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Dr. Alicia Morgans: Hi, this is Alicia Morgans. I'm an associate professor of medicine in the division of hematology oncology at Northwestern University. I have the pleasure today of speaking with Dr. Dan Spratt who's an associate professor and vice chair of research in the department of radiation oncology at the University of Michigan, to talk about a recently published JAMA article regarding radiation, external beam with or without brachytherapy boost, and comparing outcomes with those patients, and radical prostatectomy. I'm so excited to have you here to talk with us today Dan.

Dr. Daniel Spratt: Thanks so much. It's great to be here.

Dr. Alicia Morgans: Dan, can you give everyone a little bit of an overview of the study that you published? It was a retrospective cohort study I think? Can you explain that to everyone?

Dr. Daniel Spratt: Yeah, exactly. This is a paper published by first author is Amar Kishan, and it's a retrospective study from 12 academic centers, 11 of them in the United States, and 1 of them was actually in Norway of a little over 1800 men with prostate cancer. One of the unique aspects is this is by far in a way the largest data set comprised of Gleason 9 and 10 prostate cancer, which is actually a fairly small subset of localized prostate cancer.

Using this pooled data, a variety of comparisons were made between radical prostatectomy, external beam radiation therapy or external beam radiation therapy plus a brachytherapy boost regarding primarily distant metastatic outcomes, prostate cancer-specific survival, and overall survival.

Dr. Alicia Morgans: Great. Thank you. I think some of the important aspects, and some of the important findings are pretty striking. Can you summarize the findings of your study?

Dr. Daniel Spratt: Yeah. What was found is that when comparing both the unadjusted as well as the propensity-matched analysis, where the variables that were available were matched between cohorts, that external beam radiation therapy, and that was combined with androgen deprivation therapy for a variable amount of time, compared to radical prostatectomy, and again a small subset had multi-modality therapy including adjuvant radiation. The prostate cancer specific survival, distant metastasis-free survival, and even overall survival were identical, and which is very reassuring because these are the two most common standard of care therapies given at least in the United States for men with higher risk prostate cancer.

What was unexpected is that patients who underwent a brachytherapy boost, actually had significantly improved outcomes across all of those outcome measures, including overall survival.

Dr. Alicia Morgans: Yeah. That is pretty incredible. Can you tell the listeners just to inform them if they're not radiation oncologists, what exactly a brachytherapy boost is. And just confirm all of the patients that received radiation with this high-risk disease, including those patients who had the brachytherapy boost did get what was supposed to be extended androgen deprivation therapy to really augment the power of the radiation as well, right?

Dr. Daniel Spratt: That's an excellent point that you bring up. First, what brachytherapy is essentially, it can be given in one of two ways. But essentially, it's an invasive procedure. These patients almost need to be fit enough to be a surgical candidate because you undergo anesthesia. But you put the patient under anesthesia, and you place catheters essentially into the prostate, and you either leave permanent radioactive seeds, and this is on the order of 60, 80, 100 seeds in the prostate that are radioactive that are called permanent implants, or you can do a temporary implant with high dose rate brachytherapy where you can temporarily leave the catheters in with that radioactivity, and then you remove it out of the patient.

That's also called LDR for low dose rate, and HDR for high dose rate. Essentially, it's just a way to give more dose to the prostate. Now, you brought up an excellent point regarding the combination of hormone therapy. Now, the standard of care based on randomized trials to give with external beam radiation is approximately two or three years. However, in this study one of the notable points is that the external beam radiation therapy patients actually over half of them received less than two years of hormone therapy, and some of this speaks to, in general, external beam radiation therapy patients across these three different treatment types are typically the oldest, have the most comorbidities, and sometimes the most advance stage because they're not always fit enough to undergo a surgical procedure such as a prostatectomy or even brachytherapy to undergo anesthesia.

I think that speaks to many of them not receiving optimal durations of hormone therapy because we do worry about giving full duration hormone therapy for patients with significant obesity, diabetes, metabolic syndrome, and heart disease.

Dr. Alicia Morgans: Absolutely. I think in a non-randomized trial that's really important to think about. And also patient selection in a non-randomized study. If you're looking at patients who receive a prostatectomy, for example, these may be, as you alluded to and said several times, may be very different patients, than patients who had treatment with external beam radiation alone. Though of course, we might think that the patients who received external beam radiation therapy with a brachy boost may be a little bit fitter.

Can you explain how you, and the team used propensity scores to adjust the risk that patients would end up in one of these groups or another, and try to get rid of some of the confounding whatever it was. Comorbid disease or any other factor that may affect the outcome survival, but may not be accounted for as it is in a randomized control trial.

Dr. Daniel Spratt: Yeah. The data that was available consistently from all the centers really was the tumor related factors, and the treatment related factors. Propensity scores were estimated using the treatment, and age. Age would be probably the primary factor that I guess would adjust for things like comorbidity, but clearly doesn't capture all of it. A man's PSA level, there are clinical pre-treatment T-Stage in their Gleason score. These are general prognostic co-variants that I think do a reasonable job, definitely not completely, but a reasonable job at adjusting for tumor risk.

But I think as you alluded to, they've clearly been shown to not be adequate to account for comorbidities, and non-prostate cancer specific variables. What a lot of studies have shown, especially in population based registry is when you compare let's say surgery versus radiation, surgery will always show that there's improved survival. And because those patients are often younger, which can be adjusted for, but they have significantly less comorbid conditions. In fact, surgical patients have been shown, we call this a self-fulfilling prophecy, is they actually have longer survival than patients without prostate cancer.

I think that one of the strengths of this study is the ability to at least try to match on all these variables. But I do think a notable weakness of the study is the absence of comorbid information such as cardiac disease.

Dr. Alicia Morgans: Good thing, just to know as we interpret the data, but still quite a powerful message, I think, overall. As you think about incorporating this data that suggests a survival benefit to the incorporation of a brachytherapy boost into your treatment plan with your external beam radiation, as well as of course long term or prolonged course as appropriate of ADT for these high-risk patients. How are you making these decisions, and are you selecting patients specifically for this more intensive therapy?

And if you are selecting patients, just a run-on question I guess, if you are selecting patients, what criteria are you thinking about to do that?

Dr. Daniel Spratt: Yeah. The way from a high level, I view this data of what it's telling me is I think the first question is do I believe there's a survival difference between external beam radiation with adequate hormone therapy, and external beam with the same hormone therapy with a brachytherapy boost or essentially adding additional dose. I think there's been three randomized trials that have never shown even a small signal of a difference in survival form adding brachytherapy.

But what I think this study is telling us is that brachytherapy is likely a marker for patients, that are more similar to surgical patients because they have to be fit enough to undergo anesthesia. What it tells me is that patients who get good radiation, good hormone therapy have actually very good outcomes that have Gleason 9/10 disease whereas surgical patients, and this is true across the United States in many parts of the world is that only 9% of these Gleason 9/10 patients underwent adjuvant radiation.

Really, just like it is throughout most of the US, the surgical patients were essentially monotherapy. They had surgery alone, and I think that this data would strongly suggest that they would have aimed theory or distant metastasis, and even overall survival. When I look at this, when I discuss these types of patients with my urologist at our multidisciplinary clinic, what really we try to emphasize to the patient is that your best outcomes are with a multi-modality approach that involves adequate or good, well delivered local therapy as well as likely needing good, and adequate systemic therapy as well. Giving these patients very high risk of harboring micrometastatic disease.

The way I build this into my practice is given that brachytherapy does add approximately two to three-fold increased risk of either severe bowel or genital urinary such as bladder toxicity, I discuss the pros and cons with the patient that adding brachytherapy will likely result in improved biochemical recurrence-free survival as shown in the randomized studies, as well as increased toxicity. And for younger patients especially with a prostate that's not too large or not over 60 grams, and for patients that don't have significant obstructed urinary symptoms, and patients who at the MRI shows no extraprostatic disease such as extracapsular extension or seminal vesicle invasion, those to me are ideal candidates to undergo a brachytherapy boost.

But patients who potentially have extraprostatic extension, I typically favored just a high dose external beam radiation therapy with two years of hormone therapy.

Dr. Alicia Morgans: Why is that Dan? Why do you favor that?

Dr. Daniel Spratt: Yeah. One of the issues with brachytherapy is you can really only deliver the dose within the prostate. I think that for a patient that we know they have much worse side effects when patients have a high obstructive urinary symptom score, they're more likely to have side effects from getting brachy, so I don't think they're the best candidates. Patients that have large prostates or even very small prostates sometimes under 20 grams, it's hard to give a conformal or a good treatment plan with brachytherapy. It's hard to get the dose distribution to very large or very small prostates because the small prostates you often give too much dose to the urethra, and can damage it. Or in very large prostates they may be hard to get uniform coverage across the whole prostate.

Lastly, if it's extraprostatic or in the seminal vesicle, it's very hard. Not impossible, but it's much harder to get good dose from brachytherapy to extraprostatic disease. I think that is another reason of some of the confounding that may be seen in this between the brachytherapy boost patients, and the external beam patients. That's very hard in actually any retrospect of a study to adjust for is those subtle features that may make the brachytherapy patients, they may actually have less aggressive disease because you have to select them appropriately for the procedure.

Dr. Alicia Morgans: Absolutely. I imagine that all of these patients had pelvic or prostate MRIs that you could review. That would be a massive undertaking to try to review all those MRIs, and make sure, if they were even done given the span over, which this study was done to really clarify and nail down what is essentially a clinical stage for these radiation patients. It's a really good point, and it sounds like the typical risk factors for utilization for brachytherapy in localized disease are pretty similar to those that you use in your decision making regarding utilization of brachytherapy, in combination with the external beam in these high-risk patients. That's really good to know.

One of the questions I had, you were talking a little bit about multi-modality therapy for those patients who had a radical prostatectomy, and a pretty low utilization rate for men of adjuvant radiation. And I wonder if we could really even adequately capture with the data that was in this database what that rate should have been because although these patients were Gleason 9/10, it looked like a fairly small number of them were pT3b or even 4. And I didn't see anything necessarily on surgical margin status. It's hard probably to know, and perhaps I'm wrong, but it seems like it would be hard to know from the data available whether adjuvant radiation would have been really recommended.

Dr. Daniel Spratt: Yeah. They do provide in a table some of the pathologic characteristics of the patients that did undergo surgery. As you know, everyone has their own threshold as when they want to give adjuvant radiation. But it is actually pretty striking. For T3a disease, it's 29% at T3a after surgery. 40% had T3b, and about 4% had T4 disease. And there was about a 40% positive margin rate. I think that if you lumped all T3s together, you are talking to close to 70% of patients had T3 or even higher if you add T4s in there. 

But if you're just limiting to T3b patients, you're about 40% of the cohort, and I think one of the messages that especially when you combine that with a very high Gleason score because I think you're completely correct. If these were Gleason 3 + 4 patients, I think even a T3b may not, for many people, be a trigger to give adjuvant radiation. But I think when you have these very high Gleason scores with very high pathologic T-Stages, and even fairly high positive margin rates. Most diseases in the body, I think lung cancer is a great example, cervical cancer is a great example where they've done trials actually comparing surgery plus/minus adjuvant radiation therapy to just a radiation and systemic therapy approach.

And almost all of those diseases, the standard of care becomes doing a radiation, and systemic therapy approach because the surgery, when you have such advance disease it's difficult to demonstrate the benefit of it given that you almost always need post-operative radiation. I think this is a good example that if you plugged these patients into let's say the Memorial Sloan Kettering Nomogram, it's probably close to 90% would be predicted to have biochemical failure. Really, surgery by itself, which is really the most common treatment given in this paper, and what's given in the United States, is inadequate.

Obviously, it would be great if there were trials done, but I think there needs to be some greater adoption of use of adjuvant radiation therapy when you have multiple bad or poor prognostic factors. 

Dr. Alicia Morgans: Absolutely. And my apologies. That was really well outlined in table two. I was looking at table one, and that really does not adequately reflect the pathologic and treatment details, which are very clearly outlined in table two. And I agree with you, it is striking that with nearly 40% positive margin status in a Gleason 9/10 population, we've got an adjuvant radiation rate of around 9%.

Definitely, this paper is bringing to light even things that we need to work on, I think, in terms of general practice awareness that these features positive margins, and pT3b status. We really should be thinking about adjuvant radiation particularly in patients with these very high Gleason scores because there is a clear need. Thank you for pointing that out.

I have another question. I think this gets to where do we go from here? Is it time for another randomized control trial you've mentioned several that have not been able to demonstrate findings similar to the ones in this retrospective cohort analysis that you, and the team have done. Do you expect another RCT could be done that could demonstrate this difference? Or where do we go from here?

Dr. Daniel Spratt: Yeah. I think many people, I think providers and patients would love to have a randomized trial in this setting. We've been very fortunate from the Europeans who ran the ProtecT trial for primarily low, and intermediate risk patients demonstrating no difference in prostate cancer, specific mortality between surgery, and radiation. I think we probably need a group like that outside the United States to run a high risk trial. And I think that although there's a lot of controversy around this, I think that I have fairly high confidence that if the current standard of care, and really as you know a lot of the trials that are adding new agents. The STAMPEDE trials for example, RTOG is going to be publishing shortly a positive trial adding docetaxel for these very high-risk guys, that has a signal for survival benefit.

That almost all of the data in these very high-risk men is generated with radiotherapy as a backbone, and adding on additional, very effective systemic agents. What's going to happen for better or for worse is our trial's backbone will remain radiation therapy. It will remain the evidence-based standard of care for very high risk men. I think that's something that would be very helpful for urologists, and potentially for patients depending on the results of the trial is to use surgery as the backbone in some of these trials. But I think until urologists are willing to start using more post-operative radiation therapy, I think it's very hard for groups to run trials with surgery alone without post-operative radiation because there's very few diseases in the body where, for high risk patients, you're actually adjusting surgery.

Even low risk breast cancer, you usually add radiation therapy after a lumpectomy. I think that if there were trials that grouped in surgery with post-operative radiatio, and systemic therapy, I think you'd find actually remarkably good outcomes. I think that would be an amazing trial to be done is a tri-modality approach with surgery post-operative radiation, and some type of systemic therapy because again, local therapy no matter how much you treat the pelvis, these patients, many of them ... If you look at PSMA pet series, about 15% of them may have, outside the pelvic, nodal or even boney disease. I think a systemic treatment is often warranted for these patients.

That trial, if that could be done I think would be very helpful for patients.

Dr. Alicia Morgans: Great. I really appreciate you describing what it is that we need as a field, and we can continue conversations. I know that there is a study that is going through ECOG right now, and hopefully we'll be able to continue to move forward. For men with high risk disease, post-prostatectomy that does include adjuvant radiation, and a systemic therapy. We may be able to see in the United States at least one of these studies, and like you said engaging with our European partners, and learning across the globe is actually a wonderful way to do this too.

Thank you so much for sharing your insights on this paper. Really putting it into context in our clinical practice, and I'd love to hear overarching themes, final thoughts for the listeners before we wrap up.

Dr. Daniel Spratt: Yeah. I think that it's clear that Gleason 9/10 prostate cancer have fairly aggressive outcomes, and we need to appreciate that is an independent respect or in it of itself. However, with good therapy, and I think this paper showed using good radiation therapy, which is reflected by healthy enough patients to get a brachytherapy boost with full dose radiation, and adequate hormone therapy that probably results in the best outcomes. Whereas patients that get inadequate therapy, such as the external beam patients often had less ... I'd say it's a suboptimal dose of external beam radiation, and greater than half didn't receive the adequate duration of hormone therapy.

Or the surgical patients who only about 9% adjuvant radiation. I think suboptimal or monotherapy in this Gleason 9/10 cohort is going to result in inferior outcomes. To me, the biggest take home message is that when you have a Gleason 9/10 patient, they really need to know upfront that-

Dr. Alicia Morgans: But for appropriate patients with these very high risk tumors, this is something to which we might aspire, we might strive to, to try to optimize the outcomes for our patients. Thank you so much again for your time, and we look forward to hearing from you again. 

Dr. Daniel Spratt: Thank you so much.