Adjuvant treatment planning for Stage II or III microsatellite instability-high colon cancer

DR LOVE: Welcome to “Expert Second Opinion: Optimizing the Use of Immunotherapy, MRD Assessment and Other Novel Approaches for Patients with Localized Colorectal Cancer.” This is medical oncologist Dr Neil Love bringing you excerpts from a CME meeting we had at the recent 2026 Gastrointestinal Symposium meeting in San Francisco.

This meeting was moderated by Dr Chris Lieu from the University of Colorado Cancer Center in Aurora, Colorado, with faculty members Dr Stacey Cohen from the Fred Hutchinson Cancer Center, University of Washington, Seattle, Washington. And Professor Jenny Seligmann from the University of Leeds, Leeds, United Kingdom.

In the meeting, Dr Seligmann first did a presentation on neoadjuvant treatment for localized colorectal cancer, followed by a presentation from Dr Lieu on emerging novel approaches to adjuvant treatment for localized colorectal cancer, and Dr Cohen finished up with a talk on the role of circulating tumor DNA, or ctDNA, testing in localized colorectal cancer.

For this program, we did a survey of 50 community-based general medical oncologists and asked them to present cases and ask questions of the faculty and picked out the best ones to give to Dr Lieu to pose to his colleagues.

For this second issue of our series, Dr Lieu again presented a number of cases and questions from our community-based survey.

DR LIEU: We're going to start with this 58-year-old male, and we're going to talk about some of the high-risk features. So this patient had a resected colon adenocarcinoma, MSI-high, BRAF V600E mutated. What are some of the clinical pathologic features that most strongly influence your recommendation for adjuvant therapy in MSI-high disease? And does it really matter? Are you going to give the same treatment no matter what? And so for this first patient, we'll start with Dr Seligmann.

DR SELIGMANN: So first of all, I mean, I think that actually breaking down TNM is really important. I think that considering a T4 as a Stage II patient is very misleading. T4 is bad, and I think we need to be really careful about that, that we're not reassured thinking this is a Stage II patient with a T4 tumor. So I think we need to just be a little bit careful with TNM. But again, I think all of these features influence the recommendation. I mean, for Stage III combination, ATOMIC would guide what we do. The big question of ATOMIC is, what is the contribution of the chemotherapy? I can see why they couldn't, at the point, I think ATOMIC was, I echo your points, it was a wonderful trial, and it would have been too far at the time that the trial was being delivered to having an IO arm alone, but that's the real elephant in the room. Do we really want to give 6 months of FOLFOX along with immunotherapy?

DR LIEU: We're going to have some cases that ask that question. And I think that that is the missing arm. And I think you're right. I think when ATOMIC was developed, there was just no way that there was ever going to be an IO only arm, but that's the one that I think that we all really want. So in terms of skipping adjuvant chemotherapy, to that point, this is a 71-year-old female with uncontrolled diabetes, Grade 2 neuropathy, right? And so again, the concern there obviously is with oxaliplatin, has Stage III sigmoid cancer, again, MSI-high. This patient did check a postop ctDNA. It was negative, so that certainly makes us feel better.

But are there situations where you would completely skip adjuvant chemotherapy and give only immunotherapy? Very, very difficult question. Dr Cohen, let you get a stab at it.

DR COHEN: Thanks so much. So if we, let's say we said that this was an MSS patient and we didn't have the option of immunotherapy, I guess the question would be, if you were looking just at the ctDNA as a prognostic risk factor, we would argue that that makes them less likely to benefit from chemotherapy, but not yet at a point where we would not recommend chemotherapy based on ctDNA alone. So I would say I still would ideally give that patient chemotherapy, though with that level of neuropathy, I don't know that we can give them oxaliplatin.

If you switched it around and said they were ctDNA-positive and MSI-high, I would happily give them just immunotherapy and call it metastatic disease. I think the hardest situation is this one in the middle where they're ctDNA-negative, MSI-high, you really don't want to give them oxaliplatin. I'm not sure I'm quite there for immunotherapy alone, but I could see the rationale. I could also see the rationale in observation in someone who's just not appropriate for chemotherapy, and I think that we will be data free for a while in this area.

DR LIEU: Would you ever give infusional 5-FU and atezolizumab? I see shaking of the head over to your right.

DR COHEN: I don't like that opportunity.

DR LIEU: Okay, so, and Dr Seligmann, you're shaking your head. Tell us a little more.

DR SELIGMANN: You showed us the data. You showed us that for some reason, biologically, 5-FU alone does not appear to be effective. So I think the tempting thing when ATOMIC came out was, oh, we'll just drop the oxaliplatin, but the data in the adjuvant setting has never supported 5-FU alone.

DR LIEU: It's a couple levels of not having data, right? So the 5-FU is one part of it, and then is 5-FU plus atezo is another layer of data that we just don't have. So but what I'm hearing is significant concern about single-agent 5-FU, even with the addition of atezolizumab. Okay, I think that's very, very helpful. Thank you for that.

Roles of circulating tumor DNA (ctDNA), POLE mutations and advanced age in adjuvant treatment planning

DR LIEU: This is an older patient with several different comorbidities, postop ctDNA-negative. And so what you're looking at here is actually a practice pattern from a general medical oncologist. So this is a very, very interesting way of treating these patients, and would love to hear your guys' thought on this. So this practitioner does not offer patients with Stage III MSI-high colon cancer adjuvant therapy if ctDNA is negative, especially if older than 70 years old. And so what this practitioner does is actually wait for them to have metastatic disease and treat with an immune checkpoint inhibitor at that time. Luckily in the 6 years that this practitioner has been doing this, none has had disease progression. But this is a very, very different, and again, kind of evidence-free zone. Dr Cohen, what do you think about this practice pattern?

DR COHEN: I mean, I think it's great that it hasn't failed thus far. I'm not sure I'm ready to recommend it. I would say that in terms of chemotherapy, there was an analysis of MOSAIC that suggested that a 70-year-old did not really benefit from oxaliplatin, but it was still recommended to give them fluoropyrimidine.

In IDEA, the 3 versus 6-month trial, they enrolled patients up to 85, so there wasn't a 70-year-old cutoff. And then there's been analysis, I think in the ACCENT database, that suggested that older individuals still benefit from chemotherapy. So I tend to still recommend sort of standardly if someone's fit enough, I give them whatever the recommendation would be for their stage.

That being said, I do also agree that sometimes the older individuals have more indolent disease, especially the MSI-high ones. So in that specific population, I would say for me, maybe patients in their 80s, I have omitted chemotherapy and just given them immunotherapy if they were ever ctDNA-positive or metastatic, but that also predated ATOMIC. So I wouldn't say that there's a standard approach to older individuals not getting them chemotherapy, but I think it is smart to be aware of the toxicities and what your patient can tolerate.

DR LIEU: Outstanding answer. Thank you.

Another question, in regards to POLE mutations, in the NCCN guidelines, in the metastatic setting, immune checkpoint inhibitors are obviously approved in MSI-high, but also in hypermutated POLE mutations. And so that, but that's certainly in a metastatic setting. In this particular question on the bottom, is a 55-year-old gentleman with a POLE mutation and oligometastatic disease to the lung. So Stage IV, but now without evidence of disease. And so I, the question here is one that's actually very complex. Now, POLE mutations are rare. And so I've only seen a handful, even in my entire career, but would you consider that to be similar to MSI-high, knowing that that wasn't exactly studied in the ATOMIC trial, Dr Seligmann?

DR SELIGMANN: I think that's probably quite reasonable. So it's the hypermutations and the ability of the MSI-high tumors to become aware, to be recognized by the immune system that makes them able to use immunotherapy. And so it's exactly the same principle comes into POLE cancers. So I think we're never going to have perfect data for these patients because they are so rare. So I would be very comfortable in treating them in the same way as an MSI-high patient.

DR LIEU: Yeah, I agree. And I think the biology is similar. And for this patient, you know what the biology is like. So it does make sense to treat it much like MSI-high. So yeah, really, really great question. Dr Cohen, you already had addressed some of this with older patients, but, 92-year-old female or an 83-year-old female with Stage III MSI-high colorectal cancer, would you, we had had this discussion of, do you really need the 6 months of FOLFOX and obviously the 1 year of atezolizumab? Would you treat with a single-agent immune-oncology agent?

DR COHEN: Yeah, I think that in some ways, as we already had talked about, we're looking for excuses to use immunotherapy or to have an indication for immunotherapy. And to me, positive ctDNA could stand for micrometastatic disease and I would use that as a rationale to treat this 92-year-old individual if they wanted ongoing therapy. Depending on their health status, you could argue maybe you don't do anything, but we're going to assume that this person was fit enough that they underwent a surgery. So maybe they'd be fit enough to have some systemic therapy. So I would say that I have definitely given older individuals immune checkpoint inhibitors and typically would do single-agent, again, with the slight rationale that maybe there's less toxicity involved.

DR LIEU: Dr Seligmann?

DR SELIGMANN: I think that you can, and I think patients, older patients can. I'm just thinking of the IMHOTEP trial. So this was a neoadjuvant IO trial with single agent. There were 5 deaths in that trial, not so much related to the primary tumor. So I think we do need to have a bit of caution. They are generally well tolerated, but honestly, I don't think I would be offering a 92-year-old adjuvant anything.

DR LIEU: Anything.

DR SELIGMANN: But I think when we push the boundaries and we're starting to treat PS3, PS4 patients, even when there's a potential of really good responses, there does need to be some caution. And certainly when they looked at the IMHOTEP data in detail, they saw that the patients that did die were out with the recommended inclusion criteria. So it was pushing the boundaries because we're so excited about immunotherapy. We just need to remember, we can still cause toxicity and problems. I mean, there's some Grade 5, particularly things like myocarditis that we're starting to see as well. So they're not without any problems.

Role of ctDNA in adjuvant treatment planning for Stage III colon cancer

DR LIEU: This is a question that's going to come up a lot about ctDNA-guided therapy. And so Dr Cohen, a 37-year-old gentleman with Stage III colon cancer wants to be aggressive with treatment, is interested in considering immunotherapy. He asks if we can skip chemotherapy if his ctDNA remains negative. He does want benefit of immunotherapy maintenance. So based on the ATOMIC trial for a young patient who wants to be aggressive, would you give atezo with chemo if ctDNA remains negative in a postop period at 1 month and 3 months? Would you skip additional chemotherapy and continue only with immunotherapy?

And this is actually a really, really great case because I actually had a young patient getting FOLFOX/atezolizumab and really had a problem with oxaliplatin with worsening neuropathy. And the question was, well, can we stop at 2 months or 3 months? And obviously these are really, really hard questions to answer, but, in your experience, in the real world, right, because in the trial, 6 months of FOLFOX, 1 year of atezolizumab, how does that look like in your clinic?

DR COHEN: I mean, I think it's an easy answer because we just simply don't know. And so the way I view Stage III with ctDNA is you still follow stage recommended adjuvant chemotherapy. And then if someone is positive, you're more likely to want to push them through and get the full extent and see if you can help clear that ctDNA and get better outcomes. If they're negative, you may be more inclined to decrease or dose reduce or stop early in the setting of toxicity. I don't otherwise do it, but I think to some degree, you're never required to have adjuvant chemotherapy. We can never prove that that person's going to benefit. And so in a person who understands the choices, I think you talk to your patient, but I wouldn't routinely stop at a specific time period just based on the ctDNA.

DR LIEU: Yeah, and I think that we always feel a little bit more comfortable, I know we're going to talk about this with escalation decisions based off of ctDNA, but really have a hard time with de-escalation decisions just because we just don't have that data. And I know that you're going to talk a little bit about that.

DR LOVE: This concludes our program. Special thanks to the faculty, and thank you for listening. This is Dr Neil Love for “Expert Second Opinion: Optimizing the Use of Immunotherapy, MRD Assessment and Novel Approaches for Patients with Localized Colorectal Cancer.”