Munich, Germany (UroToday.com) In today’s Plenary II Debate on the timing of radiotherapy after radical prostatectomy, Dr. RJ Karnes of the Mayo Clinic gave support to early salvage radiation therapy. He began by reviewing the ASTRO guidelines, which state that physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings, including SV invasion, positive margins, or extraprostatic extension because of demonstrated reductions in BCR, local recurrence, and clinical progression.
These guidelines were based on 3 trials (SWOG, EORTC, ARO), however they were limited in that they did not include early salvage, and the endpoint of the trials is where one would start early salvage therapy. Moreover, in the SWOG trial, 1/3 of the patients had detectable PSA after RP before randomization, there was no detailed information on follow-up, the trial was performed in the early PSA era, the quality of PLND has been called into question, and 13% received salvage RT for symptomatic progression (i.e. when it was already too late). In the observation arm of the EORTC, only ½ of the patients with BCR underwent salvage RT. The ARO trial was the only one of the three that required undetectable PSA after RT, thus making it a true adjuvant trial. However, it was underpowered for survival outcomes with only 15 cancer-specific deaths. In all, our 3 landmark trials have been largely non-informative about salvage therapy.
This framing of the existing data calls into question the possibility of overtreatment, which has not been insignificant. The observation arm of the EORTC demonstrated 50% BCR-free survival at 5 years, and the number needed to treat in SWOG was 56 to prevent one cancer-specific death. Low grade tumors may have also falsely inflated the impact of adjuvant treatment in the 3 trials; up to 57% of patients had Gleason 6 disease, which may have contributed to reduced BCR after adjuvant therapy.
Cochrane meta-analysis of adverse side effects in the 3 RCTs suggests that the presence of urinary incontinence favors observation over adjuvant therapy. While toxicities have been regarded in the literature as “manageable” and not statistically significantly different between the adjuvant and salvage settings, Dr. Karnes argued that they are often clinically significant, and initial observation can lead to avoidance of these adverse outcomes.
As for effectiveness of treatment, Briganti and colleagues demonstrated in a retrospective analysis of 900 patients with pT3 disease that early salvage therapy demonstrated similar BCR-free survival as adjuvant therapy. In this study, adjuvant therapy was administered at PSA<0.1 while early salvage was administered at PSA<0.5. Fossati and associates demonstrated in a multi-institutional analysis of 600 patients that 40% of patients underwent early salvage for PSA<0.5, which means that 60% of patients avoided treatment at a median follow-up of 90 months. There was no statistical difference in mets-free survival between the groups at up to 10 years.
Dr. Karnes then addressed the need for prognostic biomarkers, such as the Decipher genomic score test, to help us determine which patients may benefit from adjuvant therapy vs. observation. His group found that patients could be risk-stratified by genomic score, with those having a low risk genomic classifier score <0.4 demonstrating no difference in cumulative incidence of mets between adjuvant and salvage groups. Those with high risk genomic classifier score > 0.4 had a clear benefit from adjuvant therapy.
Dr. Karnes concluded that high level evidence for selecting appropriate treatment timing is pending, but based on our current data, early salvage is a valid option as it offers similar survival with less treatment exposure compared to adjuvant therapy. With continued study on appropriate timing, dose, field, and hormone use, along with improved understanding of the biology of disease, we can provide the right treatment to the right patient at the right time.
Presented By:
R.J. Karnes, Rochester (US)
Reported By:
Nikhil Waingankar, MD, at the 31st Annual EAU Congress - March 12 - 15, 2016 – Munich, Germany
Fox Chase Cancer Center