"While improving local control seems to be important, especially in those with high-risk features, it’s not clear whether adjuvant EBRT is necessarily better than early salvage EBRT," writes Badar M. Mian, MD.
“Journal Article of the Month” is a new Urology Times section in which Badar M. Mian, MD (left), offers perspective on noteworthy research in the peer-reviewed literature. Dr. Mian is associate professor of surgery in the division of urology at Albany Medical College, Albany, NY.
Lymph node metastases after radical prostatectomy (RP) are associated with increased risk of recurrence and poor survival. Despite decades of experience, the optimal management (timing and choice of therapy) remains unclear since a number of management strategies are utilized, including observation with salvage treatment or lifelong adjuvant androgen deprivation therapy (ADT) alone or with external beam radiation therapy (EBRT).
According to Touijer et al, adjuvant ADT with whole pelvic EBRT is associated with better overall survival than observation or adjuvant ADT (European Urology Oct. 16, 2017 [Epub ahead of print]).
The authors performed a retrospective analysis comparing survival outcomes of LN+ patients after RP performed at three tertiary care centers between 1988 and 2010. The type and timing of treatment were driven by local practice patterns at each institution. They identified 1,338 patients who were LN+ after RP who were either observed or received salvage therapy (387, 28%), adjuvant lifelong ADT (676, 49%), or adjuvant EBRT with ADT (325, 23%). Median follow-up time was 69 months among survivors, with 368 men followed for more than 10 years.
The observation group consisted of no treatment until biochemical recurrence, which was defined variably by each institution as PSA level of >0.1, >0.2, or >0.4 ng/mL. After biochemical recurrence, the most commonly used treatments were ADT alone (72%), followed by salvage EBRT (13%) and ADT plus EBRT (8.9%).
Also by Dr. Mian: Is favorable-risk GG2 prostate Ca suitable for active surveillance?
Adjuvant ADT consisted of either bilateral orchiectomy or luteinizing hormone-releasing hormone agonist used alone as lifelong therapy. When combined with EBRT, the median duration of ADT was 5.9 years, with 75% of men receiving >3 years. Median dose of EBRT (3-D conformal or IMRT) was 68 Gy.
ADT had better cancer-specific survival compared to observation (HR: 0.64, p=.027). However, ADT was associated with an increased risk of other-cause mortality (HR: 3.05, p=.003) compared with observation, resulting in similar overall survival between ADT and observation (HR: 0.90, 95% CI: 0.65–1.25, p=.5). Lifelong adjuvant ADT was associated with an increased risk of death from other causes (cardiac, metabolic), thus wiping out any oncologic benefit from lifelong adjuvant ADT.
Radiation therapy with ADT was associated with better overall survival than ADT alone (HR: 0.46, p<.0001) or observation (HR: 0.41, p<.0001). Patients with higher risk features (T4, high grade, positive margins) derived the most benefit from combined adjuvant EBRT+ADT than lower risk patients. There was no significant difference in overall survival between men treated with adjuvant ADT and those on observation.
Recurrence patterns following prostatectomy are informative in that pN+ is not necessarily a systemic process, since 30%-40% of men will not experience recurrence for >5 years. This study points to the clinically heterogeneous nature of pN+ cohort and to the potential survival benefits derived from further loco-regional cancer control with whole pelvic EBRT after radical prostatectomy.
Several clinically relevant questions are worth further exploration. First, did all patients with pN+ disease achieve undetectable PSA level? In the observation group, nearly a quarter had very early detectable PSA, suggesting potential residual/metastatic disease. If the men with detectable post-op PSA were equally distributed among the treatment groups, then delayed treatment of men with residual/metastatic disease could result in worse outcome than early/adjuvant treatment. After biochemical recurrence, the vast majority (72%) in the observation group received lifelong ADT only. Why would those men not be good candidates for EBRT, which was given to only 13%?
Second, what was the PSA level at the time of salvage treatment in the observation group? Was the treatment initiated right after meeting the threshold of biochemical failure, or was it delayed until PSA was much higher? This information is essential to define the optimal window of salvageability and whether the timing of salvage treatment could have resulted in better outcomes.
While improving local control seems to be important, especially in those with high-risk features, it’s not clear whether adjuvant EBRT is necessarily better than early salvage EBRT. It’s important to note that the definition of biochemical failure and early treatment varies considerably among experts. Also, the side effects or functional outcomes of adjuvant pelvic EBRT are not available from this report.
Our preferred approach is that of early salvage therapy (e.g., PSA 0.2-0.4 ng/mL) with pelvic EBRT and ADT, which allows for early treatment but still provides time for functional recovery, affords these men a treatment-free period, and reduces the burden of overtreatment with EBRT and ADT in a significant number of men.
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