Initial Systemic Therapy for Metastatic Colorectal Cancer



Marwan Fakih, MD: To obtain the best outcome possible in patients with metastatic colorectal cancer, we have to first identify what our goals are in the management of that patient. I think there are many factors that play into the decision making of what agents to use, what regimen to choose, and how long to treat these patients. Is the treatment curative, or is it palliative? Is there a possibility that downstaging will lead to a resection that could be potentially curative? What is the performance status of the patient? Can the patient handle combination chemotherapy? Is the patient fit physically? Is the patient young enough to sustain combination chemotherapy?

Those are important factors, and of no less importance is the molecular profile of the tumor as well as the characteristics of the tumor clinically. Where did it metastasize? What’s the origin of the tumor? When I see a patient with metastatic colorectal cancer, the first question in my mind is where are the metastases? Are they potentially resectable for a curative outcome? The second question is sidedness, because left-sided colon cancer behaves differently from right-sided colon cancer. The third question is going to be what is the molecular profile of the patient? Does the patient benefit from targeted therapy or immunotherapy? Once I have all these factors together—and I have defined the best-possible approach, in my mind, for that patient—I have a very in-depth discussion with my patient as to what are the goals of their treatment, and what is important for that patient as far as treatment management: the toxicities of the agents, what is going to be our goal, if we are going for surgery, and if there is a potential for cure.

Axel Grothey, MD: The initial therapy of metastatic colorectal cancer is influenced by various different factors nowadays. Of course we talk about molecular factors and sidedness, but I think also patient factors like age, tumor burden, goal of therapy, performance status, and comorbidities really play a major role. The question is really what we need to use to make the largest difference for patients, recognizing the patient factors we talked about. Then of course molecular factors come into play. I do believe that we need to test for key factors to make our treatment decisions for patients. RAS and BRAF mutation status, HER2 [human epidermal growth factor receptor 2] expression level, and MSI [microsatellite instability] status, which potentially opens the door for immunotherapy. Then overarching of course is the sidedness. All these factors get taken into account.

I think we all agree that for the average patient, a chemotherapy doublet serves as a backbone for the addition of biological agents, and we use FOLFOX [folinic acid, 5-fluorouracil, oxaliplatin], FOLFIRI [folinic acid, irinotecan, 5-flourouracil], or CAPOX [capecitabine, oxaliplatin]. The choice of the biologic will depend on the molecular factors and sidedness. For instance, at least in first-line treatment, you would not use an EGF [epidermal growth factor] receptor antibody in right-sided tumors. The refined patient population, who can benefit from panitumumab and cetuximab—are these patients with left-sided tumors, RAS and RAF wild-type tumors, and potentially HER2-negative tumors? Those tumors make up about 25% to 30% of patients. These patients should preferably, if we really give a biological agent in first line, receive an EGF receptor antibody and not bevacizumab.

There are nuances in terms of do you really need a chemotherapy doublet? For instance, can you get away with a single-agent capecitabine treatment in smoldering, low-volume disease with bevacizumab added? Do you need a triplet, perhaps in more aggressive right-sided tumors, BRAF-mutant tumors, etc? That is the standard of care at this point in time. There are subgroups where we have experimental approaches toward—let’s say different—first-line treatments like MSI-high tumors, immunogenic tumors where immune therapy up front might be the way forward. We don’t have randomized data yet, but the data we’ve seen from single-arm studies are very intriguing. Potentially for BRAF V600E mutant tumors, biological regimens are now standard of care in second- and third-line treatment. Why wouldn’t they work in first line? That’s an area of investigation right now.

Scott Kopetz, MD: While there are increasing data on how we should ultimately use biologics, there are also data on how we optimally use the cytotoxic. Data that came from the original TRIBE study and more recently the TRIBE2 study have suggested an overall survival benefit for patients when we start with a triplet cytotoxic, FOLFOXIRI [5-fluorouracil, oxaliplatin, irinotecan] regimen or sometimes we call it a FOLFIRINOX [5-fluorouracil, oxaliplatin, irinotecan] regimen, the idea of using an infusional 5-FU [5-fluorouracil], irinotecan, and oxaliplatin together. This is a very different type of treatment strategy from what we think of traditionally. The idea of starting with some duration of FOLFOXIRI, 6 weeks, 8 weeks, perhaps a little more, and then backing off to a maintenance of 5-FU, this is commonly done in combination with bevacizumab as well.

If the patient progresses on that maintenance 5-FU and bevacizumab, then we would reintroduce back to the FOLFOXIRI and bevacizumab as well. In that sense, you have 2 lines of therapy that you’re providing a patient. The TRIBE2 study, when we did that in comparison with the FOLFOX and bevacizumab with maintenance, then FOLFIRI and bevacizumab with maintenance, it suggested a survival benefit. This is being utilized especially in patients with KRAS-mutated tumors or right-sided primaries where we don’t have as many biological options with anti-EGFR therapies.

Transcript Edited for Clarity

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