Introduction

Prostate cancer is a common malignancy, with 192,280 new cases and 27,360 deaths estimated in the US in 2009. Although the mortality rate for prostate cancer declined significantly during the period between 1990 and 2005, it continues to be the most frequently diagnosed cancer in men, and the second most frequent cause of cancer death, after lung cancer, in the US.[1] Although the benefit of active treatment versus surveillance for men with low-risk prostate cancer has been controversial, men with high-risk disease at presentation are acknowledged to be at higher risk of prostate cancer-related death.[2,3] Therefore, attempts to further reduce prostate cancer mortality are directed at the high-risk population.

High-risk prostate cancer has been variously defined, but the consensus is that a variety of pretreatment prognostic factors can identify patients for whom treatment is likely to fail. The primary risk factors for prostate cancer are clinical stage, PSA level, and Gleason score at presentation. the small proportion of patients who present with documented metastases are outside the scope of this Review.[4] Before concluding that a patient has localized but high-risk prostate cancer, an assessment to exclude the presence of gross metastatic disease should be performed.

Clinical stage is defined according to the American Joint Committee on Cancer staging system, which notes that patients with extensive palpable disease (stage T3) have a poorer prognosis than patients with incidentally noted (stage T1) or small volume palpable (stage T2) disease.[5] However, clinical staging of prostate cancer is subjective and potentially imprecise. It has long been recognized that the histological grading of prostate tumors correlates with prognosis. Donald Gleason described a system for the assessment and communication of primary and secondary histological grades, which has become known as the Gleason score. In his initial paper, Gleason noted that the combination of histological grading and clinical staging improved prognostic accuracy over that obtained with either parameter alone.[6] Subsequently, Gleason score has been validated as an independent prognostic factor in multiple settings. Patients with Gleason score 8-10 tumors are at high risk of recurrence, metastases, and death from prostate cancer.[7-9] Following the development of PSA testing in the late 1980s, pretreatment PSA level was also noted to be an independent prognostic factor for recurrence following primary treatment with radiotherapy or radical prostatectomy.[10-12]

Historically, patients with poor prognostic factors had low survival rates after either surgery or external beam radiotherapy alone.[13,14] It was recognized that these patients were more likely to develop metastatic disease and to die from prostate cancer. As such, this group of men became the focus of efforts to improve therapeutic approaches. It is worth noting that in the early PSA era (late 1980s and early 1990s) patients presented with higher volume disease than in the current PSA screening epoch. In recent years, a number of clinical trials addressing potential therapeutic strategies for patients with high-risk prostate cancer have been reported and many more are either underway or awaiting maturation of data. Key randomized studies of radiotherapy in conjunction with androgen suppression therapy and trials of adjuvant radiotherapy following prostatectomy are discussed below. The potential advantages provided by dose-escalated radiotherapy and the addition of adjuvant chemotherapy to other primary treatment regimens are also discussed. The wealth of data produced by these trials can assist clinicians in selecting the optimal treatment for patients with high-risk prostate cancer.