title: Chemotherapy for hormone-refractory prostate cancer.
abstract: BACKGROUND
  Prostate cancer mainly affects elderly men, and its incidence has steadily increased over the last decade. The management of this disease is replete with controversy. In men with advanced, metastatic prostate cancer, hormone therapy is almost universally accepted as the initial treatment of choice and produces good responses in most patients. However, many patients will relapse and become resistant to further hormone manipulation; the outlook for these patients is poor. Many have disease extending to the skeleton, which is associated with severe pain. Therapies for these men include chemotherapy, bisphosphonates, palliative radiotherapy, and radioisotopes. Systemic chemotherapy has been evaluated in men with hormone-refractory prostate cancer (HRPC) for many years, with disappointing results. However, more recent studies with newer agents have shown encouraging results. There is therefore a need to explore the value of chemotherapy in this disease.
  
  
  OBJECTIVE
  The present review aims to assess the role of chemotherapy in men with metastatic HRPC. The major outcome was overall survival. Secondary objectives include the effect of chemotherapy on pain relief, prostate-specific antigen (PSA) response, quality of life, and treatment-related toxicity.
  
  
  METHODS
  Trials were identified by searching electronic databases, such as MEDLINE, and handsearching of relevant journals and conference proceedings. There was no restriction of language or location.
  
  
  METHODS
  Only published randomised trials of chemotherapy in HRPC patients were eligible for inclusion in this review. Randomised comparisons of different chemotherapeutic regimens, chemotherapy versus best standard of care or placebo, were relevant to this review. Randomised, dose-escalation studies were not included in this review.
  
  
  METHODS
  Data extraction tables were designed specifically for this review to aid data collection. Data from relevant studies were extracted and included information on trial design, participants, and outcomes. Trial quality was also assessed using a scoring system for randomisation, blinding, and description of patient withdrawal.
  
  
  RESULTS
  Out of 107 randomised trials of chemotherapy in advanced prostate cancer identified by the search strategy, 47 were included in this review and represented 6929 patients with HRPC. Only two trials compared the same chemotherapeutic interventions and therefore a meta-analysis was considered inappropriate. The quality of some trials was poor because of poor reporting, low-patient recruitment, or poor trial design. For clarity, trials were categorised according to the major drug used, but this was not a definitive grouping, since many trials used several agents and would be eligible for inclusion in a number of categories. Drug categories included estramustine, 5-fluorouracil, cyclophosphamide, doxorubicin, mitoxantrone, and docetaxel. Only studies using docetaxel reported a significant improvement in overall survival compared to best standard of care, although the increase was small (< 2.5 months). The mean percentage of patients achieving at least a 50% reduction in PSA compared to baseline was as follows: estramustine 48%; 5-fluorouracil 20%; doxorubicin 50% (one study only); mitoxantrone 33%; and docetaxel 52%. Pain relief was reported in 35% to 76% of patients receiving either single agents or combination regimens. A three weekly regime of docetaxel significantly improved pain relief compared to mitoxantrone plus prednisone (the latter regimen approved as standard therapy for HRPC in the USA). All chemotherapeutics, either as single agents or in combination, were associated with toxicity; the major ones being myelosuppression, gastrointestinal toxicity, cardiac toxicity, neuropathy, and alopecia. Quality of life was significantly improved with docetaxel compared to mitoxantrone plus prednisone.
  
  
  CONCLUSIONS
  Patients with HRPC have not traditionally been offered chemotherapy as a routine treatment because of treatment-related toxicity and poor responses. Recent data from randomised studies, in particular those using docetaxel, have provided encouraging improvements in overall survival, palliation of symptoms, and improvements in quality of life. Chemotherapy should be considered as a treatment option for patients with HRPC. However, patients should make an informed decision based on the risks and benefits of chemotherapy.
authors.affiliation: Velindre NHS Trust, Research Laboratories, Velindre Road, Whitchurch, Cardiff, Wales, UK. mike.shelley@velindre-tr.wales.nhs.uk
authors.forename: Mike
authors.initials: M
authors.lastname: Shelley
authors.forename: Craig
authors.initials: C
authors.lastname: Harrison
authors.forename: Bernadette
authors.initials: B
authors.lastname: Coles
authors.forename: John
authors.initials: J
authors.lastname: Staffurth
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Wilt
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Mason
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D019008:Drug Resistance, Neoplasm; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D009919:Orchiectomy; D010146:Pain / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D016032:Randomized Controlled Trials as Topic
chemical_list: D000726:Androgen Antagonists; D007987:Gonadotropin-Releasing Hormone