Thomas D. Jones Professor of Surgery at The University of Chicago Medicine, Dr. Mitchell Posner, discusses research from clinical trials of rectal cancer.
[MUSIC PLAYING] MITCHELL POSNER: Thank you, Dr. Hyman. And I did want to take a moment to introduce Dr. Hyman for many of you who do not know him or do not know the process that has gone on for-- fairly for a long time, we've been trying to identify a leader of our newly created section of colon rectal surgery at University of Chicago and in the Department of Surgery. And after a prolonged search to identify the ideal person who could lead from both an academic standpoint-- from a clinical standpoint and from a scholarship standpoint, there was no one who stood out more than Neil. And we spent a lot of effort in trying to coerce him out of his home in Burlington, Vermont where he's been there for about 100 years. And the only way I could do it was to tell them that there are more Yankee fans in Chicago than there are in Burlington, Vermont. So that helped. So Neil, it's a real pleasure having you. And it's a real honor to have you leading our new section. I'm going to talk to you this morning. I changed the title, actually, a little bit. Because the people who really do colon rectal surgery are going to talk to you about really the innovative surgical approaches. I'm actually going to talk to you about how we can use clinical trials that are led really by surgeons to be able to change how we think about rectal cancer. By the way, I have no disclosures. So I'm going to focus on really three I think seminal trials-- one involving local excision of low-lying rectal cancer. The other, which I think is very important, is the MIS approach to rectal cancer and how to assess its adequacy. And lastly, another important issue because it has to do is quality of life is the need for radiotherapy for rectal cancer. So let me start with this. I think you all know that for most patients up to really a couple of decades ago, and in some instances still going on at a fairly high rate, standard resection for low-lying rectal cancer was an abdominal perineal resection, which of course led to a patient having a permanent stoma. However, there has been an increased focus on trying to avoid, for all the good reasons, a permanent stoma in a patient. And therefore, one of those techniques is local excision, as you can see here, which applied simply-- there are much more elegant ways of doing it nowadays-- and actually take out the cancer adequately, at least in theory, and then avoid a permanent stoma for a patient. What was noted when we looked at actually the National Cancer database that is housed here in the American College of Surgeons and started by surgeons, is that for both T1 and T2 rectal cancer, early rectal cancer, that there's been a real increase in the application of local excision over time. And you can see this both for T1 disease and for T2 disease here in blue. However, it is important to know that while we are applying it more, we have to actually balance that against what are the potential long-term outcomes with regard to the cancer itself, and understanding that our staging tools that we have nowadays are not perfect unfortunately, although they are better. That in many of these patients, even though they have early stage rectal cancer, they still are at high risk of having lymph node disease. And that leads to, of course, the potential for high local recurrence rates in both T1 and T2 disease. And this is looking at retrospective data and looking at sort of the high ends of those retrospective data. Also, if you have local recurrence, it is a disaster. And salvage of those patients is extremely poor. And finally, the evidence we are basing our decisions on are from small, heterogeneous studies from tertiary care centers, and understanding also that a prospective randomized trial in this setting is probably unlikely if not impossible. The best data we had up until recently-- one was a study that was done about now with 20 years ago led by Glenn Steele who used to be the dean of the University Chicago, which looked at the application of local excision alone for patients who had amenable disease. And what they noted in this trial that they planned to accrue about almost 200 patients. But as it turned out, only 110 were eligible for a lot of reasons, mainly because of technical reasons in applying local excision-- that T2 failures were about 20%. There was a very high rate, almost of 30% to 40% of margin positivity in doing local excision. And the six year failure-free survival was only 78%. Then Dr. Nancy You looked at, again, the NCDB data and looked now at about 35,000 patients, and looked again, as those trends in local excision that I showed you that are increased for T2 disease, from 6% to 18% over a period of time. And that T2 failures were not insignificant. And those failures, of course, do not come without cost. And if you look then at overall survival comparing standard resection, which is in green here, to local excision, you can see that there is, in fact, a statistically significant decrease in survival with the application of local excision. So this led the group, the American College of Surgeons Oncology Group with Julio Garcia-Aguilar as the PI, to design a trial to look at modern therapy and local excision. So this is a Phase II trial looking at patients with T2 rectal cancer identified by either rectal ultrasound or MRI, treating them with preoperative chemoradiotherapy, then applying local excision, and then seeing the results. The rationale, as I just showed you, was the high risk of local recurrence with T2 disease and knowing that preoperative CRT, chemoradiotherapy, can enhance local control. Looking at primary and secondary objectives that you would expect-- mainly looking at PCR rate and local recurrence rate. And also looking at disease-free survival. There were correlative studies that were built in looking at molecular markers to predict both response to radiotherapy and local recurrence. And on the right, you can see that we planned to accrue about 60 patients. We then increased that accrual goal actually, to around 100, and halted actually the trial at about 90 patients. There were amendments going on because of significant toxicity changing the capecitabine dose, as you see here, and the XRT dose as well over time. So these results, these early results looking at early markers, were published not too long ago-- actually two years ago in the Annals of Surgical Oncology. And I'll just show this on one slide. These are the early results which I think are very informative, that for T2 rectal cancer, going through this process, as you look at the upper right, you'll see that there was a PCR rate of 43%. And in fact, when you look at the two bullet points here on the bottom, you'll see that this is the highest PCR rate that's been seen actually for early rectal cancer. And in fact, most importantly, as opposed to that earlier CALGB study, there was almost 100% margin negativity rate with local excision with preoperative chemoradiotherapy. There was actually only one patient out of all the patients accrued who had a positive margin. Obviously, the more long-term results I do not have at this point because that requires some more of a time interval. But hopefully, that will be coming out in the next year or two. We also, as I said, built in some correlative science looking at markets to chemoradiotherapy response as well as looking at molecular assessment to resection margins. And of course, there are other ways to think about this going forward. And that is, there are applications-- of course TEM, Transanal Endoscopic Microsurgery, to perform a better local excision. But indeed, even looking at this idea of the concern about nodal positivity to actually think of robotic techniques to begin to look at how to sample the mesorectum going forward, which brings us to the next area, which is the application of MIS techniques. And as you know, there was a trial done in this country led by Heidi Nelson and the COST trial group looking at laparoscopy for colon cancer. And I think you all know this data very well, so I won't review it. But basically, laparoscopic application to colon cancer show that indeed, there was no diminution in terms of five year cancer outcomes, and there was a lot of benefit in terms of reducing hospital stay, reducing pain medication from a laparoscopic approach. But in applying this to rectal cancer, it is a different animal altogether, and the stakes are much, much higher. One is because we need to apply a much more complex procedure, which is total mesorectal excision. Many of these patients will be getting preoperative chemoradiotherapy. In the colon cancer group, obviously none would. There's the concept of trying to preserve the sphincter and not in any way compromising that in performing an excision with MIS. Obviously, we have to worry about anastomotic complications. But most importantly, if in fact patients fail, they're going to fail with local recurrence. And if they do, as I mentioned to you, that's a devastating complication to the patient. And of course in being able to do this and applying MIS [INAUDIBLE], we'd have to be able to achieve with an MIS approach a total mesorectal excision just like we know we can achieve with an open approach. And of course, this is just one bad picture of how to do a TME with a laparoscopic approach. We did have some data to go on before we started our own trial. This is a trial that was done in the United Kingdom, which did show, looking at overall survival, disease-free survival of local recurrence in a laparoscopic versus open technique trial, that there was no difference in any of those measures. But it was noted-- and I think it's important-- even though it didn't translate into higher local recurrence rate that the positive circumferential rectal margin, which is usually a predictor of local recurrence, was much higher, and in fact, double in the laparoscopic approach compared to the open approach. So this lead Jim Fleshman who was the PI in this trial through the American College of Surgeons Oncology Group again, to initiate what I thought was really one of the most important trials in the early part of our 21st century here, which is taking patients with stage 2 and 3 rectal cancer and randomizing them to either an open technique or a laparoscopic approach. So instead of just accepting it as being equivalent, because we could do it, is actually trying to assess its value. The patient population is what you would expect. Stage 2 or 3 rectal cancer below 12 centimeters from the anal verge, all patients received neoadjuvant chemoradiotherapy. And there were some other criteria in terms of avoiding patients with significant morbid obesity and less than 80 years old. And the sample size was about 450, and it would expand to 650 if accrual is rapid. And we in fact liberalized the ability to use both a hand-assisted technique as well as robotic techniques as the trial went on. The primary endpoints I think are very important, especially the early ones looking at ecologic efficacy, which is the circumferential margin, the distal resection margin, as well as the adequacy of the lymph node harvest, and more importantly, the adequacy of the TME. The secondary end points, I won't even focus on at this point. I think most importantly what this trial did was it assembled a dedicated group of colorectal surgeons who went through a significant credentialing process to be part of this trial, and actually for the first time in this country, begin to standardize a surgical technique in the contents of a cancer trial. And the accrual was actually quite robust. This closed in September of '13, so about a year ago, with 480 patients accrued. And the plan was to use this as a basis to then do a neoadjuvant chemotherapy trial. The early results have actually been discussed in a very close group because they are still embargoed. I can't tell you what the results of this trial are, at least the early results, even though I know them. But I think it's going to be important to focus on those results as we go forward. It might not be what you would have expected. Finally, this gave us the ability to do what I think again is an extremely important trial called the prospect trial through the Alliance. The Alliance is CALGB combined with North Central Cancer Treatment Group and ACOSOG, which was rolled into this alliance as dictated by the NCI which was looking at selective use of radiotherapy and trying to avoid radiotherapy in all trials. As you know, the current standard of care is to treat all stage 2 and 3 rectal cancer patients with chemoradiotherapy. But likely, many patients are over-treated and do not need radiotherapy. And this is especially true now that we can apply TME in most instances. Pelvic radiation is associated with short and long-term morbidity. And also understand that most patients succumb to metastatic disease. So a single center trial done at the Memorial Sloan Kettering actually showed that just by using modern day chemotherapy, we could achieve essentially the same results that we achieve with radiotherapy. And as you look at the local recurrence rate here near the bottom, you'll see that it was zero in this trial with just chemotherapy. So the objective of this trial was to use selective chemoradiotherapy and try to avoid it in a group of patients. The study design was a Phase II, Phase III study, which I'll explain in a second, over 350 patients to be accrued. And then in the Phase II setting, and then if we could prove we could do this to then go on to a better-- to Phase III study. So this is the randomization you see in the top, the standard on which is 5-FU chemoradiotherapy followed by TME, and then chemotherapy. The selective approach is to give patients preoperative chemotherapy alone. And then if they had a greater than 20% response in their primary tumor, take them to TME without radiation therapy, and then post-op chemotherapy. And if they had a less than 20% response, go to chemoradiotherapy first and then TME. The primary endpoints of what you would expect looking at the R0 resection rate and time to local recurrence. The inclusion criteria, again, of patients with fairly advanced rectal cancer-- as you can see here, the baseline clinical staging, the last bullet point, T2 N1s, T3 N0s, and T3 N1s. There are many exclusion criteria which I will not go over. These patients had to be restaged after receiving chemotherapy, as you can see on the bottom, mainly to determine the actual response to the chemotherapy. Because if patients did not respond, they should receive radiotherapy as a component of their therapy, and then go to TME. And here, you can see the criteria for how to select those patients. And again, I won't go over this because of time issues. The radiation, in fact, IMRT is allowed in this trial. Short-course radiotherapy over 5 days is not allowed. I think the most important criteria here has to do with the surgeons and in fact doing an adequate TME. And they have to actually submit photos of their TME specimens. And there are companion studies built-in as you would expect. The accrual up until now actually was initially fairly slow, but now we're up to over 200 patients on this trial. So there's light at the end of the tunnel that we'll complete this and go into the Phase III part of the trial. But again, I think the most important thing here is actually the documentation of adequate quality surgery in a TME, as you can see here, documented by photographs of the actual specimens as they're removed. As you can see here, for the uninitiated, that this actually shows a complete TME with an envelope of tissue around the specimen. And this is the other side of it. So again, my goal here was to show you how surgeons-- and this actual trial was initially designed by surgeons, then taken over by medical oncologists as they've taken over most of our care in terms of cancer care-- but designed by surgeons in a really, I think, a surgical trial. That without adequate TME and qualifications to do that that we could not do a trial like this. So again, I want to thank Dr. Umanskiy for the invitation. And again, welcome, Dr. Hyman. It's a real pleasure being here. And thank you for your attention.
