Key Takeaways in the Treatment of Advanced Colorectal Cancer - Episode 1

Key Takeaway 1: Adjuvant Therapy Optimal Duration


Tanios S. Bekaii-Saab, MD: The biggest predictor for recurrence in colon cancer is the stage, and the stage relates to at least 2 elements: the T factor and the N factor, so number of lymph nodes and the depth of the tumor. In the early stages, stage I and what we call low-risk stage II, those patients typically get cured by surgery alone, or there is no benefit at least from administering chemotherapy. For those patients who are high-risk stage II, so those with T4 and stage III—meaning lymph node-positive—those are the patients who will need adjuvant chemotherapy because of their high risk of recurrence.

There’s also the element of microsatellite status. For MSI [microsatellite instable]—high patients, those patients tend to do better, and the risk of recurrence is lower. Nonetheless, they do seem to benefit from adjuvant chemotherapy. For those patients, fluoropyrimidines alone do not seem to confer much of a benefit. Those patients seem to benefit, though, from a larger study that was a meta-analysis. A number of studies combined together showed essentially that there is a benefit with oxaliplatin and a fluoropyrimidine in those patient populations with MSI high, again with high risk of recurrence. Although they remain a better prognosis.

And then there’s the age. The age of the patient matters. Oxaliplatin seems to be less beneficial for patients who are older than 70 or 75. Those are the patients you preferentially treat with a fluoropyrimidine alone, especially those above 75. That’s a strong consideration. There’s also, of course, other morbidities. You want to start the patients within 8 weeks from their surgery. Beyond 8 weeks, you start losing benefit from the treatment, and arguably you probably wouldn’t be concerned much about a benefit for treatment. And those patients beyond 8 weeks may not benefit from having treatment.

In terms of the duration of treatment, that has been addressed by the IDEA trial, which is a composite of 6 large randomized phase III trials. In the adjuvant setting, patients had either FOLFOX [leucovorin calcium, 5-fluorouracil, oxaliplatin] or CAPEOX [capecitabine, oxaliplatin], depending on the study—some of which actually included stage IIs and high-risk of at least stage II plus stage IIIs. So this was presented and then published recently in New England Journal of Medicine, and at the last ASCO [American Society of Clinical Oncology] Annual Meeting we had an update about the high-risk stage II, meaning the T4s.

When we look at the cumulative data—remember that IDEA is a noninferiority study—what becomes clear is that from the statistical standpoint, the study did not reach its primary endpoint, meaning it was not noninferior. But it wasn’t proven to be inferior as such or superior. It was not noninferior and remains in an area of uncertainty. When you start breaking down essentially the high-risk patients, meaning the T4s, and above and then the low-risk patients, what’s clear is that for the low-risk patients, 3 months is enough with capecitabine and oxaliplatin.

FOLFOX [leucovorin calcium, 5-fluorouracil, oxaliplatin] seems to be inferior when you give it for 3 months versus 6 months. And so at this point in time in our practice, patients will receive capecitabine and oxaliplatin, and we do not advocate for FOLFOX [leucovorin calcium, 5-fluorouracil, oxaliplatin] and we do not administer this in our patients. Now, the caveat with CAPEOX [capecitabine, oxaliplatin] is that it’s a little more toxic, but you’re giving it for a limited amount of time for 3 months.

For the high-risk patients, CAPEOX [capecitabine, oxaliplatin] retains its noninferiority. When you combine the 2, CAPEOX [capecitabine, oxaliplatin] and FOLFOX is when someone loses on the noninferiority side. For those patients, I still recommend capecitabine and oxaliplatin for 3 months. And then for those patients who decide to continue through to 6 months, I would go with capecitabine alone. I don’t think there’s much of a benefit from oxaliplatin continued beyond 3 months.

So for low-risk patients, capecitabine-oxaliplatin for 3 months; for high-risk patients, the same, capecitabine-oxaliplatin for 3 months. And for a select few after discussion, you could continue for 3 more months with capecitabine. And a reminder that at the end of the day, from the chemotherapy component, the fluoropyrimidine is responsible for about 15% added benefit to the 50% we see with surgery—rough numbers—and then oxaliplatin adds only 3% to 4% but also adds significant neuropathy beyond the 3 months, as we’ve seen from the IDEA and other trials. Overall, there’s really no need to continue oxaliplatin beyond 3 months in this patient population.

When MSI is high, we check for BRAF typically because that helps us essentially decide whether to go down the path of checking for Lynch syndrome. Although now, in our clinic at least, we screen universally every patient for germline alterations. That has become less of an issue. In all frankness, you really do not need to do that other than for MSS [microsatellite stable] or MSI-high patients. BRAF, KRAS, and NRAS, of course, have some prognostic significance, but they don’t change our treatment algorithm in the earlier stages of the disease. Of course, they become much more important later stages.

Understanding that for most of these patients, if we put the whole high-risk stage II and stage III together, about half these patients—maybe a little more than half—will never have to deal with any systemic therapy beyond their adjuvant treatment because they will not recur. It’s the other 40% to 50% that will recur, and then that will have to deal with these treatment options. For those patients, a status like BRAF, RAS, or HER2 becomes important. So we don’t do these routinely on all patients with earlier stages other than the microsatellite status.

Transcript Edited for Clarity