Optimizing Systemic Therapy in Advanced Colorectal Cancer - Episode 10
Transcript:John L. Marshall, MD: Tara, give me your day-to-day management for an everyday patient with metastatic disease in the frontline setting and what you give them. When’s that first scan? When do you think about maintenance? Does FOLFOX versus FOLFIRI matter? Give me your way to plan that initial part of the chess game.
Tara E. Seery, MD: Every month, I always check a CEA. I scan every 3 months, and usually I’ll give the first-line treatment for about 6 months. After 6 months, if everything is stable, I start maintenance.
John L. Marshall, MD: You opt for FOLFIRI?
Tara E. Seery, MD: All FOLFOX patients, no matter what, you have to.
John L. Marshall, MD: You gotta, right? Because they can’t write their check for their co-pay.
Tara E. Seery, MD: Exactly. Usually I’ll do some sort of 5-FU. The majority of patients prefer Xeloda with Avastin. The FOLFIRI patients are a little unique because they’re feeling fine at month 6. They’re cruising along, and they’re like, “Why do you want to drop this?” And so, then it becomes this patient discussion about, “Okay, this is what our options are. We can make it a little bit easier. You don’t have to be tied to the infusion center this often. You can come once every 3 weeks, enjoy your life, work, and then we can always use this agent again if we need to.”
John L. Marshall, MD: Do you talk about this in the frontline setting? Right when you’re starting, do you say we’re going to give it for a while and then think about this?
Tara E. Seery, MD: Yes.
Cathy Eng, MD: But, actually, I’d probably start maintenance a little sooner in all fairness. I would probably start it at about 4 months.
John L. Marshall, MD: What’s so magical about 12 cycles?
Cathy Eng, MD: Exactly. I don’t know. I hear it all the time though.
John L. Marshall, MD: It’s like it’s a medical/legal requirement in the metastatic disease setting.
Daniel G. Haller, MD: Well, it comes from the adjuvant setting where no one should get 12 cycles. It’s not a mark or a badge. But when you do maintenance with FOLFIRI, the issue is that after the induction, people grow their hair back just in time to reinstitute the drug.
John L. Marshall, MD: But I do think a lot of our colleagues think that we expect them to give 12 cycles. They think that there’s some sort of obligation. Is this common?
Cathy Eng, MD: I commonly hear that, yes, from the patient.
Daniel G. Haller, MD: But the bottom line is, if you look at most studies, 90% of the response occurs in the first 4 to 6 cycles. The rest is just adding toxicity.
Tanios Bekaii-Saab, MD: You mean in the first 3 to 4 months.
John L. Marshall, MD: Three to four months.
Daniel G. Haller, MD: Yes.
Tanios Bekaii-Saab, MD: That’s in the OPTIMOX study that suggested that after 3 months, you plateau, your response plateaus. So, 3 to 4 months is probably optimal. For some patients with FOLFIRI, you may extend it to 6 months, but optimizing is probably a good idea for all patients.
John L. Marshall, MD: For frontline EGFR therapy, what’s your maintenance?
Cathy Eng, MD: In all fairness, I don’t do a lot of frontline EGFR therapy.
John L. Marshall, MD: Don’t do much?
Tanios Bekaii-Saab, MD: I don’t do it.
John L. Marshall, MD: Do you do much? Keep the EGFR going? Switch? I don’t know. The Europeans are doing a lot of reintroduction. They’re giving it and then bringing it back.
Tara E. Seery, MD: Usually I stop it, and I just do the 5-FU.
John L. Marshall, MD: Okay. If they’re on bevacizumab in the frontline setting, then bevacizumab is part of your maintenance?
Tara E. Seery, MD: Yes.
John L. Marshall, MD: Q3 week, Q2? Do you keep them on Q2 and then go to Q3? Does it matter?
Cathy Eng, MD: It depends on if I’m doing IV 5-FU or Xeloda.
John L. Marshall, MD: If you’re doing IV 5-FU, it’s Q2. If you’re doing capecitabine, it’s Q3.
Tanios Bekaii-Saab, MD: Yes, every 3 weeks, even with infusion 5-FU. But my preference has been to shift to capecitabine in the maintenance setting.
John L. Marshall, MD: Dosing of capecitabine?
Daniel G. Haller, MD: Metronomic.
John L. Marshall, MD: Continuous dosing like in the CAIRO-3 study. So, not 2 weeks on, 1 week off.
Daniel G. Haller, MD: The other is the chemotherapy-free interval. Although it looks bad, it doesn’t look bad in people with non—BRAF-mutant minimal disease that disappeared on induction therapy. I think some of those patients could be free and have a real vacation, not just a weekend at the Holiday Inn. For the opposite group, some patients are not good maintenance patients because you take them off the non–5-FU drug, their vacation is a weekend, and it’s a big disappointment. If people started with peritoneal disease and metastases, I’d stick with the drug. And that’s a patient where you’d want to be on FOLFIRI.
John L. Marshall, MD: Switching to biologic use in second-line, what do you like? And let’s make them RAS-mutated to start with, with asymptomatic progression.
Cathy Eng, MD: I tend to use bevacizumab in the frontline, so that I can continue it in the second-line.
John L. Marshall, MD: They’re used to it. They’re on it. Is anybody changing to the other VEGF inhibitors in those with RAS wild-type? Is there a patient where you switch from VEGF to EGFR?
Tanios Bekaii-Saab, MD: Yes. If you look at the TML study, it definitely shows that patients would benefit from continuation of bevacizumab. One thing is missing: the response rate is 4%. If you look at the EGFR studies in the RAS wild-type in the second-line, the response rate is higher. Survival and PFS are probably very similar, but you do get that additional response in the second-line—but it’s not as much as in the first-line setting. The difference in first-line response rate is not there, but in second-line, at least historically, we favor EGFR inhibitors for sure. For some patients, what I do is I actually start with FOLFIRI/bevacizumab and I just switch the biologic in the second-line. In those patients that have cruised along all the way through, they have minimal symptoms of disease. I stick with the VEGF inhibitor and just switch the chemotherapy.
John L. Marshall, MD: Well, this is part of what’s got me hooked on this depth-of-response concept. Apart from EGFR in the right patient, even in second-line, and certainly in the third, we don’t see a lot of further responses from the therapies we have. Agreed?
Daniel G. Haller, MD: Response is not an indicator, like it is with regorafenib or TAS-102. If you’re looking for response, you’ll be disappointed; you’re maintaining. Can I ask a question of my colleagues? This drives me nuts. If one does FOLFOX up front, why do we do FOLFIRI when the patient just progressed on 5-FU? There’s no interaction. You need 5-FU with oxaliplatin, but you don’t need 5-FU with irinotecan. As in the SWOG study, people went to irinotecan alone. Why do we keep people on pumps and expose them to a toxic drug that didn’t work or wasn’t working?
Tanios Bekaii-Saab, MD: So, there are two studies. One is an older study from the UK, FOCUS, which essentially started patients on 5-FU and then randomized patients to FOLFIRI or irinotecan. The FOLFIRI patients following 5-FU failures did better than the irinotecan patients. From the pancreas cancer world, in the NAPOLI-1 study, patients were actually randomized to 5-FU/MM-398, which is nanoliposomal irinotecan plus 5-FU, 5-FU alone, or MM398 alone. The combination of the two drugs, irinotecan plus 5-FU, did better than 5-FU alone, but also did better than single-agent MM-398. In fact, single agent MM-398 did not do any better than 5-FU.
Daniel G. Haller, MD: In pancreatic?
Tanios Bekaii-Saab, MD: Yes, and they weren’t exposed to 5-FU previously, so I gave you all these caveats. But that tells you that there is some level of, maybe not synergism, but at least additivity between the two. So, that would set the rationale for doing that.
Daniel G. Haller, MD: But they had not progressed on 5-FU.
Tanios Bekaii-Saab, MD: I think it is not unreasonable to drop the infusional 5-FU. But I would caution that if you do that, keep the irinotecan biweekly regimen and do not go to every 3 weeks, which is much more toxic. That would be acceptable, but I prefer to continue the 5-FU.
John L. Marshall, MD: I do it with VEGF. I drop it with EGFR because I think the bevacizumab/5-FU combination has a little magic.
Daniel G. Haller, MD: There could be some magic.
John L. Marshall, MD: And I will often change my 5-FU just because I’m old enough to remember that we used to do that, and sometimes it would work. So, if I was on the pump, I might go to pills or vice versa. Because I agree with you: it’s 5-FU beyond progression without a lot of evidence.
Transcript Edited for Clarity