Melanie Cole, MS (Host): Good morning. We have a thought leader panel for you today with three Northwestern Medicine physicians. Joining me is Dr. John Hayes, he's an Assistant Professor of Radiation Oncology; Dr. Sheetal Kircher, she's an Associate Professor of Hematology Oncology in the Department of Medicine; and Dr. Vitaliy Poylin, he's an Associate Professor of Surgery in the Division of Gastrointestinal Surgery. And they're all here today to highlight organ preservation approaches for rectal cancer.

Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. Doctors, thank you so much for joining us today. And Dr. Poylin, I'd like to start with you. What's been the general approach for rectal cancer and how has that evolved over the years?

Vitaliy Poylin, MD: Thank you. So even though colon and rectum is kind of part of the same organ, for decades, we've been treating rectal cancer differently because of the differences in anatomy, physiology of the organ itself, as well as the understanding that the rectal cancer is more aggressive and leads to more significant consequences for patients compared to colon cancer.

So for decades, it's involved combination of surgery, chemotherapy and radiation therapy. And we've been kind of playing and tweaking these approaches for a while. So for a couple of decades, based on a couple of good trials, the approach has been to start with radiation therapy to kind of shrink the tumor. Make surgery more feasible to remove everything that's there, followed by chemotherapy. But as we progressed, there were a couple of things that became clear. So first of all, a number of patients ended up not finishing all those three important components of a treatment of rectal cancer for various reasons, dependent oftentimes on the complications from one of those treatment modalities.

And the second one, as we were doing that, we realized that some patients, when we took them to surgery had no tumor left in the organ, raising the possibility that maybe in some patients we can start skipping some of parts of the treatment, whatever one of the three modalities may be, as well as realization that sometimes we can actually also tweak that and potentially improve possibility that some patients will may avoid surgery altogether by changing the order in which we approach these.

Sheetal Kircher, MD: Yeah, I agree. It really seems like it's been a one-size-fits-all for many, many, many years. It's only in the last, say, five, six years that we say, "Oh, wow, we can have some nuance to this" and really tailor our treatment to be aggressive, control disease. But we also now have a pause of to can we de-intensify therapy to improve quality of life while maintaining the same great outcomes?

John Hayes, MD: Yeah. I love the history throughout all of this from the standpoint that, as you mentioned, go back decades. In 1990 or '91 was when the NCI came out and said, "If your surgeon finds this, then add adjuvant therapy." And at that time, adjuvant therapy was one drug, 5-FU, and radiation. And then through the '90s and in the first decade of this century, what we've ended up finding is that we can identify those factors ahead of time. So we were motivated to say, "Okay. We know that a lot of these patients should have adjuvant therapy. Adjuvant therapy leads to less recurrences. What if we move it up?" Right? And we always talk about the German rectal cancer trial. But there are many other analyses that looked at patients who had radiation before surgery with the initial intent of sphincter preservation. It wasn't organ preservation, it was sphincter preservation. And that's where maybe for non-operative patients, patients who have medical contraindications or simply refuse treatment, we grew from there because that's when we first started realizing some of these patients are going to have a CR, the disease is not going to be evident. They're going to deny the opportunity to remove it. And then, they didn't have recurrences. And so, customization really built off of that observation, that pathway. And now, there's a lot more we do to really individualize for patients, folding in their desires, right? Because many of them are just, "Whatever you do, avoid surgery."

Sheetal Kircher, MD: Absolutely.

Vitaliy Poylin, MD: And this is also kind of a disease where you can actually see all of these different advances in medicine and surgery come together because, you know, our imaging modality became better and our understanding of what it means became much more sophisticated so we can start picking out small details instead of irrevelant one-size-fits-all. You know, the understanding of the surgical techniques and approaches also advanced that we can now also tweak things a little bit better, as well as with radiation. So, all these things were kind of coming together, but then starting to interact to provide this more individualized approach.

Sheetal Kircher, MD: And very interdependent too. You know, I think timings, you know, oftentimes in rectal cancer, although I think that's changing as we've seen the MSI-high tumors, but it's still moving the chairs on the deck. You know, do we put chemo first, radiation first? And the interdependency of this really lends itself to multidisciplinary, like required tumor boards, you know, essentially for all of these patients with early-stage disease.

John Hayes, MD: Yeah. Again, if you go back far enough and in my practice I have, the surgeons would have to tell me how high something was. And it was by rigid proctoscopy. Even EUS wasn't great at telling me distances. And that would determine whether or not I had a good role or it's something that I was going to be superfluous. I'm not needed in this case. And then, things like the MERCURY trial as well, they went and taught us a little bit more about the anatomy as it reflects on the surgery that's going to be performed. And then, you can make better choices and maybe, again, better choices for surgery. But then, we're talking today about how we've evolved into many patients not having surgery at all.

Sheetal Kircher, MD: Well, I think that's become especially important with what we're seeing in the incidence of especially rectal cancer in our younger population. So, the need and desire for fertility preservation really speaks to de-intensification of radiation and kind of that element of having a young population and their goals and needs is very different than our elderly population.

Melanie Cole, MS: Dr. Kircher, why do you think that is? Why are you seeing this more in a younger population?

Sheetal Kircher, MD: Man, I wish we knew. The studies are showing that we still need a lot more studies, but we're not seeing a clear risk factor that we could put our hat on.

John Hayes, MD: It's an international problem.

Sheetal Kircher, MD: It's an international problem.

John Hayes, MD: We can't look at it in a certain environment population, break it down into demographics and say, "Oh. Well, here's the link. This seems to be associated with a shift in age." It's everywhere.

Vitaliy Poylin, MD: Historically, again, this is how it started. I remember, you know, there's this trend for younger cancers, especially in Asia and Southeast Asia, and we were all pontificating how maybe it's something environmental. And then, we start seeing it here as well. So like, "Well, maybe not."

Sheetal Kircher, MD: So, you know, diet has always come up as a possible worrisome risk factor. But again, I don't think that that's a clear explanation for all patients. Definitely, the ones I see in clinic, you know, don't seem to fit a profile that you would consider high risk. So, I think this speaks to screening, and I think primary care doctors are becoming more and more aware, GI doctors are more and more aware of this phenomenon. So as we know, we've decreased the age in which screening colonoscopy starts at 45. But even in younger patients, kind of taking those serious symptoms and moving forward.

Vitaliy Poylin, MD: And I think what makes this even more important, as we've seen cancer in younger and younger folks within colorectal cancer, it's a rectal cancer that we've seen in even younger populations. So, it's for no clear reasons, but very important.

Melanie Cole, MS: Dr. Hayes, I'd like you to expand just a little bit on what Dr. Kircher was discussing. It's quality of life that's such an important aspect of this type of cancer and that multidisciplinary collaboration that you've all been discussing. But there are going to be then other people involved to help with that quality of life. And Dr. Kircher even mentioned fertility preservation. Can you expand on all of the professionals that are involved and how you all work together in that tumor board?

John Hayes, MD: Yeah. It's critical for us to know the details of the tumor and the extent of it. So, whether or not it's through the rectal wall, whether or not the nodes are positive, whether or not there's extramural lymphatic vascular invasion. All of those are signs of more advanced local disease. And then when we fold this in, we're often talking about opportunities for treatment based on the patient's desires. And Sheetal already mentioned how many of these patients are younger and we're going to maybe avoid radiation therapy for some of them because of concerns about fertility and long-term pelvic complications of radiation therapy. And to a large extent, these things require an ongoing discussion between us.

I have to talk to Vitaliy about whether or not something's going to require removal of the sphincter, an APR. And that will be critical in deciding whether or not someone is going to want to have organ preservation treatment. So, the age and then the extent, the anatomic extent of the disease, and then very importantly in something that's come up and is now nationally known, thanks to relatively early publications for small numbers of patients, there are the subtypes that they have MSI-unstable tumors because that's now a whole different animal and that's part of customizing. So, those patients may have great prolonged survival with immunotherapy. And we can step back from that, both of us, and simply look to medical oncology to manage that. So, each one of these could be different bins in which you want to place your patient, but you're going to only be comfortable there in the right place if you have a real acknowledged approach with you and your colleagues. And nowadays, it's not just phone calls, it's emails, et cetera, the texting back and forth just to touch base about this or that. So, there's a necessity of ongoing cooperation.

Vitaliy Poylin, MD: And what it emphasizes, again, what I'll tell folks when I see them, we have two priorities, right? One is take care of a cancer, and the second one is quality of life, and they're both extremely important. And that's why, you know, you're not just seeing me, and then we could go and get it treated. It requires the big team, you know, medical oncologist, radiation oncologist, surgeon. Genetics nowadays is extremely important and we'll go into more details on testing; the folks from fertility preservation and gynecology. And I'll tell them, "Look, we all talk. We talk all the time. And we're all involved in your care. It's just whoever is driving the bus at the moment, right? But we're all on that same bus with you."

Sheetal Kircher, MD: I think that when we talk about quality of life, we've become very focused on organ preservation techniques. But I think we have to be kind of respectful of the right patient for that approach and really understand that sometimes preserving that organ may not contribute to improved quality of life. So, our very low rectal cancers, either with or without surgery, sometimes we'll leave the patient with bowel dysfunction, sexual dysfunction, incontinence, and really finding the right approach is important to first maximize their survival and find what's really going to improve their quality of life. Sometimes that's organ preservation and sometimes it's not.

John Hayes, MD: Yeah. We have patients who their primary motivation is to avoid colostomy. Even though it's temporary, "Vitaliy has assured me, no, we're going to be able to hook them back up," right? When you look at the data on patients who have radiation therapy, as primary curative treatment. They go into a CR, right? And when that happens, and studies like OPRA have shown us, this could be upwards of half of our patients now. Properly selected, half of our patients may not need surgery. Although, within a few percentage either way, maybe 15% will have a recurrence. They can be salvaged surgically later on.

But again, that road is different. When we look at patients who have non-operative treatment, not the MSI -nstable patients, but in particular that have the radiation. They experience syndromes like the low anterior resection syndrome that is about as the same rate as folks who have resection, so, the location of the resection. And this gets to where I like to talk to the surgeons. You know, not everyone in my understanding, correct me if I'm wrong, not everyone's going to have a coloanal anastomosis. So depending on location, how low that is, that location is also associated with quality of life influences, right? Some of those patients will be great. They won't have any long-term problems. Lower the anastomosis, the more the resection, and that's usually associated with the extent of disease, but that leads to the risks of whether or not they're going to have significant compromise to their quality of life.

So, organ preservation, carefully selected, is not free, right? A lot of those patients will still have long-term issues, functional issues. As a radiation oncologist, I often tell patients, the way I look at this in trying to predict whether or not you're going to have a long-term problem, is think about the tissue that we've treated, separate it medically, and look at it just functionally, that part of you will be older than the rest of you, all right? It won't have the capaciousness, it won't hold as much. You're going to have more frequent bowel movements, you're going to have more urgency. Why do I compare this to aging? Well, because through the years as I've listened to patients and when I tell them this might happen if they're 70, 75 years old, they're often shrugging their shoulders. "Yeah, I know. That's been the trend. I know what life is like." You talk to somebody who's 40 or 45 or 50, that's harder for them to accept. But regardless, circling back to what we were talking about earlier, selection of patients is so critical. What's their motivation? What are they trying to avoid or not avoid? And when we find out that they really want to avoid resection, if at all possible, we have avenues for that now, right?

Sheetal Kircher, MD: We have avenues, but we also have a lot of questions still. You know, I think we're still wondering short course versus long course radiation. You know, what's the correct sequencing of the total neoadjuvant, whether we start with chemotherapy first versus radiation, and how intensified do we need to get into our chemotherapy? I think the studies so far, we've answered parts of that. You know, we know in high risk populations like the RAPIDO study had that perhaps there is a role for short-course radiation. But when we're talking about organ preservation, probably OPRA is the more appropriate study to follow, which really anchors us on long-course radiation.

Vitaliy Poylin, MD: And I think also something important is because we knew about obviously the complete response for decades now, we've seen it. But the big question was, well, some proportion of folks who will come in, it looks like we have a clinical complete response. Do they actually have a pathologic complete response, meaning is everything gone or we just think it's gone? And if it comes back, can we give them the same outcome as if we took them to surgery earlier? And it took quite a while, especially in this country. But at this point, we know with a reasonably high likelihood if you meet this very strict criteria, that we will, you know, review, apply, and then you follow. If things come back, we can give you the same outcome, meaning we can actually reliably offer people that possibility. But it's also with understanding that, yeah, some people will fail. And some people, that may not be the goal. You know, if we cure them of cancer, but they're sitting in a diaper by the bathroom for the rest of their life, I'm not sure we did them that much good, right? So, it's individualizing this and being able to offer these options.

Sheetal Kircher, MD: It's almost like we became brave enough in our studies to avoid surgery, when historically I've had patients with PCRs and wondering did I ever need to take them to surgery? It's like we got brave.

John Hayes, MD: Generally speaking, I think the human instinct is more is better when it comes to something as scary as cancer. So, studies have generally not been de-intensification studies. Studies have not backed down outside of studies in younger patients and in peds especially, but that's not the topic here. So, you can look at analogous situations and go, "Okay. It was smart not to throw everything in the kitchen sink up front out of fear that that will increase the recurrences."

And Vitaliy is speaking to the critical part of this, which is there was still fear that salvage surgery would lead to poorer overall survivals. And it doesn't. We've now got proof that it doesn't do that, that resection can be at the time of recurrence. So, it's easier to watch. And watching can be hard because sometimes these followup scans and scopes are equivocal. Knowing this, however, allows us as a team to say, often, talking to each other, "Okay. You know, it's not quite normal yet," or what we think is a bland, looks great situation, but let's sit tight because we're not working in an absolute window. We don't have to have something done at a certain time.

Sheetal Kircher, MD: Yeah. And that teamwork, it's not just with coming up with the same plan. I'd say as much collaboration is I think we communicate probably just as much in the surveillance period, especially in the watch-and-wait folks, than as we do in the initial plan.

Vitaliy Poylin, MD: And I think it allows us also to kind of include patient even more into that decision-making compared to, you know, one-size-fits-all what we had because we don't say, "Okay, it looked like you maybe have a complete clinical response. You'll qualify. This is what it means. This is what it means from followup standpoint, the function, the scans, the everything. And then actually if things change, we can circle back and change the plan."

Sheetal Kircher, MD: And that can be challenging for patients too because we do have more decisions to make and that shared decision-making piece of it, it used to be very prescriptive what we did in rectal cancer. And now, we're eliciting patients goals and that can be challenging for people. So. I think we're all learning how to better elicit the true kind of goals of the patients.

John Hayes, MD: And it can change. And I'm going to tie this together with what you mentioned earlier about choices for radiotherapy. Just as we may lay out a strategic plan for somebody, "Well, this looks like a locally advanced rectal cancer. It's higher grade. There's EMVI. It's very low," okay? Those patients, especially if it's very low, they should have longer course radiation. The pelvic control rates are better.

Let's say it's higher. It's still worrisome. It's got some characteristics that are worrisome for pelvic control. Radiation would help optimize that, knowing that based on bulk alone, but some of the other prognostic factors, those patients, they're not likely to have a 50% complete remission rate. So, we start with short course, right? We start with short course because we're also concerned about systemic disease in these patients. As Vitaliy said earlier, that's still the first goal to cure and then to optimize your quality of life and it runs in parallel. And as we've also talked about, organ preservation is a surrogate for quality of life. It is not quality of life. Quality of life varies within that. So when we look at all these things and we say, "Okay. We go down the road of I think it's best to follow a short-course radiation with chemo," because we're more worried about systemic risk in these patients.

Sheetal Kircher, MD: We need to get to chemo fast.

John Hayes, MD: Right. That was the purpose of the RAPIDO trial.

Sheetal Kircher, MD: Absolutely.

John Hayes, MD: The RAPIDO trial was maybe our pelvic recurrences are quite small nowadays with proper resection, TMEs, et cetera. The issue is not the pelvis anymore, it's distantly. So, they found that pelvic control could be just as good with short course. Let's not get into the details or the weeds of that study and who was and wasn't in it, but it was relatively advanced disease, locally advanced, but with poor prognostic factors. And that was the jumping off point for during COVID, some institutions going to short course for everything, okay?

Memorial in particular is one institution that I know did this and I've seen followup on their patients. So when you look at short course versus long course, which is a five, five and a half weeks' worth of treatment, when they look back at the results, organ preservation was better with long course, okay? It was probably a 10-15% difference, but let's just say 10%. So, in that, if I know ahead of time that someone wants organ preservation, I'm going long course. If it's a very low-lying lesion with, again, the risk factors for higher risk of recurrence, not just because of location, but because of extent, mesorectal margin threat, et cetera, it's long course. If it's higher, and I go short course and complement with systemic therapy, and it goes into a CR, you can still watch those patients, okay?

So, that's where the decision point now has moved downstream. And what if the patient says to you, "You know what, I thought I wanted this out right away. You guys talked me back from that. We've gone through this, and now my symptoms are gone. Followup scans look great."

Sheetal Kircher, MD: That'll make a world of difference.

John Hayes, MD: The decision has changed. "I don't want surgery," et cetera. You don't have to do that, and that's the point. That's where you're looking for feedback as you go. It's as if we set up the strategic plan and then we still have stopping points at which we re-evaluate.

Sheetal Kircher, MD: And I think the studies have really shown us that there are multiple pathways to getting to that path CR, whether it's intensifying chemotherapy or long-course radiation or flipping the two in sequence. Once you see that path CR, I think the data is showing us that it is an appropriate time to consider a watch-and-wait approach.

Melanie Cole, MS: Thank you all so much. This is such a fascinating conversation. And I'd like to give you each a chance for a final thought. So, Dr. Kircher, why don't you start with what you would like the key takeaways to be? You've spent some time talking about successful outcomes, quality of life, fertility preservation. I'd like you to speak about those successful outcomes, how you're gauging that, and where you see this shared decision-making going in the future. Tell us anything you'd like as far as key takeaways.

Sheetal Kircher, MD: You know, the key takeaway, actually, which we didn't have a chance to really approach too much, we've mentioned the MSI-high status, but about 3%, I know it's a small population, but you know, I'd say one of the most exciting things I'm seeing in clinic are my MSI-high patients. So, you know, New England Journal of Medicine published a paper on 12 patients. You know, when was the last time New England Journal published on 12 patients? But it was such exciting results where patients with MSI-high tumors, rectal cancers, were given six months or nine doses of a PD-L1 monoclonal antibody, a checkpoint inhibitor. And what they found in those 12 patients after 6 months of treatment that 100% of them had a pathologic complete response. They did not go on to get radiation. They did not go on to get surgery. And that's something we are seeing more and more in clinic. I think that's exciting. That's game-changing and something I haven't seen yet in rectal cancer. So, I think we're excited to find more and more of these subpopulations that we can make a game-changing impact on. I think organ preservation is one of them, but I also think molecular markers, including MSI high, we're going to see more and more of that going forward.

Melanie Cole, MS: Dr. Hayes, you're up next. What would you like the key takeaways to be? And you mentioned briefly immunotherapy earlier. Tell us what you would like providers to know.

John Hayes, MD: Well, I think the role of radiation therapy has continues to evolve. And I've always thought of myself as complementary to the resection. The surgeons and I are working to deal with the bulk and the microscopic extent of disease. The latter is my realm. And I want to appropriately add it to the local excisions. Now, I can be primary treatment for a lot of these patients. Again, as long as the message upfront is clear that we're going to see how things go. And that's where my role is also changed because it evolves and I have continued feedback with patients. And then, we'll talk to the surgeons down the line as well, make sure we're getting the right fit for each patient.

And as part of that in the immunotherapy, what Dr. Kircher was just talking about that makes perfect sense is, in all of oncology, we continue to have a theme of personalized care. And we've talked a lot today about decision-making with your patients, what our considerations are, but we're really trying to get further down the road of a selection tool. Right now, we have MSI-high patients. "Oh, well, we don't need to do anything until we find out if they have a good response to immunotherapy." If they don't, then we change directions. We don't always understand that, but that's a good starting point.

I would love to see us, as we move forward, continue this acquisition of phenotypic markers of different profiling to say, "Oh, this is a case where, optimistically, we used to hope for a 50% organ preservation rate." This group's got an 80%. Just as importantly, this group has a 10% chance. And then, we can really redirect what we're trying to do and accomplish with them. Again, fitting it into where they are in their life.

Melanie Cole, MS: So much of this has been really about the patient quality of life, shared decision-making. Dr. Poylin, bring it home for us. Summarize what you would like other providers to take away from this absolutely fascinating thought panel discussion today.

Vitaliy Poylin, MD: I think, to me, kind of a bottom line of this, you know, we made this giant leap probably in the last five years of really understanding, but as importantly, personalizing the treatment of rectal cancer. as you heard us talk over and over again, it's not one dominant trial that now this is we all switch to from one way to the other. We now have multiple pathways to take the patient to cure, to better quality of life, and to involve them into the decision-making together with us in figuring out what that path for that particular patient may be. I don't know a lot still, but it's definitely makes the tumor board very exciting for us.

Melanie Cole, MS: Such a comprehensive approach to organ preservation and thank you all for joining us today. This was just such an enlightening conversation. And to refer your patient or for more information, please visit breakthroughsforphysicians.nm.org/gastroenterology to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine Podcast for Physicians. I'm Melanie Cole. Thanks so much for tuning in today.