Chapters Transcript Video Multidisciplinary Care and Nonoperative Management For Rectal Cancer right. So I have no disclosures. I do want to give a little bit of a background on where we came, where we've come with, uh, rectal cancer. Some of the milestones, um, definitely wanna discuss about the treatment modalities. And are they really all necessary radiation surgery, I think pertinent to the both of us. Um, data on now, what's very exciting in the field is watch and wait. Eso similar to anal cancer? Are there a subset of patients with rectal cancer that can avoid surgery altogether on? Then what's next? And future directions? Just some of the brie V ations that I just wanna highlight here, uh, complete clinical response when a tumor completely disappears clinically, uh, pathologic complete response. So that's at the time of reception. Uh, removal of the rectum and then evaluated by pathology aan den watching wait terms or non operative management terms. And then these air some chemotherapies that probably all of you are familiar with. So we continue to make progress on decreasing mortality from colorectal cancer across the United States for a number of different reasons, whether that screening and better treatments, Um, but you have to be probably in a cave or underneath the rock. If you haven't seen what's going on with early onset colorectal cancer, and it's quite alarming eso that's folks being diagnosed before the age of 50 with colorectal cancer. There is an alarming rate of the incidents of this, and and this is a report from Sear just published in 2018. Where again we're seeing these decreases in colorectal cancer rates over the age of 50 but early onset, it's dramatically increasing. Um, that's for colon cancer, which is expected by 2030 to be an increase in 90% and then even for rectal cancer, a dramatic increase to even 124%. And what's scary is that we don't know 100% why this is going on. Um, it's clearly there are some risk factors, just that we do know from colorectal cancer for, uh, for with smoking and obesity, sedentary lifestyles, things like that. Obviously, family history is important, but clearly there's something else going on, and we still don't know what that is. So we have to be aware of this, especially as clinicians seeing these patients and get the word out that Of course, if you're having symptoms, even if you are under the age of 50 that you should talk to your doc and get screened. Um, and it's not just that they're being diagnosed at earlier stages. Those early on setters in the twenties thirties on dare forties. Ah, lot of times when they have maybe some symptoms bleeding. Correct? Um, something along those lines, you know, they speak to their physician or they say, Oh, it's probably just a hemorrhoid. Something like that. And before you know it, they're coming in later on with, of course, later stage diseases. If your sixties seventies and you have bleeding. Correct. Um, you know you're getting a colonoscopy, but with with younger patients, sometimes it's often the last thing you think about. So, uh, this just came out, Uh, Sears data on, uh, men becoming now number one colorectal cancer being one of the deadliest. So a number of milestones that many of you will be familiar with on the management of rectal cancer. Um, there's, uh, s a BP trial starting back in 1985 through, um, Swedish rectal cancer. Tri. Als. Um, this is kind of small for you. guys in the back. But Dutch TME tri als, uh, on DNA now even into 2017 18 where we're really using Marie and optimizing uh, radiation oncology radiation techniques as well. A surgery to really optimize patients outcomes with rectal cancer. Um, there are a number of challenges thio the treatment of rectal cancer. Difficult surgery, especially in the no lo male pelvis. Uh, we were not made for childbearing. Right? So we have very tiny narrow pelvises, um, and that low tumor Also, to try to do optimal surgery without hurting some of the important structures remain difficult and challenging for surgeons and potentially lead thio um, loss of some important quality of life. Patients still have local and distant recurrences, especially with a distant recurrence. Uh, pelvic deep pelvic recurrences, ca NBI Devastating for patients. Um, preserving quality of life trying thio avoid stones when possible. Andi also preserve general urinary dysfunction, uh, difficult to identify responders of neo adjuvant therapies and treatments and making treatment more individualized for the patient. We still way still struggle with that. So for all of these reasons, rectal cancer, I think, is the poster child for multi disciplinary care Um, And for that reason, the Commission on Cancer and the American College of Surgeons have really spearheaded, um, a new accreditation program. Maybe a lot of our institutions are already accredited, maybe breast cancer care and others. But, um, this is a new program that's still in its infancy. Only 10 programs in the whole country. We're in the process of applying for our accreditation right now because they felt that this is such a nim, Porton und disease, that should be treated appropriately with all of our teams. We do know from years past, uh, surgeon by the name of Bill Healed really coined this phrase more than anything else of good quality. What's called TME surgery. Total misery. Rectal excision. Surgery to make sure that the surgical plane not only encompasses the primary tumor, but also the draining lymph nodes and to take out the meso rectum in a complete envelope. Okay, so this is the miso rectal fashion. And we do know that cutting through this miso rectal envelope on getting specimens like this dramatically increase rates of local recurrences eso as high as 30 to 40% even especially for locally advanced rectal cancer. Um compared to good quality TME surgery that's Onley at 3.7% and TME. This total means a rectal excision does vary between surgeons and it centers. Experience. Training and techniques are critical for this. For this disease, Um, although a surgeon's like £2 our chests and say, Yes, we can cure this disease. There's no question, um, this surgery is associated with significant morbidity. Um, still ah, hospital mortality of somewhere between one and 5%. Um, complications like a nasty Matic leak balle obstructions, hernias, urinary incontinence, sexual dysfunction, difficult Torrey problems and also a permanent stone MMA. So it's fraught with complications. Um, that we still that patient still struggle with, uh, just to highlight a cup of the most important trials that have really, um, were the seminal papers, uh, the German rectal trial back in 2004 published in the New England Journal of Medicine. Looking at preoperative um, chemo radiation on versus postoperative chemo radiation, the preoperative chemo radiotherapy reduced local recurrence race rates and, uh, improves sphincter preservation. Uh, the Dutch TME try a Well, some people did feel that criticized the German rectal trial as not having ah, high TME rate. But yet here, in the Dutch TME trial, the rate of TME was excellent, and that still showed that radiation improves local recurrence. So clearly, both are modalities are very important to patients with certain rectal cancer. Um, but although rectal radiation can definitely help a number of patients reduce their risk of recurrence, as we all know, it is also associated with some complications to like low anterior resection syndrome when combined with TME clustering, stool clustering frequency. Urgency on Also to blame the medical oncologists as well. Chemotherapy is not without its complications and and some of its side effects. Um, some of the age of in, uh, the largest adamant rectal cancer trials show that, uh, many patients cannot tolerate chemotherapy in the oven setting. Um, they have, especially with some of the newer agents, newer agents like Sally Platinum, the significant neuropathy that patients are left with. So right now there's an exit. This is the existing paradigm of treatment for locally advanced rectal cancer. So the diagnosis is made and again in 2019. This is 44,000 cases. Uh, staging next takes place appropriate staging, including C T and M R I? Usually this is followed by neo adjuvant chemo radiation. 5.5 weeks or so, Uh, this is followed by TME surgery and then adjuvant chemotherapy, usually first line of five f U on axl platinum. Um, we do know that consistently response rates correlate with prognosis. And how comes pathologic Complete response rates of asshole I as orm or of 90% when you do have that complete pathologic response meaning, uh, no remaining tumor in the specimen, whereas in an incomplete responses associated which a much lower rate off, uh, improved recurrence free survival. Um, And again, these air multiple studies continues to show that best responses with tumor regression grades of four or pathologic complete response is associated with a significantly improved outcome. So naturally, because of that, it's felt that well, how can we optimize patients, uh, thio obtain mawr of a possibly pathologic complete response? How do we improve those response rates? So some have recommended if patients who are already struggling getting their abdomen therapy with compliance, Maybe they have complications from surgery. They're dealing with temporary Elias Tommy's with dehydration, readmissions to hospitals and things like that, where they can't get their chemotherapy. What if we did something called Total Neo Adjuvant therapy, which is bringing that same chemotherapy, um, upfront before surgery as either an induction, which is starting with the chemotherapy first before chemo, radiation or consolidation, which is giving it right after chemo radiation. And so there have been a number of trials. This is data, um, reviewed from the Memorial Sloan Kettering Group looking at standard chemo radiation with plans adjuvant therapy, and that leads toe PCR rates of maybe 21%. And here is, um, induction chemotherapy leading to as high as 35 or more percent in some of the other trials with regards to consolidation. And, I don't know, maybe we could talk afterwards on what you folks, if you guys are using total neo adjuvant therapy and your institution and how it's being given. But, uh, this is a phase two trial looking at giving consolidation therapy. So starting with that chemo radiation first and then and then giving the full fox afterwards. And as you could see here between the two cycles four cycles and then even as high as six cycles that correlated with higher rates of path, Um uh, cr's, um, as that dose increased. Not to say that this should be just Maura's better, but there. We definitely can possibly be increasing response rates by giving that up front therapy. So there are a number of potential advantages to total neo adjuvant therapy early treatment of subclinical micro metastases that we're clearly not seeing on our image ing. Um, improve. It improves treatment compliance, as I mentioned, giving that up front, patients are able to get all their therapy and ensures the efficacy of the chemotherapy. Um, it also reduces the time to Elias to me closure most of the time that we give chemo radiation and if patients need their Elias, to me at the time of surgery, often centers air giving their adjuvant chemotherapy while the patients have, um, their chemo. While they're the patients are getting their chemotherapy and have their Elias to me. And then after their adjuvant therapy has done, the Elias to me is reversed. If all that therapy is give given up front, then often within two months time, once they recovered from their surgery, you can reverse there really Ostuni and reduce the time of of having that Elias to me. Um, and perhaps as we discussed that enhance response of the primary tumor and can be given as mentioned before as an induction or consolidation. So for a number of these reasons, we did add, um, total neo adjuvant therapy to the NCC and guidelines a few years ago. Right now, it's in the induction manner. So starting with full fox here for t three and any tumor followed by chemo radiation, and we are waiting for some trials to add maybe consolidation or tweaking this depending on, um, some of the upcoming trials that are coming out that I'm gonna mention, Um, however, giving all of this therapy so faux fox chemo radiation, large TME surgery is, in fact, all of that necessary. Do all rectal cancer patients require this aggressive, multi modality approach? And can we do the same with more or even less? So pick your poison. Okay. I think we've made that clear. All of us, including medical oncologist radiation docks as well as myself. We do give morbidity to our patients, but clearly the data shows that all of them have a place in the management of rectal cancer. But can we individualize them so unimportant trialing called the Prospect Tri ALS is coming out with probably some preliminary results. One of the more successful trials led by surgeons in quite some time, probably about 1200 patients. I think Roswell was part was one center that joined this trial, and it looked now that we have more effective chemotherapies that we didn't have in the past, we look to see if, in fact, there are some patients that can't avoid radiation. We do see a number of patients that get chemotherapy and have excellent response during their induction phase before they get radiation. So this is a randomized. Try a looking at the standard of care of chemo radiation, followed by surgery and then adjuvant therapy versus the Selective Arm, where full Fox has given a six cycles and then depending on tumor response. And that's based on surgeons evaluation and dystopic evaluation. An m R I. If there is greater than 20 equal or greater than 20% response than those patients go onto surgery versus if there's not, then they get the standard arm of chemo, radiation surgery and then possibly adjuvant therapy. So, um, that we keep your eyes out for that is definitely practice changing in a subset of patients. Again, we'll discuss who those? Maybe now on the other side. What if the tumor disappears after neo adjuvant therapy? Um, so you do you do expose these patients toe large operations, even to give them temporary or permanent colostomy ease, and the final specimen comes out. It goes to the pathologist, No evidence of cancer. And everybody's excited. Especially the patients, right? Andi, as we showed before. That's associated with a phenomenal prognosis. However, sometimes people may say, Well, if there was no cancer there did I need this major surgery and a permanent colostomy to begin with, right? Natural question to ask, Um, TME, as we said, is associated with significant toxicity. And those PCR rates occur in as high as 38% of patients with a phenomenal, um, long term outcome. Um, so PCR we do find is associated with a complete clinical response on on colonoscopy and dystopic evaluation and memory. So is an operation always necessary? And we really have to credit Professor Haber Gamma from Brazil. That really was the first pioneer to really look at this. And she published her Siri's all the way back in 2004 where when she submitted this to a lot of the societies, everybody was just It was blasphemy. She wasn't even invited to give talks or anything, and it really has come a long way. Nobody believed that this could possibly be the case for rectal cancer. Um, but she looked at 265 patients with low rectal cancer and then evaluated 71 that had a complete clinical response on endoscopic evaluation. Um, and she did look at the non CCR rate, which was people that look like they still had residual tumor, went to surgery, and then a subset of those actually did have a pathologic complete response. And she looked at the results of those two groups the ones that went to surgery with paths er versus those that didn't and they're not exactly the same groups, right? I mean, the ones that had the pathologic complete response definitively had tumor completely gone, whereas the ones that had clinical complete response that didn't have surgery, they didn't have their lymph nodes evaluated or anything like that. But she did conclude that in the setting of a complete clinical response. Uh, there is a possibility for cure. Deferral of surgery is, in fact, can be safe when under surveillance. Appropriately, cervical salvage is effective, and there was no difference in overall survival. Since that time, Mawr, internationally there has been buying. It was fairly slow to go in the United States, but internationally, especially in Europe. There were a number centers that joined registries, mostly as maybe patients like Uncle Jack, who's 85 years old, that had his chemo radiation and then refused to have surgery. You know, no way you touching me and then don't you know, five years later, Uncle Jack is now 90 years old and he still doesn't have any evidence of disease. So clearly, Uncle Jack was cured without surgery. Eso There were centers that started just entering in data of watching weighed up Thio as high as 47 centers. Now and now it's even more. Andre looked at some of this data really showing, um, low rates, fairly low rates of tumor regrowth and excellent overall survival. And again, this is just a number of different centers, you know, putting in some of their data a lot of missing data. So it's really not high level of evidence at this point. Um, m s K Just about two months before we published our Siri's, the Memorial Sloan Kettering Group published There's and they looked at 113 complete clinical responses, uh, showing an excellent, um uh, disease specific survival as well as low tumor regrowth. Um, their overall survival here. Um, at three years? Uh, no. This was five year survival of 73% and a disease specific survival of 90%. These air just in the watching weight group with a non operative management of note 73 looks pretty low. But 60% of those died of other causes of disease other than rectal cancer. What's interesting is that they found that there was a 21% local regrowth with which many people would say, Well, that sounds kind of pretty high, that you could be maybe one in five patients of getting recurring cancer. Um, but by far away, the majority of these were still able to be salvaged as long as you're surveying these people appropriately with endoscopic evaluations, memories and those other modalities. But what's also interesting, though, and is of concern is that if you looked at specifically those local re growths in those patients, as high as 36% of those patients developed, distant failure developed those distant metastases versus those that did not have local regrowth was just 1%. So the local regrowth and keeping an eye on that primary tumor is, of course, important. Important that you don't wanna lose control of the primary tumor, and the patient can be, at that point not salvageable for TME surgery. But also those patients are at higher risk for distant failure of their metastatic disease. Andi, we'll talk a little bit about why that's so important. And are we putting some patients at risk? So their conclusion was the use of watching wait approaches carry some risk. Whether that risk would have been mitigated with upfront TME after neo adjuvant therapy is really unknown. Identification of those who will completely respond to neo adjuvant therapy are who are on who are optimal. Candidates for watching wait approaches is of yet unknown and use of watching weight in the context of a complete clinic, responses likely best done in the context of a clinical trial, if possible, So I just wanna present our experience at Roswell Park, and this is we were we currently have the second largest Siris in the country in in the U. S. On non operative management for rectal cancer. Second toe, Um, Sloan Kettering. But we did start We were one of the earlier adopters for this because, um, I, in fact, really believed in this data and just, you know, sitting across from a patient on DTA, talking to them about what tm a surgery entails and knowing the fact that this is possible for them without offering to them, I personally felt that was almost inappropriate. Negligent, You know, if it was my rectum or if it's your rectum, what would you do? Our family member. So, you know, I felt that we should, um, a t least offer this as long as you have a compliant patient that understands it is willing to follow up with surveillance and those kind of things. So we reviewed our prospective prospectively collected data base From 2012 to 2016 this publication was of 29 patients. We're now approaching 60 patients. Um, 80% had low tumors. As you would expect because those the patients that really need either temporary or permanent colostomy czar and are at higher risk for a nasty Matic leaks, um, 45% had no positive disease. So this is one of the larger Siri's to date that have even that higher later Stage three disease and 65% of our patients in our Siri's underwent total neo adjuvant therapy either with induction or consolidation therapy. So for those that say, Well, how do you monitor this? Because this is the critical part of this, um, to make sure that there isn't local regrowth. We use a mix of endoscopy with certain findings that the Haber Gamma group really popularized. Looking at that flat white scar um, tow land GIC Tasia from that scoring process and the dying of the tumor No ulcer nodule Arat e um, digital rectal exam is normal. You don't have any of that modularity or structuring. Um, we use a mix, uh, really dedicated emery rectal staging using t two weighted images and also diffusion weighted images to give us direction Also on the radiographic response. Eso we optimize this and based on these criteria will be broken down as to complete near complete or incomplete responses. Um, this is the typical surveillance. So it is quite intensive. So patients in the first year or coming back every three months until we know exactly which patients weaken risk Stratify. It's an intensive surveillance. So patients are coming back every three months. They're coming to the back of my clinic. The nurse is helping them out. Giving or the aid is helping them out, giving them enemas. We put a flexible sigmoidoscopy in clinic every three months and just check that scar. Check that area of making sure that they don't have her currents. Same thing with the Ari. And also we alternate Um, CTS every six months and alternating memory. Sometimes us is if you have patients with, you know, peacemakers or or, um, have trouble sitting in m r I machines and and claustrophobia, that kind of thing s Oh, this is the breakdown. And as some of our data at Roswell and, um, at some Kettering and even the international, when patients do recur, the majority of them occur within the first year, and outside of that, it is definitely within the two years, so outside of two years. It's uncommon. So the interval between imaging starts toe gradually increase and separate as you move later on. So this is the breakdown of all of our patients. I know it's kind of you can't see it from from your seats here, but it is in the paper. Um, out of the 29 patients to patients develop local recurrence, and 51 of them had local and, um, distant recurrence. But four out of the six patients were able to be salvaged with surgical management. Um, there were no mortalities with a medium follow up of over 27 months. We have a currently a three year disease free survival, eight of 87%. Um, and, uh, for local recurrence and also for distances 76. So what do we What don't we know right now with regards to watch and wait and patients with rectal cancer? One, we don't know how to predict who's gonna have a response or not. We just don't. So I do have this conversation with every new rectal cancer. Pray Shin, I go through what the standard of care is, and I almost wait for them to say okay, I understand and ready to get up and leave the room. And then they say, Okay, have a seat. By the way, we do have this other option that if you obtain a complete clinic response, if your tumor completely disappears, you might be able to avoid surgery altogether. And then, like, they really light up right S o. I set that precedent early on so that when they know after they get all their total neo adjuvant therapy and they're coming in to see me, they know what we're looking for. They're like, Let's do that flexible sigmoidoscopy. Let's get back there and come on, Come on. No tumor, no tumor. I mean, they are, They know. So I have that conversation with every single patient. Unfortunately, sometimes I have to give them the bad news that their tumor is still there. But sometimes, you know, I give them the news and I take pictures and show that white scar with landlocked Asia. And it's not uncommon that tears start flowing. Um, in the endoscopy suite when they know that they can avoid surgery on day may very well be cured. So how do we maximize our tumor response? we still don't know that. Um, with total neo adjuvant therapies. How are we giving it? What we should be giving When is the best time to assess response? That's the other thing. There are some patients that, you know, within six weeks after chemo radiation, they may have had already a complete clinic response. But as we know from you know, this tumor with radiation and other, um, malignancies. The radiation continues to have its effects. So sometimes we even wait a long as, you know, 12 weeks. And then if sometimes if we're still seeing, um, regression of that tumor, I even tell patients to come back in another month or so, and we'll reassess. And sometimes if you wait long enough, patients will finally obtain that complete clinical response and be able to avoid surgery. Um, so how do we identify those true responders? Making sure that they don't have residual disease may be in their lymph nodes. Or, um um, some, uh, in within their wall. And then how often do we survey these people? Right now, the surveillance that we're doing is that overkill, right? I mean, we do have surveillance. Um, anxiety patients are you know, and to make them come in every three months is that too. Is that too much? Is it too little? We're still learning that which tumors will re grow, And will they be salvageable on then, with regards to the Sloan Kettering data, as I showed before, Can occult cancer cells metastasized? So if patients do, in fact have residual disease either within their rectum or their miso rectum? Are those patients at risk for distant failure and doing the upfront surgery? When, after you know, chemotherapy and radiation, um, would that have prevented their distant failure in their metastases? We still don't know that. So are we putting some patients at risk? And that is something that we're still trying to figure out. So in conclusion, neo adjuvant treatment strategies like total neo adjuvant therapy may facilitate durable rates of complete clinical response. Um, continued responses after these treatments could possibly enable more patients to undergo non operative management. We believe in our Siri's non operative management could be offered to those seeking rectal preservation, but more research is required to select the appropriate patients. And for those patients experiencing recurrence, the majority of patients can be salvaged surgically. So just with I just want to chat with what you guys maybe seeing in the very even near future, I'm even talking within the next year or two, it's gonna be probably part of your practices. Um, first, you know, how do we find out if watching weight is safe? You know, how do we perform that trial? Because the folks that right now are really against watching, uh and wait. The naysayers with regards to this are in fact, what I was hitting on before, with who are we putting at risk? And they do worry about those patients. This would be the optimal study design, which is, you know, a distal rectal cancer patient Obtain gets neo age of in treatment. Whether that's total new adjuvant therapy or whatnot, they get re staging. If they have no significant complete clinical response, their tumors still there. Obviously, those patients are going on to TME surgery. But if they do have a significant clinical response and maybe even their tumor disappears, then you're gonna randomize thes patients to TME major surgery versus Let's just keep an eye on it, raise your hand. If you would join this trial if you had rectal cancer, right? I mean, who would really agree to being randomized thio surgery with maybe a permanent colostomy versus Let's keep an eye on things right. It's like random izing thio Ebola of ice cream or a punch in the face. Right? What would you What would you dio? I mean, so that has been the problem. You know when When we're talking about trying Thio, get the answer toe watch and wait. Is it safe? We just can't do this trial. So a number of other trials right now we're talking with the alliance group on to see what what way? We can, you know, develop this trial that that will work currently, uh, there There's a phase two trial, the Oprah trial looking at distal rectal cancers and then random izing upfront to induction therapy versus consolidation therapy. And then, um, if patients get a complete clinical response, then all of those patients would be offered watching Wait if they want Thio. So again, it's not completely answering the question. If watching weight is safe in those patients that obtain a complete clinical response but at least more and more, we're trying toe offer this a za trial to get more data and feel comfortable that this is safe for our patients. The repeat. A trial, Um, similar to what? Years and years ago of the Swedish trial. Looking at short course radiation. Um, that has been slow to go in the United States, as probably We all know, um, but more and more, we're starting to see that short course is starting to gain some mo mentum in the United States after decades. So the repeat a trial is going on right now there is wash. You has also recently done total new age of in therapy with short course radiation and really having phenomenal results for with that. So you guys probably know more than may. Yes, higher, uh, potential dosage upfront, but less overall, five weeks of treatment versus just five days of treatment. So, in summary, rectal cancer is a difficult disease to treat, and its management is clearly evolving. Tumor response to neo adjuvant therapies air variable, and it is unclear if all modalities are really needed. TM is effective but associated with significant morbidity similar to anal cancer. Some patient, there's no question, at least to me Some patients can be cured with chemotherapy and radiation alone and can avoid surgery. But who are they? We still don't know that answer. Non operative management may be feasible in a select group of patients that achieve a complete clinical response, but clinical trials are still needed to address many of the unanswered questions. So thank you very much. I really enjoyed this and thank you for having me just want to mention a few people here. Pat Boland, who are actually losing to Rutgers, which makes me very unhappy, is a medical oncologist, and his family is moving back home. Uh, Dave Mattson specifically really have worked way. Have a great team here. Hey, does a phenomenal job with our patients with rectal cancer. Matched road is the fellow who wrote up our paper, Jill Willard and Heather, nurse practitioner in cancer care coordinator Dr Mukherjee, who's our medical oncologist now, who's really taking care of ah lot of these patients with rectal cancer and specifically Josh Smith from Memorial Sloan Kettering, who gave me a number of their slides for this talk today, so thank you very much Created by
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