E84 Masterclass with Carl Brown on Rectal Cancer

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Carl Brown  00:00

It’s an exciting time to be involved in the treatment of rectal cancer because all of these new treatments and variations in their application are being used presently.

Chad Ball  00:21

Welcome to the Cold Steel surgical podcast with your hosts Ameer Farooq and Chad ball. We’ve had the absolute privilege of chatting with some amazing Canadian as well as international guests over the past year. While the topics have been broad in range, whether clinical, social or political, our aims for the podcast continue to remain the same. We hope to inspire discussion, creativity, scholarly research, and career development in all Canadian surgeons. We hope you enjoy our second season as we continue to highlight some incredible guests, deliver detailed masterclass sessions on a myriad of clinical topics and introduce some fresh new features such as debate and companion formats. We hope you relish the podcast as much as we do.

Ameer Farooq  01:21

Dr. Carl Brown is a colorectal surgeon at St. Paul’s Hospital in Vancouver, British Columbia. He gave us a masterclass in this episode on rectal cancer, starting really with the history of rectal cancer surgery, and then moving to the evidence around neoadjuvant therapy, and then giving us a peek at the future of rectal cancer treatment. We then discuss how we should best adopt new technologies such as TEM or TaTME. A reminder to listeners that we now have the transcripts for all of our episodes available on the Canadian Journal of Surgery website. This is a handy written resource to go over especially for detailed master classes like this one. As always, we welcome your feedback on Twitter at CanJSurg.ca, or via email at podcast.cjs@gmail.com.

Chad Ball  02:07

Well it’s an absolute pleasure on Cold Steel today to welcome Dr. Carl Brown from Vancouver. Dr. Brown’s a colorectal surgeon as you’ll hear about. Welcome Carl, thank you very much for visiting with us today. We know how busy you are.

Carl Brown  02:19

Oh it’s an honor to be here. Thank you very much Chad.

Chad Ball  02:21

I think most of us across the country and certainly in Western Canada and Toronto know you well Carl, but for those maybe who didn’t, could you tell us where you grew up and what your training pathway was, and maybe most importantly, how you ended up in Vancouver at St. Paul’s?

Carl Brown  02:35

I guess I’m a bit of a surgical hobo. I grew up in Ontario in a small town and went to McMaster University, both for my undergraduate and for medical school, which I really enjoyed. It was evidence-based learning. It was a great school to go to. And then I did my surgical residency in the University of Calgary, which I’m sure both of you would agree is the best residency program in the country, at least back then. And then I ended up doing my fellowship in colorectal surgery at the University of Toronto and concomitant to that, I did my master’s degree in clinical epidemiology, and really enhanced my interest in clinical research. And then there was an opportunity with Dr. Terry Pang, who was the sole colorectal surgeon at St. Paul’s hospital at that time, and I’d been to Vancouver for like one week in my entire life. But it seemed like a beautiful place. And when it came to visit, Terry had really set up what seemed to be an excellent opportunity to join him. And I must say, I’m really happy that I did end up here. Vancouver has been a wonderful place. The hospital I work here at St. Paul’s is great. We have excellent nursing and surgical and medical colleagues. So, and I’ve been here since 2006. So I’ve really set up my career here at the University of British Columbia and at St. Paul’s hospital.

Ameer Farooq  04:03

You know, one of the things that I love that you talk about is actually just the origin of the terms that we throw around but really have no idea where they came from or what they actually really mean. Which is the anterior resection, the low anterior resection and the abdominal perinatal resection. So Dr. Brown, could you walk us through those terms and sort of how they’re indicative of the evolution of rectal cancer surgery?

Carl Brown  04:28

Yeah, I’d be happy to. And I must credit my time at St. Mark’s Hospital in London. When I was at the University of Toronto doing my colorectal fellowship, there was a one-month exchange that we did at St. Mark’s and that was really an excellent opportunity to work with different surgeons. We worked with the original creators of the pelvic pouch surgery and it was an awesome opportunity. And John Northover, who was a surgeon there at the time, showed me a video of a rectal cancer operation that was done in the 1940s. And at that time, it was interesting because all rectal cancer surgeries were really done with a posterior approach. They would take the patient to the operating room and do a diverting loop sigmoid colostomy. And they have this all on video. And you can see the patient breathing, they’re using ether as an anesthetic. And then a couple of days later, they would bring the patient back to the operating room, put them in the prone position, and then do a posterior approach to the rectal dissection. It was quite remarkable to watch. There was very little use of electrocautery at the time. They used scalpel and sharp dissection. So they had to do it quite quickly. And they would often split the sacrum. So you would get quite an amazing view of the rectum from an odd posterior approach. And, well, we don’t split the bone, we often do take the kocsis when we do retrorectal cyst operations. So that was a fruitful operation for me to be able to see. And in the rare situations where we do see retrorectal cysts, I do use that sort of similar approach going cephalad to the edge of the sphincter, but just below the below the coccyx. And so, when that was demonstrated, I realized and I did a little digging into the history of rectal cancer surgery and that certainly was the approach initially. As you can imagine, in the early days, all rectal cancers were a death sentence. And not only just a conventional death sentence, as all cancers were at the time, but a miserably painful death. Locally invasive rectal cancer, which thankfully, is rare today, was not uncommon at the time. And so this approach was really an effort to try to remove the entire rectum and prevent a very painful, miserable death. And so the posterior approach was really the original approach to rectal cancer. And Myles was really the first one who identified why a lot of these patients were recurring. And the reason was not because of local recurrence because of the mesorectum or any of those aspects. But he did an autopsy on over 60 of his patients who had recurrence and death with rectal cancer. And he found that the recurrences were all happening along the inferior mesenteric artery chain. And so that was the incentive for him to change his approach to the rectal cancer operation. And the modification, he’s credited with the abdominal perineal approach, because again, as I mentioned, the historic approach was purely posterior approach. In his approach, he did both an abdominal and perineal approach in an effort to isolate and take the inferior mesenteric artery and harvest those nodes. And so that was really the first understanding of the importance of the proximal nodes on the inferior mesenteric artery chain. So the APR was really an effort to prevent local recurrence along the vascular pedicle. Now, Dixon, in the 1940s, was the first one to do, or is credited with the first person to do an anterior resection. In other words, no real posterior approach to the rectum. This was for a series of mostly high rectal cancers where the rectum was removed. And a mid-rectal anastomosis was created. And so this was a novel approach. And in fact, I should say that the Hartmann procedure, which is a rectal resection with the distal rectum left in place. Now we all think of that as a diverticulitis operation. But in fact, Hartman’s first paper was a couple of patients with rectal cancer where he removed the rectum but did not remove the anus. And this was considered revolutionary at the time, because everyone felt that if you didn’t remove the anus, that the cancer would recur there. So you can see that starting with miles and the APR with the IMA harvest, followed by a really tiny case series by Hartman, which showed that you don’t have to remove the anus for every rectal cancer. Then the incremental increase with Dixon who reported a large series of patients where not only was the sphincter left in place, but the bowel was re-anastomosed. And so we really experienced the advantage of this history and the benefits of all of this work that has been done over decades. And then of course, the subsequent problem between the 1950s and the 1980s was local recurrence. Because even though there were rectal cancer resections with marginal or variable nodal harvest up the chain of the IMA, as we all know now, the mesorectal package is so critical and is in a true anatomic plain. Prior to that, people would often use hand dissection. They would be in the mesorectum, and then Bill Heald, while he may not have invented a mesorectal excision, certainly colorectal surgical training had started and many surgeons understood mesorectal plane, but it’d never really been described as an important factor in preventing local recurrence. And so Billy Heald’s real contribution, and I should say John McFarland, a surgeon who worked many years here at St. Paul’s hospital, co-authored the paper on total mesorectal excision with Bill Heald. And this landmark publication in the 80s has changed the way we understand rectal cancer surgery. And so we know that the IMA harvest, the mesorectal harvest, and coloanal anastomosis are all reasonable approaches. Now in patients with rectal cancer, and of course, the anterior approach to the rectal resection is now just called the anterior resection.

Ameer Farooq  10:46

And so the origin of the term “low anterior resection”, I think, if I understand correctly meant that you were just going below the peritoneal reflection but doesn’t I guess, really have the same clinical significance anymore, you know, in terms of figuring out what what kind of operation you did.  So you beautifully illustrated this history of rectal cancer, which parallels so many of the advancements in many different areas of surgery, thinking of breast cancer, starting with a Halstead mastectomy to where we are today and rectal cancers have certainly been like that as well. You touched on Bill Heald. I think an equally important character in this history is Phil Quirk. Can you talk a little bit about what the contribution of Phil Quirk was to this whole concept of total mesorectal excision?

Carl Brown  11:03

Yeah, exactly. Yeah, I mean, Phil Quirk was a key partner with Bill Heald and this and that. Not only is it important to do the appropriate surgery, but it is important to do an appropriate evaluation of the mesorectal specimen. And the Quirk method, which is still used today is really the preservation and marking of the mesorectal margins with ink so that you can not only assess the integrity of the mesorectal dissection… and of course, when surgeons do operations, really the pathology is the product. If you think of the artist and the art, in this case, the surgeon and the pathology. And so, Phil Quirk’s method is not only an assessment of the integrity of the mesorectal excision, but has also had important contributions related to the importance of the distance of the tumor and/or lymph nodes from the mesorectal margin, and the relative contribution of that to the survival and the disease free survival and the prevention of local recurrence in patients with rectal cancer surgery. And so that partnership has been so critical and the work they’ve done to educate surgeons around the world about that combined importance has really revolutionized rectal cancer surgery. We know that the local recurrence rates for rectal cancer were in the 20 to 25% range in the early 80s. And now we know that globally in areas where surgeons are well trained and total mesorectal excision. And the pathologists are well trained and giving feedback as to the completeness of the mesorectal excision as well as some of the critical pathologic features of success of that resection or risk related to the disease itself have created what we now know is an important partnership between pathology and surgery at all institutions. And certainly we have our multidisciplinary conferences every week where we discuss every rectal cancer surgery, every rectal cancer case that we evaluate, and integral members of that team include our pathologists, the surgeons, and the radiologists. Not to mention, the medical and radiation oncologists who are critical members of that team. But the members of the importance of the pathologists in that multidisciplinary conference can’t be understated.

Ameer Farooq  13:55

What exactly is a total mesorectal excision, and why is that so important?

Carl Brown  13:59

The rectum has…if you think of the colon, the colon has the colonic wall and then the mesentery, which really runs typically linearly from the edge of the colon along the vascular supply to the root of the vessels, whether it be the ileocolic artery or the left colic artery. For the rectum, it’s a little different. Once the rectum that flows down to the anus and connects at the anus, is really surrounded by its mesentery. It’s a true network of vessels that stem from the inferior mesenteric artery. And so you can imagine it’s the rectum itself is wrapped in a variable amount, usually one to five centimeters of fat density circumferentially. And that circumferential fat has both the blood vessels and the lymphatic and venous drainage of the rectum. And the importance of it is that the mesorectum extends all the way down to the pelvic floor to the levators and the anal canal. And we know that for rectal cancers that are not in the anal canal, but anywhere above that, that all of the blood supply and all of the lymphatic drainage flows proximately into the mesorectum. And so, what this allows us is that in most areas when we do cancer surgery in the bowel, we need typically five centimeter proximal and distal margins on that tumor. But knowing that the mesorectum, this package of fat, which is separable from the pelvic floor, and separable from its lateral pelvic fascia, it is a very distinctive plane that we can see and dissect in to maintain this rectal mesorectal integrity that allows us to remove the rectum without removing the anus, all the way down with one centimeter. And some people would say just that microscopically clear distal margin, thereby allowing us to do a colon-to-anus anastomosis without getting a five-centimeter distal margin. So, the importance of the mesorectum is so critical in that it allows us to do an effective rectal cancer surgical operation while still maintaining GI continuity on a lot of patients. Now of course, if the cancer is invading the sphincter, in that case, we have no choice we have to remove the anus.

Ameer Farooq  16:31

I think that’s something that trips up residents all the time when we’re studying for our Royal College exams. Someone says, what’s the margin that you need on a rectal cancer or during a rectal cancer surgery? And you know, people start throwing out all these numbers; one centimeter, two centimeters. As long as you’re getting beyond the tumor, it’s not so much about the margin?

Carl Brown  16:52

Yeah, that’s right. I mean, the margin, the submucosal spread is limited. And this was another major important contribution of Quirk is that: he identified that all virtually or very little of the mesorectal spread of rectal cancer in the nose or otherwise is distal. It’s virtually all proximal. And certainly, as you get to the distal rectum, it does not typically spread distally. So, you can get just simply a clear margin.

Ameer Farooq  17:21

Is there ever a situation where you would not go for example, all the way down to the pelvic floor? And just do a mesorectal excision, you know, five centimeters beyond where the tumor is?

Carl Brown  17:32

Certainly. I mean, that’s an excellent question. Really, the question stems from, is there any disadvantage from doing a total mesorectal excision? Or the corollary is, is there any advantage to doing what we call a subtotal mesorectal excision. In other words, taking the mesorectum less than all the way to the pelvic floor. And the answer to that is, generally speaking function. That the more rectum you have, the better your post-operative bowel function is. And in tumors that are more than five centimeters from the pelvic floor, then there is an advantage. We still do believe that in upper rectal tumors that you should still get a five-centimeter distal margin. That the nodes and the potential for spread still can be five centimeters distal. But a tumor at 10 or 11, or 12 centimeters from the sphincters can still get a five-centimeter distal margin and then allow for an anastomosis to the rectum that’s not right at the top of the anus. So, that’s really the purpose for doing what we consider a subtotal or I guess, tumor tailored rectal resection. That not every rectal resection requires a total mesorectal excision. I would say the majority do. The majority of, virtually all mid and low rectal cancers do require a total mesorectal excision. But you can leave distal rectum and in a perpendicular to the rectum fashion, transect the mesorectam to allow for an anastomosis if you can get a five-centimeter distal margin on an upper rectal tumor.

Ameer Farooq  19:21

As we were talking about before, rectal cancers follow this trajectory that a lot of other cancers that we treat have followed. Which is that it’s become increasingly multidisciplinary and in particular rectal cancer, radiation and chemotherapy have become such an integral part of how we treat rectal cancer. Can you talk a little bit about how we know the importance of chemotherapy and radiation and in particular neoadjuvant chemotherapy and radiation or neoadjuvant radiation in the treatment of rectal cancer?

Carl Brown  19:52

Yeah, certainly. I mean, there’s really been two major trials that looked at the addition of neoadjuvant treatment. Both of which were short course radiotherapy, where patients were treated with short course radiotherapy, both in the Swedish and the Dutch rectal cancer trials, large numbers of patients. Again, I can’t remember the exact number to share with you now but of patients randomly assigned to either preoperative radiotherapy followed by surgery versus surgery alone. And in both of those trials, there has been a substantial improvement in local recurrence with regard to the patients treated with radiotherapy. Now, there have been a number of trials again, I can’t cite them immediately, but which have looked at the long course chemo radiotherapy versus short course radiotherapy alone, which have shown no real difference in local recurrence. But there is a difference when you do long course. And let me just take a step back and say that the short course radiotherapy is typically 25 gray over five days. And the long course is usually 50.4 gray over, typically 28 days, combined with  typically capcitabine. And so those two treatments don’t seem to differently impact the patient’s long-term survival or local recurrence. However, there is a technical advantage to doing long course, chemo radiotherapy in patients who have large bulky tumors, tumors which may not necessarily invade the sphincter, but because of their bulk may technically make a coloanal anastomosis difficult or may encroach because of technical reasons on the distal margin. And so, in those patients, long course chemo radiotherapy has the advantage of tumor shrinkage, which can help with the surgical aspect of things. Now, of course, there’s always a price to pay for any treatment that you add and certainly radiotherapy can lead to problems with bowel function after when you radiate the sphincter, radiate the pelvis. Functional outcomes can be compromised, not to mention the fact that in patients who may have subsequent…in men, prostate cancer or cervical cancer, you eliminate the possibility of using radiotherapy in the future. And so, the use of radiotherapy has been a real bonus in terms of preventing local recurrence in rectal cancer, in addition to enhanced total mesorectal excision techniques. But because of these compromises that are required, there has been some work in the last several years. The mercury trial in the UK where patients who would traditionally be treated with radiotherapy, early T3 cancers. Some patients even with early positive nodal disease, have forgone radiotherapy if they have a clear mesorectal margin of more than five millimeters, and can be clearly resected by TME, with colorectal anastomosis. And have demonstrated in these series to have good outcomes. And in Canada, led by Dr. Aaron Kennedy, a number of sites including ours have worked together to do a follow up quicksilver study where we showed similar outcomes, which were good outcomes in those patients with no radiotherapy. So, the tale of radiotherapy in these circumstances is interesting. It has been very important in reducing the risk of local recurrence typically by about half of the baseline rate. And its selective use is critically important. The chemotherapy story is a little different. There have been a number of randomised trials looking at chemotherapy after rectal cancer surgery. Certainly in colon cancer surgery patients with straight stage three colon cancer benefit from post-operative chemotherapy typically FOLFOX which is fine, was just leucovorin, 5-FU, and oxaliplatin. However, in rectal cancer, it is a bit more controversial, certainly in the United Kingdom. Most patients are not treated with post-operative chemotherapy because of the potential marginal benefit with potential harm. And the biggest harm for oxaliplatin is typically… I mean there are all kinds of harms up to it including death, but the harm that a lot of patients complain about is their numbness and neuropathy and their fingers and toes. And in fact, I had one of my patients recently just talk about how he can no longer play hockey because he can’t really balance properly because he can’t feel his feet well enough in the skate. So, you know, these are important survivorship issues in patients and that’s why we have to be quite selective. And because of the lack or the concern about the lack of efficacy with chemotherapy after rectal cancer, there was a recently published RAPIDO trial out of the UK where they had randomized patients to neoadjuvant chemotherapy combined with short course radiotherapy. And in those patients, it did seem to improve disease free survival, although it did not improve overall survival. So there is a big interest in neoadjuvant chemotherapy, particularly because there is an interest in non-operative treatment of rectal cancer and so it’s an exciting time to be involved in the treatment of rectal cancer. Because all of these new treatments and variations in their application are being used presently.

Ameer Farooq  25:30

I completely agree. Rectal cancer is such a dynamic and wide-open field. Like there’s so many different things that are being investigated. You know, there’s this tension, as you pointed out between giving people total neoadjuvant therapy where you’re giving everyone chemotherapy upfront, versus this tension, where we’re worried about, potentially over treating people. So it’s quite a complex but interesting, sort of a balance that we’re having to deal with. And I think that’s why, you know, setting up a multidisciplinary tumor board, as the group here and many other places have done is so important.

Carl Brown  26:04

Yeah, I think, you know, it’s so intriguing. Because if you had a T3N0 rectal cancer, in some jurisdictions, you may get total mesorectal excision alone, with no radiotherapy and possibly no diversion as well. So, a single operation with curative intent. Whereas in other jurisdictions, you may get chemo radiotherapy, and possibly no surgery at all. And so, if there is a complete response. And so, yeah, it’s a very intriguing time. And it does make it difficult, I think to know exactly what the right thing to do is for every patient, but as you’ve alluded, the importance of multidisciplinary conference, the importance of engaging patients to understand what their priorities are, and understanding their risks of whether chemotherapy, radiotherapy, surgery, and their risk tolerance is so important in tailoring care for each individual patient with rectal cancer. So, it is an exciting time to be involved in that care.

Ameer Farooq  27:11

You mentioned briefly non-operative management. Can you explain a little bit what non operative management is and what that entails?

Carl Brown  27:19

Certainly, so, as we’ve discussed, the use of neoadjuvant chemo radiotherapy, radiotherapy combined with chemo has effectively reduced the tumor bulk in patients and the part we didn’t touch on is how do we know that’s the case? Well, because typically, at least in the initial days, when we would do surgery for rectal cancer after chemo radiotherapy, a lot of people advocated doing the surgery at four weeks. But either through practical difficulties or by intent, many patients wait longer than that. When it could be four, six, eight, ten, twelve weeks. And with that variation in care, we started to recognize that some patients were having what appeared to be complete resolution of the tumor. We would do the surgery for rectal cancer and find no tumor in the rectum. No nodal disease, no residual tumor to speak of. At that time, this is a little bit before my time in terms of clinical practice. There was a lot of discussion about not doing surgery for these patients. But someone had to be the first to do it. And Angelita Habr-Gama and her team in Sao Paolo, Brazil, were the first to publish on this. And in fact, and I think I might have been a resident at the time, when this was presented at the American Society of Colorectal surgery meeting, she presented their data on patients who had had non-operative management that they were just following. And she was pretty much shoed off the stage by the leaders of the American Society of Colorectal Surgery. And essentially, they said that this was more or less quackery. I mean, they they were quite dismissive of this approach when it was initially presented. But as time has gone on, it has become more and more appealing, not just to patients, but to clinicians who deal with people with rectal cancer. Particularly because it’s not out of the question that you could do an operation in person who has had a complete response to rectal cancer. And they could either have serious morbidity or even mortality from the surgery. And I think any thoughtful clinician would have to wonder whether the surgery was actually necessary. So now there are a number of groups and we’re one of them in a Canadian Consortium. But there’s a group in Basingstoke, there is a group at Memorial Sloan Kettering who’s done a lot of work on non-operative management, where patients are reassessed typically anywhere from six to 12 weeks after their chemo radiotherapy with endoscopy and MRI, and if the patient has no apparent disease are offered, non-operative management. In other words, observational management. Now in those patients, observation is not similar to what we would do in a patient who has had a radical resection where we do a CT scan on an annual basis, a couple of colonoscopies in the five years after their follow up and see levels and clinical evaluation. These patients are followed intensely with frequent endoscopic evaluations anywhere from every three to six months, frequent CT scan and MRI every three to six months to ensure that the patients have not had local recurrence. And this is typically in a study protocol. And the best data that we have so far is an international consortium, where it appears that the five-year local recurrence rate in these patients is in the range of 25 to 30%. So, it depends on whether you’re a glass half full or half glass half empty person when you observe that. Some people would say, well, 25 to 30% of recurrence is a terrible outcome from cancer surgery or from cancer care. But others would say, and I think the majority of us sort of are starting to feel this way: that as long as those patients can be salvaged, and there’s a lot of data that suggests they can be salvaged with radical resection, that we’ve at least prevented two thirds of people from having a radical resection that may not have required one. And you have to remember that complete responses only happen, at least with conventional care, somewhere between 15 and 20% of the time, so the vast majority of patients are not going to get a complete response with conventional chemo radiotherapy. But for that subgroup that do, if they choose and are willing to undergo the surveillance with non-operative management, then I think this is an excellent option for them. But again, I think it should be in the context of a clinical trial. And when I say a clinical trial, I really mean a clinical registry. Where their data can help inform patients in the future about what the best course of action will be for them. And so, we are contributing to a Canadian consortia and every patient that we enroll in non-operative management, we collate and collect their data. And we’ll critically evaluate that data in the future.

Ameer Farooq  32:18

And just to be clear, people who are evaluated for non-operative management, these are people who were candidates for neoadjuvant chemotherapy and radiation upfront?

Carl Brown  32:30

Yes, of course. These are patients who, frankly, most people who do enroll people in a non-operative management strategy, we typically don’t make any promises upfront because again, so few patients do get a complete response. We identify patients who would be candidates for chemo radiotherapy, again, as I’d mentioned, in British Columbia, that is any T3 or greater disease in terms of local invasion. Or any N-positive disease with no metastatic disease, all of those patients would be offered neoadjuvant radiotherapy, and again, often chemo radiotherapy.

Ameer Farooq  33:15

But the irony here is that people with early cancers have to undergo radical surgery in our current paradigm. And they’re not even offered the chance at a complete clinical response from chemotherapy and radiation because they would never be offered neoadjuvant therapy to begin with. And I think that segues nicely into the Neo-trial, which you just finished recruiting patients for. Can you tell us a little bit about the Neo-trial and what motivated you to do that trial?

Carl Brown  33:43

There were a couple motivations. I mean, one, the idea of treating early rectal cancers with more aggressive neoadjuvant therapy is not new. I mean, there have been a number of studies that have investigated the use of chemo radiotherapy, followed by local excision in patients with T1, T2 and T3 disease historically. First, the development of transanal endoscopic surgical techniques within operating endoscope, laparoscopic camera and minimally invasive instruments has certainly enhanced our ability to do local excisions in the rectum with wide clear margins for early cancers and certainly, T1 cancers with favorable features are good candidates for that approach. Now in patients who have T2N0 disease on MRI, that has a very high risk of local recurrence and should only be really recommended in a palliative sense or in patients who refuse and are unwilling to undergo radical resection. But the CARTS trial out of the UK enrolled patients with T1 to T3N0 disease, treated them with neoadjuvant chemo radiotherapy, and subsequently had those patients undergo local excision. And in the patients who had favorable disease after local excision, they experienced very low rates of local recurrence in three year follow up of under 10% or around 10%. And so that was a good demonstration of the potential for that. And in fact, even before that, an author from Italy – Liz Oche had randomized 100 patients with T2N0 disease to chemo radiotherapy, and then laparoscopic surgery versus local excision surgery. And similarly found no difference in local recurrence or disease-free survival in those patients. So there has been building evidence for the idea of using local excision combined with neoadjuvant therapy in this context. And in fact, there’s another trial – the TREC trial was recently published. They did a similar approach and found similar short-term outcomes. As well as another one – the GRECCAR study, which is a similar sort of approach. The downside of radiotherapy followed by local excision is that the complications after local excision surgery after radiotherapy are significant. In fact, Rodrigo Perez, who was a partner of Angelita Habr-Gama in Brazil, published on some of the difficulties which include fistulas, and infections, and pain and bowel dysfunction, all of which are a result of the radiotherapy and likely the challenges of healing in the rectum when the rectum has been radiated. And we were involved, our medical oncology partner here, Hagen Kennecke had worked with us here at St. Paul’s Hospital. He was at BC cancer to recruit patients for the prospect study, which was a study ran out of the Memorial Sloan Kettering, Julio Garcia Aguilar, where patients were being treated with neoadjuvant chemotherapy alone. Typically for patients who would be typically treated with chemo radiotherapy. And so, we were enrolling patients in this trial. I must say I was a bit skeptical of using chemotherapy in a neoadjuvant setting. But we did recruit for that study. And what we found were that a number of patients had a complete response with chemotherapy alone and no radiotherapy. And so, we found this very intriguing. And certainly the surgeries were a lot easier when the patients hadn’t been radiated. And anecdotally, we had seen that patients seem to do better with neoadjuvant chemotherapy when compared with chemo radiotherapy. And so, several years ago, we put together a trial proposal where patients would be enrolled in a phase two study where we would treat them with neoadjuvant chemotherapy FOLFOX in patients with T1 to T3N0 disease, followed by reevaluation with MRI and flexible sigmoidoscopy. And as long as they hadn’t had progression or had some response, then the patients would then go on to local excision. And we had a number of centers in Canada and the US who agreed to participate. The Canadian Cancer Trials group agreed to fund the study, and we’re grateful to them for doing so. And we have completed enrollment in 2020. And we will be presenting this work at the American Society of Clinical Oncology in the coming year. And I can say without sharing the details of the outcomes that many of the patients clinically had what appeared to be a complete response. And so we are quite excited about this. Again, without sharing all the details, the complications after local excision were minimal when compared to patients who had local excision after chemo radiotherapy. So, we think this is an exciting option. We look forward to sharing the results of the study. And we are already working on a follow up study to recruit a larger number of patients to get a better sense of the longer-term outcomes in a randomized control trial.

Ameer Farooq  39:15

I do want to take a step back here and just point out that it is not easy to conduct a trial like the one that you put on with Neo, particularly in the Canadian setting and being a busy clinician like yourself. Can you talk a little bit about how you sort of set in place the infrastructure? And you know, I’m thinking about the work that you did early on doing the trial on “to close or not to close” after a transanal excision and how that maybe helped you build the collaborative relationships you needed to actually pull off the Neo trial.

Carl Brown  39:55

Yeah, certainly. I mean, I think I learned a lot about research and teams and team building during my time at the University of Toronto. Robin McLeod was certainly an inspiration in that regard. And so when I came to British Columbia, I was very interested in replicating some of the work they had done in putting together a strong team at this center, at St. Paul’s. But more than that, nationally, we had a very interested…and continued to have a very interested group of surgeons, particularly colorectal surgeons who are extremely collaborative. And despite the geographic issues that Canada has, we really all wanted to work together. We were all inspired to do research as a team. And so I feel very grateful that people like Hussein Moloo in Ottawa, and Lara Williams, who was originally at Dalhousie, but is now in Ottawa. Dave Hochman in Winnipeg and a number of others who collaborated on this trial, as well as Dr. Manoj Raval here at our site. Terry Pang as well at our site. We agreed to do a collaborative multicenter research project. We were all interested in transanal endoscopic surgery. And we had noted anecdotally that you could leave the defect unsutured, which I thought was bizarre when I first went into practice, because I’d never seen that before. It was actually Terry Pang that had showed me that you could do that. Where we would resect even an adenoma in the rectum, and not close the rectal wall. And with the mesorectal envelope surrounding the rectum as we discussed earlier, that would act as a healing matrix and the rectal wall would regenerate on top of that mesorectal base. And so we knew we could do it, we had all done it clinically. But anecdotally, we had all perceived that there might be a higher risk of pain or complications when we did that. And so we as a group, decided that we should investigate this in the way that is the best way to answer these questions. And that was in the form of our randomized trial. And so we all agreed to randomize patients to this. We got funded by the Canadian Society for Colorectal Surgery, for which we were grateful. And we recruited patients, and found that there really was no dramatic difference between suturing the defect shut or closing it after that surgery. That was the finding of that randomized trial, which we ultimately published, I believe in Surgical Endoscopy. And the lessons I learned from that trial were many fold; one is that organizing, and as you’ve said, being a busy clinician, it’s very difficult to do that work on the side of your desk. And I wasn’t sure when I started my practice whether the ideal situation would be that I would have, quote, unquote, protected time where I would do a lot of that work myself. But what I quickly realized was that it’s difficult to do that as a clinician, especially as a surgeon, where your technical abilities and your technical proficiency are dependent on your clinical activity. And so when I first came here, we worked very hard to build a team. We were involved in research, where it was funded research through different organizations, like CIHR and other funded trials. And while we originally had a nurse clinical research coordinator, we quickly realized that the funding mechanism that we would receive for the studies that we would perform or participate in, compared to the actual costs of running those trials, was onerous. And so we had to come up with another way. And when we met as a team, one of the medical students actually said, “why don’t you just check the co-op program?” And I thought this was an ingenious idea. And so we solicited the co op program, and we hired our first science Co Op student for a one year term. And really, that was the start of our research team. Now we have four Co-Op students that we hire in a cycle, cycling every four months with new Co-Op students. And they are incredible at maintaining our databases. Doing our research, ethics board approvals, coordinating the finances of these studies. Coordinating with all the different areas of the hospital and with other centers in terms of running our research. So, we are a very lean research team now and we conduct… I think we’re participating in at least 10 different trials presently. And recruiting patients. Now of course, with COVID, most of them have been stalled a little bit. But nonetheless, this has been an incredible team and we’ve talked about this model with many others, and we know at least in BC, the orthopedic surgeons as well as I believe the urologist have replicated this team structure as well. And unlike in some areas like cardiology or gastroenterology where there may be a lot more money in trial work, for us, this has been a highly effective approach. And I must give a lot of credit as well, to my colleagues here: Drs. Raval, Pang, Karimuddin and Dr. Ghuman, our newest recruit, who really all philosophically believe in the same mission. Which is that we want to provide the best possible care as a team, but we also want to create knowledge and to improve the care of future patients through the participation in trials and in research.

Ameer Farooq  45:43

I wanted to shift gears a little bit, Dr. Brown and talk about something that’s related to this but slightly different. Which is how you sort of got started doing TEM and TaTME. And really, I think Vancouver has become a leader at least nationally on both of those fronts. Can you talk a little bit about how you got interested in TEM?

Carl Brown  46:05

You know, when I came to Vancouver, I was fortunate the timing just seemed to be right, because Dr. Pang had solicited donor funds. And let’s face it, in Canada and probably across the world actually, a lot of new technology is often funded by donors. Individuals who we’ve worked with, patients typically who want to enhance the care at their local hospital. And so, the transanal endoscopic microsurgery platform, which is quite expensive, I think it was in the range of $150,000 to buy all the components, had just been purchased through a donor funding here at St. Paul’s hospital. And I had done quite a bit of laparoscopic surgery both at the University of Calgary and in the University of Toronto, when in my training. Although I didn’t have a lot of experience with transanal surgery, I felt like the techniques were somewhat transferable. And so I had endeavored to learn to do the technique. And at that time, very few people were doing it in Canada or in North America, frankly. And I give a lot of credit, really to the surgeons of British Columbia, because I spent a lot of time presenting on the technique, presenting on the availability at St. Paul’s hospital and our interest in expanding our abilities of doing that. And the surgeons here, you know, we all sort of rally around the University of British Columbia in this province. And so I must say that in in BC, there’s a really strong sense of community. And the surgeons here, once they identified that we were offering this opportunity had no problem sharing their patients with us, ensuring they knew that this opportunity was available. And very quickly, we built our experience and became proficient with transanal surgery. And again, I came here in 2006. And so, you know, by 2010, I think we were doing about 100 cases a year, which is quite a few. And it just so happened that around that time Pat Sylla, who’s now a surgeon, I believe in New York, had gone to Barcelona to work with Antonio Lacy and had started developing this concept of doing a rectal resection with a lot of the surgery done from the transanal approach. They’ve done a lot of cadaver work on this. And so really, there was just fortunate timing because not only were we interested in this technique, we saw what might be an advantage of what is really a quite difficult operation laparoscopically to get to the pelvic floor. That maybe the transanal approach might be a solution to that problem. And so we communicated with Pat and with others who were early innovators in the surgery. I traveled to Florida, worked with Sam Atala and do a couple of cadaver cases with that team. And then we partnered with our patients. We had patients who we knew would be difficult to create a coloanal reconstruction using conventional techniques, typically obese men with low tumors. And we were fortunate enough that our first patient that we did a TaTME in and was a larger patient with a carpeting adenoma. So the risk was quite a bit lower than with a cancer where those stakes are obviously very high. And so through these partnerships with patients and informing them, that this experimental new operation where we didn’t really know what the long term outcomes were, but we were optimistic really created an opportunity for us to learn this technique. And now we’ve done over 200 of these operations. I haven’t looked recently, I think we might be approaching 300. And you know, Dr. Robertson, Regan Robinson, one of our recently graduated fellows informed me that we’re getting our propensity score matching paper published in the British Journal of Surgery, where we’ve demonstrated the results in matched patients compared to conventional surgery lead to higher rates of coloanal anastomosis, strangely lower rates of leak, but equivalent oncologic outcomes in our experience. So, we were quite happy about that. And again, I think the important thing here was that we were very cautious about the introduction of the technology. We created clear guidelines about who would be appropriate for the operation, and what the steps we would do locally to ensure the safety of these patients, including presenting them at our multidisciplinary conference. Including making sure two of the surgeons attended for the perineal aspect of the operation, which was the new part. And I’m very proud of what our team has done in stewarding this new technology. And I’m grateful to both my partners and the patients who’ve agreed to embark on this journey with us.

Ameer Farooq  51:01

You have some excellent videos on TaTME on YouTube. And so rather than go through it here, I think I’ll just point listeners to your YouTube videos where you kind of demonstrate your technique. And then the second thing is we’ll link in our show notes to the webinar on TaTME where there’s an excellent discussion that you have with Marcus Bernstein and Dr. Data, Aaron Kennedy and Jason Park about the merits and benefits of TaTME. So, we won’t belabor that here. But what I did want to talk to you about and this is something I think you and I have had many conversations about is the idea and the concept of innovation. Did you always sort of think of yourself as someone who would embrace innovation? You know, they talk about people being early adopters or late adopters. Are you someone who’s an early adopter in everything? Or is this something that you specifically saw as being something that you thought would be novel and had real merit and benefit to?

Carl Brown  52:06

I wouldn’t say I embrace all innovation. I think when it comes to innovation, a couple of things. One, I think laparoscopic cholecystectomy has had an interesting impact in surgery. Where I think historically surgeons have been quite conservative. But the wave of laparoscopic cholecystectomy that swept over the world really in terms of the enhanced outcomes in patients who were treated with laparoscopic cholecystectomy, compared to open cholecystectomy really changed the paradigm in the way surgeons view new technology. Nobody wants to be the last person to learn how to do a laparoscopic cholecystectomy, which is good in some ways, but dangerous in others. I would say that we may be have gone through and maybe continue to be going through a wave where people may inappropriately or too early adopt new innovations without a critical eye on the outcomes that matter most importantly to patients. And so, I would say I’m always one who’s intrigued by new technology. But I do think that when we embark on incorporating new technology in our practice, especially as surgeons, one: there are opportunity costs when we pay for new equipment or new instruments. We are by nature foregoing other opportunities that we could use. So, I think we have to be careful about where we make those investments. And secondly, I think we have to ensure that we don’t tie our personal futures to the future of these technologies; that if we do embrace them, and we see potential opportunities for them, that we look at them critically. That we are very open to abandoning procedures, if we can’t show that they show the improvements that we think they did. And try not to prematurely widely adopt new technology until we are certain that patients are safe. Because really, you know, when you’re when you’re introducing a new technology, we don’t take the risks, the patients take the risks. And so I would say when it comes to technology, I am always interested in adopting new technology. But I want to do it in in the safest possible way with patients as our partners, not as our guinea pigs, so to speak.

Ameer Farooq  54:23

You’ve touched on this already, which is that if you’re going to introduce something new, that you really have to study it and make sure that you have good outcomes. Are there any other key components that you think are really critical when introducing a new technology or a new technique in surgery?

Carl Brown  54:42

Yeah, I think that there is, as I sort of mentioned with the partnership issue, I think that full disclosure to patients about what is known and what is not known and what your experiences are with that operation are critically important. I think that particularly in surgery, where there’s a technical element to a lot of these procedures, we know there are learning curves, we know that the first operation you do in a certain technique is never going to be as good as the 100th that you do. You know? It’s not the same as introducing a beta blocker or some other drug where if I give the drug or you give the drug or someone in Indiana gives the drug, it’s all the same drug. In this case, every operation is a bit nuanced and different and the technique and learning curve is important. I do think that critical evaluation and some form of gatekeeping at an institution is important for new technology. One of my favorite papers ever published was in the Annals of Surgery a couple of years ago, and it was entitled, “Hey, I just did new operation”, something like that. Where the Hospital for Sick Kids in Toronto, I believe, Langer was one of the authors on that paper, they outlined a very clear criteria where a proposal had to be submitted to the department head of surgery that once approved, which virtually all of them were if there were new technologies well thought out, that there was an obligatory presentation of outcomes. I believe, on a six-monthly basis at their quality assurance rounds. I think these are some of the really important aspects of introducing new technology. And I think if you are going to do a new technique, it is an obligation that you collect and share that data. In the modern world, single center series of 10 patients are not the way we understand how certain new surgeries are done anymore. Multi-institution registries are very easy to put together. And, I think that anytime there’s a new operation, that is an important part of the evaluative phase. And for us, very early on, we’re connected with Roel Hompes. He’s a surgeon at Oxford, who had put together an international TaTME registry with a partner, his PhD student, Marta Pena. And, we have shared every single patient’s data that we’ve done a TaTME on with that team. And they’ve had multiple publications in which we’ve been coauthors of 1000s of patients where we have a better understanding of this operation than we would have, through 20 different centres publishing 20 patients each. So, I think in today’s day and age, that is the standard for introducing new technology.

Ameer Farooq  57:38

Dr. Brown, it’s been fantastic to have you on the show. And so, thank you again for joining us and giving us your time and your thoughts. The last question that we ask almost all of our guests, is, if you could go back in time, having done the things that you’ve done now and having had the career thus far that you’ve had. If you could go back in time and give yourself advice as a trainee, what would that advice be?

Carl Brown  58:02

Surgery is a very humbling profession. And try not to allow yourself to get too high in the highs. And try not to let yourself get too low in the lows. Because in this career, when you have successes, you feel amazing. You feel like you’ve helped someone. You have a very positive experience there. You should always be reminded that, you know, you haven’t figured it out any more than anyone else. That you still have to be diligent and careful. And the next bad outcome is just around the corner, even though you may have done the exact same thing. So, I think one of the key ingredients to that is to surround yourself with colleagues if you can, this isn’t always possible, but surround yourself with colleagues who are in equal measure critical and supportive. You don’t want people who are only cheerleaders. Because then you may do just as many wrong things as if you have people who are only naysayers. And so yeah, I think in surgery, it’s not an individual sport anymore. It’s a team sport. So, try to find a good team and try to have both support and critical elements in that team.

Ameer Farooq 59:04
You you’ve been listening to Cold Steel, the official podcast of the Canadian Journal of Surgery. If you’ve liked what you’ve been listening to, please leave us a review on iTunes. We’d love to hear your comments and feedback. So, feel free to email us at podcast.cjs@gmail.com, or connect with us on Twitter @CanJSurg. Thanks again.