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© Translational Andrology and Urology. All rights reserved. High-risk prostate adenocarcinoma (PCa), consisting of patients with either Gleason Score (GS) of 8 to 10, prostatespecific antigen (PSA) more than 20 ng/mL, or clinical tumor-stage T3 or T4, portends a significant risk of relapse and cancer-specific mortality (1). Compared to low-risk PCa, these patients have a more than 3-fold increased risk of PCa-related death. The combination of long-term androgen deprivation therapy (ADT) and radiotherapy remains a standard management option for these patients (2). Despite combined modality treatment, a significant proportion of men with high-risk PCa, especially those with relatively aggressive features, eventually relapse after first line treatment (3). Stratification of GS into grade groups (GG) has improved the discriminatory ability of the existing risk stratification system in determining the overall prognosis for all risk groups including the highrisk category (4). In a study by Pierorazio et al., 10-year biochemical relapse-free survival was approximately 63% and 35% for patients with GG4 and GG5 disease, respectively (4). Another study by Gnanapragasam et al. showed approximately 5and 17-times higher risk of prostate cancer-specific mortality (PCSM) in patients with GG4 and GG5 PCa, respectively (5). The high relapse rates highlight the importance of further optimization of treatment for men with GG4 and GG5 PCa. We read with great interest the individual patient-based meta-analysis reported by Kishan et al. (6) in this context. A total of 992 patients were included in the study—593 with GG4 and 399 with GG5 PCa. Patients in this meta-analysis were originally enrolled and treated with radiotherapy and ADT in one of the following 6 randomized trials: Radiation Therapy & Oncology Group (RTOG) 8531 (7), RTOG 8610 (8), RTOG 9202 (9), European Organization for Research and Treatment of Cancer (EORTC) 22863 (10), EORTC 22961 (11) and EORTC 22991 (11) (Table 1). Considering local failure as a time-varying covariable, the authors demonstrated an approximate doubling of the risk of distant metastasis and PCSM in patients who had local failure. Using a multi-state disease model and Markov proportional hazard model, they found that transition to local failure was associated with approximately 7 times higher risk of subsequent PCSM and approximately 2 times higher risk of subsequent distant metastasis or death. Long-term ADT in conjunction with radiotherapy yielded reduced risk of PCSM or overall mortality in patients who had experienced local failure. These findings are consistent with a secondary analysis of RTOG 9408 where importance of local control was demonstrated based on a planned biopsy after treatment (12). The presence of a viable tumor on biopsy had a significant association with PSA failure [hazard ratio (HR): 1.7; 95% confidence interval (CI): 1.3–2.1], distant metastasis (HR: 2.4; 95% CI: 1.3–4.4), cause-specific survival (HR: 3.8; 95% CI: 1.9–7.5), and in those with GS ≥7 even overall mortality (HR: 1.6; 95% CI: 1.04–2.35), thus lending credibility to the influence of local Editorial Commentary

Implications of local failure on overall prognosis in aggressive prostate cancer