Hormone-refractory prostate cancer (HRPC) remains an incurable disease. However, therapeutic options have improved over the last several years, with the use of docetaxel-based chemotherapy, resulting in significant palliation of symptoms, objective and prostate-specific antigen (PSA)-based responses, improvements in pain and overall survival benefits [1–2]. A vast array of novel agents are currently in clinical trials using this docetaxel platform, as well as other novel combinations, with the goal of turning metastatic HRPC into a chronic symptom-free disease rather than an inevitably progressive one. New approaches to prognostic markers and resistance to hormonal and chemotherapeutic approaches have led to improved clinical stratification and identification of therapeutic targets. As chemotherapeutic options in earlier stage disease remain purely experimental at present, this chapter will focus on the clinical approach to treating men with metastatic HRPC, the current state of knowledge about the pathophysiology of hormone-refractory growth, and therapeutic strategies in the first-line setting and beyond.
DEFINITION OF HORMONE-REFRACTORY DISEASE
The most widely accepted criterion for the hormone-refractory state has been the demonstration of progressive, measurable or evaluable disease in the face of castrate levels of serum testosterone (< 50 ng/dl) . Biochemical progression after antiandrogen (bicalutamide, flutamide, nilutamide) withdrawal, as measured consecutively over a 4- to 6-week period, has been proposed for eligibility into clinical trials for HRPC. Patients are usually continued on gonadotrophin-releasing hormone agonists (GnRHa) during this time if tolerable. There is at this time no universally accepted definition of progression of hormone-refractory disease, however, and patients may have no measurable or evaluable disease with PSA-only progression and be termed hormone refractory or castration resistant . These PSA-only hormone-refractory patients represent a heterogeneous group, and time to metastatic progression and death is highly variable, with a median of 1.5–3.5 years depending on PSA and PSA kinetic characteristics . Survival in this common subgroup in the clinic is generally better than in patients with metastatic hormone-refractory disease but, as of 2006, chemotherapy remains unstudied in non-metastatic HRPC. In the TAX327 trial of docetaxel and prednisone compared with mitoxantrone and prednisone, 10% of patients had a rising PSA as the only indicator of progressive disease despite the presence of metastases . In this subgroup, the median survival was approximately 21 months, compared with 16.8 months for those with progression defined by pain or radiologically measurable disease. This illustrates the need for randomization and stratification based on known prognostic factors in clinical trials of this heterogeneous patient population.
The demonstration of progressive disease in the face of continuous androgen suppression with GnRHa often leads to the introduction of combined androgen blockade with antiandrogens as second-line hormone manipulation. This can be followed by antiandrogen withdrawal and trials of third-line hormonal therapy, often with the androgen synthesis inhibitor ketoconazole and hydrocortisone or other antiandrogens. The response time to each of these manipulations is generally of the order of several months but ...