Anthony V. D’Amico, MD, PhD, on Adjuvant vs Early Salvage Radiation Therapy After Prostatectomy
Posted: Thursday, September 1, 2022
Anthony V. D’Amico, MD, PhD, of Brigham and Women’s Hospital and Dana-Farber Cancer Institute, discusses data comparing adjuvant and early salvage radiation therapy for patients with prostate cancer who are at high risk for recurrence following radical prostatectomy and risk of death. The findings suggest that adjuvant radiation therapy be considered in those with pN1 or Gleason score 8 to 10 and pT3/4 disease, given the possibility that a significant reduction in all-cause mortality risk exists.
Disclaimer: This video transcript has not been proofread or edited and may contain errors.
There have been three prospective randomized trials evaluating the optimal timing of radiation after prostatectomy in the postoperative setting. Specifically, whether it should be given adjuvantly or early salvage? That is at the time of a PSA of 0.1 or 0.2. There were some methodological issues with these three randomized trials. First of all, two of them were designed to superiority and only one as non-inferiority. And the non-inferiority study was underpowered. The two superiority studies have issue because when you're trying to de-escalate treatment, the appropriate study design really should be non-inferiority. So we're trying to figure out if early salvage radiation and a subset is as good as adjuvant in all. The next issue is that the patient population in these studies were very favorable. Only 9% to 17% of men in these studies had what we would call high risk features at the time of prostatectomy, such as Gleason eight, nine, or 10 and extra prostatic extension and/or seminal vesicle invasion. They did a meta-analysis, but again, there's a concern about this because in those three studies, two of them looked at adjuvant versus early salvage radiation, but one looked at adjuvant radiation and hormonal therapy versus early salvage radiation therapy and hormonal therapy. When doing a meta-analysis, all the arms should really have the same treatments. And then there's the possibility of something called immortal time bias, which I'll explain in just a moment. The three studies are the RADICALS, RAVES and GETUG 17 studies. None of them showed significant differences between the two study arms. However, in a superiority study, showing lack of difference does not mean non-inferiority. The immortal time bias issue comes into play when you realize that once a person on the early salvage radiation therapy arm reached the trigger PSA of 0.1 or 0.2, they were given up to two months to get the radiation started, two months to deliver it and then three months before the first PSA assessment was made. That's seven months. It's very possible in people who have very high risk features that they could have failed before the seven-month period. And that would be picked up on the adjuvant arm but not on the early salvage arm. The early salvage arm, in fact, would've failed them later than the true failure time. And this is what immortal time bias causes. And what it does is it makes salvage actually look better than adjuvant. And in the largest of the three studies, the RADICALS-RT, the hazard ratio, looking at progression-free survival between the two arms, on average, was 1.1, suggesting that adjuvant could be 10% less effective than salvage, which doesn't make sense. And that's where the immortal time bias may have caused this issue. Because of these issues, we undertook a study of over 26,000 men. It was a multinational study, using data from Germany and several sites within the United States. And what we did is we identified a high risk cohort, that is men with Gleason score eight, nine, or 10 and either extra capsular extension or seminal vesicle invasion, as the test study cohorts, in which we would look at the question of adjuvant versus early salvage radiation. The median follow-up in that study was 8.2 years. The model that we used looked at the endpoint of overall survival. We used a propensity score to assist ensuring that known prognostic factors were matched between the two arms. We also adjusted for the time dependent use of adjuvant or salvage androgen deprivation therapy. We found that in men in this very high risk group, that is with extension of cancer beyond the prostate founded prostatectomy and a Gleason score of eight, nine or 10, that there was an association with a significant reduction in death. Specifically, the hazard ratio was 0.33 with a P-value of 0.02. Interestingly, when we looked at the selection criteria for the three randomized trials which was much more favorable, and applied it to this data set, just as the randomized trials showed, we saw no difference in survival between men getting adjuvant or early salvage radiation. Therefore, this study raised the very interesting hypothesis that adjuvant as opposed to early salvage may in fact have a curative benefit in men with high risk features at radical prostatectomy, being a Gleason score, pathologically, of eight, nine, or 10, and extension beyond the prostatic capsule or into the seminal vesicles. Therefore, given the possibility that a significant reduction in mortality risk exists for adjuvant as compared to early salvage radiation in men with a prostatectomy Gleason score eight, nine, or 10, and pathologic evidence of extra capsular extension or seminal vesicle invasion, we suggest that at least a discussion of adjuvant in these settings should be made with patients once they would get their urinary continence back. And we waited in this study up to six months before adjuvant treatment was delivered. So that provides a window of opportunity for the discussion, as well as for urinary continence to return.