The Biology of Extending Survival in Advanced CRC - Episode 9
John L. Marshall, MD: We’re going to go through metastatic disease and the new adjuvant treatment data. We’re going to quickly review the differences between the frontline approach in Europe versus the United States.
Dirk, I’ll ask you to cover the approach in Europe, and then we’re going to go through lines of therapy and talk about how we manage it and drill down on sequencing. Dirk, can you give us a quick summary of the approach for frontline metastatic disease? What guidelines would you follow?
Dirk Arnold, MD, PhD: There is a broad consensus across the guidelines that says it’s multifactorial decision making. It’s not “correct the cancer,” where we have 1 molecular alteration or 1 clinical alteration that is clearly showing us which treatment is the standard. All of these factors have to be considered. It’s tumor related, patient related, treatment related, toxicity, cost, etc.
We are asked, as medical oncologists, to consult the patients and to consider all of these factors. There are only a few points where we disagree, and we were discussing these before—this kind of scenario involving left-sided, RAS wild-type patients, where the use of anti-EGFR and the preference of anti-EGFR is considered, and to which extent this should go on.
John L. Marshall, MD: We do feel strongly about that. I think that discussion needs to keep going, but, otherwise, we are pretty much in sync. Tony, would you agree with that approach?
Tanios Bekaii-Saab, MD: I totally agree. I think, again, we speak the same language, just with different accents, essentially.
Fortunato Ciardiello, MD, PhD: I think it’s very important to have the full molecular characterization of the patients, that we agreed on, before we make all the decisions together. And then, as much as possible, we should use a doublet chemotherapy in first-line therapy. I think that most of our patients should be offered the most reasonable chemotherapy doublet with the most reasonable biologic agents.
John L. Marshall, MD: I think that’s right. Is there a value around intensity, initially, and a maintenance approach? Is that sort of an agreed-on strategy—Paul?
Paul R. Helft, MD: Well, I just want to add that when a patient walks in, de novo, I tend to put them into big buckets first. The first branch point in the decision tree is, are they ever going to be resectable or not? The definition of that, in all of our centers, has evolved over the past 10 years, greatly. Do they have an MSI-high tumor? That’s really a different subset of patients. And then, what are their molecular subtypes? And beyond that, what you’re really thinking about is—and people often use the chess analogy, but I like to use the Tour de France analogy—this is a multistage race. How are we going to maximize the benefit that we get out of each of the stages of the trajectory along the way?
Tanios Bekaii-Saab, MD: I think it’s a balanced approach. I do believe intensity is always needed in the first 2 to 3 months, but not necessarily beyond 3 to 4 months. This is where, essentially, patients go on maintenance therapy. Drug holidays—we do give holidays more and more now, for some. So, overall, it’s not a very simple decision that can just be reflected from the guidelines. Every patient is an individual, and we have to have an individualized plan.
John L. Marshall, MD: What I’m hearing—and this is really advice for folks out there—is that it is individualized. You can’t prescribe 6 months of therapy and say, “I’ll see you in 6 months with a scan.” You have to follow these people regularly and make chess moves or Tour de France moves, and switch your tires if things change. In that setting, if you’re seeing a brand-new patient, when would you say, “We’ll relook and we may start to back off of treatment on some level,” whether it’s maintenance therapy, drug holidays, or whatever? When is that? Is that at 3 months, 4 months, 6 months? When is it for you?
Dirk Arnold, MD, PhD: I start the thinking process after 8 weeks, so I would say at 2 months.
John L. Marshall, MD: Quick.
Dirk Arnold, MD, PhD: I always say to the patient, “After 2 months, we will see which direction we go.” After 16 weeks, after 4 months, we make the definite decision as to where we go. Is it maintenance therapy? Is it resection? Is it ablation? This happens after 4 months. After 4 months is the most important decision point.
John L. Marshall, MD: Are you scanning people every 8 weeks?
Dirk Arnold, MD, PhD: Every 8 weeks.
John L. Marshall, MD: Is anyone doing this differently or the same?
Fortunato Ciardiello, MD, PhD: Same.
John L. Marshall, MD: I’ve been spreading mine out a little bit if I’ve got good markers outside of a trial—maybe doing 3 months. These are style points.
Tanios Bekaii-Saab, MD: About 2 months is an important point because it’s going to tell you whether your treatment is working or not. For the last couple of years, I have not treated anyone beyond 4 months with FOLFOX (folinic acid, fluorouracil, and oxaliplatin) or FOLFIRI (folinic acid, fluorouracil, and irinotecan).
John L. Marshall, MD: You’re really backing off at that point? Is there anything magic about 6 months?
Tanios Bekaii-Saab, MD: I don’t think so. We have data from the OPTIMOX study, from the older OPTIMOX trial and from the cumulative data around the OPTIMOX trial, that you really achieve that plateau at 3 months.
John L. Marshall, MD: Three to 4 months.
Tanios Bekaii-Saab, MD: We’re pushing the 4th month as, again, insurance. Beyond that point, I don’t think we’re really benefiting patients. Now, that said, we’re talking about individuals. In some patients who need to go to resection, and they’re getting very close, I can push through another month if they continuously respond. But, for most of the patients in the pure palliative setting—ie, will never be a resection candidate or what have you—I’m really putting the stoplight on the therapy.
John L. Marshall, MD: Does it matter whether it’s irinotecan or oxaliplatin?
Tanios Bekaii-Saab, MD: Both are the same.
Paul R. Helft, MD: I may differ from my European colleagues and perhaps Tony, as well, in that I use oxaliplatin almost exclusively in the first-line setting, along with bevacizumab-based therapy. I never go beyond 4 months of therapy. I stop it and put patients on maintenance therapy at that point, irrespective of their positive response—whether they have stable disease or whether they’ve had a good PR.
John L. Marshall, MD: I hear a lot of people will continue with irinotecan.
Tanios Bekaii-Saab, MD: I’m a FOLFIRI/bevacizumab guy. I used to think that one of the advantages of FOLFIRI is to actually continue it through. But, frankly, I stop at 4 months.
Fortunato Ciardiello, MD, PhD: I agree. I am a FOLFIRI person in most cases, with anti-EGFR or with bevacizumab. But, clearly, we have data from clinical trials showing that every tumor shrinkage, or that the depth of response at the beginning, is what really makes the fate of the treatment in first-line setting.
John L. Marshall, MD: Let’s face it—after first-line, apart from EGFR therapy, there aren’t many responses after that.
Dirk Arnold, MD, PhD: Well, that’s what we have nicely learned from the analysis of the FIRE-3 trial—with the regression over time, we see that after 4 months, it’s done.
Fortunato Ciardiello, MD, PhD: Between 2 and 4 months.
Paul R. Helft, MD: The curve goes flat after 4 months, right?
John L. Marshall, MD: Our advice to our colleagues who don’t necessarily do this all the time, every time, is to stop therapy somewhere around 4 months in.
Fortunato Ciardiello, MD, PhD: In those patients in which I do more intensification with FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan), this is like pushing things to the limit (with this concept). You try to do FOLFOXIRI, maybe for 3 months, and then you do maintenance therapy.
Tanios Bekaii-Saab, MD: I agree.
Paul R. Helft, MD: There’s another lesson. Again, the French have taught us many lessons in this area, but one of the lessons that is not talked about very much in the original OPTIMOX study was the reintroduction of oxaliplatin after maintenance therapy, which was a strategy also employed in the CAIRO study, as well. And that reintroduction has disease stabilization rates of 30% or 40% and re-response rates of 20% or 25%.
Tanios Bekaii-Saab, MD: This is the same with irinotecan.
Fortunato Ciardiello, MD, PhD: With irinotecan, it was the same.
Paul R. Helft, MD: Yes.
Tanios Bekaii-Saab, MD: It’s the same with all these agents we use. That, even further, begs for us to rethink how we treat our patients—to limit exposure because we can get utility again and again and again, without compromising survival but benefiting their quality of life.
Transcript Edited for Clarity