Total Neoadjuvant Therapy (TNT) for Rectal Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepherd, a medical oncologist here at Cleveland Clinic, directing the Taussig Early Cancer Therapeutics program and co-directing the Cleveland Clinic Sarcoma Program. Today I'm very happy to be joined by Dr. Emre Gorgun, vice-chair of colorectal surgery at Cleveland Clinic. Dr. Gorgun was previously on this podcast to discuss Cleveland Clinic's Endoluminal Surgery Center and lesions in the lower GI tract, and to discuss a non-operative organ sparing approach to treating rectal cancer. Those episodes are still available for you to listen to. He's here today to talk to us about better complete response rates with total neoadjuvant therapy for patients with rectal cancer. So welcome back.

Emre Gorgun, MD: Thank you very much, Dale. It's a pleasure to be here with you today.

Dale Shepard, MD, PhD: So, give us a reminder on your role here at Cleveland Clinic. What do you do?

Emre Gorgun, MD: Sure. I'm a colorectal surgeon. I basically treat diseases of the colon and rectum. As many of us know, these are the areas of the lower GI system, lower gastrointestinal system, small bowel connects to colon, large intestine in the right side, and then all the way across the abdomen into the rectum and anus. So, all that field and disease is related to that area is treated by colorectal surgeons surgically, and I'm one of the colorectal surgeons here at the main campus in Cleveland, Ohio.

Dale Shepard, MD, PhD: Excellent. So, we're going to talk about surgery. We're going to talk about some other therapies as well. We're going to talk about some data that was presented at the Digestive Disease Week conference earlier this year about predicting complete responses to TNT, or total neoadjuvant therapy, in patients with locally advanced rectal cancer. So, give us a little bit of an overview. A lot of people might be listening in not familiar with this. What exactly is total neoadjuvant therapy?

Emre Gorgun, MD: Sure, absolutely. I'm happy to share some information about this area. Total neoadjuvant treatment, TNT, is a new approach in the treatment of rectal cancers. We were doing some new adjuvant treatments, meaning we were treating patients before the surgery with chemotherapy and radiation, but only for a short period of time, for five and a half weeks. Then we used to operate on these patients. And then subsequently, we gave them chemotherapy after surgery. So, in other words, five and a half weeks of chemoradiation followed by surgery and followed by chemotherapy. And this whole systematic treatment would take us about four or five months, period. But the downside with this was that after surgery, some of the patients were not optimal in the sense of tolerating chemotherapy agents, like sometimes these toxic medications, if they would have any complications after surgery. So, what we have seen is that as a result of that, the long-term survival rates might be a little bit lower if you would do that type of approach.

So, with the TNT, instead of giving the chemotherapy after surgery, now we started to do this maybe five, 10 years ago now in the United States, we started to give chemoradiation followed by more chemotherapy, which we refer as TNT, or total new adjuvant treatment, followed by a surgical approach if needed.

But at the same time, what we have observed is that when we did that dual treatment preoperatively, we have seen a lot of patients completely responding to this type of approach. And that's actually incredibly satisfying, meaning a lot of patients did not even have tumors left. And as a result, we decided to then put these patients, complete responders, in other words, to what we call watch and wait. So, we would monitor these patients in the long term and make sure that there's no regrowth or that their tumors or the scar site is not changing in any way that indicates their tumor is coming back. So, this type of treatment really allowed us to do a large number of organ preservations. That way, a lot of patients end up keeping their rectums, even patients that would otherwise require permanent ostomies, abdominal peroneal resections, permanent ostomies, permanent bags, these patients were saved, from a functional standpoint, to maintain their intestinal continuity in the normal route. So that's a huge gain.

Dale Shepard, MD, PhD: And so, the data that you had presented gives us a little bit about that collection of patients, what you looked at and what you found.

Emre Gorgun, MD: Sure. We initially started these efforts with the OPRA trial, which was led by Memorial Sloan Kettering, and we were part of the centers that participated in that study. And in this study, there were two arms. One was chemotherapy first, which we called induction chemotherapy, followed by radiation chemoradiation and then possibly surgery. And the other arm was what we do right now, which is chemoradiation, followed by chemotherapy, which is called consolidation chemotherapy, followed by surgery again if needed.

So, this study showed, which is referred to as OPRA trial, that in the arm that patients were treated with chemoradiation first followed by consolidation chemotherapy had a higher rate of response in terms of complete responses. So that led us to look at our own data as well as to do our own study here that included 119 patients. And that was the study that we presented at the DDW last spring. And in that study, with the combination of treatments a little bit of OPRA trial and newly learning how this TNT works really, we reached a complete response rate of 37 percent. So really, a large number of patients responded to chemotherapy and radiation or total neoadjuvant treatment that in close to 40% of patients, we were able to preserve their rectums. So that's a high number in terms of complete responders, and I anticipate that's going to go higher up.

Dale Shepard, MD, PhD: And so that's pretty impressive. So out of every 100 patients, 40 people don't need surgery, maintain a much higher quality of life.

Emre Gorgun, MD: Correct. And more so, we recently are looking for more up-to-date data and our numbers of TNT patients actually now not doubled, but a little over 200 right now. And the complete response rate went up actually over 40. Right now, we are at the rate of 42, 43 percent. But as we get to know better and learn about this, how we can better monitor these patients, I anticipate that this number will even go higher and higher.

Dale Shepard, MD, PhD: So, tell me a little bit about either tumor characteristics, patient characteristics. Are there decisions being made about who might benefit from the TNT approach, who might benefit from a traditional approach? Are these decisions being made based on particular factors?

Emre Gorgun, MD: Absolutely. Currently, TNT is offered across the United States in select centers, of course. Some centers still follow the old pathways in terms of not giving chemotherapy upfront. But generally speaking, this TNT is offered for locally advanced tumors. And what we mean by locally advanced tumors is stage two or stage three, so T2/T3, T3, T4 with no positive patients, so locally advanced patients. So, we don't necessarily recommend this approach for early cancers, meaning T1, T2s, with non-negative patients. Having said that, I think that's an area of further research and because for some reasons like really poor operative risk patients, bad surgical candidates, we have even used this technique in even T2 cancer patients when they are very low located tumors that they would otherwise require absolutely APR or permanent bags. We have a series of close to 10 patients as such that we were 100 percent complete response.

So maybe earlier stage lesions may even respond better, and then you can really preserve them from having a permanent bag, and of course, having much improved quality of life. Having said that, of course, that would also save them from complications after surgery, especially if they are poor operative risk. And what we mean by that is older patients maybe with a lot of heart, lung or liver problems, those patients would not tolerate surgery well. And sometimes, we go out of our pathway and treat them even if they are T2s or really early cancers, with the chance that they might avoid needing the surgery.

Dale Shepard, MD, PhD: I guess when we actually talked about this approach a couple of years ago, one of the things that you had noted was that despite good outcomes, the uptake, the utilization of this type of therapy was a little bit lower than what you might think. Is that improving?

Emre Gorgun, MD: It is improving, but not at the speed that we would like to see. It is, nationwide, I think improved, but we still see a lot of patients that are treated. And I think there's a little bit of confusion out there as well. Sometimes patients receive just chemoradiation and then they are left alone without giving chemotherapy, saying you got complete response by a flexible scope or MRIs, and they don't further give any chemotherapy. That's certainly a misunderstanding of the TNT and undertreatment for our patients. And we sometimes see these patients six months later that they didn't even get the chemotherapy that they needed. And then it's a kind of a puzzle how to treat them. So, I would strongly encourage listeners, if there are any family members with rectal cancer, they need to go to a good cancer center where it's known how to treat rectal cancer with the most up-to-date treatment modalities.

Dale Shepard, MD, PhD: Speaking of modalities, you mentioned endoscopy, you mentioned MRI. You've talked about how after doing treatment, you assess patients and determine who has complete responses and may or may not need surgery. Tell me a little bit about imaging and endoscopy and how you use those modalities to make decisions.

Emre Gorgun, MD: Sure. Absolutely. That was actually part of our study that was presented at the DDW as well. So how can we predict? Because if you're going to do TNT and monitor these patients, it's important that we recognize regrowth or local recurrence or residual disease early on. And so, we need to really monitor these patients like a hawk, very closely. And that includes in our care path, flexible endoscopy as well as MRI, pelvic MRI with rectal cancer protocol.

And I'm proud to state that our radiologists are fantastic and they're doing such a good job in terms of protocoling these patients and recognizing any of the early growth in that segment of rectums. Having said that, this is a very scientific and skilled technique to recognize these patients because there's a lot of fibrosis, scarring, in that area after treatment. And just by itself, radiology is not good enough. So, we really use two modalities together, endoscopy and MRI imaging. And what we found actually is if you look at them both individually, radiology, MRI versus endoscopy, endoscopy is always more sensitive and positive predictive value is much higher. But ideal, and that's our care path as well, ideally, you want to use these both modalities together. And that's what we do, and then we discuss these patients at our multidisciplinary tumor board and make a decision.

Dale Shepard, MD, PhD: If someone's being treated somewhere, they may not have the ability to get endoscopy and MRI, endoscopy would be the preferred single way to look. But ideally both.

Emre Gorgun, MD: Yes.

Dale Shepard, MD, PhD: When we think about factors that might predict a complete response, what have you found?

Emre Gorgun, MD: So, in our study that was interesting finding actually that patients with lower tumors, tumors that are located lower, closer to the anal verge, had a better response. And another factor was, so tumors that were much lower, it's hard to explain this finding, but I think it's a good, interesting finding. That may be patients that would require otherwise permanent bags. Ostomies might be even better candidates for that because they are so low into the sphincter muscles that surgically, it's impossible to shave the tumor away from the control muscles. That was one finding.

And then lack of extramural venous invasion, or EMVI, that's a finding that tumor cells being visible within venous system when they look at the radiology MRI findings. So, this is a very specific finding. It's called EMVI positivity. So, these patients did not respond well. So, these are, I think that it indicates more aggressive tumors. So maybe a little bit less aggressive, lack of EMVI. Absence of EMVI findings were associated with better complete responders in our study. So that was also another interesting finding. That helps us to look at which patients are at higher risk, in terms of responding as well as it helps us to counsel our patients and have a discussion, meaningful discussion with them.

Dale Shepard, MD, PhD: And I guess just to clarify, just to make sure that everyone sort of understands that risk consideration, when you're talking to a patient, you talk to them about this total neoadjuvant therapy, it's really more about their likelihood for a complete response, not whether it makes sense to do a traditional approach. You'd still recommend the total neoadjuvant therapy, it's just about expectations for response?

Emre Gorgun, MD: Correct, correct, correct. Correct. Typically, it's pretty much our routine approach at this time for the TNT, for stage 2 and stage 3 cancers. Unless the tumor is really very high or in the distal sigmoid colon, obviously surgery is the first modality. But if they're going to benefit from chemoradiation, we like to give chemoradiation followed by consolidation chemotherapy. Now, there is some debate around that now emerging recently, whether we should be more selective in choosing these patients or chemoradiation followed by just surgery still might be an option in low-risk patients. But I think more to come on that. I think yes, TNT comes with a lot of cost and healthcare economics perspective, some losses maybe if you think about that because there's going to be MRIs, endoscopies moving forward for five, 10 years. You need to really watch them carefully.

But at the trade-off, you're talking about removing someone's rectum and maybe it might be a little bit less expensive in the short term. But I think it's priceless to maintain somebody's organ. And then there are some studies looking into that from healthcare economics perspective as well, like how many years of life someone would trade off to keep their organ and so forth. And these findings are mind-blowing. So, I think the dollar amounts are really hard to match if you're not going to give TNT. So, I think that's something, that's ongoing research, but I just didn't want to confuse any further here, the TNT subject. But certainly, there's some alternative thought pathway from that perspective.

Dale Shepard, MD, PhD: So, patients go through their upfront chemoradiation, chemotherapy, they may or may not need surgery. But what does surveillance look like?

Emre Gorgun, MD: So, surveillance looks very standardized, and they're drafted out in our center so that every three months we do flexible sigmoidoscopy every three months, and tumor markers, CEA, for the first two years. And every six months we do MRIs. So that's of course, that's what we are talking about, about the healthcare costs. So, there's a lot of studies following that non-operative management. After two years, we're relaxed on that a little bit more, and then we go every six months, flexible scope and monitoring. So, it's not that often. And MRI as well, a little bit less frequent. But we monitor. We like to monitor our patients up to 10 years even until we get more data and can prove that, hey, you don't have to follow these patients after five years or seven years. But for the time being, we still monitor them very closely.

Dale Shepard, MD, PhD: In terms of management of this disease, occasionally there's something that hits the news, and everyone comes in for the next couple of weeks talking about it. There's a study a year or so ago, immune checkpoint inhibitors. Highly selected group of patients with rectal cancers that happen to have mismatch repair issues and where everyone had a complete response. Back to patient selection, where do you guys incorporate things like genomic testing and things to look for those rare patients that might benefit from immunotherapy?

Emre Gorgun, MD: Yeah, that's an excellent point. This group of patients is not large, but certainly there's a group of patients that have a mismatch repair gene present or absent. And in these groups of patiently immunotherapy or targeted treatment modalities are highly effective to the point that, as you said, close to 100 percent response rates. And when we identify patients like that, we have an ongoing trial right now that we assign these patients to these studies that instead of the chemotherapy arm, after chemoradiation, we do give them the targeted treatments.

Dale Shepard, MD, PhD: That's excellent. So, lots of reasons for optimism for patients with locally advanced rectal cancers for new therapies that are highly effective. And appreciate your insight today.

Emre Gorgun, MD: Thank you very much for having me. No doubt that's the case. And I really strongly encourage our patients to research, research, research and just get another opinion if they have any doubt about the suggestions or recommendations that they are getting. Again, thank you Dale, for having me today, and always pleasure talking to you.

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