• Winquist E, Waldron T, Berry S, Ernst DS, Hotte S, Lukka H, Genitourinary Cancer Disease Site Group. Non-hormonal systemic therapy in men with metastatic hormone-refractory prostate cancer: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2005 Nov 1. 48 p. (Evidence-based series; no. 3-15). [100 references]

Metastatic hormone-refractory prostate cancer

Assessment of Therapeutic Effectiveness
Treatment

Oncology
Urology

Physicians

To evaluate which non-hormonal systemic therapies are most beneficial and should be recommended for the treatment of hormone-refractory prostate cancer

Men with progressive hormone-refractory prostate cancer and evidence of metastases

First-line cytotoxic and non-cytotoxic systemic therapies

• Overall survival
• Disease control
  • Progression-free survival
  • Time-to-progression
  • Time-to-treatment failure
  • Objective and prostatic-specific antigen (PSA) response rates
• Palliative response rate
• Quality of life
• Toxicity

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

28 randomized controlled trials (RCTs) were eligible for review

Expert Consensus (Committee)

Not applicable

Meta-Analysis of Randomized Controlled Trials
Systematic Review with Evidence Tables

Reports of randomized controlled trials (RCTs) of systemic therapy in hormone-refractory prostate cancer (HRPC) date back 30 years and are highly heterogeneous in terms of patient populations, interventions, and design. Many different drug interventions have been tested, including a variety of single-agent and combination chemotherapy regimens such as estramustine phosphate (EMP) and non-cytotoxic drugs such as liarazole, suramin, and atrasentan. What constitutes standard therapy in the control arms of trials has been controversial and has included placebo, corticosteroids, estramustine phosphate, and cytotoxics. On the basis of those observations, quantitative statistical pooling of RCT data was felt inappropriate, and an interpretive summary of the data was planned with more weight given to RCTs that were adequately powered.

Although valuable for identifying potential anti-tumour activity, it is well recognized that small RCTs report less reliable results and that studies with positive results are more likely to be subsequently reported and published. Theoretically, the results of such trials require confirmation by larger pragmatic RCTs, but this does not always occur. After considering the endpoints of interest for this guideline, the Genitourinary Cancer Disease Site Group (GU DSG) chose a minimum sample size of 50 patients per trial arm. The statistical justification for this is a minimum requirement for an RCT to be powered to reliably detect a difference between a response rate of 10% versus 30% with one-tailed alpha=0.05 and beta=0.20 (i.e., power of 80%). RCTs without the ability to provide at least this level of discrimination were considered underpowered and their results potentially misleading with regard to the endpoints of interest. Because the natural history and management of hormone-refractory prostate cancer has changed in the last three decades, more contemporary studies were emphasized in this guideline to provide clinicians with the most reliable evidence relevant to their current practice. Furthermore, more emphasis on the results of RCTs demonstrating internally consistent benefits in survival, palliation, and quality of life outcomes was planned. Statistical pooling of tumour response rates for docetaxel-based regimens was performed using Review Manager 4.2.3, available through the Cochrane Collaboration, because individual trials were inadequately powered to detect differences.

Expert Consensus

Not stated

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

Following review and discussion of sections 1 (clinical practice guideline) and 2 (systematic review) of this evidence-based series, the Genitourinary Cancer Disease Site Group circulated the clinical practice guideline and systematic review to clinicians in Ontario for review and feedback.

Clinician feedback was obtained through a mailed survey of 105 clinicians in Ontario (11 medical oncologists, 19 radiation oncologists, and 75 urologists). The survey consisted of 23 items evaluating the methods, results, and interpretation used to inform the draft recommendations and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again).

The final practice guideline report was reviewed by one member of the Program in Evidence-based Care (PEBC) Report Approval Panel and was approved with minor editorial changes.

• For men with clinical or biochemical evidence of progression and evidence of metastases, treatment with docetaxel 75 mg/m² administered intravenously every three weeks with 5mg oral prednisone twice daily should be offered to improve overall survival, disease control, symptom palliation, and quality of life.
• Alternative therapies that have not demonstrated improvement in overall survival but can provide disease control, palliation, and improve quality of life include weekly docetaxel plus prednisone, and mitoxantrone plus prednisone (or hydrocortisone).

None provided

The recommendations are supported by randomized controlled trials (RCTs).

• Two recent, large trials have reported improved overall survival with combination docetaxel (75mg/m² intravenously every three weeks) over mitoxantrone-prednisone:
  • In a three-arm trial (n=1006), improved median survival was found for docetaxel-prednisone administered every three weeks compared with mitoxantrone-prednisone (median survival, 18.9 versus 16.5 months; two-sided p=0.009), but no statistically significant survival benefit was observed with docetaxel-prednisone given on a weekly schedule. Improvements in palliative and quality-of-life response were observed with both docetaxel-prednisone regimens. The docetaxel-prednisone arms were associated with more frequent mild toxicities and similar rates of serious toxicities compared with mitoxantrone-prednisone.
  • In the second trial (n=666), survival time was longer with docetaxel-estramustine compared with mitoxantrone-prednisone (median survival, 17.5 versus 15.6 months, respectively; two-sided p=0.02). Estramustine combined therapy was associated with greater grade 3-4 toxicity (54% versus 34%) and more toxic deaths (seven versus two) than mitoxantrone-prednisone.
• The docetaxel trials provide indirect evidence of similar efficacy and increased toxicity with the addition of estramustine to docetaxel.
• Mitoxantrone plus corticosteroid compared with corticosteroid alone has been evaluated in three trials and shown improved palliative and pain response, quality of life, and/or improved time-to-disease progression compared with initial corticosteroid therapy alone. These trials have not shown improvements in survival.
• Single randomized trials have reported improved time-to-progression with estramustine-vinblastine versus vinblastine alone and vinorelbine-hydrocortisone versus hydrocortisone alone and improved time-to-progression and pain response with suramin-hydrocortisone compared with placebo-hydrocortisone.

• Toxicity attributable to mitoxantrone was minimal as evaluated in three trials, and cardiomyopathy was observed in <5% of patients.
• Toxicities associated with each specific therapy are outlined in the original guideline document.

• Docetaxel-based chemotherapy is the only treatment that has demonstrated an overall survival benefit in men with hormone-refractory prostate cancer.
• The timing of docetaxel therapy in men with evidence of metastases but without symptoms should be discussed with patients and individualized based on their clinical status and preferences.
• In the largest randomized trials reviewed for this guideline, the men enrolled continued on gonadal androgen suppression and discontinued the use of antiandrogens. These manoeuvres are recommended for men with hormone-refractory prostate cancer who receive chemotherapy.
• Men with hormone-refractory prostate cancer should have symptom control optimized.
• Use of estramustine in combination with other cytotoxic agents is not recommended due to the increased risk of clinically important toxicities without evidence of improved survival or palliation.
• Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the practice guideline is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding their content or use or application and disclaims any for their application or use in any way.

An implementation strategy was not provided.

Living with Illness

Effectiveness

• Winquist E, Waldron T, Berry S, Ernst DS, Hotte S, Lukka H, Genitourinary Cancer Disease Site Group. Non-hormonal systemic therapy in men with metastatic hormone-refractory prostate cancer: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2005 Nov 1. 48 p. (Evidence-based series; no. 3-15). [100 references]

Not applicable: The guideline was not adapted from another source.

2005 Nov 1

Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]

The Program in Evidence-based Care (PEBC) is a Province of Ontario initiative sponsored by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Cancer Care Ontario
Ontario Ministry of Health and Long-Term Care

Provincial Genitourinary Cancer Disease Site Group

The members of the Genitourinary Cancer Disease Site Group (GU DSG) disclosed potential conflicts of interest relating to this practice guideline. Three of the guideline authors were co-investigators for the recent Tannock et al trial, and one of those authors was also an investigator for three other trials. Two authors reported involvement with the pharmaceutical company that manufactures the chemotherapy agent recommended in the guideline, including advisory boards and receipt of honoraria.

None available

This summary was completed by ECRI on January 25, 2006. The information was verified by the guideline developer on February 23, 2006. This summary was updated by ECRI Institute on August 11, 2008 following the U.S. Food and Drug Administration advisory on mitoxantrone hydrochloride.