Adjuvant radiotherapy following radical prostatectomy for pathologic T3 or margin-positive prostate cancer: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Results following radical prostatectomy (RP) are suboptimal in patients found to have cancer extending beyond the prostatic capsule (pT3) or present at the resection margins (R1). The optimal postoperative management of such patients is undefined. Therapeutic alternatives include adjuvant radiotherapy (RT) or active surveillance. METHODS: Randomized controlled trials (RCTs) were eligible for inclusion in this systematic review if they compared adjuvant RT in the immediate period after RP to active surveillance - with therapies held in reserve for salvage - in prostate cancer patients with pT3 or R1 disease or both. The primary outcome of interest was overall survival. RESULTS: Three RCTs representing 1,743 patients satisfied the eligibility criteria. Two trials reported data on overall survival; a meta-analysis of the data showed no significant improvement associated with adjuvant RT (hazard ratio=0.91, 95% CI 0.67-1.22, p=0.52). All trials reported data on biochemical progression-free survival (bPFS). On meta-analysis, adjuvant RT significantly improved bPFS (hazard ratio=0.47, 95% CI 0.40-0.56, p<0.00001). One trial provided comparative graded toxicity data; there were no significant differences between arms in severe (grade 3) gastrointestinal or genitourinary toxicity at five years. CONCLUSIONS: To date, adjuvant RT has not been shown to improve overall survival compared with active surveillance. Longer follow-up from completed RCTs is required to accurately assess this outcome. Adjuvant RT does, however, significantly improve bPFS and is not associated with excess severe late toxicity.

Non-hormonal systemic therapy in men with hormone-refractory prostate cancer and metastases: a systematic review from the Cancer Care Ontario Program in Evidence-based Care's Genitourinary Cancer Disease Site Group.

BACKGROUND: Prostate cancer that has recurred after local therapy or disseminated distantly is usually treated with androgen deprivation therapy; however, most men will eventually experience disease progression within 12 to 20 months. New data emerging from randomized controlled trials (RCTs) of chemotherapy provided the impetus for a systematic review addressing the following question: which non-hormonal systemic therapies are most beneficial for the treatment of men with hormone-refractory prostate cancer (HRPC) and clinical evidence of metastases? METHODS: A systematic review was performed to identify RCTs or meta-analyses examining first-line non-hormonal systemic (cytotoxic and non-cytotoxic) therapy in patients with HRPC and metastases that reported at least one of the following endpoints: overall survival, disease control, palliative response, quality of life, and toxicity. Excluded were RCTs of second-line hormonal therapies, bisphosphonates or radiopharmaceuticals, or randomized fewer than 50 patients per trial arm. MEDLINE, EMBASE, the Cochrane Library, and the conference proceedings of the American Society of Clinical Oncology were searched for relevant trials. Citations were screened for eligibility by four reviewers and discrepancies were handled by consensus. RESULTS: Of the 80 RCTs identified, 27 met the eligibility criteria. Two recent, large trials reported improved overall survival with docetaxel-based chemotherapy compared to mitoxantrone-prednisone. Improved progression-free survival and rates of palliative and objective response were also observed. Compared with mitoxantrone, docetaxel treatment was associated with more frequent mild toxicities, similar rates of serious toxicities, and better quality of life. More frequent serious toxicities were observed when docetaxel was combined with estramustine. Three trials reported improved time-to-disease progression, palliative response, and/or quality of life with mitoxatrone plus corticosteroid compared with corticosteroid alone. Single trials reported improved disease control with estramustine-vinblastine, vinorelbine-hydrocortisone, and suramin-hydrocortisone compared to controls. Trials of non-cytotoxic agents have reported equivocal results. CONCLUSION: Docetaxel-based chemotherapy modestly improves survival and provides palliation for men with HRPC and metastases. Other than androgen deprivation therapy, this is the only other therapy to have demonstrated improved overall survival in prostate cancer in RCTs. Further investigations to identify more effective therapies for HRPC including the use of systemic therapies earlier in the natural history of prostate cancer are warranted.

The use of bisphosphonates in men with hormone-refractory prostate cancer: a systematic review of randomized trials.

PURPOSE: A systematic review of randomized controlled trials (RCTs) was performed to assess the benefits of bisphosphonate therapy in men with hormone-refractory prostate cancer (HRPC). METHODS: The literature was searched to identify RCTs or meta-analyses comparing treatment with bisphosphonates to placebo or no treatment. RESULTS: Ten trials that studied clodronate (five trials, 404 patients), pamidronate (two trials, 350 patients), alendronate (one trial, 49 patients), etidronate (one trial, 51 patients), and zoledronic acid (one trial, 643 patients) in men with HRPC and bone metastases met the eligibility criteria. Pain response was the most frequently reported primary outcome (eight trials). Only the smallest trial demonstrated a statistically significant improvement in pain, but other non-statistically significant trends and subgroup analyses showing improvement in pain were observed in six clodronate and pamidronate trials. Three trials reported skeletal-related events (SREs). A trial studying zoledronic acid reported a statistically and clinically significant reduction in the number of patients having at least one SRE; however, there were higher rates of some adverse effects, and quality of life was not improved. CONCLUSION: Zoledronic acid appears to reduce the number of patients having at least one SRE in men with bone metastases from HRPC that are causing minimal or no pain. This benefit should be weighed against the associated toxicities, and the neutral effect on quality of life. Bisphosphonates may reduce bone pain in men with HRPC, but the evidence is less robust. Further investigations to identify the role of bisphosphonates alone and in combination with other therapies proven effective for men with HRPC are warranted.

Interferon-alfa in the treatment of patients with inoperable locally advanced or metastatic renal cell carcinoma: a systematic review.

A systematic review was undertaken to determine whether interferon-alfa (IFN-alpha) is an effective treatment for patients with inoperable locally advanced or metastatic renal cell carcinoma (mRCC). MEDLINE, EMBASE, the Cochrane Library, guideline databases and relevant meeting proceedings were searched. Randomized clinical trials (RCTs) or meta-analyses comparing IFN-alpha-containing regimens to placebo or non-immunotherapy controls, and that reported response rate, survival, toxicity or quality of life data were eligible. Two systematic reviews and eight RCTs met the selection criteria. A Cochrane review updated in 2005 reported higher response rates and reduced one-year mortality based on 4 RCTs in patients who received IFN-alpha. Of the eight RCTs, three reporting objective response rate showed significant differences favouring IFN-alpha. Two of five trials reporting survival data showed longer median survival in the IFN-alpha group. Adverse effects of IFN-alpha were consistent across the trials with increased intensity and frequency concordant with increased IFN-alpha dose. Meta-analyses of seven RCTs for objective response and six RCTs for mortality favoured IFN-alpha: odds ratio 6.87 (95% Confidence Interval [CI], 3.29 to 14.35) and hazard ratio 0.79 (95% CI, 0.69 to 0.91), respectively. The effectiveness of IFN-alpha in mRCC has been subject to skepticism. As IFN-alpha has been used as a control arm in RCTs of new targeted therapies, therapies which not all patients may have access to, information about its effectiveness remains relevant. These data confirm genuine, if modest, effectiveness of IFN-alpha in mRCC.

High-intensity focused ultrasound for prostate cancer: a practice guideline.

OBJECTIVE: The aim of this practice guideline was to develop evidence-based recommendations for clinicians on the use of high-intensity focused ultrasound (HIFU) in patients with localized prostate cancer. METHODS: The guideline was developed using the methods of Cancer Care Ontario's Program in Evidence-Based Care (PEBC). The core methodology of the PEBC's guideline development process is systematic review. A comprehensive literature search was undertaken to identify high-quality studies, reviews and other practice guidelines on the use of HIFU in prostate cancer. The evidence formed the basis of the recommendations, which were reviewed and amended where necessary, by clinical experts in medical and radiation oncology and urology. RESULTS: The literature review yielded limited evidence. No randomized controlled trials or meta-analyses comparing HIFU with currently accepted management approaches were identified. The body of evidence is primarily based on data from case series. Internal feedback was provided by the PEBC Genitourinary Disease Site Group membership and the Report Approval Panel. External peer review included targeted review by clinical experts specifically requested to comment on the guideline, and professional consultation through an online survey of health care professionals. CONCLUSION: HIFU is currently not recommended as an alternative to accepted curative treatment approaches for localized prostate cancer.

Interleukin-2 in the treatment of unresectable or metastatic renal cell cancer: a systematic review and practice guideline.

OBJECTIVE: We performed a systematic review of randomized controlled trials (RCTs) to assess the efficacy of interleukin-2 (IL-2) for the treatment of patients with unresectable or metastatic renal cell carcinoma (RCC). METHODS: We searched the literature to identify RCTs or meta-analyses of RCTs comparing treatment regimens with IL-2 to those without. Outcomes of interest included overall or progression-free survival, response rate, toxicity and quality of life. RESULTS: We identified 36 RCTs, and 6 met the eligibility criteria (1098 patients). We studied IL-2 alone and in combination with other agents, including interferon-alpha (IFN-a), 5-fluorouracil (5-FU), and 13-cis-retinoic acid or tamoxifen. No trials comparing high-dose IL-2 to non-IL-2 regimens were identified. A meta-analysis of 1-year mortality data from the 6 trials did not show a difference between IL-2-based regimens and non-IL-2 controls. Two of the 6 trials detected statistically significant longer survival with IL-2 combined with IFN-a and 5-FU. Of the 4 trials that assessed progression-free survival, 3 reported significantly longer progression-free intervals with IL-2-based regimens. Five trials reported response rates; pooling the rates from these trials gave an overall weighted response rate of 13.3% (range 9%-39%) and 5.3% (range 0%-20%) for IL-2-containing regimens and non-IL-2 regimens, respectively. IL-2-based regimens were more toxic than were non-IL-2 controls; the most frequently reported grade 3-4 toxicities were hypotension (range 6%-68%), fever (2%-56%), nausea or vomiting or both (6%-34%), diarrhea (1%-28%) and cardiac toxicity (11%-25%). None of the trials reported health-related quality-of-life data. CONCLUSION: Non-high-dose IL-2 containing regimens do not provide superior treatment efficacy over non-IL-2-based regimens, with added toxicity, and therefore should not be used as standard treatment for patients with unresectable or metastatic RCC. High-dose IL-2 should only be used by experienced physicians in the context of a clinical trial or investigative setting.