Adjuvant Therapy for Early-Stage Colon Cancer

Transcript: John L. Marshall, MD: All right, team, let’s sort of shift our gears a bit and talk about adjuvant therapy. And really, there is a whole lot of action going on here with important studies looking at duration. What does molecular testing have to do with our adjuvant decision making? Really controversial settings, particularly settings that are actually increasingly common the more we look. Howard, I think we’re starting with you on this. What are you doing with earlier-stage colon cancer, particularly that stage II disease? How are you managing that?

Howard S. Hochster, MD, FACP: Well, stage II disease is still a little bit controversial. If you go back to the original studies that led to the approval and the use of FOLFOX or FLOX, the NSABP trial, they both included stage II and III disease. And there may have been some benefit from stage II; it was just very underpowered for it. So in general, the difference is not that much, and I tend to not give people FOLFOX adjuvant in stage II. You could consider just fluoropyrimidine alone for some patients, but I tend to reserve adjuvant therapy for high-risk patients. So I would consider those with T4 disease, with bowel perforation. In those people, I’ll tend to give FOLFOX. If they’re kind of in the middle in stage II, T3s, I might send an Oncotype DX test to differentiate their specific recurrence rate for that particular patient, especially if they want to get treatment. They think it’s going to be beneficial for them. I like the Oncotype to help reassure people that they don’t really need treatment so much if they have a low Oncotype score.

John L. Marshall, MD: So Joleen, let me come back to Howard’s first point about this high-risk stage II disease and giving oxaliplatin. I keep looking for evidence to support that and can’t find it. There were high-risk patients in these studies, and when they did the subset analysis, the OX [oxaliplatin] doesn’t really show any added benefit over the 5-FU alone. And so I get it. I don’t want to undertreat patients, but how are you handling that? Is this an emotional reaction for us? And I get that in the adjuvant setting. We don’t want to regret. We really don’t want to regret. Do you think this is really the right thing to be doing in this high-risk stage II scenario?

Joleen M. Hubbard, MD: I think for a high-risk stage II patient, it is the right thing to be giving oxaliplatin. The reason why is, Howard mentioned earlier, there are so few patients with high-risk stage II on the adjuvant trials that we don’t really have a good sense. But when you look at the natural history of recurrence for a T4 lesion, the disease-free survival is actually worse than a T3, N1. So that, in my mind, justifies doing the combination with oxaliplatin.

Tanios S. Bekaii-Saab, MD: I agree that the data are meager, but I do agree with Joleen that I would consider those—in fact, yeah, I would argue that I’d give a 5-FU to a stage IIIa before I give a 5-FU to just a high-risk stage II, a T4 lesion, again with the caveat, and I think we’ll talk about this in a little bit, but how much do we expose our patients to?

John L. Marshall, MD: Chris, genetic testing here? Oncotype? MSI [microsatellite instability]? What are we doing?

Christopher Lieu, MD: So here, MSI is what’s within the guidelines. But we should be screening all patients for Lynch syndrome, usually by IHC, as Howard had mentioned. We want to test that. Everything else is really kind of unclear. There’s some data with PIK3CA and the use of aspirin in these patients who have the PIK3CA mutation but unbelievably small numbers. And there’s not really anything actionable. So you can test for BRAF in this early stage disease, but it tells you more about prognosis and doesn’t really tell you anything that you can really do anything actionable on. And so, here my recommendation is for MSI. You can get the other information, but you’re really just gathering information for the purposes of gathering information. It may help you if your patient has a relapse or a recurrence. Now you’re kind of dealing with a metastatic setting.

John L. Marshall, MD: And Howard, if you’re going to give this patient adjuvant combination chemotherapy, how long? How many cycles?

Howard S. Hochster, MD, FACP: Right. Well, that is a good question, and of course it brings us to the idea of collaboration and looking at 3 versus 6 months using a fluoropyrimidine and oxaliplatin. So it’s pretty clear for good prognosis stage III patients that 3 months is equal to 6 months—T3, N1s.

John L. Marshall, MD: Is everyone embracing this?

Christopher Lieu, MD: Yes.

John L. Marshall, MD: So if it’s the good half of the stage IIIs, you’re just stopping at 3?

Joleen M. Hubbard, MD: If you use CAPEOX [capecitabine and oxaliplatin].

John L. Marshall, MD: With CAPEOX.

Howard S. Hochster, MD, FACP: Yeah, that’s what I was going to say.

Tanios S. Bekaii-Saab, MD: I’ve actually done that before the idea.

John L. Marshall, MD: Well, you’re always...

Tanios S. Bekaii-Saab, MD: No, no. It’s out of pure love for my patients.

John L. Marshall, MD: From the oxaliplatin.

Tanios S. Bekaii-Saab, MD: From the oxaliplatin.

John L. Marshall, MD: But I’m talking about the total package. Do you stop the fluoropyrimidine in 3 months?

Tanios S. Bekaii-Saab, MD: It depends. I agree that for the low-risk patient, I would do 3 months.

John L. Marshall, MD: And call it a day.

Tanios S. Bekaii-Saab, MD: And call it a day. For the high-risk…

John L. Marshall, MD: So higher nodes, T4 lesions.

Tanios S. Bekaii-Saab, MD: So higher nodes, T4 lesions. I’m doing 3 months of CAPEOX and 3 months of capecitabine, and I’m still having discussions with the patients on whether they want to go through 3 more months.

John L. Marshall, MD: Of just the CAPE, or you won’t even offer more OX?

Tanios S. Bekaii-Saab, MD: No more OX.

John L. Marshall, MD: Let’s say they come in and they have 0 nodes and it’s at 3 months, and you say, “Well…”

Tanios S. Bekaii-Saab, MD: I don’t care.

John L. Marshall, MD: You don’t care. You’re done.

Tanios S. Bekaii-Saab, MD: No, I don’t care, and I’ll tell you why I don’t care. We’ve seen those patients. They’re perfect at 3 months and then at the fourth month they can barely walk into the clinic. I think to put it in perspective, when we look essentially at the cumulative knowledge with oxaliplatin and the fluoropyrimidine in colon cancer, regardless of risk, what you see essentially is that 20% of the patients who undergo surgery actually benefit from chemotherapy, from the addition of chemotherapy to their cure. At least 15% of that is coming from 5-FU or capecitabine, actually arguably maybe up to 17%. Only 3% to 5% is coming from oxaliplatin. Nonetheless, after 3 months you’re left with patients who may end up with debilitating neuropathy. It’s a wash. It’s a 1:1 ratio. You know that you can limit neurotoxicity if you actually limit the exposure to 3 months.

So you know you have a cut point in 3 months, and you also know that in the metastatic setting, 3 to 4 months is more than what you need with oxaliplatin. You put all this together, and it makes a lot of sense to limit the exposure to 3 months with oxaliplatin. What you do with the fluoropyrimidine up to 6 months is important, but you define it according to risk. What you do with oxaliplatin is essentially 3 months and no more.

John L. Marshall, MD: I mean, I go as far as showing the people the curve and saying, “All right, here’s where we are. We’ve gotten almost all the benefit we’re going to get.” And there’s another percent, a percent and a half hanging out there. Chris?

Christopher Lieu, MD: So I think this is where having an honest conversation with your patient is critically important, right? Because you may tell your patient, “Listen, there’s a 0.1% chance that it may improve your overall survival or disease-free survival,” based on the IDEA trial, “that the additional chemotherapy may give you a very, very small benefit.” There are some patients who would just take it every single day.

John L. Marshall, MD: Yeah, I’ll take it.

Christopher Lieu, MD: I would say a majority of patients, if they knew the absolute numbers that we’re talking about, would say, “Forget it. Are you kidding me?

John L. Marshall, MD: This regret component here is such a big thing, though. For us and for oncologists, you hate not to have taken every chance you can get. So we do overtreat, there’s no question in this space.

Howard S. Hochster, MD, FACP: A lot of the patients want that, and more so even in breast cancer than colon cancer, and people have looked at that.

John L. Marshall, MD: But they’re getting smarter over there in the breast cancer group. They’re getting a little bit more careful.

Howard S. Hochster, MD, FACP: I want to say that I also, as Joleen said, I’ve gotten to use more capecitabine in the 3-month treatment because that was actually better. For 6 months I tend to use 5-FU. And 1 thing that you brought up before was some people prefer to continue IV [intravenous] 5-FU compared with capecitabine. And I think some of that’s driven by even our healthcare system, because the co-pays for the oral drugs are so much higher for patients than if they come in and get 5-FU. It’s not so much that 5-FU costs nothing and the pills are expensive. It’s like it comes out of their pocket because of the co-pays. And so that actually gets to be a consideration in our current healthcare delivery system, and I think that’s unfortunate.

Transcript Edited for Clarity