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Questions Remain on Optimal mCRC Treatment

Gina Columbus @ginacolumbusonc
Published: Tuesday, Dec 19, 2017

Leonard Saltz, MD
Leonard Saltz, MD
Metastatic colorectal cancer (mCRC) is an area comprised of several unanswered questions, whether it be optimal chemotherapy regimens, use of frontline EGFR-targeted therapy, or the role of tumor sidedness, explains Leonard Saltz, MD.

Moreover, while the FDA approvals of pembrolizumab (Keytruda) and nivolumab (Opdivo) for patients whose tumors are microsatellite instability (MSI)-high or mismatch repair (MMR)-deficient were practice changing, the subset of patients for whom these checkpoint inhibitors benefit is a minority of overall patients with mCRC.

In an interview during the 2017 OncLive® State of the Science SummitTM on Gastrointestinal Cancers, Saltz, a medical oncologist at Memorial Sloan Kettering Cancer Center, highlighted the current go-to therapies and overarching questions for mCRC treatment.

OncLive: Please provide an overview on your presentation on mCRC.

Saltz: The question of chemotherapy for patients with metastatic CRC remains a complicated one, simply because we have a number of options, all of which have some advantages and disadvantages, so there really isn’t one right answer. It is one of the reasons that, if someone looks at the NCCN guidelines, it really looks like a “smorgasbord” of choices.

The first decision point, when treating a patient with mCRC, is the cytotoxic backbone. Typically, we are choosing between FOLFOX and FOLFIRI. This is nothing new; we have been choosing between these regimens for quite some time now. It would be nice if we could make enough progress that we move beyond that.

This is basically, as I think everybody is familiar with, an every-other-week schedule using a 48-hour infusion of 5-fluorouracil with either oxaliplatin or irinotecan. Now, when we look at the efficacy data of these 2 regimens together, they are quite comparable. The side effect profile is the same in terms of intensity, but different in terms of character. Oxaliplatin is of course more likely to cause neuropathy, and that is more likely to be the grade-limiting step in terms of intolerance. Whereas irinotecan, contrary to what most people think, is not more likely to cause diarrhea but is more likely to cause alopecia and that can be a considerable issue for some patients. 

In discussing [these options with] patients—who they are and what matters to them—the degree in which neuropathy would be problematic or the degree of which loss of privacy and self-esteem with hair loss would matter would come into play [to make the] decision. 

There are data supporting the use of throwing the whole “kitchen sink” in there and call it FOLFOXIRI or FOLFIRINOX, depending on which way you want to say it. There are data suggesting that this might be better; those data are based on treating patients with excellent performance status and the [studies] are mostly performed in ex-United States sites. With the use of fluorouracil, I would be concerned about American patients tolerating it. I don’t use the FOLFOXIRI regimen regularly; I use it when I have reason to believe that I need a rapid response in terms of tumor regression and the patient is otherwise in good medical shape. 

The more controversial issue becomes inclusion of the monoclonal antibodies bevacizumab (Avastin) versus either cetuximab (Erbitux) or panitumumab (Vectibix), the anti-EGFR agents. The most relevant data there come from the CALGB/SWOG 80405 study, which directly compared cetuximab with bevacizumab. In this study, patients and doctors chose FOLFOX or FOLFIRI because we didn’t care; we said, “it’s fine either way.” Then, they were randomized to receive either cetuximab or bevacizumab. For all practical purposes, all of these patients were RAS wild-type. The outcome of the study showed no difference in terms of efficacy in pretty much any parameter one wants to look at. 

That said, my personal feeling is that I don’t see a role for frontline EGFR therapy. First, it is a very difficult toxicity for patients to tolerate. The skin rash that we expect patients to get with an EGFR-targeted agent is a debilitating rash and is one of the harder things that we ask people to tolerate. If I can delay that to later in the treatment [course], I prefer it. The other issue is the price of either cetuximab or panitumumab is virtually twice the price of the 5-mg/kg dose of bevacizumab that we would use. This is less expensive and has a better toxicity profile in most patients.




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