Charles Ryan: Greetings from Basel APCCC 2019. I'm delighted to be joined by my former colleague from UCSF, Mack Roach, who's a Professor of Radiation Oncology. Taught me a lot over the years. We shared a lot of patients over the years. And you're teaching us still because we're learning now about oligometastatic disease. And we're integrating data from trials that have been ongoing for a long time where we're getting long-term followup. You've led a couple of these studies. Where do your radiation studies and the findings around node-positive disease help us move the field forward in 2019?

Mack Roach: That's a great question. One of the things I've enjoyed is the discussion about oligometastatic disease. What is it? There's no consensus about what it is, but what it seems to be is that it's something that you define based on imaging. So when your imaging is very crude, it can be a bone met, and now that we have PSMA it can be something picked up on PSMA that wouldn't have been picked up before. So people previously who would have been defined as having metastatic disease with a rising PSA, but nothing imaging would not have been called oligometastatic disease.

So I look at things a little bit differently, I think, than most people in this area. First of all, I think the most common metastatic disease is the disease that you don't see. And so if we had a perfect way to determine where metastases were, then the whole idea of what's oligo and what's not oligo would be seen very differently.

So if we go to the studies of prophylactic irradiation, where you're radiating people who are at risk for metastatic disease, but for whom no imaging can detect it, I believe that will inform you about the treatment of true oligometastatic disease. Because only people who have metastatic disease, low burden metastatic disease, can benefit from prophylactic treatment. I mean, maybe nobody benefits. But our studies have been done based on the hypothesis that if we catch the disease early in microscopic foci throughout the pelvis, that we might be able to cure some of these patients.

So you alluded to RTOG 9413. We just published, sort of, the final results of that 1200 patient study with a median follow up of 14 years in surviving patients. And it taught us several important things. One is that if you give hormone therapy before radiation and you radiate the pelvic lymph nodes, the patients have a better disease-free survival than if you give hormone therapy before and just radiate the prostate. So that sort of confirmed what we thought would happen. But it also taught us a couple of other things and those included that there were interactions between hormone therapy and radiation that were sequence and volume dependent. If you did the whole pelvic radiation before the hormone therapy, the patients did worse than the other arms. We don't know why. Possibly whole pelvic radiation is immunosuppressive, and hormone therapy stimulates the immune system. So maybe you compromise the effect of hormone therapy.

Charles Ryan: That's a tricky one to explain, I agree.

Mack Roach: Well, there's other studies that show that big field radiotherapy does suppress the immune system. In fact, if you look at patients in the old days when they had heart transplant patients that were failing before they had effective drugs, they used to do partial, very low-dose nodal radiation to prevent people from rejecting their hearts. So we know that big field radiotherapy is immunosuppressive.

We also know that there's studies that show that focused radiation tends to stimulate the immune response. So the other thing that was a bit surprising was that their traditional dogma, if you survey 100 radiation oncologists and you asked them, does it matter if you're going to just radiate the prostate, does it matter whether you give the hormone therapy before the radiation or after the radiation, they'll say you should give it before. It's neoadjuvant. That's the standard dogma.

Well, there've only been two randomized trials that have really looked at this, the biggest one is 9413. We had 300 patients where we gave hormone therapy before radiation and 300 we gave it after. And guess what? With a median follow up of 14 years in surviving patients, the patients who got the hormone therapy after the radiation did better than those who got it before the radiation. So since then, there's a Canadian study that looked at, does it matter whether you give hormone therapy before or start them at the same time? But when you use an LHRH agonist, it takes two weeks to get castrate. So even in their study, they're getting them concurrently, but it's not truly before and after. 9413 is truly before the radiation, two months, or after the radiation is completed. So that's contrary to dogma. But that is what we found in the study.

Charles Ryan: I've known about the original data from 9413 for a long time and thought about it as I talked to patients and whatnot. And I think I always think of sort of three compartments of the disease that were treated in this setting. There's the prostate tumor in the prostate with the prostate microenvironment. There's the lymph node, whether it's macro-lymph node or micro-lymph node in a lymph node microenvironment. And then there's microscopic metastatic disease that's probably outside of the radiation port but is of such a low volume. And I always wonder if hormone therapy, even of a short duration, can eradicate some of that disease that's out there in the circulation that would otherwise potentially lead to PSA relapse or even metastases and that the hormone therapy is actually doing systemic therapy, having a systemic eradicating function in addition to its radiation sensitizing function in the lymph node compartment and in the prostate compartment.

Mack Roach: Well except that then how do you explain the fact that hormone therapy plus radical prostatectomy doesn't work? There have been at least seven randomized trials. You gave hormone therapy prior to radical. So I think short term-

Charles Ryan: Short term. Four months.

Mack Roach: We're talking about four months of hormone therapy. I think that there's something that happens. Now there are data that suggests there may be crosstalk between the tumor micro environment and the systemic micro environment. So it is possible that there's something biologic that happens. For example, if you look at the first major trial using four months of hormone therapy, RTOG 8610, two months before, two months during versus radiation alone. In the patients that receive radiation alone at five years, 40% of these patients had metastases. These are very high-risk bulky disease. Back in the day we had low-dose radiation, but 40% of the patients had bone mets at five years in the group of patients that took just four months of hormone therapy, it took an additional seven years for 40% of the people to get metastatses. So that's 12 years.

So how do you explain how four months of hormone therapy can delay the appearance of bone metastases by seven years? There's some biology going on there that we don't understand. Maybe it has something to do with the prostate. But coming back to the issue of oligometastatic disease, so we keep sliding our sensitivity scale for picking up these isolated places of failure. And I don't think that we'll ever get to the point that our imaging will be sensitive enough to pick up microscopic disease. And in my opinion, the true oligometastatic disease is the microscopic disease that's happening that we are going to incidentally treat in the setting of prophylactic irradiation.

So as a follow up to 9413 in June of this year, we completed accrual to RTOG 0924. We enrolled 2,592 patients. Unfavorable intermediate risk and favorable high risk. We took the arm one and arm two from 9413 so they both get neoadjuvant before we're stratifying. We allow longer-term hormone therapy because we know that's better for high-risk patients so we're stratifying by that. We're stratifying by the type of boost. Everybody gets dose-escalated radiation. And I'm hopeful that because we gave higher doses of radiation, we'll have fewer local recurrences. I think that was a problem from 9413 because even if pelvic nodal radiation works, if the patient ultimately develops a local recurrence, they're going to progress. So we needed to improve local control.

We also needed to make our fields bigger because in 9413 our superior border was L5-S1. We know that that misses the common iliac. It's a commonplace for drainage. So we made the big feel bigger. And we made the small feel smaller. What most people don't know is that there was a French study, there was a very small study in which what they called a whole pelvic field would have been included in our prostate, only part of our field because we allowed a maximum field size of 11 by 11.

Charles Ryan: How high are you going above L5-S1?

Mack Roach: We're including L4-L5. We just added another body-

Charles Ryan: And does that take us above the bifurcation-

Mack Roach: It takes you right up there to the edge so you can get those commons. Okay. I mean if we wanted to get to the 99%, 98% we'd have to go to L3-L4 but this was a step forward. So we made the big feel bigger and we made the small feel smaller on the prostate only treatment. And we refined the criteria. And the primary endpoint is now overall survival.

We completed the study a year ahead of schedule in terms of accrual. This study opened up in 2011. I'm hoping that we will be able to analyze at least the quality of life component now. It will be some years before we can answer the survival question, but the bottom line is that we think that this will actually answer questions relevant to true oligometastatic disease. This is the kind of disease that's there at presentation in distinction from the stuff that happens later on, which is not clear just how biologically different they really are. But the bottom line is that I'm excited to ... I hope I'm not in my nursing home by the time the data become available, but you never know.

Charles Ryan: That's what's also really interesting and exciting I think is the long arc of this whole process. I mean, I don't want it to be a long arc. It'd be great to get these answers faster, but you're building on work that took 14 years to assemble, and that's just the nature of the beast.

Mack Roach: Great wine takes a long time to make.

Charles Ryan: Yeah exactly.

Mack Roach: You can't make great wine overnight.

Charles Ryan: Congratulations for your continued support and championing of these concepts, and I think a meaningful contribution, very meaningful contribution to the discussion on oligometastatic disease. Always a pleasure to talk with you Mack-

Mack Roach: Yes. We miss you at UCSF. Thanks.