Frontline Treatment and Maintenance for Metastatic Colorectal Cancer

EP: 1.Getting to Know Colorectal Cancer

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EP: 2.Frontline Treatment and Maintenance for Metastatic Colorectal Cancer

EP: 3.Progression on Metastatic Colorectal Cancer Treatment

EP: 4.Regorafenib as a Metastatic Colorectal Cancer Therapy Option

EP: 5.Regorafenib Sequencing and the Future of Metastatic Colorectal Cancer Management

John Marshall, MD: Metastatic colorectal cancer is an incredibly fascinating and challenging disease to take care of. It is not a one-size-fits-all model anymore. We used to just give everybody the same thing and see how it goes, if you wanted to work through all the lines of therapy—that sort of thing. Now we consider molecular profiling, sidedness, tumor burden, comorbidities—all sorts of things factor into decision-making around frontline treatment.

This is the way I present it to patients—we have a 4-drug recipe, say, FOLFIRINOX [leucovorin, fluorouracil, irinotecan, oxaliplatin]/[bevacizumab] or even [cetuximab]. You have 3-drug recipes, a fluoropyrimidine, [oxaliplatin] or IRI [irinotecan], and, say, [bevacizumab] or [cetuximab] and panitumumab. You’ve even got 2-drug recipes with, say, [capecitabine] and [bevacizumab] that are still legitimate. All 3 of those menu items—the 4-drug, 3-drug, and the 2-drug—have valid benefits in patients. They have similar progression-free survival [PFS], but where they differ is in toxicity and in response rate.

Increasingly, what I recognize is that you don’t get too many windows for a response in metastatic colorectal cancer, and the first line is where you have your best shot. Increasingly—I‘m in this camp—wherein if a patient has any significant tumor burden at all, I tend to be more aggressive. I’m going with more and more 4-drug recipes from the beginning to drive that cancer back as far as we can get it. The good thing is, no matter what you pick, it would only take about 3 or 4 months of treatment to get to that nadir. You almost never see further regression after that initial few months of treatment.

On the other end of the spectrum, what if I have a 45-year-old who is working full time and is the source of the revenue for their family—and the insurance and everything else—who doesn’t have time to do FOLFIRINOX and has small-volume metastatic disease? That would be a patient for whom [capecitabine]/[bevacizumab] may be a legitimate choice, even though they want to be aggressive. On the flip side, maybe the patient has stable disease or minor regressions. Four drugs gets you up to 70% response rate, with 95% disease control rates. Two drugs get you to about a 30% response rate, with 9-month PFS, but lower toxicity. You pick your poison, if you will, based on the patient in front of you.

The other piece that you always must think about with metastatic colon cancer is, are they curable? The only way to cure these patients is through surgical resection or some sort of ablative therapy. We all think about that now. We have pushed the envelope on that, to where it isn’t just isolated liver disease anymore, it’s anybody with disease that can be removed. As imaging has gotten better, as surgeons have gotten better, and as interventional radiation technologies have gotten better, all of us are getting away from just chemotherapy-only kinds of approaches to partnering with our local therapy partners to play a little whack-a-mole. Now we end up a lot with patients with no evidence of disease. Some of them are cured, and of course, some of them are not. You pick your poison based on the profile, the sidedness, the tumor burden, the comorbidities of the patient, the goals of the patient, curability or not—and then you set sail.

For the patient who is not curable, when there are too many weeds in the yard for surgery—all of them should go to maintenance therapy. The only exceptions are those that can get away with no therapy, and that is something that I hesitate to do. The standard maintenance is chronic low-dose capecitabine with some bevacizumab; it is well tolerated, easy to manage, and easy to work Disney cruises around. You can drop to maintenance, and most patients will do quite well on that for a prolonged period of time.

One of our mistakes is that we don’t use it enough. We tend to be too heavy-handed, give too many cycles, get too many adverse effects, and that burns our bridge later. Almost everybody should get maintenance. The few exceptions are those with a strong complete response, those who had bad tolerance of the treatment, or, on the other end, those with small tumor burden who could take a few months off and be watched closely. I do think there is a group that you could back off on, but the default should be maintenance therapy. Then at one point, of course, they all progress, and that takes us to subsequent lines of therapy.

This transcript has been edited for clarity.