John Marshall, MD: Dustin, as the expert on the panel, talk a little bit about the changing paradigms around rectal cancer and this idea that some people are not even having surgery. Can we get away with a no-radiation, chemotherapy-first approach? Give us your thoughts about where this is going.

Dustin Deming, MD: The treatment for rectal cancer is really evolving and has changed substantially just in the last few years with more centers going to a more complete or total neoadjuvant approach. This is driven largely by the fact that when we undergo chemoradiation up front followed by surgery, only a small fraction of those patients can complete all of the intended therapy. It’s about 60% of the patients who actually get the adjuvant therapy that you would want them to have. By moving the chemotherapy into the neoadjuvant setting, similarly to what has been done in many cancer types—and actually, neoadjuvant chemotherapy has never been inferior to adjuvant therapy—the major benefit is, you get your therapy in. What our patients really like is, if you need a temporary ostomy for rectal cancer, it’s only 6 to 8 weeks with your temporary ostomy, as opposed to 4 to 6 months with the adjuvant approach.

John Marshall, MD: Yes. There’s some new data coming out around these total neoadjuvant approaches. We have a randomized study, but PROSPECT won’t report for another year or 18 months, at the soonest. I think a lot of us have adopted this kind of strategy, even in the absence of data other than experience data. Has anybody got thoughts on whether it’s OK to start doing this? I’m hearing surgeons talk about watchful waiting. It makes me so nervous, this watchful waiting approach. I don’t mind the no-radiation approach if, in fact, you have a nice response preoperatively. Cathy, what are your thoughts on applying this momentum today?

Cathy Eng, MD: I agree that the total neoadjuvant approach is actually intriguing, and obviously we’re going to be discussing some of the data. I think surgeons are less concerned about proceeding in that fashion. They’re more comfortable now, because it may potentially reduce the tumor burden. In regard to just watching and waiting, I think all of us would like a more formal study across all the institutions and across the network groups to support that initiative, because patients want sphincter preservation if it’s possible. We just need to have concerted effort to do so. Other groups are coming up with that, and obviously no radiation is great for a lot of patients, if we could avoid it.

John Marshall, MD: Tony, talk about this FOxTROT trial and this idea of giving complete preoperative therapy in patients.

Tanios Bekaii-Saab, MD: I have a few problems with this study. What this study essentially is, is exploring the idea of moving treatment neoadjuvantly for colon cancer, which is something that US investigators were interested in, but we have never agreed on how to proceed best with it.

John Marshall, MD: Sort of stealing a page from the breast cancer doctors, right?

Tanios Bekaii-Saab, MD: This study, unfortunately, was negative in terms of the statistical piece, although there were hints that there may be a slight advantage for moving chemotherapy neoadjuvantly. The 1 thing that makes me a little puzzled about that study is, when I look at the incomplete resection rate, it was 5% to 10% of the patients. I, frankly, have never had a patient with colon cancer who actually had an R2 resection, or lo and behold, an R1 resection for the true colon. I’m not very clear about some of the entry criteria points. Overall, what that tells us is that it’s worthy of exploring, or continuing to explore, to move chemotherapy to the neoadjuvant setting. However, in actual practice for colon cancer—this is not rectal—surgery first is preferable.

John Marshall, MD: Everybody OK with that?

Cathy Eng, MD: I thought it was really interesting from that trial how little regression of the tumor was noted pathologically.

John Marshall, MD: Downstaging was much less than we would have predicted, right?

Cathy Eng, MD: Yes, I was so surprised.

John Marshall, MD: Yes.

Tanios Bekaii-Saab, MD: Pathologic complete response was 4%.

John Marshall, MD: Yes, but there’s a patient I’m treating right now who had a big tumor and has a little bit of obesity going on with it, and the surgeon would….

Tanios Bekaii-Saab, MD: Was nervous.

John Marshall, MD: He would like to give a little chemotherapy first, so this study maybe lets me say I can do that without losing any significant ground.

Tanios Bekaii-Saab, MD: Absolutely.

Cathy Eng, MD: Right, it doesn’t impact the surgery, it sounds like.

Tanios Bekaii-Saab, MD: No. I think what that tells you is that we have these patients where the surgeon is nervous about the operability of the patient—not as much as resectability, because resectability is relatively clear—like your obese patient or those with comorbidities. Let’s give the patient a little test for their biology and test for their operability. I think it’s reasonable. That tells you you’re probably not going to lose benefit.

John Marshall, MD: Mike, you have a great multidisciplinary team down in Durham. For a new patient with a mid-rectal cancer that looks node-positive with no open trial at the moment, what’s the strategy on that patient? Make him a 60-year-old person. What’s the general strategy?

Michael Morse, MD: I think we have a lot of interest in the TNT [total neoadjuvant therapy] strategy. The questions that are being asked are, is radiation necessary? Is a short-course radiation appropriate here? In which order should we give the therapies? Traditionally, people have talked about giving the chemotherapy and then following with chemoradiotherapy. In fact, there’s some data that would suggest chemoradiotherapy first, followed by the chemotherapy, and then surgery, might be more advantageous.

John Marshall, MD: So not much consensus? Are you pretty much saying, “I’m going to go chemotherapy first?” What if the surgeon has got him booked in the OR [operating room]? They don’t go there.

Michael Morse, MD: These concerns come up in terms of time until surgery and surgical rates of complications, and so on. Those discussions do come up. I would have to say, if there are any surgical concerns, that usually trumps all the other concerns in that patient, obviously, unless we’re going to totally do a watch-and-wait strategy, which is very difficult to do. It sounds good in principle, but you’re really talking about surveillance. People have to come back and be evaluated.

John Marshall, MD: I hate it.

Michael Morse, MD: Yes, it’s very demanding on everybody.

John Marshall, MD: What’s the path CR [pathologic complete response] rate—25% or 30%? That means a high proportion of patients are going to have relapse, right?

Michael Morse, MD: Yes.

John Marshall, MD: You do save some people the surgery, but it makes me so nervous. This has just been a great discussion.

Cathy Eng, MD: It makes me nervous.

Michael Morse, MD: Yes.

John Marshall, MD: Well, that’s my point. I’m always surprised it’s the surgeons who are starting this conversation with patients.

Cathy Eng, MD: I think the patients really are seeking that type of consideration. It’s been going on for years in Brazil, right?

John Marshall, MD: Yes.

Tanios Bekaii-Saab, MD: Dustin may have a perspective on this.

John Marshall, MD: Yes, he may have a perspective on this.

Dustin Deming, MD: I think the FOxTROT trial and the watch-and-wait approach both highlight that one of the major issues here is inadequacy of that clinical staging. If we really knew which patients had a true path CR, then a watch-and-wait approach might be better. There are data now that if you compare those patients with a complete clinical response to patients who’ve had a pathologic response, the disease-free survival is remarkably worse with the watch-and-wait approach, which really makes me nervous about attempting this approach outside of the clinical trials.

Transcript Edited for Clarity