BackTable / Urology / Podcast / Transcript #41

Podcast Transcript: Radiotherapy for Unfavorable Intermediate Prostate Cancer

with Dr. Neil Desai

Dr. Neil Desai, a radiation oncologist with UT Southwestern, shares his perspectives on radiation therapy indications, algorithms, side effects, and prognoses for unfavorable intermediate risk prostate cancer patients. You can read the full transcript below and listen to this episode here on BackTable.com.

(1) Criteria for additional testing for unfavorable intermediate risk prostate cancer

(2) Patient factors to consider when determining radiation treatment options

(3) Cancer treatment protocol for patients with intermediate risk

(4) Efficacy of Treatment for Unfavorable Intermediate Risk Prostate Cancer Patients

(5) Types of Radiation Procedures: Internal and External

(6) Alternative Treatment Options to Brachytherapy

(7) Proton v.s Photon Based Radiation Therapy

(8) Complication Rates with Radiation Therapy

(9) Testing and Biopsy Following Radiation Therapy

(10) Radiation Recurrent Disease and Radiation Resistance

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[Dr. Aditya Bagrodia]:
This is Aditya Bagrodia as your host this week. And I'm very excited to introduce our guests today. Neil Desai from UT Southwestern Department of Radiation Oncology.

Welcome to the show, Neil, how are you doing today?

[Dr. Neil Desai]:
Excellent. Thanks for having me, Adita. Wonderful to see you again.

[Dr. Aditya Bagrodia]:
The pleasure's all mine, Neil, you know, Neil and I have a fairly significant past. We'd lived in the same apartment building during my fellowship and his residency. We were thick as thieves at UT Southwestern, where we overlapped for five years. And, Neil, I would say unequivocally one of the brightest and finest clinicians I've ever had the pleasure of working with.

It was an absolute treat during my five years. And I'm looking forward to kind of jumping into this thoughtful approach that you take to patient care. So today, just to kind of keep it focused, I thought we'd hone in on patients with unfavorable, intermediate risk, prostate cancer. and of course there's like the standard definitions.Neil, is there any variability when you think about this term?

(1) Criteria for additional testing for unfavorable intermediate risk prostate cancer

Dr. Neil Desai]:
I think we all recognize the SCN and the other criteria for going through the number of risk factors, you know, primary pattern, for Gleason seven disease, and, more than 50% positive cores. But the main distinctions nowadays are what to do with MRI guided or MRI targeted biopsies and how that enriches the number of biopsies yielded as well how to integrate MRI findings, but, certainly an evolving space, facing many of the challenges with stage migration with imaging as any other.

[Dr. Aditya Bagrodia]:
And do you kind of get more or less excited for patients that have four plus three equals seven, versus PSA criteria that land them into intermediate risks. So specifically a three plus four equals seven PSA greater than ten.

[Dr. Neil Desai]:
Yeah, I think, there's certainly data that, I think, justified a higher concern for risks from primary pattern four as opposed to primary pattern three. Certainly there's data supporting that PSA fluctuations are highly labile, but may not be as important, especially if you regard PSA density as being, maybe lower for a larger gland. And that is still an intermediate risk factor despite that. And finally, if you look at genomic criteria for Legionella classifiers, there's clearly a trend towards, or certainly a strong correlation of higher genomic scores and risk, with Gleason gray group three now, as compared to two, that's more so than with PSA alone.

[Dr. Aditya Bagrodia]:
Yeah, whether real or perceived, for instance, if you take a favorable intermediate risk patient and the three plus four equals seven with a PSA, less than 10, they've slightly got my attention in a bigger way than a three plus three equals six with a PSA between 10 and 20, but we'll, we'll kind of dive into these nuances. Let's just start out with like 1 0 1, you know, so let's just say a newly diagnosed unfavorable intermediate risk patient, is coming your way. if they haven't been staged by the urologist, are you getting any additional staging?

[Dr. Neil Desai]:
Yeah, we had the pleasure as, you know of working with some phenomenal MRI radiologists and having high quality MRI and prostate protocols. So for us, we're spoiled by getting these easily. And, there's very much an exception, as to which patients do not get these, almost everyone we treat does get an multiparametric MRI, before treatment decisions.

[Dr. Aditya Bagrodia]:
Bone scans?

[Dr. Neil Desai]:
Highly controversial now right? So, I think, any of your elevated PSA's over 10, low density, perhaps they're still reasonable. Now we have the entry of PSMA, that's also FDA approved for this space, and what to do with all these. I think it comes down to pre-test probability and it goes back to what you were saying before.Do you see a high volume Gleason four plus three patient? I think my interest is piqued towards getting more imaging in those patients as compared to someone who barely meets criteria for unfavorable intermediate risk. So pre-test probability by what our nomogram internally or externally use, I think, has to play a role in getting systemic staging, but certainly pelvic imaging is always done in our group.

[Dr. Aditya Bagrodia]:
Yeah, I agree. I mean, there's some latitude, I think even within the guidelines that, you know, axial imaging and bone scans can be considered, kind of typical, gray guidelines. And, I like that because, if it's something I'm less worried about the MRI, which I would get in anybody, unless there was a screaming contra-indication at least checks that box.

(2) Patient factors to consider when determining radiation treatment options

[Dr. Aditya Bagrodia]:
Excellent. So maybe just kind of walk us through, you know, the kind of critical elements of the history, when you're talking to a patient and kind of considering them what options may be best for them.

[Dr. Neil Desai]:
Yeah, I think it comes down to three main issues, right? So the patient-specific factors, disease specific factors, and then your practice patterns and what your expertise and institution will allow or logistics, perhaps. So from a patient per side, I think we're always looking at urinary function, baseline, urinary symptoms, that are obstructive or irritative or mixed, trying to find that if that's important, that will certainly be of importance to radiation therapy and side effect profiles. Secondly, when it comes to a, co-morbidity, cardiac aspects of metabolic disorders, in interplay with hormonal therapy are important to us, patient preferences, where do they fear most? What do they have to adapt to over the next two years? I think we can all trade stories in what we think is the best modality within radiation and between radiation and surgery and now focal therapies.Clearly patient preference of what they are able to adapt to is so important and probably more important than a lot of what we think is different between modalities.

[Dr. Aditya Bagrodia]:
Let me pause you just real quick. Before we jump in, erections?

[Dr. Neil Desai]:
Yeah. I think, baseline sexual potency, about half men have it, half men, don't, you're at risk for losing, that potency with any of these therapies. so have to ask, how important is this to you at this stage in life is a way I put it, put it, And I think that less people will talk to what they classify is a satisfactory sexual function for their life.

And whether that be oral medication use or whether their being willing to use more aggressive interventions, I think you have to flesh that out before you treat, because that certainly be a part of life for a lot of men.

[Dr. Aditya Bagrodia]:
What about relative and absolute contraindications, ulcerative colitis, previous radiotherapy, do you kind of get into the weeds on that?

[Dr. Neil Desai]:
Certainly connective tissue disorders that are on systemic, immunosuppressants, that might impair wound healing. I think certainly Ulcerative Colitis and Crohn’s. I think, the severity of these, the amount of interventions patients have undergone before are a big part of this.

I would say, there's the patient with a 50 year history of Crohn's with several fistulas, which I would say is pretty darn near as close to absolute contraindications I can think of with surgery, sorry with radiation. and then there's also you have the patient diagnosed 30 years ago with ulcerative colitis who had steroids once.And that was it. And so those, I don't think, are an absolute contraindication. Certainly we have a discussion with the gastroenterologist. Firming up an actual tissue based diagnosis of ulcerative colitis or Crohn's I think is important. Obviously a lot of things have been grouped together over time. So a good history in that regard is important.

[Dr. Aditya Bagrodia]:
So I think historically many urologists have felt that significant, lower urinary tract symptoms are a contraindication to radiation. I think that's a myth. I think there's good data that's dispelled that. But, can you comment a bit on that please Neil?

[Dr. Neil Desai]:
Yeah, I think it comes down to what kind of urinary symptoms we're talking about and also what's the trade-off right. So I think, you know, having urinary symptoms is a part of life for most men out there to some degree. I think that the quality of life scores pre and post radiation. Do reflect some differences in the pattern timeline of symptoms, especially with accelerated course to radiation or more intensive course of radiation, which may be tougher on those men with severe obstructive urinary symptoms.But there's a lot of things we can do to optimize those men medication use, perhaps TURPs or even RASP’s before, or, radiation. and also knowing that maybe surgery, the alternative is not too much easier, sometimes in these men is also important to cite. So I think certainly the vast majority of men we treat have some degree of urinary symptoms, but, I think, I would say there are very few men who are absolutely contraindicated from radiotherapy on a urinary symptom basis. and usually those men have issues with any modality. We're talking about it in my opinion.

[Dr. Aditya Bagrodia]:
This kind of dovetails, but what about prostate anatomy, median, lobes, and size specifically?

[Dr. Neil Desai]:
You know, you and I, you and I have talked a lot about these median lobes and what to do, how to optimize before radiation. Certainly though a median lobe that correlates in terms of its hypertrophy, to the occurrence of obstructive pattern urinary symptoms in the patient. I don't think it is beyond a radiation oncologist to do a PVR or ultrasound assessment of post-void residuals and their office to get a sense of the Juul trials of alpha blockers to see what kind of buffer you're playing with on this patient.And when they get worse, will you be able to make them satisfied with medication after radiation? I think is a critical, but a substantial median lobe hypertrophy with invagination of the bladder, neck obstructive pathology that has to open your eyes to consideration this patient may be at higher risk for interventions later, and may want to have a discussion with a urologist before the procedure or radiation. In my opinion, if there's a risk of tension.

[Dr. Aditya Bagrodia]:
So if you were to have your preference and the patient has fairly significant urinary tract symptoms say they're on medical management, you know, Flomax and Finasteride and they've got persistent, moderate to severe lower urinary tract symptoms. Is it generally your preference to have the outlet handled pre-radiation?

[Dr. Neil Desai]:
Good question. I think it comes down to how close should they do the no return point? If they have elevated residuals on max alpha blockade, that I think you're asking for badness, I think if you see signs of straining outlet, obstruction about to go catheter dependent, if he gets worse, I think I would like that, addressed before radiation. This is controversial. There's no randomized data as to who's better off, with the chart before or after, certainly are at higher risk. urinary side effects and radiation had a prior TURP. I don't know if it's any better to wait until afterwards. Certainly a urologist as yourself can tell me that doing a TURP after radiation is not fun either.And certainly has side effect risks at the very least, have to consider that these are not the men for intensified radiation approaches such as brachytherapy boost. And those men based on urinary symptom profile, certainly with select out those men from that even arguably from SBRT or high dose per fraction radiation, in my opinion, in those cases.

[Dr. Aditya Bagrodia]:
Yeah, I think that's insightful. And, you know, there's never going to be a, probably a randomized study of people with a median lobe, unfavorable, intermediate risk pre- post- TURP, et cetera. But also I feel that many times you actually see a clinically significant improvement in symptoms with the introduction of hormonal therapy. You know, obviously you're going to have atrophy of cancer cells, ostensibly, as well as benign prostate tissue. What do you think about that?

[Dr. Neil Desai]:
Yeah, certainly I think it's worth a shot. Right? So for our men with larger prostates doing PSI reduction, hormonal therapy may be of benefit. I think it's just worth caution that we don't want to have a situation which we're having wishful thinking that a large median lobe, which will probably not be sensitive to hormonal blockade, will get better with that. I think in those cases it's worth again, I think just having a good chat about the anatomy that.

This is where the MRI is so helpful, and, knowing what you're trying to shrink down is a cancer in a large gland, or is it just a massive median lobe, that will not be improved by that feature now. Conversely, I think as you've also, well know, urinary symptoms may worsen in an irritative pattern, by ADT. And so I think we've seen men who get better initially then get worse over time. And so, I don't know, there's a magical bullet other than saying, you know, again, post-void residual. The main thing I would say is the closest thing to absolute contraindication is indeed a high, post-void residual before you go into radiation, as opposed to irritative symptoms.

[Dr. Aditya Bagrodia]:
Another, I think myth that exists, at least in my opinion, is that there was a size cutoff, which precludes you from radiation. How do you feel about that.

[Dr. Neil Desai]:
That's correct. I think there's solid amounts of data. Now that size, while correlated with urinary symptoms is not the end all be all. If the anatomy is forgiving, and we've had lots of papers now, with every fractionation schedule ration possible externally, at least. That have demonstrated equitable outcomes. Provided the baseline urinary function scores are satisfactory and there's not major obstructive pathology. I think the main caveat would be with brachytherapy or radioactive seed implants just by the very nature of the maybe more invasive nature of the needle placements, as well as the access to the prostate behind the pubic arch made more tough by the enlarged glance. I think there's only so much you can shrink a very, very large gland and still make them a break at therapy. With so many good options. I think the impetus is to make the easy play and pick external radiation, in those cases, as opposed to forcing brachytherapy. And I think most brachy therapists would agree in that regard.

[Dr. Aditya Bagrodia]:
Perfect. So I think that's, quintessential Neil Desai super thoughtful, consideration of these factors, which clearly have an impact on, patients in their lives. so we talked about comorbidities cardiac comorbidities and that dovetails quite nicely into ADT. Yes. No duration. I think we'll get into that in a moment. Do you like a colonoscopy on everybody before you jump in there and radiate them?

[Dr. Neil Desai]:
I do. I think if they're due for colonoscopy within one year of radiation of that diagnosis time point, that you really want to get a colonoscopy beforehand, because there have been some pretty bad horror stories of someone getting a colonoscopy and a biopsy of a radiated rectum. And that's not you, you're not asking for a good outcome there. Maybe we're just fanning a myth, but I think the preventability of that outcome is so easy that I think in colonoscopy, it’s just good medicine. Certainly we found quite a bit of colon cancers or substantial polyps that needed addressing, going into radiation along. A lot of these men are often encountering good medicine and good medical work for the first time in their lives. It's the right thing to do, being a comprehensive oncologist for all of us.

[Dr. Aditya Bagrodia]:
Okay, fantastic. So we talked about, I think you broke it down into three areas, which I kind of tend to, as well you know, symptomatology lowering, urinary tract symptoms, patient specifics, factors. I always think of anatomic factors as a part of it. Now, how about the cancer specific features that you.

[Dr. Neil Desai]:
So I think, now that we're unfavorable intermediate risk, obviously the impetus for therapy for most men with a reasonable life expectancy. I think for these men the question still remains what's the aggressiveness of their disease within the unfair- intermediate risk category. The main question for us, radiation oncologists is the impact and benefit of androgen deprivation therapy. Obviously no one wants to give ADT to patients in terms of the side effects, but every study we've done, establishes a substantial benefit and survival reduction metastasis. So it has to be ruled out as opposed to ruled in. There's clear data that the escalating rate of therapy dose itself does not obviate the benefit of hormonal therapy in those who need it. So the question is how do we get a better estimate of the absolute risk you're dealing with? So as to inform the patient, what their trade off is. The range of metastasis, as you know, you know, unfair intermediate risks can range from 5%, all the way up to 20%, depending on what nomogram you're looking at in the constellation of features. Now we have genomic scores that are playing a role in helping us. So I think pinning down the absolute risk is supremely important to hormonal therapy selection. And of course, we can talk about radiotherapy beyond that, but that's got to be key.

(3) Cancer treatment protocol for patients with intermediate risk

[Dr. Aditya Bagrodia]:
So in your ideal world, if you're prioritizing cancer outcomes, six months, four months, do you feel strongly one way or the other NCCN guidelines say four to six months. So there's some latitude there.

[Dr. Neil Desai]:
Yeah, I think that's exactly right though. I mean the largest study in the intermediate risk space was actually the four month hormone therapy. But the key thing there is, if you're going to do a shrink course hormone therapy, is certainly try based on some emerging data to ensure that you're talking about a good adjuvant phase hormonal therapy. You don't want to be four months neoadjuvant and then radiation. There's at least some suggested data from, Daniel Spratt, as well as other investigators, that are making pretty clear that maybe neoadjuvant isn't harmful, but certainly the adjuvant phase is perhaps more important for definitive radiotherapy, perhaps the sealant as it or the DNA damage caused by radiation can inhibit repair. So I think for six months is reasonable, the main decision-making there is usually a practice pattern. And number two is a patient hypogonadal older or at higher risk for a delayed castration time, a castration resolution time afterwards. So I think getting a baseline testosterone has to be standard of care. If you're doing hormone therapy.

[Dr. Aditya Bagrodia]:
Excellent. You mentioned genomic classifiers. I mean, one that I'm quite familiar with is a Decipher Score. Are you pretty much routinely getting them in these patients?

[Dr. Neil Desai]:
Yeah, of course I have a conflict of interest there being involved in the study involving Decipher though, not consulting for them. Of course. but, I certainly could decipher anyone where there's an actual decision. If I'm fairly convinced they need hormonal therapy based upon youth in the constellation of high risk features, with an unfair management risk, they will not benefit from adding Decipher other than prognosis. If they want it. I would say I get in the half for unfavorable intermediate risk patients.. Because they are legitimately not sure whether they want the side effects of hormone therapy to justify the benefits. So I think it's something that I've slowly gotten to do more and more just because it does seem odd to go into a case, not knowing what the absolute risk is of metastasis and progression, as best as we can tell. And certainly genomic stratifiers like Decipher, especially Decipher in the radiation setting, add to that information for the patient.

[Dr. Aditya Bagrodia]:
Okay, that's helpful. And so, you've made a decision that you're gonna have ADT as a part of their management of their unfavorable, intermediate risk prostate cancer. Generally, is there a certain time before start of radiotherapy that you like two weeks, four weeks, six weeks, two months.

[Dr. Neil Desai]:
I get going basically one month before radiation and start getting going after that, mainly from a practical perspective of just let the patient get used to what hormone therapy might feel like and adapt it one side effects at a time. Don't, bury them in this rough changed their life, that they have a hard time adapting to. That's purely practical from a science of what's better. The Europeans have long done hormonal therapy, day one, of radiation American trials and the RTG long did two, three months of new management and the Canadians finally try to address this by randomizing the two different approaches roughly and found no difference whatsoever. So if you're doing a six months of course of hormones, whether you start on day one or day 60 of hormones radiation makes no difference. So just go based on practical considerations, patient preferences, and going back to an earlier point you made, are you looking for, perhaps for some side of reduction that might, diminish some of the urinary function issues? If you have obstructive urinary symptoms.

[Dr. Aditya Bagrodia]:
Yeah. And one of the things that we just kind of did pragmatically. Oftentimes we had patients that were receiving some type of outlet procedure start ADT, knock out their outlet procedure, let that kind of simmer settle out. And then generally wait at least about six weeks after the outlet procedure before radiating. Is that about still what you're doing?

[Dr. Neil Desai]:
Yeah, and we've certainly done a lot of these, I think, there's a handful of publications saying, wait two or three months. There's no real data that anything beyond two months is really that crucial, as long as the patients recovered and hormone therapy gives you that time. So certainly a strong role for optimizing, and hormone therapy can, delay or, or temporize while you are allowed to do that and heal.

[Dr. Aditya Bagrodia]:
I also think an important thing is just to have open lines of communication between the radiation oncologist, assuming that they're not prescribing the ADT and the urologist, that can be just a, another step, a bit of confusion and unnecessary delay. Honestly I think as we kind of augment ADT with second generation, antiandrogens likely with a, uh, integration of a medical oncologist and true multi-d now you're looking at potentially having three providers coordinating care.

[Dr. Neil Desai]:
Right. That's where all jump in if that's all right. I think there's actually a very strong role for urologic oncologists here. I mean, as you know, a lot of folks in the community are doing the next generation anti-androgens or androgen receptor pathway inhibitors in urologic clinics. There just aren't enough medical oncologists to give these agents across the whole country. Rather than not have access to care with these. It is crucially important that we have urologic oncologists out there, able and willing to kind of prepare to give these agents alongside ADT and certainly the same for radiation oncologists, whatever the work. It's not, it's not beyond us, I don't think as long as we do our drug monitoring,

[Dr. Aditya Bagrodia]:
Totally, I think there's institutional practices. I recently transitioned to UC San Diego and, when I got here, all ADT was administered by a medical oncologist. And, by all means they're lights out with bone health and DEXA scans and, all these things, vitamin D calcium that are critically important. But having come from residency and fellowship where the urologists were kind of handling that, I was like, at least for short-term ADT, I think we're okay. And, that improves access to the medical oncologist, one less visit for the patient. But as it gets more complex, by all means, we may need to revisit that. Fantastic. So I think, you know, just to kind of summarize ideally within about a month or so of initiating ADT would be a good time if they're getting an outlet procedure, maybe the minimum six weeks. Of course, as long as the patient is healing well, recuperating, well, et cetera, that would be important. Decipher testing could be nice in patients where you're trying to really sort out what the risk is. I think there's also some fairly exciting data in terms of response to ADT, through Decipher, we don't necessarily have to jump into that. Okay. So, the patients visited with their urologist, urological oncologist. They've heard about surgery and now they're, now they're here to, to meet with you. Let's just have your, comprehensive spiel,if you will.

[Dr. Neil Desai]:
So I love coming after everyone else because I get to sit there and look great. Right? So you guys have had the fun of doing the biopsy, the initial shock of diagnosis, conversations, initial follow-up questions, lots of reading, done, lots of all over the place. The boat starts becoming more stable as the patient comes to us with a little bit more information behind them, a little bit more consulting with the ones they love and go to for advice. We have a nice calm conversation and tell them everything you guys said was wrong. I'm kidding, of course, but it comes down to reassuring the patient that there isn't one perfect choice typically. You're going to have options one A one B maybe even one C that are reasonable. And it comes down to what you feel most comfortable with and what you can adapt to in terms of the side effect profile, as well as the follow-up requirements. So for radiation, that's going to be, well, you're going to have to adapt to some urinary bother frequency, urgency, nighttime waking urination issues. Bowel symptoms are still there, but perhaps now with modern radiation techniques, I think the diarrhea aspects acutely during ratio are lesser. Certainly sexual function profiles, perhaps more acute if you're getting surgery. Certainly if you’re adding hormonal therapy to radiation you're gonna see these issues and being open about that discussion, what to see in the first month, second month, et cetera, is very important. The big thing for us is how do you calculate effects of radiation, right? So I'll say, look, all these radiation techniques, there's no clear argument for survival benefit one way or the other. It's going to be about what's going to be least likely to make it so hard for you to adapt to this as your life is totally altered. Furthermore having to consider it for radiation. That maybe there is less impact up front, but you have to also consider the late impacts of cystitis or proctitis, in terms of late effects of radiation injury. And so diabetics have you smokers, have to consider this more, so, try to estimate what's a higher risk for those men, and try and assess for them. How are you gonna adapt to that concern? Is it easier for you to take urinary bother now? When this small percent risk you have an injury later, or is it easier for you to take a big hit right now? Let's say surgery, if I'm characterizing that, right. But finding out more about the PSA response, perhaps, and, pathology, and maybe needing radiation later. But having maybe less of the long-term effects upfront. I think just coaching for them, what to expect and their likelihood of needing multimodal therapy is crucially important at this first visit. Beyond that once they get into the question. Okay, this is my baseline risk. Here are my baseline risk factors for harm from therapies obstructed urinary symptoms, et cetera. Now I go into the question of, well choose surgery radiation amongst the radiation factors going on the radiation path, there's internal or external radiation. There's BRCA therapy, and recommended seed implants.

(4) Efficacy of Treatment for Unfavorable Intermediate Risk Prostate Cancer Patients

[Dr. Aditya Bagrodia]:
I'm asking you one quick question, Neil. I know how risk averse you are and you focused on complications. Let's just start out with efficacy. For me, it's pretty straightforward, pretty much every patient that I see. Here's your age, PSA, primary Gleason score, clinical stage, percentage of positive cores. I plug it in a nomogram. I use the slow nomogram and the good news is the chance of you being alive in 10 years and not dead from prostate cancer is 98% . Slightly more sobering is the likelihood of you having a recurrence at five years is 30%. Just in terms of efficacy and, recognizing that there is this spectrum, right? I mean, unfavorable intermediate risk is a grouping. It's a lumping, but there's also nuances. How do you kind of say, you know, here's a likelihood of you being alive and not dead and not having recurred after I radiate you?

[Dr. Neil Desai]:
Yeah. So that's a good question. And we've had discussions about this. There aren't really great nomograms, with radiation, the same way as prostatectomy for unfavorable intermediate risks. We have, we go by categories and quote, a percentage recurrence rates like, well, you know, based on this trial on everyone to be at risk at five years, 15% recurrence rate, but having to acknowledge them in stage migration, you know, and there's different imaging now. So how many of those were occult metastatic disease? So for me, I come out of the gates. We can go into numbers, but just so you know, before I start, I firmly believe there is no difference in overall survival amongst any of these modalities. Whether you talk about surgery or radiation. Now within radiation, hormones or not is going to be the biggest predictor of whether or not you have a slightly better survival or not.

Okay. And how long you live is going to be a big factor in how important that is and how much those curves separate. So then I go next to, if you know, for you, I think you're on the lower end for unfavorable risk. You only have one risk factor to put you here. I think your recurrence rate is, you know, 10, 15% long-term. I think hormone therapy is the standard of care, but if we want to omit it. I would recommend getting a Decipher score to make sure we have an absolute prediction of your metastasis risk. And I roughly tell you whatever you get with that combined clinical genomic score. Roughly the benefit of hormone therapy, would be half reduction. So if you're talking about a 5% risk of metastasis, which I think is reasonably accurate from these combined models with Decipher, then I do think you have a 2.5% benefit. Whereas if you're 20%, you have a 10% reduction. That's how I go based on the benefit of hormones. But otherwise I said, they're all the same cancer control and depth, kind of the cancer wise.

[Dr. Aditya Bagrodia]:
Yeah, I think that's important because, you know, I think it's. I don't want to generalize and of course it's, urologic oncologist specific, but I sometimes feel like it's pretty easy to play in on a fear of recurrence. You know, I've heard it a thousand times. Well, maybe not a thousand times, but plenty of times over the course of my training that, if you get radiated and your cancer recurs, basically there's no curative options left. Whereas if you get surgery and your cancer recurs, we still have curative options. And I think that's a little overstated, honestly. I don't mean to kind of pin you on this, but I think 10 to 15% is that a reasonable kind of take away. I mean, for a urologic audience, that's not gonna necessarily comb through the radiation oncology literature that, you know, with radiation, there should be about 80 plus percent chance that you're going to be cured.

[Dr. Neil Desai]:
Yeah, I think for long-term PS relapses, you're going to see 15% and unfavorable intermediate risks on average numbers. And that perhaps is pessimistic, but I think we have to cite the old trials for this. I think it's easy to cite five-year data that look great. Like, oh, if you look at a library or a recent SBRT literature, including our own institutional experience, it was 98% control of five years, but we all know that ration failures can take many years to declare themselves, especially to local failures. And that if you're talking about an unfavorable intermediate risk cohort, you should be talking about, a risk cohort that has occult lymph nodes at a significant rate. So I think 15% long-term recurrence rate after radiation is a very realistic prediction, local recurrence I think is under 10% for sure.

[Dr. Aditya Bagrodia]:
What about intraductal histology? Does that kind of get your attention in any type of meaningful way?

[Dr. Neil Desai]:
yeah. I consider that high risk or high grade essentially. And I think you have to have a real discussion about it. To me, I don't think you can do hormone therapy for those gentlemen. The only big question in my mind, which I don't know if it was resolved, is. What do you do with the three plus four with intraductal and that's discordance between that biopsy finding in the, in the, you know, those two biopsy findings. Do you go beyond six months of hormonal therapy with those men? I don't know the answer to that question. And so I typically stick to six months of hormonal therapy. There is strong data that there are a subgroup of unfavorable, intermediate risk men who clearly behave like high-risk is a continuum in the end. Probably a lot of these cribriform feature intraductal feature four plus three high volumes, are those men. It is clear that at least based on, one trial already been done, that extension of hormone therapy probably improves outcome in that cohort. This study is called Trago 3 0 4 radar. And it's based upon that, that we have this trial ongoing, the cooperative trial that I'm helping co-lead. That amongst those men with higher genomic risk features amongst the intermediate risk category, we are intensifying hormone therapy in those men with darolutamide. But I don't think anyone wants us to extend hormone therapy for six months. So I think for those men, you gotta think of a way to intensify. As certainly six months as a minimum hormone therapy might look for those men and probably a more intensive radiation approach would also be my gut feeling. That's highly controversial. We haven't talked about what intensified radiation means.

[Dr. Aditya Bagrodia]:
Oh, yeah, totally. We're about to go into the external and internal radiation here in a big way. and then finally, you know, radiographic T3 disease. Does that kind of change your, your approach here?

[Dr. Neil Desai]:
Yeah, this is an area that we've long debated, I think depends on your MRI quality and the grossness of that extension. It's clear that, suspicion for early, bulge, all these kinds of hedging, features of early extracapsular extension are not the same as clinical palpated, locally advanced disease that are not, it's not as same as a high risk category. And I think people have been over prescribing long-term hormonal therapy based on those features.

There's a very good paper from Alfonso Gutiérrez, from Europe in which they very nicely defined in a radiation cohort. That those men with gross extra capsular features certainly behave like high-risk. But those men with sort of bulging capsular early EPE are not the same, should be true with six months of hormone therapy as intermediate risk.

And indeed a lot of our old trials allowed for those men to be enrolled before MRI era, and even during the MRI era. There's at least one trial that allowed those men into the intermediate risk trial. So I don't think we should overstate the need for longer hormonal therapy for those men without gross extracapsular extension.

(5) Types of Radiation Procedures: Internal and External

[Dr. Aditya Bagrodia]:
Perfect. Okay. So we've talked a little bit about efficacy. You mentioned your side or front profile counseling, a little bit of fatigue, some urinary symptoms, some bowel symptoms, generally those resolved, manageable with medications. I think digging into the weeds, I'm not sure that all radiation oncologists could differentiate between obstructive and irritative symptoms. I'm proud of you, Neil.

Excellent. So now you're kind of talking about what options are available to you and basically starting out with external radiation, internal radiation combination. So we've made a decision by ADT? Yes. No. Okay, fantastic. let's just, have you, maybe just for the sake of the urological audience here. When we talk about external beam radiation, obviously that's like a whole. Host of options, right? IMR-T, hypofractionated, ultra hypofractionated, ultra- ultra- ultra- ultra ultra hypofractionated. So maybe, can you just kind of walk us through, just the lexicon of external radiotherapy options.

[Dr. Neil Desai]:
Yeah, so I think it's easiest to think of as long into a moderate, hyper fractionation or short course, five days. I think we're seeing a continuum, that you could probably, the easiest way to think of is all continuum. And the analogy I always use is either you're going to peel off the band-aid or you're gonna rip it off in terms of the trade-off of acuity of urinary symptoms in particular, as well as perhaps bowel versus the duration of the acute phase. And that's kind of how I put it.

And I think that's very accurate. That's how I say, well, if you're ready to burst and you can't, you have terrible urinary symptoms then ripping off the band-aid with the faster ration courses with the internal break, of therapy where you act as courses are perhaps tougher on you than someone who can tolerate that better.

So now digging into these spectrum of options. On one end, I would put internal implanted radioactive seeds or brachytherapy, which can be given as permanent radioactive seeds called low dose rate brachytherapy. Or as a temporary seed, which is inserted during a procedure, and then taken out during that procedure, the same time called a high dose rate or temporary radioactive seed in unfavorable intermediate risk, prostate cancer. It is still a matter of debate as to whether you can do those alone. I think there's enough risk for most of these men that you really should consider treating a sort of bigger margin around the prostate capsule, as well as a proximal seminal vesicle at the very least. And so monotherapy with brachytherapy alone is I think debatable and patient to patient. I think for most providers, they would still argue, you need to give most of these men external beam on top of it. So you're combining a lower dose of the breakup therapy seed within the prostate to boost the dose. You can get within the prostate. With supplemental external beam to bound, half dose to treat the prostate periprosthetic areas of the seminal vesicle.

There've been two trials that show no diff benefit there. So it's controversial, but that is an option that is considered an intensified approach with higher biochemical control by about 10-15% of historical trials, but no difference in survival metastasis. So again, you're trading long-term control and sleeping well at night that your PSA is not going to come back, but for a higher risk of urinary injury in particular was the historical trade off. And that's, there's still something to read as true.

[Dr. Aditya Bagrodia]:
And the external beam component when you're doing combined external beam plus brachy. Is that 40 courses, eight weeks?

[Dr. Neil Desai]:
Uh, no, the longest will be twenty-five days of external beam radiation. So roughly half the dose, and you can also just let the external beam, you can give it with a higher dose per day treatment. and so you can get that in as few as 16 to 15 days as well, uh, in our practice. And there's some research going on to compress that part to five days as well. but not more than 25.

[Dr. Aditya Bagrodia]:
Are you also radiating the nodes as a part of the combined brachytherapy approach?

[Dr. Neil Desai]:
So I don't classically treat the lymph nodes in unfavorable intermediate risk prostate cancers. Because there's no solid data that it improves outcomes. I think the pet PSMA era is going to perhaps change a little bit of this as we see more of these things. That are occult to conventional imaging. But I don't standardly treat the pelvic nodes you're able to, and some providers do, but I would say less than 10% of men based on the last patterns now that I saw are getting pelvic node radiation for intermediate risk disease.

[Dr. Aditya Bagrodia]:
So if we think about it, like maybe you want the most intensive oncologic intervention that would be ADT plus EBRT plus brachytherapy. The pros being ostensibly best cancer control the downside, being a bit more of an intense acute phase as you're going through treatment. Is that broad strokes fair?

[Dr. Neil Desai]:
Uh, I think the main thing that the trade off side effect wise, the late injury risk for strictures, and urinary injury such as cystitis is higher, in the combination brachytherapy boost group. At least based on historical data. And you can criticize that data, that a lot written about this, that perhaps those rates were overstated because they're like 20 year ago therapy. But I think yes modern contemporary series show a lower toxicity rate, late grade three urinary events. But they are still slightly higher than the external beam alone. And that's the trade-off I think probably even more so important than the acute phase alone.

[Dr. Aditya Bagrodia]:
Yeah, and I think there's certainly some truth to it that going in and handling the outlet in somebody that's received, low dose rate seed implants can be a fairly hectic affair for the patient, with incontinence, a significant lower urinary tract symptoms. And then you'd kind of alluded to this earlier. This is going to be institution specific, right? I mean, in many places brachytherapy is kind of considered a dying art where it's not necessarily even propagated to the next level. Is that fair?

[Dr. Neil Desai]:
Yeah. so I mean, everyone, everyone likes what they do best and brachytherapy and expertise, or at least a skill set that is not everywhere. It requires more logistics. There's controversy over whether the benefits as biochemically are worth it from the side effects standpoint, and the less you do, the worse you get in terms of your outcomes certainly. And so I think a lot of providers would favor external beam alone. And I think the good part of all of this is that there really are a lot of options at this juncture that kind of spread the benefits of each approach across the continuum, more so than it used to be. So it used to be, if you wanted the best control you got brachytherapy boost and that was it. Okay. Are we though now with MRI based lesion targeting as an enlarged phase three randomized trial that was published last year showed? You're getting similar benefits in biochemical control. Again, with these MRI guarded, external beam alone approaches that may be a rival brachytherapy boost.

And so the biggest thing to brachytherapy boost is it's great if you can do it and it's great that you like it, but what if your center doesn’t offer it? What if the patient's prostate is too big? What if they had obstructive urinary symptoms that are beyond AUA IPSS score of 15, which has traditionally been a relative contraindication to brachytherapy? Not everyone can get this quote unquote gold standard. So what kind of gold is it exactly for those men? And so I don't think it's a great stance nowadays to say that only one approach is the best. I think for that patient, if they have perfect urinary symptoms and want the most aggressive control, certainly brachytherapy boost is a very attractive option for them. But you're not losing out nowadays with the other approaches either. And we can kind of go into that next, if that's import.

(6) Alternative Treatment Options to Brachytherapy

[Dr. Aditya Bagrodia]:
Yeah. So maybe just kind of walk through there. You're kind of starting to talk about this, you know, conventional, moderately, hyper fractionated, and then, you know, ultra hypofractionated. So conventional is 40 weeks with 8 treatments, is that still kind of considered a gold standard?

[Dr. Neil Desai]:
Yeah, roughly. Absolutely. You know, it's been well-proven over many, many years with long-term results, good outcomes.They pin down the actual doses that get best outcomes and exactly what trade-off of side effects. Furthermore, the delivery of radiation with conventional fractionation is considered to be failure robust across almost every practice setting, and every kind of image guidance for how you actually track the prostate. So very forgiving in this regard to baseline urinary features to practice types and expertise, or comfort level, I should say, not expertise, but different people will have different comfort levels with different fractions. With that said, there are now multiple bars trials that have been well conducted and shown that with better technology and better targeting of image guides in particular, we can deliver a higher dose per day or hypo-fractionation, meaning fewer fractions, higher dose, which can be done moderately meaning slightly higher dose per day. So over 20 to 28 days, for instance, or many different regimens. I like 20 days if I'm doing this. And that's equitable in terms of, outcome as well as side effect profiles. Again, the main difference being a little bit higher, acute urinary symptoms in most studies. And then now we even have ultra hyper-fractionation, which classically refers to five day and is what we define the United States at least. So we use, or SBRT or even SABER different acronyms for this, but very, very short course, radiation giving every other day, for five days. And that each step of the way, as you go into a shorter course of radiation with a higher dose per day. Certainly the demonstrable expertise and comfort level with the alignment by imaging to the prostate, and delivery radiation with a highly robust, accuracy with low, low emotional loud. That needs to be demonstrated more and more.

So there are very different QA requirements, physics requirements and institutional machine requirements for these things, as you get more and more. So what the good news is, they all deliver equitable outcomes, just different fractionation numbers. And so it comes down to patient preference to some degree logistics. As you know, in Dallas, most of the patients who come to see us are not going to get conventional fractionation. They're going to get either SBRT, or modi- hyper-fractionation. And, you know, I think very few of them are going to opt for the longer course. So certainly a practice pattern is different based on where you are. And, I think just doing a good job at what you do is more important than settling on the best of this.

From a resource standpoint. Yes. There was a lower cost and less burden resource-wise in terms of driving for patients for the shorter courses and from an assistance perspective. That's being considered. but no one can say, Hey , long course is bad or moderates the best. It's just a matter of, I think logistics trade-off right now.

[Dr. Aditya Bagrodia]:
And all of these are done without anesthesia?

[Dr. Neil Desai]:
Correct? Yeah. The only thing we would do anesthesia for would be brachytherapy,

[Dr. Aditya Bagrodia]:
And then in your, ultra hypofractionated and moderately hypofractionated, are you routinely using a SpaceOAR?

[Dr. Neil Desai]:
Correct. Another controversial feature, another area, which I should declare a conflict of interest because I do have a trial that's funded by that company that makes a SpaceOAR gel, as well as funding, consulting

[Dr. Aditya Bagrodia]:
I'm not, I'm not the COI here, Neil I'm you're I'm just kind of out how to teach.

[Dr. Neil Desai]:
But it's important. It's a controversial area. And so, I think, look, technology has gotten really good. We want to improve the therapeutic ratio by dialing down rectal injuries. And I think, as you know, we did a trial showing this with serilineoscopy after radiation to show that. Hey, you know, what's better than having radiation that's healable, or injuries that are healable, which won't be long relied upon that you have to dose per day and the rectum will heal from this.

Well, why not just prevent the injury all together by limiting the dose to rectum. And that's what a rectal hydrogels spacer does. You insert it and we do this for almost all our patients who do not have extra-prostatic central posteriorly. We strongly believe in it, particularly because we use predominantly high dose per day radiation, and where we think the benefit of sparing, the rectum is even higher in these men. Especially because these men are going to live for many, many years and go on anticoagulants. Who knows what's going to happen to them later in life. The last thing that you need is a rectal bleed, when they're age 80, trying to manage afib and anticoagulants. So we use spacers quite routinely, as well as fiduciaries for image guidance.

[Dr. Aditya Bagrodia]:
Perfect. So when you're talking to the patient For seed implants. I mean, typically that's going to be a procedure or you're in, it takes a couple of hours. And you know, you've got your stepper and so forth. You're familiar with the anatomy, ultrasound, guided all that. And you know, basically you have some lower urinary tract symptoms for a week or so forth. You may require a catheter and you kind of get on with it. When you tell a patient, okay, we're about to start your radiation. So you've got your MRI in your hands. Then walk me through kind of the nitty gritty of, are you gonna get your SIM then you're going to be coming in every day. Is it an hour? Is it three hours? Tell me just a little bit about that. Just when you're kind of really getting into the weeds with the patients.

[Dr. Neil Desai]:
Yeah. I always say, look for external radiation options, you're always gonna have two preparatory visits. One is for the procedure which we do under minimal sedation in our clinic in the ambulatory setting to place the gold markers for fiducials in the prostate, as well as the spacer gel between the prostate and rectum. Then you come back about five days later for your mapping scans or simulation, which are the second preparatory appointments, we always do a CT and MRI. We make a mold for the patient, so it conforms to the body replicating the same position, and perineal pressure, for instance, which can affect prostate position and stability. We have them do various maneuvers to minimize radiation dose to the bladder and rectum, for instance, having to have a comfortably full bladder to push the bladder wall away from the prostate, as well as have the empty rectum, such that there's less motion of the prostate.

We then do that mapping scan. We delineate the prostate and they come back for radiation roughly about a week later. If you're doing five day radiation, you're going to do that twice a week for two and a half. If you do 20 day radiation, you're gonna do that five times a week for four weeks. And if you do the 44 day radiation or conventional radiation. You're going to do that multi-nine week radiation almost daily. Now how long you're in department, each of these days for treatment. Roughly the longest are these five day radiation appointments, which are much more precise and demanding of our setup. And those days are probably around 45 minutes plus for the patient. For the shorter course rate or long course, radiation with a little lower dose per day and less exacting requirements, there'll be in and out roughly that 30 to 40 minutes.

The biggest nuisance I hear from these men is the bladder filling. And so we are obsessed with this. We hope it benefits, but it's all about sparing the bladder from radiation. That's got to pay off hopefully in the next 15 years. So if you don't hear about image guidance to see what the bladder is doing, if you don't hear about some bladder filling protocol, that's a concern in my opinion, because even if it's not as beneficial as we all think it is. It’s still important for a, you know, what kind of level of care you're paying attention to this patient's bladder and rectum long term.

(7) Proton v.s Photon Based Radiation Therapy

[Dr. Aditya Bagrodia]:
And then we didn't really touch on this, something that certainly well, part of our armamentarium here in San Diego protons.

[Dr. Neil Desai]:
Yeah. So I think, you know, another controversial area. It's coming down again, how can technology help establish our goals? How can technology reduce injury rates and improve the therapeutic ratio? We will establish that yes. Intensified radiation can improve outcomes a bit, though controversial how much that translates to survival benefit. So the rest of the therapy ratio benefit has to be reducing side effects. And the key question here is what does protons get you in terms of advantage or photons. Primarily reducing the amount of low dose exposure to your nearby organs at risk, such as rectum and bladder. But what dictates side effects in prostate cancer radiotherapy, is it the amount of these organs getting the low dose spread or the amount getting the high dose margin around the prostate?And this is the trade-off. If we believe that the low dose spread matters then protons will be beneficial. However, no data's really reproducibly shown this benefit. Moreover, if you extend this argument to its extreme, well, what's the best way to get low dose exposure down? Radioactive seed implant, brachytherapy.

And yet, I mean, there's no external beam there. And yet the side effect profiles are fairly comparable. If not a little bit worse at times in some patients who are poor candidates. So it's pretty clear based on every analysis we run in trials, I think that that's well believed or at least translatable across institutions that the main determinants of side-effects and radiation externally are; how much should their bladder urethra and rectum are getting the high dose area. In this regard is my personal bias and belief that photon based radiation or proton based radiation does not have any differential benefit in that regard. In fact, I think for some time now, especially for your higher dose per day, radiation treatments. The robustness of setup and certainty where your dose is going and where the dose is falling off is clearly better with photon based radiation. And so that's why you won't see it quite often, a five day radiation course with protons.They're still trying to iron that out in most institutions. So I don't think there's any clear benefit of protons. There are ongoing efforts to define this better. There is a very large trial run by Nancy Mendenhall out of the University of Florida. That hopefully will establish this as well as a particle trial from Harvard, by Jason sofitel. We'll see if there's a benefit, but right now clearly, no meaningful or rationale for benefit in my opinion, over photon based approaches.

(8) Complication Rates with Radiation Therapy

[Dr. Aditya Bagrodia]:
Perfect. Thanks for kind of rounding that out with a comment on that. So, you know, we've gone through radiation and, as is typically the case with your patients, Neil, everything goes perfectly fine. And I always tell patients this, no matter what I'm doing to them, everything's fine until it's not fine. What do you kind of quote as your, rate of, you know, catastrophic recalcitrant radiation, cystitis, fistulas. What's that kind of number that you're giving to patients?

[Dr. Neil Desai]:
Yeah, I'm telling them 5-6% rate of significant cystitis requiring a procedure. and that probably if you asked every man that we treated for years after radiation, some blood in the year, and that went away on its own. Probably higher 15% or more, but they're recalcitrant requiring a person all comers. Certainly 5-6% and that kind of starts peaking around year two to three, and then it starts diminishing over time and never goes away. But certainly the incidence rates will go down. The prevalence rates will go down.We've had multiple trials showing that.

The bowel injury rate of proctitis used to be the same number I would argue as under 1% now. To lose your organs would be a never event. That's as you know, happened to my hands. I described this in the case report. We think those contributed to my spacer gel. this should not happen. I think that's uncommon. I would almost worry more about men getting post-operation nowadays for cystitis risks. I think we appropriately started coming down and down on the dose because of that, for post-operation because a nice trial in Europe show that you won't need to go to higher doses anymore and that'll improve the side effect profile there. But cystitis requiring major procedures is certainly 5-6%. Losing your bladder should be under 1% but they do happen. It can't be ignored that secondary cancers for one last point. That's hotly debated based on what data set you look at most of our population registry show under 1%. There are a handful of studies showing just over 1% perhaps room by your baseline risk and smoking in particular.

(9) Testing and Biopsy Following Radiation Therapy

[Dr. Aditya Bagrodia]:
Yeah, I think that's fair. And I'm actually not sure if there's data on this. There probably is, but it certainly seems like the kind of quote, unquote, radiation cystitis, bladder cripples are typically post prostatectomy, salvage radiation, more so than primary radiation. And for me, you know, kind of, post prostatectomy radiation, that's going to be a long day at the office where, you know, a rectal injury is kind of a bit of a catastrophe. And you know, for the urologists. I would just say that when they have gross material, you gotta work it up. I've seen it way too often and kind of in the community. Where it's treated as radiation cystitis without a cysto and so forth and, you know, fast forward a couple of years, and they've got smoking hot bladder tumors along those lines. Okay. So, they've completed radiation. When do you typically get your first PSA's?

[Dr. Neil Desai]:
Uh, three months after radiation, for a couple of reasons. One if they're on hormones will be the first PSA we get, where, castration resolution timing, if it's super rapid or something's not going well with the hormone therapy or the shots wearing off prematurely, you want to check to make sure. Without hormonal therapy earlier than that, you're really asking for noise, that can be very distracting. And I think letting the patient adapt get three months out, see how the side effects play out. That's a good time to get the PSA, no more than quarterly thereafter. The first two years, every six months, three-year five annually thereafter. I would say.

[Dr. Aditya Bagrodia]:
And then Phoenix criteria for you in terms of a recurrence.

[Dr. Neil Desai]:
Yeah. So, I mean, that's, that's how we define it research wise. Right? So it was defined that way because it was made to correlate to events like clinical outcomes, like metastasis and death. But we know not every recurrence will correlate to death or metastasis, but will have impact on the patient's outcomes. So yes, PSA Nadir, plus two is the definition of failure biochemically. But in the pet PSMA and Oxman era, certainly a patient with the wrong trending PSA without a good reason, such as a PSA bounce timeline, or urinary flare symptoms. That patient merits, I think, an earlier workup than we have in the past. I wouldn't wait for a Nadir plus two in someone you are very convinced is on the road to, progression who you're maybe missing a window to address.

[Dr. Aditya Bagrodia]:
And obviously, patients, I think get hung up on the PSA and it's a bit of a double-edged sword, right? If you check it early with our still castrate and it's nice and super low, that could be comforting. But then you've got to do some explaining when their testosterone recovers and it's something more normal S. But how do you kind of counsel patients on the bounce phenomenon?

[Dr. Neil Desai]:
Hey, I think I also made sure to schedule a follow at the nine month mark. So as they're heading into that flare phenomenon, so this is particularly, so the piece of bounce, what is it? The PSA bounce refers to phenomenon where about a year, year and a half, particularly after intensified radiation schedules, such as BRACA therapy or SBRT we see this more. But the PSA may fluctuate upwards for a temporary period of time before it transient resolves on its own without any intervention. And we believe that it has nothing to do with the cancer. In fact, some people associate PSA bounds with a better outcome, but can be associated with urinary symptoms. So at the nine month mark, I will see these patients to remind them, there may be a PSA bounce coming, there may be urine, recent and flare coming. Find your flow match just in case that happens over the weekend. You know, terribly anxious at nighttime or what's going on here because of course you associate it with badness if it happens on a weekend. Um, and you're not sure what your doc told you about that.

[Dr. Aditya Bagrodia]:
Okay. I think that's critically important because it can be a source of a lot of anxiety. When looking at the PSA number and certainly when associated with symptoms. So let's just say that, you know, they're having a failure and I'm guessing that you're probably getting some local anatomic imaging as well as, metastatic survey and there's something suspicious within the prostate. Does the type of primary radiotherapy that they received impact your desire or lack of desire to pursue a biopsy?

[Dr. Neil Desai]:
I think the timing from the radiation probably matters more. You know, again, if it's, if it's a, within the one year mark within two years, I think doing biopsies, you're asking for. undetermined answer and potentially complication. I think if you're really feeling within a year of radiation and its contemporary radiation dosing, you're almost certainly talking about non localized disease, occultments. And so I'm not thrilled about doing biopsies on the primary, unless I think we just had a marginal miss such as a seminal vessel was under-dosed. So that will be my conditional answer. They're not really radiation techniques, but timing. In terms of salvageability and actionability of your biopsy. I would say again, timing and prior dose of radiation or fractionation matters. Most of our salvage data comes from men with conventional fractionating radiation. With best outcomes, typically a PSA below 10, doubling times are slower and usually six, seven years out from radiation in most of those studies. Because that's usually local failure. If you're significantly deviating from that path, you have to make extra sure with as much advanced imaging as possible that you're not missing occult disease and about to salvage someone locally, that will not benefit from that at all.

(10) Radiation Recurrent Disease and Radiation Resistance

[Dr. Aditya Bagrodia]:
Yeah. And you know, one of the things that I've seen, just a handful of times or early post radiation biopsies that have led to problems like fistulas and so forth. And I actually think that, transparent needle biopsy would be a nice, be a nice part of our armamentarium to basically take that off the table.That's going to be a very very small sliver of the population, but you know, I think when you're starting to, as you've appropriately pointed out. Getting into these unique clinical scenarios, people that you're worried about early failures, et cetera, I think you really have to be thoughtful. And you know one word that's kind of thrown around sometimes is radio resistant disease.Does that even mean anything to you?

[Dr. Neil Desai]:
I mean, radio recurrent disease certainly exists and there's certainly men who blow through radiation and we all feel extremely humbled at that juncture. And if you haven't seen it, you're just not following your patients clearly. You know, it's, it's tragic when we see that. I think those men are probably intermixed, with therapeutic resistant disease. If you're flying through radiation, you're probably flying through hormones. How to predict that's a whole another question. I don't think we have any reliable marker of who's a better candidate for surgery in terms of oncologic outcome. But I think, yes. I think if you have a radio recurrent disease at earlier timelines. The idea that repeated radiation is going to secure them without hormone therapy, at least is probably not a good idea. I think there's nice literature being developed as you know, from our institution when you were here with a couple of the investigators, Roger Shaw and Ganesh, Raj. That are putting out literature on this very concept of what is the phenotype of resistance. I don't know that we really know anyone's operative regime resistance or a way to identify them. Clearly, some men are right, because that's the whole point of hormone therapy is you overcoming resistance to radiation resistance, but how you do identify them. I don't know if anyone's established that.

[Dr. Aditya Bagrodia]:
Yeah. And my sense is it's going to continue to evolve. We don't. Take a deep dive, but I think the mechanism of self kill with ultra hypofractionated versus conventionally may, overcome some of these historically quote unquote radio resistant players. Um, you know, we've seen it in the kidney and I mean, you name your disease. It's really not the exact same, modality, in my opinion. Is that how you kind of think about it as well?

[Dr. Neil Desai]:
Yeah, I think, not to drink the Kool-Aid uh, you know, we're a big institution in terms of our areas, tuition. Tuition's a big proponent of higher dose per day, radiation as changing the fundamental biology radiation, therefore overcoming these resistance mechanisms. However, we still don't have level one data that, that biology of higher dose per day will overcome resistance. It has worked in other cancers like lung cancer. So there's a precedent for this and renal cancer for that matter, like you noted. Uh, but we, I think we had to prove it. And I think the only proof I have so far that higher dose per day radiation can make a fundamental difference is something called the flame trial. In which a large randomized phase three, in which they said, MR dominant disease gets a higher dose per day of radiation, than the rest of the prostate. That trial improved outcomes by about 10-50% biochemical control without increasing the side effect rate at all. So clearly MR dominant disease PI-RADS four or five is either more resistant or just more important to get cell kill on. And with a higher dose per day, integrated boosting of that area clearly improved outcomes. That's as strong as the data I know of. That hyper fractionation is cracking the nut as if it were on some radiation resistance mechanism that we don’t understand.

[Dr. Aditya Bagrodia]:
That's fantastic. And then just a practical thing. So many times patients start out their journey with the urologist and a radiation oncologist is involved. And, just to kind of coordinate, trying to be respectful of the patient's time, make sure they're not having a lot of visits. Do you have a kind of general cadence that you take with patients in your referring urologist?

[Dr. Neil Desai]:
Yeah, I think there's times when we have urologists see us or send us to any surgeon. If there's a non-operating urologist involved I always like to make sure that they see the patient back with my note to them, and a little one-liner of, hey, here's my thoughts on this. Real quick, here's my best one and two options. Here's what they're thinking. And then that helps, like you said, the patient just wants to know we're all talking to each other and if you go into an appointment, they have no idea you saw your colleague the day before. That's not a good feeling for them that they're getting multidisciplinary care, even if by name they are. So I think you're absolutely right, returning the patient and making sure they have time to think. I insist they do not make a decision that day or even that weekend. Having an open line of communication by MyChart or electronic means is also important for followup, but returning them to the urologist for discussion, and making sure they don't make a decision that day is important.

Otherwise I think it's just important to coordinate testing. So if you are going to order new testing, I think we all gotta be on board. And I think getting that cadence down that we're not booking a patient before all the testing is done is super important. It takes literally 10 seconds to check the chart and see when the next appointment is and making sure the patient's booked to do all the testing before they see that provider. I think that makes a big difference and telemedicine finally, is the last one. Has made it a lot easier to do check-ins on patients, as they go along this workup process. That's made it easier to keep on or stay on top of things. I don't know what your opinion is on how well that works, or what would help you stay on top of things when you're having patients seen in multidisciplinary. But that's, I think a challenge for all of us is to stay on the same page. And while also giving patients the earnest honest opinion that they're looking for from us.

[Dr. Aditya Bagrodia]:
Yeah. I mean, honestly, I think, early on during the acute phase, they're just kind of handling it. There may be urinary symptoms. I'd like to be a bit more involved. I think there has been some reality and humility, uh, over the course of the pandemic that despite the fact that we help these patients through their cancer journey, that they've got better things to do than to spend time speaking to like eight different doctors. So I'll usually, you know, once they've completed radiation, if things are pretty good, I'll just kind of ask them in conjunction with the radiation oncologists. Like we can coordinate visits and get your PSA and see, you know, you, for instance, Brent Rose or Tyler Siebert same day kind of knock it out. Or if you want to alternate visits. But I do think it's at least worth having the conversation because the last thing you want is this urologist kind of assuming that somebody else has taken over their care. The radiation oncologist, assuming that they've intervened and somebody else has taken over their care. So I've at opposite ends, too many visits, not enough visits. But I think just coordinating it and I mean, as kind of kitschy, as it sounds, you know, a bit of shared decision-making. And I think once you get a PSA with me in three months and then see Dr.Desai in six months and me back in nine months. I mean, and then, you know, as you get further on out kind of trying to distill it down into, um, something reasonable.

[Dr. Neil Desai]:
Yeah. And I think also critically important. They have someone with them or someone to listen while they are thinking and hearing, otherwise you're right. Sometimes the biggest tragedies, the nicest patient who wants to be respectful of everyone's time as well, doesn't think to come back. And now we've done them a big disservice by not following up by all being overly polite sometimes about not making follow-up visits without giving them time to think. So assigning priorities, assigning sort of here's your homework for the next visit. Give them time to think. And following up and cadence and coordination is important.

[Dr. Aditya Bagrodia]:
Well, this is amazing Neil, as I knew it would be. And, you know, as we kind of approach an hour, any kind of parting thoughts for the listenership.

[Dr. Neil Desai]:
Yeah, I think, uh, you know, this is an evolving field, right? I think there's a lot of different ways to, to deliver radiation to the prostate. It's about how to get the delivery robust, how to get the pacing of symptoms to something you can deal with and adapt to that, you know, what's coming. I think it's important to recognize there is no option that has a proven, this is the best cure rate of everything and balances, every side effect, it's all a trade off. And I think going through your gut on this is important, I think the last thing I'll leave you with is, you know, what's my vision of the future of radiation. I think it's going to be the integration of imaging into what part of the prostate gets the highest dose and this fits well with all the focal therapy initiatives going on as well. It's clear, not every part of the prostate matters as much as the other. And for us, at least all these new adaptive technologies are really, I think, coming prime time. So I think stay tuned for a sort of a, if you want individualized care, you don't really have to look more beyond your own prostate with MRI. Uh, just make sure we're actually looking at it and integrating that decision-making for treatment. So thanks for having me on and, again, always a pleasure to, exchange thoughts with you in, how to, and kind of best match our treatments for our patients.

[Dr. Aditya Bagrodia]:
Yeah. And I think if I may just offer a parting thought from my perspective is that, you know, we're all on the same team here. This is really kind of understanding the patient's preferences and their priorities. And really it's, it's largely about the side effect profile. You know, the need to have, for instance, like an undetectable PSA, or I want it out versus I don't want surgery. And, um, the other thing that's also become glaringly clear to me and largely, due to working with you is, you know, radiation oncologist, isn't a radiation oncologist and a radiation oncologist. You have somebody that's thoughtful. They take their time. They contour it, they contour it again. They know what they're doing. The quality of radiation can be highly variable. So take the time to get to know your local radiation oncologist. And, you know, just like pathology, radiology, or anything else, it's a surgery, certainly. You know, that there is quality as it's prioritized by any given provider. Well, Hey Neil, always a pleasure. Thank you. Thank you.

[Dr. Neil Desai]:
Thank you.

Podcast Contributors

Dr. Neil Desai

Dr. Neil Desai is a radiation oncologist with UT Southwestern in Dallas, Texas.

Dr. Aditya Bagrodia

Dr. Aditya Bagrodia is an associate professor of urology and genitourinary oncology team leader at UC San Diego Health in California and adjunct professor of urology at UT Southwestern.

Cite This Podcast

BackTable, LLC (Producer). (2022, June 1). Ep. 41 – Radiotherapy for Unfavorable Intermediate Prostate Cancer [Audio podcast]. Retrieved from https://www.backtable.com

Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.