Updates in the treatment of locally advanced rectal cancer: Dr. Ciombor (2022)

Manju George 0:00
Hello, everyone. Welcome to another round of DocTalks. Today we have Dr. Kristen Ciombor with us. She received her Bachelor’s Degree in Biochemical Sciences from Harvard University and then her Medical Degree from the University of Miami Miller School of Medicine. She finished her residency over there and then moved to Nashville, Tennessee, to pursue a hematology/oncology and a GI oncology fellowship, and a Master of Science in Clinical Investigation. And then she joined the faculty at The Ohio State University in Columbus as an Assistant Professor and then actually moved back to Vanderbilt in 2017. And she’s interested in developing new therapeutics for GI malignancies. And so we’re really excited to have her here today with us to talk about updates in the treatment of locally advanced rectal adenocarcinoma. Welcome.

Dr. Kristen Ciombor 0:52
Thank you so much. It’s great to be here. And thank you for joining us or listening later. And hopefully, this lecture is helpful. My main interest within colorectal cancer research is in genomically directed therapies. So I have several projects looking at the fibroblast growth factor receptor (FGFR), both in the preclinical space as well as a clinical trial that’s occurring right now. And then, of course, MSI in the rectal cancers space and EGFR. We have several trials and our SPORE her, one of the projects is looking at that. So there are a lot of great colon cancer labs here at Vanderbilt. So I get to work with them and help translate their findings too, which has been really fun. But yeah, mostly, as most of the field is going genomically directed in hopes of personalizing medicine a bit more for patients with the disease. What I really wanted to do today, in the next hour, is kind of given an overview of how far we’ve come, how we started treating rectal cancer even years ago, and what we’ve learned over time and how we can more closely tailor treatment to every person’s individual case. And I’ll end with some recent data, as well as a trial that I’m running, just to give you a little sense of what may be coming in the future. So I can’t do a colorectal talk without talking a little bit about epidemiology just because those trends are changing. And I want to highlight just a couple of things. And then I’ll give a quick overview just because I’m sure the audience here has varying amounts of knowledge. So I’ll talk a little bit about staging and how it differs from colon cancer, and then surgical resection and then specifically treatment. I’m a medical oncologist. So I think a lot about all of the modalities of therapy, but specifically chemo and whatnot. So as we know, unfortunately, colon and rectal cancer is very prevalent in the US.

Dr. Kristen Ciombor 2:56
These are the most recent estimates for 2022. Unfortunately, it will continue to be the third most common cancer in both males and females. And unfortunately, we’re still seeing too many deaths. And probably what is the most concerning to me, or one of the most concerning things, is that we’re seeing a huge increase in incidence in colorectal cancer in the younger population. So last year, the USPSTF changed the Official Colonoscopy Screening Guidelines to start colonoscopic screening at age 45 instead of age 50. So hopefully, that will help a little bit, but we’re still diagnosing too many patients with cancer in their 30s and even in 20s. So definitely this is a big challenge that we need to understand why this is happening and how can we stop it? The positive side of this slide is that we are seeing a decrease in the incidence of colorectal cancer in people over 50. And that should continue to improve, presumably from good screening methods. So colonoscopy really helps.

Dr. Kristen Ciombor 4:06
There are a couple of other features that I wanted to touch on that really show that one size does not fit all in terms of a colorectal cancer diagnosis. We do see differences in incidence and mortality based on gender and ethnicity and other factors. One of the important things in the disparities that we see is that, unfortunately, there is a higher incidence in mortality and lower screening rates in people who are uninsured or have not as much education history or have a lower socioeconomic- income and other factors. So clearly, we need to be able to, even from a screening perspective, make this available to everyone. We all know that there are certain risk factors for colorectal cancer with probably the most important being family history, or a longstanding inflammatory bowel disease diagnosis. There are other lifestyle factors that may contribute a little bit. But clearly this is not the whole story. But I did want to include this just a little idea of what are things that we can do, understanding that we still need much more research to figure out why this is happening, especially in the younger patients. So even in the younger patients, we’re seeing that the majority of colorectal cancer is still sporadic, meaning not hereditary. So there are certainly hereditary cancer syndromes like Lynch and others that are of importance and we definitely screen for but the vast majority is still sporadic. So many patients, especially under 50, that I see, they don’t have a family history, they don’t have a hereditary syndrome. And they’re just as puzzled as us in terms of why this is happening.

Dr. Kristen Ciombor 6:16
So moving to rectal cancer staging specifically, these are some of the things we think about from the medical side in terms of symptoms to look for and how we start the workup. Most people who have a colon or rectal cancer diagnosis already know that by the time they come to see me but I’m kind of taking a step back and seeing okay, what might this look like in terms of the process to figure out what’s going on. So, I will say that though there are several symptoms that can point us towards a colorectal cancer workup, many people can be entirely asymptomatic, and some cancers are found on screening colonoscopy alone. But if you do have symptoms, things like bleeding, sometimes abdominal pain, occasionally we’ll find it because a patient is iron deficient and anemic and they may have symptoms from that like tiredness or shortness of breath. Change in bowel habits can be very important to monitor for, and weight loss. In the clinic, there are some things that we look at or look for on physical exam. Sometimes that can be a mass on a rectal exam, and bleeding. But abdominal masses, looking to see if the liver is big, all those things are important things from our side to look at. When we look at labs, we do look for iron deficiency, we look for high platelet levels, which can go along with iron deficiency. If the liver function tests are a little bit abnormal, that may make us a little bit worried though that is a very nonspecific finding and we can see that in many other instances. And then the tumor marker, the CEA is important, though that’s not a good screening test. But once we do know the diagnosis of colorectal cancer, we do check it so that we can watch that over time. And then of course, we needed a biopsy to really confirm what’s going on, which is usually obtained through colonoscopy. And we use various imaging modalities like CTs or MRIs to get the full staging of what the cancer looks like and how best to treat it. So the vast majority of people who have colorectal cancer are diagnosed when it is localized or in the lymph nodes. But about 20% are still diagnosed with stage IV disease at diagnosis. So definitely something that we need to continue to improve. Most of the time, not all the time, but most of the time, colorectal cancer will start from a polyp and then evolve slowly over time into an invasive cancer. And then the staging really depends on how deep in the colon or rectal wall the tumor goes as well as whether there are lymph nodes involved and other organs as well.

Dr. Kristen Ciombor 9:09
So this is one example. There are some cancers that it depends how big the tumor is and that will impact staging. But for colorectal cancer, we care more about how deep it is and that will impact how we decide how to treat these cancers as well. Why do we care so much about staging? Mainly it comes down to the fact that staging correlates very well with cure with adequate treatment, as well as just general outcomes. So the earlier we can catch these tumors, the better chance we have to cure them, which is obviously the goal. So when we think about surgery, there are a couple of things that we think about and this is from a non surgical point of view, being a medical oncologist, but the goal of surgery is really to completely remove the tumor along with the major lymphatic drainage, the lymph nodes surrounding, and the blood vessels that are supplying that part of the colon or the rectum. So there are a couple of different surgical techniques that are primarily used. One is a low anterior resection and often that is for people who have high rectal tumors or mid rectal tumors, and often you will have a temporary ileostomy for that or a bag. Very occasionally, in the very superficial rectal tumors, we can get away with a transanal excision. But most of the time, patients will either have a low anterior resection, LAR, or an APR, which is more for the low lying rectal cancers and unfortunately does leave one with a permanent colostomy. Now, I will say that as we think about surgical resection, the goal and where we’re trying to go is actually to avoid the need for surgery in the future. And we’re starting to see that is more and more possible. When I see a patient who has a rectal cancer and say they have upfront surgery, or even, after some treatment, I look at the pathology report really carefully. And this goes for both colon as well as rectal cancer. There are some things that are really prognostic, meaning they tell me if this cancer is kind of a worse actor or is going to behave a little bit better.

Dr. Kristen Ciombor 11:30
And so I’ve mentioned some of these things here. One of the things that’s really important is the number of lymph nodes that are removed at the time of surgery. So our surgeons are really excellent at getting as many lymph nodes as possible. But if we have fewer than 12, we sort of consider that we don’t have a representative view of what the tumor actually is and we’re not 100% confident about what the stage is. And then if any patients have had upfront treatment, so chemo or radiation prior to the surgery, the pathologist will also estimate the amount of tumor regression that they see based on that, which is also prognostic.

Dr. Kristen Ciombor 12:09
Okay, so I’ve kind of covered just a little bit about epidemiology and staging, and what we think about for surgery, but how do we actually decide how to treat rectal cancer, specifically locally advanced and by locally advanced, I really, am talking about stage II and III rectal cancer. So I wanted to give a little bit of a historical perspective, because we have come so far in the last several decades, but I think we can kind of lose sight of the improvement we’ve seen. So I wanted to kind of really dial it back and see how we used to treat it and how that differs from what we do now. So the historical treatment of locally advanced rectal cancer, we often did what’s called neoadjuvant, or preoperative chemoradiation, often in what’s called a long course with concurrent chemotherapy. So again, that’s for stage II and III, which is the T3 and T4 tumors or any lymph node positive tumors. Why do we do neoadjuvant therapy or therapy prior to the surgery? Well, sometimes we can decrease the need for a permanent colostomy, which is clearly an important factor. We want to potentially treat micrometastases, or small microscopic cells that may be on the verge of escaping from the primary tumor area that will be resected. We can also tell, as I mentioned, the tumor regression grade, we can actually tell how how useful chemoradiation has been at the time of surgery, which tells us how well the cancer has responded. And then what we have come to know is that the more treatments we give before surgery, as opposed to after surgery, the less difficult it is from a side effect perspective. So that’s clearly an important thing too. So traditionally, until I would say the last 5-10 years, we really did chemoradiation, the long course chemoradiation, and then surgery would happen about 6 to 10 weeks after that completion of chemoradiation. And then once patients had recovered from the surgery, they would go on to get some chemotherapy for a total of about six months of perioperative or before and after surgery treatment.

Dr. Kristen Ciombor 14:34
And this was some of the now pretty old data that led us to that paradigm I’m going to walk you through. So this was one of the very original studies that showed that patients who had a locally advanced rectal cancer, they went to upfront surgery and then they were randomized to either radiation or radiation with chemotherapy. And the 5FU radiation is what we do now or the oral 5FU, which is capecitabine. Semustine was actually one of the old nitrogen mustards and we don’t use it anymore. So this really goes back quite a few decades now. What we found from this trial was that adding chemotherapy to radiation after surgery for rectal cancer gave significant improvement, not only in decreasing local recurrence, but also decreasing distant metastasis and recurrence there. So that’s what led us to say okay, chemo with long course radiation is important here. So chemoradiation is better than radiation alone. It also did decrease the death rate significantly. But the downside was that it can increase GI and hematologic or blood count toxicities when you give chemotherapy with radiation. So at that time, largely, there were two ways to give the 5 fluorouracil chemotherapy, one was in a bolus fashion, and one was in PVI, or protracted venous infusion or continuous infusion, kind of how we give it now most of the time. We do know that giving bolus fluorouracil might be a little bit more convenient because you don’t have to carry around the pump for two days or five days if you’re doing it with radiation. But the bolus fluorouracil did cause more low blood counts as well as side effects, mouth sores and other things.

Dr. Kristen Ciombor 16:28
And then this study, actually in the 90s, looked and saw that not only did the choice of how you administer the 5FU matter on side effects, but it also affected survival, with the longer course of 5 fluorouracil being better than the bolus form. So that’s primarily why we change to that.

Dr. Kristen Ciombor 16:47
And then how about the combination -preoperative versus postoperative chemoradiation. So in this study, this is one of the seminal rectal cancer studies. They randomized patients with rectal cancer to to stage II or stage II again to either chemoradiation, surgery and then chemo or surgery, radiation and chemo after surgery and then chemotherapy. And both overall survival and relapse free survival was really pretty equivalent whether you gave chemoradiation before surgery or after surgery. There did seem to be less local recurrence with preoperative chemoradiation. And there did seem to be lower rates of more significant side effects from preoperative chemoradiation, and that’s both in the acute setting, meaning as you’re going through treatment, but also in the long term setting. And we often think about whether if we are radiating, for instance, a rectal field and then removing it surgically, then you’re left with fewer longer term radiation toxicities than if you are, say, radiating a freshly resected rectal field and you’re left with that inflammation and other potential long term side effects. We also saw from this study that more patients were able to avoid a permanent colostomy or to have what’s called a sphincter sparing surgery. And that is clearly an important in endpoint as well. So as a result, prior to what we do now with what we call total neoadjuvant therapy or TNT, we really did see that preoperative chemoradiation was the way to go. So what did we learn kind of historically from the older studies? We learned that chemoradiation improved survival when compared to either chemo or surgery alone. infusional 5FU improved survival and tolerability compared to bolus 5FU. Preoperative treatment allows for a greater conversion to the sphincter sparing surgery and also can be better tolerated. And then preoperative treatment is associated with a reduced rate of local recurrence of the cancer. Other things that we think about with preoperative therapy for rectal cancer, I mentioned briefly that capecitabine can be given as an oral alternative to the protracted, the longer 5FU infusion so we do that very commonly. And now in addition to long course radiation, we also have the option to do short course radiation, which is really high dose radiation daily for five days, and that is without chemotherapy concurrently. So I’ll talk a little bit about when we might choose those modalities.

Dr. Kristen Ciombor 19:44
What about adding more chemo in the neoadjuvant setting to radiation? Several studies have actually shown that adding Oxaliplatin, for instance, in the radiation portion doesn’t really help very much in terms of survival and efficacy and also increases toxicity significantly. Until recently we gave adjuvant FOLFOX or 5FU and Oxaliplatin chemotherapy after surgery. But we know that both because of healing that has to happen after surgery and possible complication, some patients didn’t get to that chemotherapy and may have inferior outcomes as a result. So what do we do now? How do we learn from our past studies and our past ideas about what might be better, both from a cure standpoint, but also from a side effects standpoint. So now we largely do what’s called total neoadjuvant therapy or TNT. We’ve had a lot of studies in this space in the last few years that have been really helpful to give us different options for patients. I’m gonna really briefly cover three of those studies, the PRODIGE 23 Study, the RAPIDO Study and OPRA because I think all of these are unique and give us additional ideas on how to treat stage II and stage III rectal cancer.

Dr. Kristen Ciombor 21:11
So first of all, the PRODIGE Study. So all three of these studies were presented at ASCO 2020 and so we had a lot to really work through at that meeting. But the PRODIGE 23 Study was one of the studies that looked at a total neoadjuvant therapy approach with rectal cancer. So patients here were randomized to either what we call the historical chemoradiation arm so it was kind of what I told you was the standard prior to TNT, chemoradiation followed by surgery followed by chemo, or what we call the TNT arm. And in that instance, the patients actually got FOLFIRINOX. So a more aggressive chemotherapy with the addition of Irinotecan then they went on to chemoradiation, surgery, and did more chemotherapy afterwards. So really escalating the amount of chemotherapy that was given. And what they found was that the TNT approach with more chemotherapy did lead to more pathologic complete responses, meaning more patients did not have any residual tumor at the time of surgical resection. This is a caveat, but we don’t know if that will translate to better cures and better survival over time. We know that in other tumor, types like breast cancer, that there seems to be a correlation. But we still have to wait for these long term data to know if this is a good surrogate endpoint. But certainly, it seemed encouraging to see fewer and fewer cells, even no cells at the time of surgical resection. So with the TNT in the PRODIGE Study, we also saw that the three year disease free survival rate was better in the patients who got TNT, and the three year metastasis free survival was also a better. So overall, they also found that FOLFIRINOX for most patients was manageable, and was able to be done, was feasible. Doing FOLFIRINOX upfront did increase the probability of path CR, curative intent surgery, and improved disease free and metastasis free survival. They did not see any differences in quality of life scores over time, between FOLFIRINOX and the historical way to give to give chemoradiation and surgery and chemotherapy. So I would say that this is an option certainly for patients with stage II or III rectal cancer. Though. again, these trials give us options, they don’t lend us to a clear one way, one size fits all kind of approach.

Dr. Kristen Ciombor 23:53
Okay, moving on to the RAPIDO Study which was also presented at ASCO last year. How this study differed from their PRODIGE Study is that patients here could either, again, go to chemoradiation followed by surgery followed by chemo, or the experimental arm in this study was short course radiation, so that five day radiation, followed by chemotherapy for about 18 weeks followed by surgery. So truly doing everything neoadjuvantly or preoperatively. And what we saw here was that the experimental arm which was all the TNT is that it did increase the path CR rate. It doubled it basically, which was very encouraging. And it did decrease the disease related treatment failure. So the amount of times that the cancer would come back, It decreased the probability of distant metastasis as well. And it did show a pretty equivalent local regional failure rate. So not much difference there between the two arms. The overall survival was pretty equivalent and quite good. We’ve definitely made strides over the years in terms of curing rectal cancer. So the take home messages from this study, from the RAPIDO Study, showed that doing short course radiation followed by chemo followed by surgery did have improvement in all of these endpoints. There were no endpoints in which it was worse, including postoperative complications, quality of life, toxicities, and surgery. And then finally, of these three trials presented at ASCO 2020, the OPRA Study has gotten a lot of press for good reason in terms of looking at how we can save the sphincter, save the rectum, for patients with rectal cancer. So this study basically randomized patients who had the low lying rectal cancer, distal rectal cancer. They either got upfront chemoradiation followed by chemotherapy and then restaging or they got what’s called the induction chemotherapy, so chemo first then chemoradiation. Now, it’s important to know when I show you the figures of the results from the study that the study was not powered to compare the two, but really to compare it to the historical control, which is again the chemoradiation, surgery and then chemo.

Dr. Kristen Ciombor 25:27
So what we saw though, was that really the disease free survival in both the induction chemotherapy and the consolidation, chemotherapy arm were pretty similar and favorable, and the distant metastasis free survival was pretty similar as well, even though technically we can’t compare them. However, what was different is that patients who were in the consolidation chemotherapy arm, meaning they got radiation first and then chemotherapy after that were more likely to be able to not need surgery. And that was really provocative because we would love to be able to not have to do surgery. But that’s been kind of a standard paradigm for us for a long time. So in this study, and in many studies that are ongoing now, really what’s called this watch and wait algorithm where patients if on endoscopy and colonoscopy, they don’t have evidence of tumor after the preoperative treatment, the chemo and chemoradiation, and they also don’t have any radiographic evidence of disease, usually by MRI, if they’re willing to have close follow up, they can do what’s called a watch and wait protocol. And if the tumor regrows at some point, they will likely have to get surgery to be able to cure it. But there can be a good number of people who may be able to avoid surgery altogether. So the takeaway points from OPRA was that the treatment plan includes this TNT approach and watch and wait for complete responders led to organ preservation in about half of patients who had that clinical complete response. They did not see any difference in most of the other endpoints including survival and distant metastasis. So really, you could do either sequence, but it did seem like the radiation first might be better if trying to spare the rectum.

Dr. Kristen Ciombor 29:28
Okay, so we’ve come a long way. So we’ve covered sort of the historical approaches and how we learned how to treat rectal cancer in the beginning. Now we’ve talked about really in the last decade or so doing this total neoadjuvant approach. And now we’re, much like we do in the in the stage IV setting, starting to break these treatments down into how we can we personalize these? So not just one size fits all again, but how can we use genomic information to treat cancer specifically, and I wanted to cover one subset of interest, which is the microsatellite instability high or deficient mismatch repair rectal cancers.

Dr. Kristen Ciombor 29:30
So we heard just very recently at ASCO GI really interesting data from Memorial Sloan Kettering from Andrea Cercek’s group about PD-1 blockade alone for MMR deficient locally advanced rectal cancer. This is a single institution phase II study that’s ongoing right now. What do we know about this mismatch repair deficient rectal cancer? Probably it’s about five or so percent of all patients with rectal cancer. So certainly we think about it with Lynch Syndrome, but there also are sporadic cases of MSI-high rectal cancer we find that’s not associated with Lynch Syndrome. Their group actually published a couple of years ago now that giving upfront chemotherapy, you could actually have a lack of response to chemotherapy. And that was not a small number. So that always makes us worried that, you know, we never want to give treatment that’s not going to be helpful to patients. And we know, we’re kind of extrapolating, that in this stage IV setting, immune checkpoint blockade with things like nivolumab and Pembrolizumab, etc. it’s very responsive to these MSI-high tumors. So their study overall schema was to take patients with rectal cancer that was MSI-high or deficient mismatch repair, and they treated them with Dostarlimab, which is another PD-1 blocker, and patients got treatment every three weeks for nine cycles. And then they got restaging and colonoscopies. If they had residual disease, then they would go on to chemoradiation and ultimately surgery if needed. However, if they achieved this clinical complete response, they could go on to nonoperative management or the so called watch and wait. So this is a small study, of course, and this is just the preliminary data. But 11 patients so far have completed the course of anti-PD-1 therapy. And most of these patients did have pretty advanced disease. Tthey had T3 or T4 or node positive, the vast majority of patients did. So that’s telling me that this is not just, you know, really early stage disease that was bound to respond to other things as well. And what they saw in these early findings was that everyone really responded extremely well.

Dr. Kristen Ciombor 31:59
So you can see that the complete response, the CRs, are in the dark blue here. And really of the 11 patients who have finished the prescribed Dostarlimab treatment, all of them have had complete clinical responses so far. So there are a lot of questions still, I think. This is very, very nice data to see and I think we are all excited to hear about it. I don’t think that this is practice changing quite yet because there are a lot of things we don’t know. How long is this going to persist? Will patients really be able to avoid surgery completely? I think it’s a little bit early to know that but this is very welcome data to see. And it was not just the endoscopic complete response, but also when they looked at scans. So both of those together comprise the endpoint of clinical complete response and that was really well seen in all of the patients treated thus far.

Dr. Kristen Ciombor 32:58
So where do we go from here? We have several studies ongoing looking at this subset of patients with rectal cancer. I have a study that is currently enrolling through ECOG, the ECOG network called the ECOG-ACRIN 2201. It’s a phase II study looking at nivolumab plus Ipilimumab and short course radiation in patients who have MSI-high rectal cancer. I’ve kind of covered a little bit of this, but why did we choose this particular regimen? Well, we know that in MSI-high disease, doing chemoradiation can actually lead to higher PCR rates. So we think that radiation may be important. And then radiation fraction sizes, especially larger ones, may enhance immunogenicity, which is something we’re looking for with immune checkpoint blockade. We know that nivo/ipi has incredible response rates in the metastatic setting as well as in the early stage setting, with one study showing about a 95% major pathologic response in very early stage MSI-high colon cancer and a 60% path CR rate with very little immunotherapy given before surgery. So our hypothesis was that doing the upfront nivo/ipi and then short course radiation will lead to increased path CR rates when patients went to surgery, but also that that might translate to cures, better survival, lower toxicities. You’ll notice that no one here is getting chemotherapy, which is a big difference from the standard. So in our ECOG study, the objectives, the primary objective is that pathologic complete response rate, but we’re looking at a host of other things with disease free survival, toxicities from the treatment, if we can avoid colostomies for some patients. We anticipate, and especially with the Memorial data, that many patients may be able to avoid surgery altogether. And then we are looking into correlatives looking at how we can assess how much is enough in terms of immunotherapy. Is the two cycles before and after radiation going to be enough? Do you need more like the Memorial data has been doing? All those things are important questions that we need to answer. So who’s eligible for our study? So anyone with rectal cancer, adenocarcinoma, that is stage II or III. Again, you have to be MSI-high or have deficient mismatch repair. And that is a very standard test that’s really done nationwide, I would say in most places, as a reflexive test, because we need to know that information, not only for treatment considerations, but also to screen for Lynch Syndrome. You cannot be in the study if you have significant autoimmune disease because that predicts for increased side effects from immunotherapy, and you can’t have had prior therapy for rectal cancer. So overall, the schema here is patients will get nivo/ipi be for two cycles, so one treatment a month for two months, then they’ll go to one week of radiation without any chemotherapy, they’ll go back to two more cycles of nivo/ipi immunotherapy, and then they’ll undergo reassessment and ultimately surgery if there’s residual tumor left. Now we are in the process of discussing the schema. There may be some upcoming modifications to see if we can avoid some surgery and other things if the immunotherapy is working very well. But overall, I think this is a really important study, and really encouraging to see that the field is moving this way in terms of treating these genomically selected subgroups in colon and rectal cancer, very specifically, and perhaps even moving away from our recently updated paradigm of the total neoadjuvant therapy. And so with that, I’m happy to take any questions. And hopefully I’ve taught you something this hour. Thank you.

Manju George 37:16
Dr. Ciombor, that was excellent. Thank you for taking us, you know, along the history, like what all was happening before and where we are now. So I want to ask you a couple of questions. You talked about medical history, right? Is that just a history of colorectal cancer? What is the role of prior history of polyps in the family?

Dr. Kristen Ciombor 37:40
Yeah, so that’s a really good question. So whenever I meet a patient with colon or rectal cancer, I try to extensively go through that. And we do include that in our family histories too. And because it helps us know, we do know that even if there’s not a genetics or hereditary syndrome present, that there is an association with family history or an increased risk of first degree relatives who might be at risk for developing colorectal cancer. So I also tell patients, you know, even if we don’t find a genetic link here, your first degree relatives, siblings, kids need to start colonoscopies 10 years younger than your diagnosis unless there’s another factor to consider. So we do think about polyps. We think about family history. We try to be pretty comprehensive. The guidelines have been updated pretty recently and kind of on an ongoing basis. So it changes a lot. And some of the gastroenterologist certainly know better than i in terms of how often the colonoscopy should be done if you have a history of certain kinds of polyps and those sorts of things. But the important thing is, you know, to find out your family history, find out those things. I talk to a lot of patients and they say, You know, I never asked about my family history until this happened. And then I found out, oh, my mom had polyps and my sister had this and so it’s important to kind of know your family history as well as your personal medical history.

Manju George 39:08
Okay, thank you very much. And then in one of your earlier slides you talked about high risk features where grade differentiation and signet cell features were all listed. So I’m kind of curious about how do these factors account for prognosis? Because nowadays people are talking about ctDNA and when compared to that, if you have a well differentiated tumor versus a not so well differentiated tumor, how scared should they be? Because, you know when people get diagnosed they come and tell us, oh my god, I googled and I found this and now I’m scared.

Dr. Kristen Ciombor 39:47
Yeah. So yes. It happens all the time. Yes, that’s a great question. And I would say, until recently, with the advent of ctDNA and MRD testing, I think that this will change over time, but really the main thing that we could use as prognostic markers were the pathologic features of the tumor when it was resected. But everything has a double edged sword because, for instance, differentiation, most tumors are moderately or well differentiated. But you see a poorly differentiated one and I always tell patients, that’s kind of like, the pathologist looks under the microscope and sees that the cancer just looks a little more raggedy, more aggressive. However, there’s an important caveat to that in that most MSI-high tumors are poorly differentiated. So it’s not every poorly differentiated tumor is a bad actor. So you do have to take it in context with the other features. And I’ve had patients who’ve had signet ring cell, and they Google that and they say, oh, no, this is terrible. But really, in every case, it may not factor in, it may not be the so called dividing factor. So I kind of try to keep it as part of the overall context. I don’t think any one feature can really tell you, oh, this is destined to come back or not. But we try to get an overall gestalt of what we think about the tumor. But we are hopeful that in the future, we may have better markers, better predictive and prognostic markers, to really look, like ctDNA and other things, where we don’t have to rely on these features that we see under the microscope alone.

Manju George 41:35
Okay, thank you very much. And then another participant question. I’d love to hear your thoughts about duration of chemotherapy, four, six, or eight treatments of XELOX. What are things you think about when you make a decision?

Dr. Kristen Ciombor 41:49
Ah, that’s a great question. Yes. And you know that’s another area where our thinking has really changed over the last five or so years, with the advent of the IDEA Trial, and all the data that’s coming out from those study. So, including at ASCO GI this year, we had an update about early treatment discontinuation and early Oxaliplatin discontinuation. So we’re really trying to nail it down. Now that we know that a lot of our chemotherapy, and a lot of our treatment algorithms are potentially curative, we don’t want to overdo them. So we don’t want to expose patients to more toxicities, side effects, long lasting things if we can help it, but we but we want to maintain that cure. So how I think about it, prior to the IDEA Study, I did not give much CAPOX, to be honest, because I do think that Americans definitely tolerate less capecitabine than Europeans, but even at the prescribed schedule of CAPOX, I think that for a lot of people, there are more toxicities, so it can be tricky. But with the IDEA results showing that, in many cases, three months of CAPOX is equivalent to six months of FOLFOX, that can be a really hard trade off, because a lot of patients say I’m willing to do three months of anything if I only have to do three months and not six months. So I think there’s probably an in between and that’s why I was glad to see the data at ASCO GI of the early treatment discontinuation. Seeing that okay, probably the overall amount matters, but we might be able to get away with say less Oxaliplatin. And I think that’s largely what we do in clinical practice, too. We plan to do six months of FOLFOX, but really how often do we continue that? Really hardly ever. We have to stop and it’s really difficult to guess because sometimes the longer lasting neuropathy from Oxaliplatin isn’t happening during the treatment, so we can stop it and then still have long lasting toxicity. So that’s really where I see the field is going is trying to optimize for each patient. How much is enough, both to optimize cure, but minimize side effects? And fortunately, we’re starting to learn a lot more about that. But it is still definitely a case by case basis.

Manju George 44:19
Okay. Thank you very much. So, I’m going to ask you this. You said that American tolerated less capecitabine. There is this thought among patients that because we have lots of folic acid fortified foods, do you think that’s the reason? What do you think is behind that?

Dr. Kristen Ciombor 44:38
Yeah. That’s certainly been a hypothesis. I don’t think that’s the only reason but it does seem to be metabolic somehow. But it certainly seems to be the case. And it’s been interesting because now as a result of the mostly European based IDEA studies where so many patients were getting CAPOX, it sort of forced us to use it more often. And certainly I used it in the stage IV setting at a different dosing and with radiation, but every three week cycles, not only of the capecitabine but the Oxaliplatin at the higher dose, can be really hard too. So it’s definitely a tricky situation. And I have really in depth conversations with my patients when those are the two options and we try to come to an agreement. And because they are equally efficacious. I do say, you’re not going to make a bad decision. We can always switch if we need to, but yeah, we don’t completely understand what’s behind that capecitabine dosing to be honest.

Manju George 44:50
Okay, so another question is from Sylvia. How low of an Oxaliplatin dose can you go and still get the benefit?

Dr. Kristen Ciombor 45:54
So very good question. I don’t know that we completely know the answer to that. I think we think more about it in terms of dose intensity, so the cumulative amount of Oxaliplatin, more than potentially how much in each dose is important. And I think that’s where the recent data at ASCO GI kind of showed us or started to show us that maybe there is a threshold where you don’t need above a certain amount, but on an every cycle kind of standpoint, I start to wonder if I’m giving efficacious doses, if I’m giving less than 50% of the starting dose. So, it really depends, because, again, you can have those late side effects after the Oxaliplatin ends. So I try to be really cautious. And if I’m having to dose reduce by that much, it may not be worthwhile, but it is a little bit of an art more than a science at that point.

Manju George 46:58
Okay. In Colontown we have this thing, we call it icing. So, a lot of people have been doing it, and that really helps with the Oxaliplatin acute cold sensitivity. And then for people who have to only do four cycles of CAPOX, then it helps them get through it without much problem. And then again, with COVID, with CAPOX you only have to go to the clinic four times in three months, right?

Dr. Kristen Ciombor 47:31
There are a lot of benefits to it, for sure. And definitely, I would say, of my patients who I give them both options, most of them really want to do the three months of CAPOX and I totally understand it and I try to support them through it and we make dose modifications if we need to, but for a lot of practical reasons, it really makes a lot of sense. So it’s nice to have that option and not just six months of FOLFOX for everyone, for sure.

Manju George 47:58
Okay. So I will just ask one more question and then we’ll go to your trial. So when you give patients, three months of CAPOX, how are you giving the Oxaliplatin? Do you have a port for all patients? Or do you give it via peripheral vein?

Dr. Kristen Ciombor 48:12
Yeah, good question. I do preferentially use a port if I can unless there’s some reason or the patient really wants to avoid a port. But I do think it’s a bit safer. Certainly it’s not as bad as other chemotherapies, but it can cause damage to veins over time. And so I do try to give it preferentially through a port.

Manju George 48:36
Okay. Thank you very much. So my question about the trial will be that when you look at your trial schema,the total amount of time that somebody is getting treatment is only two cycles of ipi/nivo and then five days of radiation and then two cycles, right? So how many months is that?

Dr. Kristen Ciombor 48:55
Yeah. We went through various trial designs before we settled on that one. And again, it may change, but we decided that we wanted more time after radiation to allow the radiation to really continue to work because with OPRA, radiation was first and so maybe those patients just had more time to respond. So we did the two months of nivo/ipi to get sort of that immune activation and then the radiation and then two more months. But really it’s very little time in getting active treatment. Most of it is kind of in between or the cycle length because nivo/ipi is just given once every 28 days and then the short course radiation is just five days. So much of it is kind of downtime just waiting for the tumor to respond in hopes of maybe having as much tumor response and not needing potentially other future modalities.

Manju George 50:08
Yeah. And the reason I asked is one of the big concerns of rectal cancer patients when compared to colon cancer patients is with colon cancer, you have the surgery, and then you have three months of chemo, and then you go on with your life, right? So the whole thing is about maybe five months, you have surgery, about two months of recovery, and then you have chemo. Whereas with rectal cancer, especially if you’re getting long course, it is 28 days of radiation and then many people get eight cycles of FOLFOX, and then wait, and then surgery and then recovery. So young people, especially, it’s a long time off work or scheduling all of that. And I was thinking this trial design is great in the sense that getting the ipi/nivo infusion is just such a short time, and then the five day radiation. So I feel like lots of patients would be able to go back to their regular life without much problems at all, right?

Dr. Kristen Ciombor 51:00
Yeah. That is definitely the hope. When I see patients getting the traditional TNT and surgery and everything, we try to calculate it out, I tell them it’s going to take about a year, all things considered. Even though there’s some downtime, it really is a full time job for that year. So that’s one of the hopes, really not only to cure these patients and have fewer side effects, but try to maintain normal life as much as possible. So we’re hopeful that that will be a good side effect as well.

Manju George 51:36
And something to look forward to. So then I have one question. :Last year, I think it was after main ASCO, there were some trials from Europe where they had used durvalumab are avelumab in MSS patients and they were seeing some responses, which were surprising. So do you have any comments? This is great for the MSI-high patients, but what for the MSS patients, right?

Dr. Kristen Ciombor 52:05
Yes. Absolutely. So, you know, we do see MSI-high more in the localized colorectal population. So it’s about 10 to 15%, especially in right sided tumors. The rectal cancer, because they’re the left sided, is less common. But yes, it’s still a small percentage of the overall people who have to deal with colon and rectal cancer. So that’s the big holy grail right now is trying to figure out how immunotherapy might work in the microsatellite stable population. And there have been a lot of ongoing efforts with different combinations, because we know that the monotherapy, Pembrolizumab or nivolumab or any of these checkpoint blockades by themselves, is not going to be effective for the vast majority of people. There are a couple of exceptions to that, like POLE mutations and things, but for most microsatellite stable patients, it’s just not going to work by itself. So we’re trying to figure out how to sort of prime the immune system so that the checkpoint blockade can occur and that can be effective. It’s been a little bit of a daunting task, because we haven’t had much success yet. But we have started to see at least in some studies, some hints of activity. And so I think we just need to explore those more deeply and see how we can more effectively combine these different agents. Because to me, the immunotherapy, the two best parts of immunotherapy, in general are the fewer side effects for the vast majority of people, I know, some people can have significant side effects, but for the vast majority, it’s very well tolerated. And probably the best is the long duration of response where some people can have functional cures without surgery. We always thought the dogma of oncology was it has to be cut out, you know, and what we’re doing is just helping the surgeon but now we’re starting to see that our treatments can do that all by themselves and we want to offer that to as many people as possible. So that’s definitely the biggest area of study right now. I just had several meetings this morning with different companies talking about that very topic. So I think there’s more to come in the next few years. There are lots of studies either going on right now, about to be reported out, or even in design. So we’ll keep working on it for sure.

Manju George 54:30
Okay. Thank you. That’s exciting to hear. And then one last question, because I think you have just two minutes left. So is there any difference in response between say rectal cancer and colon cancer when you think of response to immunotherapy in the early stage setting?

Dr. Kristen Ciombor 54:47
Yeah. Yeah, that’s a really good question. We don’t think so for the vast majority of people. So we think that there’s not, but that’s a great question, because when we think about biologics, primary tumor sidedness matters. And that’s both prognostic and predictive. So we always have to think about that. We have not seen a clear signal to my knowledge that colon versus rectal will matter in terms of immunotherapy response. We do see more MSI-high tumors in the right side. So that’s just an obvious difference, but we think the response is pretty equivalent.

Manju George 55:31
Okay, okay. Thank you so much. This has been really informative. And I’m going to edit the video a little bit and then I’ll post it on Colontown University and now with our new Colontown University website, you can access it too. You don’t have to log in or anything. Once I have it, then I’ll post it on Twitter and then the link will be freely available for everyone to watch. Thank you very much for your time.

Dr. Kristen Ciombor 55:53
Thank you for inviting me, Yeah, it’s it’s been great.

Manju George 55:56
Thank you. Bye.