Is Chemo Needed in Patients With MSI Colon Cancer?

John L. Marshall, MD


August 10, 2015

Editorial Collaboration

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John Marshall for Medscape. How is everybody today? I'm not feeling all that well—a little grumpy today. I didn't have the greatest weekend.

I've been stewing on this issue that I'm going to review since I saw a patient on Tuesday. She's a woman with a brand-new diagnosis of stage III colon cancer, one positive lymph node, and she clearly is going to have DNA mismatch repair [MMR] deficiency. (I don't know whether the MMR deficiency is inherited or acquired yet; it might be inherited.) Everybody reflexively says that this woman needs to have FOLFOX (fluorouracil, leucovorin, and oxaliplatin), but I'm not so sure.

I recall the abstract presented at ASCO a couple of months ago by Aziz Zaanan and colleagues,[1] which was a good attempt to answer this question. Their study used the PETACC-8[2] and [North Central Cancer Treatment Group trial]-N0147[3] adjuvant trials, found the MMR-deficient or microsatellite instability (MSI) tumors from each, sorted them into inherited and acquired, and then analyzed them.

The punchline was that patients with MMR-deficient tumors seemed to benefit from FOLFOX just the same as the others. There wasn't a big difference. The patients had a better prognosis, though one conclusion was that they should get FOLFOX. But I'm not sure that that's what the data say.

The premise we started with is that patients with MMR-deficient tumors have a better prognosis and that chemotherapy might harm these patients. What I would have liked to see in this analysis is that some patients got FOLFOX and some patients got no treatment, because it's possible that instead of pushing the survival curve up—which is what we think chemotherapy generally does—chemotherapy might be pushing the curve down. If we had just left those patients with MSI tumors alone, even the stage III patients, they may have performed better than those with microsatellite stability (MSS).

We come to this conclusion that the outcomes were about the same whether there was MSI or MSS; if anything, the prognosis was a little better with instability. But that doesn't answer the question I confront as a clinician, which is: Should I be giving chemotherapy to MSI patients?

The time is right for us to find a cohort of patients, or create a cohort of patients, who are randomized to receive no chemotherapy. It will take nerve for us to do that.

Maybe once we are confident that our immune therapies can capture those patients who do relapse, and solve their problem, we'd be willing to do it. But I'm not sure that we're ever going to do a clinical trial of stage III colon cancer MSI-high, where half of the patients get some treatment and half get none.

The next time this kind of patient comes to your clinic, question yourself: Am I pushing the curve up with chemotherapy—am I improving survival? Or am I in some way pushing the curve down, particularly in MSI-high stage III colon cancer?

Food for thought on a Monday. I know I'm grumpy. Don't hold that against me. John Marshall for Medscape.


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