Risk of local regrowth after watch and wait in rectal cancer: Dr. Perez

Manju 01:24
Okay, hello, everyone. Let’s get started. I’m Manju George, I’m the Scientific Director at Paltown Development Foundation. Welcome to Doc Talks. Today we have with us, Dr. Rodrigo, Perez, all the way from Brazil. And he’s going to talk to us about Watch and Wait, the risk of local regrowth. So before we start, I want to ask Dr. Perez, how he got involved in doing the kind of work that he’s doing. So could you tell us a little bit about how you got into this?

Dr. Perez 01:57
Of course, Manju, thank you very much for having me. It’s really a pleasure and an honor. So basically, I work with the surgeon who actually had the initial idea that perhaps a few patients with rectal cancer did not require an operation and she was Dr. Angelita. I’ll show you her picture in a minute. She really, you know, had the vision that there may be patients who had a complete clinical response after chemo or radiation therapy. Maybe they did not require surgery and in the beginning, it was quite, you know, controversial. People were nervous about the idea of not operating on rectal cancer. And now after maybe nearly 30 years, it’s become you know, a lot of people accepted it, and this has been done worldwide. So and now basically, we kept on looking at the data constantly to make sure we were not doing any harm to our patients. And what I’ll share with you today is just just a little piece of the work that shows that well, you know, even though this looks perfect, there are some problems and you really have to be careful about it and simply knowing what the problem is and inform people that you know, maybe you have a perfect outcome, but there is a chance that problems may come down the line. So this is just a word of caution that like anything else in medicine, there’s there’s always a price to pay for everything we do right

Manju 03:49
Okay, sounds good, then. Let’s get started.

Dr. Perez 03:53
Okay, so, um, basically what I will show you is, you know, these are my disclosures, by the way, I work for Johnson and Johnson and Medtronic. Basically educational talks.

Dr. Perez 04:06
So, basically rectal cancer used to be a surgical disease meaning that if you had rectal cancer, you required radical surgery and this is basically the specimen that we come up with. And you know, I’m a surgeon, and I like to do this operation. But the problem is that this operation, you know, no matter how good the surgeon is, and how good the surgery was, this operation has significant consequences to our patients. You know, patients can get really sick after this operation. Now, actually, some of these patients actually die after this operation, because it has many related complications and even if you know you do well after surgery, there are several problems that you have to face down the line including urinary dysfunction, sexual problems, fecal incontinence, even when you don’t have to cope with a definitive stoma. That for many people is, you know, quite a significant limitation of rectal cancer management. So these are problems that we often have to face when we do surgery for rectal cancer. And this is why this particular surgeon who is Professor Angelita, we used to call her the queen of coloproctology. She was really the one who, you know, had the idea that perhaps patients who had a complete response to chemoradiation therapy perhaps these patients would not require rectal surgery and avoid them and potentially protect them from the morbidity from the mortality and from all the consequences that I’ve listed to you in this slide. So basically, some of the patients who actually had you know these nasty cancers they underwent chemoradiation therapy and it seems like magic but really some of these patients when they do chemoradiation therapy, even though you don’t really expect this to happen, and this is an actual patient of mine. The tumor is gone the complete clinical response after chemoradiation therapy and these patients sometimes we cannot see any cancer at all, after the patient has undergone chemo or radiation therapy. So it is true and it happens to a quite significant number of patients depending on baseline stage and depending on the actual chemoradiation regimen, this is something that may happen to a quite significant proportion of these patients. Now, as this has become very popular, it is my task today to show you what the problems may be.

Dr. Perez 06:52
So the first message I’d like to make sure that everybody gets is the fact that we would only offer this kind of treatment without surgery if the tumor is really low. I mean, you need to have a rectal cancer that needs to be below this dotted red line there. And I use magnetic resonance imaging to point out that the cancers need to be very distal, very close to the anus. Why? Well because if you have a cancer that is above this line, you’re probably best suited for surgery. The complications are less, the dysfunctions are less catastrophic, and the mortality is not that significant. But when the tumor is located below this dotted line, then is that’s when the problems begin in terms of the functional outcomes in terms of morbidity in terms of definitive stoma has but also when the tumor is located below this line, it means that we have an additional tool to assess tumor response which is our finger. So when we as doctors examine these patients, we are actually using a very important tool in assessing tumor response because if your tumor is located above this line, it is very likely that the finger will not reach the area of the initial cancer and which means we are less we are you know we cannot assess the tumor with a finger which is an important tool as I will show you in a bit. So when we do chemoradiation therapy, basically what we want to see something like this: so we want to see a complete response with our finger. We want to see this white little scar as you see that, there is no ulceration. The tumor is completely gone. Now I’ll show you some examples. This is a cancer on the left-hand side prior to chemoradiation therapy and then when you look at after chemoradiation therapy, it’s completely gone. This is the perfect scar we want to see. And these are the patients that we are actually considering for a watch and wait, which means that we’re not going to operate these patients. We’re going to be following them up with all these, you know studies that the finger, the endoscopy, as I just showed you. And finally, MR has become an integral part of this assessment criteria. So we usually use the finger, we use the endoscopy and finally the MR. Which shows you basically there’s nothing around the rectum which is the mesorectum. So we don’t see any lymph nodes. We don’t see any affected vessels there. And then now the radiologists have become so proficient. In looking into this, we want to see this really low signal black scar in the rectum, suggesting that there is a complete response both clinically endoscopically and radiologically. So that’s what we want to see to really consider a patient candidate for a watch and wait strategy.

Dr. Perez 10:19
Now. I have an important message for you all regarding the role of biopsies a lot of people have now are disregarding endoscopic biopsies, and I want to clear this information for everyone. So a Biopsy is not a criteria for watch and wait. It means that if you have a negative Biopsy, it doesn’t mean you have a complete response. It only means you have a negative Biopsy. So you have to be careful because we you fulfill the three criteria I just told you about: endoscopy, radiology and clinical assessment, you really don’t need a negative Biopsy. Now people often mistake because they have a negative Biopsy, they start saying they have a complete clinical response. It has nothing to do with it. If you have a negative Biopsy, all you have is a negative Biopsy. Now be careful because if you don’t fulfill the three criteria I just mentioned, then the negative Biopsy may actually be misleading. It means that if you have a negative Biopsy, but you don’t fulfill the three criteria, you actually be may be looking at residual cancer, but simply the biopsies weren’t able to detect the residual cancer. So be careful with a negative Biopsy because often people think that a negative Biopsy is you know, a Go-ahead signal for watch and wait and is absolutely not. Be careful with negative biopsies because they actually may be misleading in this scenario. So really have to think about the three criteria I just mentioned which are endoscopy, radiology and clinical assessment as the most relevant features.

Dr. Perez 10:19
Now another question is what chemoradiation do I have to undergo to really think about organ preservation and we have some interesting data to suggest that whenever you achieve something like this, like a perfect complete clinical response with all three criteria, it doesn’t really matter what kind of treatment you’ve undergone. So if you’ve done short-course radiation, long-course radiation, consolidation, induction chemotherapy, it really doesn’t matter. Once you’ve achieved this, you’re good to go for a watch and wait like I said, it doesn’t really matter exactly what kind of treatment you have undergone. And this is what the conditional survival data shows. It shows that regardless of the actual treatment that you’ve received, and then a second variable comes into play- achieving a complete clinical response, but even more important is sustaining a complete clinical response. So the longer you sustain a complete clinical response, more likely you are to never require an operation at all. So it really accounts in your favor as long as you sustain a completed response. And then it doesn’t matter what baseline stage you had and what kind of treatment you had. The fact that you achieved and sustained a complete response are the two most relevant factors in a successful watch and weight program.

Dr. Perez 13:10
Now, what’s the problem? The problem is when you have something like this, you’ve achieved a complete clinical response and then you have not anymore. What does this mean? It means that the cancer has regrown. What we usually call these regrowths, and the definition is quite tricky here. And what everybody has to be careful about this. This is not a new cancer. It’s the same cancer. It simply has grown back again. A lot of people think it is a new cancer. It’s not a new cancer. It’s the same cancer. So if this is the same cancer, it means what we thought was a complete response wasn’t. It means it really you had an incomplete response apparently looked like a complete one, but it was never a complete one, it was an incomplete response that we have mistaken for a complete clinical response.

Dr. Perez 14:54
Now the second important concept here is once you have something like this, an incomplete response or a regrowth, which are basically the same thing. You’re actually looking at a cancer now, that may be worse than it was in the beginning. Now this is quite tricky again, and why is that so? Now this is the concept that when you treat a cancer like this with chemo radiation, you end up killing the good cells, and you’re left with the bad cells. And once the cancer is growing back again, it means you’re looking now at the very resistant cancer cells. And now this cancer may actually be worse than the one you had in the beginning because the proportion of resistant cancer cells is bigger. So these two concepts are really important. That we’re looking at number 1). regrowths are really incomplete responses that look like a complete response. That’s number one. And 2), the cancer now may be worse than it was in the beginning.

Dr. Perez 16:09
Now how often does this happen? Well, apparently 1/4 of all patients who achieve a complete clinical response will develop a local regrowth. So one out of four patients will have a local regrowth over time. That’s number one. Number two when it happens, it usually happens within the first three years of follow-up. You can see the plateau in this curve here. When you reach three years, the risk of local regrowth becomes minimal. So the three-year period we as surgeons here we have become obsessive in surveilling these patients to make sure that we don’t have a local regrowth and I’ll show you in a minute why we are so obsessive.

Dr. Perez 17:00
Now, surveillance needs to be done and we have some good news. The first good news is whenever you have a local regrowth, the vast majority of local regrowth there is a endoluminal component. There is a rectal wall component of the local regrowth in 95% of these regrowths. Now this is very important because it means that the finger and the eye will be able to detect 95% of them. You don’t really need you know fancy studies as long as you do proper surveillance. You will be able to detect 95% of them. And that’s why clinical assessment is so important. Now I always show this picture because this video is a patient of mine. If you look at it, it looks like a perfect complete response. But the clinical examination was somewhat suspicious that I thought there was something there. So endoscopy may sometimes be almost perfect, but the finger is really important. And some of the local recurrences can only be detected by the finger you can actually feel irregularities and this is a patient of mine that actually had a local regrowth and the only study that could actually detect it was the finger no MR. No PET CT, no endoscopy. Only the finger was able to detect it. So it shows how important clinical assessment and clinical examination is.

Dr. Perez 18:41
Now the second part of the surveillance has to do with endoscopy. Now this used to be what we did — normal endoscopy — and this is also an actual patient of mine. Now if you look at this with the endoscopy, it looks like a perfect complete response. But when we do NBI imaging, which is narrowband imaging, we change the colors of the light and you can see how things start to appear once you use this advanced endoscopy, when we use this kind of light, look at the difference again, when we use NBI. This is the same patient we start seeing some whitish areas here. This is a local regrowth that is detected very early on, thanks to the NBI imaging. And there’s another example here. If you see the normal light on your left, it looks a perfect complete response. And when we do this same patient with the NBI you can clearly see there’s something wrong with the endoscopy there. And you start looking around and you can see there is an area and this is a local regrowth that was early detected thanks to the NBI imaging now the finger is not able to detect this but NPI can detect it. So we’ve implemented NBI as a routine endoscopic imaging for these patients.

Dr. Perez 20:12
Now, third is obviously radiology. Now, you’ve noticed in the beginning I mentioned that 95% of the rectal regrowths have some kind of endoluminal component suggesting that the finger and the endoscopy are able to detect it but sometimes the only study that will detect the regrowth may be actually the magnetic resonance. Radiology is important because it may detect sometimes a local regrowth not only in the rectal wall as in this case here you can see it looks like a complete response but the MR shows a progressive thickening of the rectal wall somewhat suggesting there’s something wrong. Or something like this: You can see there’s a complete response within the rectal wall but radiology was able to detect a node in the follow-up. This is the first MR we can see the node shows up in the subsequent MR imaging. So yes, MR has become an integral part of not only the assessment of tumor response, but also surveillance of these patients as sometimes these local regrowths may happen away from the primary tumor in mesorectal nodes. So you have to be careful with those as well. So this is why we are so obsessive in the follow-up of these patients. So during those three years that I mentioned, we see these patients at the most, two to three months every two to three months. These patients come back for digital rectal examination endoscopy with NBI imaging and for MR imaging. So Magnetic Resonance has become a part of the follow-up of these patients particularly during those three years, which are the high-risk period for development of local regrowths.

Dr. Perez 22:24
What do we know about risk factors for local regrowths? Well apparently the only factor that we know that seems to be a risk factor for local regrowth is baseline T stage. So it’s very intuitive. So the more aggressive the tumor is in the beginning, the higher the risk for subsequent local regrowth and it’s very easy to remember. A T2 cancer as a 20% risk a T3 cancer as a 30% risk and a T4 cancer as a 40% risk. So it means that you have to be careful, you know, the more advanced the cancer is more careful you need to be in terms of surveillance because there is a subsequent risk of local regrowth the more aggressive the cancer is in the beginning.

Dr. Perez 23:12
Now during the 30-year experience with watch and wait, we were always very careful because people were concerned when the local regrowth happened, we would not be able to salvage these patients. Patients thought and a lot of surgeons thought that when you had a local regrowth it was going to be unresectable disease and this is not true whatsoever. Apparently the vast majority of local regrowths, yes, are amenable to salvage resection, that seems not to be a problem. As a matter of fact, once you have a local regrowth, it appears we can do the same operation the patient was a candidate in the beginning. It means the patient was a candidate for an APR for an abdominal perrenial resection, if she or he has a local regrowth, he’s probably going to receive the same operation he was in the beginning. We usually don’t change from one operation because of the local regrowth but there is an exception to this which is in favor to our patients. Some of the local regrowth have been detected so early on, we were able to salvage them with the local excision because it was so tiny, so very small and so superficial that we were able to resect them locally without having to do total mesorectal excision and by doing this providing them with an opportunity of another type of organ preservation which is local excision which clearly doesn’t have the same problems of total mesorectal excision. So provided you do proper surveillance and you detect these early regrows very early on in a very small area, you are actually able to do a local excision. In our experience, these patients were more likely to be early cancers in the beginning, so they were really more frequently T2s in the beginning. Those were the patients that at the time of regrowth were more likely to be successfully salvaged by a local excision instead of a TME. And if you look at the outcomes of patients managed by local excision, they actually did as good or as or even better than the patients that we needed to salvage with a radical procedure. So local excision here doesn’t seem to compromise survival to these patients. And at the end of the day, it means that what we were concerned about which is really the resectability of these cancers at a time of local regrowth. That’s why it seems not to be a problem.

Dr. Perez 26:06
But as there always is an Achilles heel of anything that we do, there’s an Achilles heel of watch and wait and this has to do with systemic recurrences. It has to do with distant metastasis. And why is that a problem? Well, because when you look at the patients who underwent watch and wait and the risk of distant metastasis, you look into these tables and you figure it out very easily. Patients who have successful watch and wait, no local regrowth, the risk of distant metastasis is really low.

Dr. Perez 26:48
Whereas patients who have undergone watch and wait and then have a local regrowth and then are salvaged, successfully salvaged. They still have a very quite significant risk for subsequent distant metastasis. And the differences here are quite striking. And this is the first study that really pointed out this and the problem with this study is they were looking into very small numbers of patients. And then we looked into the International Watch and Wait Database, looking at multiple values, and you can see variables and you can see the number of patients here we’re almost looking at 800 patients with a complete clinical response managed by watch and wait. The only significant feature associated with a higher risk of distant metastasis was not the initial stage, was not the kind of treatment. The only feature was the fact that the patient had a local regrowth or not. Patients who have a local regrowth have a higher subsequent risk of developing distant metastasis. Now, when we have a patient with rectal cancer, regardless of the treatment, when these patients complete five years of treatment and there is no metastatic disease we used to congratulate them. We tell them Congratulations, you’ve completed five years. There’s almost zero risk for subsequent distant metastasis.

Dr. Perez 28:26
Now when you think about it, if a patient has a local regrowth, then the story is slightly different. The patient has a rectal cancer and one year after he or she develops a local regrowth. After this, the patient only has minimal risk of having distant metastasis when he or she completes five years, not from the initial cancer, but five years from the local regrowth is somewhat like the clock needs to be restarted at the time of the local regrowth as if we’re looking at a second cancer. So you have to be careful because when you have a local regrowth, the five years need to be counted not from the baseline cancer but from the time you’ve developed a local regrowth. Now, if you think about it, this comparison is probably unfair. Because as I mentioned in the beginning, local regrowths are really incomplete responses. And we’re comparing them to complete responses. So no wonder Rodrigo there are differences between complete an incomplete responses in many ways and of course, with the risk of distant metastasis. So perhaps if we had to compare the local regrowths with a proper comparator of incomplete responses, instead of comparing them to complete responses, because then we will be comparing apples to oranges. So when we compare incomplete responses to local regrowths, apparently there are no differences. The comparison of patients with local regrowth and those operated on for incomplete pathological response seems to be no differences in terms of survival. This is a retrospective study done long ago by our own group showing that patients with suspected for a complete response but ended on to have a local regrowth salvaged. The risks of distant metastasis was no different from patients with an incomplete response right off the bat managed by TME, managed by radical surgery, so no difference. And as a matter of fact, a recent randomized clinical trial showed the same outcome. This is the OPRA trial recently published and you can see patients in the red line the ones who had a local regrowth and needed to be salvaged, did similar to patients managed by TME, by surgery, at the time of restaging without local regrowth, suggesting that you know a local regrowth is the same as an incomplete response. So it doesn’t really matter if you operate them early on or at the time of the local regrowth. But I think that comparison is not fair as well. Because when you look at patients with local regrowth, yes, they are incomplete responses. I agree with that. But they actually had almost perfect response in the beginning. And patients who underwent TME had never a perfect response. And that’s the reason they underwent TME so that’s not a fair comparison. We need to compare patients who undergo radical surgery but had excellent responses similar to the ones who were managed by watch and wait and when we do so, then there seems to be a difference.

Dr. Perez 32:24 
And this is a study we did comparing patients with local regrowth to the ones who underwent radical surgery but had also excellent responses. And when we balanced these groups by excellent response we start to see differences in the risk of subsequent metastasis. Patients who undergo TME upfront have less distant metastasis than patients who have an initial complete response, local regrowth, salvage of the local regrowth and then a higher risk of distant metastasis. And when you break out into the actual pathological stages, you can see that patients with more advanced disease at the time of local regrowth, these patients do even worse. So if you detect a patient with a local regrowth early on, superficial disease, small, they do as well as those who undergo radical surgery upfront but the ones that you fail to detect properly when they have significant disease at the time of salvage, these patients are actually doing worse in terms of subsequent risk for distant metastasis once they had a complete response. So at the end of the day, when you balance for response, these patients seem to do somewhat worse in terms of the risk of distant metastasis. So it’s difficult to interpret this data because we are talking about a very small number of patients because if you remember when I mentioned, you know, only a fourth of patients would actually have a local regrowth and then 25% of the 25% will develop subsequent metastasis. We’re really talking small number of patients here, but when you look at a big number of patients with local regrowth, you start seeing these subtle differences in terms of the risk of distant metastasis, and this is something we should be really careful about. So in summary when you think about it, a local regrowth so far, seems to be the only risk factor for subsequent distant metastasis development once you’ve undergone a watch and wait strategy once you’ve achieved a complete response. Now, if you have a local regrowth, you need to be starting the risk of distant metastasis at the time of local regrowth and not at the time of the primary cancer. Sometimes these regrowths may happen as long as three years from the baseline cancer, which means you need to compete now eight years from the primary cancer and not only five.

Dr. Perez 35:38
Be careful because the local regrowths, they seem to have similar outcomes to incomplete responses managed by TME. But again, these groups are not balanced for the response, the initial response, and remember patients who have a local regrowth they by definition had so good response, we actually mistaken them for a complete clinical response and not operate on them. So when we balance these patients by excellent response, we really start to see some differences in terms of the risk of subsequent distant metastasis, particularly if these patients have at the time of salvage, advanced disease for their local regrowth. So these we believe are important messages that people thinking about organ preservation these days need to be considering when embarking on this treatment strategy. And I’m not by any chance saying we shouldn’t be doing watch and wait. This is definitely something that we need to consider. But we need to look at these numbers carefully, when we think about watch and wait. And number two, we have to absolutely be obsessive about local regrowths because we really need to detect them early on and at the very slight possibility or suspicion of a local regrowth means that we need to be probably salvaging these patients with with some kind of surgery. So thank you very much Manju. I’m sure there are people want to ask questions and yourself and I’ll be happy to answer any questions from you.

Manju 37:32
Okay, thank you so much, Dr. Perez. I think there are a couple of questions. We can look at those first. So there are two questions. So one is that when under watch and wait protocol, when there are when 2 lymph nodes shrink from 5 millimeters and 4 millimeters to 3 millimeters and 2 millimeters at six weeks after, would that constitute a complete response?

Dr. Perez 37:58
So yeah, I think it’s a very important question, Matthew. I think that you know, radiologists usually you know, they over-call lymph nodes. So we are very careful in not over-calling lymph nodes positive simply because we are seeing them. We really need to look at all the criteria for really calling a positive lymph node a positive lymph node. So size is not as clearly not the sole criteria for calling a lymph node positive. That’s number one. We need to be looking at border regularity, signal intensity– all these features need to be considered. Now number two, when we see a complete response within the rectal wall, that’s usually a very good surrogate marker for response within the mesorectum as well. So it’s not a rule, but usually when you see a complete primary tumor response, usually the mesorectal component of the disease has a similar response to the primary. So whenever we see a complete response in the primary, and we see very, very tiny little areas of lymph nodes, we can definitely watch and wait in them. Now we don’t ignore them. We look for them in the subsequent surveillance studies. And definitely we should be careful about them. I hope this answers the questions, Manju

Manju 39:34
I think then he’s asking if having a local excision first followed by chemo radiation, is watch and wait still a good path?

Dr. Perez 39:43
Yeah, I think this is an alternative treatment in rectal cancer that is also considered to be organ preservation. We usually think that this is a very acceptable alternatives particularly, if the cancer was initially staged as a T2 and N0 disease as it was stated. We have good data from prospective trials that T2s and N0s managed by chemoradiation therapy, followed by local excision is a good alternative.

Now when you when you turn things around when you do first local excision and then chemo radiation, we are not sure that the outcomes are the same. But one would, you know, consider that the outcomes are pretty similar, but we don’t have as good evidence as we have for the neoadjuvant approach of chemo-radiation therapy first. Now the advantage of doing local excision first is that we are actually looking at the cancer and making sure it’s a T2N0 or at least T2 because we’re never sure that the N0 component once we’ve done a local excision but it has the advantage of properly staging the T components of the disease. And there is some data to suggest that it’s pretty good in terms of local excision alone, followed by chemoradiation therapy as a good alternative for organ preservation strategy.

Manju 41:24
Okay, thank you. So the other question is that if there is metastatic spread, after watch and wait, like what you were talking about? You have a local regrowth and then you’ve seen that with the local regrowth, there is a high chance of distant metastasis. In that case what is the average overall survival? Is it much different then?

Dr. Perez 41:45
Yeah, that’s a very good question. I think that the problem with watch and wait is watch and wait has begun in 1991. So we are really 30 years old, of watch and wait, so we really don’t know what the overall survival of patients with metastatic disease is after we have a local regrowth. We’ve been able to, you know, catch the differences for the appearance of distant metastasis, and we are now looking what happens to these patients, once they have metastasis. One would think that there would be no differences in terms of the outcomes of these patients, once they have distant metastasis as any other patient with distant metastasis, but the truth is, we still don’t know what the outcomes of distant metastatic diseases is once we’ve done watch and wait. We really don’t know whether these cancers are any worse or any better than patients treated by the standard regimen. So that’s a very good question. And this is something we are definitely looking into exploring into the data. And one of the limitations is that you know, as I said in the beginning, watch and wait is a very, very new young treatment alternative. So we really don’t have a sufficient amount of data in terms of long-term data to really make sure that the overall survival is not any better or any worse than the usual patient with metastatic disease.

Manju 43:27
Okay, thank you. The next question is, what are your thoughts on going on watch and wait after having an excision of the small remaining tumor post chemo radiation. So this patient was originally T2N0, but she had refused APR and then the surgeon did a TAE. Then she was downstaged to Stage 0 as no cancer was found in what he excised.

Dr. Perez 43:50
So that’s really good. And that’s something that we would like to see in any patient, I think Britta, that’s almost perfect because once you did chemo radiation therapy, #1, there’s the original stage of the cancer wasn’t an advanced one. And then you’ve confirmed by local decision that there is a complete pathological response. I think you’re very likely to not have a local recurrence or a systemic relapse whatsoever. This is the patient or the situation that is probably one of the best in terms of the outcomes. So that’s clearly the case that we would recommend watch and wait, as a matter of fact, in the beginning, we were worried, in a number of patients that there was really a complete clinical response, or there was a question whether there was a complete clinical response. So we did a lot of local excisions among these patients, many of which had a complete pathological response, as you stated, and those patients are the ones who do the best. So I think that you’re, you know, very promising that this is never going to recur, both locally and systemically. But again, you need to be properly surveilled and followed at least five years from the primary cancer and being careful. Now, the problem is with the local excision is once you do a local excision, there is scarring of the rectum and distortion of the rectum. So sometimes it’s challenging to surveil these patients, as opposed to patients on watch and wait where we never did any kind of local excision, because the rectum is perfect in a way that we didn’t do any resection. So there’s really no scarring effect, both for the endoscopy, clinical assessment and finally, also for radiology. So that’s one of the things that you have to be careful about when you do a local excision, but definitely that would be the situation that is most promising in terms of a good outcome.

Manju 46:09
I’m going to skip that question or the overall survival and then go to what Matthew asked. I understand watch and wait considering the scar appearance, would it make sense if a full thickness or ESD procedure was done to pathologically verify the complete response?

Dr. Perez 46:25
Yeah, so Matthew, that’s a very good question. It makes sense. But you have to consider the following. A local excision in the setting of chemoradiation therapy may be somewhat painful, because scarring and healing of the defect that we create by doing a local excision, suturing it up, sometimes breaks down because of radiation therapy. And sometimes these wound dehiscences may be quite painful. If you think about it, if you’ve done a local excision, and there is no cancer, you really didn’t add much by doing a local excision. You simply made sure and confirmed what you suspected in the beginning anyway, and then you have to deal with the pain and sometimes with the with slight functional consequences of the local excision itself. Very few patients actually have significant complications after local excision, but I’ve seen patients who actually require the stoma, simply because of complications following a local excision. So, you know, it may be a very good alternative, but it’s clearly not the perfect alternative for everyone. We still think that if you have a perfect complete response, you’re better off with close surveillance than a local excision simply to confirm that this is a complete clinical response. Now, a minor comment in terms of ESD– I don’t think ESD is a good procedure for this. Now ESD for those of you who don’t know what ESD means it means endoscopic submucosal dissection. When you have a rectal cancer, if you do ESD it means you’re removing only the superficial layers of the rectum. It doesn’t make you absolutely certain that there is no residual cancer in the muscularis proper layer which is never resected by ESD. So you have to be careful with ESD. Number two, yes, these may be somewhat challenging because of the scarring of the radiation therapy itself. Sometimes it’s very difficult to perform ESDs among these patients, so we really don’t know yet what’s the role of ESD. There is a subset of patients who develop residual adenomas in the vicinity of the scars that may be resected by ESD. So apart from those very particular patients, I believe ESD is not the best alternative here.

Manju 49:04
Thank you. So we’ll go to the next question. And then we’ll come back to the survival one. So this question is about recurrence in the mesorectal fascia outside the rectum. And if this is not compromising the rectum itself, and there is no other systemic sign of disease, is there a consensus on using sphincter-sparing surgery depending on where the lesion is, or you know, could radiation achieve total response and spare the patient a Low anterior resection?

Dr. Perez 49:33
So that’s more of a challenging question. So when we think about disease outside of the mesorectal fascia, basically we should be talking about the lateral pelvic compartments. If we see lateral pelvic compartment disease, and it looks radiologically like a lymph node, those are the patients that we would go on and do a lateral pelvic compartment surgery. It doesn’t necessarily mean we need to do an LAR or in other words, it doesn’t necessarily mean we need to do radical rectal surgery, but the lateral compartments need to be somewhat approached. Now we are careful when we see something outside of the mesorectal fascia that it doesn’t look like a node, then the outcomes may be quite disappointing. When we see vascular disease outside of the mesorectal compartment, when you start seeing lateral pelvic disease other than lymph nodes, then we are less keen on doing lateral pelvic surgery because we know that the outcomes are not as good. So, in terms of radiation therapy, they’re usually if this was part of the disease in the beginning, the lateral compartment is part of the radiation field or should have been part of the radiation therapy field. So it means that we’re not going to be able to re-irradiate those areas anymore. Once you have disease after chemoradiation therapy in the lateral compartments it means you usually need to consider surgery because there is no other form of giving additional therapy because it has been included in the original radiation therapy field. I hope this answers the question.

Manju 51:28
Yes. So if the patient did not have like for example, if it was if the patient was originally stage IV, and they didn’t get chemoradiation, then the lateral pelvic lymph nodes would be able to be irradiated, right?

Dr. Perez 51:42
Yes. Yeah. So if you have disease outside of the mesorectal fascia, and the pelvis has never been irradiated, then there is an opportunity to use radiation therapy for local control. But if the if the pelvis has been irradiated in the past, it’s very unlikely that we’re going to be able to to attack this disease with radiation therapy alone.

Manju 52:11
Okay, thank you. I think there’s another question about the high-risk features like lymphovascular invasion, PNI etc. With nonoperative watch and wait do these pathological features no longer matter?

Dr. Perez 52:26
Well, okay, so I’ll address both questions. Both of the high-risk features and also the ctDNA. So number one, once you have lymphovascular invasion, perineural invasion, you can only assess those invasions pathologically, there’s no other way to see vascular invasion unless you have extramural vascular invasion, which is, you know, a big vessel invaded. Microscopic disease can only be detected microscopically. So if you’ve done chemo, radiation and the parameter of tumor is gone, endoscopically radiologically and clinically, the vast majority of these patients will not have disease microscopically. Do we disregard them? No, we’re not disregarding them. We’re simply suggesting that the only way of confirming residual disease would be removing the rectum and we know that removal of the rectum has some significant consequences to our patients. And taking into consideration there’s a high chance there is no residual disease we are not going to be doing this simply to confirm the options. Now, are we disregarding them? Not? Not at all. We are surveilling these patients because we truly believe there’s a risk for microscopic residual disease and that’s the sole reason we are obsessive about a local recurrence. Now, you always have to balance the risk of having residual microscopic disease and needing radical surgery which may be an acceptable balance for some patients and an unacceptable balance for others. And this is something we you have to discuss ahead of time before you embark on a watch and wait program.

Dr. Perez 54:27
Now ctDNA I’ve noticed there’s two questions about ctDNA. ctDNA is very promising. However, so far, we don’t really know how to interpret the outcomes of ctDNA and I’ll show an example. When you do chemo radiation therapy and the tumor is gone. If you do ctDNA and the ctDNA is positive, what does it mean? Does it mean we have circulating distant metastasis, or does it mean we still have residual cancer in the rectum? We don’t really know. So when you have a positive test, what should we do? Should we remove the rectum or should we start chemotherapy? We don’t know because there’s a risk that we’re treating microscopic metastatic disease and we don’t need surgery or we may be giving chemotherapy for microscopic residual disease, when really what we’re seeing is macroscopic residual disease in the rectum. So we don’t really know once we have a positive test. And the other way around happens as well. If we have a negative test, we have data to suggest that there are patients with residual disease so microscopic that the ctDNA is negative, so it’s a false negative test. So because of that, we are not taking into consideration yet ctDNA as the sole driver of Decision Management among patients undergoing Watch and Wait, I totally agree. It’s a very promising tool. We could certainly look at it. We’re actually looking at it as we speak, but we don’t really rely on ctDNA data yet to consider Watch and Wait.

Manju 56:25
Okay, so I have a couple of questions. So initially, when you were talking about the risk of local regrowth, you were talking about how you know the T1, T2, T3– the risk of local regrowth increase as the T stage increases. So, for patients who want to undergo watch and wait like the staging of their tumor is very, very important. Right? And then you’re using endoscopy, MRI, all of those to stage, and from what I have seen, there is a lot of variability between like clinicians assessing what stage it is, right? What can we do as patients to make sure that there is no difference, or when we are being counseled for a chance of watch and wait, how to make sure that the staging and all of that is properly taken care of?

Dr. Perez 57:16
That’s a very good question. Manju, I think that whenever I give these talks whenever I talk about Watch and Wait, people ask me, should everyone be doing Watch and Wait in the world? I honestly don’t think so. I honestly don’t think that rectal cancer should be managed everywhere in the world. I honestly think that this has become such a complex disease, with so many little details that we need to be doing this in specialized centers that have people in radiology, radiation oncology, medical oncology, colorectal surgery that are focused in rectal cancer management. I often tell my patients I almost only do rectal cancer surgery or rectal cancer. All of my you know, practice is dedicated to that and still, you know, I have some difficult cases and I have some problems. Now, if if you’re doing this in a center where you know people taking care of you are doing this once a month, or once every two to three weeks. You probably should be seeing people that do this a lot. Because you know, it takes hours of practice and hours of doing this to really minimize the risks of miss-calling their disease. Now, I’m not really concerned only about the T stage but there’s so many other features that we have to look into you know, to make a long story short, that the number of patients that come to me with an MRI for rectal cancer, that the MRI needs to be repeated because of poor quality of the way it was taken, is nearly 100%. I rarely see a patient with an MR being done for rectal cancer and I live in a large city, where you would expect that many centers would be dedicated for rectal cancer, and I still see a lot of non proper MRs and it’s a problem we have to deal with. So I think when we’re talking about rectal cancer, and some of these, you know, very controversial organ preserving strategies, these need to be done in very specialized cancer centers that really are including people that are dedicated to rectal cancer management.

Manju 1:00:02
Okay. Okay. Thank you very much. And so the other question that I had is about in say, for example, in COLONTOWN, one of the concerns that a lot of people have is that they are really worried that they do watch and wait and then like you said, you know, they have a local regrowth. They’re worried that local regrowth will be responsible for the distant metastasis, there is a concern. So, my question would be do we have any evidence to know that the people that you see the local regrowth are what you call the incomplete responses, which were misclassified as complete responses, are those diseases or are those tumors biologically different and have a higher chance of both local regrowth and distant metastasis? Or is the local regrowth somehow resulting in an increased chance of distant metastasis? Do we know more about these questions?

Dr. Perez 1:00:58
So that’s a very good question. We are currently looking into this Manju. And it appears that there is something wrong with the local regrowth themselves. There’s something you know, biologically intrinsic to those regrowths that make them particularly worse in terms of distant metastasis, and we are not sure that doing surgery upfront would actually change anything. But you know, it’s very difficult. And then the difficulty here is, the challenge here is we cannot operate someone– the same patient cannot be operated at two different times. He’s either operated upfront, or he’s operated at a time of local regrowth. So we don’t know whether this would make a difference. We are doing the best that we can to look into this. And we’re actually looking at this right now. It appears, because one of the things is, it could be the time. The time that it took for us to detect a local regrowth is responsible for the worse outcomes. And we are actually looking into this and apparently it isn’t the time. Because the local regrowth that develops very early on, and those that develop two years after chemoradiation therapy. It doesn’t make a difference. The time make no difference in the risk of subsequent metastasis. So there’s more, there’s something more about it that we still don’t know. Apparently, there is something biologically intrinsic to the local regrowth that made them particularly prone to the risk of this now, this doesn’t mean we don’t need to be obsessive about them. We are obsessive about them, because we want to detect them very early on, and we want to be able to salvage them as early as we can. And there’s another message behind this story. We become you know, more strict even more stringent in terms of criteria. You know, if you have a near complete response, you shouldn’t be doing watch and wait. You need to be a perfect complete response, if you’re thinking about watch and wait. When you’re not sure you should not be doing watch and wait if there’s a small little ulcer. No, no, no, no, we are not, you know, permissive. We have become even more strict over the years because of the risk of a local regrowth. Does that make sense?

Manju 1:03:30
Okay, I think that’s one question that we should answer. What is the usual time to survival for rectal cancer patients with distant metastatic disease? What are you seeing these days?

Dr. Perez 1:03:42
So yeah, that’s a very good point. So, you know, over the years, the pharma industry is very much interested in patients with colorectal cancer, for obvious reasons, because of numbers. And numbers mean money for them. So it means that we have a lot of treatment alternatives for metastatic disease in patients with colorectal cancer. Now, it used to be that metastatic disease had an average survival of one year, and now the average survival has gone up to three years, which means that we can treat these patients in many ways. And remember you know, a proportion of patients with metastatic disease is still, amenable to be cured by by resection of their metastatic disease. So 25% of these patients are actually cured by radical surgery, so, metastatic disease is by far the end of the line in rectal cancer. And the average survival was beyond three years currently, with the amount of treatments that we have. There’s so many details and complexities in metastatic disease, it depends on where it happens when it happens, and how it happens and the alternatives that we have available to us. And remember, now we know rectal cancer has become two different diseases. The ones with microsites satellite instability, and the ones with microsatellite stability are completely different diseases simply because we now have Immunotherapy available to us. So it’s, you know, it’s an ongoing target and you know, a moving target and the outcomes of metastatic disease has improved dramatically over the years. So we’re really talking about almost like a chronic disease, rather than terminal disease, how it used to be called.

Manju 1:05:51
We are past the time, I don’t know if you have time to stay or not

Dr. Perez 1:05:55
Yeah, I have a few minutes to take a few last questions if you’d like.

Manju 1:06:01
Yeah. So Matthew is asking about is there any way to refine staging in rectal cancer so are they looking at like later T stage and then influence a T2N1, what are your thoughts?

Dr. Perez 1:06:14
Yeah, so refinement of these of rectal cancer staging is definitely a reality. Now, we are looking at so many different features that are not taking into consideration of the T stage of rectal cancer. If you look at the NCCN guidelines, they’re very, very simple. Rectal cancer is not that simple anymore. And rectal cancer has so many different variables that need to be taken into consideration. So that means meso rectal fascia, lateral nodes, the height of the cancer in addition to EMVI and so on, tumor deposits. So yes, we definitely need to refine rectal cancer staging, but then the problem becomes who is going to be staging those patients. We need to train so many radiologists across the world, to be able to properly stage these patients, but I think there’s no other way and there’s no turning around. Rectal cancer needs to be dealt with in very specialized cancer centers and staging needs to be refined. I cannot even discuss guidelines anymore because the guidelines are so gross in terms of separating patients that are not compatible anymore. So, yes, refining rectal cancer staging has become a reality now and it really depends on where you go. If you go to a very specialized rectal cancer center, they are going to talk to you about many other things that you know in a more basic institution probably will even be considered because they’re not looking at it properly.

Manju 1:08:11
Yeah, I think the last question is about chemo. So the use of CAPOX 4 infusions or 4 cycles as adjuvant treatment after TAE with no evidence of disease.

Dr. Perez 1:08:25
I love that question. Manju. You know the reason I love that question, Britta, thank you, is the fact that I am in a war against the medical oncologist and the war is because I think the medical oncologists give too much chemotherapy to our patients with rectal cancer. We’re actually running a trial in Brazil, a prospective randomized trial in Latin America, I’m sorry, and we’re doing de-escalating the treatment of these patients. We’re doing only four cycles of chemotherapy, instead of six cycles of chemotherapy, and we’re comparing CAPOX to capecitabine alone because we think oxaliplatin, particularly for the T2s, there is no real benefit of oxaliplatin in this scenario. We honestly think that oxaliplatin only adds toxicity without adding any benefit to our patients. So we’re running a trial comparing CAPOX capecitabine alone because we think that the T2s only need capescitabine, both for achieving a complete clinical response and for adjuvant purposes. So I don’t believe CAPOX is the answer for all patients with T2 rectal cancer. I really love the question because this is the question that needs to be addressed. And that’s the reason we’re running a trial because if you look at the data, there is absolutely no data comparing CAPOX to capecitabine alone. And if our trial was negative. I suspect that medical oncologists will be convinced we do not need to give oxaliplatin to all our patients with rectal cancer simply because we’re treating patients on the safe side. Because it really gives a lot of toxicity to our patients.

Manju 1:10:26
Okay, okay. Thank you very much. So basically that is like stage two colon cancer, almost going that route.

Dr. Perez 1:10:34
Absolutely. Absolutely. Yeah. And if you think about it, the IDEA trial shows that we need we don’t need to give so much chemotherapy in terms of time and we are over-treating a lot of our patients with chemotherapy. If you think about it ctDNA will probably change management here because a lot of patients with Stage II with ctDNA negative probably don’t need chemotherapy at all. So it’s, I think medical oncologists give too much chemotherapy. And every MDT session in my institution is a fight against the medical oncologist because they do want to give a lot of chemotherapy to our patients and it gives a lot of toxicity. And sometimes it’s really just a lot of false hopes. And you have to deal with you know, it’s a problem.

Manju 1:11:31
Yeah. Okay. Thank you so much. This was very, very, very informative and useful. So the video of the recording we will put on COLONTOWN University in about two weeks. Okay, so yeah, it has been great having you.

Dr. Perez 1:11:47
Thank you, Manju. I’ll be happy to come again whenever you need me. All right?

Manju 1:11:52
Okay. Okay. All right. Thank you have a good weekend.

Dr. Perez 1:11:56
Thank you. So much.

Manju 1:11:58
Bye