Non-operative management of rectal cancer: Dr. Smith (2021)

Manju George  0:00 
Hello, everyone. I am Manju George, the Scientific Director at Paltown Development Foundation, the nonprofit that supports Colontown. Welcome to today’s DocTalk. And we have with us Dr. J. Joshua Smith, a surgical oncologist from Memorial Sloan Kettering. Dr. Smith finished his MD at the University of Texas Medical School at Houston, and then completed a PhD in cell and developmental biology from Vanderbilt University Medical Center, and then finished his general surgery residency there, and then joined MSKCC and completed his complex surgical oncology fellowship there. We are really excited to have you with us today. And I think lots of people in Rectalburgh already know you from the OPRA Trial. So thank you so much for making this time to talk to us.

Dr. Joshua Smith  0:53 
Great, Manju. Thanks for inviting me. Thanks for the kind introduction. And welcome to everybody who’s on. And I think we’re recording this as well. So people can take a look later as they have time. So I’ll just cover what I think is an increasing problem as it relates to rectal cancer. The issues that I think are important for patients with rectal cancer and then talk about my perspective related to TNT, watch and wait, give you my input as it relates to the OPRA Trial and what’s next.

Dr. Joshua Smith  1:26
Here are some of the abbreviations that I’ll use throughout my talk ad then my Disclosures. So how do we treat rectal cancer and locally advanced rectal cancer in 2021?

Dr. Joshua Smith  1:38 
So I’ve made a slide of what I think kind of sums up the NCCN Guidelines. And these, of course, have changed recently, with the advent of short course introduction relative to the RAPIDO Trial, which I’ll talk about, then, of course, I’ll talk a little bit about long course radiation later and what that means in the context of total neoadjuvant therapy, but we know this is an important problem with almost 44,000 cases documented in 2021. Locally advanced rectal cancers is essentially T3N0 or any T, node positive tumor or a T4 tumor. And these can be treated with chemoradiation, followed by radical resection, and then adjuvant therapy surveillance, or this idea of total neoadjuvant therapy, which is chemotherapy, chemoradiation, followed by radical resection, and then surveillance. Chemoradiation can take on the form of long course or short courses which we’ll talk about later. So what are the challenges remaining in rectal cancer? Of course, we want to reduce the risk of distant metastasis, preserve quality of life, and it would be nice to identify those people who are going to respond to these treatments so we can make treatment more individualized. The real problem here is that we see this big increase in patients less than 50 with rectal cancer.

Dr. Joshua Smith  2:54 
You see this sharp increase in the black line here. And our patients look more like this. So things at risk are their GI function, their GU function, obviously, sexual function, people are in their prime of life. So the patients aren’t, you know, 60, 70, 80 years old anymore. They’re in their 30s and 40s and some even in their 20s. We do know that radiation is the primary form of treatment for rectal cancer. This has been the case for almost 100 years.

Dr. Joshua Smith  2:54 
This is a paper from Annals of Surgery from our group at MSK. This is the first Chief of Colorectal Surgery. And you can see that one of the statements from this paper is we prefer to use radiation therapy as a principal factor treatment for rectal cancer and supplement with surgery in the cases in which interference may provide an advantage. So radiation has been around for a long time.

Dr. Joshua Smith  3:45 
This is a text from one of my patients so you can see how it makes people feel. I think this is self explanatory.

Dr. Joshua Smith  3:53
So we did a paper a few years ago that showed that certainly neoadjuvant radiation, I think this sums up a lot of data in a number of other papers, but that neoadjuvant radiation certainly does impair bowel function. And we know that by looking at patients who’ve received neoadjuvant radiation versus those who got treated with chemotherapy alone, no differences in bowel function scores with chemotherapy alone. And we know that the closer you get to the anal verge plus adding radiation, that your bowel function gets worse. So if you add in surgery plus radiation and you get closer to the anal verge, of course your bowel function scores are going to be worse. We know from looking at recent trials, for example the NSABP R-04 Trial where they added in Oxaliplatin to chemoradiation, that patients had more toxicity either with 5FU or capecitabine and then, of course, when we looked at the IDEA Trial, three months versus six months, there’s significant differences in peripheral neurotoxicity if you do six months versus three months of FOLFOX or CAPOX. So these are important things to know. We know that consequences of radical surgery are real with permanent stoma in 30% of the patients. Of course, mortality, even in this day and age, can be an event. We’re better with surgery in many ways, but these things are still things that patients can face with anastomotic leak, wound infection, bowel obstruction, hernia, I talked a little bit about and I alluded to sexual dysfunction for both men and women, problems with defecation, the LARS Syndrome, urinary incontinence, all these things can affect patients.

Dr. Joshua Smith  5:34
So how have we impacted our patients locally advanced rectal cancer? Well, we know that we have excellent local tumor control based on a lot of gold standard randomized controlled trial data which I’m not going to go into in detail, but with chemoradiation, we have good pelvic control. However, treating with chemoradiation and radical surgery, we know there’s a lot of morbidity, as I’ve alluded to in my prior slides, and there’s variable tumor response, meaning some patients have a dramatic response. Others don’t have as dramatic of a  response, and this can affect both oncologic outcomes and their clinical and patient reported outcomes. So do all patients require this aggressive approach of chemoradiation, surgery, and then also chemotherapy? Could we potentially accomplish more with less? And, you know, do I always need to take out a rectum if I see this? What if the tumor disappears after chemo radiation.

Dr. Joshua Smith  6:35
So, for example, this rectum on the right lower, do I always need to take this out to show and to prove that there’s no tumor there? Because we know that radical surgery has toxicity. And then if I see this where there’s no tumor in the pathologic specimen, we know that the outcomes are quite good with 85 to 90% disease free survival rates. Now path CR does not always equal a clinical complete response, meaning no tumor on endoscopy or digital exam. But nonetheless, this brings up the point, do we always need to take out the rectum? Is an operation always necessary? And this idea was, of course, pioneered by Professor Habr-Gama, from Brazil, where she showed in this seminal Annals of Surgery paper that clinical complete response was associated with possible cure, that you could defer surgery, and that if somebody did have a local regrowth, that you could salvage them, and that these patients, when you compare their overall survival, there’s no significant difference between those who had radical surgery and had a pathologic complete response versus those who had a clinical complete response. Now, they’ve gone on almost 14 years later in a International Watch and Wait Database to show that this idea can be done in multiple different centers. So this is 1000s of patients across multiple different centers showing that the tumor regrowth rates are still in that 24 or 25% range, overall survival is quite good. But that there are local regrowths and it’s difficult to say about salvage surgery in this International Watch and Wait Database. We know that the patients with local regrowths have a higher rate of distant metastasis in this database. We’ve also seen that and I’ll show that in a little bit.

Dr. Joshua Smith 8:22 
But recently they’ve updated this and I think of relevance to our patients that are younger. And they always ask is watch and wait a good idea in patients that are young? And this is a recent look at that in their International Watch and Wait Database. They looked at those who are less than 50 versus greater than 50. And interestingly, no differences in local regrowth rate, and also overall survival, distant metastasis free survival, they didn’t see any differences. So I think this is an important database. And something that’s worth looking at, although there’s certainly limitations with missing data and some other things that you can’t get away from when you look at database analysis.

Dr. Joshua Smith 8:59 
So what about our experience? So this is our JAMA Oncology paper from a couple of years ago, where we looked at off protocol patients, not on trial, but patients who had radical resection and were found to have a path CR in parallel to those who are managed on a watch and wait protocol, who had a clinical complete response. We see about a 21% local regrowth rate, the overall disease specific survival was quite good at 90%. And if those patients had a local regrowth, more than 90% were able to be safely salvaged with either TME and very few with local excision. And you can see that the vast majority are able to have a sustained clinical complete response or organ preservation. We did see in this series that if you had a local regrowth, you did have a higher rate of distant metastasis, which I think is quite similar to what they showed in the International Watch and Wait Database. We’ll look to the the prospective data that’s upcoming to see if this is going to pan out in the prospective series.

r. Joshua Smith 9:54 
This is how we follow patients who are managed by watch and wait, both on and off protocol, every four months the first year, and the second year, six month MRIs and in years three to five, we start to space things out, you can see six and 12 month intervals. And at year five, we start to go at annual intervals. Now after year five, we’ll have to use the prospective data to really help us identify what’s the best way to look at these patients after five years. And you might say, how many patients do you have? We have hundreds of patients now who’ve been managed this way after five years, and we’ll use both our retrospective and prospective data to help us inform this going forward.

Dr. Joshua Smith 10:32 
What about quality of life? So if you look at those patients who had a radical resection compared to those managed by watch and wait, this is a case control study that was further kind of reinforcing data from our friends in the Netherlands. But if you look on just basic bowel functions for patients who had a watch and wait approach versus radical surgery had better bowel function scores. And then if you break this down into dietary frequency, urgency and soilage, you see significant differences in those patients managed by watch and weight versus radical surgery. And then this has been, like I said, reinforced by our friends from the Netherlands. So the limitations of the current evidence on watch  and wait are 1) prospective trial, small subset, highly selected patients, studies completed in resource rich settings, variable patient selection, nonuniform definitions of response, I’ll get to that in a little bit, inconsistent surveillance protocols, and relatively short follow up, although now the Watch and Wait Database is gathering more data over time. And of course, our data set is acruing with some additional follow up. So what about this idea of now TNT to optimize response and maybe get more patients to the possibility that they could preserve the rectum. So some of the potential advantages are that you could treat micrometastasis earlier, you can improve compliance, reduce the time to ileostomy closure in those patients who do have to go to surgery, enhance response of the primary tumor and of course, you could give it either before or after chemoradiation.

Dr. Joshua Smith  12:07
So this was pioneered by Len Saltz and Andrea Cercek and so you take the standard approach which I talked about earlier with chemoradiation, radical surgery and chemotherapy and then give patients chemotherapy, chemoradiation, and total mesorectal excision. So this was described in a JAMA Oncology paper about three years ago. And you can see the response rate is 21% in the standard approach and 35% with an induction approach, and these data then recently updated this paper since submission. And this is the entire cohort, complete responders versus incomplete responders. And we know that complete response remains an important prognosticator in rectal cancer and this is just further shown here, whether you look at chemoradiation alone, or patients who are undergoing TNT.

Dr. Joshua Smith  12:53 
So, if you look at induction approach and watch and wait, this is a paper that just came out earlier this year. These are, again, off protocol patients managed at MSK. 88 patients undergoing induction TNT approach, you can see 32 had a clinical complete response and 55 incomplete response. The local regrowth rates here are quite small. And I think this is, you know, patients managed very carefully here at MSK. But again, just the point of this is that you have a complete response. We know that disease free survival outcomes are better than if you have an incomplete response. This is, again, just supportive of the data that I showed before and suggestive that complete responders, the biology there is a bit different than the tumors that don’t completely regress.

Dr. Joshua Smith  13:37 
So what about the prospective TNT data? So this is the what we call the Timing Trial. So again, taking this idea of chemoradiation and radical surgery, and supplanting that some and then starting with chemoradiation, and then chemotherapy, and then radical surgery. So all the patients in this trial went to surgery. There wasn’t a watch and wait option. But the idea here was to increase the time after chemoradiation and what you can see is that with two, four and six cycles of FOLFOX, you see a dose dependent increase in pathologic complete response. So these are the highest rates of pathologic complete response that have been seen in a prospective trial to date. This was led by Dr. Garcia-Augilar, who’s the Chief here at MSK. And this led to other trials that I’ll talk about here shortly.

Dr. Joshua Smith  14:21
So the German trial randomized people to an induction approach versus a consolidation approach which I’ve introduced and this was about 140 patients per group and this trial did not report on oncologic outcomes but did report on pathologic complete response. And so what you can see is this is the induction arm and this is the consolidation arm. So consolidation meaning similar to what I showed you in the Timing Trial wth chemoradiation followed by chemotherapy and then surgery, so 27% path CR versus 19% in the induction arm. Everybody went to surgery, with few exceptions, no significant differences in postoperative complications. And then if you look at another, essentially surrogate for path CR, but a little bit more quantifiable, the NAR score, there was also a nudge up toward a higher rate of complete response in those who are managed by a consolidative approach.

Dr. Joshua Smith  14:21 
Now, another interesting trial has been led by Tom George at the University of Florida is what’s so called the TNT Trial. And this is a platform trial comparing an induction approach. So FOLFOX and then standard chemoradiation and surgery, compared to what if you put in some different components here as a radiosensitizer to try to increase the rate of response in patients with locally advanced more distal, bulkier tumors, to see if we drive up the rates of complete response. So this trial was reported in two phases, one at ASCO GI in 2019, and then recently at ASCO, and now recently reported in JAMA Oncology. So the one that I’m going to focus on is this idea of FOLFOX and then chemoradiation plus pembro as a radiosensitizer. And then these patients went on to surgery. And you can see there was, what they reported, is no differences in the NAR scores. And just to make it kind of a simplified version of that is, you know, a quantifiable way to look at response instead of just standard pathologic complete response. But there was no differences in either complete response or the NAR scores in the standard arm, which is the FOLFOX, chemoradiation and surgery versus the experimental arm, which is this, adding pembro to chemoradiation. Now, whether or not there’s going to be differences in the survival, or the oncologic outcomes is yet to be determined. But again, an interesting design, and then this trial is currently being retooled. We’ll see what they come back with in terms of other designs in the future. But using this induction approach, no differences in response rates.

Dr. Joshua Smith  17:02
Now, many of you’ve heard of the RAPIDO Trial. This was presented at ASCO in 2020, with the PRODIGE Trial and OPRA and then recently published, and then comparing long course radiation, surgery and adjuvant therapy versus short course and then chemotherapy in a consolidative approach similar to the Timing approach. And you can see, when they looked at their experimental versus their standard arm, they saw in their primary outcome, disease related treatment failure was lower in the experimental arm and rates of distant metastasis were lower. Importantly, their path CR rates were higher at 28% versus 14%. And so this trial was thought to be essentially a practice changing trial. And in Europe many places have adopted this as now the standard of care with short course, consolidative chemotherapy, and surgery. And you might say, well, did any of these patients go on to watch and wait and very few refused surgery and elected to do that, and it wasn’t built into this trial. But you can imagine that what if they waited and then potentially allowed patients to do that you could very well think of that as a as an option. And I’ll get to that later.

Dr. Joshua Smith  18:17 
This is another important trial from the French Group, the PRODIGE 23 Trial. And this is a TNT like trial, not true TNT, but patients were randomized either long course chemoradiation, radical surgery, and FOLFOX for 12 cycles, or modified FOLFIRINOX, long course radiation, radical surgery, and then FOLFOX for six cycles. So everybody got 12 cycles of chemo. But this is essentially perioperative chemotherapy, not true TNT.

Dr. Joshua Smith  18:44
The interesting part about this trial is that it did meet their primary endpoint. So they did change the rates of three year disease free survival, so 75% in the experimental arm, so here in the red, and then metastasis free survival is 78% versus 71%. And also the path CR rates were higher at 28% versus 13%, or 12.6%. In the control arm. So this is a really important trial, and I think fed some of the designs that you’ll see here in a second.

Dr. Joshua Smith  19:13 
Another important trial that I think and hope that you’ll hear about next year at ASCO is led by Deb Schrag, who was at Dana Farber and now is the Chief of Medicine here at Memorial, is the PROSPECT Trial. And this trial, I think, will be important especially for patients with upper rectal cancers. But patients were randomized to either a chemoradiation and radical surgery and then adjuvant therapy or to FOLFOX and then their response was gauged by MRI and endoscopy. If they had a great response, they went on to surgery. If they had not a great response or the tumor was still residual with not much change, then they went on to standard chemoradiation and then surgery. And so this will be really important for us to see, can we selectively use chemoradiation to avoid some of that toxicity I told you about earlier in the talk about chemoradiation.

Dr. Joshua Smith  20:02
So now the OPRA Trial. So the OPRA Trial was the developed to identify a way to put watch and wait in to optimize patients who could get to a clinical complete response using an optimal neoadjuvant therapy, let people preserve the organ without compromising survival for the entire group of patients. And if you get to the idea of patients with a distal rectal cancer optimal treatments and you restage them, I think it’s hard to argue that if they have tumor remaining that you could manage them with watch and wait. That’s not hard to argue. But the optimal design would be to then randomize patients at the end and see if those who went to radical surgery had the same outcomes as those with watch and wait. But the argument here is that you can’t talk patients into doing this. And we’ve asked many patients about this. And you say, Well, how do you know nobody will agree to that?

Dr. Joshua Smith  20:52 
Well, I’ll give you two examples. One is a patient that I share with Dr. Garcia-Aguilar, this Mr. M and I said, basically given him that prior scenario, if I gave you the chance to enroll in a trial like that, would you do that? And his answer was hell, no, the reason I enrolled was because there was a chance for me to keep my rectum. And then one of my other patients, I’ll just give you a chance to hear what she says. So, Carly, if we proposed the trial that we just described, would you be willing to be randomized to radical surgery or watch and wait after I told you had a clinical complete response? “Absolutely not. And I would put an F word in there, if I could” “Got it, Thank you”. So I think this gets to a little bit about the genius of the design of the OPRA Trial because it allows patients to anticipate that at least they have a chance to keep the rectum. So the design was a historical control versus the study group where patients were randomized to an optimal neoadjuvant approach. Patients were restaged, if no significant response they had radical surgery, and then if they had a significant response, of course, they were managed by watch and wait.

Dr. Joshua Smith  22:10 
So here’s the schema. Induction chemotherapy, consolidation chemotherapy, as I talked to you about. They were restaged, obviously, if tumor remained, they had to go to surgery and if they had a clinical complete response ,  they were managed by watch and wait. It was a multicenter trial across the US and some centers in Canada. You saw from the prior slide that the initial accrual was thought to be 202 patients, but it rapidly accrued and we kept it up to 324 patients, I think, because of patient interest. And this trial accrued about a year and a half ahead of schedule.

Dr. Joshua Smith 22:45 
We introduced this MSK Regression Schema. As I mentioned before, with the retrospective data, there wasn’t kind of standardized ways to assess the tumors throughout treatment. And so we thought this was an important way to do this prospectively. So there are three categories: complete response, near complete response, and incomplete response. Incomplete response is easy to think about. Complete response is no tumor by endoscopy, digital exam, or MRI. Near complete response is maybe there’s a small change in the scar, small change by digital exam or some small changes by MRI. We allowed patients who had these small changes another four to eight weeks. If they progressed to a clinical complete response, they were allowed to move on to be managed by watch a wait. If they didn’t, obviously, they have to go to surgery.

Dr. Joshua Smith  23:30 
So these are the data. In the patient’s managed by consolidative approach, so chemoradiation followed by FOLFOX versus an induction approach, you can see 60% organ preservation rates at three years versus 40%. No differences in disease free survival, distant metastasis free survival, or local recurrence free survival. And the local regrowth rates are similar to what we see in the retrospective series with 27%, in the consolidation group versus 40% in the induction group. And even when we thought we were wrong, you can see the path CR rates were pretty similar at 10% versus 8%, which I think is reassuring. So for the first time we have prospective data that suggests that patients can keep their rectum using a watch and wait approach. Now, is TNT controversial and I’d say yes. You know, many people in Europe think that TNT is overtreatment.

Dr. Joshua Smith  24:20
And this is a recent paper from a group in the northeast suggesting that some of these regimens like the German trial or PRODIGE 23 have high rates of toxicity as it relates to some of the chemotherapeutics that were used. And they argue that why not do a true TNT versus standard arm? For example, if you took OPRA and RAPIDO and then you say, Well, why don’t we just do the next trial of chemoradiation, and then radical surgery plus adjuvant therapy versus chemoradiation plus chemo and TME almost as a radiation first strategy, and I think this is a fair point.

Dr. Joshua Smith 25:01
So the issues that remain for our patients, and I think many of you might be able to add to this list even is that we need to improve survival outcomes. We need to know how to best improve disease free survival. We need to really help people in terms of quality of life, try to mitigate toxicity and identify responders to allow more individualized treatment approaches. So some of the ways that we can do this is try to integrate patient preference. And I’ll talk a little bit how to better engage patients along the way. And so in the design of trials, kind of after the trials I’ve just talked to you about, we really thought it was important to get patient input. And so Manju and I started to really collaborate on this in 2019. And I really appreciate her openness and willingness to collaborate as we designed the next watch and wait trial. And we really tried to engage both people in Rectalburgh through Colontown, and then also eventually Fight Colorectal Cancer, using some decision choice analysis and kind of discrete choice analysis tools and using real data based on what we think chance for cure was, chance for ostomy and then just asking very practical questions based on what we knew at the time in terms of clinical trial data available, and then also, what we thought there might be, in terms of survival rates and things like that. So our patient cohort, at the time we did our initial survey, was 90% of patients who had either history of permanent or temporary ostomies, many patients with distal third tumors, many of those who had a prior LAR and, of course, had experienced LARS, many patients that were less than 50 and many women. So we just asked first, you know, would you want to be in a trial where your input was asked and I think that’s an easy question and, of course, everybody wanted to have their preference or their input when a trial was being designed. And then we went through many iterations with this, but then we settled on the idea that maybe the input based on recent data, so the PRODIGE Trial, OPRA, and then there was also a BOOST Trial where they were trying to get more radiation to try to get people’s responses higher. So we asked patients, really, what would you prefer? Would you rather be on a trial where they gave you more chemo or more radiation to get your response rate higher. And interestingly, what we found, and this was just a kind of an old design of the trial that I’ll talk to you about in a second, but if we gave you a trial where you got more chemo, and thought that maybe we could increase your disease free survival, your response rate, which of these would you prefer? And by a large margin, people chose more chemo versus more radiation. And I think for many different reasons, I have a lot of responses that I can read to you, but for the sake of time, I won’t. So this led to the current design of the Janus Trial, which I presented to the NCI last Monday and will know I think relatively soon whether or not they have approved this. But now we’re thinking about locally advanced mid or low rectal cancers and patients are randomized to either to essentially the winner arm of OPRA versus long course and FOLFIRINOX. And we take this a little bit from PRODIGE with the primary endpoint being clinical complete response. And the idea for clinical complete response is that that’s a surrogate for organ preservation, as I showed you, in OPRA and we think that might also be something that could translate to oncologic outcome differences in future. So, I have worked obviously, with Manju from kind of a sketch on a drawing to then input from patients. So you can go from an iPad drawing to something a little bit more sophisticated over time with a lot of help and input. So we’re obviously appreciative of patient input as we designed this. And I think the Germans have done something similar.

Dr. Joshua Smith  29:14 
So this is a paper that they published back in 2019 where they did also a similar questionnaire, looking at asking just about 40 patients, how they would accept this frequent surveillance that you have to do with watch and wait, how they would accept local regrowth, how would they accept toxicity that they would need to undergo to get to clinical complete response. And interestingly, this led to their recent Watch and Wait Trial, which is randomizing to either the short course approach, so the RAPIDO approach, or the long course followed by CAPOX approach. So this is essentially the winner arm of OPRA and then this is the RAPIDO arm.

Dr. Joshua Smith  29:51 
They’re looking at the number of patients who go on to watch and wait versus TME. When this was originally shared with me by Dr. Fokas who is in Germany, they had 100 patients, and they recently presented at our CME Course and now they have almost 200 patients in this trial. So many patients are interested in this, obviously, both in the US and in Europe.

Dr. Joshua Smith  30:16 
So, as I’ve told you, the treatment of rectal cancer just continues to evolve at a very rapid pace. OPRA, for the first time, shows that watch and wait is safe. It’s best done in high volume centers and on protocol, if possible, although I realized that’s not always possible. I’ve shown you that patient input has really shaped the design of the next iteration of watch and wait trials, both here in the US and in Europe. And then identifying those patients who respond completely is really tricky. But I think what I’ve shown you is that TNT is one way to do that, to optimize response. And I’ve shown you a few trials that allow us to do that in a way that gets many patients to organ preservation. And one is the consolidation approach that I demonstrated in OPRA, you saw data from the German trial, the RAPIDO Trial and then PRODIGE. And we see improved response rates and all those trials using varying options and in the context of TNT. So with that, I’ll end and be happy to take questions, and I will stop sharing and then open it up. And I think everybody, hopefully you can unmute, and pepper me with questions. I think I gave us plenty of time for questions.

Manju George  31:40 
Yes. Thank you. Thank you, Josh. That was a great talk. So I have some questions with me. So we can start with that and then people can type in their questions, and then we can go through them. So one is a very general question. What, in your opinion, is causing an increase in rectal cancer rates? Do you want to comment on that?

Dr. Joshua Smith  31:59
That’s a million, if not billion, dollar question. Yeah, I mean, I think that is an area of active investigation. You know, maybe it’s related to some changes in the microbiome, maybe the exposures along the way, whether it’s dietary or otherwise, those things need to be very carefully investigated. I mean, our group is looking into this. Dr. Cercek established the Young Onset Colorectal Cancer Research Center here and in collaboration with her group and then Robin Mendelsohn, we’re looking into why this might be by investigating the microbiome. I think that’s one potential reason. You know, there are some papers suggesting that maybe it’s not just as simple as the mutational analysis because some papers are suggesting the mutational changes are not really that different in early onset versus average onset cancers. And so it’s probably not that simple. You know, I think there’s much more to be learned in that regard. So that’s a great question. And I don’t think we know the answer to it by any stretch now, and I don’t think we’re gonna know the answer in time that will be good for the patients who are being diagnosed right now who have early rectal cancer, unfortunately, but hopefully, within the next few years, we’ll have some answers for people that could potentially lead to differences in treatment and things that might change the outcomes for those patients with early cancers.

Manju George  33:45 
Thank you very much for that. So another questioon. The patient’s care team, they were concerned when the patient asked for watch and wait. They were concerned that being on watch and wait means a lot of additional screening, and that they were kind of arguing that that means lower quality of life and the patient was really confused. In their mind, it was like with LARS, that would be more loss of quality of life. So have you heard such concerns from patients when you talk to them about the increased surveillance during watch and wiat? Could you comment on that?

Dr. Joshua Smith  34:19
Yeah. I think the argument that we make is that patients that are good candidates for watch and  wait need to be able to come back for surveillance. And so if you can’t live with that as a option, then you’re not a good candidate for watch and wait. Because, yes, you do need to come back. And that’s the reason I show that surveillance slide because you do have to come back for endoscopy and exams and MRI. But we’ve found that patients are very willing to do that. And over the course of time, we’ll see in terms of cost analysis and other things like that in the prospective trials, whether or not that’s going to pan out in terms of is it more cost effective to do one versus the other? I think at the end of the day that patients are willing to come back if they’re highly motivated to preserve the organ. I’ve found that patients that want to keep the rectums are willing to come back and travel and do the things that they need to in order to potentially avoid an ostomy.

Manju George  35:31 
Thank you. So the surveillance is like every three months, you have digital rectal exam and endoscopy? And then could you explain a little bit?

Dr. Joshua Smith  35:39
Yeah, you know, I think what I’ll do is show that slide again, because I think it’s important to see that. So the first couple of years, you see, it’s four months for the endoscopy and digital exam, and then six months, and then annual imaging, CT and then CEA. And then you start to space it out at years three to five– six months, 12 months. And the reason for this is because we see that most of the local regrowths occur within the first 24 months. The vast majority.

Manju George  36:30 
I was kind of wondering what additional preparation would people need? The CT imaging and CEA, everyone gets for surveillance, right, normally?

Dr. Joshua Smith  36:38 
Yeah.

Manju George  36:39 
And then the MRI is every six months. So that’s also okay. And for the digital rectal exam and the endoscopy, what kind of preparation do patients need to have?

Dr. Joshua Smith  36:48
For us, they just come to clinic, then we prep them in clinic. This is very simple.

Manju George  36:54 
Okay.

Dr. Joshua Smith  36:55 
Some clinicians like them to do an enema or something the day before. I think it’s somewhat practice specific. But for us, it’s very straightforward.

Manju George  37:08 
Okay, thank you. The next question is, does tumor location, which is the distance from the anal verge matter when considering watch and wait?

Dr. Joshua Smith  37:17 
I think that it probably does. The reason I brought up the PROSPECT Trial is because some patients who have upper rectal tumors may have a little bit less to gain from an organ preservation approach. I think PROSPECT will help us in that regard, because patients could be treated with FOLFOX, have a dramatic response by endoscopy and MRI, go to surgery, avoid radiation, avoid the morbidity and toxicity of radiation, not have the significant LARS, etc, that patients face and I showed early on that if you have surgery plus radiation, and you have a low tumor, you get all of the adverse effects. At the end of the day, you also may have a path CR, but you’re going to be faced with the toxicity. So can we do watch and wait in upper rectal tumors? Sure, you can, and some patients opt to do that. But do you have as much to gain, as somebody who has a tumor at the anal verge or the very distal rectum? Because you’re not going to be faced with a permanent stoma if you have an upper rectal cancer. Because yes, if you have an LAR, you may need a temporary ileostomy, but you’re not going to need a permanent stoma assuming that your LAR is relatively uncomplicated. So I think PROSPECT will help us in many ways and you saw the design of the new Janus Trial, we’re thinking of mid to low rectal cancers as the optimal patients, but at the end of the day some patients with upper tumors may say, I would like to avoid surgery altogether. And I don’t think that that’s necessarily an absolute contraindication.

Dr. Joshua Smith  37:34 
Okay. But I think the optimal patients are those that their sphincters are involved, they’re faced with a permanent colostomy or a coloanal. Those are the patients where their bowel function is a concern if they have a stapled or a hand sewn coloanal or they’re faced with a permanent colostomy, those are the ones that I think have the most at stake.

Manju George  39:38 
Okay, so this other question is in your talk you said, for example, with watch and wait, everyone is really worried about local recurrence, right? And then among patients there is a strong belief that if you have local recurrence, then the ability to salvage that with additional surgery is difficult and also, they think that if the tumor grows locally then there are increased chances of it growing distally also.

Dr. Joshua Smith  40:04
Yeah.

Manju George  40:05 
And then you made a comment that the biology may be different and that the tumors that have a tendency to show local regrowth may be aggressive even otherwise, right?

Dr. Joshua Smith  40:14 
Yep.

Manju George  40:14 
And whether the patient had watch and wait or not, that might be independent of their chances of getting mets.

Dr. Joshua Smith  40:21 
Exactly. Yeah, so I’ll answer it first with my scientific hat on to say that you could argue that biology is set before we ever see the tumor disappear, and then the mets might have been there all along. And that taking the rectum out at the beginning or at the local regrowth had no bearing on the development of metastasis. So removing the rectum upfront or at the time of regrowth, does that really make a difference in the overall biology of the tumor? It’s hard to know for sure. I think from the prospective data, from the OPRA data and those local regrowth patients that we see, will we see an increased kind of a correlation between the patients who have local regrowth and distant metastasis. I think in the prospective data, if we see that same trend, then we can say that, yes, maybe this suggests an increased risk and more aggressive biology. We do see it in the International Watch and Wait Database. I showed that and we showed that in our Jama Oncology paper. But the difficulties there are those are retrospective analyses and many flaws when you think about retrospective data. So certainly, it’s something that we’re paying attention to, and we think about, but in the patients with local regrowth, as long as they are under careful surveillance, the vast majority of those patients undergo the same operation they would have undergone at the time that they were ready for TME if they had undergone TME in a standard fashion. The people that had difficulty, at least in our series, were those who refused the standard surveillance or just fell out and they didn’t come back. And that’s why I say that patients that are the best candidates for watch and wait are those who are willing to come back for surveillance because if we can detect the local regrowth and take you to surgery, you’re going to, in the vast majority of cases, get the same operation that you would have gotten at the beginning.

Manju George  40:21 
Okay, thank you for that.

Dr. Joshua Smith  42:47 
After neoadjuvant therapy has been done and whether that’s chemoradiation or totally adjuvant therapy, whatever your team has decided is the optimal way to get the tumor to respond.

Manju George  42:59 
Okay, okay, so I’m reading the chat. We have a patient. He says he’s from Slovenia. So he had first four cycles of CAPOX and then chemoradiation and then he was put on a watch and wait. And then he had MRI, digital rectal exam, CEA, etc. But then nine months later, on PET/CT, it’s showing possible recurrence and lung mets. So, you know, he’s kind of asking is PET/CT reliable to know that it is an actual recurrence. And, Tomas, correct me if I’m wrong, so do you have a local recurrence as well as lung mets or is it just the lung mets?

Dr. Joshua Smith  43:37 
We do see this sometimes, though, while he’s responding, where you have no local regrowth in the primary, but you may have distant disease, and some patients would choose to preserve the rectum and the distance disease is treated. We have some patients where the lung metastasis is treated with either ablation or resection or systemic chemo. So that is one possibility. Some people would argue that patients that have metastatic disease are not good candidates for watch and wait. I tend to agree in that regard, especially if you have metastatic disease upfront, but there are cases where patients, in a case by case basis are managed with watch and wait when they really want to preserve the rectum in the context of metastatic disease. But this is a unique case where it sounds like metastatic disease has developed in the context of a clinical complete response. That has been reported and seen and I think you just have to decide how to best manage the metastasis and the motivation to keep the rectum.

Speaker 1  44:21 
I hope that answers your question Tomas. The treatment strategy will depend on what you want, right?

Dr. Joshua Smith  45:08 
It sounds like he may have both local regrowth and distant metastasis. So if you have both, I think we know that with local regrowth, those are best dealt with with surgery. There’s not another good solution with local excision and local approaches. Unless we think that it’s just add adenomatous tissue, which is very rare, we don’t think there are great local approaches. You would typically need the same TME type operation that you would have required. And in the context of metastatic disease, it’s usually a combination approach or a staged approach where the metastatic disease is dealt with, and then the rectum or in a combination approach.

Manju George  46:00 
Thank you very much. So the next question is from a patient whose initial diagnosis of the tumor was T3N0M0 and the tumor was about five centimeters the anal verge and about three centimeters in size. And she had chemoradiation, and then they found that she had a complete clinical response. But the oncologist wants to do a watch and wait and the patient is a little worried that she has not had chemo. So the question is, what is your experience about these patient’s going on watch and wait with just chemoradiation and without having chemo? What is the data available?

Dr. Joshua Smith  46:39 
So a lot of the retrospective data, so many patients in some of the older studies just had chemoradiation. The data from the Brazilian group were chemoradiation and then they started doing more of a consolidated approach where they did chemoradiation followed by chemotherapy. So there are a number of patients that achieve a clinical complete response after chemoradiation alone. Now to say that, in the current age, where we have data like RAPIDO, where we have data like OPRAR, where we have data like the Timing Trial, we have data from the German trial where we see these increased response rates where we do chemoradiation followed by chemotherapy, I think to just say we’re going to only do chemoradiation alone and expect to see optimal response, I think would be a little bit blind to the current data that we have. Now, sure, adding chemotherapy on top of it does add in a layer of possible toxicity, so we have to think about that. And if your goal is organ preservation, you can always think about layering in two of the three treatments if you’re trying to avoid one of them. But if you want to preserve the rectum, then I think it makes sense to add in chemotherapy versus if you’re not too worried about preserving the rectum, then probably chemoradiation and surgery and then potentially avoidance of adjuvant therapy might be an option. Because if you’ve completely downstaged the tumor, and let’s say you have chemoradiation, you go to surgery and you have a path CR, you’re probably not going to need adjuvant chemotherapy. So I think they may just need to decide which of the three of the trimodal options they want to use. But it sounds like there’s a promising response there and they could probably maximize it with consolidative chemotherapy.

Manju George 47:34 
Okay, thank you very much. So the next question is if a patient had chemoradiation and chemo and then got surgery, and then they still find tumors left, like an incomplete response, does it reflect on the chances of distant metastases or overall survival now, that tumor is actually out of the body, right?

Dr. Joshua Smith 49:20 
That’s the scenario in most cases, right? In the vast majority of cases, we still see residual tumor. The best response is a pathologic complete response, but in most cases, we just see some downstaging. Some cases we don’t see downstaging We just see essentially the same tumor, the same clinical tumor as the pathologic tumor that was there. So, the pathologic staging does dictate some what the disease free survival is likely going to be and then the nodal status, as well. But, at the end of the day, response is a bit of a surrogate for the outcome. I showed you that the complete response in our data, albeit retrospective, and then we see the same thing in the long term data from the older German trials suggest that with path CR patients there’s an association with better disease free survival. The MD Anderson group shows something similar. And our data shows something similar. So we know that the disease free survival outcomes are better in those patients that have complete response versus when there’s residual tumor. And there’s different grades. There’s complete response, and there’s almost like a near complete or incomplete response versus minimal response. And that can be looked at by MRI or by pathologic grading.

Manju George 51:02 
Okay, okay. Thank you very much. So do you suggest that if someone has an incomplete response or a minimal response, then they can be more careful about surveillance and use additional techniques like ctDNA testing?

Dr. Joshua Smith 51:15 
Yeah, that’s something that we can learn from by doing some exploratory analysis in rectal cancer. There’s a lot of interest in that right now. But we don’t have any good prospective data in rectal cancer to inform us in that regard. The data right now is mainly in stage II and III colon. But in rectal cancer, there’s a lot to be learned in that regard. I think, for now, we just follow the standard NCCN Guidelines for surveillance, but integrating things like ctDNA could be very useful. We just don’t have the data in front of us to inform us in a useful way yet.

Manju George  51:53 
Okay. Okay. So as far as patient’s wanting to do it, so you think that when compared to somebody who has a complete clinical response, or a complete pathological response, you can be a little more casual about surveillance, like not using over the board techniques, but if you have a minimal response, then from a patient perspective, it seems to make more sense to go after, with everything possible, right? Including ctDNA?

Dr. Joshua Smith  52:20 
The level of anxiety is probably a bit higher. That being said, we do know, some patients with pathologic complete response can still develop distant metastases. So it’s not like you have a free lunch if you have a complete response. Some of those patients still have distant and sometimes local events, but usually distant metastasis. So the biology is still a very strange beast, unfortunately.

Manju George 52:51 
Okay. Then, there are a couple of questions about do you have any advice on when people are on watch and wait, or after they have surgical resection,  on what they can do to minimize the chances of recurrence, like can diet or supplements, of probiotics help?

Dr. Joshua Smith  53:08 
Yeah, it’s a great question. I mean, this is a question that my patients ask me once we get to the point of clinical complete response, and they say I don’t know how I got here, but now what do I do to maintain it? And I think the modifiable factors are diet and exercise. We know that high fat foods and then red meat are associated with the development. These are big, kind of associated from the nursing health studies and some other studies looking at modifiable factors as it relates to lifestyle. But we do know, from some basic science data, as well as epidemiology data, that red meat is not good, the more fruits and vegetables you eat the better. So those are dietary factors that you can control and then exercise. So when you can keep your exercise level at a reasonable input, and that means walking or whatever you choose to do, but some sort of physical activity does help. And I think somebody that has an active mind, active body and is careful about what they eat, I think those are things that they can do. Of course, we know things like smoking and other things like that are obviously associated with development of cancers, but the things that you have control of are what you put into your body, and of course taking care of yourself.

Manju George  54:55 
Okay, and what about aspirin? Do you suggest that patients be on low dose aspirin? Is that something that you recommend?

Speaker 1  55:02 
There is some association of use of aspirin and a reduction of colorectal cancer incidence. I think I don’t see a harm in a low dose aspirin for patients as long as there’s no medical contraindication.

Manju George  55:18 
Okay. So there is another question about complete clinical response. Is there any association between tumor grade and what you see? Or what happens with watch and wait? Is tumor grade even a factor in considering any of it?

Dr. Joshua Smith  55:33 
Yeah, so that an interesting question. Node positivity doesn’t seem to necessarily correlate. And there’s an interesting paper from the Brazilian group a couple of years ago. There was always this question of if you have node positive versus negative disease, should you be a good candidate or not? And they show essentially equivalent rates of clinical complete response, oncologic outcomes, as it relates to the clinical factors on the front end. We stratify according to T stage because we think that the higher the T stage, the worse outcomes. Bigger and bulkier tumors after often associated with worse outcomes. The higher nodal burden can also be associated with worse outcomes. But we do see some big, bulky tumors that have complete responses. So it’s not a complete contraindication to say that, Oh, you have a T4 tumor, so therefore, you can’t be a candidate for for watch and wait. So I gave a talk last week, and it’s not a complete contraindication to say, because you have a T4 or a T3 tumor that you can’t be a candidate for watch and wait, because the nodal disease and the initial clinical T stage. Sure, do we think that maybe a T2 might have a better chance to respond than a T4? Maybe. But I think we’ll be able to say for sure when we look at the prospective data over the long haul.

Manju George  57:19 
Okay. And then I wanted to ask you one or two questions about your comments. What are the other studies that are coming up to get to higher rates of clinical complete response or pathologic complete response? You mentioned radiosensitizers. And then I think there are a couple of trials like the Ave-Rec Trial with the avelumab, and things like that, right? So do you have any comments about adding immunotherapy together with chemoradiation for MSS rectal cancer patients?

Dr. Joshua Smith  57:51 
Yeah, I showed the trial from Tom’s group that was in JAMA Oncology earlier this year. There was no differences. So we don’t have any good data right now to suggest that adding immunotherapy is a compelling way to essentially turn a cold tumor hot yet. In MSI-high tumors, there’s some compelling data and some excitement. So there’s a trial at Vanderbilt run by Kristen Ciombor. And then also a trial here run by Andrea Cercek for MSI-high tumors where patients are getting immunotherapy. And I think that’s very exciting. Now, could we find MSI-high like tumors in the microsatellite stable cohort who might be candidates for an immunotherapy approach? Or are these the patients who are really responding to chemoradiation upfront approach? I think these are really interesting questions. And whether or not there’s novel radiosensitizers that we could use these are open questions that we’re trying to address, but nothing right now. And the reason that people are excited about Tom’s trial is because he was adding in things like a PARP inhibitor and then pembro and there was a thought that that would drive up the path CR rates, and then that could potentially, as you could imagine, would translate to potential organ preservation strategies. Because if he’d even seen a 10% or 15% increase, you could say, oh, well, why don’t we give pembro to try to give more people a chance to preserve their organ?

Manju George  59:30 
Yeah, I think we have run out of time. This is very interesting. And thank you so much for spending this hour with us. What I’ll do is that I will collect some questions if we have more when people start watching the video, then I can email them to you. Thanks, everyone, for attending. Thank you very much.

Dr. Joshua Smith 59:47
Yeah. Thanks Manju. Thanks everyone.