Androgen deprivation therapy in combination with radiotherapy for high-risk clinically localized prostate cancer

Androgen deprivation therapy (ADT) has remained the main therapeutic option for patients with advanced prostate cancer (PCa) for about 70 years. Several reports and our findings revealed that aggressive PCa can occur under a low dihydrotestosterone (DHT) level environment where the PCa of a low malignancy with high DHT dependency cannot easily occur. Low DHT levels in the prostate with aggressive PCa are probably sufficient to propagate the growth of the tumor, and the prostate with aggressive PCa can produce androgens from the adrenal precursors more autonomously than that with non-aggressive PCa does under the low testosterone environment with testicular suppression. In patients treated with ADT the pituitary-adrenal axis mediated by adrenocorticotropic hormone has a central role in the regulation of androgen synthesis. Several experimental studies have confirmed the potential benefits from the combination of ADT with radiotherapy (RT). A combination of external RT with short-term ADT is recommended based on the results of phase III randomized trials. In contrast, the combination of RT plus 6 months of ADT provides inferior survival as compared with RT plus 3 years of ADT in the treatment of locally advanced PCa. Notably, randomized trials included patients with diverse risk groups treated with older RT modalities, a variety of ADT scheduling and duration and, importantly, suboptimal RT doses. The use of ADT with higher doses of RT or newer RT modalities has to be properly assessed.