The evolving role of systemic therapy in high risk prostate cancer: Strategies for cure in the 21st century

High-risk prostate cancer is a heterogeneous group that includes patients with clinically locally advanced stage disease at diagnosis. Unlike overt locally advanced disease, prediction of risk in clinically localized disease at an individual patient level, is not always easy or accurate with present knowledge. Gleason score, pretreatment prostate specific antigen (PSA), and stage (capsular invasion, seminal vesicle and nodal involvement) are the universally recognized criteria used to define risk. Overall, this group of patients have a greater than 50% risk of relapse. Historically, local treatment modalities with radical prostatectomy or radiation therapy constituted the mainstay of therapy in the majority of localized prostate cancer patients. However, the primary cause of failure and disease mortality stems from the development of systemic metastases. As we continue to witness stage migration towards earlier stage disease (presumably PSA related) and mortality reduction, devising better strategies for cure is a must. Recently completed randomized trials indicate a benefit from the use of hormonal therapy in patients with locally advanced prostate cancer treated with radiation therapy or node positive patients, post radical prostatectomy. While hormone-based combined modality trials have consistently shown improvements in local and systemic disease control, only two of these demonstrated improvements in overall survival. The palliative benefit of chemotherapy in hormone refractory disease and the promising response rates with newer agents has evoked interest in the use of chemotherapy in high-risk prostate cancer in the adjuvant and neoadjuvant settings. Several phase II and III trials are ongoing. Novel avenues of therapy such as tyrosine kinase inhibitors, gene therapy and angiogenesis inhibitors incorporated in a multimodality treatment strategy are likely to impact the course of this disease in the future.