Multidisciplinary Approach for Rectal Cancer - Discussion with Dr. Deb Schrag & Dr. Krishan Jethwa

Introduction Welcome back to another episode of the Oncology Brothers Podcast. I'm Rahul Ghosein, joined as always by my Co host and brother, Rohit Ghosein. So far in our GI series, we've covered HCC, colon cancer, liver directed therapies and understanding the needs of different patient populations with colorectal cancer. Today we're going to shift the focus on rectal cancer, particularly localized or locally advanced disease. While locally advanced cases require an aggressive multi modality approach to maximize the chances of cure, we must also be cognizant of the potential long term complications associated with our treatments. Absolutely. Speaker 2 Rahul, the key challenge in managing locally advanced rectal cancer is achieving that perfect balance between therapeutic efficacy and limiting the chronic side effects. To dive deeper into our current strategies, you're joined by Doctor Deb Schrag, a medical oncologist from Memorial Sloan Kettering Cancer Center, and Doctor Christian Jethwa, a radiation oncologist from the Mayo Clinic. Deb and Krush welcome. Speaker 3 Thank you, it's nice to be here. Speaker 4 Likewise, thanks so much for the invitation. Speaker 2 Perfect. Thanks so much again for joining us, Deb. Last year just around this time, can't believe it's about a year already. Prospect Study You presented Prospect Study as one of the ASCO plenary discussions. Before we talk about this algorithm to lay the foundation, let's just talk a bit about PROSPECT Study. Rectal cancer is a multidisciplinary approach where we know that patients need systemic therapy, radiation, and surgery. PROSPECT study focused on a limited patient population where radiation could be avoided mainly to limit chronic side effects. What did the study generally show and how are you utilizing this study in your practice today? Speaker 3 Yeah. So first, I would say it wasn't such a limited patient population. So we excluded patients who needed AP, Rs, abdominal perineal resections, which are patients with distal disease. And we excluded patients who had really bulky tumors like T4 tumors and four lymph nodes over a centimeter. But the majority of patients with locally advanced rectal cancer actually were prospect eligible. So it was not such a limited subset. It's also not such a low risk subset. A lot of the patients had no positive disease. So I would say prospect patients are pretty typical garden variety rectal cancer patients. Look since 1990, curing rectal cancer has involved 3 modalities, surgery, chemo, radiation and chemotherapy. And we've been playing this three card Monte of moving the order around, OK. But essentially for 30 years we've been playing with each of those 3 modalities and just rearranging the sequencing. And you know, maybe we could do capacitabine instead of IV 5 FU, but that's it. What Prospect did is, is say, could we now that we've had all these amazing therapeutic advances and diagnostic advances, we've got MRI so we can stage better. We're doing colon screening, colonoscopy. So we're finding smaller tumors. We have Fullfox rather than just plain old five FU which is what we had in 2002. All these advances combined, can we trim our sales a little bit as you said to make it easier to get through treatment and that was what prospect was trying to do. So we basically did this big randomized trial where we compared the tried and true method since 1990 with a selective method where we said if your tumor melts to full fox, we're not going to give you chemo radiation. And the bottom line is that outcomes were identical it the trial met it's non inferiority endpoint. So if you meet your endpoint in a non inferiority and there's no oxygen between the survival curves, not between the disease free survival curves, not between the overall survival curves and the quality of life favors not giving chemo radiation, then you know you can give patients the choice and let them vote with their feet. And I think that is the right answer. Give patients a choice. So you know, I say, look, if I have a violin player and they just can't have any oxaliplatin, go with the chemo radiation. But most people who don't have neuropathy or contraindication to oxaliplatin choose to avoid the chemo radiation because it has long term consequences. We know it impairs bowel sexual function. Second, malignancies in the radiation field, one that I think is often overlooked, has to do with if you're unlucky enough to have your cancer come back, if you've had radiation to the pelvis, you have less stamina to withstand metastatic therapy when we give it in the metastatic gear setting. But again, we cured 80% of these folks, so hopefully that's not too many people. You know, when we have options for patients, that's just a win. So prospect is a win because it says that we can cure. You got a good chance of being cured with two modalities, not 3. The outcomes were identical, with an quality of life edge for the strategy that eliminated chemo radiation. Speaker 1 Deb, thank you for going over that and congratulations on this tremendous effort. The importance of a patient-centered approach to cancer care Like you've pointed out, this is not a small patient population. A lot of our patients with locally advanced rectal cancer, we have to keep this in mind, Deb. This was a study that enrolled patients during 2012 to 2018 and at least during that time and now when comparing to 2024, our systemic treatments have not changed much. But one can argue that radiation modalities have improved in this period. Right now majority of our patients coming in the office, we have to entertain this versus total neo adjuvant treatment in the community settings. We have to be mindful to ensure that we can omit radiation in the right patient population but also understand the right current available radiation treatments. Chris, this brings up the point on this evolving paradigm of radiation. How do you decide on the radiation course for the patient in front of you? How do you decide on the radiation course for the patient in front of you? Speaker 4 Yeah, I think that's a a great question. I'd also like to piggyback on some of the comments that Deb made. I I think it's the prospect study was truly a tremendous study. And I think it's, it's really broadened our perspective on the overall care of our patients with rectal cancer such that I think one of the beautiful concepts that I think has really evolved since the trial was presented and we've discussed it is that it's really emphasized this balance between quality of life and cancer control for our patients. And I think it's become an even more kind of predominant concept amongst our discussions. I'm also a believer very much like Deb is that we can use MRI based risk stratification and these contemporary trial data to really direct patients to an approach that may optimize that balance between quality of life and cancer control. And sometimes, often it could be selective emission of radiation therapy for candidates just like for those that were included in Prospect, which I also would agree over kind of that standard risk cohort, garden variety cohort of patients with rectal cancer or in patients that have more mid or distal tumors in whom we could potentially better spare function and quality of life with a selective organ preserving approach, we could use chemo radiation and consolidated chemotherapy and selectively omit surgery and those that have a complete response. So at least from a radiation therapy perspective, there are really two predominant regimens that are used in the care of patients. It's short course radiation therapy or long course chemo radiation. Randomized trials in general suggest that each of those two approaches are relatively equivalent in regards to oncologic outcome. But we do know from a a large volume of data that MRI based risk stratification can really guide us towards patients that may be at higher risk of pelvic recurrence versus distant recurrence. And in addition to that, the RAPIDO trial has provided some suggestion that patients with essentially high risk rectal cancer may be at a higher risk of pelvic recurrence if treated with a short course TNT paradigm compared with long course chemo radiation. So at least in my practice, if I am considering the use of radiation therapy, I'm often very supportive of short course radiation therapy platform. But in patients with high risk rectal cancer, specifically high risk of pelvic recurrence, which I think of as clinical T4B compromised mesorectal fascia involved lateral pelvic lymph nodes or distal tumors approximating the anal verge, I tend to favour long course chemo, radiation and that subset of patients. Speaker 2 Thanks so much for covering that question. Of course, we have to appreciate that none of this is black and white situation. It's always multidisciplinary approach and a lot of discussion takes place before 1 decides the treatment course. Deb, just to make the matters a bit more complicated, which chemo arm that you utilize in general? Which Chemo Arm Do You Utilize? Is it FOLFOX or kpalk space which is what rapido and stellar studies have shown, or FOLFIRINOX in some patient population which is by protege? Speaker 3 Yeah. So for high high risk patients, so patients with T4 or N2 were very high, absolutely FOLFIRANOX intensification makes sense. But for patients with atypical locally advanced rectal cancer and by typical I mean mid rectum clinically node positive but not big bulky nodes not encroaching up on the on the pelvic sidewall. FOLFOX is fine. FOLFOX and K Pox I consider to be interchangeable if I have concerns about compliance or adherence. It's not really compliance, it's adherent medication adherence. I I think Fullfox is more strategic and that tends to be what I use. But we really have voluminous data that Cape cited being taken appropriately and five, if you intravenously are inter interchangeable. So K pox and FOLFOX are for all intents and purposes interchangeable. So I I think that that's, you know, that works with respect to your question. And the first thing is to determine whether an individual is MSI high. If someone's MSI high, and we didn't know this when we started prospect, we figured this out, but it took a while, First figure out who's MSI high. That's a small group of people, maybe 5%, maybe as high as 8%, but it's small. If you're MSI high, go get your immunotherapy because we may be able to could cure you not with two modalities but with one modality. It's like. Speaker 2 Even. Speaker 3 It's the dream. OK, so that's first. If you're MSI high, go get your immunotherapy and hopefully you're done. If you're not MSI high and you're intermediate risk, it's a choice, but more and more patients are opting to avoid the long term sequelae of chemo radiation. However, if you have a distal tumor and you're going to require an APR or you have a distal tumor and you would require a low resection with a Co anal anastomosis and you're going to be left running to the bathroom, then I think chemo radiation is the way to go with a total neoadjuvant therapy approach. So if it's a low tumor, go TNT. If you're going to need a choloanal or a really low anastomosis that's going to mess up your quality of life, go with TNT. So I don't know if you just want to take centimeters, understanding that everyone's anatomy is a little bit different. If you are, if you have a tumor that's going to require an APR and let's say is below 4 centimeters, go TNTI think if you're in the four to five centimeter range, it probably also makes sense to consider TNT because the anastomosis is going to be pretty low. Even if it's an LARI think if you're above 5 centimeters, you got a choice because again, prospect showed us that the outcomes are identical, but the edge for quality of life, I go chemotherapy only. And remember in prospect, if you didn't have a great response to chemotherapy, you had a second, second chance, you could then get chemo radiation, which is essentially TNT. So you know, I would do chemo first for sort of the those intermediate risk above 5 centimeter folks. And I also want to put in a plug for surgery first. We got some people whose tumors are right at the junction. They're basically sigmoid tumors. Sometimes it's OK to take those people straight to the operating room. Sometimes they don't have any nodes and and you can be done. So it's really about it's become a sorting game. Who can have just immunotherapy, who can have just surgery, who can have TNT and then no surgery and who needs everything. A few people still need all three modalities and everything, but this is really about application of our existing technologies and just sorting people into to get what they need but not what they don't need and and dynamic approaches that use the responses to tailor treatment. Speaker 1 Absolutely. Again, we've seen this recurrent theme that more is not always good, and that is what we're trying to figure out. Can we get away with one or two modalities rather than sticking with our old paradigm of triplet? The other thing I want to bring up from ASCO 2023, of course, prospect was presented there as a plenary discussion. Deb, you mentioned K Pax when using Cape cytabine with hand foot syndrome. Another study from ASCO 2023 was diclofenac gel that improved hand foot syndrome significantly. So something for us to keep in mind for supportive measures. So we've touched a little about emitting radiation. Who can we safely perform surgery with MRI? Chris, your thoughts? And who can we safely emit surgery now that we have MRI as our modalities to wait and watch and monitor and scopes in your multi D tumor board discussions when this comes up the right patient to admit surgery. What does that look like? Speaker 4 Yeah. I mean, I think that's a good question. And, and I do think that the shape of future rectal cancer practice is really going to be based upon this concept that we're trying to think of a single local treatment modality for the vast majority of patients such that we can better preserve function and quality of life. At least in our multidisciplinary clinic. We've, we've taken the approach that if patients have tumors within 5 centimeters of the anal sphincter complex, so not anal verge, but within 5 centimeters of the top of sphincter complex. Those are patients that were increasingly considering a total new adjuvant therapy approach and selective emission of surgery if they have a complete clinical response to therapy. And that's for the same reasons that Deb just mentioned, that having patients that have a low tumor, that has a low anastomosis is associated with very significant bowel dysfunction after an operation. But in addition to that, any operation inside of the pelvis is also associated with significant bladder and sexual dysfunction. And sometimes that function can better be preserved with a single local treatment modality, whether it's chemo, radiation or surgery. But the combination of both chemo radiation plus surgery is without a doubt worse than the combination in either one or the other. So at least in in our practice, we're very comfortable with proceeding percent to the Oprah study with giving long course chemo radiation followed by consolidated full Fox based systemic therapy or in those that have very high risk tumors. If we are still considering organ preservation, we will often intensify with the use of fulfurinox and we tend to obtain response assessment around 8 weeks after completion of chemotherapy. That's also a little bit debatable, but I think anywhere in that range of four to 12 weeks would be reasonable. And then just like many others, we follow the MSK direction of of response assessment per MRI, digital exam and endoscopy. And if there's a complete response with each of the modalities, then we're very comfortable proceeding with an with an active surveillance approach. I think we're all having challenges with that near complete response group because just like the Oprah study has taught us, we're seeing very discreet differences in outcomes between those that have an initial complete response versus near complete versus incomplete response. And while Oprah did allow near complete responders to continue to be surveyed and if they either stayed stable or converted to a complete response, continued along that pathway, I think the recent update has at least given us some pause that disease free survival outcomes may be poorer in that group. I'm still comfortable if a patient has a near complete response at that first response assessment with performing in another close response assessment about 8 weeks later or so. And if they have a complete response at that point and they're well informed on the potential risks, still proceeding with an active surveillance approach. But Deb, I'm curious, how have you all or have you all changed your practice based upon your more recent update of the Oprah study? How have you all changed your practice based on the Oprah study update? Yeah. I mean, I think that we continue to tailor. I think interpretation of the Oprah study is controversial. Remember, this was a randomized phase two, not a phase three. It wasn't, you know, it's been interpreted as though it were a phase three, but it actually wasn't. So yeah, I think that they're different perspectives on how meaningful the differences in outcome and Oprah are and whether that sequencing is essential or not. I think there are a good number of physicians who continue to think that whichever modality you can start the most quickly is the best one to get the patient some relief. Speaker 2 Thank you so much for covering that, Christian Deb. And well, this talk would not be complete if we don't stress the importance of MSI high as you mentioned, Deb, it was your colleagues from MSK who published this data about two years ago and what a significant improvement in quality of life and decreasing the modality use of surgery and radiation, especially when they have complete response. So congratulations to you. Speaker 3 Yeah. I would just say that we have even more data now. That study only included around 16 patients, but now we have more than double, triple that actually. And essentially the response rate is 100%, and it's been validated by centers around the country and around the world. We figured out the biology and we know what to do. And it's a win for our patients, which is great for everybody. Speaker 2 Indeed, it's a small population, but it is very important to test for MSI High before proceeding with any modality to see if they would qualify for single immune checkpoint inhibitors. Deb and Chris, thank you so much for taking the time to cover this very important topic and discussing our current available treatment options for locally advanced rectal cancers for our listeners. Conclusion Stay tuned for a short recap. Speaker 1 With the increasing incidence of rectal cancer, we need to get comfortable in appreciating the nuances of treating locally advanced rectal cancer. In this discussion with Doctor Deborah Schragg, a medical oncologist from Memorial Sloan Kettering, and Doctor Christian Jetba, a radiation oncologist from Mayo Clinic, we had a chance to focus on our current available options. Base of PROSPECT trial. A plenary discussion at ASCO 2023. We can potentially emit radiation in the right patient population for rectal cancer. We also need to be mindful of organ preservation with selective emission of surgery in the right patient. Speaker 2 However, with improving radiation modalities, total neoadjuvant treatment still remains a viable option for the right locally advanced rectal cancer patients. Selecting the right patient for short course versus long course radiation based on their risk of recurrence is extremely important. Another critical aspect is testing for MSI high status as these patients can have a great response to a single agent immune checkpoint inhibitors. Thank you for joining us. Keep an eye out for more episodes as we continue to bring you the latest in the rapidly evolving world of oncology treatment. We are the oncology brothers.