PSA monitoring and early salvage therapy appear to be safest in these patients.
In “Journal Article of the Month," Badar M. Mian, MD, offers perspective on noteworthy research in the peer-reviewed literature. Dr. Mian is professor of surgery in the division of urology at Albany Medical College, New York.
Despite previous randomized controlled studies demonstrating a benefit from post-prostatectomy adjuvant radiation therapy (RT), urologists have been slow to adopt this approach. This may be related to inconsistencies in the reported outcomes as well as the timing of salvage RT, which was thought to have been initiated much later than the contemporary clinical practice. Consequently, 3 randomized controlled trials (RADICALS-RT, GETUG-AFU 17, and RAVES) were initiated nearly a decade ago to evaluate the oncologic outcomes after adjuvant RT or early-salvage RT in post-prostatectomy patients with high-risk and/or locally advanced pathology. Recently, a combined analysis of these 3 trials was reported, which did not demonstrate any advantage to adjuvant RT when compared to early-salvage RT; that is, following rise in prostate-specific antigen (PSA) level after prostatectomy.
Vale and colleagues prospectively planned a systematic review and meta-analysis of the combined data from the 3 trials before the final results were available to assess whether adjuvant RT was superior to early-salvage RT.1 Individually, the 3 trials were powered for different primary outcomes such as time free of metastases (RADICALS-RT), event-free survival (GETUG-AFU 176), and biochemical progression (RAVES). Inclusion criteria for the trials varied slightly but included the following: postoperative PSA less than 0.2 ng/mL, and one or more high-risk features including stage pT 3 or 4, Gleason score 7–10, or positive surgical margins.
After randomization, adjuvant RT was to be initiated within 6 months after surgery while early-salvage RT for biochemical recurrence was to be initiated at PSA level of 0.2 ng/mL (0.1 ng/mL for RADICALS-RT). The RT dose was quite similar in all 3 trials; that is, 64 to 66 Gy in 32 or 33 fractions. The concurrent use of hormone therapy was variable across the 3 trials. For this meta-analysis, the agreed-upon primary outcome measure was event-free survival. An event after randomization was defined as the first evidence of any 1 of the following: biochemical progression (PSA ≥ 0.4 ng/mL), clinical or radiological progression, initiation of additional treatment, and PSA level of at least 2.0 ng/mL at any time after randomization.
In the 3 trials combined, 2153 patients were recruited between November 2007 and December 2016. Of these, 1075 patients were randomly assigned to receive adjuvant RT and 1078 were assigned to early-salvage RT. Median age was 64 to 65 years. A majority of patients had either stage pT3a/b disease (79.8%), positive surgical margins (70.9%), and extracapsular extension (76.9%). The median follow-up ranged from 60 to 78 months.
There were 270 (12.5%) events recorded out of the 2153 randomized patients. The pooled event-free survival analysis yielded an overall hazard ratio of 0.95 (95% CI, 0.75-1.21; P= 0.70) which translates into only a 1% absolute difference between adjuvant RT and early-salvage RT groups. Further, there was no advantage to adjuvant RT on event-free survival when analyzed based on pre-specified subgroups including pre-surgical PSA, Gleason score, seminal vesicle involvement, surgical margins, or CAPRA-S risk group. In the group assigned to early-salvage RT, only 421 (39.1%) had required RT at the time of this analysis. A majority of the men remained free of biochemical progression at 5 years (87% in RAVES, 88% in RADICALS-RT, and 94% in GETUG-AFU 17).
It seems clear from this meta-analysis that adjuvant RT for men with high-risk, localized, or locally advanced prostate cancer after prostatectomy does not improve event-free survival. These results are in contrast to the previous trials (from EORTC and SWOG), which had demonstrated improved biochemical recurrence rates following adjuvant RT in these men. However, the enthusiasm for adjuvant RT remained limited due to the timing of salvage RT in previous trials (which was initiated much later than the contemporary practice), and concerns about the risks of over-treatment and adverse effects of adjuvant RT (such as urinary, bowel, and sexual dysfunction).
The unique design of current meta-analysis can remove some of the biases associated with retrospective meta-analyses and provides an increased number of subjects to allow for sufficiently powered analysis of longer-term survival outcomes. The authors were able to include up-to-date, event-free survival results from 100% of patients randomized in all 3 trials. However, it should be noted that the recurrence events were dominated by biochemical recurrence and not clinical or radiological recurrence, and the overall event (recurrence) rates were low.
The results of additional analyses (which are pre-planned by the authors), of the effects of adjuvant vs early-salvage RT on metastases-free survival, prostate-cancer specific survival, and overall survival are awaited. It’s possible that after longer follow up, the timing of RT and the use of hormone therapy may yield different results in a subgroup with multiple high-risk features. For now, avoiding adjuvant RT (and associated adverse effects) in favor of PSA monitoring and early-salvage therapy appears to be the safest initial option for post-prostatectomy patients with adverse pathology.
1. Vale CL, Fisher D, Kneebone A, et al. Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data. Lancet. Published online September 28, 2020. doi:10.1016/S0140-6736(20)31952-8