Weighing the Addition of Androgen Suppression Therapy to Radiotherapy Dose Escalation for Intermediate-Risk Prostate Cancer

Men with intermediate-risk prostate cancer have a number of treatment options. These include external-beam radiation therapy (EBRT) alone and EBRT combined with short-term androgen suppression therapy (AST), among others such as brachytherapy and prostatectomy. When EBRT is the selected primary treatment option, short-term AST for 4 to 6 months should be strongly considered because the data supporting its use are overwhelmingly positive. The Harvard study reported by D’Amico et al and the Radiation Therapy Oncology Group (RTOG; now part of NRG Oncology) trial 9408 reported by Jones et al both randomly assigned intermediate-risk men between EBRT alone or EBRT plus 6 or 4 months of short-term AST beginning 2 months prior to the start of EBRT; both showed a survival benefit in the short-term AST arms. In addition, there is no evidence that shortterm AST longer than 4 months confers additional benefit in patients with intermediate-risk prostate cancer. In the RTOG 9910 trial, Pisansky et al compared 4months of short-termASTwith 9months of intermediate-term AST (7 months of neoadjuvant and 2 months of concurrent AST with EBRT) in 1,579 men who were randomly assigned to treatment. These investigators found no difference in the primary end point of cause-specific survival or in other end points, including biochemical-based end points. All of these trials involved relatively low total doses of EBRT, termed standard-dose EBRT, of 66 to 70 Gy in standard fractionation of 1.8 to 2.0 Gy per day. Level I evidence supports the use of 4 months of AST with standard doses of EBRT for men with intermediate-risk prostate cancer. In the article accompanying this editorial, the results of European Organisation for Research and Treatment of Cancer (EORTC) trial 22991 are described by Bolla et al. Approximately 75% of the 819 men were at intermediate risk and 25% were high risk. The study adds to our body of knowledge concerning the efficacy of short-term AST plus EBRT, showing a significant and substantial improvement in the primary end point of biochemical disease-free survival when 6 months of short-term AST was combined with institution-selected total EBRT doses of 70 (n 5 200), 74 (n 5 416), or 78 (n 5 197) Gy. The overall biochemical disease-free 5-year survival rates were 83% for those with AST versus 70% for those without AST. The 10-year survival rates appear to be more pronounced, with further separation of the curves. A statistically significant benefit from ASTwas also seen in clinical disease-free survival. As expected, at this juncture in a predominantly intermediate-risk cohort, there was no difference in overall survival (OS). The study relates well to prior randomized trials on this topic. Dose-escalated EBRT has been shown in several studies to improve biochemical freedom from failure in patients with intermediateto high-risk prostate cancer. However, the impact of adding AST to EBRTon cause-specific and overall survival has been much more consistent and pronounced. With long-term follow up in an MD Anderson Cancer Center dose-escalation study comparing 70 Gy to 78 Gy (no AST was used), patients with intermediate(levels of prostate-specific androgen . 10 ng/mL) or high-risk disease experienced longer survival; however, patient numbers were small in this subgroup analysis. Preliminarily, Michalski et al described an interim analysis of the RTOG 0126 dose-escalation trial comparing 70.2 Gy with 79.2 Gy. With a median follow up of 76 months and 329 events (in 1,532 men who were randomly assigned) at the interim analysis (715 events were planned for the final definitive analysis), there was no difference in OS, the planned primary end point. Notably, there was a robust reduction in biochemical failure in the higher-dose arm. The interim analysis was reported because the OS end point crossed the futility boundary. In contrast, in virtually every phase III trial comparing EBRT alone to EBRT plus AST, a cause-specific or overall survival benefit has been seen over time. Although dose escalation has become the standard for men with intermediate-risk prostate cancer, the addition of AST is a powerful adjunct. An interesting aspect of EORTC-22991 is the dose-escalation component. The balance between the use of AST and radiation dose is a topic of much interest. However, as the investigators point out, this is an exploratory subgroup analysis. At each dose level, the benefit of AST was maintained; yet, in the multivariable analyses described, no significant interaction was found with EBRT dose. There are a number of questions related to the combination of radiotherapy and AST, including: (1) whether there is a benefit from adding AST to dose-escalated EBRT (dose escalated EBRT 6 AST), which seems to be the case in EORTC-22991; and (2) whether EBRT dose escalation improves results when AST is given (standard dose EBRT 1 AST v dose-escalated EBRT 1 AST), which was not statistically significant in the EORTC-22991 heterogeneity analysis. In