Objective: To discuss the current evidence supporting the use of adjuvant radiation therapy (ART) versus early salvage radiation therapy (eSRT) in the post-prostatectomy setting, and the available tools for patient selection.
Research process/evidence synthesis: Post-surgery radiation therapy (RT) is commonly used as a secondary therapy to maximise local control and long-term oncological outcomes in patients who present with adverse features at radical prostatectomy (RP). According to most guidelines, the presence of seminal vesicle invasion, positive surgical margins, extraprostatic extension, and/or positive lymph nodes may indicate a beneficial use of post-surgical RT.1,2 ART is the administration of RT with an undetectable postoperative prostate-specific antigen (PSA), while eSRT is prescribed to patients with biochemical recurrence (BCR), low PSA levels (<0.5 ng/mL), and no evidence of systemic spread. The three main randomised clinical trials dealing with ART versus initial observation have shown a benefit in reducing BCR; only one trial (SWOG 8794) suggested a benefit in metastasis-free and overall survival,3–5 though it received sharp criticism.6 Unfortunately, these trials share some critical limitations: two of them did not require an undetectable PSA for inclusion, the approach at BCR was unstandardised (only a fraction of patients received salvage radiation therapy [SRT]), and many patients who underwent SRT did so at an advanced stage (clinically detectable or even symptomatic local recurrence).
ART carries a risk of overtreatment as a substantial proportion of men with few adverse pathological characteristics will not recur after surgery,3–5,7 and uniform RT represents a source of potential morbidity.8
Administering immediate RT to the patients at highest risk of early progression without compromising the opportunity of cancer control in men with BCR is a challenge within modern urological oncology. The three randomised clinical trials say little about the role of eSRT in comparison to immediate ART.
In recent years, many centres have gathered retrospective evidence supporting SRT. Positive results (5-year BCR-free survival of 71%) were shown by a 2014 systematic review by Pfister et al.,9 which included 10 retrospective studies, though most of these studies did not have the power to make any comparison between ART and eSRT. However, one study by Briganti et al.10 used a propensity-score matched analysis in a population of T3pN0 R0/1 patients who underwent ART or observation with eSRT, and did not find differences in 2 and 5-year BCR free survival. Abdollah et al.7 confirmed that not all patients with adverse pathological features achieve the same benefit from ART; only two or more risk factors (pGS 8, stage pT3b/4, and positive lymph node count >1) were associated with significant ART benefit on survival in their study, while monitoring with or without eSRT might be an option for the others. Nonetheless, there is a clear need for higher quality evidence. Currently, at least three ongoing randomised clinical trials (RADICALS RT, GETUG 17, and RAVES) are expected to provide valuable answers, but mature survival results will not be available for several years.
Multivariate models and nomograms (CAPRA-S score,11 Stephenson,12 and Abdollah7 nomograms) have shown good accuracy and may be used to predict post-RP mortality and inform risk-adapted decisions for ART or initial monitoring. However, deeper knowledge of prostate cancer intimate biology is expected to provide more precise tools. As an example, a genomic classifier has outperformed CAPRA-S in post-RP outcome prediction and demonstrated accuracy in identifying patients who may benefit more from ART versus those amenable to observation with or without SRT.13
Conclusion: The optimal timing of post-operative RP is still an unresolved issue for many. Until higher level evidence is available, initial observation may be a viable option in an effort to balance cost, toxicity, and oncological control. Risk-adapted approaches, using clinical and biological information, are becoming more and more promising.