Brachytherapy for Rectal Cancer: Dr. Krishan Jethwa (2025)

Manju George 0:00
Hello everyone. Welcome to DocTalks. I’m Dr Manju George the Scientific Director at PALTOWN Development Foundation, the non profit that supports COLONTOWN. And today we have with us Dr Krishan Jethwa from Mayo Clinic, and he’s going to talk to us about brachytherapy. Welcome, Dr Jethwa. But before you start, could you please tell us how you got interested in clinical research and to be doing the kind of work that you’re doing.

Dr. Jethwa 0:29
Yes. So thank you very much, Dr George, for the invitation. How I got into clinical research. So for me, it all comes down to patient care. I’m a clinician first, type physician. I love taking care of patients. It’s a privilege every single day to be involved in the care of them and guiding through them the complexities of their diagnosis journey, supporting them through the process. And I think almost anyone who’s involved heavily in clinical care will eventually identify gaps or limitations in the available literature, identify patients that the current level of evidence or current level of available treatment is just not sufficient to care for their needs, and it compels us to want us to learn more about how we can helpthose patients that we’re seeing today and very likely to see in the future. So for me, that’s what it’s all about, identifying ways that we can improve the care of patients that I see, and hopefully improve the care of patients that others are seeing across the country. And so with that, I’d like to talk about an area that I’m particularly passionate about, and that’s how we can optimize the care of patients with rectal cancer, with the overarching goal of balancing quality of life, function and oncologic outcome and and one of those areas happens to be organ preservation options for patients with rectal cancer. So this is really what it’s all about. In 2025 we have dramatically shifted the care of patients with rectal cancer. When I was a trainee, which is not that long ago, but approaching 10 years at this point, almost every patient with advanced rectal cancer got long course chemo radiation surgery, and they got four to six months of post op FOLFOX. It was very cookie cutter. That was the standard approach. Almost everyone got it. And as many of you know, that’s very much not the case at this point. Care of patients with rectal cancer is very much personally stratified based upon risk stratification, and it can include surgery alone. It can include pre operative chemotherapy followed by surgery, radiation treatment followed by surgery, radiation treatment, chemotherapy and surgery, or potentially even ways of omitting the surgery piece if there’s a complete response to chemotherapy and radiation treatment. And the whole crux of that decision making process is based upon what offers the best balance in cancer control, quality of life, and most importantly, what fits best with the patient’s goals and interests and how they want to live their life. And so that is the critical component of this conversation, is, how can we balance what we offer for treatment but what works best for our patients?

Dr. Jethwa 3:13
So I’m going to segue into organ preservation, because this talk is really about brachytherapy and what that can offer, and it’s predominantly in the organ preservation space. So the real goal of organ preservation is to maximize quality of life and function. It is not to spare the sphincter, for example, that’s a surrogate outcome for improved quality of life. But we also know the patients who have a low rectal tumor that’s amenable to a low anterior resection, but would result in a low or ultra low coloanal anastomosis generally have relatively poor bowel function after the operation. So even though the sphincter can be preserved, there’s still an opportunity to maximize quality of life by sparing the surgical component of treatment. We know based upon a wealth of data that combine modality- local treatment, radiation treatment plus surgery, is associated with poor function related to bowel, bladder and sexual health. We also know that selective omission of one of those two treatments, either the radiation treatment or the surgery, can better preserve that function in a significant proportion of patients. Of course, there will still be some patients that we feel are best served with both radiation treatment and surgery, depending upon their risk profile, but hopefully some can avoid one of those treatments. And at least in my institution, we tend to more strongly consider organ preserving strategies when the distal margin of the tumor is within five centimeters from the top of the anal sphincter complex, so not the anal verge opening, but the top of the actual sphincter muscle internally. And we use that measurement because we know that if the tumor extends within five centimeters that the anastomosis will be relatively low and close in proximity to the anal canal, and bowel function is likely to be poor after that type of an operation. So that’s our rough rule of thumb, at least in our clinical practice.

Dr. Jethwa 5:14
So I’m going to talk about some of the trials that have shaped this. So the Opra study was a study done in the US, predominantly at a Memorial Sloan Kettering Cancer Center and some affiliated, collaborative institutions. The study included about 300 patients with Stage II to III rectal cancer, and patients were treated with both chemo radiation and eight cycles of FOLFOX based chemotherapy over four months, they are randomized to alternative sequence, either chemo radiation first or chemotherapy first. And if they had a complete response to treatment, they then proceeded with an active surveillance, non surgical strategy. Initially, about three fourths of patients in each treatment arm proceeded along that path, but if there was ultimately local regrowth of the tumor or an incomplete response to the treatment, patients proceeded with a cancer directed operation called a total meso rectal excision, which removes the rectum and the tumor. Ultimately, about half of patients were able to successfully proceed with organ preservation long term, with no local regrowth and without the requirement of oncologic resection and so and that was better in the group that got chemo radiation first. So that’s really grown as the preferred treatment sequence for patients hoping for organ preservation, chemo radiation followed by chemotherapy. So that study very much shaped the practice in the United States, but it’s led to many questions.

Dr. Jethwa 6:44
Of course, 50% were able to achieve organ preservation, but I view that as positive, but I also view it as that’s 50% of patients who wanted organ preservation but were not able to do so because our treatment was not successful in completely clearing the tumor. So for me, that’s tremendous opportunity to help more patients. So how can we do that? There’s some investigation into systemic therapy intensification, transitioning to use of FOLFIRINOX, so adding irinotecan to the FOLFOX backbone by intensifying to see if that offers benefit. But there are also data looking at radiation therapy treatment intensification, such as brachytherapy. So this is one study called the OPERA study, done in Europe. This study was smaller of 141 patients with favorable risk tumors, clinical t2, to 3b so limited to the second layer, the muscular layer or just extending beyond the wall by a short distance. Most of the patients were lymph node negative in this study, patients had to have tumors less than five centimeters in diameter and involving less than 50% of the rectum circumference. Patients were treated with long course chemo radiation with a pretty standard regimen, 54 gray and 30 fractions. So that’s over six weeks. That’s the same regimen being used on the JANUS study, for example, versus 45 gray of radiation over five weeks, so slightly lower external beam radiation dose combined with a brachytherapy boost. The brachytherapy boost is a rather niche technique that’s not universally done in the United States. This is a technique where they give a very high dose of radiation over three treatments. It was delivered once per week, and the radiation type that was used delivers very superficially. It essentially only sufficiently treats the innermost lining of the rectum mucosa. And the thought is you would treat one treatment, once per week. You would kill off the superficial layer of the tumor, and over the success of two weeks, you again treat the next deep layer and the next deep layer of the tumor, and ultimately, hopefully have a complete response to treatment. Those who had a complete response in the study proceeded along an organ preserving treatment pathway. The study taught us that brachytherapy boost offered a significant improvement in organ preservation at three years. So on the y axis, here is the organ preservation rate. This is time on the x axis, this is the brachytherapy boost in blue. And at three years, the organ preservation rate was 81% with brachytherapy, compared with 59% with this with the external beam radiation treatment alone, suggesting that brachytherapy was actually quite successful in this cohort of patients. What’s really exciting is this figure. So this is a subset analysis from that study looking at patients who had tumors less than or equal to three centimeters in size. Now you’ll see the brachytherapy boost again here in blue, the three year organ preservation rate in this group was 97% compared with 63% with external beam radiation therapy alone, suggests. saying that those with tumors less than three centimeters has have an exceptional opportunity for long term organ preservation with this treatment strategy.

Dr. Jethwa 10:09
There’s another study that I don’t have the slide shown here, but it was done out of Montreal McGill University. They also did external beam radiation treatment versus external beam radiation treatment plus a brachytherapy boost, their studies are quite analogous to what I’ve shown in this study, again, demonstrating that brachytherapy boost offers improvement in clinical complete response and improvement in organ preservation rates long term. I also showed that those studies were mostly representative of patients with low risk disease. So in the past month, this publication came out. It’s from the same group that reported the OPERA brachytherapy study I just showed. This study included patients with high risk features, so that were things like compromised mesorectal fascia, more extensive lymph node involvement, extramural venous invasion, so higher risk features. And the way they did this was that they would give the external beam radiation treatment over about five weeks, and they would wait till give the external radiation time to shrink the tumor. They would wait a month or two if the tumor shrank, ideally less than five centimeters, but preferably less than three, they then would perform brachytherapy, focusing in on the residual tumor seen in the rectum, so more selective approach, and by doing that, they demonstrated that the organ preservation rate was actually comparable to what they saw in that lower intermediate risk cohort, again, now suggesting that perhaps we can move beyond that favorable risk disease cohort patients and offer brachytherapy more selectively in a group of patients with high risk disease that had sufficient shrinkage of the tumor to make the brachytherapy feasible a couple months after the initial external beam radiation treatment.

Dr. Jethwa 12:08
So if I were a patient listening to this, I would think, Wow, this all sounds really great, but I’m a little bit fearful about what increasing radiation dose could do from a functional standpoint, how am I going to feel after that type of treatment? What will my life be like long term? So I’ve tried to summarize this here. So what are the pros of brachytherapy boost? I think the clear, obvious opportunity here is that it improves complete clinical response rates and improves opportunity for long term organ preservation. The other key takeaway is the point that I’ve shown here, and that’s the long term. The randomized studies we have to date suggest that greater than one year and certainly beyond two years after the treatment, that bowel function is very comparable to what we see, which is standard dose, long course, chemo radiation alone. And in fact, one of the studies showed that the brachytherapy was associated with a lower risk of bowel dysfunction long term, and that is because the group that got standard external beam radiation had a higher risk of the tumor regrowing and ultimately requiring an operation to cure it. So it wasn’t that the Brachy really offered benefit compared with standard external beam, but when you average out the outcomes in the external beam cohort of patients, because some of them required surgery with a poor functional outcome and made it that the overall brachytherapy group had a better functional outcome as an overall assessment. But I think the greatest takeaway isthat in long term, one to two years beyond the treatment, long term bowel function is quite favorable despite the increased radiation dose with brachytherapy.

Dr. Jethwa 13:57
Now, what are the cons of treatment? With the heightened radiation dose, there is a higher risk of typically moderate severity rectal bleeding, and that’s directly attributable to heightened radiation dose and the types of vascular type changes we see in the rectum after that type of treatment. Most of the time it’s mild to moderate severity, meaning it doesn’t require any additional intervention to clear, usually a small volume spotting with bowel movements. It’s intermittent. Resolves on its own. Nothing needs to be done about it. There is a small proportion of patients., it’s generally in the range of about one to 10% that will have more severe rectal bleeding and that might require some form of endoscopic intervention to help resolve. The other con is that, because of the height and radiation dose, bowel function is a bit worse in the short term period, typically immediately after the treatments delivered and extending, certainly within the first six months, we see a bit worsened in bowel function, some of it lags closer to 12 months, but generally, that’s a temporary phenomenon. And like I said, beyond one year, bowel function is typically back to what we would anticipate without the brachytherapy boost. And in general, the bowel function for a distal tumor with this treatment strategy is better than what it would be with a LAR with a low anastomosis, for example.

Dr. Jethwa 15:28
So in summary, brachytherapy is associated with a significantly improved chance of complete response and long term organ preservation based upon the prospective studies that we have to date, it’s mostly limited to patients with tumor limited to the muscular layer of the rectal wall or having limited extension beyond the wall, mostly lymph node negativeand tumors that are relatively on the smaller side, so less than five centimeters, preferably less than or equal to three and involving less than half of the rectum circumference. I do think that there may be selective use of brachytherapy forpatients with higher risk disease, and the way I would approach that would be to first treat them with external beam chemo radiation, and then reassess for down staging at least a few weeks later, and then if the tumor has shrunk to a volume that’s suitable for brachytherapy delivery, then you could proceed with brachytherapy targeting the residual tumor at that point with a goal of improving response rate and ultimate organ preservation.

Dr. Jethwa 16:29
So next, I’d like to talk about what a brachytherapy approach may be like, at least how it is in my practice, because there’s some institutional practitioner differences in how you’d approach this. So for me, the first step would be external bean chemoradiation in general, that’s about five to six weeks of treatment. The usual dose is 45 to 54 gray and 25 to 30 treatments. And the brachytherapy can either be delivered immediately with this course. So either embedded in that five to six weeks or there could be a delay after the external beam radiation to allow the tumor to shrink a little bit, let some of the early side effects resolve, and then use brachytherapy at that point. That’s the approach I tend to use. I tend to wait about three weeks after the external beam radiation treatment, and then I do brachytherapy, only treating the residual tumor at three weeks. So it’s a bit more focused on brachytherapy delivery. So the first step in my practice, when I’ve identified a patient three weeks later planning to proceed with brachytherapy is I will get another MRI to assess for how responsive the disease was and what the residual tumor is. I also have them undergo a flexible sigmoidoscopy. That flexible sigmoidoscopy is done the same day as brachytherapy. In my practice, I actually join the gastroenterologist in the endoscopy suite, and I do that, do the procedure with them. That way I can visualize the tumor myself, see how responsive it’s been. During that sigmoidoscopy, we place markers. They’re basically like biopsy clips or hemostatic clips, the types of things they would do if there’s a small bleeding vessel in the rectum. We put little clips inside the rectum, that outline where the tumor is positioned, the residual tumor. That’s what assists me in delineation of where I need to treat the brachytherapy so I can be more focal in the treatment delivery. This is optional. Not all practices do this, but it’s a personal bias that I like doing purely with the goal of, number one, assessing response, but secondly, so a way to be a bit more focal with the treatment delivery. The next step is actually the brachytherapy itself. So we use moderate sedation for this procedure. That means we use some mild to moderate sedatives, analogous to what will be done with like a flexible sigmoidoscopy, potentially in the office with the colorectal surgery team. We also provide intravenous pain medication if need be, during that procedure. The first step is a physical examination. It’s basically a digital finger examination in the rectum to assess exactly where the tumor is located. The next step is placement of the brachytherapy applicator. I have shown one example of a brachytherapy applicator on this slide, so it’s a cylinder.

Dr. Jethwa 19:23
Essentially, what we’ll do is we’ll use lubrication over the cylinder. The diameter of the cylinder we use in practice is about two centimeters, so so just under one inch, and we’ll advance this applicator through the anal canal into the rectum, just shortly beyond where the tumor is located. Once the applicator is inserted in the rectum, we position it in place, get a CAT scan of the pelvis, and then we use that CAT scan to design the radiation treatment field. While we’re planning the treatment, we typically remove the applicator because it takes about 45 minutes to an hour to develop the treatment plan. Once the treatment plan is prepared, we will reinsert the applicator into the rectum position it, deliver the treatment. The treatment itself takes about five to 10 minutes. Then once the treatment is delivered, we’ll remove the applicator, and patients are then free to go on home. It’s an outpatient procedure. Patients are not radioactive after leaving the procedure. They’re perfectly safe to be around other people without exposing them to any radiation whatsoever. The treatment itself takes about one and a half to two hours, and like I mentioned, we would often repeat that treatment anywhere between one treatment to three treatments. It’s what’s typically done. I did show this applicator here, which is analogous to the applicator that we use in our practice at Mayo Clinic, but there are a number of other applicators that are in use across the country as well. So in conclusion, effective treatment of rectal cancer very much requires multi disciplinary collaboration. We know that the optimal neoadjuvant treatment for many patients is dependent upon accurate risk stratification, and like what I’ve tried to share here is that there’s increasing consideration for a local treatment modality for select patients with rectal cancer, and that local modality should largely be determined by the impact on function and quality of life. For many patients, chemoradiation followed by chemotherapy is associated with long term organ preservation in about 50% of patients, we know that brachytherapy boost is associated with a significantly improved chance of complete response and organ preservation. And for many of us, we’re using selection criteria that are analogous to the prospective trials that have been done to date, which includes clinical t2 to 3b tumors, mostly node negative and relatively smaller, typically less than five centimeters, less than 50% circumference, and as I did mention, brachytherapy could also selectively be used in patients with higher risk disease. So that was a pretty brief overview of brachytherapy, since it’s a relatively niche topic, but I’d be more than happy to go through any questions that you may have. Thank you very much

Manju George 22:23
Thank you so much, Dr. Jethwa, this is very interesting to listen to. So one question I had is like, is there a specific distance from the anal sphincter that you usually use for brachytherapy?

Dr. Jethwa 22:36
Yeah, that’s a very good question. So in general, I would say within eight to nine centimeters would be ideal. That would be from the anal verge. The applicator we use is 13 centimeters in length, so we could treat something that’s more distant than that. But brachytherapy delivery is very much about geometry and how we can position the applicator in closest proximity to the tumor, just from a radial dimension. And as you get higher up in the rectum, there’s two things that can change that. Bowel gas can sometimes extend or distend the rectum and make it that the distance between applicator and the mucosa is more lengthened. And I think perhaps the second more notable consideration is, is that, aspatients have tumors that are more proximal in the rectum, sometimes best or ideal functional outcome could actually be obtained with selective omission of radiation treatment, with the use of surgery as opposed to Radiation treatment.

Manju George 23:40
Okay. So the next question I had is, when patients generally think of chemo radiation, like external beam chemo radiation, there are these side effects, right? Like, people are worried about long term side effects, like effect on the hip and things like that. So when you have an applicator and you’re only positioning the instrument inside the rectum, and that basically what you said is that it the radiation only penetrates a very superficial layer. So will it avoid the other effects from radiation, like in the pelvis by this approach?

Dr. Jethwa 24:19
That’s a good question. So most of the dose of brachytherapy is delivered to the rectal wall itself and a pretty limited distance beyond it. So for example, when we prescribe the radiation dose, we prescribe to one centimeter depth, which is quite limited if you think about it, so the femoral heads gets next to no radiation exposure, really quite a negligible amount when we use that technique. Depending upon the location of the tumor, some adjacent tissues may receive radiation exposure. So for example, if the tumor is in the front wall of the rectum, then other organs directly adjacent to it, like the back wall of the vagina may receive some radiation exposure, but it would be relatively modest, at least to the front part of the vagina. Bladder could receive some radiation exposure, but again, it wouldn’t be substantial doses to a large volume of the bladder. Small Intestine receives very limited radiation exposure in most patients with this technique.

Manju George 25:21
Okay. And then I was really curious, with the picture of the the instrument, so, can you tell us more? Like, how is the radiation delivered? Like is it a pellet or something that is embedded into it? Like, how does it work? I’m just really curious.

Dr. Jethwa 25:37
Yeah, that’s a very good question. So the way it works is we insert that applicator into the patient inside. Let me share my screen again.

Manju George 25:48
Okay,

Dr. Jethwa 25:52
All right, so this is the applicator here, and you’ll notice that there’s this central channel here, and then that central channel inserts to the applicator. It goes all the way to the end. And then everything around this is essentially a mechanism of basically going flush with the organ that you’re treating. So all of this white is is essentially this right here you see that there’s different sizes. These all fit onto this central channel. These sizes are determined by making an applicator that goes all the way flush with the organ that you’re treating. So for example, applicators like this can also be used for patients with uterus cancer, to treat the margin where the uterus was touching the vagina. So we would treat things like this when we’re doing vaginal brachytherapy for endometrial type cancers. So, but the actual radiation source advances through this central channel. It’s attached essentially to a rigid wire, but it’s like a pellet of radiation. We use Iridium 192 as radiation source. It’s attached to essentially like a metal wire. That metal wire is guided by electronic technology, which can guide how it traverses the central channel as it goes on in it stops at different points, and our radiation planning process essentially tells it, how long should it stop at each point along the way in order to sufficiently deliver the radiation amount that we want to deliver.

Manju George 27:30
Okay, okay, okay, it makes sense. No, I think I understand it a little bit more.

Dr. Jethwa 27:35
So we would do, to add to that is you can imagine that if the radiation source is going through this central channel, it will deliver radiation in somewhat of a sphere around it. But if you have a tumor that’s limited to half of the rectum, but ideally would not deliver radiation to the opposite side of the rectum. So what we have done here is that we’ve generated applicators like this, and we can insert a shielding device one wall of the applicator so that radiation does not penetrate and treat that opposite side of the rectum..

Manju George 28:11
Okay, okay, yeah, thank you for explaining it. It makes a lot more sense now. So the other question is, all of this is happening immediately after the patient has got the sigmoidoscopy, right? So from a patient perspective, like, say, I’m coming in for the treatment, so I’m first getting a sigmoidoscopy, and then while I’m on that same bed, is when I’m getting the applicator, and then you’re doing all the measurements and figuring out how like the radiation plan, right? Is that right?

Dr. Jethwa 28:48
Not quite. We do our flexible sigmoidoscopy in the gastroenterology endoscopy suite. We usually have patients do it there and then come down to the radiation therapy department for the secondprocedure. I suppose you could do it in the same procedure, in the same room.

Manju George 29:04
OK, Imean, I was guessing, like you said, you will be there. So then they come here, and then you have the the instrument placed, and then there is a planning and you said it takes about one hour for you to figure out the radiation, treatment plan, and then the patient is again, back in, so I’m just imagining the patient is back in the bed. You do a CT scan with the instrument, and then you probably come back, right? And then after that, it is, like five to 10 minutes, the actual radiation, right? Did I get that right?

Dr. Jethwa 29:38
And we have patients stay laying in the treatment room, while we do the radiation planning process.

Manju George 29:46
Okay, okay. And then the other thing that you were saying is that like, so I’m listening to this, and my mind is wandering so, so if there was a patient, and the other question I had was, like, the two sequences where you have chemo first, then chemo radiation versus chemo radiation first, and chemo next. Do you have a preference that when you do for like, a little higher stage patients? Do you prefer the chemo radiation to be first, or is it after chemo? Like, is there some preference?

Dr. Jethwa 30:22
You could go either way. I tend to favor doing chemo radiation first, just because the Opra study show an improvement in long term organ preservation with that treatment strategy compared with chemotherapy. First, there’s not a ton of literature looking at brachytherapy in the context of total neo adjuvant type treatment, including chemo radiation and follow up eight cycles of FOLFOX. But we have done that in our practice. The way we would typically do it is, do the external beam radiation. I again bring patients back around three weeks to deliver the brachytherapy, and then I wait another two to four weeks after the brachytherapy, really two to six weeks before initiating the consolidated chemotherapy phase.

Manju George 31:08
Okay, so and then I think that it’s not probably so much with long course chemo radiation, but some people develop symptoms like the burning pain and the glass shard feeling towards the end of the 28 day cycle, right? So when I’m thinking of the sequence, then it’s about three weeks later that you’re bringing patients in for this. And then what you were saying is that if there’s a bleeding or some kind of side effects that might be towards the end, like after the next three weeks, right?

Dr. Jethwa 31:43
Yeah, so you’re exactly right. After you have long course chemo radiation, most of the side effects will peak in the week to two after that radiation therapy is delivered, many of the side effects do start improving by the third to fourth week, which is in part why the McGill Montreal group that did the MORPHEUS study waited three weeks. They wanted some of the acute response to radiation therapy to resolve a bit as well as getting the tumor shrinkage. And so I do also find that that timeline works pretty well from a side effect perspective, there is that risk of rectal bleeding from treatment. That’s something that would generally happen in the first three to 12 months, and it can extend greater than that. That’s not typically an acute early side effect of radiation treatment, per se. It’s something that can happen months or years later, and that risk is a little bit higher with brachytherapy than what it is with standard chemo radiation,

Manju George 32:42
okay, okay, I think there is one question. Let me look in chat. So the question is, I am to have 5.5 weeks radiation after my eight rounds FOLFOX. Did I understand correctly this brachytherapy would follow a 5.5 week radiation?

Dr. Jethwa 33:00
That would be reasonable. That 5.5 week is a very standard course of radiation treatment. It’s usually 50.4 gray in 28 treatments, and brachytherapy could be used after that treatment strategy, just depending upon what other components there are. From a risk strategy stratification perspective, I would also add, there’s not that many centers in the United States doing brachytherapy for rectal cancer at this point. So if, that is of interest to you, it may be worth an early conversation with your radiation oncologist.

Manju George 33:34
Okay. Thank you. So for now, like, could you share something more about a couple of cases that you have done, like, what has been the experience, if that’s okay?

Dr. Jethwa 33:48
Yeah. So the the cases in our experience here has been that we do, like I said, about five weeks of external beam radiation treatment, and that we follow the exact pathway that I shared. The patients that I’ve cared for have actually tolerated the procedure exceptionally well. The applicator insertion. It’s a two centimeter applicator, but of course, there is some discomfort with its insertion. It is a little bit larger than a standard colonoscopy scope, and it is, of course, advancing through the anal sphincter, so there is a bit of discomfort with that placement, but we can use lidocaine anesthetic around the anal canal, and of course, the intravenous pain medications and mild sedatives to help with thattolerance. Once it’s placed, most folks do quite well once it’s advanced through the anal canal. From an early side effect perspective, I’ve been very pleasantly impressed with how patients tolerate it. They really have not reported much heightened toxicity from the treatment. And I think part of that is that we’ve been rather selective with the patients that we’re choosing. Tumors really have fit the criteria of around three centimeters or less, less than 50% circumference. And our applicator, with the ability to shield the opposite wall of the rectum from radiation dose, really does limit the radiation exposure to the tumor without much extra normal healthy tissue beyond it. And so the body, I think, is able to accommodate and heal despite having that heightened radiation dose. So they’ve done very well. And pretty much all the patients we’ve cared for here in the recent past have then received the consolidated chemotherapy after they’ve finished the brachytherapy, and they’ve done quite well from a response perspective. So I’ve been very pleased with the patients we’ve cared for so far.

Manju George 35:42
Okay, and then the size limit that you’re talking about, this is prior to treatment, not after CRT?

Dr. Jethwa 35:52
That’s a good question. So in the clinical trials, it was a size limit before the radiation began. But that’s just from a clinical trials eligibility standpoint. How we would generalize that to practice now– they use that size purely because that was a size they thought they could feasibly deliver the brachytherapy treatment, at least with the OPERA brachy therapy technique. Treating tumors greater than three centimeters in size, it was very challenging for them to do with the techniques we would use in the US and how we would do it here, we would not be size limited in that regard, but it would be more so if you’re treating a very, very large tumor, you may worry about some of the side effects of having to treat such a large area. So I would think about it now as if a tumor had shrunk to less than three to five centimeters, not involving more than half the rectum circumference that we could very feasibly deliver brachytherapy, boost,

Manju George 36:56
Okay, okay, and then, like the 50%, sorry I have all these questions– but with the applicator that you put in with the shielding, so I’m imagining it’s the other side not exposed to the tumor that you’re shielding, but even in this wall, if it’s spread across to 50% then do you turn the thing, or will it get exposed in one go, the entire half the circumference of the wall?

Dr. Jethwa 37:23
That’s a good question. So it all comes down to geometry. If a full 50% is involved, it is challenging for us to also shield the full opposite half. Because then the very edges of the tumor are challenging to get full radiation dose. So in those scenarios, we may opt to only shield one quadrant of the rectum from the radiation exposure so that we could at least sufficiently treat the tumor itself.

Manju George 37:53
Okay, I think my other question would be so in the cases that you have used brachytherapy, did all the patients then, could they all avoid surgery? What’s the like? So the next part of that question is, what’s the surgical outcomes after brachytherapy? Does it affect it? What’s your experience?

Dr. Jethwa 38:14
Yeah, good question. So I wouldn’t say that we’ve treated enough patients here to provide you strong quality, low confidence interval estimates, but we have had complete response in all of our patients so far. And if you look like I showed you at the OPERA study was 81% of patients had a complete response in long term organ preservation. So there’s clear signal of benefit with that technique. If you look at the surgical outcomes, I think we’d also need to go to the prospective trials to guide us on this. Both the OPERA and MORPHEUS studies suggest that oncologic resection can can be done with high quality, without significant impact on surgical quality.

Manju George 38:58
Okay, thank you. The other thing was, I thought that how you expressed the side effects, that you said that when compared to CRT, brachytherapy, did not have side effects over and above what’s expected from chemo radiation, right? So I think that a lot of people, are a little bit scared about the radiation side effects. And then also you said there would be some bowel changes expected for six to 12 months. So what exactly do you mean by that, like, what kind of side effects? What should patients know?

Dr. Jethwa 39:35
Yeah, that’s a good question. So the the side effects from radiation therapy, we tend to split them into two phases, the acute phase and long term phase. Acute phase is typically what happens during radiation treatment, and the first three months afterwards. The typical trajectory of side effects is that patients will feel tired from treatment and as they get further into the treatment course, typically around weeks three, four and five of a five to six week course. They’ll notice that they have an increase in bowel frequency, bowel urgency and potentially a feeling of incomplete emptying, makingit that they have to take further trips to the bathroom. Usually it’s urgency and incomplete emptying symptoms. Sometimes it’s a phenomenon called clustering, which is really a symptoms of incomplete emptying around the time of bowel movements. Frequency can happen, or like diarrhea, but that’s not a predominant symptom from typical radiation is usually frequency, but not high volume diarrhea. The other side effects, that can happen, depending upon where the tumor is located, is that if it’s a very distal tumor around the anal canal, you may have pain from treatment because of the anal canal irritation of treatment, and also the skin around the anal canal can get more irritated, almost like a sunburn in the region around the anal canal. So we would help manage and support those side effects, each of them with medications and support. Urinary symptoms can also happen, urgency or frequency of having to urinate, alsopotential pain with having to urinate. Apart from those, those would be the main things that happen, at least around the time of radiation period. Other things that could happen would be nausea, some vomiting, depending upon how much small bowel is down in the pelvis.

Dr. Jethwa 41:24
In the long term, there’s certainly some side effects that can happen. There can be some long term changes in bowel function long term. Mostly, it centers around the things of urgency or frequency of bowel movements, not being able to hold it for quite so long, clustering or that sensation of incomplete emptying, is quite common after radiation treatment.It is very rare to have incompetency of the sphincter, meaning complete loss of control. That risk is generally less than 10% after radiation treatment. The bladder is quite resistant to radiation treatment. There can be some mild urinary frequency or urgency long term, but it’s usually not quality of life impacting. The femoral heads and sacrum receive some radiation exposure. There’s a relatively low risk of severe injury to those organs. A sacral insufficiency fracture happens in typically, five to 10% of patients. That means radiation has caused weakness of the sacrum, and it can develop a fracture. Most commonly, we’ll see that on imaging, but it’s asymptomatic. Patients won’t know about it. Less commonly, it would be symptomatic, and we would typically manage it with pain support, pain medication. The femur has received some radiation exposure, but the risk of injury or fracture of the femur is very low with conventional radiation therapy techniques.

Dr. Jethwa 42:51
The side effect that is critically important to discuss centers on the concept of sexual health and long term fertility and endocrine function. It, sadly, is often one of the side effects that is most neglected in the conversation. So we know that patients after they receive rectal cancer treatment, whether they are male or female, will have some degree of sexual side effects from treatment, the greatest severity side effects happens with the combination of radiation therapy and surgery, depending upon tumor location. If it’s a very low tumor, next preferred option, so lowest morbidity is actually chemo radiation and organ preservation. If it’s an upper tumor, it would actually be selective omission of radiation treatment that would offer the best balance in sexual function. And those functional declines happen in both men or women, and there are things that can be done to potentially mitigate those risks even during the treatment. So for example, for women, you can’t treat them with a vaginal dilator in place to displace the front wall of the vagina away from the rectum, and thereby potentially reduce radiation exposure to the vagina and potentially reduce the risk of sexual side effects. There’s also that risk of endocrine dysfunction that I mentioned. We know that with standard photonbased pelvic radiation that essentially 100% of women will go through menopause within one year of after the radiation therapy delivery. They will also become infertile because of that radiation therapy delivery. If fertility preservation is of interest, women should undergo ovarian stimulation and egg harvesting prior to the radiation therapy delivery. If that segment of family planning is not important to that particular patient, but endocrine function is, the most evidence based approach would be called ovarian transposition surgery, which is an outpatient surgical procedure typically donelaparoscopically, where the ovaries can be moved outside of the pelvis, placed into the abdomen, outside of the radiation treatment field, and therefore we can reduce radiation exposure to the ovaries.

Manju George 45:11
Okay, thank you. Yeah, sorry. Was I interrupting? So that’s really interesting. I did not know that for mostly endocrine purposes, ovarian transposition was better. And did it have some issues with the fertility? I thought that they it could be moved back after radiation and maybe I misunderstood it.

Dr. Jethwa 45:35
That would be pretty niche in that context. The goal of ovarian transposition surgery is not fertility, to preserve ovarian endocrine function, and part of the challenge would be, is that when the uterus is exposed to radiation, the uterus may no longer be implantable with an embryo, and it may not be flexible enough to be able to carry full term pregnancy.

Manju George 45:58
Okay, okay, That’s that’s the more important risk from the radiation exposure?

Dr. Jethwa 46:03
A little bit of both. But yeah, in general, if a woman’s interested in child bearing, you would want to harvest eggs before the radiation is delivered. And it would be worthwhile to have the conversation that if you want natural biologic children, you may require a gestational carrier, a surrogate, to assist in that process.

Manju George 46:26
Okay, okay, okay. I think that I have asked all the questions that came to mind, okay, maybe the other thing is more practical, right? Like so this was as I remember. This was a couple of years ago in the UK. They did the original first study with the with brachytherapy, right? So how long has it been? Have you started doing this at Mayo? And then the other related question is, do you know of other places in the US? Do you have, is there a group that meets, or, you know, some kind of conversation about it?. So for example, if there was a patient who listened to this talk and they wentback to their radiation oncologist and they’re like, Oh, we don’t do it. Or, I’m thinking of what’s the way to spread the word about this, that you are doing it and you have experience that they could potentially learn or start or whatever?

Dr. Jethwa 47:22
Yeah, that’s a good, very, very good question. So this technique has been used for decades. In France. They actually have the greatest experience doing it. Europe is certainly more active in it than we are. We’ve been doing it here at Mayo, predominantly within the past year or so. We’ve mostly used it, although we have selectively used this technique also for a couple decades, just not in large volume of patients, because we didn’t have prospective randomized trials to guide us. Now that we do, our practice is definitely growing, certainly within the past year, and myself and some of my colleagues have multiple cases coming up over the next few months. I am not aware of many practices doing this in the United States. In fact, I cannot think of a single practice that is growing a large volume experience here in the US. Now, that being said, my colleagues and I have had this conversation because we have been getting external patients, referring themselves here, or their providers referring them here for consideration of brachytherapy. So in general, we would prefer to deliver the external beam radiation therapy ourselves and also the brachytherapy. But because we recognize that this may be a niche practice, we are open and more than happy to care for patients who have received external beam radiation treatment elsewhere, and who refer themselves here in a timeline that we think is suitable to make it make sense that radiation therapy with brachytherapy treatment would still offer them benefit.

Manju George 48:59
Okay, okay, okay. So I think the other question, I have a string of questions now. For example, when you have a local regrowth, the standard practice is salvage surgery, right? I’m kind of wondering, is there a role of brachytherapy in that situation?

Dr. Jethwa 49:20
Good question. So I think the answer is maybe, but I can’t tell you with evidence to support it. And I can tell you that I’m a little bit hesitant about it. Let me explain why. If we’ve already delivered radiation treatment and the tumor has proven that it either is not responding to that radiation treatment, or it regrows after initial, complete response, we already know that from a prognostic standpoint, the outcomes of those patients are a bit poorer. We’ve also to some extent proven that radiation treatment was not successful in eradicating the tumor. So if I saw a patient like that today and they were open to an operation, I think the best chance at curability will be proceeding with with a standard rectal cancer curative intent operation. And repeat radiation treatment, I think would first and foremost, likely be associated with a fair amount of side effects from the treatment, and secondly, I would have less optimism that I would be able to subsequently achieve a complete response,

Manju George 50:44
Yeah, that’s a great answer. Thank you. So that was the other question that I had. So, there is this idea that once a tissue is exposed to radiation, then re irradiating it, there are some dose limitations or something like that, right? So in this strategy, you’re doing it within a three week window. So is that considered as one treatment altogether? What governs all of that, I think I don’t know. So just asking

Dr. Jethwa 51:19
You ask such fantastic questions. So it turns out, when you expose a tissue to radiation therapy, it never really forgets the radiation therapy it had in the past. There’s some degree of recovery, and as a field, we’ve tended to adopt some rules of thumb, like, if you’ve extended greater than six months to a year after the treatment, maybe 50% of that radiation therapy dose has recovered. We can selectively use repeat radiation treatment. When we do this with the external beam radiation followed by brachytherapy, we would consider that a single treatment course. The advantage is that we would deliver the brachytherapy to a more limited area. And it isn’t really like giving a double dose of radiation, it’s giving a focal boost of radiation to a limited area. If we deliver that treatment, let’s say we give standard 50.4 gray 28 fractions, the tumor initially goes away, and then it regrows two years later to be another grossly apparent tumor. If we were to try to achieve a complete response, we would generally, hypothetically, scientifically speaking, ideally come up with at least another 50 gray of radiation to try to fully eradicate that gross tumor. Potentially, we could argue we may need even more radiation dose, because the prior 50 Gray was not sufficient to get rid of the tumor completely. Well, in that context, now we’re thinking about cumulative doses of 100 gray in the rectum. And so that dose level might not be sufficient to promote long term functional outcome from that organ. So typically, if we were needing to re irradiate in the rectum for a recurrent tumor, we would be re irradiating with the subsequent plan of surgically removing that segment of the colon or bowel.

Manju George 53:27
Okay, I think this will be my last question. So this sort of brachytherapy you don’t recommend as the only radiation treatment, right?

Dr. Jethwa 53:41
Typically, yes,

Manju George 53:42
okay, and that that’s because, like, the sterilising effect is very limited to the wall, and the chemoradiation is more like the field. And is that why?

Dr. Jethwa 53:52
Yeah, good question. It all comes down to tumor stage. So there are data that I’ve looked at brachytherapy alone, but it’s mostly limited to very early stage rectal cancers like t1 tumors, for example, brachytherapy alone can be used. But the alternative forms of therapy, like endoscopic resection or trans anal excisions are also great options in that case, and those are also great options, because for patients with t1 tumors without high risk features, they don’t have a strongrisk of occult lymph node metastases inside of the pelvis. When you start getting into high risk t1 disease, t2, or t3 disease, there’s a risk that even if the MRI does not identify lymph node involvement, that there could be occult lymph node involvement inside of the pelvis. So for most of the patients, we would treat t2 to three disease, we use external beam radiation to both treat the main mass, but also cover potential pathways of lymph node involvement inside of the pelvis.

Manju George 54:52
Okay, okay, okay. Thank you so much. Even though you had a limited talk, I hope we covered quite a bit, and this gives a much more a broader idea of what this is. So thank you so much. This was very informative. And as usual, we love to have you give talks in COLONTOWN. So thank you so much.

Dr. Jethwa 55:18
Well, thanks so much. Thank you. Take care.

Manju George 55:21
Okay, bye, bye.