Neoadjuvant Strategies for Rectal Cancer

Transcript: John L. Marshall, MD: Let’s close out our discussion by really focusing on what I like to call the Wild West of rectal cancer. I remember the day when you didn’t really move standard of care without really thoughtful and sometimes repeated randomized clinical trials. And what seems to have happened, for me, is we’ve gone from everybody gets neoadjuvant chemoradiation to now lots of people are getting frontline chemotherapy, and maybe some radiation and surgery. So everything is front-loaded. And we’ve done that based on institutional experiences. We don’t have big data out there. Joleen, you get to set the stage for this. So discuss this transformation that’s happened in what is the standard for rectal cancer today.

Joleen M. Hubbard, MD: If you go by the textbook, the current standard would be concurrent chemoradiation therapy with a fluoropyrimidine followed by surgical resection, followed by 4 months of adjuvant therapy, based on their pathologic stage. I think we have 2 trials.

John L. Marshall, MD: And that’s still right.

Joleen M. Hubbard, MD: That’s still right.

John L. Marshall, MD: Is everybody OK with that? That’s still right.

Christopher Lieu, MD: Yes.

Joleen M. Hubbard, MD: It’s still right. But, you’re right. The trend has been to move the treatment up front—to start with a systemic therapy as kind of an induction therapy, then move on to concurrent chemoradiation therapy. And we’ll see an abstract from ASCO GI [Gastrointestinal Cancers Symposium] 2019, at this meeting, showing that we could use short course radiation therapy in this setting. It looks comparable to the long course. So it’s hypothesis-generating. And we actually have 2 great clinical trials looking at this neoadjuvant approach. We have the PROSPECT study, which is the higher-up rectal tumors, looking to see, if we do oxaliplatin-based therapy up front and they have a good response, can we omit radiation therapy?

John L. Marshall, MD: Let’s put the radiation doctors out of business. We’re the ones taking care of the chronic pelvic syndromes, right? And so, if this was really going to happen, this would be great. Now that study just finished accrual, I think, too, right?

Joleen M. Hubbard, MD: I believe so, yeah.

John L. Marshall, MD: Now we’re watching the clock.

Joleen M. Hubbard, MD: It’s a really good study because it randomized it to standard of care versus a neoadjuvant approach. So I think it’s a very well-designed, very clean study. The other exciting study is the TNT study. That’s been a great study to enroll to, and patients are getting the systemic chemotherapy up front.

John L. Marshall, MD: So that’s 6 rounds of FOLFOX? Isn’t that what’s going on in that study?

Christopher Lieu, MD: Four months.

John L. Marshall, MD: Four months. So 8 doses and then chemo-RT [chemoradiotherapy]?

Joleen M. Hubbard, MD: And then chemo-RT.

Howard S. Hochster, MD, FACP: With a novel agent.

Joleen M. Hubbard, MD: Yes. And so they’re randomized now to get, potentially, in the latest amendment of the trial, immunotherapy with radiation therapy.

John L. Marshall, MD: Is that trial also the middle and upper cases, or does that let the lowers in?

Joleen M. Hubbard, MD: Actually, it encompasses all patients. Since we have both trials open at our institution, I save the upper ones for PROSPECT and the lower ones for TNT. But I think, also, again, it’s a very well-designed study that’s going to give us a lot of very good clean data to suggest that this is the approach. What I am hopeful for is that the systemic therapy up front reduces the distant metastasis rate because that’s really what kills people. The local recurrences are fairly low. It’s that metastatic disease that is life-threatening.

John L. Marshall, MD: Our surgeons have gotten better at mesorectal excisions. Chris, do you look at them differently—low, middle, and high?

Christopher Lieu, MD: Well, we obviously worry about the low rectals. We kind of worry more about pelvic recurrence in that situation. And then we also encourage, obviously, radiation, as we do for all our patients. For high rectals, you should see the debates that we have at our multidisciplinary clinics. Should they receive up-front chemotherapy, or chemoradiation? Can we take them to surgery?

John L. Marshall, MD: In a 12-cm up tumor, is that…

Christopher Lieu, MD: This is where having a multidisciplinary team is critically important, so you can argue about this to the benefit of the patient. This is where your radiologic imaging is just key. And this means not only getting a high-quality MRI [magnetic resonance imaging] but having a radiologist that specializes in reading pelvic MRIs. And so I think that in the absence of data, and hopefully we’ll have some more with PROSPECT, this is not a clear situation.

John L. Marshall, MD: But your point is that we’re not agreed, right? We don’t have enough evidence to say what is right or wrong, and so it comes back to our transmitting all this information to patients who are going to, at the end of the day, say, “What do you think I should do, doctor?” Joleen?

Joleen M. Hubbard, MD: I think there a couple of other important points for this neoadjuvant therapy. Number 1, If we do everything up front and the patient has lower anterior resection with a diverting ostomy, they’re done with their treatment. And so they can reverse that ostomy much more quickly than we did in the past. And I think that will be a very big life changer. So I think that’s another very important thing.

The other thing is the nonoperative management for patients. We’re seeing more and more data coming out showing that this can feasibly be done for patients who would otherwise have to have an end colostomy if they have a complete clinical response. And I think a total neoadjuvant approach. We have some data to show we are increasing the complete clinical response for these patients. And then, could they feasibly watch and wait with very strict surveillance? I think it’s feasible.

John L. Marshall, MD: I hate these patients. I hate watching them. I’m so nervous.

Howard S. Hochster, MD, FACP: I think the 2 big issues for rectal cancer today are not operating on the low rectals that would require APR [abdominoperineal resection] and short-course radiation because it’s only 5 days, and you don’t have to give it with chemotherapy. So I think those are the big questions. Personally, I’ve followed quite a few people with the surgeons at Memorial Sloan Kettering Cancer Center who have gotten chemotherapy up front and then chemoradiation. And if they have a CR [complete response], they’re watched. That’s not really what we’re talking about with total neoadjuvant therapy, because they’re not getting surgery, they’re getting watch and wait. And I think that that is feasible, as long as the surgeons know what they’re doing and the surgeons are willing to scope the patients. I trust the people who really do this every day and know how to do it, and they’re the surgeons who are actually doing the flexible sigmoidoscopies or whatever they have to do to follow them. So I think that’s a very important step forward in rectal cancer.

John L. Marshall, MD: Sort of like high-risk head and neck patients, where you’re sitting and waiting for it to come but you’re trying to save them.

Christopher Lieu, MD: So there will be data presented at the 2019 GI ASCO symposium. There is already retrospective data looking at fairly large case cohorts. It’s pretty remarkably similar when you look at the data. The local recurrence rate is somewhere around in the 20% range, and a vast majority of these patients, 85% to 90%, are going to go on to a salvage surgery. So that should give you at least a little bit more comfort that with a 20% local recurrence rate, a majority of those patients are going to then go on to surgery. There’s also, in these studies, somewhere between a 5% to 10% metastasis rate, right? So that also gives you some pause. If we had gone on to surgery, were those distant metastases already there, or was that something that kind of developed over time?

Tanios S. Bekaii-Saab, MD: Which is very unlikely, right?

Christopher Lieu, MD: And I completely agree with that.

Tanios S. Bekaii-Saab, MD: So there is more comfort with metastatic disease.

Christopher Lieu, MD: That it was there.

Tanios S. Bekaii-Saab, MD: Exactly. It probably is there and is not the result of the fact that they didn’t get.

Christopher Lieu, MD: But when you think about a 20%, 22% local recurrence rate without doing surgery, that’s still very, very good.

John L. Marshall, MD: But it’s also sort of backward.

Howard S. Hochster, MD, FACP: Three out of 4 people don’t really need the surgery. That’s the people who have a biopsy-proven, clinical complete response, and they need really close follow-up.

John L. Marshall, MD: I guess that’s the selection bias, but if you look at the data that are out there, the pathological CR rate from surgery series is 20%, 30% at most. So maybe in this selected patient, that number, when there are clinical CRs, is a higher percentage.

Tanios S. Bekaii-Saab, MD: Yeah. You’re selecting the selected. I think the key point from this discussion is that you cannot just do it anywhere. You have to do it at a very highly specialized center that knows what they’re doing. They know how to follow-up. You have dedicated surgeons and dedicated oncologists. These patients can have horrible recurrences if you don’t do the right things. They won’t die from it, but they will die miserably, and that’s the worst part. So we want to avoid the misery of having to live a lifetime with diarrhea and with an ostomy. At the same time, we want to also make sure that our patients don’t end up dying miserably with a rectal tumor that’s just eating up their bones, and muscle, and blood vessels, and all that good stuff.

Transcript Edited for Clarity