Androgen deprivation therapy use and risk of death in men treated with high‐dose radiation for intermediate‐risk prostate cancer

Men with intermediate-risk prostate cancer (PC) have multiple potential accepted treatment options and significant variation in the risk for prostate-specific antigen (PSA) recurrence, distant metastases, PC-specific mortality and overall survival. In an effort to improve outcomes in this population, randomized controlled trials (RCTs) conducted before the era of dose-escalated radiotherapy (RT) demonstrated that the addition of 4 to 6 months of androgen deprivation therapy (ADT) to low-dose RT improved PC-specific and overall mortality. However, the role of ADT in the era of doseescalated RT remains unknown. The 2016 National Comprehensive Cancer Network guidelines, therefore, include dose-escalated RT in the form of external-beam radiotherapy (EBRT) or EBRT with a brachytherapy boost with or without 4 to 6 months of ADT, brachytherapy alone, or radical prostatectomy with pelvic lymph node dissection as potential treatment options for men with intermediate-risk PC. To help determine which treatments or combination thereof is needed for intermediate-risk PC, investigators have proposed dividing patients into unfavorable and favorable subgroups on the basis of clinical factors, including the number of intermediate risk factors (clinical tumor category of T2b-T2c, PSA level of 10-20 ng/mL, and Gleason score of 7), the primary Gleason pattern (eg, Gleason score of 4 1 3 vs 3 1 4), and the percentage of positive prostate core biopsies. Patients with unfavorable intermediate-risk PC have been consistently found to have worse outcomes in comparison with patients with favorable intermediate-risk PC. Moreover, men with favorable intermediate-risk disease appear to have excellent outcomes overall, with rates of survival comparable to those of patients with low-risk disease. These results include many patients treated with RT alone, including low-dose RT (70 Gy), suggesting that for favorable intermediate-risk PC, ADT may not be necessary to maximize outcomes. Refining the role of ADT in the era of dose-escalated RT is of particular interest because of its potential associated toxicities. Although a meta-analysis of 8 randomized trials did not show an increased risk of fatal myocardial infarction with ADT use, these analyses did not look within subgroups by the extent of comorbidities, and observational studies, including a recent meta-analysis, have consistently shown associations between ADT use and fatal and nonfatal cardiovascular disease. Short-term ADT use is also not without risks, particularly in older patients or patients with significant comorbidities. The long-term follow-up of an RCT of RT with or without ADT has demonstrated the risks associated with ADT in this patient population. Although ADT use with RT was associated with an improvement in overall survival at 5 years, there was no benefit with the addition of ADT to RT at 8 years in patients with moderate or severe comorbidities. Moreover, at a median follow-up of 16.62 years, 6 months of ADT use with RT was associated with an increased risk of fatal myocardial infarction and overall mortality in comparison with RT alone in patients with moderate or severe comorbidities. Even for those patients who are younger or do not have significant comorbidities, the risk/ benefit ratio of ADT must still be carefully weighed. The side effects of even short-term ADT use, including fatigue, weight gain, and decreased libido, can have a significant impact on a patient’s quality of life and must be seriously considered. In this issue of Cancer, Falchook et al use data from the National Cancer Data Base to provide the largest study to date investigating the role of ADT in favorable intermediate-risk PC. They performed a propensity score weight–adjusted overall survival comparison and sensitivity analyses with multivariate Cox proportional hazards models to determine the