Podcasts about capox

JCO Editorial Fellow Dr. Peter Li and JCO Associate Editor Dr. Andrew Ko discuss the ASCO 25 Simultaneous Publication paper "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Peter Li: Hello, everyone, and welcome to our 2025 ASCO Annual Meeting Series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Peter Li, JCO Editorial Fellow, and I'm joined by Dr. Andrew Ko, JCO Associate Editor, to discuss the Journal of Clinical Oncology article and abstract presentation "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study." Now, let's start off with the relevance of this article. Andrew, can you please explain this to our listeners? Dr. Andrew Ko: Sure. Thanks, Peter. So, this was a very large international study evaluating the combination of lenvatinib and pembrolizumab. And just for context, that combination has been approved for use in other solid tumor types. It's FDA approved for renal cell carcinoma, for example, and endometrial carcinoma. But this study was looking specifically at this combination together with a chemotherapy backbone - so either FOLFOX or CAPOX - and comparing that to what at the time was a standard of care, which was just standard chemotherapy by itself. So, this very large study was intending to look at this particular novel combination. And we can get into some of the nuances of this study because the way that the experimental, the combination arm, was designed was perhaps a little bit more on the unusual side and led to maybe some imbalance in terms of how we think about the respective arms. Dr. Peter Li: Okay. We can definitely talk more about that as we go on. So, what are some of the key results of this study, and how do you think this will impact practice in the future? Dr. Andrew Ko: That's a good question. Technically, it was not a positive study. Well, it was positive in the sense that the co-primary endpoints - which included both progression-free survival and overall survival - so, progression-free survival, it did technically meet its endpoint, both in terms of the overall population and the preplanned subgroup analysis of patients who had a PD-L1 CPS of greater than or equal to 1. So, there was a PFS benefit with the experimental combination - the lenvatinib, pembrolizumab, plus chemotherapy - compared to chemotherapy alone. I will say the benefit was on the more modest side. So, if you even look at the medians, it was not a marked difference. If you look at the hazard ratios, they did meet statistical significance. On the other hand, this did not translate into a benefit for overall survival. So, when you ask, "Well, is this going to inform practice?" I'd have to say no. It highlights, I think, that JCO does want to publish articles that aren't necessarily going to be practice-changing, but that I think offer a lot of insights into trial design and important aspects of investigating novel treatments, even if they don't end up moving the needle in routine clinical practice. Dr. Peter Li: I totally agree with you. I mean, it was significant in terms of progression-free survival, but again, not clinically significant. And then overall survival, the interventional arm actually appeared to do slightly worse overall. Can you make some comments on the strengths and the weaknesses of this study, and where do you see us going from here? Dr. Andrew Ko: So, I think a couple of things worth highlighting in this study, very well designed, more than 800 patients in total. So, first of all, as I mentioned at the beginning, the combination was a little bit unique in terms of patients enrolled to the experimental arm got the combination of lenvatinib, pembrolizumab, together with chemotherapy for a very finite duration. So, that period of chemotherapy they received was only three months. And per protocol, patients then just segued to, quote unquote “maintenance treatment” with just the lenvatinib and pembrolizumab combination. Whereas patients on the control arm, meaning chemotherapy alone, would continue chemotherapy basically in perpetuity until their disease progressed or intolerable toxicity. So, there really was an imbalance in terms of, if you think that chemotherapy or continuing chemotherapy beyond that initial three-month period of time may be significant, that could have had some impact on the robustness or the efficacy of the experimental arm. There were some other aspects in terms of perhaps some differences in the rates of post-progression treatment, in other words, patients going on to receive second-line treatment. I think the other very relevant aspect, Peter, in this study was that the control arm - and no fault of the investigators - but the control arm at the time the study was ongoing just consisted of chemotherapy, FOLFOX CAPOX, by itself, without an immune checkpoint inhibitor, right? And we clearly know, based on results of several large phase III studies, and it's now in standard clinical practice, that we routinely use chemotherapy plus an immune checkpoint inhibitor. Certainly for patients with CPS PD-1/PD-L1 scores that are, well, you could argue greater than 1, or perhaps greater than 5 or 10. But the point being that the control arm of the study probably doesn't reflect what is currently used in clinical practice. And that's just always a challenge in clinical trial design, right? That when a study is designed and when it rolls out, you're always at risk in a rapidly changing and moving field that the standard of care may evolve during the lifetime of that particular trial, which is what I think you see in LEAP-015. Dr. Peter Li: Totally understand. And the survival we see from this study is also roughly similar to the combination of immuno-chemotherapy that is the standard of care today, which is, the authors mentioned, 12 to 14 months. Thank you so much, Andrew, for your input and for speaking about the JCO article "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. 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.

A recent #study from Assiut University Hospital in Egypt, published in #Oncotarget, presents a promising strategy for patients with metastatic #colorectalcancer (mCRC). The #research introduces a gentler yet effective maintenance therapy that may extend survival, enhance quality of life, and offer a more accessible treatment option for mCRC patients worldwide. The Challenge of Treating Metastatic Colorectal Cancer Colorectal cancer is one of the most common causes of cancer-related deaths worldwide. When it spreads to other parts of the body—a stage known as mCRC—it becomes much more difficult to treat. At this stage, clinicians often use strong drug combinations like FOLFOX or CAPOX, which mix chemotherapy drugs to stop cancer growth. FOLFOX combines three drugs given intravenously, while CAPOX includes two of the same drugs, with one taken as a pill. While effective, these treatments can cause serious side effects. For example, one of the main drugs, oxaliplatin, can lead to nerve damage, making it painful or difficult to use the hands and feet. Fatigue, diarrhea, and other issues are also common. Over time, these side effects may force clinicians to stop or adjust the treatment, even if it is working. That is where maintenance therapy comes in. After the cancer is controlled, clinicians often switch to a gentler treatment plan to keep it from returning. The challenge is finding a therapy that continues to work without causing too many side effects, especially in places where access to expensive or intensive treatments is limited. Full blog - https://www.oncotarget.org/2025/05/07/panitumumab-and-low-dose-capecitabine-a-promising-maintenance-therapy-for-metastatic-colorectal-cancer/ Paper DOI - https://doi.org/10.18632/oncotarget.28687 Correspondence to - Doaa A. Gamal - doaaalygamaal@gmail.com Video short - https://www.youtube.com/watch?v=wuPSS0EdK-8 Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28687 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, Panitumumab, maintenance, colorectal cancer, Capecitabine About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

On October 18, 2024, the FDA approved zolbetuximab plus fluoropyrimidine- and platinum-containing chemotherapy for the frontline treatment of adult patients with locally advanced unresectable or metastatic, HER2-negative, CLDN18.2-positive gastric or GEJ adenocarcinoma. This regulatory decision was backed by findings from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials. In SPOTLIGHT, In SPOTLIGHT, patients who received zolbetuximab plus mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) achieved a median progression-free survival (PFS) of 10.6 months (95% CI, 8.9-12.5) vs 8.7 months (95% CI, 8.2-10.3) in those who received placebo plus chemotherapy (HR, 0.750; 95% CI, 0.601-0.936; 1-sided P = .0053). In GLOW, zolbetuximab plus CAPOX (capecitabine and oxaliplatin) generated a median PFS of 8.2 months (95% CI, 7.5-8.8) vs 6.8 months (95% CI, 6.1-8.1) with placebo plus CAPOX (HR, 0.771; 95% CI, 0.615-0.965; 1-sided P = .0118). In our exclusive interview, Dr Ajani discussed key considerations for the clinical use of zolbetuximab, including its anticipated adverse effect profile and the introduction of CLDN18.2 as a biomarker for assessment prior to treatment initiation.

Dr. Shaalan Beg highlights practice-changing studies in GI cancers featured at the 2024 ASCO Annual Meeting, including the ESOPEC trial in esophageal adenocarcinoma and durable responses to PD-1 blockade alone in mismatch repair-deficient locally advanced rectal cancer. TRANSCRIPT Geraldine Carroll: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Shaalan Beg, an adjunct associate professor at UT Southwestern Simmons Comprehensive Cancer Center. Dr. Beg will be discussing practice- changing abstracts and other key advances in GI oncology that were presented at the 2024 ASCO Annual Meeting. His full disclosures are available in the transcript of this episode.  Dr. Beg, thanks for being on the podcast today.  Dr. Shaalan Beg: Thank you for having me. Geraldine Carroll: Let's begin with LBA1, the ESOPEC trial. This was featured in the Plenary Session, and this study compared two treatment strategies for locally advanced esophageal adenocarcinoma that could be treated with surgery. The strategies include the CROSS protocol, which consisted of chemoradiotherapy before surgery, and the FLOT protocol of chemotherapy before and after surgery. Can you tell us about this practice-changing study, Dr. Beg? Dr. Shaalan Beg: Yes. According to this study, perioperative chemotherapy with FLOT was better than neoadjuvant therapy with chemoradiation and carbo-taxol for people with adenocarcinoma of the esophagus. There were 438 patients enrolled on this phase 3 study. R0 resection rates were fairly similar across both groups. The PCR rates were a little higher on the FLOT group. But when you look at the median overall survival difference, 66 months in the FLOT group versus 37 months in the CROSS group, 3-year survival was 57% versus 50% favoring FLOT therapy as well.  So a couple of caveats on this clinical trial, because the first thing to note is that the standard treatment for this disease has evolved because we now don't only give CROSS chemoradiation, we also give immunotherapy after the completion of chemoradiation for this group of patients. And in this study, since it predated that standard of care, patients did not receive immunotherapy. But having said that, the take home for me here is that chemotherapy is better than chemoradiation for this group of patients, recognizing the fact that 1) they only enrolled adenocarcinoma patients, and 2) patients with high T stage were not included. So the folks with high T stage would be those who we would expect would benefit from the radiation aspect. So my take home here is that more chemotherapy is better in the perioperative space. Radiation should be considered for individuals who need more local control. But in general, I think we're going to see us moving more towards chemotherapy-based regimens with FLOT for this group of patients. Geraldine Carroll: Great. So moving on to rectal cancer, in LBA3512, investigators reported durable, complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer. Can you tell us more about the promising durable responses that occurred in this trial?  Dr. Shaalan Beg: On first glance, seeing that immunotherapy has good activity in patients with mismatched repair deficient rectal cancer isn't really headline breaking news anymore. We've known about this activity for this group of patients for many years. Earlier at ASCO, the investigators presented early results of this compound for people receiving six months of dostarlimab therapy for people with mismatched repair deficient, locally advanced rectal cancer, and showed that they had a very high complete response rate. At that time, it generated a lot of interest and there was a lot of curiosity on whether these outcomes will be sustained. We don't know other characteristics of their biologic status and whether this was some sort of reflection of the patients who are selected or not.   So here in this presentation at ASCO 2024, they did come back to present follow-up data for people with mismatch repair deficient colorectal cancer, having received 6 months of dostarlimab. Forty-seven patients had been enrolled, and the 41 patients who had achieved a clinical complete response continued to have disease control with no distant metastases. So that's very compelling information. There were no additional serious adverse events greater than grade 2 that they saw, and they did follow circulating tumor DNA, and those did normalize even before they had their colonoscopy to examine their tumors.  So, again, we're continuing to see very encouraging data of immunotherapy, and the response rate with dostarlimab seems to be very interesting for this disease, and it will be interesting to see how this pans out in larger studies and how this translates into the use of dostarlimab across other diseases where other checkpoint inhibitors are currently being used. Geraldine Carroll: Absolutely. So, moving on to LBA3501. The COLLISION trial looked at surgery versus thermal ablation for small cell colorectal liver metastases. This was an international, multicenter, phase 3, randomized, controlled trial. How will this study change clinical practice?  Dr. Shaalan Beg: Kudos to the investigators here. They looked to understand the difference in outcome in treating people with colorectal cancer with liver only metastases. These clinical trials are extremely difficult to design. They're very difficult to enroll on because of the multidisciplinary aspect of the interventions and patient and provider biases as well. So on this clinical trial, the investigators enrolled people with resectable colorectal cancer, liver metastases so they did not have any metastases outside the liver. Patients were required to have 10 or less known metastases that were less than 3 cm in size. There were other allowances for larger tumors as well. And after an expert panel review, patients were randomized to either resection or ablation. It was up to the physicians whether they performed these laparoscopically or openly or percutaneously, depending on the biology of the patient and the anatomical presentation.  There was a predefined stopping rule at the half-time for this clinical trial, which showed a benefit in the experimental arm of ablation compared to standard of care. The overall survival was not compromised. Progression-free survival was not compromised with local therapy. But there were differences in morbidity and mortality, as we would expect, one being a surgical procedure and the other being ablation, where, according to this study, of the 140 or so patients who received either treatment, 2.1% of people who underwent resection died within 90 days of surgery. The AE rate was 56% in the resection sample compared to 19% in ablation, and the 90-day mortality for ablation was 0.7%. So less morbidity, improved mortality, reduced adverse events with ablation versus surgical resection without compromising local control and overall survival.   And I think for practice here in the United States, this does provide very interesting data for us to take back to the clinic for lesions that are relatively small and could generally be addressed by both surgery and ablation. Historically, there are various non biologic factors that could go into deciding whether someone should have surgery or ablation, and it could be based on who the physician is, who's seeing the patient, what the practice patterns in a specific organization are, and where their expertise lie. But here we're seeing that ablation for the small lesions is a very effective tool with very good local control rates, and again, in this selected group of patients with liver only metastases. And I think it is going to make tumor board discussions very interesting with data backing ablation for these lesions. Geraldine Carroll: Well, let's move onto the MOUNTAINER study. This study created some buzz in the colorectal cancer space. That's Abstract 3509. Can you tell us about the final results of this phase 2 study of tucatinib and trastuzumab in HER2-positive metastatic CRC? What are your thoughts on this treatment option, which seems to be well tolerated? Dr. Shaalan Beg: So, HER2 overexpression or amplification occurs in about 3 to 5% of patients with metastatic colorectal cancer and up to 10% of people who have a RAS/RAF wild type disease. On the previous episodes of the podcast we have covered precision targeted therapy in colorectal cancer, focusing on c-MET, focusing on BRAF, and here we have updated results targeting HER2 for colorectal cancer. And the results of the MOUNTAINEER study have been out for a while. This is a phase 2 study looking at combining tucatinib which is a highly selective HER2 directed TKI with trastuzumab, the monoclonal antibody for HER2 targeting. And what they found on this study is the confirmed overall response rate was 38%. Duration of response was 12 months, overall survival was 24 months and these are the results that have been already released and now we have an additional 16 months of follow up and these results continue to hold on. PFS and overall survival gains were held, which makes it a very interesting option for people with colorectal cancer. You mentioned the tolerability aspect and side effects. I think it's important to know the spectrum of side effects for this disease may be a little different than other TKIs. There's hypertension, but there's also the risk of diarrhea, back pain and pyrexia, with the most common grade 3 treatment related adverse event was an increase in AST level seen in 10% of people of grade 3 and above.  So where does that really leave us? There is a confirmatory randomized first-line trial of tucatinib and trastuzumab in the first line setting, which is currently ongoing. So we'll stay tuned to see where that leads us. And with the HER2 space right now for colorectal cancer with the development of antibody drug conjugates, we may have more than one option for this group of patients once those trials read out. Geraldine Carroll: Excellent. Well, moving on to LBA4008, that's the CheckMate-9DW trial. This trial reported first results looking at nivolumab plus ipilimumab versus sorafenib or lenvatinib as first-line treatment for advanced hepatocellular carcinoma. Can you tell us about this trial? Will there be a potential new standard of care in advanced HCC? Dr. Shaalan Beg: When we think about patients with advanced HCC, the only treatment option that they had for about a decade and a half were just oral track tyrosine kinase inhibitors that had modest to moderate clinical activity. Since then, we've seen that combination therapy is better than TKI therapy, and the combination therapy has taken two different forms. One is a combination of checkpoint inhibitor and antiangiogenic therapy, such as in the combination of atezolizumab and bevacizumab. The other is a combination of dual checkpoint inhibitor therapy. Here we are talking about the results of nivolumab and ipilimumab. Previously, we've talked about the combination of durva and tremi for the treatment of patients with HCC.   So in this study, nivo was given for the first 4 cycles, nivo and ipi were given together, nivo 1 mg per kg, and IPI 3 mgs per kg every 3 weeks for 4 cycles. And then the CTLA-4 inhibitor ipilimumab was stopped. And this was followed by monotherapy nivolumab every 4 weeks until disease progression or up to 2 years. And it was compared to dealers' choice, lenvatinib or sorafenib. The median overall survival of nivo-ipi was 23 months versus 20 months with lenvatinib-sorafenib. The 24-month overall survival was 49% with ipi-nivo versus 39%. And the overall response rate with nivo-ipi was 36% compared to 13%. So again, significantly improved clinical activity.   And when we talk about immunotherapy combinations, the question that comes to mind is how well is this tolerated? There's a lot of work and iteration that took place in figuring out what the right combination strategy of ipi and nivo should be, because some of the earlier studies did demonstrate fairly high adverse events in this group of patients. So on this study, we saw that grade 3 or 4 treatment related adverse events were seen in 41% of people who received nivo-ipi and 42% if they received lenvatinib or sorafenib. So, certainly a high proportion of treatment related adverse events, but probably also reflective of the disease population, which is being tested, because those numbers were fairly similar in the control arm as well.  So we've known that nivo-ipi is active in HCC. There is an approval in the second-line space, so it remains to be seen if this data helps propel nivo-ipi to the first-line space so we end up with another combination regimen for patients with advanced hepatocellular carcinoma.  Geraldine Carroll: Excellent. Well, before we wrap up the podcast, I'd like to ask you about LBA3511. In this study, investigators looked at total neoadjuvant treatment with long course radiotherapy versus concurrent chemoradiotherapy in local advanced rectal cancer with high risk factors. So this was a multicenter, randomized, open label, phase 3 trial. What are your key takeaways here? Dr. Shaalan Beg: Key takeaway here is that total neoadjuvant therapy was better than the conventional chemoradiation followed by chemo. So this clinical trial enrolled people with T4a/b resectable disease with clinical N2 stage, and they were randomized, as you mentioned, to receiving chemoradiation with radiation capecitabine followed by surgery, and then CAPOX or capecitabine versus chemo, short-course radiation, and additional chemotherapy followed by surgery.  And when we compare both arms, the total neoadjuvant therapy led to improved disease-free survival, improved PCR rates compared to standard concurrent neoadjuvant chemo radiotherapy in this group of patients. The two arms were fairly well-balanced. The number of T4 lesions was a little higher in the chemoradiation group. There were 49% in the chemo radiation group versus 46% had clinically T4 disease, but the nodal status was fairly similar. We should keep in mind that the other baseline characteristics were fairly well balanced.  And when we look at the outcomes, the disease-free survival probability at 36 months was 76% in the total neoadjuvant group compared to 67% with chemoradiation. And the metastasis free survival in total neoadjuvant therapy was 81% versus 73%. So a fairly compelling difference between the two arms, which did translate into an overall survival of 89% versus 88% in the two groups. So definitely higher disease-free survival and metastasis free survival, no difference on the overall survival with these groups. And it talks about the importance of intensifying chemotherapy upfront in this group of patients who can have a fairly high burden of disease and may struggle with receiving chemotherapy postoperatively. Geraldine Carroll: Excellent. Well, thank you, Dr. Beg, for sharing your fantastic insights with us on these key studies from the 2024 ASCO Annual Meeting. It's certainly a very exciting time in GI oncology. Dr. Shaalan Beg: Absolutely. Thank you for bringing these studies out, because I think a lot of these are practice-changing and can start impacting the clinical care that we're giving our patients right now. Geraldine Carroll: Thank you to our listeners for joining us 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 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. 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     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  

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

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

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.      

Dr. Mohamed Salem, Dr. Myriam Chalabi, and Dr. Andrea Cercek discuss pivotal neoadjuvant immunotherapy clinical trials for patients with MSI-H/dMMR colorectal cancer, focusing on the development of active therapies in the neoadjuvant setting—where patients are treated without surgery, radiation, or chemotherapy—and the importance of patient selection in finding the right target and treatment to improve outcomes. TRANSCRIPT Dr. Mohamed Salem: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host today, Dr. Mohamed Salem. I'm a GI oncologist at the Levine Cancer Institute at Atrium Health. Today, we will be discussing very promising advancements in the neoadjuvant immunotherapy for patients with MSI-H/dMMR colorectal cancer. And I'm very delighted to welcome two world-renowned oncologists whose research has tremendously helped shape the treatment landscape of colorectal cancer. Dr. Myriam Chalabi is a GI medical oncologist at the Netherlands Cancer Institute, and Dr. Andrea Cercek is a medical oncologist at Memorial Sloan Kettering in the United States.  Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/DNpod.  Dr. Chalabi and Dr. Cercek, welcome to the ASCO Daily News Podcast. Dr. Myriam Chalabi: Thank you for having me. Dr. Andrea Cercek: Thank you very much for having me. Dr. Mohamed Salem: It's a pleasure to have two world-renowned stars like you. Thank you for taking the time.  So, before we start going deep into the topic, obviously, now we are seeing emerging data in CRC using immunotherapy as the neoadjuvant approach, which actually can reduce or even eliminate some of the other treatment modalities and potentially save patients from toxicities. Both of you led what I think are landmark studies in this field. I wanted to give you the chance to tell our audience about your studies and why you think they're important. Dr. Cercek? Dr. Andrea Cercek: Sure. Thank you so much. So, our study was a neoadjuvant study in early-stage, locally advanced rectal cancer with tumors that were mismatch repair-deficient or MSI-H. And rectal cancer normally is treated with chemotherapy, chemoradiation, and surgery. And the goal of the trial was to utilize PD-1 blockade alone in this subpopulation and evaluate the response.  Patients received six months of dostarlimab, which is a PD-1 blocking agent, and then were evaluated for response. If there was no residual disease, they were able to avoid radiation and surgery. And what we've seen thus far in the presentation at GI ASCO in 2022 was that all patients who received six months of dostarlimab had a clinical complete response, so no residual tumor, and were able to avoid chemotherapy, radiation, and surgery and are on observation. And the study is ongoing and actively accruing patients. Dr. Mohamed Salem: All of us were very excited seeing that presentation at ASCO. And when we came back to the clinic everyone was talking about it, including patients, obviously. Thank you for this, Dr. Cercek. Dr. Chalabi, you also led a similar study that was actually presented in ESMO in 2022. Can you please give us, like, a brief description of that trial? Dr. Myriam Chalabi: Yeah, sure. So, this is the NICHE trial, and actually the NICHE trial has been ongoing for quite some time now. We recently presented a larger NICHE-2 study, but basically– so what we started out by doing in NICHE is giving patients what we considered back then a window of opportunity study. We treated patients with MMR-deficient tumors, which I'll be focusing on for now, with two cycles of nivolumab and one single cycle of low-dose ipilimumab. And patients all undergo surgery within six weeks of registration within the study. And back in 2020, we published the first data of NICHE-1 showing 100% pathologic responses with 60% pathologic complete responses and decided that this should definitely be a treatment that we need to explore in a larger group of patients. And that's where NICHE-2 was born, which we presented at ESMO last year, where we treated over 100 patients with this neoadjuvant approach of two cycles nivolumab, one single cycle ipilimumab, showing 99% pathologic responses, including 95% major pathologic responses and 67% pathologic complete responses. And this was all within five and a half weeks of the first treatment with immunotherapy, so a very short treatment duration with dual checkpoint blockade. Dr. Mohamed Salem: Amazing results, too. And I know you had a standing ovation when you presented the outcome of the study. And again, congratulations to you, your investigator, and also all the patients participated. Dr. Myriam Chalabi: Thank you so much.  Dr. Mohamed Salem: I guess the first question that comes to my mind - we have two trials, obviously, now we're moving from one size fits all to precision therapy, like getting actually the right treatment for the right patient. But in the NICHE study, it was a checkpoint inhibitor, and the rectal study was a single agent. I want to start with you, Dr. Chalabi. In your opinion, when should we use single agent or double blockade immunotherapy? Dr. Myriam Chalabi: That is a great question. I'm going to start off by saying that I don't know the exact answer. I don't think we know that answer. And Dr. Cercek is going to share also her thoughts on this because we're seeing, of course, fantastic responses with monotherapy as well in Dr. Cercek's study. And we've also seen that in a study by Dr. Overman with monotherapy. So that may suffice in some patients, although what we're seeing is that you need to treat patients longer, probably to achieve that response, at least clinically. And I think that is the difference with dual checkpoint blockade, that we're giving in NICHE where we're seeing these very deep responses in just under six weeks' time.  So, I think it may be more of a question of how long we want to treat patients for to achieve the endpoint that we're aiming for. And, of course, there may be, at some point, patients that need dual checkpoint blockade, but so far, we're seeing great responses in both of our studies. So I think we need more patients, more data to see whether we're going to see non-responders. And hopefully, the studies that are ongoing in the metastatic disease setting will give us at least a little bit of insight into what the differences are in response to mono and dual checkpoint blockade and whether we can tell which patients might benefit more from the combination. But I think there's still a lot of work to be done in that field. Dr. Mohamed Salem: I totally agree. Dr. Cercek, same question to you. What do you think?  Dr. Andrea Cercek: Dr. Chalabi answered beautifully and very comprehensively. I agree completely with what she said. It's hard to argue with the responses that we're seeing with PD-1 blockade alone. But then again, dual checkpoint inhibitors in the NICHE study with just one month of therapy had phenomenal responses as well. So I think it's a question of duration of therapy and, really importantly, what we're trying to achieve. If our goal is organ preservation, then perhaps longer duration is better. The question then becomes, can we do, should we do longer duration with dual checkpoint inhibitors versus single agent? So I think, as she concluded, I couldn't agree more that we just need more information, we need more work to do, basically to answer this question for our patients. Dr. Mohamed Salem: More to come and more studies, which is fascinating.  So, Dr. Chalabi, you created actually a new term on Twitter called ‘Chalabi Plot'. It was amazing to see such a response. But we're curious, among those patients who achieved complete response so far, did you see any relapse? Dr. Myriam Chalabi: Short answer, no.  we're waiting, of course on the disease-free survival data, the three-year DFS data for NICHE-2, and we hope to have that by the end of this year, beginning of next year. But as of now, we showed that data, and so far, we haven't seen any recurrences in, actually, any of the patients treated in NICHE-2. Dr. Mohamed Salem: Fantastic. Dr. Cercek. So I think your slide -- I remember clearly from the ASCO presentation -- was all complete response, every single patient.  Same question, did you see any relapse so far? Dr. Andrea Cercek: So far, no, we have not. Dr. Mohamed Salem: Amazing. So, Dr. Cercek, as you know, and obviously, this is metastatic disease, but in KEYNOTE-177, as you know, about 30% of patients with MSI-high tumors did not respond to checkpoint inhibitors. So that makes some of us feel nervous about using checkpoint inhibitors alone in colorectal cancer, even with MSI-high status. I was curious if you can comment on this and if there is a way we can perhaps sort out who actually is likely to respond and who is likely not going to respond. Dr. Andrea Cercek: I think that's a really important question and an excellent point. And we believe that the difference lies in the fact that in KEYNOTE-177, the patients had metastatic disease, whereas in our neoadjuvant studies that we're discussing, they have early-stage disease. And whether that has to do with the tumor differences, young tumors versus older tumors once they become metastatic, or the microenvironment, remains to be determined. But certainly, there is this pattern of incredible responses with checkpoint inhibitors in early-stage dMMR tumors. And in KEYNOTE-177, as you mentioned, about 30% of patients progressed. And I think we don't know why that is. We are seeing this, about a third of progressors repeatedly in the metastatic setting with checkpoint inhibitors. And so perhaps there is a population. But whether this is driven by genomics or something else, we don't know. Dr. Mohamed Salem: Great. So, along the same lines, especially rectal cancer, obviously, because surgical resection is a key component in the treatment paradigm, do you feel patients who achieve pathological complete response should still go under surgical resection or should go under the ‘watch and wait' approach? Dr. Andrea Cercek: In general, I'm a fan of organ preservation. I think in rectal cancer, the reasons are obvious. It's a challenging surgery. It's very toxic to the patients. It changes their lives forever. In survivorship, 30% of them require a permanent colostomy because of the location of the tumor. So there, the field of rectal cancer, in general, is moving towards non-operative management, even in the MSI-proficient patients, by trying to optimize therapy to increase clinical complete responses and therefore omit surgery. So that's the difference with rectal cancer. In colon cancer, it's a different discussion. I think for many patients, surgery is very straightforward. It's a hemicolectomy. It doesn't alter lifestyle in survivorship, so it's not as morbid as it is in rectal cancer. Of course, I think if a patient is older with MSI-deficient tumor perhaps can undergo surgery, then clinical complete responses become critical because then we can monitor them after just checkpoint blockade, and they don't need surgery.  The challenge there, and I would love to hear Dr. Chalabi's comments on this, too, is just that imaging is challenging. We have a hard time in colon cancer determining whether someone has a clinical complete response or not. It seems to be very different than in rectal cancer, where with endoscopy and with the rectal MRI, we really can't tell whether the tumor is still present or not. This remains a challenge in colon cancer. Dr. Mohamed Salem: Dr. Chalabi, I would like to hear your thoughts and also how you practice in Europe. I don't know if it's the same like here in US or different. Dr. Myriam Chalabi: I completely agree with Dr. Cercek. Well, if we look at the rectal cancer patients, I think this is fantastic. That even though this is a small population achieving this high clinical complete response rate, not having to operate or even give any chemotherapy or radiation therapy to these patients, it is extremely important both in the short term but also in terms of long-term complications and morbidity. When it comes to the colon cancer responses that we're seeing in NICHE, those are all pathologic responses, of course. And we have been evaluating also preoperatively using scans to see whether we can assess these complete responses based on imaging. That doesn't seem to be the case. We do see responses in all patients, so we see these are all very large bulky tumors that we're treating in NICHE-2. And we do see responses in almost all of these patients, but it's not close to complete responses, definitely not in all of the complete responders that we're seeing. So that makes it difficult.  And the question is, what if we would be waiting or treating longer because these bulky tumors need more time to disappear or to be cleared before you're going to see it on the imaging? So that is a question that I don't have an answer to just yet. We may be getting some more data on that with the currently ongoing trials. And as Dr. Cercek pointed out, the endoscopies when you have a right-sided colon tumor are different than doing just a sigmoidoscopy for a rectal tumor. So, we actually do have one patient who hasn't undergone surgery, and that is actually a patient with an MMR-proficient tumor within the NICHE trial who had a complete response. And that patient has a sigmoidal tumor, and he actually had toxicities which prevented him from undergoing timely surgery and now has a complete response after two years, both endoscopically and on imaging. So, he hasn't undergone surgery, and that is a great example of how we may be doing this in the future. It's an interesting case within the trial to follow and see how we can do it in the future. Dr. Mohamed Salem: That's fascinating news. So, was it MMR-proficient? Dr. Myriam Chalabi: Yes, this is an MMR-proficient tumor.  Dr. Mohamed Salem Wow. Any particular biomarkers that you think he or she had to predict that? Dr. Myriam Chalabi: We have treated more patients with MMR-proficient tumors. We have 31 patients, and we have seen actually responses in 9 out of 31 patients in the MMR-proficient tumors with the same combination of two doses of nivolumab and one of ipilimumab. We previously published on half of the cohort approximately on what the possible predictive biomarkers of response could be, and that was a costimulation for CD8 and PD-1. So PD-1 positive CD8 T cells. And we're currently doing the same work for the rest of the cohort. So hopefully, we'll be able to show that soon and see whether this still stands for the completed MMR-proficient cohort. But definitely also very exciting data for the MMR-proficient. Dr. Mohamed Salem: So, this is actually a very good segue to my next question because I know all of us are looking for this. Like, obviously, we're seeing a fascinating response in those patients with MSI-high tumors, but majority of colorectal cancer, as you know, they actually have MSS-proficient tumors. Any thoughts about how we can overcome the primary resistance for this tumor to checkpoint inhibitors? So let me start with you, Dr. Cercek.  Dr. Andrea Cercek: I'm very much looking forward to Dr. Chalabi's data on this because, honestly, we have not seen such amazing responses to immunotherapy in MSS tumors. The initial studies were complete flatline, no responses at all. And here, she just described a patient that had a complete response to just a month of checkpoint inhibitors. So that's phenomenal, and hopefully, we'll learn from the responders.  We believe that there is a subpopulation of MSS colorectal cancer that is more immune sensitive, immune hot, whichever term you like to use. And it's just a matter of appropriately identifying those patients. And personally, I think the answer lies in the neoadjuvant setting in early tumors where they're treatment-naive, not exposed to chemo, not exposed to radiation, younger, have their innate microenvironment. And so, I think it's likely a combination of the above. But obviously, the ultimate goal is to find out who those patients are and then potentially treat them just like this with immunotherapy. And that would be another nice chunk of the pie where we could utilize immunotherapy for our patients. Dr. Mohamed Salem: Very true. Dr. Chalabi, especially with your experience and just showing there is a chance for those people to respond, what are your thoughts about how we can overcome this primary resistance? Dr. Myriam Chalabi: It's great to be here with Dr. Cercek because, obviously, we have very similar interests but it's also good to see that we think the same way because I completely agree with what she just said in terms of neoadjuvant. I think that was one of the most important things that we did here, giving this neoadjuvant treatment in non-metastatic tumors. It's probably a very important driver in the responses that we're seeing. So, we've been seeing data now a bit more in the metastatic disease setting where MSS tumors seem to be responding to new generations of checkpoint blockade. And the question is how those would do in the neoadjuvant setting that would be even different than what we're seeing now. But there's definitely some proof of MSS tumors that can respond to immunotherapy. The question on how to overcome the primary resistance, I think that question is for us: Who are the patients with primary resistant tumors and why are they primarily resistant? And then we can think about how to change that and how to change them into the tumors that are responding. I think these types of data will be key to understand more and know; hopefully, even you said, in the metastatic disease setting, to make these tumors more pliable in response to immunotherapy. Dr. Mohamed Salem: I agree. So, both of you are leading us toward how to choose the right patient with the right target for the right treatment. That's an amazing journey you're taking all of us on.  So, Dr. Cercek, I have to admit that with your data, it created some problems for us in the clinic because all patients the following day came in asking for immunotherapy. We had a hard time trying to explain that maybe this is not the right treatment for them or, like, not the right platform. But I wanted to ask you, if we'll have a patient tomorrow in the clinic with localized rectal cancer and happen to have an MSI-high tumor, what would be your recommendation in terms of how to approach that patient? Dr. Andrea Cercek: I think, ideally, you would discuss clinical trials with the patient. We have opened the study now to not just rectal cancer but colon cancer and, in fact, all solid tumors that are mismatch repair-deficient. So I think at this time, the patients really should be treated on a clinical trial. As we learn more, in particular, until we are more comfortable assessing for a clinical complete response and follow-up. I think the surveillance piece will be critically important. In rectal cancer, it's well established, but it's not in the other tumor types. So my recommendation would be to enroll the patient on a trial. Dr. Mohamed Salem: Just to add to that too, obviously, as you know, there is now the cooperative group trial that's looking at that option and we obviously encourage all centers to participate and open that study to have this option for our patients. Dr. Chalabi, so what do you guys do in Europe for these patients? Dr. Myriam Chalabi: In Europe, it's a very different situation. I would have answered this question differently by saying, well, we don't have that option of treating patients outside of clinical trials. So basically, we have to make sure that we have clinical trials for these patients. And that's something that we've had for colon cancer patients. That is still the case. And we're getting rectal cancer trials also for patients with MMR deficient tumors and have those also for MMR proficient tumors. For us and I agree completely that we should be treating patients within clinical trials, we don't have another option. But still, even if we did, I think it's important to create data within clinical trials to be able to ultimately also show why this should be standard of care and how we can make it standard of care. Because if you're not accumulating that data, then it's going to become very difficult if accrual is lacking. Now, we treat patients either with standard-of-care treatments, but usually, we try to find something within clinical trials.  Dr. Mohamed Salem: I totally agree. And as we always say, the standard of care should be a clinical trial participation. So, I must say, both of you, Dr. Cercek and Dr. Chalabi, you made 2022 a very exciting year for us in GI cancers. You really changed the way we look at how to treat these patients and give them a huge chance of, I would say, actually cure and obviously organ preservation. So, I'm very curious to know what you are both are working on now and what we should expect in 2023 and 2024.  Dr. Andrea Cercek: So, for me, the study is ongoing, as I mentioned, and we've expanded to all mismatch repair-deficient solid tumors with the same approach of six months of dostarlimab and then the option of nonoperative management. And I think that it'll be important for us to learn in terms of responses on the luminal versus some of the other tumor types, like, for example, pancreas cancer, where we don't see these robust responses in the metastatic setting, that will be important to do. We're doing some correlative analysis, as Dr. Chalabi described as well in our patients.  And then, I'm interested in optimizing neoadjuvant approaches to minimize therapy in rectal cancer specifically. So, we have a study now for HER-2 amplified RAS wild-type patients with locally advanced rectal cancer with a similar approach of utilizing HER-2 targeted therapy first and then in combination with chemotherapy. In our case, it's a combination of trastuzumab and tucatinib and then chemotherapy with CAPOX and assessing for response and potential omission of radiation and surgery depending on responders. So, I'm very excited that study is open and actively accruing, and hopefully, we can get similar responses that we did in the MSI population with PD-1 blockade. Dr. Mohamed Salem: Is that only available at MSK? Dr. Andrea Cercek: It is at this time. However, we will likely be expanding, so if there's any interest, let me know. Dr. Mohamed Salem: Great. I'm sure many centers will be. Great. What about you, Dr. Chalabi? Any sneak peek in the future? Dr. Myriam Chalabi: So many sneak peeks, where to begin? I think it's very exciting to be working in this space at this time, and we're very lucky to be in it. So, for NICHE, we're actually accruing now in new cohorts for both MMR-deficient and MMR-proficient tumors. For the patients with MMR-deficient tumors, we're actually testing a new combination of nivolumab plus relatlimab, so anti-LAG-3 plus anti-PD1. And we're testing the same co-formulation in patients with pMMR tumors. In addition to another cohort for the pMMR tumors with nivolumab, all within this window of opportunity, as we did previously in NICHE, and to see if we're going to see more responses if these are going to be different tumors than the ones responding to nivolumab and ipilimumab. And for the MMR deficient tumors, we're treating longer with this combination now. So, we're operating after eight weeks instead of six weeks. We're giving two cycles, four weekly cycles, to see whether we can even improve the PCR rates, even though this is, of course, a different combination treatment. So, very exciting times for NICHE, and we'll have the readout for the DFS at the end of this year, so that's also very exciting. And then, well, it's similar to Dr. Cercek. So again, we're on the same page when it comes to these neoadjuvant treatments. We have actually an ongoing trial for neoadjuvant treatment of patients with MMR proficient rectal cancers, and that is using a combination of radiation therapy followed by a combination of atezolizumab or anti-PDL1 with Bevacizumab with the aim of organ sparing approach in these patients. And we actually presented stage 1 of this trial as a poster at ASCO GI, showing that we achieved 56% complete or near complete responses clinically at 12 weeks. And after at least a year of follow-up for all patients, we have 50% organ preservation. So those are very exciting data as well. Also, in the MMR proficient tumors, I'm very excited to hear about the HER-2-positive tumors and Dr. Cercek's study. So there's definitely a lot going on that we hope to share as soon as the data are available. Dr. Mohamed Salem: We'll be looking forward to your next presentation and seeing that. So again, most of your work showed us that we really have to choose the right patient with the right target for the right treatment to achieve the best possible outcome. So we're getting short on time here. But before we conclude, ASCO Daily News Podcast has a huge audience of oncologists, I wanted to give you the chance to share anything you'd like to share with our audience today before we finish. Dr. Cercek? Dr. Andrea Cercek: I believe this is an incredibly exciting time in colorectal cancer. I think it's finally our turn, which feels really nice, and obviously, we have a lot more work that needs to be done. But my personal belief is to keep trying to chip away at the pie and identify responders and keep working to have better-targeted drugs and better treatment options that will improve responses and improve outcomes for our patients. But I certainly believe that we are well on our way there, and it's very exciting. Dr. Mohamed Salem: I totally agree. Dr. Chalabi, any thoughts? Dr. Myriam Chalabi: I think after 2022 and the data that we've been showing, I think it's important to– and I think by now, maybe it's not even necessary anymore to say it– but I think it's important to really look at the tumors and look at these MMR proteins or MSI, and to make sure that you're treating the patient in the right way, and to consider that. Before, it wasn't as important in the neoadjuvant setting or these localized tumors, but now it's becoming essential.  And I think if you would have looked five years ago and you would say, yeah, these MSI tumors are important to find, it's a very small proportion of patients, in rectal cancer even lower than in colon cancer. But still, it has such a huge impact on what you're doing in these patients and your chances of cure. So I think that would be my most important giveaway to test for MMR deficiency before deciding on a treatment for your patients. And we're working on trials with neoadjuvant immunotherapy. Also in other tumor types, Dr. Cercek is also doing the same. I think those will be very important also outside of the GI field to see whether this approach works for a much larger patient population, despite the low incidence.  Dr. Andrea Cercek: Dr. Chalabi just made a critical point that that is most important is to remember that we do have biomarkers in colorectal cancer that, in the neoadjuvant setting and in the metastatic setting, especially MSI, that we need to test for. And then, just to add from a clinical perspective, in rectal cancer, the large majority of patients that have mismatch-repair deficient or MSI tumors actually have Lynch syndrome. So really, if you identify a patient that's mismatch-repair deficient or MSI-high anywhere, but especially in the rectum, they absolutely should get germline testing. Dr. Mohamed Salem: I echo that and second that. And Dr. Cercek, thank you, and I know you did a lot of work in colorectal cancer in the younger adult population, too, so I think you've had a huge impact on that area too. I would like to thank both of you again for being here today, but more for the great work you and your teams are doing to advance the field. It's really a very exciting time in GI cancers now, and thank you so much for your work and for sharing your insights with us today on the ASCO Daily News Podcast. Dr. Myriam Chalabi: Thank you so much for having me. It's been great. Dr. Andrea Cercek: Thank you for having me. Dr. Mohamed Salem: Of course, and thanks to our listeners for your time today. 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. Thank you very 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. Find out more about today's speakers:     Dr. Mohamed Salem @SalemGIOncDoc   Dr. Myriam Chalabi @MyriamChalabi   Dr. Andrea Cercek @AndreaCercek   Learn about other key advances in GI Oncology: SWOG 1815, PARADIGM, and Other Advances at GI23   Follow ASCO on social media:      @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Mohamed Salem: Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, Exelixis, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca Speakers' Bureau: Genentech/Roche, Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck Dr. Myriam Chalabi: Consulting or Advisory Role: MSD, Bristol-Myers Squibb/Celegne, Numab Research Funding (Institution): Bristol-Myers Squibb, Roche/Genentech, MSD Travel, Accommodations, Expenses: Roche/Genentech, Bristol-Myers Squibb Dr. Andrea Cercek: Consulting or Advisory Role: Bayer, GSK, Incyte, Merck, Janssen, Seattle Genetics, G1 Therapeutics Research Funding (Institution): Seattle Genetics, GSK, Rgenix          

Featuring perspectives from Dr Samuel Klempner, including the following topics: Introduction (0:00) Case: A man in his mid 70s with gastric adenocarcinoma and oligometastatic disease to the liver (PD-L1 10%, HER2-positive) — Ranju Gupta, MD (2:47) Case: A man in his early 70s with locally advanced HER2-positive gastroesophageal junction (GEJ) adenocarcinoma who undergoes chemoradiation therapy and surgery but develops progressive disease on adjuvant nivolumab and is now receiving CAPOX with trastuzumab (PD-L1 10%, microsatellite stable [MSS]) — Bruce Bank, MD (9:39) Treatment of Microsatellite Instability-High Disease (20:46) Case: A woman in her late 60s with GEJ adenocarcinoma metastatic to the liver (MSS, PD-L1 2%, HER2-negative) — Warren S Brenner, MD (36:32) Case: A man in his late 50s with GEJ adenocarcinoma who receives neoadjuvant fluorouracil/leucovorin/oxaliplatin/docetaxel (FLOT), is found to have 8/18 positive nodes at surgery, receives adjuvant FLOT and currently has no evidence of disease (PD-L1

El Dr. David José Heredia Vázquez, oncólogo médico adscrito al Departamento de Tumores Torácicos del Instituto Nacional de Cancerología, en la Ciudad de México, México, nos comenta en este podcast sobre los highlights del día 4 del Congreso Anual de la Sociedad Americana de Oncología Clínica 2022. Cáncer de ovario: ATHENA-MONO: Estudio fase III, aleatorizado y doble ciego, que evaluó rucaparib en monoterapia vs. placebo como tratamiento de mantenimiento después de la respuesta a la quimioterapia (QT) de 1L basada en platino en pacientes con cáncer de ovario. Cáncer colorrectal: OPTICAL: Estudio fase III, multicéntrico y aleatorizado, que evaluó la QT perioperatoria con mFOLFOX6 o CAPOX vs. el estándar de tratamiento, en pacientes con cáncer de colon localmente avanzado. IMPROVE: Estudio fase II, prospectivo, aleatorizado, no comparativo, abierto y multicéntrico, que evaluó panitumumab intermitente o continuo + FOLFIRI como tratamiento de 1L en pacientes con cáncer colorrectal metastásico, irresecable, sin tratamiento previo, RAS/BRAF w/t. TRIPLETE: Estudio fase III, aleatorizado, de etiqueta abierta, y prospectivo, que evaluó mFOLFOXIRI + panitumumab vs. mFOLFOX6 + panitumumab, como tratamiento inicial en pacientes con cáncer colorrectal metastásico RAS/BRAF w/t no resecable. Sistema Nervioso Central: Alliance A071102: Estudio fase II/III, aleatorizado, que evaluó veliparib o placebo + temozolomida adyuvante en pacientes con glioblastoma recién diagnosticado con hipermetilación del promotor del gen MGMT. Cáncer de pulmón: BTCRC LUN 16-081: Análisis del ADN tumoral circulante del estudio fase II, aleatorizado, que evaluó la consolidación de nivolumab + ipilimumab vs. nivolumab solo, después de QT + radioterapia concurrente en pacientes con cáncer de pulmón de células no pequeñas en estadio III irresecable. Fecha de grabación: 06 de junio de 2022. Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

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]

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/

[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]  

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      

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.

Dr. Thiago Jorge, autor do MOC, comenta os resultados do importante estudo fase III GO2, apresentado na ASCO 2019. O estudo analisou se a redução da dose de CAPOX no tratamento do câncer gástrico metastático em pacientes frágeis e idosos resultaria em prejuízo no desfecho.

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.

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.

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.

 Key Takeaways from the 2019 Gastrointestinal Cancers Symposium with Dr. Stephen Leong   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. Welcome to the ASCO Daily News podcast. I'm Lauren Davis, and joining me today is Dr. Stephen Long, associate editor of ASCO Daily News. Dr. Long is associate professor in the division of medical oncology and is a translational researcher in the GI and developmental therapeutics programs at the University of Colorado Cancer Center. Dr. Long, welcome to the podcast. Thanks for having me. It's a pleasure to be here. Dr. Long, you've just returned from the Gastrointestinal Cancers Symposium. How was this year's event compared with previous years? First of all, I love you GI ASCO. I always find it informative. And I love the format of the talks and presentation. This year there was no significant practice changing presentations like in years past. However, there were still some excellent presentations and talks. And what were some of the presentations that stood out to you? There were some reports of a couple of clinical trials that sort of intrigued me. One was KEYNOTE-181. This was a phase III study comparing pembrolizumab monotherapy versus standard chemotherapy in patients with local events and metastatic esophageal cancer in the second line setting. They reported a significant improvement in overall survival in patients with PD-L1 combined positive score of greater than 10. And these patients received 9.3 months overall survival compared to 6.7 months for those who received [INAUDIBLE] choice of chemotherapy, which then consists of paclitaxel, docetaxel, or irinotecan. In addition, pembrolizumab was better tolerated and had a better safety profile. What made it really intriguing was of the total 628 patients that were enrolled in the trial, 64% of them had squamous cell carcinoma of the esophagus, which is unusual, especially in a phase II setting. And even though the study had a statistic overall survival benefit, in the squamous cell carcinoma cohort, there was a non-statistical trend in overall survival of 8.2 months versus 7.1 respectively. Pembrolizumab did boost the objective response rate compared with chemotherapy in the PD-L1 CPS greater than 10 and a response rate of 21.5% versus 6.1%. And then squamous cell carcinoma, it was 16.7% versus 7.4%. That leads to a whole bunch of questions. One, should we improve our PD-L1 scoring by including a CPX score greater than 10 and making our predictions based off that? In addition, should pembrolizumab expand its indications to include squamous cell carcinoma, since presently in the United States, pembrolizumab is only approved for adenocarcinoma. Also, there were the reports of the phase II ROAR study, which was looking at biliary tract cancers with BRAF V600E activating mutations. And these patients received a combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor. There were 33 patients. And they had an objective response rate of 42%. All of them with partial responses. And 7 of the 14 patients with responses had the responses lasting more than six months. And adding those with stable disease, they had reported a disease control rate of 88%. They looked at survival data. And the median progression free survival in this cohort was 9.2 months with an overall survival of 11.7 months. And to put this into context, usually second line biliary tract cancers we rarely ever see survival being more than five months. And these PFS and overall survival is very comparable to the first line setting for gemcitabine cisplatin, where the original study showed a PFS of eight months and overall survival of 11.7 months. So this potentially could be another treatment option for people with V600E biliary tract cancers. And then there were the preliminary results of a single phase II study at Memorial Sloan Kettering, which was evaluating pembrolizumab in conjunction with trastuzumab HER2 antibody with CAPOX and those with HER2 positive metastatic esophageal gastric adenocarcinoma. They had 32 patients with the overall response rate of 87%. They reported three CRs and 25 partial responses. And then when you factor in the stable disease, they had 100% disease control rate. And all the patients had some degree of tumor regression. The PFS were 11.4 months with an overall survival having not been met after six months. This is extremely exciting, and this has already led to the development of a global phase III study, which will be known as KEYNOTE-811. That's great. That sounds very promising. Were there any research presentations that you were interested in? Oh, yeah. There was a lot of great preclinical work. One of the most intriguing was in pancreatic cancer, where the Canadians did a study known as COMPASS, where they took advanced pancreatic ductal adenocarcinoma, and these patients underwent whole genome sequencing, as well as RNA sequencing of their tumors, prior to the initiation of first line chemotherapy with either modified FOLFIRINOX or gemcitabine and abraxane. Treatment outcomes were then compared to their molecular characteristics. The data suggests that chemotherapy differs depending on the transcription features of the tumor. So for example, the best survival data came out of those patients with the classical ductal adenocarcinoma subtype that were treated with FOLFIRINOX. And they had a median survival of 7.17 months. And when they were compared to the basal-like subtypes and were treated with FOLFIRINOX, they had a median progression free survival of 2.5 months. Now, patients with the basal-like subtype actually had a better response to gemcitabine and abraxane, which had a PFS of 5.65 months compared to the classical subtype, where they had median progression free survival of 4.93 months. So in summary, those with the basal-like subtype actually had a resistance for FOLFIRINOX. In addition, the researchers also mentioned that GATA6 RNA expression significantly correlates to the PDAC classic and basal-like molecular subtype. So it could actually be used as a marker in determining subtypes. And all this put together means that we could potentially identify patients who have a better chance of responding to FOLFIRINOX versus gem abraxane in the first line setting in pancreatic cancer. And obviously there needs to be more work to validate this, but this actually is quite intriguing. Also, there was data from the amino scoring testing, which was looking at its test in high risk stage 2 colorectal cancer patients. And for those who are not familiar, patients with stage colon cancer have a poor prognostic if they had a T4 disease, had fewer than 12 lymph nodes removed, had a point differentiation subtype, and also had evidence of vascular emboli, lymphovascular invasion, perineural invasion, or actually had a presentation of bowel obstruction or bowel perforation. And these patients are often offered adjuvant chemotherapy following curative resection due to their high risk of recurrence. The amino score test measures the density of CT3 positive T cells, as well as cytotoxic CDH cells within and surrounding the tumor to gauge the strength of the host immune response at a tumor site. So therefore a high amino score indicates a high anti-tumor immunity, which correlates with a low risk for disease recurrence. And these investigators looked at 1,130 patients with stage two colon cancers. And their conclusion for time to recurrence was those with high risk disease with high amino scoring compared to those with low risk disease had a very similar five-year survival of 87.4% versus 89.1% respectively. In contrast, if you have a high risk disease and a low amino scoring, your five-year time to recurrence was only 72.2% in the absence of adjuvant therapy. So this could potentially be used as a prognostic tool for those who are high risk stage two in the future. What about education sessions? Were there any that caught your attention? So my favorite was the neuroendocrine session. Neuroendocrine, as most people know, is a pretty rare disease population. However, there has been significant advances in the past few years with new drugs, new understanding of the biology, new diagnostic procedures, as well as testing. And it was a great panel of leading experts to help us navigate the new landscape of neuroendocrine and understanding how we should be approaching this. So that was my favorite session. Were there any other takeaways that were important during the symposium? There were a few other presentations I thought that were quite interesting. The Japanese presented their Prep-02 or JSAP-05 trial. And this was the first study to ever demonstrate the efficacy of neoadjuvant therapy in resectable pancreatic cancer. And their neoadjuvant chemotherapy regimen was a combination of gemcitabine with an oral drug S1. And they showed that it met its primary endpoint of overall survival of 36.72 months in those patients who received neoadjuvant therapy versus 26.65 months in those who went from upfront surgery. And for the Japanese, which tend to do upfront surgery followed by adjuvant chemotherapy in the past, I think this may be a shift in their paradigm, where this could be the new standard in Japan of using neoadjuvant therapy prior to surgery. Also, there was the oral drug trifluridine and tipiracil, which was studied in a phase III metastatic gastric and GE junction adenocarcinoma for those who have received two previous line of therapies. And they were randomized to the drug versus placebo. And it demonstrated a 2.1 survival benefit over placebo. And their main concern was a lot of these patients end up getting gastrectomies. But being an oral drug, could that affect its efficacy? And it seems like this benefit was also seen in those who had a gastrectomy versus those who didn't as well. So this potentially could be another option for those in the third line setting for gastric cancer. However, the big debate is even though it met its overall survival, is 2.1 months clinically significant? And I guess we'll have to have more data regarding safety and tolerability before we can make that decision. There is also the French GRECCAR-6 trial, which was evaluating the optimal time to surgery following chemoradiation for rectal cancer, where patients who underwent neoadjuvant chemoradiation were randomized to waiting 7 or 11 weeks prior to a mesoresection of the rectal cancer. They demonstrated that they had very similar path CR rates between the two. But more interesting, they found that if you had a good disease response to chemoradiation, there was no difference in disease free survival if you waited 7 weeks versus 11 weeks prior to surgery. However, if you were a bad disease responder, you had a poorer disease free survival if you waited more than seven weeks. However, this was not statistically significant. And then the authors concluded that we shouldn't be waiting more than seven weeks prior to surgery following neoadjuvant chemoradiation for rectal surgery. Thank you so much. Again, today my guest has been Dr. Stephen Long. Thank you for being on our podcast today. And to our listeners, thank you for tuning into the ASCO Daily News podcast. If you're enjoying the content, we encourage you to rate us and review us on Apple podcast.  

Dr Iveson speaks with ecancer at ASCO 2017 about results from the SCOT trial, a non-inferiority assessment of adjuvant oxaliplatin chemotherapy for 3 or 6 months to treat colorectal cancer. He describes how, by meeting these non-inferiority endpoints, 3 months of oxaliplatin can reduce cost for healthcare providers and improve patient quality of life, with less risk of peripheral neuropathy. The SCOT trial contributes to a larger international trial schema called IDEA, an international collaborative assessment of oxaliplatin with capecitabine or FOLFIRI at different fractions and staging. Findings within IDEA have identified high and low risk groups, Dr Iveson encourages to be considered eligible for 3 months CapOx.

Diese dreiarmige Phase-II-Studie ist die erste prospektive randomisierte Studie, die drei verschiedene Zweifach-Kombinations-Chemotherapien beim fortgeschrittenen duktalen Adenokarzinom des Pankreas vergleicht. Die Daten zum Zeitpunkt der Auswertung sind insbesondere bezüglich dem primären Zielkriterium Progressfreies Überleben (PFS) und dem sekundären Zielkriterium Gesamtüberleben (OS) und bezüglich der Auswertungen der Nebenwirkungen als reif anzusehen. Die Ausgangskriterien und die Strata sind relativ gut über die drei Arme verteilt. Im Median sind die Patienten 63 Jahre alt. Bei der überwiegenden Mehrheit der Patienten (82%) liegt ein metastasiertes Stadium vor, 68% hatten nachgewiesene Metastasen in der Leber. Ein Großteil der Patienten hat bei Einschluss einen ordentlichen KPS (84% mit KPS ≥80%) aufgewiesen. Keine der drei Kombinationen hat den primären Endpunkt einer Rate des PFS nach 3 Monaten von über 70% erreicht. Das PFS nach 3 Monaten lag aber für die randomisierten Patienten insgesamt mit 60% (95%-KI: 54% - 68%) über dem unter einer Gemcitabin- Therapie zu erwartenden PFS nach 3 Monaten von 50%. Hier schneidet im Trend der CAPGEM-Arm mit 64% (95%-KI: 53% - 77%) und der mGEMOX-Arm mit 60% (95%- KI: 49% - 74%) etwas besser ab als der CAPOX-Arm mit 51% (95%-KI 40% - 65%). Der Median des PFS als sekundäres Zielkriterium wurde im CAPGEM-Arm mit 5,7 Monaten geschätzt. Dies war im Trend besser als unter CAPOX (p=0,42) mit 4,2 Monaten und unter mGEMOX (p = 0,47) mit 3,9 Monaten. Die Gesamtansprechrate (ORR) als weiterer sekundärer Endpunkt war ebenfalls im CAPGEM-Arm mit 25% im Trend besser als die mit jeweils 13% identischen Ergebnisse im CAPOX-Arm und mGEMOX-Arm (jeweils p = 0,11). Beim sekundären Zielkriterium medianes Gesamt-Überleben (OS) besteht zwischen den Behandlungsarmen kein statistisch signifikanter Unterschied, es erreichte 8,1 Monate für CAPOX, 9,0 Monate für CAPGEM und 6,9 Monate für mGEMOX. Insgesamt ist die Effektivität der drei Therapiearme bezüglich der Zielkriterien PFS nach 3 Monaten und OS statistisch nicht signifikant unterschiedlich. Bei den paarweisen Vergleichen ergibt sich aber ein Trend im PFS, in der objektiven Remissionsrate und im medianen Gesamtüberleben (OS) zuungunsten des mGEMOX-Arms. Bei Betrachtung der Sicherheit sind die Häufigkeiten von Grad-3- oder Grad-4-Nebenwirkungen insgesamt mäßig. Alle drei Therapiemodalitäten konnten bei vertretbarer Verträglichkeit gegeben werden. Es konnten jedoch signifikante Unterschiede im Spektrum der Nebenwirkungen beobachtet werden. Die hämatologische Toxizität ist signifikant am geringsten im CAPOX-Arm (p

ResearchToPractice.com/VPC109 - Case 6: A 63-year-old woman with T3N2M1, K-ras wild-type colon cancer underwent right colectomy and received CAPOX/bevacizumab for 10 months before discontinuing therapy and one year later underwent a pancreaticoduodenectomy for a tumor involving the duodenum, jejunum and pancreas. Interviews conducted by Neil Love, MD. Produced by Research To Practice.

ResearchToPractice.com/VPC109 - Case 2: A 77-year-old woman with a 9-cm, K-ras wild-type colon cancer and 42 out of 47 positive nodes who underwent resection of her primary tumor followed by adjuvant FOLFOX and subsequently developed a retroperitoneal metastasis treated with CAPOX/bevacizumab. Interviews conducted by Neil Love, MD. Produced by Research To Practice.

ResearchToPractice.com/VPC109 - Case 1: A 61-year-old woman with an obstructing, K-ras wild-type colon cancer and three synchronous liver metastases who underwent subtotal colectomy followed by CAPOX and partial hepatectomy. Interviews conducted by Neil Love, MD. Produced by Research To Practice.

MeetTheProfessors.com – 72yo w/left hemicolectomy for 9.2-cm, Grade II adenocarcinoma, 42/47 positive lymph nodes; 6mo of adj. FOLFOX; asymptomatic for 16mo, recurred w/retroperitoneal mass; rcvd 5mo of CAPOX & bev for progression