Surveillance after locally advanced rectal cancer (LARC) treatment: Dr. Schlechter & Dr. Smith (2024)

Manju George  0:00
Hello everyone. Welcome to Doc talks. I’m Dr Manju George, the Scientific Firector at Paltown Development Foundation, the nonprofit that supports Colontown. And today, we have Dr. Ben Schlechter and Dr. Josh Smith to talk to us about surveillance after treatment for non metastatic rectal cancer. Dr Schlechter, do you want to start first?

Dr. Schlechter  0:24 
Sure. So I’m Ben Schlechter. I’m a GI oncologist here at Dana Farber in Boston. My main clinical interest is rectal cancer, and my main research interest is actually on immune therapy for these diseases. And I know that’s been a hot topic. Always happy to talk more about things like Botensilimab, emerging therapies and things like that. But rectal cancer obviously we know is very important topic.

Dr. Schlechter  0:43 
All right, so I’m going to talk a little bit about how we got to the modern treatment of rectal cancer and what the modern treatments are, because there’s this laundry list of things and that I think is going to lead us into, how do we monitor patients after they’ve had all these cool, developed treatments? These are my disclosures. So there’s a few major paradigms for the treatment of rectal cancer. Obviously, there’s the conventional treatment, which now would be considered old news, and that was a 40 year effort to get there. There’s the modern total neoadjuvant therapy, everything before surgery. There’s these intensification, de-intensification projects. So can we use more or less chemotherapy to make quality of life better while maintaining safety and cure? And then there’s the where to from here. And Dr Smith has a lot to say on this topic, with new trials that are open enrolling in the US, with JANUS and the ACO trial in Europe. So this conventional approach is a 40 year effort, and really going back to the 80s, we had finally, in the late 70s, early 80s, surgeries that worked in rectal cancer, there was an observation that radiation was helpful. Radiation became a pre operative treatment, chemotherapy was added, and then finally, by 2014 we could publish mature data with a paradigm that was already out of date, of chemoradiotherapy, before surgery, then surgery, then adjuvant chemotherapy to prevent recurrence with FOLFOX. And that really sets a standard for rectal cancer, entering, really the last 10 years for us. Throughout this era, there was lots of observations that there’s more than one way to do this. And one of the important things was something called short course radiation, which is used widely in Northern Europe and to a lesser degree in the US, but in many centers, it’s becoming popular. And short course also moved to the total neoadjuvant therapy era where everything was done first. Five days of this more intensive radiation, followed by chemotherapy, and then followed by surgery. And that was compared to that good old fashioned chemoradiotherapy, take a break, surgery, take a break, FOLFOX. This is the RAPIDO trial. Its name tells you what it does. It moves things a lot faster. Everyone who was treated with either that standard, good, old fashioned, adore style treatment and with the repeater approach had about the same overall survival. There’s lots of little nuances here, which is there were some people had more local recurrences with the RAPIDO approach compared to the conventional approach, but it didn’t jeopardize cure. So this is an important treatment when you think about the convenience of therapy, and what do we do here? And the German rectal cancer study group that we mentioned earlier is looking at this to try to understand non operative management here. The non operative management story in the US looked at that conventional long course chemotherapy, but moved it to a sequencing question. And this was work really led initially from observations in Brazil by Dr Habr Gama, that we could maybe avoid surgery, and then really excellent work at Sloan Kettering to try and define what’s the best way to get someone non operative management. The goal wasn’t necessarily set out to do this, but it’s what it really achieved. And what we could see is that you could do sequencing of therapy without jeopardizing cure, and that a substantial number of people could get cancer-free, and about 44% after all this treatment. When I say FOLFOX here, I mean FOLFOX and CAPOX for convenience and space purposes. And that many of those people, maybe half of them, could go on to never require surgery. And that’s really important when you’re thinking about folks with low cancers who are at risk of a permanent ostomy. Equally important is the intensification de intensification story. So in OPRA– that was looking at, how can we avoid surgery entirely, whereas the PRODIGE study, which came out of France, this was, let’s give the most we got, and let’s see if we can get things better. And this is a hard study, but it’s an important study. The reason it’s hard to interpret was this was using FOLFIRINOX, which is good old fashioned FOLFOX, plus the addition of irinotecan. That’s the regimen FOLFIRINOX. Patients received that three months before surgery, then chemoradiation, then surgery, and then additional three months of FOLFOX. Compared to that good old fashioned, ADORE paradigm of chemoradiotherapy, surgery and then additional chemo. One of the challenges here is that patients didn’t really complete the post operative chemo. And in fact, a third of patients didn’t really get any chemo after surgery. And you end up with a trial where one group got FOLFIRINOX for three months before surgery, comparing to a group who didn’t get any chemo, at least a third of them. And that makes it hard to interpret. So while this trial definitely showed that in this data set, in this approach, FOLFIRINOX is better, it may be that if you complete all your treatments, it may not be better. And that’s a question that’s being answered in a lot of ways. And one of the ways it’s indirectly being answered is with the Janus trial, which is chemoradiotherapy, followed by chemotherapy, and the randomization is to FOLFOX versus this boosted regimen, FOLFIRINOX, to understand non operative management and boosted chemo.

Dr. Schlechter  2:02 
The flip side of that is prospect, which I seem to have lost my slide. So prospect, we’ll just talk about in this context. Prospect was a recognition that for the lowest risk cancers, maybe radiation is too much. And if you give people chemo, maybe if they do well, you don’t need radiation at all. And in fact, that turns out to be the case. So for patients in whom a permanent ostomy is not a risk, and where their cancer is sort of the best possible risk for the surgeon to get the patient cancer free, maybe good modern FOLFOX is so good that we could skip chemoradiation. And in fact, we could, 91% of the time, the responses were so good that patients could avoid radiation entirely, and that improves fertility, or preserves fertility, that improves bowel function, that improves sexual function. Those are really important quality of life metrics. And then finally, JANUS. So I think for everyone in the US, if you have the option, you should join this trial. It’s rapidly enrolling. We’ll hear from Dr Smith about when it’s going to complete, hopefully. But this is a great study. This takes those modern paradigms of radiation first as a great pathway to avoid surgery. For patients where that’s relevant, right? If you’re one of the patients who could avoid radiation entirely, maybe that’s a consideration. And looks at FOLFIRINOX versus FOLFOX is going to help answer the question of the role of FOLFIRINOX and help us better understand non operative management.

Dr. Schlechter  6:47 
The other thing that I was tasked with talking is so called talking about liquid biopsies and CtDNA, and this is a hard topic, because we don’t have agreed upon language. There’s lots of different tests, lots of different advantages, using it lots of different ways. In the advanced disease setting, there’s different commercial tests like Guardant 360 and Foundation One and others, and that’s about identifying driver mutations that maybe we have a drug for. And that’s important. And in the early stage setting, that’s about trying to figure out, can we predict the risk of recurrence, and can we do anything about that risk? And that’s a hard question to answer. So generally speaking, when we’re talking about in the context of early stage disease, stage two and stage three and maybe resected stage four, a disease, we’re talking about assessing risk. And it’s important to note that rectal cancer and colon cancer should not be considered the same disease, really ever, but in particular, in this situation. And I think that the better way to look at this at this time, from the data we’ve got, is, can we use these tools to avoid chemo in some patients? And it’s not really clear if we can use these tools to add chemo that we don’t know about just yet. So I think we’re not quite there, but we can talk a lot more about that. And there’s some other sort of cool, interesting numbers to know about here. So first of all, a positive CtDNA after surgery is uncommon, 5% of stage II and 20% of stage III, give or take a few percent that has been shown in multiple clinical trials. It’s very clear that a positive result means that your risk is higher, but that’s no guarantee of recurrence. And it’s very clear that a negative result means your risk of recurrent cancer is lower, but that’s no guarantee that you’re protected from recurrence. And when you look at these trials time and again, the number of people who get recurring cancer is the same. And sort of an interesting thing about the lens that you look at. If you’re sitting in the room and if you’re a patient with recurrent cancer, it’s a 50-50, your CtDNA was positive a month or two after surgery. But if you look at the people after surgery where it’s negative, chances are they’re not going to be those 50-50, and so you have to be really careful the lens in which you examine these numbers and how you think about them. But just be aware that of the folks with cancer, long after surgery, half of them will have been CT DNA negative. So have to be really careful how we use these numbers. And this is an example of that. This is from the Bespoke study presented by by Pashtoon Kasi at ASCO last year, GI ASCO. And you could see that top bar looks great, but it’s not 100% and you can see that bottom bar doesn’t look great, but it’s not 100% and so these are important studies, but they’re not the only study we got.

Dr. Schlechter  9:20 
The other thing to know about CT DNA is it has certain blind spots. It’s less good at lung mets than it is at liver mets. Actually quite good at liver mets. It’s less good in what are called t4 tumors, tumors that are penetrating into surrounding tissue, which is particularly relevant with rectal cancer, where t3 and t4 are conflated concepts biologically. And once again, t4 cancers are more likely to have lung metastases and peritoneal metastases. And so this is a really meaningful test, an important test. I think this is important thing for us to be doing and studying, but we have to let ourselves be carefully reassured or worried at the right moments. And the other thing is, when we look at rectal cancer and colon cancer. Actually, the results give us different things. This is from Jeanne Tie’s study out of Australia, this DYNAMIC-Rectal study looking at rectal cancer, not colon cancer, and you can see the absolute number of people get cancer at the end is about the same from the CtDNA negative and CtDNA positive. But how they get cancer is different. So CtDNA negative. These the numbers it’s usually going to be lung Mets. And lung Mets have a totally different biology and outcome than liver Mets, and the CtDNA positive, that more conventional liver metastasis. So this is confusing stuff, right? But here’s my take home. I would say no test that we ever do for cancer should ever be the only test. We should always think of this as one of many factors. The other thing to think about whenever you’re talking about treatment for cancers, curative intent therapy, post operative therapy, adjuvant therapy, even new adjuvant therapy, that’s about reducing risk. So if the risk is low, chemo doesn’t add much. Chemo adds risk. If the risk is high, then chemo adds a lot. And rectal cancer is a great example of a cancer that’s often high risk. And so chemo and radiation, things that often add something to rectal cancer, because the cancer is a problem. CtDNA is an excellent test for risk, but there’s lots of other ways of assessing risk, and that’s the important lesson. So I think we should think about CT DNA as a powerful tool we should incorporate into clinical trials, and we’re trying to do that, and we should remember that it’s not an absolute, but it’s really, really important, and it leads to a lot of stress and confusion, but also think it leads a lot of helpful info and gives us a warning about what may happen. So sort of my final thoughts rapidly moving through a hard topic, the modern treatment of rectal cancer has been many decades of work focusing on increasing cure and quality of life, and that’s important for patients interested in non operative management, a radiation first approach is best, and I would encourage folks to enroll in the JANUS trial. But there is the OPRA approach for patients where non operative management isn’t really an important factor for upper rectal cancers, or just something understood in I think that the PROSPECT approach of chemo first and see if you can avoid radiation is important to improve quality of life without jeopardizing the chance of cure. For the situations where intensification makes sense– very symptomatic cancers, very high risk cancers, FOLFIRINOX is appropriate, and it’s a very important, important regimen. Short Course. Radiation is fast, just as effective as good old fashioned treatment. These all have about the same cure rates, and so I think it’s out there, and was vital during covid to get patients quickly through therapy without exposures and CtDNA and liquid biopsies are an important new test. We’re getting better at using them. We’re getting better tests, but I think we have a lot to learn still, so hopefully a lot more to talk about, and hopefully that was fast but concise, which is not my natural state.

Manju George  12:44 
Okay, thank you very much. Dr. Schlechter. Dr. Smith?

Dr. Joshua Smith  12:50 
Great job, Ben. Great, great topics and very insightful. I’m Josh Smith. I’m one of the colorectal surgical oncologists here at Memorial Sloan Kettering, and I’m going to talk about one of my favorite topics, other than non operative management, but surveillance in non metastatic rectal cancer. And I’ve adapted this just because it hits a couple of my pet peeves. And actually, I see why Ben and I get along so well because he hit on one of mine. So Manju, thank you so much for having us. And I’ll just cover my disclosures. I just want to say from the colorectal surgery group at MSK, Greetings to everybody. We’re so happy to take care of patients for rectal cancer. And one of the things that really, I think, is important is where you start in rectal cancer and then where you finish. And part of that is, I think, intimately connected, is the appropriate pre op staging is, I think, very well connected to how we surveil patients. So my overview is the context of that pre op staging for rectal cancer, and then post op surveillance, the little bit of data in that regard, and then how we do surveillance and watch and wait. So these are my general principles, and I teach these to anybody who will listen. And then, then I have one thing in common and our slides, that’s that rectal cancer is not colon cancer. And I think this is something that I try to drive home to fellows and medical students and residents. But when we are faced with a rectal cancer patient. I try to make it very simple for the patient and the people who are taking care of the patient, but you have to name it, stage it, treat it. But then I think really important now in the rectal cancer space is we have to survey the response and then also what that outcome is going to be and how we determine and assess that outcome.

Dr. Joshua Smith  15:04 
So what’s the standard for staging and rectal cancer? These things sound obvious, but it really almost every week I have to redo or undo or re establish how these things are done in clinic and the basic things that we need for rectal cancer– an exam, you need endoscopy. You need a biopsy. You need pathology, which is going to tell you whether this is a mismatch repair proficient or deficient tumor. You need a complete colonoscopy, if it’s possible, or an early interval endoscopy after all the treatment is done. And of course, lab work. And then what we often do are series of imaging results and tests. And these are important because they also become integrated in the surveillance. Typically it’s a CT test, abdomen and pelvis. We typically do not do a PET CT, and we oftentimes have to talk people off the edge about getting a whole body scan. But these can give you all sorts of things to chase down that are irrelevant, but really what’s important is an MRI on the rectum. Very rarely these days, are we using a direct ultrasound that can be helpful in early stage rectal cancer, but very rarely. You can use MRI abdomen and pelvis, or an MRI liver, but I’ll go into why we do those in a second. If you have contrast allergies, then, of course, we can do special studies like an MRI Abdomen and or pelvis without contrast, but this is for people who have renal dysfunction or severe allergies. So there are certain tests that we can do that we coordinate with radiology to do that. And then if there’s a concern for a liver lesion, we typically do a triple phase CT abdomen or an MRI of the liver. This is very common if there’s any concern about metastatic disease in the liver. And then if there’s suspected liver disease, we often talk about these patients in our disease management team meetings. We definitely confirm the mismatch repair status, and then also discuss whether or not it’s important to do additional genomic profiling of the tumor. And then, in some cases, you may use a PET CT, but that’s typically after treatment has been given, if you’re worried about multifocal disease. And then you can consider surgical resection in the cases of obstruction bleeding, or if there’s high risk for perforation or significant symptoms.

Dr. Joshua Smith  17:24 
So what’s the standard monitoring schedule when we when we get treatment? And so, of course, at presentation we do endoscopy and MRI, and it’s important, because we want to know the distance from the anal verge, the tumor length, the tumor stage, how this tumor is related to the mesorectal fascia, the nodal stage, and another really important thing now is a thing called extramural vascular invasion. There’s no real clear consensus on reporting of this yet, but we know that this is associated with higher risk disease, and so we need to know that on the baseline MRI. And then after neoadjuvant therapy, we look at all of these same things, but we want to make sure that we have comparison with the baseline endoscopy and MRI, so that we can determine what the changes or what the delta is from the baseline. So can we can we see are the mesorectal fascia planes clear if we’re going to surgery, or the sphincters that were involved? Are they still involved? And because all these things are important for our surgical planning.

Dr. Joshua Smith  18:12
So what about stage specific surveillance? So for early stage tumors, we can do like I mentioned an endorectal ultrasound, but typically, most rectal cancers nowadays are managed by MRI. And for early stage cancers, we do this for the first two years and then every six months for the next five years. Really, I think that’s changing now really, to up to three years, and then if clinically indicated in years four and five, and I’ll tell you why that is in a second, and then colonoscopy we do at one year after diagnosis, and if there’s an advanced adenoma, then you may repeat that with your gastroenterology colleagues. And if not, then we move to every three years. And you’ll see that this theme persists in terms of how we look at stage I tumors, and then also, even as we go forward to stage II to IV, you can see, though that the history and physical exams are increased in frequency when we have more advanced tumors. And then we also started measuring CEA, and you can see chest, abdomen, pelvis at more frequent intervals for Stage IV disease, and then you can see every six to 12 months as clinically indicated for patients with stage II and III disease. And colonoscopy is very similar, but again, PET CT is not something that we just standardly recommend.

Dr. Joshua Smith  18:12 
So what about stage specific imaging surveillance? So for Stage I, it’s very important to note that we don’t recommend routine imaging for these patients. It’s just exams, and then some people check CEA and then check them based on  symptoms, because these people are it’s an extremely high rate of of cure for these patients who have stage I, or, you know, carcinoma in situ rectal cancer. Stage II and III, we do CT chest abdomen, pelvis  every six to 12 months, and then for five years. And I’ll just reiterate again PET-CT we don’t typically recommend. And stage IV, we do image these people more often, for a couple of years, every three to six months, and then as they get further out with disease stability, we may extend that. So what does the recent literature add to our guidelines that are in the NCCN and what we’ve adapted clinically, both here at MSK and other high volume centers? I’ll just let you know that there is limited modern evidence on frequency of surveillance, but there are some good studies, and I think there are recent trial data that even informed what we do, and has also informed how the NCCN has recommended some surveillance studies, because there’s certainly limited consideration of underlying recurrence risk in terms of the biology that’s there, and there’s certainly lack of standardized approaches in many routine clinical practices. And I would suggest that you be managed by somebody who has a very standardized approach, because that’s important.

Dr. Joshua Smith  19:38 
So I’ve just been talked a bit about OPRA and I think this is really critical to know, because in the randomization, we did see that there were lower rates of local regrowth in those patients who got chemoradiation followed by chemotherapy, versus those who had induction chemo followed by chemoradiation. And what you can see here, where that arrow is, is the one year time point, and you can see that very high number of the local regrowth occurred in that one year time point. And by the end of two years, you can see that it almost plateaus out. And then in the five year data, you can see that that persisted, that there were lower rates of local regrowth in that consolidation group versus the induction group, and that the disease free survival rates were similar. Sphincter preservation rates were similar if you went to surgery up front versus later. And this is important, because we know that if we go down this road, this route of a non operative management approach all comers, it’s about a 36% rate of regrowth, and 94% of these occur in the first two years, 99% in the first three years. And as I mentioned, a lower rate in the consolidation group versus the induction group, with very similar rates of disease free survival, and that you could have the same operation at restaging versus at regrowth with very similar disease free survival.

Dr. Joshua Smith  21:18 
The reason I bring this up is because previously, the NCCN guidelines and other guidelines had recommended MRI for up to five years, just routinely. But you can see that after three years, the chance of detecting or even developing what we call a local regrowth is extremely low and so now what’s been done is up to three years we go every six months, but then you can then move to as clinically indicated in years four and five, which is, I think, a very interesting change. And based on, I think, what is pretty good data, both on and off protocol. So there’s a study that was run by a woman named Rebecca Snyder, who’s now at MD Anderson, that I think is also informative in terms of surveillance, whether we do what’s called high intensity surveillance or low intensity surveillance. And I picked this study. It was published in JAMA. It reflects about 8000 patients after exclusions, but both colon and rectal cancer patients, and they basically just said, you know, we’re going to randomly sample patients from multiple different sources, from the Alliance, from the Commission on Cancer stage I, II and III patients, both who had colon, rectal cancer and those who had low intensity or high intensity imaging, CEA surveillance, and then also see if there was any differences in outcome. And what you can see here in terms of recurrence and the disease free survival, you can see really no differences. It’s really hard to see if you can even get a tip of a pencil between these lines. And then overall survival, you can’t even imagine getting a tip of a pencil between any of those lines, high intensity versus low intensity surveillance. And when you look at the data of these 8000 patients across almost 1200 facilities, you can see the median time to recurrence here is not very different. So in the high intensity group, 15.1 versus 16 months for low intensity, and then for if you did imaging versus CEA, and then 15.9 versus 15.3 months. So you can see that that’s it’s very difficult to determine whether, if you got a CT at three months versus six months, or a CEA at three months versus six months, are you going to make any difference in the in the outcome and the NCCN does speak to this in some ways, and says that the panel endorses surveillance, but they’re not really forcing your hand on how you’re going to, I guess, enforce your surveillance other than just trying to stick with a surveillance plan that makes sense, and I think as long as you stick with something that has some structure and that, I think follows what’s been advised, I think it makes some sense.

Dr. Joshua Smith  25:09 
So what do we do at MSK? Well, we have a model where we integrate both practitioners and physicians in a multidisciplinary fashion. We have some variation toward the end in terms of active surveillance, where we share visits with our practitioners, and we also do some of that in the beginning. And then the important part of survivorship is trying to see, when can we then let patients go back to their primary care physicians, which is typically around five years and make sure that we’re screening for new cancers, making sure that they have all their regular health checks done and don’t lose them to follow up. So who can go back to their primary care doctor? I think you know rectal cancers that have undergone surgical resection and have no disease after five years. We don’t typically do that with patients who are under watch and weight or have serious effects of treatment, the young onset patients, stage IV hereditary syndromes— typically don’t go back to the primary care doctors. So stage 0 rectal cancer patients, we use this same model, where we can start off with a multi disciplinary approach, but then pretty quickly move them to the physician extender model, versus more advanced tumors, we do a shared model, of course, with medical oncology, radiation oncology, and then eventually, once they’ve either been cured or their disease is stable, then we move to our survivorship model.

Dr. Joshua Smith  26:35 
So I’ll end with just talking about, what do we do about watch and weight and surveillance? So what’s the role for Ct DNA? Should we be doing more frequent endoscopy? Should we be doing more frequent imaging or CT scans? And I’ll just address with what we’re doing currently in the JANUS trial, and maybe that’ll inform the discussion and maybe some questions. But as of Monday, we had 391 patients accrued to this trial, and Dr Schlechter talked about this, so I’m not going to further go through the methodology here, but this is more than 50% accrued. It’s well ahead of accrual, and I think it’s just because patients want to keep their rectum so this trial is similar to OPRA, and saying that it gives you a chance to do that, should you achieve a clinical complete response. And so how are we surveilling patients? So these are the surveillance schedules based on data. It’s based on the OPRA data and also off protocol data. You can see for the first two years, it’s more frequent. Digital exam and endoscopy every three months, MRI every six months, CT scans are once a year throughout the trial, and then colonoscopy, you can see is based on what I just told you, in terms of the NCCN guidelines, depending on what we find at that first colonoscopy. And then years three, four and five, you can see we start to move toward every six months digital exam and flex sig endoscopy, and then the MRI starts to space out based on what we saw in OPRA to every 12 months versus every six months, and then years four and five are just as clinically indicated, which I think is important, and based on data that’s essentially hot off the presses earlier this year from OPRA.

Dr. Joshua Smith  28:17 
So and then in terms of what are we doing for CtDNA? Well, this is a hot topic because a lot of people say, Well, why don’t you just use CtDNA to make your choice about whether or not you keep the rectum or not. And I don’t think we’re anywhere close to that making that decision or integrating that decision into the trial. So what we’re doing is we are collecting plasma for both patients who are undergoing watch & weight and surgery, and that’s done right before treatment, between the period between radiation and the initiation of chemotherapy, and then at the time of restaging, after they complete TNT. And then, of course, at the time of surgery, we can also get an additional draw and then throughout the surveillance. So right now, we’re slated to get seven draws on the patients, but we have not yet decided on the platform. And I think the reason for that, is really clear when you hear what Dr. Schlecter just talked about in terms of detection, we’re not really sure, is whole exome the best way to detect circulating tumor DNA in these patients, because of the issue with lung metastasis, and also, can we detect local regrowth at a reliable detection rate? Because really, that’s the the problem that we still face in rectal cancer, as I mentioned. So to keep it simple, name it, stage it, treat it, then surveil smartly. I think it’s really important to think about the NCCN guidelines. They get updated about twice a year. And as I mentioned, more surveillance is not always better, but I think smart surveillance is. I’ll end there, and I’m happy to take questions in conjunction with Dr Schlechter, and hopefully we’ll have some time for good discussion.

Manju George  30:07 
Okay,  thank you. Dr Smith, that was very helpful. So I think before we start with the questions, I wanted you to, if you can tell us a little bit about CRM and MRF involvement, I think this is a question that we see in the group. People are really confused about what they see on their reports and how they have to think about it. So it’d be great if you can spend, like, a few minutes.

Dr. Joshua Smith  30:34 
You broke up when you said the question, I didn’t hear what you said it

Manju George  30:37 
The circumferential resection margin and the MRF environment, both of them a little bit in simple terms for people to understand what it is, because we often get questions and it’s a little bit technical, right?

Dr. Joshua Smith  30:51 
Yeah, yeah. So circumferential resection margin, essentially, that’s going to be the radial margin. If you think about the rectum as it’s facing the tailbone. That’s an area that sometimes can be at risk, and so you worry, can you get that area off cleanly? Because when you do a meso rectal excision, you want that meso rectal fascia to be intact. That’s really important. So one of the key quality indicators of a good rectal operation is the mesorectum intact, so that envelope should come out cleanly. So if you think about a Coke can, for example, that you just bought from the store, you’d want it to be pristine, not have any scratches on it, right? And so in that way, the mesorectum needs to be nice and clean and intact. The mesothelectal fascia is just another way to say that’s the fascia that’s around that circumferential resection margin. And so sometimes that’s invaded by tumor. And so that’s where our radiation colleagues are really important, because they target those areas that are potentially at risk. And so these all can be areas where the margin can be close. And so we want to make sure that that margin is,  an R0 resection, meaning there’s no tumor anywhere near that margin. And less than, you saw in the slide I put up, you want to be much less than one millimeter. If it’s more than one millimeter or close to one millimeter, can be considered an R1 resection, which is not, you know, the end of the day, but it’s still not ideal. And R2  means there’s gross tumor left behind, which is unfortunate, a positive radial margin. Then you have a discussion. So that would lead, you know, if Ben and I were managing a patient together, then we would have to discuss, are we, you know, do we need to do any additional treatment, or how are we going to monitor that? And, you know, this is something that’s very difficult, because one thing that we think about in terms of margin status. If you knew that the tumor was invading, for example, into the sacrum, then you wouldn’t do just a standard total meso rectal excision. You would start thinking about a beyond what we think about as beyond TME resection, right? Because if tumor is invading into the pre sacral space or into the sacrum, then I need to start thinking about a resection that removes a part of the sacrum so that the backside of where that means rectal fascia is, is negative, right? So then, that way, I don’t have to have a challenging conversation with Ben and the post operative setting or with the patient that you know our margin is grossly positive, I think, in the current day and age with the imaging that we have, it’s, it’s typically an avoidable scenario. It can happen, but it certainly can be avoided with really careful preoperative planning.

Dr. Schlechter  33:54 
That speaks to the choice of the new agent therapy that we offer. You know, if someone, if you really think a margin is threatened, you have to make a number of assessments and one of them is with radiation and timing. So radiation is really, really powerful in clearing a margin, but radiation needs a lot of time. And so for paradigms where someone does chemo first and then radiation, then surgery, happens quickly. That may be positive under a microscope, but that does not mean that those are viable cells. And so there’s a lot of context in what those margins mean and the sequencing of therapy. And we know from other cancers, like anal cancer, which is a similar cancer, but not the same, that if you biopsy a cancer three months after radiation, and then don’t do surgery, you go back six months after radiation from the start of radiation, and look again, actually that cancer can be gone. And so a positive margin happens, and it’s really stressful, but it needs a lot of context, and the effort is always on my side as the chemotherapist, my job is to make his job, Dr Smith’s job easier. And the radiation oncologist job is to make Dr Smith’s job easier for the sake of the patient. And so as much as possible, we need to, like, line up our various modalities to try and avoid that situation. But if we avoid that situation, we have to always put it in context.

Manju George  35:15 
Okay. Thank you very much. So I think the fact that all of these are different ways to describe the extent and location of the tumor, but having the involvement doesn’t mean that it’s the end of the world, right? These are different ways of assessing it. So maybe that’s a very important and great message for patients. Because I also see this that like, somebody gets a TNT and then they don’t have a path CR, and then patients are really concerned that that’s really not good for them. But if you look at  even in OPRA, there is a certain amount of path CR rates, right? It’s not like every patient will get pathCR, and then that also doesn’t correspond to an increased chance of recurrence, right? So it’s not not completely corresponding, right?

Dr. Schlechter  36:06 
No, and PROSPECT informs us a lot. So PROSPECT, again, that was the study arm got three months of FOLFOX. If it worked, they went right to surgery, and then post operatively, give or take, three months of FOLFOX. If it didn’t work, then they got radiation and so forth. And the control arm was good, old fashioned chemo radiation, and everyone was the same. So the people who had an under response but got all the bits, people got the old fashioned chemo, radiation, surgery, people had a good response and got chemo. On balance, it all worked out. And so yeah, of course, everyone wants to have their cancer die, but at the end of the day, the most important question is, are you cured of cancer and how is your quality of life. And it turns out that it’s okay to get a passing grade. We don’t all have to be overachievers at every step along the way, and that and outcomes are pretty darn good. Okay, that’s how I think, as I’m overdue for my grades with the the Harvard medical students, all of them are above average. Yeah.

Dr. Joshua Smith  37:01 
And I, you know Manju, I think it’s really important to start and the reason I started with stage the cancer appropriately, because that’s where you manage expectations, right? Because not everybody’s going to have a clinical complete response, and not everybody’s going to have pathologic complete response. And if you look back across the evolution, like Ben showed a really nice diagram from the last 40 years of rectal cancer treatment that we’ve moved the needle some in terms of overall survival, disease free survival in certain situations, but at the end of the day, the three to five year disease free survival still sits in that range of about 75% sometimes it’s up a little bit. So PROSPECT, the numbers are a little bit higher. I think as we move into the more modern rectal cancer paradigms, maybe we can push those numbers a little bit higher. And so, you know, our goal with, JANUS, for example, is, can we improve survival? And I think in the PRODIGE 23 study. He talked about, there was a goal to improve survival, which is why I think that trial gets some additional attention, because we want to improve survival. And yes, move that average number of three year disease free survival of 75% up, can we get that up to 80% or 85% but, you know, just because you don’t have a complete response doesn’t mean you should give up hope. Because, you know, still 75% is still pretty good, right?

Dr. Schlechter  38:31 
And then, of course, we have hope for new treatments as well,

Dr. Joshua Smith  38:34 
Correct? Yeah, there’s a lot of things coming a lot of things coming around the the corner, it will be helpful in many different situations.

Manju George  38:46 
Okay, the other question I had was that in your OPRA trial, with the different either induction or chemo or chemo, radiation or consolidation chemo, you were talking about, there was a difference in local regrowth, but the DFS rates were similar. So basically, then patients don’t have to worry that they got the sequence versus that sequence. It’s only in terms of, if you have radiation first, the chances of them getting to a non operative management is higher, right? But overall, the outcomes for the patient, even if there’s a local recurrence, they are salvageable and so the disease free survival rates don’t don’t vary much, could you both expand on this?

Dr. Joshua Smith  39:30 
Yeah, disease free survival was quite similar in both groups, not significantly different. There is a pretty significant difference in local regrowth, however, so that means that, you know, more patients preserve the rectum in the group that got radiation first followed by chemotherapy. So higher rates of organ preservation, which is important to think about. So if you’re thinking about a patient who wants to preserve the organ, and if you’re putting your bet on getting a clinical complete response, you would want to start, the best data we have right now would suggest you would start with long course, chemoradiation, followed by chemotherapy.

Dr. Schlechter  40:14 
And I think it’s important to remember that all the components of rectal cancer treatments pretty much with some nuance achieve the same survival end point. And so what we’re doing is shifting around the sequence of events to maximize the quality of life impact. And that is really, really important that you correctly stage the patient, make an assessment of risk. You gotta weigh in on honestly, on what do you think you can achieve, and then use the tools we’ve got to achieve the best possible outcome for the patient, knowing that, frankly, sequencing matters for a lot of different outcomes, but good surgeons can make up for I don’t want to say good circumstances can make up for bad radiation, but good surgeons can make up for sub optimal sequence if you don’t get what you want, and that’s okay.

Dr. Schlechter  40:17 
Okay, so there are some questions. So Leanna asks in the event you have a positive radial involvement, post op example with an APR. I think that’s what she means. And have had TNT, is surveillance preferred over adjuvant chemo.

Dr. Schlechter  41:23 
I think if you’ve already had the full course of chemotherapy, more chemo is not necessarily better, and it’s important to remember that chemotherapy does what’s called a log kill. So let’s say we just make up numbers, and it kills a half with the first cycle, and then a quarter with a second. Another half get to an eighth and 16th and 32nd and 64th, and a 120 you end up with it with sort of just levels off and benefit. So I don’t know that more chemo is more better, but I do think that’s a hard situation, and surveillance is hard there, because we don’t actually know what the best surveillance is. And we had the conversation of CtDNA earlier. We don’t actually know if CtDNA is a really valid test for that type of regrowth. CtDNA is probably best for detecting things like liver metastases, and may miss that. So I think that’s a situation where, unfortunately, it’s a hard conversation and good judgment and a lot of worry and careful watching is what we have to do. But I don’t know that more chemo is more better if you’ve already had what you need.

Manju George  42:25 
Okay, okay. Thank you very much. Yeah, okay. And Dr Smith, when you were talking about MRI, and the frequency of MRI as we go past many years in surveillance, you’re, talking about a pelvic MRI, or you’re talking about a rectal MRI.

Dr. Joshua Smith  42:47 
It’s a great, that’s a great question. So you can have an MRI of the pelvis, but it needs to have, it needs to be on a rectal protocol, right? Because you don’t want to do an MRI of the pelvis that cuts off at the top of the sphincters, right? You need a rectal protocol that goes all the way down to the anal skin and below. So you need to make sure that you have the entire pelvis, including the the sphincter complex and the anus in the view. So there is a classic rectal protocol that’s done that is key for the appropriate and proper staging of a rectal cancer. So many times it’s not done. You just get a regular MRI pelvis and that needs to be redone so that the rectal cancer is appropriately staged. That’s important for multiple different reasons. One is because you need a really good pre treatment staging exam. It’s also helpful to the radiation oncologist who use images to stimulate the tumor to provide the best chance to kill the tumor and also the lymph nodes, and so they want to target it in the best way that you can. So a really high quality pre treatment MRI is absolutely critical.

Manju George  44:12 
Okay,okay.

Dr. Schlechter  44:13 
Just an imaging thing. You know, sometimes what happens is patients get the CAT scan before the MRI, and there’s something questionable in the liver, and an MRI that can best assess the liver actually can’t really be done at the same time as an MRI that best assess the rectum. And so rectal protocol MRI cannot be done at the same time as a liver protocol MRI because the timing of the sequences. It’s two separate days, it’s two separate scans, and it’s really frustrating, because it’s a stressful, like, really miserable situation when you have to, like, do the scan, do it again. But that is because the best way to see the rectum, the best way to see the liver, just can’t be done at the exact same moment.

Manju George  44:50 
Okay, okay, great. Thanks very much. Yeah. And there was also a recent discussion about, when patients are told that they are getting an MRI, there were many people who commented that they got contrast into the rectum, whereas in some places they don’t do that. So is there an advantage to doing a contrast in the rectum versus MRI with the regular IV contrast, or is it just what is practiced in different places?

Dr. Joshua Smith  44:50 
It’s it’s a different practice at different places. There’s been an attempt by the radiology groups to make it standardized. Some places have moved to doing what’s just a mini enema to clear any stool out of the rectum, which is very helpful, because a rectum full of contrast distorts it some and makes it difficult to see very carefully. So there’s certainly a standard protocol that’s done, but there’s been a move away from filling the rectum full of contrast, because it can distort the rectum unnecessarily.

Manju George  46:00 
Okay, yeah, it was news to me, because I have not had one of those. So it was surprising that there is so much difference in how it’s being done in different places.

Dr. Joshua Smith  46:09 
Yeah, there’s a wide range. Right, which makes people feel a little woozy, especially if they’ve not eaten in preparation for flex sig on the same day.

Manju George  46:25 
Okay, what you’re saying, is that there is variation in how these procedures are done in different places.

Dr. Joshua Smith  46:33 
Yeah, yeah. I think it goes back to the point that was made, is, if you’re thinking about doing something like non operative management. It’s important, if there’s a protocol available, to do it on protocol, because those things are all protocolized. So you’re not just getting things here and there in a very heterogeneous fashion, to try to do it in a similar fashion, on a protocol that’s been vetted and been very well, carefully selected by radiologists and the group of radiologists have agreed across multiple different groups. But that’s that’s why I refer people to the NCCN guidelines, because that’s also there.

Manju George  47:18 
Okay, okay, sounds good. Okay, how far out post surgery does CT DNA provide useful information on recommends, example, years four and five? Is there value to doing it?

Dr. Schlechter  47:43 
Almost want to try not to answer that question. So I would say CtDNA that far out is important about assessing risk. And I would say, if CtDNA becomes positive that far out, you have to start looking really hard for where it’s coming from. The test that you use is really, really important. So if five years from rectal cancer surgery, you’re using a tumor agnostic test–so not one that looks for the mutation specific to that tumor–but a general test that may be detecting any number of things, something called CHIP, which is sort of like random mutations in your bone marrow that contaminate your blood with meaningless mutations that may or may not become a problem. You may be identifying a woman who’s got a second primary breast cancer unrelated to their colon cancer, so CtDNA testing matters, and if it’s tumor informed versus tumor agnostic, matters. So I think it’s a hard question to answer, because it depends what test is being used and how, but I would say tumor informed test that becomes positive four and a half, five years out. The reason we do all these testing, the reason we do CAT scans for five years and CEA, it may not change the outcome, as Dr Smith pointed out, but we’re doing that to look for cancer. And so if you’re doing this to look for cancer, that should trigger you to go look for cancer and look really, really carefully. That’s how I would interpret it. If it’s tumor informed, if it’s tumor uninformed, you have to do that plus a mammogram or a pelvic exam or a prostate exam. You have to look at the blood. That’s a much harder test to interpret.

Manju George  49:13 
Okay, okay, so what you’re saying is that if it’s a tumor informed, CtDNA, MRD test, then that gives you more specific information about the recurrence of the colon or the rectal cancer. Whereas, if it’s like, almost like a liquid biopsy, which is looking at tumor markers, then you don’t know if it’s coming from the same the same primary.

Dr. Schlechter  49:35 
And some of them have only a few hot spot tests. So for example, this  KRASG12D mutation, you can have two independent cancers, both with the exact same mutation on that hot spot. So it’s hard. It’s really stressful. I actually saw a patient today about it, but it requires a lot of diligent surveillance and looking. You got to find where that’s coming from, if you can. And then sometimes it goes away, which is even more maddening.

Manju George  49:57 
Okay, okay. And. Then I’ll ask my question that I ask every every year, I guess. I mean, Dr Smith has heard this before, but this is a question that comes often up in Rectalburgh, is, you know, those people who havedon’t have a PCR, and there is, like tumor found at surgery, they’re always concerned that what treatments they have had is that enough? Or, you know, would they need something more to prevent or to reduce their chances of a future recurrence or progression?

Dr. Schlechter  50:35 
So my perspective is that if you have had adequate chemotherapy, you’ve had adequate chemotherapy, we have a lot of information about that, like fractional benefit of later lines of therapy, and again, you don’t know the trajectory. You don’t know if you’re seeing dead bits or living bits. So if you have had the appropriate chemo, I don’t think that more is going to do it, and I don’t think that there’s evidence that suggests that you should switch to chemo that you take a metastatic regimen like FOLFIRI and start trying that in the post operative setting, especially when we have adjuvant clinical trials going back now a decade, some of them led here in Boston, where FOLFIRI failed. So I think that just speaks to the wide variation of what you see in surgery, that doesn’t mean that the cancer is growing. It just means you had cancer in the first place, and some people have more of a response than some people less.

Dr. Schlechter  51:30 
Okay, but yeah, of course, it’s significant.

Dr. Joshua Smith  51:33 
Yeah. I think what we like to see there, is that the tumor has responded. And I think I tried to bring that up that you want to see that at least you’ve seen some response. You’ve downstaged. Some from,maybe you had a T4N2 tumor, and now it’s a T2N0 tumor. That’s a great response. You know, you’ve seen a significant down staging, and then that makes surgery easier on the patient and on on the surgeon. So it just suggests that you’ve taken this big, bulky nasty tumor and made it a little bit more tame. And I think that’s that’s helpful. Sometimes we’re not fortunate enough for that to happen. Sometimes tumors don’t respond, and I think that’s a difficult situation where then maybe there is a discussion about changing modalities of therapy. But sometimes, those discussions can happen before you get to surgical resection. But those are few and far between.

Dr. Schlechter  52:34 
But switching it to a regimen that’s not known to change the outcome, I think, is probably not a good idea. Obviously the better chemo works the better the outcome. The better radiation works, the better the outcome. But that doesn’t mean that if the chemo fails, trying to different chemo is going to change the outcome. So, of course, the dye is kind of cast biologically.

Manju George  52:51 
okay, okay, so what I’m hearing is that it’s not patients should not be really caught up about the degree of response. But any degree of response that any kind of down staging indicates that their tumor is responding, and patients should look at it as good news, rather than only thinking that, if I only have a PCR, then my outcomes are better because in some cases, people with the PCR, can also have recurrence, right, correct? It’s not 100% Yeah,

Dr. Schlechter  53:25 
Yeah, it’s stressful, because there’s no guarantees. And, and it’s, it’s, I’ve described it in a variety of things, as spooky music, right? Like, you have this big tumor that’s left behind. You’re like, Oh, that’s really bad. And you hear the, like, you know, the background music from some scary movie, but then it doesn’t come back, and then sometimes it comes back when you don’t expect it. And so obviously that informs how we think about risk, but I don’t know that we can change that risk.

Manju George  53:27 
And the lack of response, or if you don’t see any sort of response, that might speak more to the biology of the tumor better? Yeah. Okay, correct? Yeah. I think one person who joined late is asking, Is pathological complete response significant? And I think this is the discussion that we just had, yeah,

Dr. Schlechter  54:10 
we always celebrate when we see it, but it’s okay if we don’t see it,

Dr. Joshua Smith  54:13 
But, but it’s not a free lunch, right? Patients with clinical complete response still develop local regrowth. Patients with pathologic complete response still develop metastatic disease. So 6 to probably 10% of patients with a pathologic complete response meaning no tumor seen in that rectum. It’s not a single viable tumor cell in the rectum or on the lymph node basin, with negative margins. Some of those patients still develop metastatic disease. So it’s not likeyou win the lottery and you’re free forever,

Dr. Schlechter  54:55 
so you’re committed, right?

Dr. Joshua Smith  54:57 

You still have to, you still have to be under surveillance, so you. Yes, pet lives, a complete response is an amazing outcome. And the overall oncologic outcomes are better for those patients. However, we still have to have them under surveillance.

Manju George  55:10 
Okay, okay, we have a question. What would be the surveillance program you would set for someone who has had a LAR to fix a rectovaginal fistula and the growth or regrowth of a polyp. Precancerous at the time of colonoscopy, not precancerous after LAR. I’m talking about a polyp that reappeared 8.5 months after the end of radiotherapy for a stage zero rectal cancer, positive margins after transanal resection of what was thought to be a pre cancerous polyp. So what would be a good surveillance program for such a patient?

Dr. Joshua Smith  55:50 
So the LAR was for rectovaginal fistula, initially?

Manju George  55:55 
yes, to fix a rectovaginal fistula.

Dr. Joshua Smith  56:03 

And then had a polyp,

Manju George  56:07 
Yes, a regrowth of a polyp. So it was precancerous at the time of colonoscopy.

Dr. Joshua Smith  56:11 
This regrowth of the polyp was in the rectal stump. I assume?  You have an LAR, and then you have distal rectum below that. Well, it was never really an invasive cancer, right? It was a question of in situ . Yeah, yeah. So this, this person is going to just have endoscopic surveillance and exams, right? There’s no invasive cancer here.

Dr. Schlechter  56:38 
Yeah, I would say this is a situation where the best we can probably offer is maybe vitamin D helps with preventing polyps, and maybe aspirin is worth considering. There is data that aspirin can change those outcomes. So I think baby aspirin may be the really, really careful surveillance, like scans and colonoscopies, but probably baby aspirin would reduce the lifetime risk of colon cancer in that individual who seems to get polyps by a few percent.

Dr. Joshua Smith  57:02 
Okay, so

Dr. Joshua Smith  57:02 
To be concrete about it, the way that we typically would do it here is within six to 12 months post surgery, you would have a endoscopic exam with the surgeon, and then you would have your full colonoscopy a year from surgery, with the GI physician, and then, based on what’s found at that time, if it’s a another high risk adenoma is found somewhere else in the colon, then they’re going to scope you again in a year. Some of them would even do it in six months, depending on the nature of the polyp, or start to move you out to three years if there’s no evidence in further polyp growth.   If it’s if you’re making polyps that frequently, you need to start thinking about

Dr. Schlechter  57:48 
attenuated FAP, but so I think seeing a GI oncology geneticist type thing very important to make sure there isn’t something else going on. We have to look for polyps elsewhere.

Manju George  57:59 
Okay, okay, that sounds good. Okay, we are at the end of the hour, so thank you very much for the fabulous talks. A recording of the video will be placed in colontown University in about two weeks, thanks to everyone who was able to attend, and thanks to both of you.

Dr. Joshua Smith  58:19 
Okay, thanks so much. Bye, bye.