Adjuvant Radiation for Node-Positive Disease After Prostatectomy: More Good News, but Who Will Listen?

Pathologically positive regional lymph nodes (pN1 or pN positive) after radical prostatectomy (RP) for prostate cancer (PCa) have long been recognized as a poor prognostic factor. The scope of this problem has decreased dramatically from as high as 40% in the pre–prostate specific antigen (PSA) era to as low as single digits in the contemporary PSA era, which undoubtedly stems from PSA screening stage migration. However, given the recent shift of surgical focus to high-risk, localized PCa, as well as the recent forecast of less PSA screening that was prompted by the US Preventive Services Task Force’s grade D recommendation, there is every reason to believe that pN-positive PCa is likely to become a larger clinical entity as we move forward. Historically, pN-positive disease had been synonymous with systemic disease, so much so that discovery of positive regional lymph nodes at the time of pelvic lymph node dissection (PLND) usually resulted in aborting the RP. However, this perception is changing. Unfortunately, there is no high-level evidence to support the practice of completion of RP or any local therapy in men with pN-positive disease, but an increasing amount of lower-level evidence, primarily from academic centers of excellence, has advocated for this approach. The landmark Eastern Cooperative Oncology Group (ECOG) study by Messing et al showed an improvement in survival with immediate versus delayed androgen-deprivation therapy (ADT) in men with pN-positive disease after RP-PLND. This combination of RP-PLND with ADT has become to some a de facto standard and is a commonly reported treatment regimen in patients with pN-positive disease, with reasonably good long-term outcomes (10-year overall survival [OS] from 51% to 80%). Similarly, retrospective series from academic centers of excellence and the Radiation Therapy Oncology Group (RTOG) have reported use of definitive radiation therapy (RT) with ADT in men with pN-positive disease, also with relatively good results (10-year OS, 47% to 67%). Perhaps these favorable outcomes in patients with pN-positive PCa who are treated with ADT and definitive local therapy are merely a surrogate for care at the highest-quality institutions and cannot be generalized to the broader health community? A study using the SEER database (which broadly captures information from approximately 25% of the US population) from 1995 to 2005 has recently validated the benefit of local therapy from RP and/or RT in patients with pN-positive PCa (10-year OS, 65%). An attempt to determine the merit of definitive local therapy in men with pNpositive disease was launched by the RTOG in their randomized trial 9608, which was closed prematurely because of poor accrual. So, to summarize, there is no level 1 evidence in support of definitive local therapy in the form of RP or RT in combination with ADT for men with pN-positive disease, but we do have a considerable amount of lower-level, retrospective evidence to back such a treatment strategy. Despite these limitations in the state of the evidence for men with pN-positive PCa, an obvious next question emerges. What is the role of adjuvant RT (aRT) in men with pN-positive disease? The study by Abdollah et al that accompanies this editorial evaluates this question. This particular group of investigators has been leading the field with respect to aRT for men with pN-positive PCa and draws from an impressive combined cohort of 1,107 consecutive patients with pNpositive disease from the San Raffaele Hospital (Milan, Italy) and the Mayo Clinic. In their study, patients were all treated in a fairly homogeneous fashion that included RP and extended PLND followed by ADT. Of these patients with pN-positive disease, 386 (35%) received aRT on the basis of physician preference, with a large fraction of the patients treated with relatively modern conformal techniques and contemporary aRT dosing (median, 68.4 to 70.2 Gy). Abdollah et al performed regression tree analysis to stratify this population into risk groups on the basis of a number of known patient, disease, and treatment-related prognostic factors, holding out as the exception aRT treatment status. From this analysis emerged five risk groups that were stratified on the basis of number of positive lymph nodes (PLNs), pathologic Gleason score, tumor stage, and surgical margin status. Each risk group was then analyzed for the effect of aRT on cancerspecific mortality (CSM) and overall mortality (OM). A nomogram was also created that was based on a more limited number of pathologic factors. Propensity score matching was then performed on the five risk groups to help minimize confounding in this heterogeneous cohort. Last, the resultant model was validated on a SEER data set, from 1999 to 2009, of 3,158 men with pN-positive PCa, with slight modifications to account for peculiarities of the SEER database. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 35 DECEMBER 1