Novel Approaches in Prostate Cancer Treatment - Episode 5

Early Salvage Radiotherapy for Early Prostate Cancer


Daniel George, MD: Let’s turn to the salvage setting, because there were some data at ESMO [European Society for Medical Oncology Congress] this year that I think have been building, and there were some at ASTRO [American Society for Radiation Oncology]. Joe, walk us through a little bit of that data and how they’re shaping our thinking behind adjuvant versus salvage radiotherapy, with or without these hormonal therapies.

Joe M. O’Sullivan, MD, FRCPI, FFRRSCI, FRCR: There have been controversial data until now with regard to adjuvant radiotherapy or salvage radiotherapy as a way to go in patients who have either high risk of recurrence after radical prostatectomy or in those who develop a PSA [prostate-specific antigen] or a biochemical recurrence. We had 2 sets of data at the ESMO meeting here in Barcelona, Spain. We had the interim analysis of the RADICALS-RT trial, which is the largest trial. It’s nearly 1500 patients from the United Kingdom, Ireland, and Denmark. That was presented by Chris Parker.

We also had a very nice meta-analysis presented by the UK Medical Research Council’s Claire Vale, and she brought together 3 trials. She looked at data from RADICALS-RT but also a TROG [Trans-Tasman Radiation Oncology Group] trial and the GETUG-AFU 17 trial, and she tried to bring the data together to give an answer sooner. This is because the real challenge with these patients is that the surgery works pretty well, and the recurrence rates and the frequency of events is quite low. So it takes a very long time for these data to mature. We’re seeing 5-year results from RADICALS-RT, and then the meta-analysis was helping us to bring the data together.

Previously there was some conflicting evidence. There was an EORTC [European Organisation for Research and Treatment of Cancer]—22991 trial, which suggested a benefit of adjuvant radiotherapy versus wait. But actually, this data presented at ESMO tells us that actually there doesn’t seem to be much difference between immediate radiotherapy versus waiting for the recurrence and then treating the recurrence—especially if you have a low threshold for when you decide to do the salvage radiotherapy. In the RADICALS-RT trial, it was 2 consecutive rises above 0.1. That’s very early salvage, and I think that’s a very important factor. Some of the earlier data, whether it’s for some of the retrospective data, some of the patients’ PSA was well into whole numbers, and that’s not really salvage. You really missed the chance.

What was really interesting about this was if you follow the patients properly and have a low threshold for starting salvage, then you are able to de-escalate treatment in quite a lot of patients. That’s very important. This is because, not surprisingly, the patients who were randomized to receive immediate or adjuvant radiotherapy had more adverse effects because they were having radiation closer to the time of surgery. Therefore, perhaps there wasn’t full recovery from the surgical complications. Second, more patients were being exposed to radiation.

Daniel George, MD: That’s right.

Joe M. O’Sullivan, MD, FRCPI, FFRRSCI, FRCR: There are some controversies within this. I think the RADICALS-RT data are not yet fully mature, and certainly it will be a very long time before we see a survival difference, if ever, because of subsequent therapies. But to me, I think the data have given me great reassurance that early salvage is the best approach. It means that quite a significant proportion of patients will not need radiation.

Daniel George, MD: Yeah, I think it was like 75%.

Joe M. O’Sullivan, MD, FRCPI, FFRRSCI, FRCR: Yeah.

Daniel George, MD: So this is the majority.

Joe M. O’Sullivan, MD, FRCPI, FFRRSCI, FRCR: That’s very important, because we don’t like overtreating patients. We just had the discussion about active surveillance, and we as doctors don’t like doing harm. If we can get away without doing a therapy, I think that’s what we should be trying to do. I’m reassured by the data. I think the meta-analysis was also very powerful, because it brought together 3 trials designed around the same time with fairly similar inclusion criteria and fairly similar salvage and protocol. I’m pretty reassured now that we can safely get away with salvage. I think it will be interesting to see the data mature, but I honestly don’t think we’re going to see much change over time. I really think that the concept of adjuvant radiotherapy makes sense, at least for the patients described in this risk category.

Within the data, there was some devil in the detail because there are some patients who are perhaps at higher risk of recurrence than others, of course. In the RADICALS-RT trial, you were considered high risk of recurrence if your PSA at baseline was 10 or above, your Gleason score was 8 or above, you were T3, and you were positive margin. But that describes very different disease. A focal positive margin may have very low risk of recurrence; however, a Gleason 8 might have a much higher risk. Also, the PSA level at baseline is quite variable as well. I know it does predict for a higher risk, but there’s not much difference between a PSA of 5 or 6 and a PSA of 10 in my view, with regard to recurrence postsurgery. Then of course there is the quality of the surgery. The quality assurance of the surgery is difficult to monitor for that kind of study.

Charles Ryan, MD: Can I interject? What I’m hearing Joe talk about is really interesting, and it’s a great evolution of treatment. I’m beginning to think about testicular cancer and how we began to reduce the treatment intensity because here you’re saying that clearly there are patients who benefit from radiation therapy; that’s established. But now we need to ask the question, who are the patients who won’t benefit from radiation therapy for whom we are over-radiating? The question is about what parameters we can use, whether it’s PSA doubling time—obviously, novel imaging were baseline factors—if we can say not that this patient is going to benefit from radiation but that this patient already is likely to have systemic disease.

We, as medical oncologists and those who treat advanced disease, all have these patients in our practice who got radiation, recurred, and developed metastatic disease anyway. Maybe they’re still suffering from the adverse effects of their radiation. The test in this cancer analogy is to say, “How can we figure out how to de-escalate some of this treatment?” and “Are we moving in that direction?”

Christopher Sweeney, MBBS: Can I jump in with 1 thing? A major epidemic of PSMA [prostate-specific membrane antigen] PET [positron emission tomography] imaging of these patients. I 100% agree with everything Joe and you just said, but we need to counter the notion that, “Let’s wait and let the PSA rise a little, so I can get a PSMA PET and maybe find where the cancer is.”

Charles Ryan, MD: Interesting. Good point.

Christopher Sweeney, MBBS: The message is, if you’re going to do salvage, do it early. Don’t wait for the PSA to be 0.2 to send them to Scandinavia to go and get a PSMA PET from whichever country they can get it. Do what the standard of care shows because the earlier you institute the salvage, the more likely you are to cure them. Don’t wait.

Daniel George, MD: Sure.

Christopher Sweeney, MBBS: The next thing is, when would you put androgen deprivation into this mix?

Daniel George, MD: I was going to ask that because 1 thing RADICALS-RT didn’t really address was the hormonal therapy question. It was there. It was allowed, but it wasn’t a prescribed regimen per se. There are other studies that are really addressing this. Do you want to summarize that?

Joe M. O’Sullivan, MD, FRCPI, FFRRSCI, FRCR: Actually, there is a separate part of RADICALS-RT that is the hormone randomization. The data presented here were pure radiation, but there’s a subsequent randomization that if you were deciding to treat the patient—either they were randomized to adjuvant or then they were receiving salvage—you could also then randomize them to receive no hormones, 6 months of hormones, or 12 months of hormones.

Daniel George, MD: Interesting.

Joe M. O’Sullivan, MD, FRCPI, FFRRSCI, FRCR: That data are yet to evolve, so we don’t know that. This is because, obviously, the biochemical recurrence data for that would be very much delayed because of the hormonal therapy. I think there would be subsequent data from RADICALS-RT, which will help us with that. But I think what we have right now is telling us that it’s safe. If you have a low threshold for when you do the salvage, its safety is PSA. I totally agree with Chris that waiting for the PSMA scan to be positive is not the way to go.

Daniel George, MD: That’s great.

Transcript Edited for Clarity