Is There a Standard of Care for Pathologic Stage T3 Prostate Cancer?
Authors: Ian M. Thompson, Catherine M. Tangen, Eric A. Klein
Journal: Journal of Clinical Oncology (2009)

As many as one third of patients undergoing radical prostatectomy will be found to have pathologic stage T3 (pT3) prostate cancer (PCA) with positive margins, extraprostatic extension, or involvement of the seminal vesicles. A debate has raged for decades over the utility of adjuvant radiotherapy in treating these men. Case studies have argued for and against this treatment without the establishment of a clear standard of care. Three randomized clinical trials have provided initial data from more than 1,800 patients with similar outcomes. The first of these studies, S8794, was initiated in 1987 and conducted by the Southwest Oncology Group (SWOG). In this study, 425 men with pT3 PCA were randomly assigned to observation or adjuvant radiotherapy with 60 to 64 Gy within 4 months of surgery. In 2006, with a median follow-up of 10.6 years, the first report of results of this study described a highly significant reduction in biochemical failure rate (median prostatespecific antigen [PSA] relapse-free interval, 10.3 years for radiotherapy v 3.1 years for observation; hazard ratio [HR], 0.43; 95% CI, 0.31 to 0.58; P .001), but the study fell just short of achieving significance for the primary end point of metastasis-free survival (median metastasis-free estimate, 14.7 years for radiotherapy v 13.2 years for observation; HR, 0.75; 95% CI, 0.55 to 1.02; P .06). Notable as well was a significant reduction in requirement for hormonal therapy in those receiving radiation. The second study, initiated in 1992 by the European Organisation for Research and Treatment of Cancer (EORTC), included 1,005 patients with a design similar to that of the SWOG study. Its first report with 5-year median follow-up indicated significant improvement in biochemical failure (74.0% [95% CI, 68.7% to 79.3%] v 52.6% [95% CI, 46.6% to 58.5%]; P .0001). In this issue of Journal of Clinical Oncology (JCO), Wiegel et al report the results of a third randomized trial of adjuvant radiotherapy for pT3 PCA by the Working Group on Radiation Oncology and Association of Urological Oncology of the German Cancer Society. Beginning in 1996, this study called for random assignment of patients within 2 weeks of surgery before establishment of an undetectable PSA. This unusual study design was developed specifically for local care practices. Three analysis plans were predetermined, including analysis of all eligible patients (ITT1), of patients with an undetectable PSA (ITT2), and by treatment ultimately received (per protocol). The second method of analysis constitutes the report in this issue of JCO. Wiegel et al reach conclusions similar to those of the two previously reported trials, with a biochemical progression-free survival rate of 72% with adjuvant radiation (95% CI, 65% to 81%) versus 54% in the observation group (95% CI, 45% to 64%; P .0015). The overall intent-to-treat rates were 55% and 44%, respectively, with a log rank P value (summarized in Fig 2) indicating a one-sided P value of .054. Wiegel et al note few significant complications from radiotherapy. It is important to place these three trials in a historical perspective. When the SWOG trial began, the importance and definition of a detectable PSA after surgery were not yet clear. As a result, an undetectable PSA was not required, and 33% of patients for whom postoperative PSA data were available had a PSA 0.2 ng/mL after surgery. Similarly, 30.5% of patients in the EORTC trial had a PSA 0.2 ng/mL. The most recent of these studies, the German Cancer Society trial, included an analysis plan (ie, ITT2) to exclude the 20% of randomly assigned patients without an undetectable PSA using a range of PSA assays with several lower limits. The results of the SWOG and EORTC studies were reported according to preplanned intent-totreat analyses, and several subsets of patients were examined. In all three studies, adjuvant radiotherapy was found to delay biochemical progression, including in the subset of patients with an undetectable PSA after surgery. The question of whether adjuvant radiotherapy should now be the standard of care for these patients remains. The answer is elusive for two reasons. First, the final results of the SWOG trial have just been reported but similar results of the EORTC trial are pending. The updated results of the SWOG trial with median follow-up of 12.6 years found a significant improvement in metastasis-free survival (HR, 0.71; 95% CI, 0.54 to 0.94; P .016) and overall survival (HR, 0.72; 95% CI, 0.55 to 0.96; P .023) with radiotherapy. We look forward to the results of longer-term follow-up of the EORTC study for these end points; meanwhile, the results of the SWOG trial are compelling. The second reason why adjuvant radiation may not yet be the standard of care is that some experts feel that salvage radiotherapy may be equivalent. Salvage radiotherapy refers to radiation administered at the time a measurable PSA is detected. In the past few decades, the threshold of detection for PSA and the time threshold at which radiotherapy is recommended have changed. A decade or so ago, an undetectable PSA might have been 0.4 ng/mL; today, with an ultrasensitive assay, it may be 0.01 ng/mL. Likewise, a decade ago, radiotherapy was initiated before PSA level reached 1.5 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 18 JUNE 2