Adjuvant Therapy for Stage 2/3 Colorectal Cancer


John L. Marshall, MD: Bert, let’s shift gears to the world of adjuvant therapy, and in particular, one of the hardest topics there is—so I’m picking on you for this—is stage 2. How do you decide who gets it? How much do you give? Does oxaliplatin play a role? Does the 3- versus 6-month have a role in that? Just a few questions.

Bert H. O’Neil, MD: Fair enough. If we’re talking about stage 2, we really only still have 1 good study to guide us, which was the old QUASAR study. It tells us that there is a small but real benefit in survival to giving fluoropyrimidine for 6 months. So, when I discuss this with a patient, I don’t think I choose who to give adjuvant therapy to or not. Now, we take out the MSI-high patients because we don’t offer them adjuvant chemotherapy at all. But for your microsatellite-stable patient, I might try to talk them into it a little more strongly if they have higher-risk features, if they were understaged. Most patients aren’t. Most patients fall into that gray zone of their standard-risk stage 2. I think I pretty much just show people a bar graph, “This is your chance of a cure without chemotherapy, and this is your chance of cure with it. Is that worth it to you to have 6 months of capecitabine?”

John L. Marshall, MD: Are there some patients who you give oxaliplatin to if it’s the right setting?

Bert H. O’Neil, MD: Only if they were T4 or had multiple high-risk features.

John L. Marshall, MD: Anybody give oxaliplatin?

Marwan Fakih, MD: Again, high-risk feature, very high-grade tumor, perforated.

Gabriela Chiorean, MD: I do.

John L. Marshall, MD: The high-risk?

Wells A. Messersmith, MD, FACP: They’d have to be very high-risk. My conversation with stage 2 generally starts with, “I do not recommend chemotherapy. I would need to treat 35 people just like you to save one. I’m just as likely to harm someone.” And the problem is all of these tests that are done to say who’s high risk or who’s low risk, it’s an answer looking for a question. My question is, should I treat them or not, not whether or not it’s going to come back regardless of what I do. And so, hopefully, over the next few years, we’ll get more predictive tests rather than the prognostic tests.

John L. Marshall, MD: Oncotype, ColoPrint, any of those molecular tests useful in your practice to determine, in stage 2, who gets treated?

Gabriela Chiorean, MD: So, I tell my patients the same thing as Wells. You do not need chemotherapy. And in the past 5 years, I routinely did Oncotype for all my patients, MSS with stage 2. And all my patients came back low score. I reassured them one more time that you don’t need to have chemotherapy just for 2 out of 5, just in the past year to recur, among the low recurrence rates. So, I don’t trust, unfortunately, these tests anymore to guide me at the same level as I was a few years ago.

John L. Marshall, MD: Anybody using them?

Marwan Fakih, MD: I use them occasionally in discussion with patients, but I agree, most of the time you will end up with a 15% risk of recurrence. And you end up with the same discussion. I’m with Bert with certain patients, you’ve got a 40-year-old, they got a stage 2 disease. Even if it’s a low risk, I think it’s important to have that discussion that yes, I may be treating 96 patients to save 4, and yet you’re going to have those patients who will say, “Hey, I want to do it. I want to maximize my chances,” and I think that’s a fair discussion.

John L. Marshall, MD: Our breast cancer colleagues will treat 100 and help 1.

Marwan Fakih, MD: So, this actually ends up being a simple, good prognosis but this is the 1 hour and a half consult that we typically get, and I had 2 of them this week.

John L. Marshall, MD: Gabby, I’ll come back to you. What’s the right duration? I’ve seen all sorts of editorials, smart people—some of them I even trust—about, is the IDEA study good enough? Is it not good enough? Should we be giving more versus less? How’s your approach to 3 versus 6 months right now in stage 3 disease?

Gabriela Chiorean, MD: I recommend all my T1, T3N1 patients—low-risk—3 months of CapeOx chemotherapy. For patients who don’t tolerate CapeOx and they choose to have a pump, we go with 6 months and then drop the oxaliplatin as needed, due to toxicities after 3 months. For the T4s and N2s, I recommend everybody 6 months of FOLFOX. The data with CapeOx were actually pretty similar with 3 versus 6 months even for the high-risk, but I feel more uncomfortable and I still recommend 6 months of CapeOx.

John L. Marshall, MD: Do you keep the oxaliplatin going or do you get about 8 cycles and you call it a day?

Gabriela Chiorean, MD: I very much decrease the dose and I discontinue it for toxicities, yes.

John L. Marshall, MD: I thought the French portion of the IDEA trial showing that most got FOLFOX, they showed that the benefit was held in the 6 months in that higher risk group, I think.

Wells A. Messersmith, MD, FACP: I would find it hard to justify though to give 6 months of CapeOx. It was detrimental. So, I don’t give 6 months. And the number needed to treat for FOLFOX is considerable.

John L. Marshall, MD: Yes, and it’s 1.7 people even in the high-risk group that you save by giving that 6 months. So, other strategies, Bert? You giving some oxaliplatin and then finishing off with 5-FU? How do you… or do you try to push as far as you go for a high-risk patient?

Bert H. O’Neil, MD: Yes, for the higher-risk patients, I’m still doing 6 months of FOLFOX, dropping the oxaliplatin. I think one thing about these studies is they made me more comfortable dropping oxaliplatin early. So, I think I already had a little bit of an itchy trigger finger to do that when someone started getting neuropathy, but now it’s even more so.

John L. Marshall, MD: This is a pooled 12,000 people. We’re not going to do the study again, so we either have to believe it or not.

Marwan Fakih, MD: So, I have to say the NSABP (National Surgical Adjuvant Breast and Bowel Project), to start with, did 9 cycles of oxaliplatin. So, even before the IDEA trial, we don’t have great data that you need to get to 12 cycles even for the high-risk for the oxaliplatin per se. So, we routinely drop oxaliplatin after 8 cycles in our high-risk and finish the 12 cycles. Because, really, you can’t time that grade 3 neuropathy. You push it to 10 cycles and a month later or 2 months later, you’ve got that limiting neuropathy.

John L. Marshall, MD: Does this translate to stage 2s?

Wells A. Messersmith, MD, FACP: I feel like the lesson we’ve learned over the past couple of years or couple of decades is stage 2 and stage 3 are not totally translatable one to the other.

John L. Marshall, MD: So, if you want to treat for that 3%, 4%, you’d still give 6 months?

Wells A. Messersmith, MD, FACP: If I’m going to. Yes, it’s very rare I’m treating stage 2.

John L. Marshall, MD: I get you.

Wells A. Messersmith, MD, FACP: I’m skeptical that we can extrapolate stage 3 to stage 2.

Marwan Fakih, MD: We don’t have data on fluoropyrimidine 3 months alone. The idea was oxaliplatin-based.

John L. Marshall, MD: Well, you actually do. There is infusion versus bolus, which started the whole thing. It was the supporting study. It was 5-FU only, and it was infusion 5-FU.

Marwan Fakih, MD: That is correct. That was protracted infusion 5-FU, yes.

Gabriela Chiorean, MD: If your stage 2 is a T4N0, I think many would argue that’s even a worse prognosis than a T3N1, so I would recommend the same principle for the T4N0s as the T4N2s.

John L. Marshall, MD: So, I’m hearing less comfort in translating it without. But are we ever going to do a study of stage 2 again?

Bert H. O’Neil, MD: Oh, absolutely not.

John L. Marshall, MD: Not until we get another drug made and learn to enrich maybe.

Wells A. Messersmith, MD, FACP: Yes. Hopefully, this sort of data-to-patient value issue of can we take 50,000 patients from all the various computer systems in our hospitals and start pulling these together and answering some of the questions without doing a big expensive trial, it would be really interesting if we did that.

Transcript Edited for Clarity

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