection with microvascular invasion (MVI). HAI is a very specific technique and it requires a highly skilled center in the placement of HAI pumps. And we're seeing more and more trials across the U.S. as well investigating the role of HAI in advanced disease and in perioperative approaches. And so, I think this is an area of much-needed continued research. There are, of course, a number of ongoing adjuvant studies looking at immunotherapy in the adjuvant setting. And so, it'll be really important to see how those read out and then to try to put all of these in context so that we can better understand local therapy like HAI FOLFOX versus more systemic adjuvant approaches like immunotherapy. Dr. Shaalan Beg: Thank you very much, Dr. Shroff for sharing your valuable insights with us. I really appreciate you taking the time to spend with us and our listeners. Dr. Rachna Shroff: Thanks so much. I enjoyed it. Dr. Shaalan Beg: And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. Finally, we'd really like to hear your feedback. If you could please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much! Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Rachna Shroff: Consulting or Advisory Role: Exelixis, Merck, QED Therapeutics, Incyte, Astra Zeneca, Taiho Pharmaceutical, Boehringer Ingelheim, SERVIER, Genentech, Basilea Research Funding: Pieris Pharmaceuticals, Taiho Pharmaceutical, Merck, Exelixis, QED Therapeutics, Rafael Pharmaceuticals, Bristol-Myers Squibb, Bayer, Immunovaccine, Seagen, Novocure, Nucana, Loxo/Lilly, Faeth Therapeutics Disclaimer: 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.

university science food chinese abc os consulting sticking gi cart astrazeneca herb bayer hai abstract oncology merck m1 nk asco genentech drug administration fda bristol myers squibb adc hcc goyal her2 pfs boehringer ingelheim egfr kras hematology oncology ut southwestern cd4 tmb pd l1 shroff ild novel therapies asco annual meeting traes mvi seagen servier trastuzumab cholangiocarcinoma incyte fgfr medimmune folfox folfirinox t dxd merck serono transcript dr 5fu array biopharma disclosures dr qed therapeutics astrazeneca medimmune

The Time Toxicity of Cancer Treatment

The Cancer Pod: A Resource for Cancer Patients, Survivors, Caregivers & Everyone In Between.

Play Episode Listen Later Apr 21, 2022 12:59

Dr. Arjun Gupta, a GI medical oncologist at the University of Minnesota Masonic Cancer Center in Minneapolis, speaks with host Dr. John Sweetenham, associate director for Clinical Affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, about the concept of time toxicity in cancer treatment. Dr. Gupta proposes a measure of time toxicity and a framework for how it could be implemented in research and clinical practice. Transcript Dr. John Sweetenham: Hello, I'm John Sweetenham, the Associate Director for Clinical Affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News podcast. I'm delighted to welcome Dr. Arjun Gupta to the podcast today. He's an assistant professor and gastrointestinal medical oncologist at the University of Minnesota Masonic Cancer Center in Minneapolis. We'll be discussing the concept of time toxicity and its relevance for patients with cancer, especially those with advanced cancer who face treatment decisions in the context of limited time. Dr. Gupta will share his insights on how to measure time toxicity and discuss a framework for how it could be implemented in research and in clinical practice. My guest and I have no conflicts relating to our topic today. Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcasts. Dr. Gupta, it's great to have you on the podcast today. Dr. Arjun Gupta: I'm an avid listener of the podcast. It's a joy to be here. Dr. John Sweetenham: Thank you. It's a joy to have you on the podcast as well. We're particularly pleased to have you discuss this important topic that you and your co-authors addressed recently, in your commentary in the Journal of Clinical Oncology. Can you first explain the concept of time toxicity, particularly as it relates to cancer treatment? Dr. Arjun Gupta: Yes, we conceptualize time toxicity as the time spent in pursuing a treatment for cancer. Now, this includes time spent in coordinating treatments, in travel to treatments, in waiting rooms, in actually getting that treatment, in getting anticipated and unanticipated adverse events, follow up tests and rehabilitations, frequent visits to a health care facility, all of this time that a patient and their care partner are spending is what we think of as time toxicity. This concept of time toxicity is perhaps applicable to all patients but is perhaps most applicable to people with advanced solid tumors, who are facing treatment decisions in the context of limited time. And in some cases, the overall survival benefit, or the time benefit offered by treatment may actually be overtaken by the time spent in pursuing that treatment. So, that's how we came up with this concept of time toxicity. Dr. John Sweetenham: Thanks. In your article, you propose a measure of time toxicity provides a framework for how it could be implemented in research and in routine clinical practice. Can you tell us a little more about this? Dr. Arjun Gupta: The measure we describe and propose is days with physical health care system contact. This is the measure of time toxicity that we propose. So any day in which a patient has any contact with the health care system, whether that be for a 30-minute blood draw, whether that be for a 3-hour procedure, whether that be for a 6-hour chemotherapy infusion, a 12-hour visit to the urgent care center, or an overnight stay is treated the same. It's a day with physical health care system contact. And we recognize that not all of these are the same but for the patient and their care partner, these often represent that an entire day is lost. As a corollary, days not spent with health care contact are home days. So, in essence, your overall survival or the time from diagnosis to death is nothing but the sum total of time toxicity or days with health care system contact and home days. Now me and my mentors, Dr. Chris Booth, and Dr. Elizabeth Eisenhower spent a lot of time thinking about whether we should propose a metric at all, or wait for the science to be advanced even more. But there are a couple of reasons we decided to go forward and propose this metric. Even though there are some deficiencies that I'll come to. First of all, this metric recognizes that oncology care is delivered in multiple settings. It's delivered infrequent trips to the outpatient clinics and infusion centers, and patients often require inpatient admissions for rest and rehabilitation. My mentors, Dr. Chris Booth and Dr. Elizabeth Eisenhower, and I discussed long and hard whether we wanted to propose a metric or wait for the science of time toxicity to progress. Ultimately, we decided to propose this metric because it's practical and can easily be measured. It is patient-centered, which is perhaps the most important thing. And third, it recognizes that cancer care is delivered in multiple settings, both inpatient and outpatient. There are a couple of things that we need to keep in mind while thinking about this metric. The first is that people with cancer are often sick because of underlying cancer and cancer care and physical health care system contact by itself is not a bad thing. So, we need to separate the additional time imposed by a specific cancer treatment over and above the time toxicity of cancer itself, and we also need to keep in mind that this metric has some limitations in that decreased health care contact or decreased time toxicity could represent poor access to care and could widen disparities in health care access. Furthermore, care is increasingly being delivered in the home of patients. And while that may decrease time toxicity, and may be more comfortable for certain families, for unprepared families, this may be very burdensome. So, we recognize that this metric is not perfect but we hope that this can at least start conversations about time toxicity, to fulfill our ultimate goal for clinical trials to actually report time toxicity alongside more traditional endpoints. Dr. John Sweetenham: Yes, I think one of the things that really struck me from reading your commentary was the fact that of course, for a patient, a 1-hour or 30-minute trip to the laboratory for a blood draw can disrupt the whole day. And in many respects, that can be as disruptive as spending 12 hours in the emergency room from a family and caregiver perspective that really kind of sank home with me, I must say, having read the commentary. On that note, you know, could you give us some specific examples to show how time toxicity negatively impacts patients? Dr. Arjun Gupta: Yes, so for a couple of trials that we described in the paper, we demonstrated that the time toxicity associated with pursuing the treatment was actually more than the average survival benefit offered by the treatment. Now we have to keep in mind that traditionally, oncology clinical trials don't report time toxicity. So, this was my co-authors and myself getting together and getting a best-case scenario from clinical trial publications. But as an example, for people with advanced biliary tract cancers, or cholangiocarcinoma, in the second line, there was a recent trial that demonstrated that FOLFOX chemotherapy, on average, improved survival by 27 days. And we demonstrated through the trial level publication, that for the average patient who was getting the average number of chemotherapy doses, coming in for blood work, coming in for scans, coming in for oncology assessments, that for the average patient, the time toxicity was more than this 27-day benefit, it was 30 days. And so, this is a very clear example of a patient who potentially loses more time than what they gain. It's very important to recognize that patients may value these decisions differently, and we're not saying that this treatment is bad or should not be pursued. People have different values, and we should explore that, but the biggest issue right now is that oncologists don't have the data from clinical trials to even have these conversations with patients. Dr. John Sweetenham: Thanks. And so, I'll pick up on that point. Obviously, the literature is very full of studies that have looked at oncologists and their skills for wanting a better word at having the end-of-life discussions and goals of care discussions with their patients. Do you sense that there is or will be a reluctance on the part of oncologists to have these kinds of conversations about time toxicity for patients who may be nearing the end of their lives? Dr. Arjun Gupta: I don't think so at all. I will share that I've become much more humble since I've become an oncologist myself, and I've become less critical of oncologists. I think our jobs are incredibly difficult. And most, if not all, oncologists want to do the right thing and have these conversations. The 2 things that are missing right now are data. So, we just don't have the data, which is why we wrote this commentary as a call for clinical trials to report this. And the second is our own time toxicity or delay limitation of time in the clinic. A wise person recently said that the biggest technological advance in medicine will be more time with patients. So, I think we need more data on time toxicity and we need more time for ourselves with patients to have these conversations to help them reach the best decision for their own goals and values. Dr. John Sweetenham: Are there any other key takeaways that you would like to share with our listeners today? Dr. Arjun Gupta: I feel—yes. As the next steps, our team is looking at doing secondary analyses of completed clinical trials to show that using this metric of days with physical health care contact is feasible, even in the secondary analysis of clinical trials. While we advocate for this to be included prospectively in clinical trials. It's very important to note that in retrospective work, looking at time toxicity, we remember that the time toxicity of a treatment retrospectively represents not just the treatment itself, but the entire health care delivery system, and social determinants of health. So, we shouldn't get too far ahead of ourselves in interpreting treatments against each other. But that perhaps offers us an opportunity to look internally at ourselves and add our processes to see how we can improve. Lastly, there are several quality improvement initiatives going on to reduce time toxicity for patients, such as triage, and decreasing waiting room times, and we should perhaps advocate for and promote such work more broadly. Dr. John Sweetenham: Thanks so much, Dr. Gupta, for coming on to the podcast today and for sharing your thoughts on a subject, which I'm sure is going to be something that will provoke a lot of discussions and will make many of us think harder in the future. And we look forward to seeing your ongoing research in this area. Dr. Arjun Gupta: Thank you for this platform. Dr. John Sweetenham: Thank you to our listeners for your time today. If you're enjoying the content on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Arjun Gupta: None disclosed. Disclaimer: 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 or service organization activity or therapy should not be construed as an ASCO endorsement.

university journal treatments minneapolis associate director gi toxicity gupta oncology cancer treatment asco end of life care clinical oncology clinical affairs ut southwestern folfox arjun gupta transcript dr disclosures dr

Supplements 101: Folate

Play Episode Play 50 sec Highlight Listen Later Feb 16, 2022 27:16

In this episode, Tina and Leah cover what you need to know about folate, otherwise known as vitamin B9 or folic acid. What could be so important about folate that a whole episode is dedicated to it, you ask? Well, there are times when supplementation is needed and other times when it could be detrimental. Companies selling supplements aren't going to tell you the whole truth and nothing but the truth, but we will.Plus, there is a lot of misinformation out there on folate/folic acid, and who better to help clear the air? As always, their discussions are related to cancer treatments and aftercare, but there's plenty of general information to help non-cancer people understand folate better too. Links we mentioned on this episode and other cool stuff:Vitamin B9/Folate from The Nutrition Source, Harvard T. Chan School of Public Health Linus Pauling Institute Micronutrient Information Center: FolateFolic acid/Folate and Colorectal Cancer: The ParadoxThe Role of Niacin/Vitamin B3Absorption of folate (food) v. Folic acid v. 5-methyltetrahydrofolate (5-MTHF)The enzyme “glitch” (MTHFR) explained in plain languageDhremotherapy Inspired IV Decals for Chemotherapy on EtsyCheck out the video for our "Unofficial Theme Song," DNA by BTS.Support the show (https://www.buymeacoffee.com/thecancerpod)

dna cancer nutrition diet companies supplements bts sherman colon integrative chemotherapy naturopathic chemo colon cancer mthfr b9 folate folic methotrexate kaczor folfox

Adjuvant Therapy for Stage II Colon Cancer Guideline Update

ASCO Guidelines Podcast Series

Play Episode Listen Later Dec 22, 2021 17:42

An interview with Dr. Nancy Baxter from the University of Melbourne in Melbourne, Australia, and Dr. Jeffrey Meyerhardt from Dana-Farber Cancer Institute in Boston, MA, co-chairs on “Adjuvant Therapy for Stage II Colon Cancer: ASCO Guideline Update.” This guideline updates recommendations for adjuvant therapy for patients with resected stage II colon cancer. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines. TRANSCRIPT [MUSIC PLAYING] ANNOUNCER: 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, I'm interviewing Dr. Nancy Baxter from the University of Melbourne in Melbourne, Australia, and Dr. Jeffrey Meyerhardt from the Dana-Farber Cancer Institute in Boston, Massachusetts, co-chairs on adjuvant therapy for stage II colon cancer ASCO guideline update. Thank you for being here, Dr. Baxter and Dr. Meyerhardt. NANCY BAXTER: Thank you for having us. JEFFREY MEYERHARDT: Thanks. BRITTANY HARVEY: First, 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 full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Baxter, do you have any relevant disclosures that are directly related to this guideline topic? NANCY BAXTER: I don't, Brittany. BRITTANY HARVEY: Thank you. And Dr. Meyerhardt, do you have any relevant disclosures that are directly related to this guideline topic? JEFFREY MEYERHARDT: I don't, either. Thank you. BRITTANY HARVEY: Thank you, both. And getting into the content of this guideline, what prompted this guideline update, and what is the scope of this guideline? NANCY BAXTER: Well, it's been since 2004 that we've had a guideline that gives us advice about stage II colon cancer and the use of adjuvant therapy in this group of patients. And it's one where clinicians often have a lot of challenges in helping patients make decisions about what's best for them in terms of long-term survival from colon cancer. There have been changes in guidelines for stage III colon cancer. And so we thought it was timely to reevaluate our best practice recommendations for stage II colon cancer patients. JEFFREY MEYERHARDT: Yeah, I agree, Dr. Baxter. I think that this is one of the most challenging conversations that oncologists have with patients. Should they get chemotherapy? What type of chemotherapy? And as you know, there are a variety of higher risk features, of which we're able to sort of tease out a little better relatively, in terms of thinking about someone's stage II disease and trying to bring all that data together and provide some framework in the conversation for clinicians to have with patients. BRITTANY HARVEY: Great, thank you both for that background information. So then this guideline covers four clinical questions. And I'd like to review the recommendations for each question. So Dr. Baxter, starting with question 1, what does the guideline recommend for patients with resected stage II colon cancer regarding the benefit of fluoropyrimidine-based adjuvant chemotherapy versus surgery alone? NANCY BAXTER: So overall, what we did was we looked at the risk that individual patients with stage II colon cancer have. So for patients that are at low risk of recurrence-- and so those are patients with stage IIA or T3 tumors that have at least 12 sample lymph nodes in the surgical specimen and don't have any high-risk features, and I'll go over those with the later recommendations-- these patients do not need adjuvant chemotherapy. It should not be routinely offered to them because the harms may outweigh the benefits. And so the evidence of that, although the quality of the evidence was relatively low, there is quite a bit of evidence that, really, the benefits do not outweigh the risks in this particular group. That is different for patients that are at higher risk, though, within the stage II group. And so those are the patients with stage IIB or stage IIC colon cancer. So those are T4 lesions that either penetrate through the visceral peritoneum or invade surrounding organs. And in those patients, adjuvant chemotherapy may have more benefit. And so a discussion of the potential benefits and risks of harms associated with chemotherapy should be had with patients. And those are patients that should be offered adjuvant chemotherapy for their disease. Now, there's a group of patients with high-risk features-- so not the stage IIB or stage IIC-- but there's a group of patients within stage IIA. So these are patients that are T3 patients where there are high-risk features. And chemotherapy may be offered to these patients, based on their risk features. So I'll go over a little bit about what the high-risk features are that might make patients included in this group. So that is sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphatic invasion, poor or undifferentiated tumor grade, intestinal obstruction, tumor perforation, and grade BD3 tumor budding. That's more than, or equal to, 10 buds in the tumor. And so that's because these patients are at higher risk of recurrence, and the chemotherapy may be more beneficial in these patients because they have a higher baseline risk of recurrence. There were a few risk factors that it was really challenging to make any decision on. And that was specifically circulating DNA. We know that that's an area of great interest, but there really was not enough evidence of the predictive value of ctDNA when you're looking at adjuvant chemotherapy in this group to make a recommendation. We'd expect future versions of this guideline to have some recommendations about that. We do know that there is controversy around the timing of chemotherapy. So we didn't include reports on this for the guideline because we didn't have enough related to stage II colon cancer and the role of adjuvant therapy. But the trials have generally started patients on chemotherapy within six to seven weeks of surgery. And finally, all of this needs to be a part of shared decision-making. So particularly for patients at higher risk-- so stage 2A at higher risk-- it's important that this is discussed-- the risks and benefits of chemotherapy, and the possible benefits with respect to the risk of recurrence for these patients-- is discussed as part of the shared decision-making process to come to an ultimate decision about the use of chemotherapy. BRITTANY HARVEY: Understood. Thanks for detailing those recommendations stratified by risk and identifying what those high-risk features are. So then, additionally, Dr. Meyerhardt, is there a benefit of fluoropyrimidine-based adjuvant chemotherapy for patients with tumors that exhibit mismatch repair deficiency or microsatellite instability or patients with proficient mismatch repair, or microsatellite-stable, tumors? JEFFREY MEYERHARDT: Yeah, so this was a specific question that we also looked at. What we know is about 15% of stage II colon cancers have evidence of mismatch repair or microsatellite insufficiency. And data that was realized now several decades ago on several different papers-- one larger one published in The New England Journal by Dan Sargent-- showed that patients who have stage II disease who receive a fluoropyrimidine only seem to not benefit if they have microsat instability. And there was actually some evidence that they may actually have harm, or have a worse outcome. So it is not a routine recommendation to use a fluoropyrimidine-only treatment regimen in patients who have MSI-high or deficiency of mismatch repair in stage II disease. However, there are some qualifying statements that we reviewed and were important to think about in patients. So what we know is, again, some of those patients will have some high-risk features and particularly T4 tumors or some other high-risk features, except for poor differentiation, that the use of oxaliplatin may actually be a consideration in those patients. And that's basically from indirect evidence of a disease-free survival benefit with the addition of oxaliplatin in the population of patients with stage II disease that were included in the MOSAIC trial, one of the original trials that looked at the addition of oxaliplatin to a fluoropyrimidine as adjuvant therapy for colon cancer. We specifically carved out poor differentiate is not considered a high-risk prognostic feature in those patients. And so poorly differentiated tumors alone should not be a part of the decision in offering adjuvant therapy with a fluoropyrimidine or fluoropyrimidine-oxaliplatin for MSI-high or deficient mismatch repair protein tumors. And the other patients who have either proficient mismatch repair proteins or microsatellite instability are actually including the other parts of the guideline, so what Dr. Baxter just talked about and some of the other questions that we tackled that you'll be going to next. BRITTANY HARVEY: Great. Thank you for covering those recommendations for that particular patient population. So then, Dr. Baxter, if adjuvant therapy is recommended, is there a benefit to adding oxaliplatin to fluoropyrimidine-based chemotherapy? NANCY BAXTER: Well, this is obviously a question that oncologists will face when they're deciding to give adjuvant chemotherapy to high-risk stage II colon cancers or people with T4 stage IIB or C colon cancers. And you know, here's where it's challenging to make recommendations. Because we don't have a lot of evidence for this specific group. And this is why clinicians have such a challenge making recommendations for these patients. Because actually, there's insufficient evidence to routinely recommend the addition of oxaliplatin, meaning that we have to base our decisions on the best evidence that we have. And the best evidence we have, as we've talked about, is the MOSAIC trial. And so in the MOSAIC trial, a time to recurrence was longer with oxaliplatin-based adjuvant chemotherapy. And so it may be for some patients that the addition of oxaliplatin makes sense in terms of improving their overall outcome. And again, it needs to be a shared decision-making approach with the discussion of the potential benefits and risks of harms of the addition of oxaliplatin to fluoropyrimidine-based chemotherapy, so again, discussions between the oncologist and the patient. But that is with the exception of patients who are MSI-high. So those patients need oxaliplatin. If they're going to get chemotherapy, they shouldn't have 5FU-based chemotherapy alone, as we've just discussed. BRITTANY HARVEY: Great. And definitely, that shared decision-making is key. And I appreciate you reviewing the evidence behind these recommendations, as well. So then, the last clinical question addressed in this guideline, Dr. Meyerhardt, if adjuvant oxaliplatin-containing chemotherapy is considered, are outcomes affected by reducing the treatment duration from six months to three months? JEFFREY MEYERHARDT: Sure. So this was the last clinical question that the committee considered. And it is based on the IDEA collaboration. So the IDEA collaboration was the International Duration Evaluation of Adjuvant Chemotherapy. It was six trials that were done internationally-- one in the United States, one in Japan, and four in Europe-- that included patients both with stage II and stage III colon cancer. They receive three versus six months of therapy. Each of the trials had different chemotherapy choices in the sense that the United States trial, FOLFOX was the only choice that could be offered to patients, where in all the other trials, it was a physician and patient choice regarding the use of FOLFOX or capecitabine and oxaliplatin. And that, as people who know the data, is relevant to some of the discussion. And so the goal of the collaboration was to look at if we can give patients three months of therapy and not compromise outcome. And the main reason for that is we know that the peripheral neuropathy that's cumulative with oxaliplatin increases with more months of treatment. So patients who only receive three months of oxaliplatin have less likelihood of more significant cumulative neuropathy and will have less impact on function by receiving less oxaliplatin overall. Four of the trials included patients with stage II disease. And those trials, again, pooled their data and looked at the duration question in terms of for stage II patients. Those patients had high-risk disease, some high-risk feature, as discussed earlier. And what was shown is that for the patients, overall, there was not clear evidence of noninferiority with three versus six months. But when you looked at the patients who received capecitabine and oxaliplatin, the absolute five-year disease-free survival was 81.7% versus 82% for three versus six months of CAPOX, so essentially the same, with a hazard ratio of 1.02, and the confidence interval spanned across 1. And so those really didn't look like there was any compromise in outcome for patients to receive CAPOX for three months versus six months. For those patients who received FOLFOX, three months of chemotherapy led to a five-year disease-free survival of 79.2% versus 86.5% if you received six months of FOLFOX with a hazard ratio 1.41. So again, those data would suggest that if one was to choose FOLFOX, giving six months of therapy for high-risk stage II patients may be preferable to not potentially compromise some benefit in terms of disease-free survival. So again, the overall conclusion was it's a discussion with a patient regarding choice of therapy, whether receiving capecitabine, oxaliplatin or FOLFOX and then, based on that, consideration of the duration where we were most comfortable saying that three months of capecitabine, oxaliplatin is sufficient for high-risk patients when appropriate discussion between the clinician and the patient. BRITTANY HARVEY: Great. Thank you for explaining the nuance of that trial and your recommendation. So finally, to wrap us up, in your view, how does this guideline impact both clinicians and patients? JEFFREY MEYERHARDT: Yeah, so again, the last time ASCO had addressed guidelines for stage II patients was over 15 years ago. And there are more data. It was really early in the days of understanding the incorporation of oxaliplatin. There was no data versus the three versus six months. And there were less analyses trying to look at some of those particular high-risk features. So these are all important considerations in those discussions with stage II patients. And the importance of the guidelines are really to provide that framework on the various things you think about when you have a stage II patient and how to have those shared decision-making discussions with the patient. Again, it's not, probably, appropriate for all patients to receive adjuvant therapy, particularly lower risk. And even for higher risk patients, it is weighing the plus or minuses of the potential toxicities with what we know potentially are benefits. NANCY BAXTER: Yeah, I think that's very true. And I think, as anyone who treats colon cancer, or stage II colon cancer patients, is aware, this is not a homogeneous population. So in terms of the outcomes, there are people that do extremely well with surgery alone and people who, unfortunately, recur even after chemotherapy and surgery. And the future needs to focus on being able to differentiate those patients most likely to benefit from chemotherapy from those that are not likely to benefit. What we found in reviewing the evidence is we've moved forward from 2004, but we still have a long way to go. So I really hope when the next guideline is written that we're much closer to being able to identify those patients who would most benefit from chemotherapy in this group. Because we know there are patients who benefit from chemotherapy in this group. It's just we're still not perfect at identifying those people. So again, these conversations with patients are so important to talk about the limits of our knowledge, which I think is another important thing of this guideline is establishing what the limits of our knowledge are. But I think there are patients that you can confidently not give chemotherapy to. And that's very reassuring, both to clinician and to patients. And then this guideline kind of outlines the limits of our knowledge. And that's also important for clinicians and patients to understand. BRITTANY HARVEY: Definitely. I appreciate you both highlighting the importance of shared decision-making throughout this conversation that we've had. So I want to thank you so much for your work on this important guideline update and for taking the time to speak with me today, Dr. Baxter and Dr. Meyerhardt. NANCY BAXTER: Thank you very much. JEFFREY MEYERHARDT: Thank you. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. 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 iTunes 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. [MUSIC PLAYING]

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#88 IDEA - Duração da QT adjuvante para pacientes com CCR (estadio III): resultados finais.

Play Episode Listen Later Sep 21, 2021 33:18

A Colaboração IDEA é a união de dados de 6 estudos prospectivos que fizeram a mesma pergunta no sentido de investigar a sobrevida livre de doença em relação à não inferioridade de 3 versus 6 meses de quimioterapia adjuvante para pacientes com câncer de cólon estadio III.Os pacientes foram recrutados de julho de 2007 a dezembro, 2015, em 12 países (CALGB / SWOG 80702, IDEA, SCOT, ACHIEVE, TOSCA e HORG). Todos os ensaios clínicos foram randomizados para 3 ou 6 meses de adjuvância com fluorouracil, leucovorin e oxaliplatina (FOLFOX) a cada 2 semanas ou capecitabina e oxaliplatina (CAPOX) a cada 3 semanas, a critério do médico assistente.Saiba sobre esse incrível paper com os Doutores Ranyell Spencer, Thiago Biachi e Allan Pereira, além de tirar suas dúvidas sobre estudos de não-inferioridade.Sejam bem-vindos ao episódio 88 do Clinical Papers PodcastPara saber mais sobre o paper, acesse: https://pubmed.ncbi.nlm.nih.gov/33271092/

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#85 – PRODIGE 23 – FOLFIRINOX associado a RT neoadjuvante para pacientes com câncer de reto localmente avançado

ASCO eLearning Weekly Podcasts

Play Episode Listen Later Jul 31, 2021 33:31

Publicado agora em abril de 2021, o PRODIGE 23 traz em seu resumo a conclusão de que, esse esquema de quimioterapia neoadjuvante deve mudar a prática clínica. Mas, como diz o Mário Sérgio Cortella: Será?!?!Ouça esse episódio 85 do Clinical Papers Podcast e descubra que a adição de irinotecano ao TNT com FOLFOX pode ser “demais” para melhorar os resultados relacionados ao tratamento de câncer de reto localmente avançado.Com uma revisão !TOP! sobre o tratamento de câncer de reto, os drs. Ranyell Spencer, Tiago Biachi e Allan Pereira mostram o que está nas entrelinhas desse importante estudo.Sejam bem-vindos ao episódio 85 do Clinical Papers PodcastPara saber mais sobre o paper, acesse: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00079-6/fulltext

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Young-onset Colorectal Cancer

Play Episode Listen Later Jul 28, 2021 21:47

The incidence of colorectal cancer among people under 50 is rising. In this ASCO Education podcast episode, medical oncologist Nilofer Azad (Johns Hopkins Medicine) and epidemiologist Caitlin Murphy (UT Southwestern Medical Center) discuss risk factors, screening, and treatment. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: elearning.asco.org | Contact Us Air Date: 7/28/2021 TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. NILO AZAD: Welcome to the ASCO learning podcast episode focusing on early-onset colorectal cancer. My name is Dr. Nilo Azad, and I'm a medical oncologist and Associate Professor of Oncology at Johns Hopkins Medicine. I'm joined today by Caitlin Murphy, an Assistant Professor of Epidemiology at the University of Texas Southwestern Medical Center. We wanted to start today with a patient case, just to give a little bit of context about the kinds of patients that we are dealing with. A year ago, a patient presented to my clinic who was 32 years old. She was having significant symptoms of rectal obstruction. She was having trouble going to the bathroom. Her bowel movements were difficult. She was having bloody stools, and she had gone to see a gastroenterologist who had done a colonoscopy, biopsied her tumor, and found that she had adenocarcinoma of the rectum. Now, luckily, at that time, she didn't have any metastatic disease. But her tumor was quite large, 15 centimeters in size, and so we decided to move forward with doing chemotherapy in the neoadjuvant setting. She got aggressive chemotherapy with FOLFOX for three months. And when we did a scan, unfortunately, we found that the tumor had grown. Now, she still didn't have any disease outside of the rectum but, during that time, we had gotten some molecular testing back which showed that the patient had mismatch repair deficiency or microsatellite insufficiency. So we decided to try something a little outside of the box at that time, where we started treatment with immunotherapy. She had a dramatic response to immunotherapy. Her tumor shrank. And, six months later, she went to surgery and, though on scan it still looked like she had a large tumor, it turned out that that tumor was only scar and that she'd had a complete response. She came back to see me, last week, in clinic. She looks fantastic, and she's moving forward with planning for a family with her husband. So, Dr. Murphy, can you tell us a little bit about the trends in early-onset colorectal cancer incidence in the US and globally? CAITLIN MURPHY: Of course. I'll start, first, by talking about trends in early-onset colorectal cancer in the United States. Incidence rates began increasing here in the early 1990s and have nearly doubled over time, from about eight cases per 100,000 persons in the early 1990s to 16 per 100,000 persons in today. The largest increases have occurred in 40 to 49-year-olds. They account for about 80% of all cases. And we've also noticed that incidence rates of rectal cancer versus rates of proximal colon or distal colon cancers have been the largest increases in incidence. We've also seen a similar increase in local and distant stage disease. And, to me, one of the most compelling observations that we've made is that incidence rates have increased successively across generations, or about the year that you were born. There's a very clear and marked increase in incidence rates starting with persons born in and around 1960, or who we sometimes call Generation X. Epidemiologist like to call this a birth cohort effect because essentially we see incidence rates increasing across birth cohorts. More recently, we've observed that incidence rates have started actually increasing in people in the early 50s, the 50 to 54 age group, and this really does not appear to be driven by early stage disease as we might expect with more screening in that age group. But perhaps the increase in this early 50s age group is driven by the same things happening in people under the age of 50. Globally, we've seen a similar increase occurring in countries that have colorectal cancer screening and even in countries that don't have colorectal cancer screening. There was a recent analysis of 36 countries, and it found that incidence rates have increased in 19 of those 36 countries. Nine of those countries had stable or declining trends in incidence in older adults. There really wasn't a clear pattern among those countries in terms of the degree of Westernization or income level that might explain those trends. And, importantly, that birth cohort effect that I mentioned as occurring in the United States, where we see increasing incidence rates starting with Generation X, has also been reported in many other countries, including Canada, Australia, and some East Asian countries. NILO AZAD: And, Dr. Murphy, what is the current thinking regarding causes of this increased incidence of colorectal cancer that we're seeing in young people? CAITLIN MURPHY: Generally, there are two schools of thought about what's going on here. The first thought is that this is the same disease that's happening in older adults, but it's just now occurring at a younger age. For example, we've seen a steady rise in factors that we know increase the risk of colorectal cancer in older adults, like obesity and diabetes. And, these factors, we also know are now increasingly occurring at a younger age. But many of my clinical colleagues like you, Dr. Azad, tell me that most of the patients they diagnosed with early-onset colorectal cancer are otherwise fit and healthy and have no obvious risk factors like those. And so this second school of thought about what might be going on here is that this is really a different disease than what's happening in older adults, driven by as of yet unknown risk factors that have also increased in the population. NILO AZAD: Yes, I definitely feel like that the cohort of patients that I see in my clinic-- and, of course, at a place like Johns Hopkins, we see a little bit more of a skewed cohort in terms of seeing more younger patients-- that most of them aren't people that I would traditionally look at and say that they've got a risk factor that explains the situation. What are the main risk factors for early-onset colorectal cancer? CAITLIN MURPHY: There's still a lot of research to be done in understanding what the risk factors for this disease are. And I like to think of the risk factors that we know about as affecting early-onset colorectal cancer as falling into one of four sort of categories. The first category is having a genetic predisposition, so either having a family history of colorectal cancer or even a family history of an advanced adenoma or having a hereditary syndrome like Lynch syndrome or polyposis. Together, these account for about 40% of all new cases and many of the cases that don't have a traditional phenotype or mutations associated with colorectal cancer. So, for example, many of the patients we see with Lynch syndrome don't necessarily have the typical phenotype that we've expected to be associated with Lynch syndrome over the past however many years. The second category is what I like to call established risk factors. Or maybe another way to think about this is usual suspects, so already known causes of colorectal cancer in older adults. I mentioned these earlier, obesity, diabetes, but then there's also smoking, physical activity, and sedentary behavior. Then the third category is what I call early life factors, and the importance of understanding early life factors is really driven by the fact that incidence rates have increased by generations. Remember that first cohort effect I was describing to you earlier. This birth cohort effect tells us that risk factors in very early periods of life or vulnerable periods of growth and development are important. It also tells us that we should rethink some of those usual suspects or established risk factors as occurring very early in life. For example, instead of just thinking about obesity, thinking instead about birth weight or childhood obesity as well as growth trajectories in infancy. And then, finally, the fourth category is unknown risk factors. So the trends in incidence point to some clues, whether things in the population have increased over time or by generation, that might help us understand what's going on here. Some examples of those unknown risk factors might include environmental chemicals like flame retardants or endocrine disruptors, antimicrobials, or other infectious agents. And there really has been no research on these unknown risk factors but, again, people think that these might be related to early-onset colorectal cancer just because the trends in their prevalence have mirrored the trends in incidence. NILO AZAD: So, Dr. Murphy, you've really laid out wonderfully both the risk factors that we're seeing in some of these younger patients and then just the changes in incidence and occurrence as well. So how has that affected screening guidelines, going forward, as well? CAITLIN MURPHY: In 2018, the American Cancer Society recommended lowering the age to initiate average risk colorectal cancer screening from starting at age 50 to age 45. At the time, when this was done, all of the GI societies and the United States Preventive Services Task Force recommended still continuing at age 50. This recommendation from the American Cancer Society was a qualified recommendation, meaning that it's based on simulation modeling and not necessarily empirical evidence driven from randomized trials or other clinical studies. More recently, just last fall, in 2020, the United States Preventive Services Task Force released a draft recommendation to do the exact same thing, so lowering the screening age for average risk people from 50 to 45. The idea of a draft recommendation simply means that they put the recommendation out there for public comment and then consider some of those comments before either revising that recommendation or making the recommendation official. Like the qualified recommendation, initiating average risk screening at age 45 has a grade B recommendation from the task force, meaning that they have fair compared to strong evidence to support that recommendation. And I expect that we'll be seeing a final one coming this spring or summer. NILO AZAD: Is there anything unique about colorectal cancer in young patients biologically? CAITLIN MURPHY: That's a good question and something we still don't know a lot about. I'll just give one example of that. We know from certain studies that early-onset colorectal cancer seems to be enriched for certain molecular subtypes like an immune subtype, although the research in this area is really limited by a small number of studies. And most of the studies have been conducted just as a single center and not at the population level. NILO AZAD: And how do our patients that are younger do in terms of survival, compared to their older cohorts? CAITLIN MURPHY: Most studies that have looked at this report no difference in survival between younger and older patients with colorectal cancer. We do know, however, that younger patients are more likely to be treated aggressively with surgery, multimodality chemotherapy, and/or radiation therapy. This really raises an important question. If younger patients have no survival advantage despite more aggressive treatment, this could mean that younger patients have tumors that are more aggressive or that they respond differently to treatment regimens that have been developed for older patients with colorectal cancer or risk disease are over treated. With that in mind, I want to revisit our patient case, the 32-year-old woman with rectal cancer. Dr. Azad, what should be discussed with a young patient before starting therapy? What kind of testing needs to be done? NILO AZAD: So when we have young-onset colorectal cancer, just as you mentioned, there are a subset of these patients that have a genetic predisposition to developing colorectal cancer and other tumors as well. And so these patients absolutely need to be assessed for these genetic syndromes. So for my patient, in particular, I mentioned that she had mismatch repair deficiency or microsatellite instability. That suggests that she had what was called Lynch syndrome. And Lynch syndrome is something that, now, luckily, we actually have therapies for in terms of having immunotherapy. But knowing about that kind of a syndrome is important for this patient for her future planning, for the other tumors that she might develop, and of course for counseling for the rest of her family as well. And what was actually interesting about this case was that she had traditional mismatch repair testing with immunohistochemistry of her tumor, and that testing came back that she had microsatellite stable disease. So initially we actually didn't think that she had microsatellite instability. But because her family history was such that I was still suspicious that this was true, we sent second testing using a different kind of assay, and that's where it became clear that she had mismatch repair deficiency. So it's really important to maintain a high index of suspicion and recognize that even some of the tests that we send are not perfect and, if you still have a high index of suspicion for reasons like the family history or a patient having a second cancer previously, that you should follow that instinct and make sure that you're doing as deep testing as necessary. The other issue, of course, with younger-onset colorectal cancer, especially for people as young as my patient was, is the question of fertility. And so because she had rectal cancer and, as part of the paradigm for rectal cancer, these patients will have radiation, she was not going to be able to carry a fetus or embryo to term after completing therapy. So that's something that we need to understand early, have those conversations early, and get a multidisciplinary team involved that usually involves fertility experts as well as gynecologists. And so, for her, what we ended up doing was doing an egg harvest. And then she had in vitro fertilization performed, and then they were able to store embryos for her and her husband. And now they're actually looking forward to moving forward with surrogacy. CAITLIN MURPHY: So it sounds like your patient had to navigate a lot at the beginning of her diagnosis, considering fertility options, grappling with a new diagnosis at the age of 32, and then going through all of the workup and diagnostic testing. After that, what kind of treatment options would be appropriate for her? NILO AZAD: So, at this point, we actually aren't treating early-onset colorectal cancer any differently, in terms of how we actually treat the cancer, compared to people who develop colorectal cancer at a more average age. That said, our patients do have specific needs that we need to incorporate and discuss, both when they're diagnosed and as they start treatment and then later as they complete treatment and for their survivorship. So, clearly, we talked about the fertility issues. But when you've got a patient who's in their 30s or 40s and they're undergoing chemotherapy that's going to leave them with potentially lifelong neuropathy as one of the long-term side effects, that's really something that we need to discuss with patients, both so that they know about it, but what impact could that have on their professional function. For example, this week, I saw a 40-year-old woman who is newly diagnosed, and she is actually a concert musician. And so the idea that this may actually result in meaningful disability for her for what her chosen profession is, it's something that we need to discuss with these patients because they likely have 20 or 30 more years of professional life that is ahead of them and makes a huge difference for them, and financially as well. And, on that front, when you are treating people who are kind of in the prime of their life when it comes to their earning potential, that's also a really big issue that needs to be discussed. Sometimes people, in fact, lose their jobs because of the amount of time that they have to take off for treatment during that time. And so working with social work and making sure that we are addressing these issues and not just focusing on the things that are physical is really important. I'm a believer that impact on sexuality and body impact is not something that is only for the young. But, clearly, that's something that we need to discuss for all ages of patients when it comes to the kind of therapies that we have, especially with rectal cancer where, a lot of times, patients are left with a temporary or permanent colostomy. And I also think that there is some real issues around feeling isolated from your peers. It's still very rare to develop colorectal cancer, or any cancer, below the age of 50. And so because of that, even though we are seeing an increase in incidence, a lot of times, this is an area where patients can really have significant mental anguish because they feel so isolated from their peers that aren't having to deal with these issues. So I think all of these are really important features of dealing with early-onset colorectal cancer. CAITLIN MURPHY: I think you said it exactly right, that these patients are in the prime of their life and not necessarily just navigating cancer treatment-related factors, but also having to deal with family and care-giving responsibilities, their job, their economic situation, and their social situation. If all other disease factors and patient characteristics were similar, though, but the patient that you talked about was older, let's say, aged 55, would you do anything different in terms of her care? NILO AZAD: So, you know, with that particular patient, we were trying very hard to see if we could find a way that she might not have to have radiation because we knew that radiation was going to take away her fertility. And so when she had that initial progression on chemotherapy, what we did was a little bit out of the box, at that point, using data that existed in the metastatic setting showing that immune checkpoint therapy was very effective in patients with mismatch repair deficiency and treating a patient that didn't have metastatic disease, hoping for an excellent response, which is what we got. Now, fortunately or unfortunately, while she had a fantastic response, because the tumor didn't regressed completely and left her with that scar tissue, she did end up getting radiation because we couldn't be confident that we had gotten a complete response with just the immunotherapy. But I do think that, with younger onset colorectal cancer, what often happens is that we dance a little outside of the box in terms of trying to do things that would help preserve patients' fertility or preserve some of their overall function that might be a little bit different than what we might do for people 20 or 30 years older. I think that, in the right circumstance, that can be the right thing for our patient. But it is something that you have to do very carefully because, as you mentioned, it may well be that sometimes our younger patients are being treated more aggressively than they need to be just because they come in, and they have less comorbid conditions. And people feel comfortable being more aggressive when they might not need it. CAITLIN MURPHY: This is a really great conversation. And, as an epidemiologist, I often get lost in the numbers and forget about the real impact that this disease has on patients. And so I really appreciated learning about the patient case. NILO AZAD: Thank you, Dr. Murphy, for joining us as well. I think that this is such a great way for us to put some of those really objective data together in terms of what we're seeing with more patients that are developing young-onset colorectal cancer; what groups that we're seeing that in, both in terms of ethnic groups and risk factors; and then combine it with some of the key features that are important in terms of patient care, which I would say means that all patients should be getting genetic testing, all patients should be treated aggressively, and that there are many both physical and psychosocial factors that we need to be taking into account when we're treating our young-onset colorectal cancer patient. So thank you so much for your time. I've really enjoyed talking about this with you. [MUSIC PLAYING] SPEAKER: Thank you for listening to this week's episode of the ASCO eLearning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive eLearning Center at elearning.asco.org.

A Landmark Trial (without an FDA approval)

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Play Episode Listen Later Apr 29, 2021 13:24

An abbreviated edition of our Landmarks in #OncoPharm series returns to discuss weekly cisplatin + radiotherapy for locally advanced cervical cancer. As a bonus, we cover a new study establishing FOLFOX as the standard-of-care for 2nd line treatment of metastatic biliary cancer. All of this is discussed against the backdrop of the relative importance (or lack thereof?) of obtaining an approved indication.

Episode Five: The Breaking News

Life with Lindy

Play Episode Play 17 sec Highlight Listen Later Apr 21, 2021 7:20

Lindy takes a break from the cancer story timeline to talk about the current breaking news: an early chemo bell ringing followed by emergency gall bladder removal surgery. Lindy explains why she stopped chemotherapy two rounds early and why she had her gall bladder removed two days later. Lindy was diagnosed with stage 3 rectal cancer in May 2020 during the pandemic.

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Episode 143: Administer FOLFOX Chemotherapy Regimens With Confidence

The Oncology Nursing Podcast

Play Episode Listen Later Feb 19, 2021 34:01

ONS member Jennifer Turcotte, RN, BSN, OCN®, clinic manager at New England Cancer Specialists in Scarborough, ME, and member of the Southern Maine ONS Chapter, joins Stephanie Jardine, BSN, RN, oncology clinical specialist at ONS, to discuss safety considerations and what nurses need to know when administering FOLFOX chemotherapy regimens. Music Credit: "Fireflies and Stardust" by Kevin MacLeod Licensed under Creative Commons by Attribution 3.0 Earn 0.5 contact hours of nursing continuing professional development (NCPD) by listening to the full recording and completing an evaluation at myoutcomes.ons.org by February 19, 2023. The planners and faculty for this episode have no conflicts to disclose, and the episode has no commercial support. ONS is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center's Commission on Accreditation. Episode Notes Check out these resources from today's episodes: Complete this evaluation for free NCPD. ONS Voice article: Outpatient Oncology Drug Series: Confidently Administer 5-Fluorouracil ONS Voice article: Outpatient Oncology Drug Series: Don't Forget Leucovorin Calcium, the Superhero Sidekick ONS Voice article: For Oxaliplatin Hypersensitivity Reactions, Prevention Is the Best Strategy, but Here's How to Manage Them ONS Voice article: Outpatient Oncology Drug Series: Oxaliplatin Hates the Cold ONS Voice article: What It Takes to Be an Infusion Room Nurse: Part One ONS Voice article: What It Takes to Be an Infusion Room Nurse: Part Two ONS/ONCC Chemotherapy Immunotherapy Certificate Course ONS course: Fundamentals of Chemotherapy Immunotherapy Administration ONS course: Safe Handling Basics, which is free NCPD for ONS members ASCO/ONS Chemotherapy Administration Safety Standards com National Comprehensive Cancer Center guidelines involving FOLFOX

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ESMO 2020: Late-breaking and practice-changing studies on COVID-19 and breast, lung, gastrointestinal, and other cancers

Caris Molecular Minute Podcast Series

Play Episode Listen Later Oct 1, 2020 59:19

There were a number of practice-changing and ground-breaking studies presented at the ESMO 2020 Virtual Congress, according to our guest in this episode. Alan P. Lyss, MD, subprincipal investigator for Heartland Cancer Research NCORP, joined host David H. Henry, MD, to review highlights from ESMO 2020. The pair discussed studies on gynecologic, breast, lung, gastrointestinal, and genitourinary cancers, as well as studies of anemia and COVID-19 in cancer patients. COVID-19 and cancer LBA77: Anti-SARS-CoV-2 antibody response in patients with cancer and oncology healthcare workers: A multicenter, prospective study. https://bit.ly/3cNNkar This study suggests SARS-CoV-2-specific IgG antibody response is not different between cancer patients (n = 61) and subjects without cancer (n = 105). Overall, 83.8% of subjects were IgG-positive, and there was no significant difference in IgG positivity between the cancer patients and the health care workers (P = .39). LBA83: Outcomes of the 2019 novel coronavirus in patients with or without a history of cancer: A multi-centre North London experience. https://bit.ly/2EJMpv4 This study suggests COVID-19 patients with a history of cancer may have a similar risk of death as COVID patients without a history of cancer, with exceptions. The odds ratio for mortality, comparing the cancer patients (n = 30) to the non-cancer patients (n = 90), was 1.05. The odds ratio for mortality was 4.05 for cancer patients who had received systemic therapy in the prior 28 days. Lung cancer: Radiotherapy LBA3_PR: An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement: Primary end-point analysis of LungART (IFCT-0503, UK NCRI, SAKK) NCT00410683. https://bit.ly/3jtojUo This study enrolled 501 patients with completely resected NSCLC and mediastinal N2 involvement, and they were randomized to PORT or no PORT. There was no significant between-arm difference in disease-free survival (DFS) or overall survival (OS). The 3-year DFS rate was 47.1% with PORT and 43.8% with no PORT. The 3-year OS rate was 66.5% and 68.5%, respectively. These results suggest conformal PORT should not be standard care in all completely resected N2 NSCLC patients, according to Dr. Lyss. “This may have been the most obviously and immediately practice-changing study among those I heard presented,” he said. Endometrial cancer LBA28: A randomised double-blind placebo-controlled phase II trial of palbociclib combined with letrozole (L) in patients (pts) with oestrogen receptor-positive (ER+) advanced/recurrent endometrial cancer (EC): NSGO-PALEO / ENGOT-EN3 trial. https://bit.ly/2SanTX1 This study enrolled 77 patients with ER+ advanced or recurrent endometrial cancer, and they were randomized to palbociclib plus letrozole or placebo plus letrozole. The median progression-free survival (PFS) was 8.3 months in the palbociclib arm and 3 months in the control arm. Dr. Lyss called this a “small” but “important” study. He and Dr. Henry agreed that a confirmatory study is needed. Breast cancer LBA5_PR: Abemaciclib in high risk early breast cancer. https://bit.ly/3igxbvw This trial enrolled 5,637 women with hormone receptor-positive, HER2/neu oncogene-negative, early breast cancer. They were randomized to receive standard endocrine therapy (ET) alone or standard ET with abemaciclib. The 2-year invasive DFS rate was 92.2% with abemaciclib and 88.7% with ET alone (hazard ratio, 0.747; P = .0096). Dr. Lyss said these data suggest abemaciclib could have “the potential to save many thousands of lives.” However, he noted that 16% of patients discontinued abemaciclib prematurely due to adverse events, and more than 300 of the 463 patients who stopped abemaciclib also stopped ET – a “disaster,” according to Dr. Lyss. LBA12: PALLAS: A randomized phase III trial of adjuvant palbociclib with endocrine therapy versus endocrine therapy alone for HR+/HER2- early breast cancer. https://bit.ly/2GbuluE This trial enrolled 5,760 patients with hormone receptor-positive/HER2-negative early stage breast cancer. They were randomized to palbociclib plus ET or ET alone. Results from this trial run counter to results from the abemaciclib trial, in that adding palbociclib to ET did not improve invasive DFS. The 3-year invasive DFS rate was 88.2% in the palbociclib arm and 88.5% in the ET-alone arm (HR, 0.93). Dr. Lyss said he can see no explanation for the different results with abemaciclib and palbociclib, but longer follow-up and analyses of biospecimens may shed some light. LBA17: ASCENT: A randomized phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). https://bit.ly/3ilHwGd The study enrolled 529 patients with relapsed/refractory metastatic TNBC. They were randomized to SG or single-agent physician’s choice of therapy (capecitabine, eribulin, vinorelbine, or gemcitabine). SG outperformed physician's choice. The median PFS was 5.6 months with SG and 1.7 months with physician’s choice. The median OS was 12.1 months and 6.7 months, respectively. LBA16: IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. https://bit.ly/33fYYb7 This trial enrolled 902 patients with locally advanced or metastatic TNBC. They were randomized to first-line nab-paclitaxel plus placebo or nab-paclitaxel plus atezolizumab. The median OS was 21 months in the atezolizumab arm and 18.7 months in the control arm (HR, 0.87, P = .0770). The 3-year OS in PD-L1-positive patients was 36% and 22%, respectively. “I think anybody would choose the combination with atezolizumab with a difference like that,” Dr. Lyss said. LBA15: Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC). https://bit.ly/36iEoIS This trial enrolled 651 patients with locally advanced or metastatic TNBC. They were randomized to first-line paclitaxel plus placebo or paclitaxel plus atezolizumab. Dr. Lyss noted that, unlike IMpassion130, the results of IMpassion131 were “completely negative.” In the PD-L1-positive population, the median PFS was 5.7 months in the placebo arm and 6.0 months in the atezolizumab arm (HR, 0.82; P = .20). In the overall population, the median PFS was 5.6 months and 5.7 months, respectively (HR, 0.86). It’s unclear why results from IMpassion130 and IMpassion131 differ, Dr. Henry noted. Steroid use, study design, or chance might all play a role, according to a discussant at ESMO. Urothelial cancer LBA24: TROPHY-U-01 cohort 1 final results: A phase II study of sacituzumab govitecan (SG) in metastatic urothelial cancer (mUC) that has progressed after platinum (PLT) and checkpoint inhibitors (CPI). https://bit.ly/3kYvq7R This study enrolled 113 patients with unresectable locally advanced or metastatic urothelial cancer. All patients received SG. The overall response rate was 27% in the overall population and 25% in patients with liver metastasis. The median PFS was 5.4 months, and the median OS was 10.5 months. Dr. Henry said the response and survival data were “rather impressive,” and Dr. Lyss noted that biomarker studies might allow for better selection of patients who should receive SG. Gastrointestinal cancer LBA6_PR: Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): First results of the CheckMate 649 study. https://bit.ly/2GcOroj This study enrolled 1,581 patients with GC, GEJC, or EAC, and 60% of patients were PD-L1-positive with a combined positive score (CPS) of at least 5. Patients were randomized to first-line treatment with nivolumab plus chemotherapy or chemotherapy alone (XELOX or FOLFOX). In patients with PD-L1 CPS ≥ 5, the median OS was 14.4 months in the nivolumab arm and 11.1 months in the chemotherapy arm (HR, 0.71; P < .0001). The median PFS was 7.7 months and 6.2 months, respectively (HR, 0.68; P < .0001). Dr. Lyss noted that using checkpoint inhibitors in the frontline or even adjuvant setting appears beneficial in this patient population, as demonstrated by additional trials presented at ESMO 2020: LBA7_PR (https://bit.ly/2GfXW65) LBA8_PR (https://bit.ly/3kYokQM) LBA9_PR (https://bit.ly/3ikBaaa). Lung cancer: Checkpoint inhibitors Dr. Henry briefly discussed three abstracts on checkpoint inhibitors in NSCLC — LBA51, LBA52, and LBA53. LBA51: KEYNOTE-024 5-year OS update: First-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%. https://bit.ly/2ELdNsE The 5-year OS rate was 31.9% with pembrolizumab and 16.3% with chemotherapy (HR, 0.62). LBA52: EMPOWER-Lung 1: Phase III first-line (1L) cemiplimab monotherapy vs platinum-doublet chemotherapy (chemo) in advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. https://bit.ly/3jjSiy9 The median OS was 22.1 months in the cemiplimab arm and 14.3 months in the chemotherapy arm (P = .002). LBA53: Precision immuno-oncology for advanced non-small cell lung cancer (NSCLC) patients (pts) treated with PD1/L1 immune checkpoint inhibitors (ICIs): A first analysis of the PIONeeR study. https://bit.ly/2GbjhO0 This study revealed biomarkers that might help guide treatment with immune checkpoint inhibitors. Renal cell carcinoma 696O_PR: Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: First results from the randomized phase III CheckMate 9ER trial. https://bit.ly/30lEMmg This study enrolled 651 patients with previously untreated metastatic renal cancer. They were randomized to cabozantinib plus nivolumab or sunitinib. The median PFS was 16.6 months with the combination and 8.3 months with sunitinib. The median OS was improved with the combination as well (HR, 0.61). Dr. Lyss said these results support the use of nivolumab plus cabozantinib in this patient population. However, he also expressed reservations related to tolerability, quality of life, eligibility criteria, and short follow-up. Anemia 1822P: Impact of iron-deficiency management on quality of life in cancer patients: A prospective cohort study (CAMARA study). https://bit.ly/2Sf1TdE This study enrolled 248 patients with solid tumors, including 74.5% with absolute iron deficiency (transferrin saturation coefficient < 20%) and 191 with anemia. Patients were treated with intravenous iron, and their quality of life (FACT-An scores) improved significantly between study enrollment and each assessment. Dr. Henry said the take-home message is that clinicians shouldn’t miss anemia or iron deficiency, and they shouldn’t transfuse patients automatically but, instead, consider iron supplementation. Disclosures: Dr. Henry has no financial disclosures relevant to this episode. Dr. Lyss writes a column for MDedge Hematology/Oncology called Clinical Insights. He has no other conflicts of interest. * * * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd

covid-19 practice er cancer patients md os studies pac port results primary pioneer steroids breast sars cov cpi lung interact oncology dfs north london gc checkpoint cps checkmate sg camara tps anemia renal gastrointestinal hematology igg phase iii david h tpc her2 pfs 1l n2 nsclc eac endometrial plt pd l1 esmo lyss tnbc muc clinical insights folfox disclosures dr mdedge podcasts mdedge hematology oncology

Interview with Dr. Michael Korn: MI FOLFOXai™

Play Episode Listen Later Aug 19, 2020 20:22

Caris Precision Oncology Alliance™ Chairman, Dr. Chadi Nabhan, sits down with Dr. Michael Korn, Chief Medical Officer at Caris Life Sciences®, to discuss the MI FOLFOXai™ predictor of response to FOLFOX chemotherapy in metastatic colorectal cancer. For more information, please visit: www.CarisLifeSciences.com/MI-FOLFOXai/

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Dr. S. Lindsay Davis Highlights Key Abstracts on GI Cancers from the #ASCO20 Virtual Scientific Program

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Play Episode Listen Later Jun 9, 2020 19:26

Dr. S. Lindsay Davis, medical oncologist and assistant professor at the University of Colorado Cancer Center, highlights key abstracts on GI cancers that were featured at the #ASCO20 Virtual Scientific Program. Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carol, a reporter for the ASCO Daily News. I'm delighted to welcome Dr. Lindsay Davis to the podcast today. She's a medical oncologist and assistant professor at the University of Colorado Cancer Center, where her clinical focus is gastrointestinal tract cancers. She joins me today to discuss key abstracts in the GI field that were featured at the ASCO20 Virtual Scientific Program. Dr. Davis reports no financial conflicts of interest relating to the issues discussed in this podcast. Full disclosures relating to all daily news podcasts can be found on our episode pages. Dr. Davis, it's great to have you on the podcast today. Dr. Lindsay Davis: Thank you, Geraldine. I am excited for the opportunity to discuss some of the key abstracts related to GI malignancies with you today. I must say the virtual scientific program was a bit of a different ASCO experience than we're accustomed to. However, the high quality of the data and presentations we expect at the annual ASCO meeting was really beautifully maintained in the virtual sessions. ASCO Daily News: Well, what are the abstracts, Dr. Davis, that really caught your attention in the GI field this year? Dr. Lindsay Davis: To me, the results from the KEYNOTE-177 study, abstract LBA4, which was presented at the plenary session, is really the standout in terms of GI malignancies from this ASCO meeting. KEYNOTE-177 is a randomized, open label, phase III study, comparing pembrolizumab to standard of care chemotherapy as first-line treatment for microsatellite instability-high and mismatch repair deficient metastatic colorectal cancer. With a median follow-up of 32 months, the primary progression-free survival endpoint was met, with a median PFS in the pembrolizumab group of 16.5 months, as compared to 8.2 months in the chemotherapy group. So that's a doubling of PFS and a hazard ratio of 0.6. In addition, and as expected, the toxicity rates were significantly lower in the pembrolizumab versus chemotherapy arms, with grade 3 or higher events occurring in only 22% of patients treated with pembrolizumab. And that's compared to 66% of patients treated with chemotherapy. This, of course, provides us the best case scenario of a treatment that is more effective, but also less toxic. And though the MSI high population represents a relatively small proportion of our patients with metastatic colorectal cancer, this study is still clearly practice changing, making pembrolizumab the first-line treatment of choice for patients with metastatic MSI high disease. In addition, I think this object is also important, as it provides further direction toward the biomarker-driven treatment of metastatic colorectal cancer. So I would encourage our listeners to look at abstract 4000, the DESTINY-CRC01 study. There are a couple of additional biomarker-based trials in colorectal cancer that I wanted to touch on as well. The first is the PANDA study. This is abstract 4002. This is a randomized phase II trial, evaluating 185 patients aged 70 and above. The median age in this study was actually 77. These patients had untreated RAS and BRAS wild-type metastatic colorectal cancer and were treated with FOLFOX plus the EGFR inhibitor panitumumab, or with 5-fluorouracil plus leucovorin and panitumumab for up to 12 cycles, followed by panitumumab maintenance. So really, the key difference between the arms here is that oxaliplatin was not included in the second arm. Interestingly, approximately 20% of patients treated in each arm on the PANDA trial had right-sided primary tumors, which we now have data to suggest in a general population, not specific to age, would be less likely to benefit from EGFR inhibitor therapy in the first-line setting. The primary endpoint for this study was progression-free survival in each arm, with no direct comparison made between the arms in this trial. The median PFS was 9.6 months in the FOLFOX panitumumab arm and very similar at 9.1 months in the 5-fluorouracil leucovorin panitumumab arm. This was accompanied by a significant decrease in grade 3 and greater toxicity, including, of course, neurotoxicity-related to oxaliplatin as well as neutropenia and diarrhea. In general, these results are promising for our elderly patients with RAS and BRAF wild-type metastatic colorectal cancer and warrant further assessment in a phase III study for formal comparison of the arms. And importantly, I'll say in clinical practice, we do encounter elderly patients who are not candidates for oxaliplatin or who are unlikely to tolerate intensive chemotherapy due to competing medical risks. So this data provides us some evidence for proceeding with 5FU and EGFR inhibitor therapy in this population. That said, given the data regarding the decreased benefit of EGFR inhibitor therapy as part of first-line treatment for RAS wild-type right-sided colorectal cancer, I would limit the use of this strategy to elderly patients with left-sided tumors that are RAS and BRAF wild-type. I would also like to just briefly mention a third biomarker-based abstract for metastatic colon cancer, abstract 4001, which detailed the updated survival results from the phase III BEACON CRC trial. And I wanted to mention this study because these results are the basis for the recent FDA approval of the encorafenib cetuximab doublet for the treatment of BRAF V600E mutant metastatic colorectal cancer beyond first-line. This subset of metastatic colorectal cancer has historically been associated with a very poor prognosis with minimal response to cytotoxic chemotherapy. The BEACON CRC trial evaluated the doublet of encorafenib plus cetuximab, as well as a triplet of encorafenib plus cetuximab and MEK inhibitor binimetinib, as compared to standard chemotherapy for the treatment of BRAF V600E metastatic colorectal cancer. This was in the second or third-line setting. The results presented at this ASCO are a post-hoc analysis of the previously published BEACON data, including an additional six months of follow-up. This data demonstrated a median overall survival of 9.3 months for both the encorafenib, cetuximab doublet, as well as the encorafenib, cetuximab, binimetinib triplet. And this was compared to only 5.9 months in the control arm with chemotherapy. As expected, there was added toxicity in the triplet arm as compared to the doublet arm, consistent with the known toxicity of MEK inhibitor therapy. So as the FDA approval supports, this targeted regimen of encorafenib, cetuximab should be considered the standard of care for this population in the second-line setting and beyond, given improved survival outcomes as compared to standard chemotherapy and improved side effect profile as compared to the triplet combination. ASCO Daily News: Dr. Davis, are there any new agents that will potentially change standard of care moving forward? Dr. Lindsay Davis: Some very promising data was presented on the compound trastuzumab deruxtecan, or T-DXd, an antibody drug conjugate composed of anti-HER2 antibody with a topoisomerase I inhibitor payload. Studies evaluating this compound were presented both for patients with HER2 expressing metastatic colorectal cancer, as well as HER2 expressing gastric cancer. We'll talk about each of these. In the DESTINY-CRC01 study, T-DXd was evaluated in patients with HER2 expressing RAS wild-type metastatic colorectal cancer in the third line and beyond. 78 patients received T-DXd, of whom about 90% had left colon rectal cancer, which was heavily pre-treated with a median prior lines of therapy of 4, and it ranged from 2 to 11 prior lines. The primary endpoint in this open label phase II study was objective response rate in patients with HER2 IHC 3+ or HER2 IHC 2+ with a positive ISH test. Confirmed overall response rate in this population was 45% with one complete response, which was quite impressive, given these patients are heavily pretreated with the median of four prior regiments. Also of note is the overall response rate in patients with prior HER2 treatment, which actually represented 30% of the population. The overall response rate in this group was 44%. In terms of toxicity, grade 3 and greater treatment emergent adverse events were documented in 62% of patients, with the most common being cytopenias, neutropenia, and anemia mostly. However, in addition, five patients developed interstitial lung disease related to treatment. This is a toxicity that has been seen in other trials of this compound. But in this study, it included two fatal grade 5 events of interstitial lung disease. So in terms of HER2 positive RAS wild-type metastatic colorectal cancer, I think T-DXd represents an encouraging option for treatment of this molecular subgroup, with notable effects in patients pretreated with HER2 targeted agents. However, given the notable risk of treatment-related interstitial lung disease, this will need to be further vetted in a phase III trial. I think the study further highlights the importance of broad molecular testing in colorectal cancer, as though HER2 positivity is only identified in 2% to 3% of patients with this disease. Effective targets for this and other uncommon molecular alterations are being developed. Similarly, promising results were presented in the DESTINY-Gastric01 study. This is abstract 4513, an open label, randomized, phase II trial evaluating T-DXd and HER2 expressing advanced gastric or GE junction adenocarcinoma. Patients had centrally confirmed HER2 positive disease, according to the same definition as the CRC01 study with progression on at least two prior lines of therapy. Patients were randomized 2 to 1 to T-DXd or physician's choice of chemotherapy, which included irinotecan or paclitaxel. All patients in the trial had received prior HER2 therapy, of course, as this is standard of care for HER2 positive gastric and esophageal cancers. The primary endpoint on the study was overall response rate. And in the 187 patients treated, the overall response was 51% in patients treated with T-DXd, as compared to only 14% in those treated with chemotherapy. With central confirmation of response, this overall response rate was a bit lower at 43% in the T-DXd arm, versus 13% in the control group. In addition, overall survival was prolonged in the T-DXd arm at 12.5 months versus 8.4 months in the chemotherapy group with a hazard ratio of 0.59. Grade 3 and greater adverse events occurred in 86% of patients treated with T-DXd, as compared to 57% treated with standard chemotherapy, and were similar to those documented in the CRC01 study, including treatment-related interstitial lung disease documented in 12 patients. Though there were no grade 5 events of ILD documented in this Gastric01 study, one grade 5 occurrence of pneumonia was noted in the treatment arm. These results are important, as they suggest a potential effect of a HER2 targeting therapy beyond trastuzumab, the only HER2 targeted therapy shown to be effective for the treatment of HER2-positive gastroesophageal cancers to date. However, similar to the CRC01 study, the pulmonary toxicity documented in this trial remains a concern. We will look forward to a phase III study to further expand upon these findings. ASCO Daily News: Are there any additional biomarker-focused studies of interest presented for GI malignancies outside of metastatic colon cancer? Dr. Lindsay Davis: Yes, there are two additional studies focused on HER2-positive gastroesophageal cancers that were presented at this meeting. Here, they're evaluating the addition of HER2 targeted agents in the curative setting. The PETRARCA study, which is abstract 4502, evaluated perioperative FLOT, or FLOT with trastuzumab and pertuzumab, followed by nine cycles of trastuzumab plus pertuzumab in patients with resectable HER2-positive gastric or GE junction adenocarcinoma. The primary endpoint for this study was pathologic complete response rate, which was significantly improved in the trastuzumab pertuzumab arm at 35% versus only 12% in the FLOT alone arm. There's also suggestion of benefit on PFS and OS in this study, though it was not powered for formal analysis. Important to note is the added toxicity of trastuzumab pertuzumab to the FLOT regimen, which is already associated with a significant burden of adverse effects. Grade 3 or greater adverse events were documented in 85% of patients in the trastuzumab pertuzumab arm versus 75% of patients in the FLOT alone arm. And diarrhea and leukopenia were the most notable in the arm that added trastuzumab and pertuzumab therapy. It should be noted that this trial was originally designed as a phase II/III study, but it was halted at phase II due to the emerging results from the JACOB trial. The JACOB trial was a phase III study which failed to meet its primary endpoint of improved overall survival for the addition of pertuzumab to trastuzumab and chemotherapy in the metastatic setting. Despite this, I believe these phase II results from the PETRARCA study suggest there is rationale for proceeding with further assessment of this combination in the phase III setting. In contrast to these promising results for the addition of HER2 targeted therapy to standard chemotherapy and HER2-positive gastric and GE junction adenocarcinoma, the RTOG 1010 study, abstract 4500, did not meet its primary endpoint. This study evaluated the addition of trastuzumab to tri-modality therapy with carboplatin, paclitaxel chemoradiation, followed by surgery in 571 patients with HER2 overexpressing esophageal or GE junction adenocarcinoma. Patients receiving carboplatin paclitaxel chemoradiation followed by surgery had a median disease free survival of 14.2 months as compared to 19.6 months in the trastuzumab arm. However, this did not meet the prespecified primary endpoint of increasing disease free survival from 15 to 25 months. These results further confirm that defining the role of anti-HER2 therapies for the treatment of HER2-positive gastroesophageal cancers in the curative setting is complex, though deserving of continued attention and investigation. ASCO Daily News: Dr. Davis, are there any updates on immuno-oncology therapies for the treatment of GI malignancies beyond colorectal cancer? Dr. Lindsay Davis: Yes, updated results from the randomized phase III KEYNOTE-061 study were presented at this virtual meeting in abstract 4503. The KEYNOTE-061 study is a randomized phase III trial evaluating pembrolizumab versus paclitaxel as a second-line therapy for advanced gastric or GE junction adenocarcinoma in patients with PDL1 combined positive scores greater than or equal to 1. In the previously presented primary analysis of this study, the primary overall survival endpoint was not met. However, duration of response was significantly longer at 18 months in the pembrolizumab arm versus 5 months in the paclitaxel arm. Presented in this abstract is data from an additional two years of follow-up, as well as further assessment according to additional combined positive scores of greater than or equal to 5 and greater than or equal to 10. The survival benefit of pembrolizumab over paclitaxel seemed to increase with increasing combined positive score. In the general cohort of CPS greater than or equal to 1, patients treated with pembrolizumab had an overall survival of 9.1 months versus 8.3 months with paclitaxel. This is a hazard ratio of 0.81. This is compared to an overall survival of 10.4 months with pembrolizumab versus 8.3 months with paclitaxel, a hazard ratio of 0.72 in the CPS 5 or greater population. And finally, in patients with CPS 10 or greater, the overall survival in the pembrolizumab versus paclitaxel arms was 10.4 versus 8.0 months, with the hazard ratio of 0.69. In addition, the duration of response numerically increased with increasing CPS score, from 19 months in the CPS 1 group to 33 months in the CPS 5 group. And the duration of response has actually not been reached in the CPS 10 group. I think the conclusion from these updated results is that a proportion of patients have long-term survival benefit from second-line pembrolizumab, which might be somewhat improved with higher CPS. This calls into question a need to adjust our selection criteria for pembrolizumab in patients with gastroesophageal cancers. In summary, I think the underlying theme of this group of abstracts focused on GI malignancies is that we are continuing to move toward personalized cancer care for the treatment of gastrointestinal tract cancers. These studies also highlight the importance of broad molecular testing for GI cancers, as well as the importance of involvement of our patients with targetable alterations in clinical trials in order to help us continue to improve the individualized care we provide our patients. ASCO Daily News: Well, thank you, Dr. Davis, for sharing your valuable insights with us today on these promising developments in the GI field. Dr. Lindsay Davis: Thank you, Geraldine. It was my pleasure. ASCO Daily News: And thank you to our listeners for joining us today. If you're enjoying the content on the podcast, please rate and review us on Apple Podcasts. Disclaimer: 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

university cancer virtual patients os studies fda grade scientific ge keynote gi confirmed panda bras beacon oncology cps ras ish asco gastrointestinal msi her2 pfs egfr ii iii mek abstracts petrarca flot pd l1 braf ild lindsay davis braf v600e folfox rtog colorado cancer center 5fu

Revisiting Stacy Hurt - Overcoming Stage IV Colorectal Cancer Through Integrative Medicine, Diet and Faith

WE Have Cancer

Play Episode Listen Later Apr 21, 2020 35:31

Stacy was diagnosed with Stage IV colorectal cancer on her 44th birthday, September 17th, 2014 after experiencing symptoms of abdominal pain and bleeding. Stacy put off a visit to her doctor since she was a health-conscious, athletic, non-smoker who maintained a normal weight. The symptoms were merely “an annoying inconvenience.” At the time, she was balancing a full-time job with raising her 2 sons, Griffin (now 13) and Emmett (now 11). Emmett suffers with a rare chromosome disorder (one of three in the world) which renders him without the ability to walk, talk, or function for himself in any way. He has multiple special needs and demands constant supervision. He has the mental and physical capacity of a 6 month old baby. Caring for Emmett requires the attention of not only Stacy and her husband Drew, but also a nurse. To say Stacy had her hands full would be an understatement. So, busy with her day to day role as supermom, Stacy self-diagnosed irritable bowel syndrome (IBS) or internal hemorrhoids until the pain was too much to bear. A colonoscopy revealed the most shocking and most unexpected horror imaginable: a tumor in her rectum so large that a scope could not get around it. A subsequent scan revealed cancer in her liver, 5 spots on her lungs, and 19 lymph nodes. She was given a 10% chance to survive 5 years and a treatment plan which included chemotherapy, radiation and ultimately surgery ONLY IF she responded, which was a 50/50 shot in itself. The doctors could not believe it, especially considering Stacy’s lack of risk factors, lack of family history, and age (colon cancer is typically diagnosed in people over 50). With her usual vigor, determination, and sense of humor, Stacy took to the task of beating colorectal cancer. She was fortunate enough to have a response to chemotherapy (a protocol called FOLFOX coupled with a drug called Avastin) which qualified her as a candidate for a 5 hour colon and liver resection surgery in April, 2015. Unfortunately, a medical mistake during surgery caused Stacy severe internal bleeding where she lost half of her blood volume. She was immediately rushed back into a second, 5 hour emergency surgery and spent a week in the ICU fighting for her life. As her oncologist later remarked, “anyone else would have died.” But not Stacy. She was declared as NED (no evidence of disease) in March, 2016. Stacy continues maintenance chemotherapy for life (43 rounds and counting…) every 3 weeks. She feels and looks great. You would never suspect what all she is dealing with. She credits her faith, family, friends, exercise, positive attitude, and integrative oncology modalities for her remarkable recovery. “If it were just Stage IV colorectal cancer or just raising a profoundly disabled child, I could probably handle it. But managing both is completely overwhelming. I am enormously blessed to have a support system who helps me, when thee last thing I want to do is ask for help. It’s really not my style.” Stacy offers a unique perspective. Professionally, she has spent 20 years in healthcare management on the provider and delivery sides, including roles in operations, strategy, sales and training. Personally, her battles as a patient and an advocate for not only herself but also her disabled son have fueled her recent work as a public speaker, fundraiser, and consultant. Stacy’s mission is to raise awareness of inclusion for all persons with disabilities and exemplify a “keep it real” approach to fighting and beating cancer. Learn more about Stacy and connect with her at: Her website: http://www.stacyhurt.net/ Her Facebook page: https://www.facebook.com/stacyhurt17 On Twitter: @Stacy_Hurt On Instagram: stacy_hurt WE Have Cancer Links Subscribe to the WE Have Cancer Podcast - https://pod.link/wehavecancer Follow WE Have Cancer on Social Media Like our Facebook page - https://www.facebook.com/wehavecancershow/ Join our private Facebook group - https://www.facebook.com/groups/wehavecancershow/ Follow us on Twitter - https://twitter.com/wehavecancerpod Follow us on Instagram - https://instagram.com/wehavecancerpod Follow us on LinkedIn - https://linkedin.com/company/wehavecancer Know someone touched by cancer who has an inspiring story? Nominate a guest to appear on the podcast - https://wehavecancershow.com/guest Email Lee Lee@wehavecancershow.com

Pre - HOPA News Dunp

Play Episode Listen Later Mar 5, 2020 29:04

A plethora of #oncopharm updates! Isatuximab is approved and neratinib gets another breast cancer indication (2:00) Pembrolizumab with chemo for triple-negative breast cancer (8:50) New EPOC updated survival analysis on FOLFOX+cetuximab in isolated liver metastatic colon cancer (15:00) Precision medicine in pancreatic cancer (19:30) Cladribine + rituximab for hairy cell leukemia (23:30)

precision pembrolizumab hopa folfox isatuximab

Key Scientific Takeaways from the GI Cancers Symposium with Dr. Emily K. Bergsland

Play Episode Listen Later Feb 4, 2020 20:28

[MUSIC PLAYING] ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Kara Nyberg. Joining me today is Dr. Emily Bergsland, who is a GI medical oncologist and professor of medicine at the University of California San Francisco. Welcome to the podcast, Dr. Bergsland. We're here to discuss highlights from the 2020 Gastrointestinal Cancer Symposium, for which you served as the program chair. Let's begin with research presented at the meeting that has a direct bearing on clinical practice. Are you and your colleagues going to change your practice based on data coming out of this symposium? And if so, how? Dr. Bergsland: There were a couple of important advances reported at the meeting that are likely to support new standards of care moving forward. We know that BRAF V600E mutated metastatic colorectal cancer is associated with a very poor prognosis. The BEACON trial was a randomized phase III study of encorafenib plus cetuximab, with or without binimetinib, in previously treated BRAF mutant metastatic colorectal cancer. The BEACON investigators had previously reported that triplet therapy seemed to be better than doublet therapy and improved survival and response rates compared to standard of care treatment. Dr. Bergsland: At ASCO GI, Dr. Kopetz presented updated results showing that encorafenib plus cetuximab, with or without binimetinib, demonstrated longer maintenance of quality of life, and there was no difference in the quality of life benefit between the doublet and triplet regiments. Furthermore, the median survival is now the same in both groups, 9.3 months, which is significantly better than the 5.9 months seen in control. As a result, the study team is moving forward with doublet therapy instead of triplet therapy, and this filing is now under review by the FDA. Dr. Bergsland: Updates to the IMbrave150 study were also reported. The IMbrave150 study was a randomized phase III trial of atezolizumab plus bevacizumab versus sorafenib as first line treatment for unresectable hepatocellular carcinoma. As reported at ESMO Asia, atezolizumab improved overall in progression-free survival compared to sorafenib. At ASCO GI, the study team reported that atezolizumab was also associated with significant and consistent benefits in quality of life, functioning, and key symptoms, providing further support for atezolizumab as a new standard of care for untreated hepatocellular carcinoma. Dr. Bergsland: Finally, the results of a randomized phase II trial of gemcitabine and cisplatin, with or without the PARP inhibitor veliparib, in patients with pancreatic cancer and germline BRCA or PALB2 mutations were presented. Surprisingly, both arms were highly active, with an overall response rate of 74% with triplet therapy and 65% with chemotherapy alone. Olaparib added little benefit, possibly because of heme toxicity limiting the dose delivered. But the high response rate and overall survival of 15 to 16 months in both groups provide support for gem/cis as a new reference treatment for pancreatic cancer in patients with germline BRCA or PALB2 mutations. ASCO Daily News: Are there any new treatment approaches or agents in development that you're particularly excited about? Dr. Bergsland: Several presentations focused on biomarkers and liquid biopsies in particular, which I think is where the field is going. The potential value of circulating tumor DNA to guide therapy was highlighted by a study presented at GI ASCO comparing tumor tissue genomic profiling to plasma circulating tumor DNA sequencing using the SCRUM-Japan GI screen and GOZILA combined analysis. Dr. Bergsland: Investigators found that plasma genotyping significantly reduced turnaround time compared to tumor tissue, 35 days versus 12 days, and led to a shorter interval between genotyping and enrollment to match trials. Dr. Bergsland: There are many prospective clinical trials incorporating circulating tumor DNA underway to validate the use of liquid biopsies to guide treatment, monitor for resistance in GI malignancies, and assess for minimal residual disease after resection, an example of the latter being the COBRA study for stage II colon cancer. Expanding on the idea of blood-based biomarkers, Brian Mulpin described development of a methylation-based cell-free DNA early multi-cancer detection test that can also predict the tissue of origin. Samples were collected as part of the circulating cell-free genome atlas in individuals with and without different cancers. Dr. Bergsland: Plasma cell-free DNA was subjected to a cross-validated targeted methylation sequencing assay, and the study included both training and validation data sets. The data suggests that a targeted methylation assay from cell-free DNA in the blood may represent a novel non-invasive way of detecting different GI cancers and identifying site of origin. Finally, another interesting finding relates to the fact that identification of the optimal duration and type of adjuvant therapy for patients with resected colon cancer remains a challenge. Dr. Bergsland: The Immunoscore, which measures immune infiltration in tumors, has emerged as a prognostic marker for patients with localized colon cancer. At ASCO GI, researchers presented an analysis of the Immunoscore in modified FOLFOX-6 treated patients enrolled in the France cohort of the idea study. The results confirm that the Immunoscore is prognostic in these patients. Interestingly, only patients with Immunoscore intermediate or high benefited from six months of FOLFOX treatment compared to three months. Dr. Bergsland: This was true in both clinical low and high risk subgroups with stage 3 disease. This means that Immunoscore low patients not only have a higher risk of relapse, but they have no obvious benefit from six months of FOLFOX compared to three months. Validation of the results in an independent cohort is planned, but the findings could represent an important step towards improving our ability to individualize adjuvant chemotherapy in patients with resected stage 3 colon cancer. ASCO Daily News: I know that immunotherapy with checkpoint inhibitors has captured much of the limelight in recent years. Were there any new and notable findings with regard to these therapies? Dr. Bergsland: Given the IMbrave150 results showing the value of atezo-bev in first line hepatocellular carcinoma, the CheckMate 040 study results are of interest. This was a study of 71 patients with advanced hepatocellular carcinoma randomized to receive nivolumab plus cabozantinib, with or without ipilimumab. Radiographic responses were seen in both groups, 19% with the doublet and 29% with the triplet, and a high disease control rate was observed in both arms. Overall survival after two years of follow-up was at least 22 months in both arms. Dr. Bergsland: The triplet regimen was associated with more toxicity. Additional studies integrating safety, efficacy, and patient reported outcomes will be needed to determine the relative value of either of these regimens compared to other treatment options for hepatocellular carcinoma. Updated CheckMate 142 data were also presented regarding the use of nivolumab plus low-dose ipilimumab as first line therapy in MSI-high metastatic colorectal cancer. Nivolumab, with or without ipilimumab, is already FDA approved for chemotherapy-resistant MSI-high metastatic colorectal cancer, but the role of combination therapy in the first line setting is unknown. Dr. Bergsland: CheckMate 142 included 45 previously untreated patients with MSI-high or defective mismatch repair metastatic colorectal cancer. At a median follow-up of 20 months, the overall response rate is 64%. The median overall survival and progression-free survival have not been reached. Combination therapy was well tolerated. This may represent a new first line treatment options for these patients, but longer follow-up is needed to see if the high response rate translates into improved overall survival. ASCO Daily News: Interesting. Let's move now to earlier stage disease. What advances were discussed related to the treatment of localized GI malignancies? Dr. Bergsland: There were several presentations focused on the treatment of localized disease, and the theme seemed to be that less may be more. In terms of surgical questions, Dr. Yamada presented preliminary results from the TOP-G trial, a randomized phase II study showing that omentum-preserving gastrectomy is associated with similar short-term outcomes compared to standard of care gastrectomy with omentectomy. The results are not definitive, but support enrollment to an ongoing phase III study, JCOG1711, which would provide a definitive answer on the role of omentectomy. Dr. Bergsland: In another randomized study, extensive peritoneal lavage did not improve survival compared to surgery alone. This is not recommended for patients undergoing curative gastrectomy for cancer. Finally, researchers from Japan reported on the results of the randomized phase III iPAC study. Primary tumor resection followed by chemotherapy did not improve overall survival compared to chemotherapy alone, thus can't be routinely recommended for colorectal cancer patients with an asymptomatic primary tumor and synchronous unresectable metastases. 87% of patients in the control arm were able to avoid surgery. Dr. Bergsland: In terms of adjuvant therapy, the RESONANCE trial assessed the use of perioperative SOX chemotherapy in patients with resectable gastric cancer in China. 772 patients were randomly assigned to receive pre- and post-op SOX or adjuvant therapy alone. Neoadjuvant SOX was associated with a higher R0 resection rate, acceptable adverse event profile, and no differences in short-term outcomes. The primary endpoint of three-year disease-free survival has not been reached, though, so this approach remains investigational. Dr. Bergsland: The results of CCOG-1302 were also presented, a randomized phase II trial assessing CAPOX with continuous versus intermittent use oxaliplatin as adjuvant chemotherapy for stage 2 and 3 colon cancer. CAPOX with planned intermittent oxaliplatin substantially reduced long-term peripheral sensory neuropathy in patients treated with six months of adjuvant therapy, and three-year disease-free survival was similar between groups. Dr. Bergsland: While intriguing, the results are not practice-changing, as it was a relatively small phase II study. Finally, the Dutch Art-Deco phase III study showed that radiation dose escalation, up to 61 gray to the primary tumor, increased toxicity without increasing local control or overall survival compared to standard dose radiation in patients with esophageal cancer receiving definitive chemoradiation. ASCO Daily News: The theme for the GI Cancer Symposium this year was accelerating personalized care. Based on research presented at the meeting, what is the field currently doing well, and what can the field be doing better? Dr. Bergsland: Generally speaking, I think we're making significant progress. One big area of study relates to identification of patients at risk for GI malignancies and modifying cancer screening guidelines accordingly. For example, there was a session on screening in high risk populations. Providers should offer germline testing to any patient with a personal history of pancreatic cancer, since approximately 10% of patients will have an inherited germline mutation. Dr. Bergsland: Guidelines for screening continue to evolve, but their emerging data support the use of MRI or EUS in mutation carriers. Cholangiocarcinoma rates are increasing globally, and we know that the risk factors vary by location and that type 2 diabetes, a non-alcoholic steatohepatitis, or NASH, may also be contributing. NASH cirrhosis is also a risk factor for hepatocellular carcinoma. Screening practices are evolving as our recommendations for chemo prevention, which may include aspirin and statins in high risk patients. Dr. Bergsland: Another important area is early onset colon cancer. Colorectal cancer incidence has been declining for several decades in people over the age of 55, but rates in people younger than 55 are increasing at nearly 2% annually, and this has been ongoing since 2006. Younger patients present with more advanced disease and more poorly differentiated tumors. As such, there's an ongoing debate surrounding the optimal age to start screening. Better colorectal cancer risk prediction tools are needed. In the meantime, high risk groups should be prioritized, such as those with a family history of cancer, inflammatory bowel disease, or polyps. Dr. Bergsland: In addition to improvements in our identification of high risk patients, we're also making great strides in translating advances in our understanding of the molecular underpinnings of GI malignancies to the clinic. The BEACON data are certainly encouraging with respect to the treatment of BRAF V600E metastatic colorectal cancer, and the molecular basis for cholangiocarcinoma is now much better understood, with biomarker-based trials now available for FGFR and IDH-mutant cancers. Despite the many advances presented at the meeting, though, there were a few disappointments, suggesting that there's still a lot of work to be done in the area of biomarker selection and drug development. Dr. Bergsland: The HALO-109-301 study of nab-paclitaxel/gemcitabine, with or without PEGPH20 in patients with previously untreated hyaluron-high metastatic pancreatic ductal adenocarcinoma was a negative study in a biomarker-selected population. There were also several negative studies in biomarker-unselected patients. The SEQUOIA study of FOLFOX with or without pegylated interleukin-10 as second line therapy for metastatic pancreatic cancer was negative, and there was no benefit in adding ramucirumab, a VEGFR-2 antibody, or merestinib, an oral MET inhibitor, to gem/cis and biomarker on selected metastatic biliary cancer. Dr. Bergsland: Finally, Australian researchers reported results from the Christoral NET study. Adding chemotherapy to lutetium-177 dotatate in mid-gut neuroendocrine tumors added toxicity without improving efficacy. The results of these studies highlight the ongoing need to identify validated biomarkers that facilitate drug development. This trend is reflected in our clinical trials, with biomarker selected patient populations using tumor-based biomarkers, germline alterations, or circulating tumor DNA increasingly under study. Dr. Bergsland: Adaptive platform trial designs, such as the platform study of maintenance therapy in gastroesophageal cancer and PanCAN's Precision Promise clinical trial in the first line and second line treatment of metastatic pancreatic cancer, are being incorporated to more efficiently test new therapies by requiring fewer patients to understand if a potential therapy is working and support the testing of multiple investigational therapy simultaneously. ASCO Daily News: To take things one step farther, how are we doing in terms of actually delivering personalized cancer care? Are we making improvements in patient access to treatment and follow-up? Dr. Bergsland: The available data suggests we have a long way to go in terms of ensuring equitable access to care across all patients. Disparities in health care delivery were highlighted in several presentations. An analysis of NCDB data revealed that young adults with colorectal cancer in the lowest income and education population had worse overall survival. And regardless of income, patients in metropolitan areas have a lower risk of death, presumably due to greater access to care. Another group analyzed health care in Canada and determined that 1/3 of patients with non-curative gastroesophageal cancer never see a medical oncologist, and only 1/3 of patients receive chemotherapy. Dr. Bergsland: Care delivery and overall survival showed high geographic variability, with location of residents influencing access to care and overall survival and inferior outcomes for those living further from a cancer center. Dr. Yousef Zafar gave a keynote lecture focused on how advances in precision oncology can be realized equitably across all patient populations, communities, and health care systems. He reminded us that in 2017, only 60% of patients with metastatic colorectal cancer were getting appropriate molecular testing. He also reviewed the costs of cancer care and the impact financial toxicity has on patients. Dr. Bergsland: Dr. Zafar outlined a need for what he calls "precision delivery of care," which, to be successful, will require collaboration between drug manufacturers, insurance providers, health care providers, and patients, and discussions of clinical benefit toxicity and cost. In the era of precision oncology, novel methods for assessing the value of new drugs are needed, as our reimbursement models that incorporate cost effectiveness. Dr. Zafar stressed that all stakeholders will need to collaborate to find solutions that ensure precision delivery of molecular and immunotherapies to all patients. ASCO Daily News: Did we learn anything new or unexpected about the pathobiology of GI malignancies at this year's meeting? Dr. Bergsland: I think one of the most interesting sessions at the meeting was a keynote lecture given by Susan Bullman, a scientist at the Fred Hutchinson Cancer Research Institute. Dr. Bowman reviewed the importance of a microbiome in the human body and in disease. She explained that the naturally occurring microbes in our bodies may confer susceptibility to certain cancers, promote cancer progression, and modulate response to therapeutics. Dr. Bergsland: For example, tumor associated bacteria are metabolically active and can potentially increase or decrease the activity of certain chemotherapeutic agents, such as gemcitabine. In addition, there is a growing body of evidence that tumor microbiome may modulate the response to immunotherapy. Dr. Bullman's presentation highlighted this exciting new area of study as well as the many unanswered questions in the field, including whether the tumor microbiome itself might be a valid target for cancer therapy. Studies of the microbiome in colon cancer and other diseases are ongoing. ASCO Daily News: I agree, that was a very fascinating keynote lecture. Given the legalization of marijuana in an increasing number of states, an entire session at the symposium was dedicated to symptom management in the era of legalized marijuana and the opioid crisis. What notable points came out of that session? Dr. Bergsland: There is great interest in the use of cannabinoids in the face of increased access and legalization in a number of states in the US. The data suggests that patients prefer information about safety and efficacy from their health care providers, but many providers cite inadequate training in this area. Our understanding of the role of these agents is limited by a lack of prospective clinical trials. The strongest evidence for efficacy is in the area of the control of chemotherapy-induced nausea, but it's unclear if cannabinoids impact tumor growth, as most of the studies in this area have been preclinical. Dr. Bergsland: In terms of practical treatment considerations in the absence of high quality data on strain, dosing, ratios, and potencies of active ingredients and modes of use, a harm reduction model of care is recommended starting with very low doses, with THC-CBD combinations preferred over THC only preparations. Definitive recommendations are further complicated by the lack of information about drug-drug interactions and limited information about quality control. Overall, the panel felt that cannabinoids were not likely to ever replace opioids, so prescribers still need to know how to use opioids in the clinic, keeping an eye out for patients with risk for abuse of these agents and remembering to incorporate a bowel regimen as well as an antiemetic in the first few days. ASCO Daily News: This was truly an excellent recap. I think we can summarize by saying there was a wealth of research that was presented at the GI Cancer Symposium this year, both positive and negative, that's moving the field forward. It's been a pleasure speaking with you, Dr. Bergsland. Thank you for your time and your insight. To our listeners, thank you for tuning into the ASCO Daily News Podcast. If you are enjoying the content, we encourage you to rate us and review us on Apple Podcast. [MUSIC PLAYING] 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING]

Pancreatic Cancer | Michael J Pishvaian, MD, PhD

Play Episode Listen Later Jan 24, 2020 65:05

Pancreatic Cancer Update, Issue 1, 2020 — Our interview with Dr Pishvaian highlights the following topics as well as cases from his practice: Key biologic features of pancreatic cancer (0:00) Genetic alterations and potentially actionable mutations in pancreatic cancer (2:02) Targeting BRCA mutations in pancreatic cancer; incidence of microsatellite instability-high disease (4:44) Current recommendations for genetic testing for patients with pancreatic cancer (6:45) Molecular profiling for patients with pancreatic cancer: The Know Your Tumor® initiative (11:36) Ongoing trials investigating targeted therapies for pancreatic cancer (12:56) Case: A woman in her early 60s with metastatic pancreatic cancer (mPC) and a germline BRCA2 mutation is enrolled on a clinical trial of veliparib with FOLFOX as first-line therapy(14:46) Activity, safety and ongoing evaluation of PARP inhibitors in combination with chemotherapy for mPC (18:05) Case: A woman in her early 60s with mPC and a somatic BRCA2 mutation receives FOLFIRINOX followed by maintenance rucaparib on a clinical trial (20:29) POLO: Design and results of a Phase III trial of olaparib as maintenance therapy for patients with mPC and a germline BRCA mutation after first-line chemotherapy (23:38) Tolerability of maintenance olaparib on the POLO trial (27:42) Clinical implications of the POLO trial results (30:09) Case: A woman in her late 50s with locally advanced pancreatic cancer and a germline ATM mutation is enrolled on a clinical trial of irinotecan, a PARP inhibitor and an ATR inhibitor (34:31) Response to FOLFOX in patients with locally advanced pancreatic cancer and ATM mutations (37:37) Case: A man in his early 60s with mPC with a ROS1 fusion receives entrectinib on a clinical trial (41:22) Clinical experience and dosing considerations with FOLFIRINOX or gemcitabine/nab paclitaxel (44:03) Use of nal-IRI (nanoliposomal irinotecan) with 5-FU/leucovorin for mPC (46:58) Importance of supportive and palliative care for patients with mPC (48:19) Perspective on the use of medical marijuana for patients with mPC (51:47) Choice of gemcitabine/nab paclitaxel or FOLFIRINOX as first-line therapy for mPC (53:43) Selection of adjuvant therapy for patients with pancreatic cancer (55:53) Case: A woman in her mid-50s with localized pancreatic cancer receives neoadjuvant FOLFIRINOX (57:49) Potential role of PARP inhibitors for pancreatic cancer in the adjuvant setting (1:02:24) CME information and select publications

Episódio #28: SWOG Trial - FOLFIRI ou FOLFOX com Bevacizumab vs. Cetuximab em CCR

Play Episode Listen Later Nov 8, 2019 23:41

A combinação de anticorpos monoclonais com quimioterapia oferece benefícios para pacientes com tumores avançados ou metastáticos. HOWEVER qual deles tem maior eficiência em pacientes não tratados previamente? Estamos falando do cetuximab e bevacizumab novamente! Estamos quase lá! O objetivo é fazer um “background” sobre o assunto e discutirmos em breve a questão da lateralidade para câncer colorretal (ccr). O SWOG Trial, publicado no JAMA em 2017, teve o objetivo comparar a combinação de cetuximab vs. bevacizuma com FOLFIRI ou FOLFOX no tratamento de pacientes com ccr “KRAS wyld-type”. Siga-nos nas redes sociais e faça seus comentários! Sejam muito bem vindo a mais um episódio do Clinical Papers Podcast! Para saber mais sobre esse paper, acesse o link abaixo e tenha acesso grátis na íntegra! https://www.ncbi.nlm.nih.gov/pubmed/28632865

trial estamos epis siga jama sejam kras bevacizumab swog cetuximab folfox folfiri

Episódio #27 - ADORE Trial - FOLFOX vs. 5-FU adjuvante em câncer de Reto - "Long Terms Results"

Play Episode Listen Later Nov 3, 2019 27:51

Nesse episódio eu e Tiago iremos discutir o ADORE Trial e seus resultados de longo prazo. Esse foi um estudo importante para o tratamento de câncer de reto pois avaliou a utilização de FOLFOX vs. 5-FU adjuvante em pacientes estádio patológico ypII/III pós neoadjuvância com RT/QT. Publicado recentemente na JCO, o ADORE Trial mostrou uma superioridade em DFS com o uso do FOLFOX ás custas de uma maior toxicidade com esse esquema. MAS, será que essa superioridade em DFS teve impacto em Sobrevida Global? Para saber a resposta e muito mais ouça o Clinical Papers Podcast! Tenha acesso ao paper através do link: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.3501 Siga-nos nas redes sociais e faça seus comentários!

trial terms nesse esse epis tiago reto dfs tenha publicado jco folfox

#092_ESMO 2019 | Câncer de Cólon_Bevacizumabe + quimioterapia na primeira linha_Dr. Fábio Kater

MOC Brasil

Play Episode Listen Later Oct 30, 2019 2:15

Dr. Fábio Kater, autor do MOC, comenta importante estudo chinês que avaliou a eficácia de bevacizumabe + FOLFOX como tratamento de primeira linha para metástases hepáticas colorretais irressecáveis mutantes do RAS.

primeira ras kater linha moc esmo quimioterapia folfox

GI malignancy case review

ASCO eLearning Weekly Podcasts

Play Episode Listen Later Aug 29, 2019 29:59

Daniel G. Haller, MD, of the University of Pennsylvania, Philadelphia, joins Blood & Cancer host David H. Henry, MD, also of the University of Pennsylvania, to discuss two real-world gastrointestinal cancer cases and how the latest research should influence the approach to care. Plus, in Clinical Correlation, Ilana Yurkiewicz, MD, of Stanford (Calif.) University talks about pressure from patients to overtreat indolent cancer. This week in Oncology: Perceived discrimination linked to delay in ovarian cancer diagnosis for black women Perceived everyday discrimination was associated with an extended duration between symptom onset and cancer diagnosis in black women with ovarian cancer. Time Stamps: This week in Oncology (04:47) Interview with Dr. Haller (07:27) Clinical Correlation (26:20) Show Notes Patient case #1: Patient presents with a T2 tumor with right-sided colon cancer with invasion of a large right vessel. What is the best management? The IDEA collaboration: Large analysis to evaluate CAPOX vs. FOLFOX therapy for colorectal cancer and to determine 3 months vs. 6 months of therapy. Researchers at the 2019 American Society of Clinical Oncology annual meeting presented an evaluation of the treatments in stage II colon cancer with high-risk features (Abstract 3501). Definition of high risk: T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation or vascular/perineural invasion. Difficult for pathologists to diagnose T4 disease. The definition of high-risk disease was slightly different in each individual trial. T stage makes the most difference of all. Overall data: Difference in survival is 3% between 3 months and 6 months of therapy. Results by regimen: CAPOX: 3 months vs. 6 months, the difference in survival is almost identical. FOLFOX: 3 months vs. 6 months, difference in survival was 7%, with 6 months being superior. Link: asco.org/239/AbstView_239_257383.html Refresher on grading colorectal cancers: net/cancer-types/colorectal-cancer/stages Patient case #2: A 38-year old woman with past medical history of diverticulitis presents with left lower quadrant pain and is treated with antibiotics but does not improve. She was referred for colonoscopy, which reveals sigmoid polyp; pathology shows moderately differentiated adenocarcinoma. A CT scan is performed, which reveals a lesion that is transmural, circumferential in the sigmoid, and requires surgery. Sigmoid is colectomy performed for a large tumor and serosal and pericolic and immediately adjacent retroperitoneal soft tissue is noted. Other notable features included lymphovascular invasion but no metastases. Genetic testing shows RAS/BRAF negative and MMR analysis notes PMS2 negative. Concern for Lynch syndrome given right-sided disease, female, large tumor; therefore, genetic testing for Lynch syndrome is recommended. This is important because patient requires more frequent colonoscopies. Work with surgeons to recommend keeping clips in place to minimize area that gets radiation. Approach to treatment: Dr. Haller recommends the “sandwich approach,” in which the patient receives chemotherapy, then radiation, then more chemotherapy. FOLFOX or CAPOX are both chemotherapy options. Show notes by Ronak Mistry, DO, resident in the department of internal medicine, University of Pennsylvania, Philadelphia. For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc Ilana Yurkiewicz on Twitter: @ilanayurkiewicz

university interview work philadelphia pennsylvania patients md idea concerns difficult large definition researchers results lynch gi american society genetic abstract interact oncology perceived t2 refresher haller t4 mmr gastrointestinal david h daniel g clinical oncology blood cancer malignancy sigmoid folfox capox clinical correlation mdedge podcasts

2019 ASCO Annual Meeting Research Round Up: Gastrointestinal Cancers and Leukemia

Cancer.Net Podcasts

Play Episode Listen Later Aug 22, 2019 18:59

ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer. 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. The 2019 ASCO Annual Meeting, held May 31 to June 4, brought together physicians, researchers, patient advocates, and other health care professionals from around the world to present and discuss the latest research in cancer treatment and patient care. In the annual Research Round Up podcast series, Cancer.Net Associate Editors share their thoughts on the most exciting scientific research to come out of this year’s ASCO Annual Meeting and what it means for patients. First, Dr. Jeffrey Meyerhardt will discuss 4 studies in gastrointestinal cancers, including 1 on colorectal cancer, 1 on gastric cancer, and two studies related to pancreatic cancer. Dr. Meyerhardt is the Douglas Gray Woodruff Chair in Colorectal Cancer Research, Clinical Director and Senior Physician at the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute, Deputy Clinical Research Officer at the Dana-Farber Cancer Institute, and Professor of Medicine at Harvard Medical School. He is also the Cancer.Net Associate Editor for gastrointestinal cancers. Dr. Meyerhardt: My name's Jeff Meyerhardt. I'm a gastrointestinal medical oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts. Today I'm going to discuss research on gastrointestinal cancers that were presented at the 2019 ASCO Annual Meeting. And let's talk about four studies: 1 in colon cancer, 1 in gastric cancer, and 2 studies related to pancreatic cancer, all of which are going to affect how patients are treated in the upcoming years. Starting with the studies on colon cancer, there were 2 additional studies looking at the duration of adjuvant therapy for colon cancer. Adjuvant therapy is the chemotherapy that's given after surgery for people who had a resection of their colon cancer that didn't have evidence of metastases. We give adjuvant therapy to try to prevent and reduce the risk of recurrent disease. The standard of care up till a few years ago was to give 6 months of adjuvant therapy. And for most patients who had stage III or lymph node positive disease, that was 6 months of a fluoropyrimidine, either 5-FU, or an oral form capecitabine with oxaliplatin. This was also given to some patients who have higher-risk stage II disease. Two years ago at ASCO, we learned that giving 3 months of therapy was sufficient, or what we'd describe as non-inferior, for some patients who have stage III colon cancer, particularly those who had what would be considered a better-risk stage II colon cancer, and actually particularly if they got a particular regimen of combining capecitabine and oxaliplatin. At this year's ASCO, there was a study looking at patients with stage II disease. Most of them had higher-risk stage II disease, something where they didn't have positive lymph nodes, but some other feature that made you a little bit more worried that there was a relatively higher-risk of recurrent disease. And the findings were essentially very similar to what we saw for stage III disease; that for some patients, 3 months of treatment was adequate, particularly if you gave capecitabine/oxaliplatin, and had less toxicity than 6 months of therapy. But if you gave 5-FU/leucovorin/oxaliplatin, a regimen called FOLFOX, 6 months of treatment was necessary. These studies add to the conclusion that first, we can't treat all colon cancers in the adjuvant setting the same, that we should think of them as risk adjustment, and we also have to make decisions regarding what type of treatment, which will help determine the duration of therapy. The next study I'm going to focus on is looking at gastric cancer and looking specifically at the role of immunotherapy. So what we've already known is that patients who have gastric cancer and esophageal cancer can benefit from immunotherapy in later-line therapy, so after an initial first-line or second-line chemotherapy is no longer helping a patient or is too toxic to continue. The study that was presented at ASCO this year, what is called the KEYNOTE-062 study, was actually looking at 3 different arms of therapy. One was giving a drug pembrolizumab, one of the immunotherapies alone. The second arm was giving chemotherapy alone. And the third arm was giving pembrolizumab with chemotherapy. In looking at what would be the best strategy for patients who are initially being treated for metastatic gastric cancer. They specifically looked at patients where we think there may be a higher chance of activity. So there are certain ways to look at the tumor and score what's the potential in immunotherapy would be helpful. And this is what's called the CPS score. Patients who had had a CPS score of at least 1, and they also broke it down for people that had even a higher score, greater than 10, in the analysis. And what they found is compared to doing standard chemotherapy, in this case, of fluoropyrimidine, 5-FU, or capecitabine with a platinum, cisplatin, giving pembrolizumab could be non-inferior in terms of overall survival for patients as initial therapy for metastatic gastric cancer; that they saw that in patients who had a CPS score greater than 1. They showed actually that it was superior to give pembrolizumab in terms of overall survival if the CPS score was greater than 10. What is a little curious in this study is that progression-free survival, which is how long it takes until you have to switch to therapy, wasn't actually better with pembrolizumab compared to chemotherapy for the people who had relatively lower CPS scores. But it was non-inferior for those who had a greater than 10. The second part of the study was looking at should we give chemotherapy and pembrolizumab at the same time, like the whole kitchen sink, at the same time of both giving chemotherapy and an immunotherapy. And that actually didn't add any benefit to chemotherapy alone. So it was not improvement in overall or progression-free survival. So what do we conclude from KEYNOTE-062? Well first is that there are some patients where giving an immunotherapy upfront by itself can be just as good as starting chemotherapy, particularly those who have a score that's a relatively higher likelihood of benefiting from immunotherapy. But we also learned that combining them together does not add extra bang for the buck as initial treatment. There should still be a therapy considered later, whether you start with pembrolizumab and then later get chemotherapy or vice versa. But doing them all at the beginning does not seem to add additional benefits. There were then 2 studies of note for pancreatic cancer. One of them was an adjuvant study, which again, adjuvant therapy is giving chemotherapy after surgery to try to reduce the risk of recurrent disease. What we know for pancreas cancer, there are several options to consider in terms of adjuvant therapy after surgery. For quite a few years now, the standard was giving a drug called gemcitabine. There was then a study looking at gemcitabine with an oral drug called capecitabine, again, the oral form of 5-FU, and that looked to be a little better than gemcitabine alone. And then several years, a study from the Canadian Cancer Treatment Group and then a Unicancer GI PRODIGE Group looked at a combination of folfirinox, a 4-drug regimen that's now very standard for some patients with metastatic pancreas cancer. In looking at that regimen as adjuvant therapy, compared to gemcitabine alone, that study showed a real significant improvement in terms of recurrence rate and disease-free survival for patients who got this 4-drug regimen compared to gemcitabine alone, and has really become a standard for patients who have a good performance status after their surgery. The current study that was presented at the 2019 ASCO Meeting was looking at a different combination, looking at gemcitabine plus another drug called nab-paclitaxel. It's a combination also used in metastatic pancreatic cancer. It was shown to be better than gemcitabine by itself in metastatic pancreatic cancer. And the hope would be another option for patients in the adjuvant setting. Unfortunately, the study fell a little short in terms of the primary endpoint as initially determined when the protocol was being developed, what was called an independent assessment of disease-free survival. So sending the scans and sending all the data to independent reviewers, and that again just fell a little short statistically. If you look at investigator-assessed disease-free survival, it actually was statistically significant, as well as overall survival. The conclusion for the study is even though it didn't quite meet the mark in terms of what was predefined, it does give suggestion that it is better than giving gemcitabine alone. And there are patients in the adjuvant setting for pancreas cancer where folfirinox is probably not as good of an option: it's a fairly toxic regimen. People who have a performance status having a little more difficulty recovering from the surgery or have more comorbidities, gemcitabine plus nab-paclitaxel probably still should be considered an option for these patients, compared to gemcitabine alone. The final study, which led to a plenary session, which is basically one of the 4 most attractive abstracts in the 2019 ASCO Annual Meeting this year, was looking at maintenance therapy for people with metastatic pancreatic cancer using what's called a PARP inhibitor olaparib. It was specifically for patients who had received a platinum-based chemotherapy and they had a germline mutation of BRCA. So BRCA mutations are commonly known to affect the risk of developing breast and ovarian cancer. There are 2: BRCA 1 and BRCA 2. Those also have association with increased risk of pancreatic cancer. And what we know is the PARP inhibitor, through what are called DNA repair mechanism, do seem to have activity in these various type of cancers, including for patients with metastatic pancreatic cancer. This was specifically looking at people who had metastatic pancreatic cancer. Could you get them off the more cytotoxic chemotherapy for a period of time to do something more of what would be considered a maintenance therapy. So having them for period time off toxic therapy and not impacting their overall outcome. It ends up about 4 to 7 percent of metastatic pancreatic cancer patients harbor a BRCA mutation. What we know about BRCA-mutated pancreatic cancers, they have an increased benefit from a platinum-based chemotherapy, cisplatin or oxaliplatin, so patients had to have had a platinum-based therapy to go on the study. They were on chemotherapy for at least 16 weeks and then they were randomized to stop their chemotherapy and receive elaborate versus placebo until there was disease-free, disease progression, or increased toxicity. And what we saw is that the progression-free survival, the time till they had to restart chemotherapy, actually was doubled with the group receiving the maintenance therapy with olaparib. So that was really an exciting finding and a really important finding where you can get people off of chemotherapy for a period of time until you have to restart chemotherapy. Now there is not a survival benefit that was noted yet on the study. It is still very early to look at overall survival. There are also patients who are able to crossover in terms they got olaparib, another part in their cancer treatment, because of the known benefit in metastatic disease. So overall survival may be a little harder to fully interpret, but I do think that this will become a standard for patients with BRCA-mutated colorectal cancers, to receive chemotherapy for some period of time, several months, and then if they're doing well, then to switch them to a maintenance therapy. So that is our summary of the GI cancer research from the 2019 ASCO Annual Meeting. Again, my name is Jeffrey Meyerhardt, and thank you for listening. ASCO: Thank you, Dr. Meyerhardt. Next, Dr. Guillermo Garcia-Manero will discuss a study on a new immunotherapy drug that offers promising results in patients with acute myeloid leukemia or myelodysplastic syndromes, as well as 2 additional studies that looked at t-cell therapies. Dr. Garcia-Manero is the Deputy Chair of Translational Research and Professor, Department of Leukemia, at The University of Texas MD Anderson Cancer Center in Houston, Texas, and the Chief of the Section of Myelodysplastic Syndromes at MD Anderson Cancer Center. He is also the Cancer.Net Associate Editor for Leukemia. Dr. Garcia-Manero: Hello. I am Guillermo Garcia-Manero. I am a professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center. I'm very happy to summarize some of the key presentations at this year's ASCO meeting in Chicago. Of course, ASCO is big on solid tumor malignancies, but there is more and more information regarding leukemia treatment for our patients, also, at the meeting. This year, there were a number of very interesting presentations. First, I want to start briefly saying that there was a very interesting educational symposium where Drs. Al-Kali, Sekeres, Craddock, and myself discussed how to use these hypomethylating agents, drugs like azacitidine or decitabine in patients with leukemia. This meeting was very well attended by multiple community physicians that attend ASCO, and it contained, I think, very useful information in terms of the use of these compounds for our patients. In terms of research presentations, there were multiple. The one that I actually felt was perhaps more interesting was a presentation by Dr. Sallman from the Moffitt Cancer Center in Tampa where he was describing the first results of a new therapy for patients with MDS and AML and potentially other hematological malignancies and cancers known as Hu5F9-G4. This agent is an antibody that targets a molecule called CD47. This was discovered by Dr. Maute and Dr. Weissman at Stanford. It is known to be a “don’t eat me” signal in a way kind of an alternative immune checkpoint inhibitor type of process. But this is interesting because it's focusing more around macrophages more than lymphocytes and it could have a broad use, again, not only in leukemia and hematological malignancies but potentially many other cancers. I think that this data is very striking because the results of Dr. Sallman indicate a very high level of activity with the combination of the hypomethylating agent azacitidine, in this case, both in MDS and AML. This was agnostic of molecular and cytogenetic alterations. It was well tolerated, although there was a little bit of anemia early on with administration of this therapy. But I think this was one of the most innovative and promising new potential therapies for our patients with leukemia. This drug has been shown to be active in lymphoma and now, we expect that the studies initially done in the UK and in Tampa are going to be expanded to other centers in North America, and they may actually provide with a very interesting innovative and very active new form of therapy for our patients. So I thought that was the most innovative presentation at the ASCO meeting. Of course, there were multiple other presentations. There was additional data on new FLT3 inhibitor known as gilteritinib. This drug recently approved for patients with AML. There was also further information on a new compound known as CX-01 for patients with acute myelogenous leukemia. Again, this is an interesting compound that seems to be a heparin analog, and the early studies are showing significant activity as well for our patients. There was also very interesting data in terms of the phase I results of the ZUMA-3 trial. This is a CAR T-cell type of approach for refractory patients with acute lymphocytic leukemia. And finally, this interesting presentation from the MD Anderson group with an off-the-shelf viral-specific T-cell therapy against patients with adenovirus disease that are immunosuppressed. It's actually very important in a way-- kind of similar therapies for patients that have viral complications, this group have shown, actually, significant activity of similar type of approaches for patients with BK virus and other conditions. So in summary, I think that the meeting was very important like it is every year. I think that we're starting to see presentations at ASCO for new agents of high relevance. I think that the community, at least in MDS and AML, it is very interested on the follow-up with the Hu5F9-G4 agent in combination with AZA for MDS and AML. And we're looking forward to be part and see the results of expanded phase II and potential phase III studies with this compound. And with that, I want to thank you for your attention. ASCO: Thank you Dr. Garcia-Manero. Learn more about these topics and other research presented at the 2019 ASCO Annual Meeting at www.cancer.net, including additional Research Round Up podcasts. And if this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play. This Cancer.Net podcast is part of the ASCO Podcast Network, a collection of 9 programs covering a range of educational and scientific content offering insight into the world of cancer care. You can find all 9 shows, including this one, at podcast.asco.org. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/support.

#030_ASCO 2019 | Gastrintestinal_Duração da terapia adjuvante_Dr. Pedro Usón Junior

MOC Brasil

Play Episode Listen Later Aug 14, 2019 3:33

Dr. Pedro Usón, autor do capítulo de aparelho digestivo do MOC, fala sobre análise prospectiva combinada de quatro estudos randomizados que investigaram a duração da terapia adjuvante com base em oxaliplatina (3 versus 6 meses) em pacientes com câncer colorretal de alto risco em estágio II, confirmando que existe a não inferioridade de CAPOX (3 meses), o que não ocorre com FOLFOX.

terapia asco moc dura o folfox capox

ASCO Guidelines: Duration of Oxaliplatin-Containing Adjuvant Therapy for Stage III Colon Cancer Guideline

Play Episode Listen Later Jul 24, 2019 13:20

TRANSCRIPT 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Hello, and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin. And today, I'm interviewing Dr. Nancy Baxter from St. Michael's Hospital in Toronto, senior author on "Duration of Oxaliplatin-Containing Adjuvant Therapy for Stage III Colon Cancer: ASCO Clinical Practice Guideline." Thank you for being here today, Dr. Baxter. Thanks very much, Shannon, for speaking with me. I'm happy to share our work developing this guideline. So first, can you give us a general overview of what this guideline covers and the studies which provide the evidence? Absolutely. So use of adjuvant therapy for patients with stage III colon cancer is common, and it's effective. We know that these patients are at substantial risk of recurrence of their disease and that adjuvant therapy can reduce that risk. But we also know that comes with a cost. The most effective adjuvant therapy is FOLFOX or oxaliplatin-containing chemotherapy regimens. And we know that a really substantial number of people will end up with neurotoxicity, with peripheral sensory neurotoxicity, that can be long lasting and certainly affects their quality of life. So the whole question was whether the duration of oxaliplatin-containing chemotherapeutic regimens could be shortened when they're used for adjuvant therapy, so if we could give three months instead of six months. Because we know that if we give three months of therapy, the risk of neurotoxicity is much lower. So if we had the same effectiveness with the shorter duration, then we could spare patients the negative consequences of the agent given for a longer period of time. So in developing these guidelines, we looked at the results of international group of trials, the six trials from the IDEA collaboration. So these were six randomized trials in various jurisdictions that tried to look at this question, so three months of an oxaliplatin-based chemotherapeutic regimen for adjuvant therapy for stage III cancer versus six months duration of therapy. And so there was a planned analysis to bring all of these data together to develop the evidence base to make this recommendation. So our guideline and our systematic review basically identified this is the key piece of literature to base our recommendations and guidelines on. That's essentially the main study, so the meta-analysis of these six randomized controlled trials that formed the basis of the IDEA collaboration. So the IDEA collaboration studies-- there were six individual randomized trials that formed part of the IDEA collaboration. And they were conducted in Italy, Greece, Japan, North America, through CALGB/SWOG, the UK, Denmark, Spain, Australia, Sweden, and New Zealand, as well as France. So data came from, really, around the world. The median age of people in the studies was 64 years of age. And these people had a really good performance status, so almost all of these patients had an ECOG performance status of 0 or 1. So they were healthy patients that were in the study. And so some patients received CAPOX, and some received FOLFOX. That wasn't part of the randomization scheme. Other than the CALGB/SWOG study, this was up to the discretion of the investigator or patient. In the SWOG/CALGB study, only FOLFOX was given. And the authors planned a prespecified subgroup analysis to look at differences between CAPOX and FOLFOX. There was also a prespecified analysis to look at differences based on stage. What they found when they looked at the results was that, overall, the difference between groups in terms of the three months versus six months was that the hazard ratio between these two was 1.07, meaning a small difference between the groups in terms of recurrence or death between three months and six months overall. But because the prespecified confidence interval, noninferiority interval, for the difference in outcome was 1.12, the 95% confidence interval for the hazard ratio was above this. So it was 1.15, indicating that this prespecified noninferiority margin was exceeded. And so the study did not prove noninferiority of the three-month regimen. So we're left with an inconclusive result. So that's why our guidelines don't have a strong recommendation for the three months, because we can't rule out a small but potentially important difference between the two groups in terms of recurrence or death. Now, interestingly, when they looked at the prespecified subgroup analysis, which was looking at CAPOX versus FOLFOX, a difference was found. So they actually found that for FOLFOX chemotherapy, three months of therapy was inferior to six months of therapy, while for CAPOX, actually, three months and six months were the same. So it met the criteria of noninferiority. So these are kind of two different conclusions based on which type of chemotherapy was used. This was surprising to the investigators and was not expected. And certainly, it was not consistent with the randomized trials that we have comparing these regimens. So we therefore did not make any conclusions in our recommendations about CAPOX versus FOLFOX. But this is certainly something that requires further investigation in the future. In terms of stage, we did not find that there was an interaction between T stage or end stage when you looked at the differences between the three and the six month. And that was the prespecified analysis. But in non-prespecified analysis, which was the higher risk versus lower risk categories, you did find this difference where the patients with high-risk disease had inferior disease-free survival with three months versus six months of therapy, while those at low risk of disease, it seemed quite safe to give three months versus six months. So that's a long story. But essentially, because the high risk versus low risk analysis was not prespecified, there's a limitation to how strong our recommendations can be to have three months of therapy. However, given that the hazard ratio associated with three months versus six months of therapy for this lower risk group was only 1.01, indicating they were the same, and the risk of neuropathy was substantially higher with six months, this has led to us making recommendations that the three months of therapy is adequate for patients with low-risk disease after discussion with patients about the possible pros and cons. And what are the key recommendations of this guideline? Well, so the recommendations of this guideline do depend on the pathology, so how high risk the patient is. So based on the evidence from the IDEA collaboration, the researchers found that patients who had a high risk of recurrence-- so had T4 disease or heavily node-positive disease, N2 disease-- the six-month duration of therapy was better than the three-month duration of therapy. These studies and the meta-analysis were designed as noninferiority meta-analyses. But it was clear from the results that the three-month duration was inferior when compared to three months for these high-risk patients. So that seems clear, although we know that those patients will also be at more risk of neuropathy. And so that needs to be discussed with patients, as well. So for the second group, which are patients who are at lower risk of recurrence, what we found was there was less of a clear benefit of six months of therapy. The recommendation was that patients who are in this low-risk category-- so T1, T2, or T3 cancers that are N1, so not heavily node-positive-- clinicians can offer three months versus six months of therapy after having a discussion with their patients about the pros and cons of that. So the clinicians can go ahead and offer that to patients and still be within the common guidelines based on evidence for treatment of stage III colon cancer. So because there's some uncertainty after analysis of the IDEA collaboration, one of the really important recommendations that we make is about this shared decision-making approach. So the third recommendation that we make is that oncologists should discuss these factors with their patients who have stage III resected colon cancer and that the duration of therapy needs to take into account the tumor characteristics-- the surgical resection, the number of lymph nodes examined, the comorbidities, the patient functional status, all of these various things-- and there needs to be a discussion of the potential for benefit and the risk of harm based on the duration of therapy. And oncologists definitely discuss these things with their patients. And this just emphasizes how this is yet another component of the discussion that needs to be included, particularly when speaking with low-risk patients who are at substantial risk of harm from neuropathy and are unlikely to benefit greatly by extending chemotherapy to six months. So why is this guideline so important? And how will it change practice? Well, I think, until now, the standard recommendation has been six months of FOLFOX or six months of oxaliplatin-based chemotherapy. And again, there are many patients who have quality of life-affecting neuropathy because of this. So for a substantial proportion of patients who present to us with stage III cancer-- so those that are low risk-- I think this provides some options to them. So they can opt for a shorter duration of chemotherapy with a lower risk of toxicity. This saves time. This saves cost to the patient and to the system and potentially improves their quality of life without a great impact on outcome in terms of disease recurrence. So that's a substantial number, a substantial proportion of our patients, who can be treated in this way. So I think that this is a real benefit. Again, oncologists need to have a conversation with their patients about the pros and cons. But this is an option for their patients, whereas from an evidence-based perspective, it wasn't before the publication of the IDEA collaboration. Finally, how will these guideline recommendations affect patients? So for patients who have heavily node-positive disease-- so high-risk patients with T4 or N2 disease-- it's not going to affect care. So the expectation would be those patients would be treated with six months of therapy, similar to previous recommendations. So this will be for people who are at lower risk of disease recurrence, so patients with T1 to 3 tumors that are N1 positive, so not heavily node positive. So these patients will have the opportunity to opt for a shorter duration of therapy. So that's a major benefit to patients. Again, it's important that there's a discussion and that patients understand the pros and cons. But this is now an option for them, which is excellent. Thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, please go to www.asco.org/gastrointestinal-cancer-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

australia france japan italy toronto spain united kingdom north america new zealand sweden idea greece denmark baxter t2 t3 colon cancer t4 asco t1 n1 n2 stage iii adjuvant therapy ecog folfox oxaliplatin capox asco guidelines shannon mckernin asco guidelines podcast

Gastrointestinal Cancers | Addressing Current Questions and Controversies in the Management of Gastrointestinal Cancers

Play Episode Listen Later Jul 11, 2019 151:30

Proceedings from a CME symposium held at the 2019 ASCO Annual Meeting. Featuring perspectives from Prof Dirk Arnold and Drs Tanios Bekaii-Saab, Joseph Chao, Anthony El-Khoueiry, Richard S Finn, Yelena Y Janjigian, Scott Kopetz and Eileen M O'Reilly. Introduction (00:00) Program overview: Dr Love Hepatocellular Carcinoma (HCC) — Dr El-Khoueiry and Dr Finn (2:01) Case (Dr Gujja): A man in his mid-70s with Child-Pugh A multifocal HCC and a tumor thrombus in the midhepatic vein extending into the floor of the right atrium (2:12) Case (Dr Park): A woman in her early 70s with Child-Pugh B HCC who developed hand-foot syndrome and required a dose reduction while receiving first-line sorafenib and now has progressive disease (16:11) Pancreatic Adenocarcinoma (PAD) — Dr Bekaii-Saab and Dr O'Reilly (41:01) Case (Dr Ibrahim): A man in his late 50s with symptomatic metastatic PAD who experienced a dramatic response to modified FOLFIRINOX (52:14) Cases (Dr Park and Dr Morganstein): Elderly patients with metastatic PAD, poor performance status and disease progression on nab paclitaxel/gemcitabine (1:00:22) Case (Dr Gujja): A woman in her late 60s with metastatic PAD and a germline BRCA2 mutation (1:06:00) Gastric/Gastroesophageal (GEJ) Cancers — Dr Chao and Dr Janjigian (1:20:30) Case (Dr Favaro): A man in his late 30s with HER2-positive metastatic gastric cancer who received paclitaxel/ramucirumab after disease progression and worsening neuropathy on FOLFOX/trastuzumab (1:35:52) Case (Dr Morganstein): A man in his mid-60s with microsatellite-stable, PD-L1-negative metastatic GEJ cancer who attained a complete response to second-line nivolumab (1:39:34) Colorectal Cancer (CRC) — Prof Arnold and Dr Kopetz (1:52:56) Case (Dr Morganstein): A woman in her early 40s with widespread RAS wild-type, microsatellite-stable, left-sided metastatic CRC (mCRC) (1:57:43) Case (Dr Ibrahim): A woman in her late 70s with MSI-high mCRC who refused chemotherapy and experienced a completed response to pembrolizumab (2:04:01) Case (Dr Favaro): A woman in her late 80s with RAS wild-type, microsatellite-stable, right-sided mCRC with a BRAF V600E tumor mutation who received BRAF-targeted therapy (2:13:49) Select publications

Oncology Grand Rounds Series: Part 1 — Gastrointestinal Cancers

Play Episode Listen Later Jun 24, 2019 89:42

Video proceedings from the first in a series of 6 integrated symposia held at the 2019 ONS Annual Congress. Featuring perspectives from Ms Jessica Mitchell, Dr Eileen M O'Reilly, Dr Philip A Philip and Ms Amanda Wagner. Introduction 0m0s Program overview: Dr Love Colorectal Cancer (CRC) (5:43) Case (Ms Wagner): A man in his mid-70s with metastatic appendiceal carcinoma who received third-line TAS-102 after disease progression on FOLFIRI/bevacizumab and FOLFOX/bevacizumab (8:11) Case (Ms Mitchell): A man in his early 40s with MSI-high metastatic CRC who experienced a dramatic response to pembrolizumab (29:59) Hepatocellular Carcinoma (HCC) (36:14) Case (Ms Wagner): A man in his mid-40s with metastatic HCC who developed hand-foot syndrome while receiving sorafenib (38:21) Case (Ms Mitchell): A woman in her mid-60s with metastatic HCC who had a good response to nivolumab but developed arthralgias (58:07) Pancreatic Cancer (1:04:33) Case (Ms Mitchell): A woman in her mid-70s with locally advanced pancreatic cancer who received neoadjuvant FOLFIRINOX (1:04:47) Case (Ms Wagner): A man in his mid-60s with metastatic pancreatic cancer who received nab paclitaxel/gemcitabine and nal-IRI (1:12:13) Gastroesophageal Cancers (1:20:20) Case (Ms Wagner): A man in his early 70s with metastatic esophageal adenocarcinoma who received FOLFOX followed by paclitaxel/ramucirumab upon disease progression (1:20:43) Case (Ms Mitchell): A woman in her early 60s with metastatic gastric cancer who experienced an excellent response to pembrolizumab but developed autoimmune hypothyroidism (1:24:02) Select publications

video cancer series select rounds oncology tas pancreatic cancer crc gastrointestinal msi hcc iri grand rounds jessica mitchell folfox folfirinox folfiri eileen m o'reilly

Colorectal | Investigator Perspectives on the Current Utility of Validated and Emerging Biomarkers to Guide Treatment Decision-Making for Patients with Metastatic Colorectal Cancer

Play Episode Listen Later May 21, 2019 133:02

A roundtable discussion featuring perspectives from Drs Tanios Bekaii-Saab and Alan P Venook on emerging research and cases from their practices. Introduction — Indications for and Practical Implementation of Biomarker Analysis for Patients with Metastatic Colorectal Cancer (mCRC) Biomarker assessment for patients with mCRC (0:00) Perspectives on genomic testing platforms used to perform biomarker analysis for mCRC (3:16) Role of rebiopsy and repeat biomarker assessment for patients with progressive mCRC (7:11) Biology of mCRC and Role of Tumor Sidedness in First- and Later-Line Decision-Making Implications of RAS testing for selection of therapy (10:22) Tumor sidedness and therapeutic decision-making (13:55) Similarities and differences in the design and primary endpoints of the Phase III CALGB-80405 and FIRE-3 trials evaluating first-line chemotherapy in combination with cetuximab and/or bevacizumab for KRAS wild-type mCRC (18:12) Prognostic and predictive relevance of primary tumor sidedness in patients with RAS wild-type mCRC on the CALGB-80405 and FIRE-3 trials (22:11) Efficacy of EGFR inhibitor- versus bevacizumab-based treatments for left- versus right-sided RAS wild-type mCRC (23:28) Choosing between EGFR inhibitor- and bevacizumab-based treatments as first- and second-line therapy for patients with symptomatic left-sided RAS wild-type mCRC (31:39) Case (Dr Venook): A woman in her thirties with left-sided RAS wild-type mCRC receives first-line FOLFOXIRI (40:14) Therapeutic options for younger patients with left-sided RAS wild-type mCRC and disease progression on first-line FOLFOXIRI (43:58) Case (Dr Bekaii-Saab): A man in his sixties with left-sided RAS wild-type mCRC and disease progression after 2 years of first-line “stop-and-go” FOLFIRI/bevacizumab receives FOLFIRI/panitumumab (45:56) Activity of cetuximab versus panitumumab and practical considerations for use (49:37) Clinical experience with and management of EGFR inhibitor-associated dermatologic toxicities (51:45) Second opinion: Second-line therapy options for patients with left-sided RAS wild-type mCRC and disease progression on first-line FOLFIRI/bevacizumab (55:48) Faculty perspectives on therapeutic algorithms for first- through later-line therapy for left- versus right-sided RAS wild-type mCRC (1:00:43) Current and Future Treatment Options for Patients with BRAF Mutations Efficacy of EGFR inhibition in patients with mCRC and atypical (non-V600E) BRAF mutations (1:08:18) Clinical presentation of and prognosis for patients with mCRC and a BRAF V600E tumor mutation (1:12:22) Activity and tolerability of EGFR/MEK/BRAF-inhibitor combinations in patients with mCRC and a BRAF V600E tumor mutation (1:13:59) Importance of BRAF testing in mCRC; strategies for first-line therapy and beyond (1:16:13) Improved tolerability with triplet EGFR/MEK/BRAF-inhibitor combinations in comparison to anti-EGFR monotherapy or doublet combinations (1:19:54) Case (Dr Venook): A woman in her forties with mCRC, a BRAF V600E tumor mutation and rapid disease progression on first-line FOLFOXIRI/bevacizumab attains long-term disease stabilization with encorafenib/binimetinib/panitumumab (1:22:13) Case (Dr Bekaii-Saab): A man in his fifties with mCRC and a BRAF V600E tumor mutation receives second-line encorafenib/binimetinib/cetuximab on a clinical trial (1:23:27) Optimal Management of Microsatellite Instability (MSI)-High or DNA Mismatch Repair-Deficient mCRC Assessment of MSI status and tumor mutation burden as predictors of response to immune checkpoint blockade (1:26:47) Sequencing of anti-PD-1/PD-L1 checkpoint inhibitors for MSI-high mCRC (1:33:19) Neoadjuvant ipilimumab with nivolumab for early-stage colon cancer (1:36:39) Activity and tolerability of immune checkpoint inhibitors alone and in combination in patients with MSI-high mCRC (1:37:34) Case (Dr Bekaii-Saab): A woman in her fifties with MSI-high, right-sided mCRC and a RAS mutation receives second-line pembrolizumab (1:42:11) Case (Dr Venook): A woman in her forties with Stage III CRC initially treated with adjuvant FOLFOX experiences disease progression and receives an assessment of MSI-high disease (1:46:37) Perspective on pseudoprogression in patients undergoing immune checkpoint inhibitor therapy (1:48:50) HER2 Positivity and Other Potential Biomarkers Biology and epidemiology of mCRC with HER2 amplification/mutation (1:51:16) Activity of and duration of response to dual HER2-targeted therapy in patients with mCRC and HER2 amplification/mutation (1:54:09) Therapeutic options for patients with mCRC and HER2 amplification/mutation (1:55:45) Case (Dr Venook): A man in his fifties with left-sided, RAS wild-type mCRC and HER2 amplification/mutation receives fourth-line trastuzumab/pertuzumab (2:00:13) Case (Dr Bekaii-Saab): A woman in her sixties with left-sided, RAS wild-type mCRC and HER2 amplification/mutation receives third-line trastuzumab/tucatinib on a clinical trial (2:01:57) Activity of tucatinib in patients with mCRC and HER2 amplification/mutation (2:04:40) Optimizing the risk-benefit ratios of systemic therapy options for patients with mCRC (2:07:36) Modulation of the gut microbiome to enhance response to anti-PD-1 immunotherapy; effects of antibiotics on response to immune checkpoint inhibitors (2:11:12) Select publications

guide fire current patients treatments perspectives perspective biology decision making emerging activity faculty clinical optimizing improved select utility pd therapeutic similarities tumors efficacy ras biomarkers sequencing colorectal cancer msi validated modulation metastatic her2 egfr kras prognostic pd l1 braf neoadjuvant mcrc braf v600e folfox calgb folfiri investigator perspectives

ASCO GI 2019

ASCO Guidelines Podcast Series

Play Episode Listen Later Apr 25, 2019 21:33

Daniel G. Haller, MD, of the University of Pennsylvania, Philadelphia, joins Blood & Cancer host David H. Henry, MD, also of the University of Pennsylvania, to review the top research presented at ASCO GI 2019. Plus, in Clinical Correlation, Ilana Yurkiewicz, MD, of Stanford (Calif.) University shares the story of a patient who had no questions about the details of his treatment but needed answers about the “big picture.” Show Notes By Emily Bryer, DO, resident in the department of internal medicine, University of Pennsylvania, Philadelphia Phase 2 trial of pembrolizumab (Keytruda), chemotherapy, and trastuzumab (Herceptin) in gastric cancer: Patients had previously untreated HER2 IHC+ or FISH+ tumors. Patients received pembrolizumab, trastuzumab/CAPOX (capecitabine and oxaliplatin) or FOLFOX (folinic acid, fluorouracil, and oxaliplatin). Patients all had a 100% response rate, prompting an ongoing phase 3 trial (KEYNOTE-811). Third-line therapy for gastric cancer – TAGS, a phase 3 trial: supportive care vs. trifluridine plus tipiracil (Lonsurf): Gastrectomy did not affect outcome, safety, or pharmacokinetics. Neutropenia, a major toxicity, is manageable. Trifluridine and tipiracil are now a National Comprehensive Cancer Network Level 1 guideline for third-line therapy in patients with gastric cancer. Neoadjuvant chemotherapy in pancreatic cancer: Compared neoadjuvant gemcitabine and S1 (NAC-GS) with upfront surgery for patients with pancreatic ductal adenocarcinoma and planned resection. Saw a significant survival benefit (37 months) of NAC-GS over upfront surgery (26 months). Circulating tumor cells (CTC) in colorectal cancer: Studied patients with planned colonoscopies for colorectal screening. Took blood at the time of the procedure. Identified an absolute correlation with CTC and an increased disease burden in patients with colon cancer. Additional reading: Lancet Oncol. 2018 Nov;19(11):1437-48. Oncotarget. 2018 May 11;9(36):24561-71.

american university care doctors research society philadelphia pennsylvania cancer healthcare professional patients md fish phase nurses physicians med clinical keynote rn clinic oncology identified bsn np chemo immunotherapy haller studied asco ctc hematology david h circulating daniel g phys blood cancer neoadjuvant meded neutropenia keytruda herceptin folfox asco gi oncotarget lancet oncol capox clinical correlation

Duration of Oxaliplatin-Containing Adjuvant Therapy for Stage III Colon Cancer Guideline

Play Episode Listen Later Apr 15, 2019 13:20

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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Hello, and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin. And today, I'm interviewing Dr. Nancy Baxter from St. Michael's Hospital in Toronto, senior author on "Duration of Oxaliplatin-Containing Adjuvant Therapy for Stage III Colon Cancer: ASCO Clinical Practice Guideline." Thank you for being here today, Dr. Baxter. Thanks very much, Shannon, for speaking with me. I'm happy to share our work developing this guideline. So first, can you give us a general overview of what this guideline covers and the studies which provide the evidence? Absolutely. So use of adjuvant therapy for patients with stage III colon cancer is common, and it's effective. We know that these patients are at substantial risk of recurrence of their disease and that adjuvant therapy can reduce that risk. But we also know that comes with a cost. The most effective adjuvant therapy is FOLFOX or oxaliplatin-containing chemotherapy regimens. And we know that a really substantial number of people will end up with neurotoxicity, with peripheral sensory neurotoxicity, that can be long lasting and certainly affects their quality of life. So the whole question was whether the duration of oxaliplatin-containing chemotherapeutic regimens could be shortened when they're used for adjuvant therapy, so if we could give three months instead of six months. Because we know that if we give three months of therapy, the risk of neurotoxicity is much lower. So if we had the same effectiveness with the shorter duration, then we could spare patients the negative consequences of the agent given for a longer period of time. So in developing these guidelines, we looked at the results of international group of trials, the six trials from the IDEA collaboration. So these were six randomized trials in various jurisdictions that tried to look at this question, so three months of an oxaliplatin-based chemotherapeutic regimen for adjuvant therapy for stage III cancer versus six months duration of therapy. And so there was a planned analysis to bring all of these data together to develop the evidence base to make this recommendation. So our guideline and our systematic review basically identified this is the key piece of literature to base our recommendations and guidelines on. That's essentially the main study, so the meta-analysis of these six randomized controlled trials that formed the basis of the IDEA collaboration. So the IDEA collaboration studies-- there were six individual randomized trials that formed part of the IDEA collaboration. And they were conducted in Italy, Greece, Japan, North America, through CALGB/SWOG, the UK, Denmark, Spain, Australia, Sweden, and New Zealand, as well as France. So data came from, really, around the world. The median age of people in the studies was 64 years of age. And these people had a really good performance status, so almost all of these patients had an ECOG performance status of 0 or 1. So they were healthy patients that were in the study. And so some patients received CAPOX, and some received FOLFOX. That wasn't part of the randomization scheme. Other than the CALGB/SWOG study, this was up to the discretion of the investigator or patient. In the SWOG/CALGB study, only FOLFOX was given. And the authors planned a prespecified subgroup analysis to look at differences between CAPOX and FOLFOX. There was also a prespecified analysis to look at differences based on stage. What they found when they looked at the results was that, overall, the difference between groups in terms of the three months versus six months was that the hazard ratio between these two was 1.07, meaning a small difference between the groups in terms of recurrence or death between three months and six months overall. But because the prespecified confidence interval, noninferiority interval, for the difference in outcome was 1.12, the 95% confidence interval for the hazard ratio was above this. So it was 1.15, indicating that this prespecified noninferiority margin was exceeded. And so the study did not prove noninferiority of the three-month regimen. So we're left with an inconclusive result. So that's why our guidelines don't have a strong recommendation for the three months, because we can't rule out a small but potentially important difference between the two groups in terms of recurrence or death. Now, interestingly, when they looked at the prespecified subgroup analysis, which was looking at CAPOX versus FOLFOX, a difference was found. So they actually found that for FOLFOX chemotherapy, three months of therapy was inferior to six months of therapy, while for CAPOX, actually, three months and six months were the same. So it met the criteria of noninferiority. So these are kind of two different conclusions based on which type of chemotherapy was used. This was surprising to the investigators and was not expected. And certainly, it was not consistent with the randomized trials that we have comparing these regimens. So we therefore did not make any conclusions in our recommendations about CAPOX versus FOLFOX. But this is certainly something that requires further investigation in the future. In terms of stage, we did not find that there was an interaction between T stage or end stage when you looked at the differences between the three and the six month. And that was the prespecified analysis. But in non-prespecified analysis, which was the higher risk versus lower risk categories, you did find this difference where the patients with high-risk disease had inferior disease-free survival with three months versus six months of therapy, while those at low risk of disease, it seemed quite safe to give three months versus six months. So that's a long story. But essentially, because the high risk versus low risk analysis was not prespecified, there's a limitation to how strong our recommendations can be to have three months of therapy. However, given that the hazard ratio associated with three months versus six months of therapy for this lower risk group was only 1.01, indicating they were the same, and the risk of neuropathy was substantially higher with six months, this has led to us making recommendations that the three months of therapy is adequate for patients with low-risk disease after discussion with patients about the possible pros and cons. And what are the key recommendations of this guideline? Well, so the recommendations of this guideline do depend on the pathology, so how high risk the patient is. So based on the evidence from the IDEA collaboration, the researchers found that patients who had a high risk of recurrence-- so had T4 disease or heavily node-positive disease, N2 disease-- the six-month duration of therapy was better than the three-month duration of therapy. These studies and the meta-analysis were designed as noninferiority meta-analyses. But it was clear from the results that the three-month duration was inferior when compared to three months for these high-risk patients. So that seems clear, although we know that those patients will also be at more risk of neuropathy. And so that needs to be discussed with patients, as well. So for the second group, which are patients who are at lower risk of recurrence, what we found was there was less of a clear benefit of six months of therapy. The recommendation was that patients who are in this low-risk category-- so T1, T2, or T3 cancers that are N1, so not heavily node-positive-- clinicians can offer three months versus six months of therapy after having a discussion with their patients about the pros and cons of that. So the clinicians can go ahead and offer that to patients and still be within the common guidelines based on evidence for treatment of stage III colon cancer. So because there's some uncertainty after analysis of the IDEA collaboration, one of the really important recommendations that we make is about this shared decision-making approach. So the third recommendation that we make is that oncologists should discuss these factors with their patients who have stage III resected colon cancer and that the duration of therapy needs to take into account the tumor characteristics-- the surgical resection, the number of lymph nodes examined, the comorbidities, the patient functional status, all of these various things-- and there needs to be a discussion of the potential for benefit and the risk of harm based on the duration of therapy. And oncologists definitely discuss these things with their patients. And this just emphasizes how this is yet another component of the discussion that needs to be included, particularly when speaking with low-risk patients who are at substantial risk of harm from neuropathy and are unlikely to benefit greatly by extending chemotherapy to six months. So why is this guideline so important? And how will it change practice? Well, I think, until now, the standard recommendation has been six months of FOLFOX or six months of oxaliplatin-based chemotherapy. And again, there are many patients who have quality of life-affecting neuropathy because of this. So for a substantial proportion of patients who present to us with stage III cancer-- so those that are low risk-- I think this provides some options to them. So they can opt for a shorter duration of chemotherapy with a lower risk of toxicity. This saves time. This saves cost to the patient and to the system and potentially improves their quality of life without a great impact on outcome in terms of disease recurrence. So that's a substantial number, a substantial proportion of our patients, who can be treated in this way. So I think that this is a real benefit. Again, oncologists need to have a conversation with their patients about the pros and cons. But this is an option for their patients, whereas from an evidence-based perspective, it wasn't before the publication of the IDEA collaboration. Finally, how will these guideline recommendations affect patients? So for patients who have heavily node-positive disease-- so high-risk patients with T4 or N2 disease-- it's not going to affect care. So the expectation would be those patients would be treated with six months of therapy, similar to previous recommendations. So this will be for people who are at lower risk of disease recurrence, so patients with T1 to 3 tumors that are N1 positive, so not heavily node positive. So these patients will have the opportunity to opt for a shorter duration of therapy. So that's a major benefit to patients. Again, it's important that there's a discussion and that patients understand the pros and cons. But this is now an option for them, which is excellent. Thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, please go to www.asco.org/gastrointestinal-cancer-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

australia france japan italy toronto spain united kingdom north america new zealand sweden idea greece denmark guidelines baxter t2 t3 colon cancer t4 asco t1 n1 n2 stage iii adjuvant therapy ecog folfox oxaliplatin capox shannon mckernin asco guidelines podcast

GI | Meet The Professors: Clinical Investigator Perspectives on Key Questions and Emerging Research in the Management of Colorectal, Gastric and Hepatocellular Cancer

Play Episode Listen Later Mar 29, 2019 120:52

Meet The Professors: Clinical Investigator Perspectives on Key Questions and Emerging Research in the Management of Colorectal, Gastric and Hepatocellular Cancer. Proceedings from a CME symposium held at the 2019 Gastrointestinal Cancers Symposium. Featuring perspectives on the following topics and cases from Dr Ghassan Abou-Alfa, Dr Peter C Enzinger, Dr Tim Greten, Dr David H Ilson, Dr Wells A Messersmith and Prof Eric Van Cutsem: Gastric and Gastroesophageal Cancer Case (Dr Enzinger): A 72-year-old woman with metastatic squamous cell carcinoma of the esophagus and a high PD-L1 combined positive score (CPS) receives third-line pembrolizumab (00:00) KEYNOTE-181: Results of a Phase III trial of pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal carcinoma (4:34) Sequencing anti-PD-1 checkpoint inhibitors for patients with metastatic HER2-negative gastric cancer and a PD-L1 CPS of 1 or higher (7:37) Case (Dr Ilson): A 71-year-old man with microsatellite-stable gastroesophageal junction (GEJ) adenocarcinoma and a high PD-L1 CPS (11:57) Research supporting the FDA approval of pembrolizumab for recurrent or advanced gastric or GEJ adenocarcinoma with a PD-L1 CPS of 1 or higher after 2 or more lines of chemotherapy (16:03) Clinical implications of the negative Phase III KEYNOTE-061 trial of pembrolizumab versus paclitaxel for previously treated advanced gastric or GEJ cancer (17:26) ATTRACTION-2: Results of a Phase III trial of nivolumab versus placebo for unresectable advanced or recurrent gastric or GEJ adenocarcinoma after at least 2 previous chemotherapy regimens (19:51) Second-line therapy options for patients with metastatic microsatellite-stable gastric cancer who experience disease progression on first-line FOLFOX (20:51) Results of the Phase III TAGS study: Efficacy, tolerability and potential clinical role of TAS-102 for patients with heavily pretreated metastatic gastric cancer (23:52) INTEGRATE: Results of a Phase II trial of regorafenib for patients with refractory gastric cancer (28:03) Select ongoing Phase III studies of other novel agents and strategies for metastatic gastric or GEJ cancer (30:30) Approach to second-line therapy for patients with metastatic HER2-positive, microsatellite-stable gastric cancer who experience disease progression on FOLFOX/trastuzumab (33:24) Case (Dr Enzinger): A man with moderately differentiated HER2-positive metastatic GEJ adenocarcinoma (35:18) Case (Dr Ilson): A 67-year-old woman with proximal gastric adenocarcinoma receives neoadjuvant FOLFOX (37:54) Hepatocellular Carcinoma (HCC) Perspective on the recent advances in the treatment of HCC (42:10) Selection of first-line therapy for patients with HCC (46:05) Case (Dr Abou-Alfa): A 63-year-old man with a history of hepatitis C is diagnosed with HCC with metastasis to the bone (47:23) Choice of lenvatinib versus sorafenib as first-line therapy (50:15) Efficacy and tolerability of lenvatinib versus sorafenib as up-front therapy in the Phase III REFLECT trial (Study 304) (51:27) Therapeutic options for patients with HCC in the second-line setting (54:00) Results of the Phase III RESORCE trial of regorafenib for patients with unresectable HCC who experience disease progression on sorafenib (57:28) Case (Dr Abou-Alfa): A 71-year-old man with Stage IV hepatitis C-related HCC requires a dose reduction with second-line cabozantinib (59:42) Activity and side-effect profile of cabozantinib; results from the Phase III CELESTIAL trial of cabozantinib for patients with advanced HCC (1:00:59) Case (Dr Greten): A 72-year-old man with a history of hepatitis B and high alpha-fetoprotein (AFP) receives ramucirumab after disease progression on sorafenib (1:03:09) REACH-2: A Phase III study of ramucirumab as second-line treatment for patients with advanced HCC and elevated AFP after first-line sorafenib (1:04:05) Case (Dr Greten): A 37-year-old man with HCC metastatic to the omentum achieves a pathologic complete response with durvalumab (1:07:21) Role of molecular profiling for patients with HCC (1:11:18) KEYNOTE-224: A Phase II study of pembrolizumab in patients with advanced HCC previously treated with sorafenib (1:13:4) Activity of nivolumab in the Phase I/II CheckMate 040 study for patients with advanced HCC (1:15:47) Response and tolerability of atezolizumab/bevacizumab for patients with advanced HCC on a Phase Ib trial (1:17:14) Ongoing investigation of anti-PD-1/PD-L1 and anti-CTLA-4 combinations in HCC (1:19:52) Colorectal Cancer (CRC) Treatment algorithm for metastatic CRC (mCRC) based on tumor sidedness and biomarker status (1:22:06) Efficacy and tolerability of anti-EGFR antibodies (1:26:52) Case (Prof Van Cutsem): A 59-year old woman with mCRC, a BRAF V600E mutation and microsatellite-stable disease receives cetuximab, encorafenib and binimetinib on the BEACON CRC trial after disease progression on FOLFOX/bevacizumab (1:31:07) Management of mCRC with a BRAF V600E mutation (1:33:42) Results of the SWOG S1406 trial of irinotecan and cetuximab with or without vemurafenib for mCRC with a BRAF mutation (1:37:13) Efficacy and safety of encorafenib, binimetinib and cetuximab in the Phase III BEACON CRC study for patients with mCRC and a BRAF V600E mutation (1:38:35) Case (Dr Messersmith): A 40-year old man with microsatellite instability (MSI)-high mCRC and Lynch syndrome achieves a near-complete response after receiving an anti-PD-L1 antibody on a clinical trial (1:40:16) Role of checkpoint inhibitors for patients with MSI-high mCRC (1:41:42) Efficacy of anti-PD-1/PD-L1 antibodies in patients with microsatellite-stable disease (1:45:40) Ongoing Phase III trials evaluating immune checkpoint inhibitors for patients with MSI-high mCRC (1:47:55) Case: A 56-year-old woman with mCRC and a KRAS exon 2 mutation receives regorafenib as third-line therapy (1:49:17) ReDOS: Optimal dosing of regorafenib in refractory mCRC; REVERCE: Sequencing of regorafenib and cetuximab for previously treated mCRC (1:57:01) Efficacy and safety of TAS-102 in mCRC (1:58:58) Select publications

research management reach study cancer fda attraction results activity clinical selection keynote ongoing lynch select pd therapeutic professors efficacy cps proceedings afp cme tas key questions sequencing phase ii msi colorectal stage iv phase iii gastric hcc her2 egfr kras pd l1 braf ctla mcrc emerging research clinical investigator braf v600e folfox investigator perspectives gastrointestinal cancers symposium

ESMO 2018 and more

cancer experiences surgery symptoms side effects chemotherapy chemo colon cancer stage iv neuropathy stage 4 cancer hipec folfox

Play Episode Listen Later Feb 14, 2019 23:46

David Henry, MD, welcomes Daniel G. Haller, MD, to rehash research from ESMO 2018 as well as the way the meeting itself was run. And Ilana Yurkiewicz, MD, stops by for this week’s Clinical Correlation. Dr. Yurkiewicz is a Hematology Fellow at Stanford and is also a columnist at MDedge Hematology/Oncology. More from Dr. Yurkiewicz here. Contact us: podcasts@mdedge.com MDedge on Twitter: @mdedgehemonc Dr. Ilana Yurkiewicz on Twitter: @ilanayurkiewicz SHOW NOTES By Emily Bryer, DO Resident in the department of internal medicine, University of Pennsylvania Health System CheckMate 142: Durable clinical benefit with nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite high (MSI-H) and non-MSI-H colon cancer Phase 2 study included 45 patients with metastatic colorectal cancer Overall response rate (primary end point) was 60% and disease control rate was 84% Almost every patient had some response and the therapy was well-tolerated https://bit.ly/2TljlQE Tribe 2: FOLFOXIRI plus bevacizumab followed by reintroduction of FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab Phase 3 study of 654 patients with unresectable metastatic colorectal cancer Progression free survival (primary end point) of FOLFOXIRI regimen was 18.9 months, compared with 16.2 months of the FOLFOX then FOLFIRI regimen Side effects of FOLFOXIRI: febrile neutropenia, neutropenia, GI toxicities https://bit.ly/2EMKBOa Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomized, double-blind, placebo-controlled, phase 3 trial Phase 3 study included 506 patients with metastatic gastric cancer Trifluridine/tipiracil (oral drug) provided a 2-month overall survival advantage (primary end point), compared with placebo Major side effect: neutropenia https://bit.ly/2tW7PMI Safety and clinical activity of 1L atezolizumab plus bevacizumab in a phase 1b study in hepatocellular carcinoma (HCC) Phase 1B study included 100 patients with HCC who had not received prior therapy Disease control rate was high as was duration of response Primary outcomes included safety and efficacy The overall response rate was 34% and the most common side effect was hypertension https://bit.ly/2EEPKaO

university health care doctors society european cancer safety patients md drugs medical disease trials cure phase stanford tribe primary med clinical gi progression oncology efficacy durable chemotherapy upenn haller oncologists hematology hcc daniel g radiotherapy 1l saftey esmo david henry folfox msi h folfiri mdedge clinical correlation mdedge hematology oncology

Ep 3 Cancer Recap Part 2

VixMix

Play Episode Listen Later Dec 20, 2018 437618:21

Hi! Listen to the second part of my cancer summary. This episode covers the side effects I endured during the start of my chemotherapy, FOLFOX, and the surgery I had (HIPEC surgery). It was a crazy and unexpected ride but I would do it all over again.Contact info to send questions to the podcast are listed below.Email: vixmixpodcast@gmail.comVoiceMail: 505-333-8232Instagram: @vixmixpodcast

cancer hipec folfox

Ep 3 Cancer Recap Part 2

VixMix

Play Episode Listen Later Dec 20, 2018 24:11

FOLFOX (MOSAIC Trial)

ASCO eLearning Weekly Podcasts

Play Episode Listen Later Dec 13, 2018 20:16

The Landmarks in Oncology Pharmacy series returns with a discussion of MOSAIC: FOLFOX adjuvant chemotherapy for stage ii & STAGE III colon cancer.

trial mosaic landmarks stage iii folfox oncology pharmacy

ASCO Guideline: Metastatic Pancreatic Cancer

Play Episode Listen Later Oct 17, 2018 7:11

TRANSCRIPT [MUSIC PLAYING] Welcome to the ASCO Guidelines episode of the ASCO University weekly podcast. My name is Alexander Drilon, and I'm the clinical director of the early drug development service at Memorial Sloan Kettering Cancer Center and editorial board member for ASCO University. Today we feature an ASCO guideline published in the Journal of Clinical Oncology. The episode you are about to hear was originally aired on the ASCO Guidelines podcast series. The ASCO Guidelines podcast series features interviews with panelists of recently published ASCO clinical practice guidelines products, highlighting recommendations and noteworthy qualifying statements made by the expert panel. [MUSIC PLAYING] Hello, and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin, and today I'm interviewing Dr. Davendra Sohal from Cleveland Clinic, lead author on Metastatic Pancreatic Cancer American Society of Clinical Oncology Clinical Practice Guideline update. Thank you for being here today, Dr. Sohal. Thanks for having me. It's a pleasure. So this update is focused on revising the recommendations on second line treatment for metastatic pancreatic cancer. Can you tell us about the studies that informed this update? Certainly. The first study is a paper published in Science on PD-1 inhibition and solid tumors. This study included 86 patients with mismatch repair deficient tumors, also known as microsatellite instability high tumors. In this study, 53% of the patients had an objective response with a disease control rate of 71% across multiple histologies. The study also included eight patients with pancreatic cancer, two of whom had complete responses with a disease control rate of 75%. This is the study that informed our recommendation for checkpoint inhibitor therapy in the second line setting. The second study is the PANCREOX trial published in JCO, which randomized patients to 5-fluorouracil or FOLFOX. With 108 patients, the primary outcome of overall survival was 9.9 months in the control 5-fluorouracil arm, and surprisingly, only 6.1 months in the FOLFOX arm. This study informed our recommendation for chemotherapy regimens in the second line setting. And what are the new and updated recommendations for second line treatment? For second line treatment of metastatic pancreatic cancer, our first recommendation now is to consider testing for mismatch repair deficiency or microsatellite instability in patients who are candidates for checkpoint inhibitors therapy. Any standard form of testing is acceptable, whether IHC or PCR or next-gen sequencing. Patients who have mismatch repair deficient or microsatellite instability high tumors should be treated with pembrolizumab given the excellent responses noted in the study we just discussed. For patients who do not meet these criteria for checkpoint inhibitor therapy, second line therapy with gemcitabine plus nab-paclitaxel can be offered to those who received FOLFIRINOX in the first line and meet other criteria for aggressive chemotherapy as detailed in the guideline. Now, for patients who receive gemcitabine plus nab-paclitaxel in the first line, fluorouracil plus nanoliposomal irinotecan is the preferred second line therapy. Where nanoliposomal irinotecan is not accessible, fluorouracil plus regular irinotecan is an acceptable alternative. As I mentioned the combination, of 5-fluorouracil plus oxaliplatin can be considered as an option in this setting, but we have noted a qualifying statement about the PANCREOX study whose results are inconsistent with the CONCORD-3 study using the same agents as the off regimen. Given these conflicting results from different studies of 5-fluorouracil plus oxaliplatin, the recommendation for its use in the second line setting has been softened. Can you also give us an overview of the recommendations from the original 2016 version that the expert panel decided were still valid? Sure. In 2016, the expert panel made recommendations which span from initial assessment through to follow up and surveillance. For every patient with metastatic pancreatic cancer, a multi-phase CT scan should be performed and baseline performance datas and comorbidities should be evaluated. Goals of care should be discussed with a multidisciplinary team, and all patients should be offered information about clinical trials. Outside of a clinical trial, standard first line treatment options include FOLFIRINOX, gemcitabine plus nab-paclitaxel, or gemcitabine alone. And the full guideline provides details on which treatment is appropriate for which patients. The panel also recommended that every patient should be offered palliative care early in their treatment. These recommendations were endorsed in the update and are reprinted in totality in the bottom line box on the second page of the article. And finally, what are some important things to note about communicating with patients with pancreatic cancer, especially in the metastatic setting? Excellent point. It is important to communicate that participation in clinical studies is strongly encouraged. These studies could include new treatments, or supportive care measures, or collection of blood and tumor samples for further research, et cetera. While chemotherapy forms the backbone of treatment, it is only one component, and that is an important point to make. The use of supportive care or palliative care is strongly encouraged for all patients with metastatic pancreatic cancer in order to maximize not just the quantity, but also the quality of life. Great. Thank you for your work on this important guideline, and thank you for your time today, Dr. Sohal. Sure. Thank you very much. I'd like to thank our panel for diligent data review and dedicated discussions and the ASCO staff for all their support in producing the update. Thank you. And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague. [MUSIC PLAYING] 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

science goals journal patients guidelines pd concord pcr cleveland clinic asco pancreatic cancer memorial sloan kettering cancer center metastatic clinical oncology ihc jco folfox folfirinox asco guidelines asco university shannon mckernin

Adjuvant cetuximab in the PETACC8 trial for stage III colon cancer

ESMO 2016

Play Episode Listen Later Aug 3, 2017 3:14

Prof Taïeb speaks with ecancer at ESMO 2016 about the improved patient outcomes following the addition of cetuximab, an EGFR inhibitor, to standard FOLFOX therapy for patients with full RAS and BRAF wild type. This follows similar results for adding cetuximab to FOLFOX in RAS wildtype metastatic colorectal cancer, reported at the ESMO 18th World Congress on Gastrointestinal Cancer. Prof Taïeb outlines the results of this trial, and considers what this might mean for patients depending on their tumour genotype, tumour location, and the suitability of similar combinations with panitumumab and bevacizumab.

trial ras colon cancer world congress egfr adjuvant braf stage iii esmo cetuximab folfox

SCIARADA del 11/06/2016 - Mussida-Concato/Bosso-Afterhours

Sciarada

Play Episode Listen Later Jun 11, 2016 26:46

Franco Mussida, ex PFM, presenta il suo progetto "CO2-controllare l'odio" che porta nelle carceri l'emozione della musica; Fabio Concato e Fabrizio Bosso raccontano il loro incontro sul palco che ha portato alla realizzazione dell'album "Non smetto di ascoltarti"; Gli Afterhours e il loro nuovo lavoro "Folfiri o Folfox" spiegato da Manuel Agnelli e Rodrigo D'Erasmo

cultura co2 spettacolo erasmo pfm rodrigo d bosso manuel agnelli folfox folfiri franco mussida

VPC1_2010 | Case03

Play Episode Listen Later Sep 7, 2010 13:58

ResearchToPractice.com/VPC110 – A 72-yo man develops pulmonary hilar lymphadenopathy with multiple retroperitoneal lymph nodes two years after a sigmoid colectomy and anastomosis followed by adjuvant FOLFOX for T3N2M0 colon cancer. Interview conducted by Neil Love, MD. Produced by Research To Practice.

interview md neil love folfox researchtopractice

VPC1 2009 | Case 13

Play Episode Listen Later Sep 14, 2009 13:06

ResearchToPractice.com/VPC109 - Case 13: A 49-year-old man with inflammatory bowel disease presented with T3N1 rectal cancer and underwent complete mesorectal excision followed by adjuvant FOLFOX until CT revealed a hepatic lesion, at which point bevacizumab was added to the FOLFOX and the patient underwent resection of the hepatic lesion. Interviews conducted by Neil Love, MD. Produced by Research To Practice.

interview md neil love folfox researchtopractice

VPC1 2009 | Case 11

Play Episode Listen Later Sep 14, 2009 7:42

ResearchToPractice.com/VPC109 - Case 11: A 57-year-old man with T3N2, right-sided colon cancer, a large hemangioma and multiple hepatic metastases who was treated with FOLFOX/bevacizumab. Interviews conducted by Neil Love, MD. Produced by Research To Practice.

interview md neil love folfox researchtopractice

VPC1 2009 | Case 8

Play Episode Listen Later Sep 14, 2009 8:52

ResearchToPractice.com/VPC109 - Case 8: A 53-year-old man with T3N1 rectal cancer eight to 10 centimeters from the anal verge received neoadjuvant capecitabine and radiation therapy followed by laparoscopic mesorectal excision and postoperative FOLFOX. Interviews conducted by Neil Love, MD. Produced by Research To Practice.

interview md neil love folfox researchtopractice

VPC1 2009 | Case 9

Play Episode Listen Later Sep 14, 2009 16:44

ResearchToPractice.com/VPC109 - Case 9: A 57-year-old woman with poorly differentiated T3N0 adenocarcinoma of the sigmoid colon with minimal lymphovascular invasion received adjuvant FOLFOX. Interviews conducted by Neil Love, MD. Produced by Research To Practice.

interview md neil love folfox researchtopractice

VPC1 2009 | Case 3

Play Episode Listen Later Sep 14, 2009 8:36

ResearchToPractice.com/VPC109 - Case 3: A 57-year-old woman with T3N1 sigmoid colon cancer who received adjuvant FOLFOX. Interviews conducted by Neil Love, MD. Produced by Research To Practice.

interview md neil love folfox researchtopractice

VPC1 2009 | Case 2