Evolving Strategies for Advanced Colon and Rectal Cancer - Episode 4

Recent Clinical Trial Data in Locally Advanced CRC


John L. Marshall, MD: Well, we actually do have some data. We all have used the word chemotherapy carefully, and not specifically which drugs or how much of the drugs. Wells, why don’t you start. There’s the PETACC-6 update that’s being given at this meeting. Quick summary of what that showed?

Wells A. Messersmith, MD, FACP: Absolutely. So, this is one of the largest rectal trials that’s being presented at the meeting, and it had over 1000 patients. And they either received oxaliplatin or not following chemoradiation. What was interesting is that overall, the trial was negative, so it’s sort of a check in the minus column of using oxaliplatin in the setting of rectal cancer. But what’s interesting about it is in subgroup analysis, they found that the addition of oxaliplatin had a trend toward harming German patients and a statistically significant benefit for non-German patients. Of course, we see some of these issues in many of these multinational trials or global trials. You and I have seen that pendulum swing back and forth a few times in terms of should trials be global and how applicable results are in certain populations.

But it’s interesting to me that in the non-German patients, the hazard ratio was around 0.65, whereas in Germans, it was greater than 1.3. So, as someone who went from a Messerschmitt to a Messersmith, I’m not really sure what to do. My whole world is changing because now I found out I have to get a colonoscopy too. It’s been a rough week for me, and I’ll do my best to move on.

John L. Marshall, MD: I have been a minimalist. I think as you get older, you get less aggressive, I would think, in terms of treatment, particularly in the adjuvant setting. And I’ve been not using a lot of oxaliplatin at any point in rectal cancer. Preoperatively, I tend to use capecitabine with some radiation. Postoperatively, I haven’t been convinced that there is a role for oxaliplatin in this subgroup of patients regardless of age, except in that patient Bert sort of alluded to. If they didn’t downstage or if they didn’t really respond very well, I might throw in some postop based on nothing, but when I read this result, I’m like, “OK, then I’m feeling good, this is good.”

Wells A. Messersmith, MD, FACP: Right. Yes. I should have pointed out, they also found some trends of patients who had that higher risk. So, for less tumor regression or multiple nodes, there seemed to be some benefit.

John L. Marshall, MD: So, it justified that practice pattern that was being used in patients. Marwan, on the other side, there were a couple of other studies looking at oxaliplatin in different roles. You want to review those couple of studies?

Marwan Fakih, MD: Sure. I think one important study that’s being updated is the ADORE trial. I think one thing that is unique about this study is that it’s looking at those patients who don’t downstage well, right? Because it’s looking at patients with YT3 tumors with nodal-negative disease or any nodal-positive disease. And we know that those patients, following chemoradiation, don’t do well. They have a higher risk of relapse, and those patients were then randomized to receive either fluoropyrimidines alone or to receive FOLFOX. Interestingly, on that trial, there has been a significant improvement in disease-free survival in favor of the oxaliplatin arm with more than 10% absolute improvement in disease-free survival. I think this is, in a way, nice to see. It’s a small study. It’s a large randomized phase II, but for those of us who make a case for oxaliplatin in the postoperative setting, at least for those patients, they do not downstage well with chemoradiation. I think that is something that supports the use of oxaliplatin in the postoperative setting.

John L. Marshall, MD: And so I think about that. The issue is that if you’ve given preoperative chemotherapy/RT, you don’t have a Mediport, then they have surgery, then you’ve got to put a Mediport in and give them some OX-based therapy. I think that’s what that’s telling me I have to do in that patient. Is that the way you interpret it?

Marwan Fakih, MD: I think so. I think those patients, clearly, are getting fluoropyrimidine with radiation, they’re going to get Xeloda (capecitabine), so your port is going to be postoperative, and then they will get 4 months of intravenous chemotherapy.

John L. Marshall, MD: The other study, the Chinese study?

Marwan Fakih, MD: Yes. The FOWARC trial is a randomized phase III trial, but it’s a small randomized phase III trial, and that’s looking at 3 different strategies: fluoropyrimidine plus radiation versus fluoropyrimidine/oxaliplatin/radiation versus FOLFOX alone. And all 3 arms are followed by surgery. And that study, interestingly, did not show any difference in disease-free survival or overall survival. I think what’s so interesting about that trial is that the overall survival is actually quite good. At 3 years, all the arms had more than 90% overall survival. I still don’t know what to make of that study because all the radiation arms are not conventional chemoradiation arms. Everybody got about 3 months of chemotherapy, and you’ve incorporated the radiation with those 3 months of preoperative chemotherapy. And then the fluoropyrimidine arm was also not a continuously, protracted continuous infusion arm, so it’s also not the typical treatment we do.

But what’s comforting is that the FOLFOX arm did well and without radiation, which basically supports looking at that strategy of no radiation. There wasn’t any higher risk of recurrence in the FOLFOX arm. The local relapse rates were the same. You would expect radiation to reduce local relapse, and the overall survival was good. So, I think that’s a point for neoadjuvant chemotherapy without radiation to support looking at that strategy further.

Transcript Edited for Clarity