Goals of Systemic Therapy in Colorectal Cancer

Transcript:John L. Marshall, MD: So, Dan, let’s talk about initial lines of therapy, specifically the goals of front-line therapy. You’ve got all sorts of patients. Some may be resectable, some clearly aren’t. Some are symptomatic, some not. Give me your broad overview of how you make that assessment and what those goals are going to be for that patient walking in the door.

Daniel G. Haller, MD: A bone I have to pick is with mutational testing. We’re talking about individual personal therapy, but I’ve been doing that for 40 years. I make individual decisions in every patient. If you say statistically the most common front-line regimen in the United States is FOLFOX/bevacizumab, that can’t be the right treatment for everybody. If someone has five small pulmonary nodules and is asymptomatic 4 years out from their primary colon, that patient is very different from someone with peritoneal metastases, symptoms, weight loss, pain, and a BRAF mutation. One could live for 5 years and the other one probably will live 1 year.

John L. Marshall, MD: That one you can just rub a little Xeloda on them and they’d be fine, right?

Daniel G. Haller, MD: Yes, and for that patient, they’ve had metastatic disease for 4 years. I think in the first patient, single-agent capecitabine might be the right answer. But in the other patient, probably FOLFOXIRI—or FOLFIRINOX, whichever term you want to use—probably is important because they may never get to second-line therapy. You’re never going to shrink a tumor with single-agent therapy. That’s not going to happen to any great degree.

That’s how I balance the pace of the disease. How did it occur? Synchronous? Metachronous? What is their mutational status—not so much for RAS but BRAF—in terms of prognosis? And then the tools and what our expectations are. For the potentially resectable patient, I think you need most therapy up front. It turns out cetuximab didn’t really make a difference in its trial. Although in the CALGB 80405 trial, more people got resections—I think 2:1 in the cetuximab arm. We’ll talk more about neoadjuvant therapy and when you should use it, but I think—as Cathy was saying—you have to make a decision about resectable and non-resectable up front, not after seven lines of therapy.

John L. Marshall, MD: I’ve been struggling with this induction concept. Just as Dan laid out, give the least amount of chemotherapy to control the patient and then save things for downstream. We’re seeing combinations more and more in randomized clinical trials—kitchen sink combinations—that are resulting in OS, PFS, and resection rate improvements in an unenriched, anybody-walks-in-the-door, metastatic cancer population. Is your mindset changing away from the capecitabine single-agent to giving them at least some induction therapy?

Cathy Eng, MD: Once again, it depends upon the patient. I evaluate the patient, and then I make that decision. If you’ve got someone with borderline resectable disease, you want to provide them significant therapy up front to get them that chance of having a curative resection. Then you’ll have the really young patient with high degree of tumor burden that you may want to be very aggressive on. So, I think it really just depends upon your patient population.

John L. Marshall, MD: But didn’t we just see Dr. Bendell’s study with combination chemotherapy and the old FOLFIRINOX study, or FOLFOXIRI—I never remember which it is—that actually show an OS and PFS? It’s not just in the more aggressive bad tumors, but in all-comers. That’s what I’m getting at. Are we still individualizing, as we’ve been doing, based on the clinical scenario, or is anybody up here ready to say that almost every patient with front-line colon cancer needs 2 months of induction chemotherapy?

Tanios Bekaii-Saab, MD: I don’t think so. I think the studies with the three drugs—with a more aggressive regimen—do suggest that there is a subgroup of patients who would benefit. The one that is clearer now is the liver resection. The liver resection I think is now—and I’m changing my mind about that—consistently showing that you probably benefit from a 3-drug approach for 2 to 4 months. I increase the rate of R0 resection and perhaps even resection.

The BRAF-mutated group, which does the worst, seems to benefit—at least in two studies; albeit one is small, the other is a piece of a stud. But it does suggest that that subgroup of patients seem to benefit from the 3-drug approach. The others, frankly, if you look overall at the survival of the three drugs, plus biologic factors, look at CALGB 80405 or FIRE-3, and you look at the survival, they’re in the same range. So, a sequential approach would still make more sense. In the BRAF-mutated population, you may not have the luxury of that sequential approach because patients barely make it to second-line.

John L. Marshall, MD: So, what’s the control arm on a cooperative group front-line study?

Daniel G. Haller, MD: It remains FOLFOX/bevacizumab because that is primarily what people use in an 80405 trial—I think 70% of individuals chose that when they were asked. It is what we use. In Europe, it may be the same. FOLFIRI is more commonly used.

Tara E. Seery, MD: I have to admit, I’m turning to the FOLFIRI train. FOLFOX has so many long-term side effects and patients tolerate FOLFIRI much better. You actually have some better response with irinotecan.

Cathy Eng, MD: I actually like FOLFIRI best.

Tara E. Seery, MD: If they’re okay with the hair loss, then I go with that one.

Transcript Edited for Clarity