Evolving Strategies for Advanced Colon and Rectal Cancers - Episode 14

Adjuvant Therapy for High-Risk Colon Cancer

Transcript: John L. Marshall, MD: There’s a little bit of adjuvant data that was presented at ASCO GI [the Gastrointestinal Cancers Symposium] this year. Joleen, review that for us.

Joleen M. Hubbard, MD: Yeah. So this was a Japanese study, and what it looked at was using S-1 in combination with oxaliplatin, versus using fluoropyrimidine alone. This is essentially repeating the adjuvant studies that have already been done in the cooperative group. What they saw was that overall, there was no significant benefit from adding the oxaliplatin to the fluoropyrimidine for stage III disease. But what was interesting is when they broke it down, the patients who did appear to have some benefit were those high-risk patients we’ve been talking about—the T4 lesions, the N2 disease. Those patients appeared to have some benefit compared with the lower-risk patients. So I think this study actually kind of confirms the IDEA trial, that we know we need to have a more intense regimen for those patients with higher-risk features.

John L. Marshall, MD: Tony was saying, too, that in even that stage II patient, where you’re justifying bringing in oxaliplatin, this is sort of supportive of that as well. Howard?

Howard S. Hochster, MD, FACP: I just want to point out that that study used 2 different oral fluoropyrimidines that are available in the rest of the world and not in the US, and they’re better oral fluoropyrimidines than capecitabine. UFT, which didn’t quite make it to the market here, and S-1, which again because they were both developed in gastric cancer, did not make the grade for FDA approval, even though the rest of the world found that they were approvable. It’s unfortunate.

John L. Marshall, MD: So I live in Washington, as you guys know. It is 1 of the places that’s a hotbed for HIPEC [hyperthermic intraoperative peritoneal chemotherapy], or debulking peritoneal surgery. And I think this pendulum, in my long career, has swung back and forth from enthusiasm at the beginning to dampened—just risky, not benefit—to now people are doing this a lot. Surgeons are really good at this. There are a lot of highly skilled surgeons doing it. So I think collectively we sort of believe that the surgery has a role, but they’re throwing the chemotherapy in and that’s our world, right? So what are those guys and gals doing throwing chemotherapy in? Are there any data that says we should or shouldn’t, Howard?

Howard S. Hochster, MD, FACP: I’ve given a lot of intraperitoneal chemotherapy in my career for ovarian cancer, and for gastric cancer, and some for colon cancer with FUDR, mainly for the GI [gastrointestinal] tumors. I think it’s probably not too effective. I don’t think warming it up and pumping it around for 2 hours is going to make any difference.

John L. Marshall, MD: So we have a study, right?

Howard S. Hochster, MD, FACP: All of the studies that looked at HIPEC really look at IV [intravenous] chemotherapy versus surgery plus the intraperitoneal treatment. It’s the surgery that really makes a difference, in my opinion. There’s no good study of surgery debulking with or without HIPEC, and that’s what we need. The problem is, once people invest in HIPEC, they kind of create the need to do the HIPEC, and it is really not supported by level 1 evidence.

John L. Marshall, MD: Any data?

Joleen M. Hubbard, MD: Yeah. As we have seen in abstracts—there was 1 from ASCO [the American Society of Clinical Oncology Annual Meeting] last year, as well as 1 from ASCO GI this year, from this meeting—both studies did not show a benefit to adding the intraperitoneal chemotherapy beyond surgery, itself, compared with using systemic therapy. So at our institution, we have actually stopped giving the…

John L. Marshall, MD: You are so responsible. Because ours are like, “No, they used the wrong drug,” right? They used oxaliplatin and whatever.

Tanios S. Bekaii-Saab, MD: But I think it’s important to just make it very clear that there are still some patients who may benefit from HIPEC.

John L. Marshall, MD: The surgery with chemotherapy, right?

Tanios S. Bekaii-Saab, MD: So let’s separate this into cytoreductive surgery, chemotherapy, and then heated chemotherapy. So the cytoreductive surgery itself works. It helps those patients that are eligible for it. But the HIPEC…I totally agree that for patients specifically with high-grade cancer, HIPEC does not add much value. We don’t see that. We don’t see it anywhere. For the low-grade malignancies, there’s a question mark that remains. I think for those patients, HIPEC may have a better role.

John L. Marshall, MD: My theory on this has always been that it wasn’t the actual chemotherapy. You were sort of preventing regrowth locally. You are disrupting the bed in some way.

Tanios S. Bekaii-Saab, MD: Who knows.

John L. Marshall, MD: Because PK on this is terrible.

Tanios S. Bekaii-Saab, MD: The key is with the high-grade tumors, why do you need local? Systemic seems to do the job. The lower-grade tumors have zero response to chemotherapy, and it’s hard to believe that if you put it in the belly it’s better. Maybe it’s actually the solution. Maybe it’s something else. We published a manuscript a while ago that essentially looked at 3 institutions’ experiences. One didn’t have access to HIPEC. The other 2 did. And again, adjusting for a lot of factors, HIPEC did seem to add value for patients with low-grade appendiceal tumors versus the institution that didn’t. We didn’t name the institutions, so as not to shame anyone.

John L. Marshall, MD: You could also talk about the quality of the surgery and experience.

Tanios S. Bekaii-Saab, MD: For most patients, to Joleen’s point, we jump too quickly into HIPEC. We should take a step back and really assess whether this is the right patient or true patient. At this point of time, there’s no blanket statement, except that if you want to use it, you really have to have some level of data that support it.

John L. Marshall, MD: Chris, it’s not like the surgeons are calling and asking whether they should give chemotherapy. They’re just doing it if they want. But if they were to call, what would you tell them?

Christopher Lieu, MD: I’d say no. I agree with what everybody has said on this panel. The cytoreductive surgery and the quality of the cytoreductive surgery is seriously what is key. When you look at the PRODIGE 7 study that was presented at ASCO, the overall survival benefit of over 41 months for those patients who have peritoneal disease is incredible. Of course, those 2 arms, whether you got HIPEC or not, were exactly the same. The problem with HIPEC is the morbidity of it. We see that on the medical oncology side. When patients have peritoneal sclerosis or they have like these just horrible, horrible [adverse] effects from this treatment that probably really doesn’t give them benefit outside some few instances of low-grade appendiceal cancers or something like that, I would definitely recommend not to give it. And my surgeons joke that they can now go home 2 or 3 hours earlier.

John L. Marshall, MD: Yeah. The control arm, then, should it be going forward, just the quality of the cytoreductive surgery in the experimental arm as adding something?

Howard S. Hochster, MD, FACP: I think that should be done, but, again, there are a couple of issues with it. One is the pharmacologic advantage of giving the drug in a region compared with systemically. So that’s really high for FUDR, a little bit for platinums, not so much for Taxol—yet Taxol is the 1 drug that really works in that ovarian cancer if you give it intraperitoneally [IP]. So that is really hard to understand. But also, the patient needs to really have optimal debulking. It only really gets a couple of cell layers down into the surface. So if they still have gross disease left, it probably doesn’t pay to do intraperitoneal anything.

Tanios S. Bekaii-Saab, MD: So IP and HIPEC are different, to make that very clear. Giving chemotherapy intraperitoneally is…

John L. Marshall, MD: More continuous or chronic.

Tanios S. Bekaii-Saab, MD: HIPEC is the shake and bake.

John L. Marshall, MD: That’s what we called it.

Tanios S. Bekaii-Saab, MD: But it’s really, you put the solution in, you heat it to 42 [degrees centigrade], and then you just shake. That’s all that it is. It’s not really administering effective chemotherapy. On another note, this study used oxaliplatin, whereby the standard is really mitomycin C.

John L. Marshall, MD: Something different.

Tanios S. Bekaii-Saab, MD: I don’t know if there’s a difference, but this is a little different than the experience that we’ve had, at least with the appendiceal cancer.

Transcript Edited for Clarity