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PROSPECT trial: Dr. Schrag

Doc Talks

In this DocTalk, Dr. Deb Schrag from Memorial Sloan Kettering discusses the PROSPECT trial with PALTOWN Scientific Director Dr. Manju George. Recorded in June, 2023.

Manju George
Hello everyone, Welcome to DocTalks! I’m Dr. Manju George, the Scientific Director at Paltown Development Foundation, the non-profit that supports COLONTOWN. Today we have the pleasure of having Dr. Deb Schrag from MSK here with us. She’s going to talk to us about the PROSPECT trial. But before we begin, I want to ask Dr. Schrag how she got interested in GI oncology and she has done a lot of work on different things and I would like her to tell us a little bit about that. Welcome, Dr. Schrag

Dr. Schrag
Thank you very much, Dr. George. Thanks to everybody who is able to join online today, and it was great to see quite a few people at the recent ASCO meeting and thanks to everyone for what you are doing.

So I’ve been a GI Oncologist for about a quarter of a century and you know, I think I got into it when I was a house officer, an intern & a resident, resident, I had some patients who I really connected with and they had some GI malignancies, CRC, and those encounters left a strong impression on me. I started reading about it and got interested in the research & trying to understand what cause these diseases, why we are seeing more of these diseases at younger ages, concerned about nutrition and what we are eating, and environmental exposures and also genetics.

So right at the time I was training in the mid-90s was when we first identified inherited cancer susceptibility, it was right when BRCA1 in1994 when we identified BRCA1 before when I was in training and shortly thereafter we figured out the genes for HNPCC (Hereditary Non-Polyposis Colorectal Cancer) and every couple of years we have identified something new in GI cancers. Over the course of my career, I have had the privilege of participating and taking care of so many patients. Early on the prognosis wasn’t so good, but it just got better and better. Not only do we cure more patients, when we don’t cure people we help them live longer and better. We are still not where we need to be, I have seen so much progress, I remember when irinotecan was a new drug, that’s how old I am. I remember when oxaliplatin was a new drug, I remember when we 1st got the 1st box of cetuximab. It came in a box and it was part of an investigational trial, and the compound was called Imclone C225 and the 1st early study had a 22.5% response rate, we were joking that we should have named it 99.5, then it would’ve had a higher response rate.

That was in 2004. At that time we were giving lots of cetuximab to everybody. Then we figured out that cetuximab does not work in people who have KRAS mutations and nobody likes the acne rash you get from that drug and we were able to start testing people for KRAS mutations and really bring precision medicine to GI cancers, colorectal cancer in particular.

So I think you know, every few years we had a major breakthrough discovery. When I started, it was pretty much 5FU and leucovorin. Now we have more and more drugs and we truly have personalized therapy for GI cancers. So it’s been incredibly rewarding to participate in the conduct of these trials to take the results from trials and implement them in practice and ensure that the benefits get passed on to people. It’s not as fast as we like, but there is progress. So I guess I’m an optimist. Thank you very much.

I’m gonna talk about the latest study which I recently presented at ASCO, which took a very long time to conduct and I can give you a little bit of context if that will be helpful.

At the recent ASCO meeting in Chicago, I presented the results of a trial that looks at changing of the way we approach curative treatment of locally advanced rectal cancer and this is the PROSPECT trial. This study was done as part of the NCI’s National Clinical Trials Network (NCTN). It was really a collaboration of surgeons, medical, radiation oncologists,radiologists, pathologists, of course statisticians from across North America, most from United States and Canada.

Probably as known to most of you, globally there will be some 800,000 cases of rectal cancer in 2023, and about half of these diagnoses present with locally advanced rectal cancer. There’s probably a quarter on either side, a quarter with very early localized rectal cancer, and a quarter who unfortunately present with metastatic disease. We for the last 30 years, have been giving pelvic chemoradiation and that is radiation to the pelvis, with a little bit of either intravenous 5FU or oral capecitabine, because it helps radiation work better and the reason we do this is because it helps reduce the risk of rectal cancer coming back in the pelvis, which is a terrible outcome. And I remember from my training, these are folks who come in and say, I can’t sit down, it feels like I’m sitting on a tennis ball, it’s miserable and it’s terrible and it was not uncommon. It occurred in a quarter or a third of patients back in the 70s & 80s. And when radiation began to be applied consistently, as a result of clinical trials starting in the 90s, the incidence of local recurrence dropped dramatically. And there was less suffering. So I just want to start by saying that radiation was hugely beneficial, hugely important and an incredible advance when it was introduced really in the 90s as a result of trials. And for that reason, it has been the standard of care for how we approach rectal cancer treatment really since 1990. A very important trial was published in 2004 that showed us that if we are gonna give this pelvic radiation, it is better when we give it preoperatively than when we give it post operatively. It doesn’t influence how long people live or how likely they are to be cured, but it is better tolerated, quality of life outcomes are better, so since 2004, so now about twenty years, we give pelvic chemoradiation before surgery. This is kind of the standard paradigm when PROSPECT began. We have had some investigational approaches recently, but we give pelvic chemoradiation with 5FU or capecitabine over 5.5 weeks, we let people get better, then people go to the operating room where they have surgery, with a special technique of operation called Total Mesorectal Excision (TME) 4-6 days in the hospital. They recover and then they go on to receive some adjuvant chemotherapy. So that’s kind of the basic approach.

But our motivation is that there is some long term toxicity from pelvic chemoradiation. It can impair bowl, bladder and sexual function, which are not things we always talk about because we are like we need to cure you, ok , you will put up with these things, because our goal is to cure you.But when we are treating patients who are younger and younger, these are non-trivial. There is an increased risk, it’s slow, but there’s an increased risk of fracture and second malignancies many years later. There’s a concern that if we once radiated the pelvis, it is harder for your bone marrow to have resilience and reserve, which is really an issue if we need to give people lots of chemotherapy in the future. For women, the infertility and premature menopause are considerations. And that’s relevant because of the increasing incidence of rectal cancer before the age of 50. So here we are, it’s the end of the oughts and we have had all these incredible advances. We have had better chemotherapy, FOLFOX, it came on board around 2004, 2005 surgical technique has gotten better. Because of colorectal screening, we actually are seeing fewer grapefruit sized rectal cancers. People are more aware. There’s more screening on the part of patients and physicians. So between screening and symptom awareness, fewer people are presenting with gigantic tumors and they’re getting detected earlier and we’re also taking better pictures and better able to figure out which tumors can be sort of safely treated and easily resected because it’s the ones that can’t that are at highest risk for having the dreaded pelvic recurrence. So we essentially wondered whether we could capitalize on all this progress and we were in 2011 and wondering, could we give chemotherapy first, hold the radiation and only give the radiation to people whose tumors did not respond or melt to the chemotherapy. This was a high risk proposition, because at this point in 2011, we’re curing 75 to 80% of people, cure rates are 75 to 80%. So when cure rates are 75 to 80%, you don’t really want to do anything that might compromise that or might make things worse, kind of a “don’t, let’s not mess with success”. “Don’t get greedy”. You’re trying to optimize quality of life and get rid of these sorts of nuisance things. But really, people want to live and survive even if they have to put up with this. So you can imagine that this was a little bit controversial. But we forged ahead with a very carefully designed trial and I’m proud to say that we have lots of patients. And thank you if any of you were on the call. You will remember those meetings they were in 2010 2011 many iterations. doctors from around the country polling, patient participation, patient advocates, mostly at the Alliance for clinical trials, bad coffee in hotel rooms next to the O’Hare Airport, which I remember vividly. But this was the study design that we agreed upon. It was for patients with T2 node positive T3 node negative and T3 node positive rectal cancers. And these were patients who didn’t have very distal tumors that needed an APR or very large bulky tumors where doctors were afraid that it was just too risky. So we were careful in the group that we selected. And the trial design was for people to be randomized either to the standard of care shown in the red box, or to get FOLFOX6 and then to have a restaging with an MRI and only undergo the pelvic chemoradiation If the tumor wasn’t melting away to the FOLFOX and FOLFOX was still you know, relatively new, less than a decade old at that time.

So this slide shows the full schema that I just showed you is kind of across top that was sort of the tried and trued approach. The investigational approach is at the bottom six cycles of FOLFOX. Then repeating imaging which was for most people, a pelvic MRI for some people with a CAT scan and an endorectal ultrasound, which is a suitable alternative. Some people have hardware other indications that they can’t have a pelvic MRI. Again, if the tumor was responding more, was decreased in size by more than 20%. They went straight to surgery and then got adjuvant therapy, but if they weren’t responding, then they sort of got a second crack at the Apple if you will, and got the pelvic chemo radiation, and then to surgery. And we left some latitude to sort of local physician discretion about the specifics of the adjuvant regimen, some things about the surgical technique and the staging. This really allows flexibility and I think the generalizability of the results. These are the inclusion and exclusion criteria. And again, these were developed carefully with a large group of physicians. Things that we looked at were disease-free survival. We also looked at of course, local recurrence rates because that’s such a critical outcome, overall survival. How many patients could have their tumor completely removed, the complete pathologic response rate, toxicity and quality of life. So I’ll go through this quickly, but essentially, the statistical design of the study was as a non-inferiority. So we didn’t need for the chemotherapy to be better. We just needed it to be essentially no worse. The idea then being that patients could choose. So we designed the study to have adequate power to test our non inferiority hypothesis.

So we recruited over 1000 patients, the mean age is 57. More than two thirds of patients were men that just reflects the gender distribution of rectal cancer. Most patients had tumors about eight centimeters from the anal verge. So these are really classic mid rectal cancers, about 84% in each group had staging performed with MRI and you can see the stage distributions. Little more than half were T3 node positive so here’s kind of the main result. You can see the results at five years. The blue line shows the group who got FOLFOX and selective radiation and that was 80.8%. And the standard tried and true method was 78.6%. So that’s a 2% difference. But that’s not a statistically meaningful difference. It’s small, the hazard ratio was 0.92. And what that means is that we can definitively say with a study that met its endpoint, that FOLFOX is not inferior to chemo radiation, and that’s with the median follow up of just shy of five years.

So you can see here this is sort of the statistical hypothesis. It met the non-inferiority criterion. So we really proved, the study met its endpoint. We looked at other endpoints, including local recurrence, and the red and blue line are right on top of each other, which is kind of why it’s hard to see the red there. But you can see that the rates of local recurrence were very low. It’s actually shown here is freedom from local recurrence. So 98.2 and 98.4% of patients were free from local recurrence, almost exactly the same number 9 and 7 in each group. So there’s really no difference in local recurrence rates at five years. Here’s overall survival. And this is really good news. Also, at you know, at five years, median survival was 89.5% and 90.2%, which is statistically indistinguishable, so no impact on survival. We looked at lots of sort of intermediate endpoints that are of particular interest to rectal surgeons to patients to doctors. How many patients had all the tumor resected in the surgical specimen: 99% versus 97% of very high in both groups. How many patients had a type of operation that’s called a low anterior resection, the kind that really spares the anal sphincter? 98%. And remarkably, perhaps most remarkably, we’re very interested in how many patients when you took them to the operating room was the tumor completely gone, had it just disappeared?. And we know that that can happen with radiation, but we also saw it with the chemotherapy so the rates were 22 versus 24%. And that perhaps is one of the most remarkable findings. That’s that’s a good finding what’s shown there on the slide in orange.

What’s not such a good finding is and the situation that we really don’t want to have happen is to have a positive radial margin and that means that in the surgical specimen, you see tumor at the edge, because if you see tumor at the edge of a specimen, it means that you probably left some tumor behind and when tumors left behind at the edge of a surgical specimen, you are going to want to administer radiation. You can see that the concern was of course that, you know, that could be much higher and the investigational group shown in blue, but it wasn’t. It was 1.2% versus 1.5%. So very low in both groups.

Of course, we also looked at the proportion of patients who got postoperative adjuvant chemotherapy, and this was very similar in both groups. People who need to be treated with rectal cancer, it is a marathon. It goes on and on and on and on and people want to get done. And so we also looked at how long was the whole shebang from start to finish. People have got jobs and lives they need to get on with and the median duration from the day patients were randomized to the day that they got their last dose of chemotherapy. It’s very similar between the two groups. 35 versus 37 weeks. So again, the intervention arm wasn’t no radiation, right? It was just, we’re only going to give you radiation if you don’t respond to the FOLFOX. And only 9% of patients randomized to FOLFOX went on to get the preoperative chemo radiation. And they did so for essentially two reasons. Either the restaging showed that the tumor didn’t melt to FOLFOX. Or, in a few cases, not too many, but a few. They didn’t actually tolerate the FOLFOX Some people have cardiac issues from 5FU and so on. And if we gave you FOLFOX and it wasn’t well tolerated, it wasn’t safe. It was like okay, this is not safe. This is not working. We’re going to treat you that tried and true pelvic chemo radiation. So that was the total rate there was 9%. So we’ve looked at toxicity in the study, of course, and essentially, I’m gonna give you the upshot here, which is that it’s kind of a wash. It’s just timing. If we give you the FOLFOX because of the neuropathy and fatigue associated with chemotherapy, and because it’s six cycles, two weeks apart, or 12 weeks, you’ve got higher symptoms, higher severe symptoms in the pre operative period. So the blue intervention group more toxicity 41 versus the standard, because it’s only six weeks, so the periods half as long and you know, there’s a little bit less fatigue, more diarrhea, less fatigue, but it flips exactly almost exactly in the post operative setting, where postoperatively the red group has higher toxicity and the blue group, the intervention group has lower. so it’s really about timing. In general, there’s more diarrhea in the radiation group and more neuropathy in the FOLFOX group, but it evens out postoperatively but I’m really proud of the fact that we also asked patients directly to tell us about their own toxicity during the trial. And I think, in my opinion, that this is the way we should do all trials, and I think it should be integrated into every single trial. We had 90% of patients do this. It didn’t take a lot of time. It wasn’t burdensome, it wasn’t onerous. It was once a week and then we could we could have done it more often. But essentially, patients told us how bad their symptoms were. And this shows you the data. Over 12 weeks, which is double that period of time. We got higher, severe symptoms scores for the FOLFOX and selective chemoradiation and for the chemoradiation, but you can see diarrhea was worse in the radiation group shown in red, appetite loss, fatigue, nausea, and neuropathy were worse in the FOLFOX group. Which yeah, people may wonder about how did you get constipation? Well, we give FOLFOX we give Zofran and we give Zofran to control the nausea from chemotherapy and the Zofran causes constipation. So that’s why the constipation was higher.

When we look, however, at symptoms that were reported as severe, 12 months by which time we expect both groups to be well past the acute phase, the good news is that the rates of severe symptoms are super low in both groups. So the take home is, this is good. There’s small rates in both groups, but the neuropathy was actually more severe in the chemo radiation group which is kind of interesting. The intervention group got more of chemotherapy sooner and earlier preoperatively so their neuropathy was probably just better by 12 months, even though everybody was offered it can take some time for the neuropathy to subside. We also looked at quality of life and I’ll walk you through this slide because I think especially for patients this is a really critical slide. So in the upper left hand panel is overall health related quality of life, and the FOLFOX group is shown in blue and the standard of care chemo radiation group is shown in red. You can see that at baseline quality of life for both groups is identical. The blue circle and the red triangle are superimposed because quality of life starts out the same. When we look a couple of weeks before people went to the operating room, so sort of at the preoperative assessment, you can see that overall health related quality of life and this is a pretty crude five question measure it’s called EQ five days quite standard is was actually better at that time point for the FOLFOX group. You can see that n is actually gone up. So for the blue group, it’s actually gone up so when you know people are starting to feel better as their tumors get smaller 12 months postoperatively you can see that there’s a little bit of decline, but it’s a decline in both groups. It’s not huge, but it’s, you know, if you look at the Y axis, it’s pretty small, but it’s there. And at 24 months, it’s better in both groups, but the blue line is better. But we have very stringent criteria for statistical significance. And those differences between the blue line and the red line didn’t meet the statistical significance threshold. So formally, we would have to say there’s no formal difference in quality of life, but there’s clearly a trend for the FOLFOX being easier. When we look at bowel function. Again, it starts out similarly but the bowel function improves more quickly and better for the intervention group than for sort of a control group. But again, rates kind of converge and aren’t so different at 12 and 24 months. Where we see the biggest differences in sexual function and we use validated instruments to ask both men and women they’re slightly different questions and those p values there show you that those differences were statistically significant. So you can see I’m just going to go through the slide but the men the sexual function sort of starts out and is identical and preoperatively it’s worse than baseline for both groups. Now, you know, sexual function when you’ve just finished either chemotherapy and or radiation or about to have surgery for rectal cancer, are you can kind of imagine maybe it’s not your top of mind priority and it’s declined for both groups, but really similarly, but in the red group, it continues to get even worse at 12 months, and it’s declined still further, whereas in the blue intervention group, it kind of plateaus, right? It never goes back to baseline, but it kind of plateaus. Whereas in the red group it it doesn’t really recover very much. And you can see, actually an even starker difference in the women are in female sexual function. Are these quality-of-life metrics perfect? Of course not. They’re not.

So they’re important limitations. As for all trials, we excluded patients who were really high risk who had very distal tumors, very large tumors, lots of big and large lymph nodes. We had some patients who didn’t have MRI staging, our European colleagues love to tell us how they get MRIs and everybody but we can’t do that or we certainly couldn’t do that before. Not everybody could get their MRIs paid for. So we had some CAT scans and pelvic ultrasounds. And I think a key issue is that there still may be some patients who in order to achieve these high cure rates, we over treat, we give folks more treatment than they might really need to achieve kind of the 90% cures that were going forward. When I started, we were at 70% cure rates. And it’s just so amazing now that we’re sort of pushing these cure rates higher. So when it takes this long to do a trial and error, it took us five years to accrue and then we had to follow people for five years to make sure that the outcomes were good. time marches on, and thank goodness other strategies have emerged. That includes shorter courses of adjuvant FOLFOX that we learned from the idea study that I believe Dr. George I’m sure you’ve had people talk about some of my collaborators were part of that initiative.

There’s other ways of delivering radiation over a short course it’s often very good for particularly for people who are sort of at the extremes of age. Total neoadjuvant therapy I’m sure you’ve talked about and now increasingly, particularly for very distal tumors, non operative management, and for the 5% of people who have an MSI high tumor, actually, immunotherapy can work. It’s just unfortunately, not so helpful for the other 95% obviously, the vast majority. So really our conclusion of this trial and again, you know, we have over 1000 patients from across the United States that we can give neoadjuvant folfox and only use radiation selectively and that that is a safe and effective treatment option for patients with T2 node positive or T3 node negative or T3 node positive breast cancer. And I just want to be clear, we can’t say it’s better than pelvic chemo radiation, but we can say it is non inferior and you saw those curves. It’s the outcomes are identical. I think you know, I would say that when patients have choices, everyone wins. And so I’m proud that as a result of this trial, we have created new options for people. This was funded by the cooperative group networks which I think many of you are familiar with. Mostly North America, a little bit of Canada and Switzerland just a little bit. But mostly North America. And I would say there were 1194 amazing courageous patients who participated in this trial. You guys are all heroes. 90% of you are alive and well. I’m sorry for the 10% who are not, but salute everyone’s contributions. And I think people should be really proud for having created new knowledge that will help the next generation of people have more options that will hopefully improve their quality of life. And maybe I can stop there and take your questions.

Manju George
OK thank you so much. That is very good. I have one question for you, you know as part of the task force, what can we do to have our trials use here, you know, pro CTCAE measures and especially the sexual function, what can we do?

Dr. Schrag
So, um, I think you guys just have to speak up. I mean, look at you know, I’m a champion. I think that when clinicians rate it, it ends up being like, excuse my, it ends up being like a child’s game of telephone, right? So what happens is, I go in a room to see a patient and we’ve talked about the MRI, we just talked about the surgery. When you talk about the chemotherapy, there’s a million things and yes, I’m like, Okay, tell me about your nausea, your diarrhea. We need to go down the symptoms. And maybe I write it down and maybe it’s legible. Maybe I put in the chart, maybe I forget, but maybe I’m like rushing to the next patient or somebody’s reacting in the chemo infusion and I forget the details. And maybe I’ve talked to the research nurse who may be talking to the CRA, but usually it’s a data manager putting it in or reconstructing it from a note when I saw the patient at 3:30 and I did the note at 1130. It often goes from a patient to a doctor to a nurse to a research coordinator who’s putting something in the computer and just like the kids game of telephone, a lot of information is lost, which is completely different than just ask the patient and have the patient score it directly themselves. I think we just need to upend the way it’s done and trust patients and I think, I don’t know I’ve spent the last 20 years trying to show that the toxicity data aren’t exactly the same, but there’s no reason to think that the physicians assessments are more accurate. It’s just they’re not. What I will say is we understand a lot about how physicians score and I’ll just explain that briefly because it’s kind of interesting. Toxicity is graded on a score of 01234 where zero is I don’t have it. So let’s take knowledge. Zero is no nausea. One would be mild, 2 moderate, 3 severe and 4 very severe. And what we know is that patients use the full range of the score. And doctors tend to dichotomize it’s either zero or three. Why is that? Because mild nausea is usually something that they ignore. They’re like, of course you’re on chemo, you have mild nausea. I don’t need to do anything about it or it’s in the order set or the nurses taught you that at the chemo teach at the beginning. There’s no action for me. So it’s zero when they ignore it. Whereas patients are writing that it’s one or two, because it is because it’s their lived experience. Because the doctor doesn’t think it’s surprising or unusual or a cause for action on their part. Other than that, like we’ll take more of the medicine I gave you the beginning. They don’t write it down, or they don’t record it. The reason they record 3 is when it’s three it’s maybe they need to change the dose or add a new medicine. So doctors kind of collapse into all or nothing, whereas patients use the full scoring range so you get more nuanced, more informative data about what people’s experiences are really like. I think that the patient community just needs to say what patient reported endpoints are you including in your trial? You know, you really need to ask the trial participants what their experiences have been and give us a chance to answer and you don’t want to be filling out 50 questions a day. These were three minutes once a week, at the most and not even just in the active parts of the trial. So you need to respect my time not drown me with questionnaires, keep my data private. But you need to offer me the opportunity to contribute my experience. Because now when you guys are looking at what this treatment is like, you don’t have to take our word for it. You have the word of 1000 other patients of what it was really like and it’s just better data. I mean, it’s just I can’t I just believe that it’s better data. But I mean, that’s my opinion.

Manju George
Yeah, I feel like you know, people talk about not having a validated instrument. Now that you’ve tested it in 1000 plus people, there is no reason to say there isn’t anything available. It’s already there and validated. Right.

Dr. Schrag
But I would also say like we’ve developed this instrument which has been completed by over 100,000 people at this point so this is good. And it’s you have to have something validated but you can’t you can’t have people spending five hours answering questions that’s people have lives to lead.

Manju George
Yeah, yeah. I think Kathleen has a question. Yeah, go ahead.

For clarification. When you say mid rectum how far from the anal verge? Yeah, so I think that that was on the slide here. Yeah, I didn’t read it fast enough. Oh, that’s okay. I was trying to not keep you. Um, the UK was eight centimeters and the standard deviation there is three. All right, you see that? It’s like, can you see my slide there? It’s like,

Manju George
Yeah, five to 11 something Yeah.

Dr. Schrag
Okay. Some patients who were, you know, down at four, but the minority. And there were some at 5678. There were very few, you know, above 12. So that it’s really more mid rectal tumors, but that’s the vast majority.

Okay. So this was only LAR No APR is what you said.

Dr. Schrag
So, at the beginning, I think it’s an eligibility criteria. If you look during the inclusion, the surgeon had to look at the beginning and say I can do an LAR make sense? Yeah. Sometimes when the surgeon actually got in the operating room, the on the ground conditions were no I can’t I’m changing my mind doing an APR and sometimes they did, but not too often. I think I have that. And another slide. Here. Yeah. Yeah. The 98% of cases they were able to do an LAR so and 2% they made an on the ground change. Okay. Does that answer your question?

It does. I’m asking from the perspective I’m, I’m the I’m an admin and rectal Berg and colon town. And I’m an admin. I’m one of the people who moderates and onboards members into rectal Berg which is a neighborhood of COLONTOWN. Yep. We have 1800 members who when they see a study like this get quite excited. And I need this clarification so they understand who who was eligible for your study. And they don’t get upset because Oh, I didn’t get to have that treatment. So this will help me help them understand what your study was about. And that they may or may not have been eligible, but you know, sometime in the future other people will be so next question. Are there any plans for a study with tumors closer to the Verge is still T3 positive T3, negative T or T3 positive, closer to the verge and eligible for APR. Are there any plans to extend and do another study that would include?

Dr. Schrag
Yeah, so we would love to Yeah, we would love to do that. So I should just add one other thing that your the folks in Rectalburgh may be interested in. When you do rectal surgery, people often need a temporary ostomy and what I didn’t put on the slides here are that in the standard group 90% of people needed a temporary estimate. In the intervention group, it was 75%. We’re still scrubbing and cleaning the data to see how many patients went on to have a reversal. So that’s another advantage for the intervention group. But we didn’t present that at the meeting because we really want to get the reversal data and that takes a while to come in and we didn’t have all the follow up planes in time. So that’s why we didn’t.

Okay, that’s interesting. Thank you.

Dr. Schrag
Is that helpful? Yeah, I would say in terms of other studies is, you know, kind of the studies are like, planes on a tarmac. You can’t do a million studies at once. And the study that there’s the most interested in right now is to try to pursue for low rectal cancers, non operative management which has pros and cons, but that’s the priority. So that’s the study that’s kind of underway nationally by the cooperative groups right now. And will we need to prioritize that one.

Yeah, we have a number of members who are part of non operative management, the protocol and we we featured that in the month of March with a lot of personal stories and we try to give people as much information as possible in terms of what a clinical complete responses for example, yeah, so yeah, that’s not for everybody.

Yes, yeah. When we were just generally trial, I’m sorry, excuse me. How many what is the percentage that’s something else I need to emphasize? How many what percentage of people who have TNTthen would qualify is that like 25%? Because I’ve seen a couple numbers. But I want to again, but that wasn’t part of prospects. Let me just be, and it really depends on what the inclusion criteria are. And it varies from trial to trial. Okay, yeah. Yeah. Yeah.

So that was my question for you Dr. Schrag this like you know, one something like this comes out and everyone wants to see if they can you know, not they can avoid chemo radiation. So, what we’ve been telling them is like, you know, if your tumor is similar to the group in the trial Exactly. Get that was able to skip radiation. And have like non inferior outcomes, then, you know, skipping radiation might be something for you. It’s definitely not for everyone. And then again, you of course, can’t get out over our skis. If you have a very big tumor or a very low tumor. You weren’t eligible for the trial. So we can’t say that this wouldn’t work. But we can just say we don’t have evidence. We don’t have like, for this group, we have definitive rock solid proof. But for groups that weren’t included in the trial, we don’t have evidence.

Yes, yes. I think that a couple of questions. Brita, you have your hand raised? Do you want to go next?

Can you hear me? Yes. Okay. Hi, thank you. This is amazing information. So I was curious. I think you just answered one of my questions was about do you think that it would work for a very distal tumor like, you know, located near the sphincter and secondly, I was wondering if you had any of your participants in the study have a complete clinical response and not require surgery?

Dr. Schrag
Yeah, so you know, we follow the protocol and this protocol was designed in 2010 and 2011. And the plan was either chemo radiation or chemo and if people had the complete clinical response they were going to surgery so the surgery here was part of the protocol. So we did have I think two in one group and one in another, this were deviations. So out of you know, 1100 people we had three who essentially were okay forget the protocol. My tumors melted away so beautifully. I’m not having surgery. But that back a tiny little group, but everybody else kind of followed the protocol. This was not a non operative protocol. And I would just say, you know, it kind of almost shows you that perhaps we’ve been over treating rectal cancer for many years and that we probably can treat rectal cancer with chemotherapy and surgery and leave out the radiation. And in other people, we can probably treat it with chemotherapy and chemo radiation and leave out the surgery. Right. So it’s probably like we can de escalate different modalities. But not everything. Does that.

Yes, it does. I have one more question. Is there a reason that so you didn’t include anyone that was stage one, really?
We did not because if you have stage one, you should just get your tumor operated on and move on and not have to suffer? Through either chemotherapy or chemo or radiation
in the West, unless you have stage one and they want to give you an APR. So that’s what I was just curious about. Yeah, that’s
a special group. Right. Okay. Thank you so much.

Dr. Schrag
You’re so welcome.

Manju George
Allison, you have a question.

Sure. I’m sorry. I joined a little late, but I saw your presentation at ASCO. So my question is sort of related. Not specifics like the others but so you have this amazing information which is great. I’m a colorectal cancer survivor. I have a permanent ostomy I had radiation I have lots of long term effects from radiation. So you have this information.

Dr. Schrag
So just to be clear, so you understand why we did the study.

100% I appreciate it. I am very excited to help spread awareness among the community that that I work with because I’m in I’m in the medical field. How do we get and I don’t know if they’re if you talked about this earlier or, or there’s a plan how do you get this to all the oncologist all over? So that standard of care is options because I feel like there’s still going to be people that are gonna say, Well, if there’s no difference we’re still gonna go with the more aggressive or is it or should we have

Dr. Schrag
A more aggressive so I guess, I’m just gonna tell you one little pet peeve of mine actually hate the word aggressive because like, every time my fellows or my junior faculty put the word aggressive like we’re going to pioneer this more aggressive treatment on like, a cross it out. Because nothing that physicians administer should be aggressive, intensive. Like we’re not aggressors, like we’re trying to, we’re trying to be healers. Aggressive is just such an awful word like, we shouldn’t even be using it. But I hear you I take your point intensive, intensive treatment. I think that we are physicians, and we have to not get ahead of the evidence. I think we all know there’s a lot of misinformation out there. You know. I’m a physician and I have been taking care of patients for 25 years. And all I have is my reputation and trust. I am not a televangelist. I am not a marketer. I am not trying to sell anything. I get a paycheck whether you get chemotherapy or radiation. I get the same. You know, I’m saying like we are healers. We are here to help patients to give people choices to explain the data and we have to be trusted. So we have to present scientific meetings. clearly but without hype or exaggeration, acknowledging the limitations acknowledging the uncertainties. You know, we just can’t be doing like marketing campaigns or exaggerating because then trust gets eroded and that’s how trust gets eroded. You know, this was NIH sponsored research. Everyone participated in the design, including patients. I don’t know for all I know you were there at some of those meetings and in Chicago, but I actually have the names of all the patients who were so I actually don’t remember you from there. But, you know, yeah, we have to just be careful. So we can’t really be proselytizers because it erodes trust in the credibility of the integrity of what we’re doing. And we need to be trusted so I’m sorry. I don’t have an answer for you. But we have scientific meetings and I don’t know I spent my nights and weekends making slides and it’s seven o’clock and I still have patients to see and I’m talking to you so I guess that’s my answer.

Yeah, I mean is it is it on and I this is why I think this is so important, is it? Is it part of what we should be doing to help make sure patients know so they can advocate for someone that might not have seen the amazing work that you’ve done? Because, I mean, I was treated at NCI designated cancer center, amazing place. But I got very standard of care for someone much older than me. And I think certain things could have been left out from my treatment that might have you know, but again, like, still make so much amazing research. Like yours and other people are coming out that I think, would you suggest I think that’s part of what Kathleen was bringing up because I’m one of the moderators in colon town for the Texas Group. Like and I’ve shared some of some of this information there and through other channels. I’m SWOG Patient Advocate, by the way, so I probably help with certain things related to some of this, but I’m like, I want to make sure everybody knows about this. That’s awesome. Yeah.

Dr. Schrag
I think that you are a more effective spokeswoman than I would be. You know, my job is to do the trials and treat the patients and write the orders, understand the science. And I think you are going to be a more effective spokesperson. than I will be

Yeah, so what you’re doing sorry to interrupt but Alison, that’s why we are having this. This call. Right so this video will be on COLONTOWN University, and you know you you’re free to share it with anybody and it’s great that we have this specific discussion, because when you say you know about being able to skip radiation, I want you to stress what Dr. Schag said that for this very specific group we know that skipping radiation is non inferior, but for anybody who doesn’t belong to this group, there is no evidence to suggest that it may be non inferior. I think that’s the key thing that we have to stress when we talk to patients and then have them come in you know, watch the video. Watch it a few times if they’re not able to understand it the very first time and you know Dr. Schag is fascinated in very, very simple and easy to understand terms. So they can take this to their clinician and then discuss it because their care team will be able to explain it more if they have more questions. I think that’s our role, right? Like as patient advocates. This is how we can make more people aware of it so that you know for the patients who are in this select group, they are they get to discuss this with their care team.

Yeah, yeah. Okay, thank you so much. I mean, the only thing
thanks, everybody. Thank you guys so much for everything that you do. Yeah, you’re very welcome. And thank you for staying so late and explaining all of this to us. Take care everyone. Have a good day. Bye.

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