Targeted therapy for advanced renal cell carcinoma.

BACKGROUND: Advanced renal cell carcinoma has been resistant to drug therapy of different types and new types of drug therapy are needed. Targeted agents inhibit known molecular pathways involved in cellular proliferation and neoangiogenesis, the induction by the tumour of host microvascular networks. Angiogenesis is of special interest in the clear cell histologic subtype of renal cancer because of its vascularity and constitutively activated hypoxia-inducible path in the majority of tumours. OBJECTIVES: 1) To provide a systematic review of studies testing targeted agents.2) To identify the type and degree of clinical benefit, if any, of targeted agents over the prior standard of care, particularly any impact on overall survival. SEARCH STRATEGY: 1) Electronic search of CENTRAL, MEDLINE and EMBASE databases.2) Hand search of international cancer meeting abstract and other sources specified in the protocol. SELECTION CRITERIA: Randomized controlled studies of targeted agents in patients with advanced renal cell cancer reporting major remission rate or overall survival by allocation. Progression-free survival (PFS) was adopted as an additional outcome because PFS was a commonly chosen primary outcome, and because several pivotal studies allowed crossover from the control to the investigational arm after closure to accrual thereby making overall survival a problematic endpoint. DATA COLLECTION AND ANALYSIS: Nineteen fully eligible studies tested ten different targeted agents (Table 04). One additional study was excluded because no outcome data by allocation have been reported (Hutson 2007). For purposes of comparison, the studies were divided into three groups: Group 1 studies compared different doses of the same agents; Group 2 studies examined the impact of targeted agents in patients who had received prior cytokine or other systemic therapy; and Group 3 studies tested targeted agents in systemically naive patients, either against standard interferon-alfa or against another control therapy. Meta-analysis was not utilized because there were very few situations where the same agents had been tested in the same group in more than one study. MAIN RESULTS: In systemically untreated patients in studies using subcutaneous interferon-alfa as control therapy, the major findings were: 1) An improvement in overall survival has been demonstrated only with the use of weekly intravenous temsirolimus in patients with unselected renal cancer histology and adverse prognostic features (median survival 10.9 months versus 7.3 months for temsirolimus or interferon-alfa respectively, HR 0.73, P = 0.008 log rank, Hudes 2007). However, the chance of major remission was low and not improved with temsirolimus. 2) In patients with mostly good or intermediate prognostic risk with clear cell renal cancer, oral sunitinib improves the chance of major remission, the probability of symptomatic improvement, and freedom from disease progression (Motzer 2007); in a similar setting, the addition of biweekly intravenous bevacizumab to interferon-alfa also improved the chance of major remission and prolonged progression-free survival (Escudier 2007b); overall survival had not changed at the time of interim reporting of either study. In patients with clear cell renal cancers who had failed prior cytokine therapy, oral sorafenib gives a better quality of life than placebo as well as improved chance of being free of disease progression; overall survival may have improved but is hard to evaluate because of crossover of placebo-assigned patients after the study closed to accrual (Escudier 2007a). AUTHORS' CONCLUSIONS: Based on less than a decade of experience, some targeted agents with specified molecular targets have demonstrated clinically useful benefits over the previous standard of care for patients with advanced renal cancer. Much more research is required to fully establish the role of targeted agents in this condition.

Five-alpha-reductase Inhibitors for prostate cancer prevention.

BACKGROUND: Five-alpha-reductase inhibitors (5ARI) are frequently used to treat bothersome lower urinary tract symptoms associated with benign prostatic hyperplasia and male androgenic alopecia. They have potential as chemopreventive agents. OBJECTIVES: We sought to estimate the effectiveness and harms of 5ARI in preventing prostate cancer. SEARCH STRATEGY: MEDLINE, PreMEDLINE, and the Cochrane Collaboration Library were searched through April 2007 to identify randomized trials. SELECTION CRITERIA: For prostate cancer outcomes we included randomized controlled trials of at least 1 year in duration published after 1984. For non-prostate cancer outcomes, randomized trials were included if: they were at least 6 months in duration published after 1999. DATA COLLECTION AND ANALYSIS: The primary outcome was prostate cancer period-prevalence "for-cause." "For-cause" was defined as prostate cancer clinically detected based on symptoms, an abnormal digital rectal exam, or detected as a result of an abnormal prostate specific antigen value. Trials were categorized as long (> 2 year), mid (1-2 years) and short (< 1 year) term. MAIN RESULTS: Nine trials reported prostate cancer period-prevalence. Three trials using finasteride lasted 4 years or longer but only one (the Prostate Cancer Prevention Trial) was specifically designed to assess the impact of 5ARI on prostate cancer period-prevalence. The mean age of enrollees was 64.6 years, 91% were white, mean PSA was 2.1 ng/mL. For-cause prostate cancers comprised 54% of all cancers detected. Finasteride was associated with a 26% relative risk reduction in prostate cancers detected for-cause among all randomized subjects (relative risk 0.74 [95% CI 0.67 to 0.83]; absolute risk reduction = 1.4% (3.5% versus 4.9%). Six trials assessed prostate cancers detected overall with a pooled 26% relative reduction favoring 5ARI (relative risk 0.74 [95% CI 0.55 to1.00]; 2.9% absolute reduction (6.3% versus 9.2%). Reductions were observed regardless of age, race or family history of prostate cancer but not among men with baseline PSA > 4.0 ng/mL. A greater number of high Gleason score tumors (7-10 or 8-10) occurred in men on finasteride in the PCPT. Impaired sexual or erectile function or endocrine effects were more common with finasteride than placebo. AUTHORS' CONCLUSIONS: 5ARI reduce prostate cancer risk but may increase the risk of high-grade disease in men who are undergoing regular screening for prostate cancer using prostate specific antigen and digital rectal examination. Effects are consistent across race, family history and age and possibly 5ARI but were limited to men with baseline PSA values <4.0 ng/mL. The impact of 5ARI on absolute or relative rates of prostate cancer in men who are not being regularly screened is not clear. Information is inadequate to assess the impact of 5ARI on mortality.

Cryotherapy for localised prostate cancer.

BACKGROUND: Prostate cancer is a common cancer in elderly men and in some will prove fatal. Standard treatments for localised disease include surgery ( radical prostatectomy), radiotherapy and active monitoring. New emerging therapies are being evaluated with the aim of reducing the complication rate associated with standard therapies, as well as developing an effective treatment. One such modality is cryotherapy, a procedure that introduces probes directly into the prostate tumour and kills the malignant cells by a freezing process. OBJECTIVES: This review aims to evaluate the relative clinical and economic benefits of cryotherapy compared to standard therapies for the primary treatment of localised prostate cancer. SEARCH STRATEGY: Our search strategy included an electronic search of MEDLINE from 1996 to December 2006, plus EMBASE (Excerpta Medica Database), the Cochrane library, ISI Science Citation Index, Database of Abstracts and Reviews of Effectiveness (DARE), and LILACS to identify all relevant published randomised trials of cryotherapy for localised prostate cancer. Cancerlit and HealthSTAR databases were searched to their final date. Handsearching of relevant journals was undertaken. SELECTION CRITERIA: Only published randomised trials comparing the effectiveness of cryotherapy with radical prostatectomy, radiotherapy or active monitoring for the primary treatment of men with localised prostate cancer were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: Data were extracted from eligible studies, and included study design, participants, interventions and outcomes. Primary outcome measures were biochemical disease-free survival, disease-free survival and treatment-induced complications. Secondary outcomes included disease-specific survival, overall survival, quality-of-life outcome measures and economic impact measures. MAIN RESULTS: There were no randomised trials found comparing cryotherapy with other therapies for the primary treatment of localised prostate cancer. All studies identified were case series. To indicate the level of the available evidence, studies that evaluated cryotherapy as a primary therapy, using transrectal ultrasound guidance and urethral warming in at least 50 patients with localised prostate cancer, and a minimum of one year follow up, were reviewed. Eight case series were identified that complied with these criteria; two were retrospective. The patients recruited (n = 1483) had an age range from 41 to 84 years, stages T1 = 0 to 43%, T2 = 24 to 88%, T3 = 1 to 41%, and T4 = 0 to 14%. The mean preoperative PSA level ranged from 9.7 to 39 ng/mL, with Gleason scores < 7 and ranging from 6 to 37%. One additional study that compared cryotherapy (total cryotherapy and standard cryotherapy with urethral preservation) with radical prostatectomy was also identified and reviewed. In this study the success rates, defined as a post-treatment PSA of 0.2 ng/mL or less, were reported as 96% for total cryotherapy, 49% for standard cryotherapy and 73% for radical prostatectomy. Four studies did not monitor the temperature of the cyro-procedure and reported 17 to 28% of patients had a positive biopsy following cryotherapy with a mean PSA nadir of 0.55 to 1.75 ng/mL (median 0.4 to 1.85 ng/mL). The other four studies used thermocouples to monitor the temperature of the cryo-procedure and reported progression-free survival rates of 71 to 89% with 1.4 to 13% of patients having a positive biopsy post-cryotherapy. At 5 years, overall survival was reported as 89 to 92% in two studies, and disease-specific survival as 94% in one study. The major complications observed in all studies included impotence (47 to 100%), incontinence (1.3 to 19%), and urethral sloughing (3.9 to 85%), with less common complications of fistula (0 to 2%), bladder-neck obstruction (2 to 55%), stricture (2.2 to 17%) and pain (0.4 to 3.1%). Most patients were sent home the following day (range 1 to 4 days). AUTHORS' CONCLUSIONS: Cryotherapy offers a potential alternative to standard therapies for the primary treatment of localised prostate cancer. However, the poor quality of the available studies makes it difficult to determine the relative benefits of this modality. Randomised trials are needed to fully evaluate the full potential of cryotherapy in men with this disease. Patients selecting cryotherapy as their therapeutic option should be made fully aware of the reported efficacy, complications and the low-grade evidence from which these data are derived.

Microwave thermotherapy for benign prostatic hyperplasia.

BACKGROUND: Transurethral resection of the prostate (TURP) has been the gold-standard treatment for alleviating urinary symptoms and improving urinary flow in men with symptomatic benign prostatic hyperplasia (BPH). However, the morbidity of TURP approaches 20%, and less invasive techniques have been developed for treating BPH. Preliminary data suggest that microwave thermotherapy, which delivers microwave energy to produce coagulation necrosis in prostatic tissue, is a safe, effective treatment for BPH. OBJECTIVES: To assess the therapeutic efficacy and safety of microwave thermotherapy techniques for treating men with symptomatic benign prostatic obstruction. SEARCH STRATEGY: Randomized controlled trials were identified from the Cochrane Collaboration Library, MEDLINE, EMBASE, bibliographies of retrieved articles and reviews, and by contacting expert relevant trialists and microwave manufacturers. SELECTION CRITERIA: All randomized controlled trials evaluating transurethral microwave thermotherapy (TUMT) for men with symptomatic BPH were eligible for this review. Comparison groups could include transurethral resection of the prostate, minimally invasive prostatectomy techniques, sham thermotherapy procedures, and medications. Outcome measures included urinary symptoms, urinary function, prostate volume, mortality, morbidity, and retreatment. Two reviewers independently identified potentially relevant abstracts and then assessed the full papers for inclusion. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted study design, baseline characteristics and outcomes data and assessed methodological quality using a standard form. We attempted to obtain missing data from authors and/or sponsors. MAIN RESULTS: Fourteen studies involving 1493 patients met inclusion criteria, including six comparisons of microwave thermotherapy with TURP, seven comparisons with sham thermotherapy procedures, and one comparison with an alpha blocker. Study durations ranged from 3 to 60 months. The mean age of subjects was 66.8 years, and the baseline symptom scores and urinary flow rates, which did not differ across treatment groups, demonstrated moderately severe lower urinary tract symptoms. The pooled mean urinary symptom scores decreased by 65% with TUMT and by 77% with TURP. The weighted mean difference (WMD) (95% confidence interval) for the symptom score was -1.36 (-2.25 to -0.46), favoring TURP. The pooled mean peak urinary flow increased by 70% with TUMT and by 119% with TURP. The WMD for peak urinary flow was 5.08 (3.88 to 6.28) mL/s, favoring TURP. Compared to TURP, TUMT was associated with decreased risks for retrograde ejaculation, treatment for strictures, hematuria, blood transfusions, and the transurethral resection syndrome, but increased risks for dysuria, urinary retention, and retreatment for BPH symptoms. Microwave thermotherapy improved symptom scores (IPSS WMD -4.75, 95% CI -3.89 to -5.60) and peak urinary flow (WMD 1.67 mL/s, 95% CI 0.99 to 2.34) compared with sham procedures. Microwave thermotherapy also improved symptom scores (IPSS WMD -4.20, 95% CI -3.15 to -5.25) and peak urinary flow (WMD 2.30 mL/s, 95% CI 1.47 to 3.13) in the one comparison with alpha blockers. No studies evaluated the effects of symptom duration, patient characteristics, prostate-specific antigen levels, or prostate volume on treatment response. AUTHORS' CONCLUSIONS: Microwave thermotherapy techniques are effective alternatives to TURP and alpha-blockers for treating symptomatic BPH for men with no history of urinary retention or previous prostate procedures and prostate volumes between 30 to 100 mL. However, TURP provided greater symptom score and urinary flow improvements and reduced the need for subsequent BPH treatments compared to TUMT. Small sample sizes and differences in study design limit comparison between devices with different designs and energy levels. The effects of symptom duration, patient characteristics, or prostate volume on treatment response are unknown.

Intermittent versus continuous androgen suppression for prostatic cancer.

BACKGROUND: After lung cancer, prostate cancer is the most common cause of death among males. The aim of treatment is to prevent disease-related morbidity and mortality while minimizing intervention-related adverse events. Androgen suppression therapy (AST) to reduce circulating serum testosterone and disease progression is considered a mainstay of treatment for men with advanced prostate cancer. It has been increasingly utilized for early stage disease despite a lack of evidence of effectiveness. OBJECTIVES: Evaluate the effectiveness and safety of intermittent androgen suppression (IAS) compared to continuous androgen suppression for treating prostatic cancer. SEARCH STRATEGY: The following databases were searched to identify randomised or quasi-randomised, controlled trials comparing intermittent and continuous androgen suppression in the treatment of any stage of prostate cancer: the Cochrane Central Register of Controlled Trials; EMBASE and LILACS. SELECTION CRITERIA: Studies were included if they were randomised or quasi-randomized, and compare the effects of IAS versus CAS. DATA COLLECTION AND ANALYSIS: Two reviewers selected relevant trials, assessed methodological quality and extracted data. MAIN RESULTS: Five randomized studies involving 1382 patients were included in this review. All the included studies involved advanced (T3 or T4) prostate cancer, had relatively small populations, and were of short duration. Few events were reported and did not assess disease-specific survival or metastatic disease. Only one study (N = 77) evaluated biochemical outcomes. A subgroup analysis found no significant differences in biochemical progression (defined by the authors as PSA >/= 10 ng/mL) between IAS and CAS for Gleason scores 4 - 6, 7, and 8 - 10. For patients with a Gleason score > 6, reduction in biochemical progression favoured the IAS group (RR 0.10, 95% CI 0.01 to 0.67, P = 0.02). Studies primarily reported on adverse events. One trial (N = 43) found no difference in adverse effects (gastrointestinal, gynecomastia and asthenia) between IAS ( two events) and CAS (five events), with the exception of impotence, which was significantly lower in the IAS group (RR 0.72, 95% CI 0.56 to 0.92, P = 0.008). AUTHORS' CONCLUSIONS: Data from RCTs comparing IAS to CAS are limited by small sample size and short duration. There are no data for the relative effectiveness of IAS versus CAS for overall survival, prostate cancer-specific survival, or disease progression. Limited information suggests IAS may have slightly reduced adverse events. Overall, IAS was also as effective as CAS for potency, but was superior during the interval of cycles (96%).

Screening for prostate cancer.

BACKGROUND: Any form of screening aims to reduce mortality and increase a person's quality of life. Screening for prostate cancer has generated considerable debate within the medical community, as demonstrated by the varying recommendations made by medical organizations and governed by national policies. Much of this debate is due to the limited availability of high quality research and the influence of false-positive or false-negative results generated by use of the diagnostic techniques such as the digital rectal examination (DRE) and prostate specific antigen (PSA) blood test. OBJECTIVES: To determine whether screening for prostate cancer reduces prostate cancer mortality and has an impact on quality of life. SEARCH STRATEGY: Electronic databases (PROSTATE register, CENTRAL the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CANCERLIT and the NHS EED) were searched electronically in addition to hand searching of specific journals and bibliographies in an effort to identify both published and unpublished trials. SELECTION CRITERIA: All randomised controlled trials of screening versus no screening or routine care for prostate cancer were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: The search identified 99 potentially relevant articles that were selected for full text review. From these 99 citations, two randomised controlled trials were identified as meeting the review's inclusion criteria. Data from the trials were independently extracted by two authors. MAIN RESULTS: Two randomised controlled trials with a total of 55,512 participants were included; however, both trials had methodological weaknesses. Re-analysis using intention-to-screen and meta-analysis of results from the two randomised controlled trials indicated no statistically significant difference in prostate cancer mortality between men randomised for prostate cancer screening and controls (RR 1.01, 95% CI: 0.80-1.29). Neither study assessed the effect of prostate cancer screening on quality of life, all-cause mortality or cost effectiveness. AUTHORS' CONCLUSIONS: Given that only two randomised controlled trials were included, and the high risk of bias of both trials, there is insufficient evidence to either support or refute the routine use of mass, selective or opportunistic screening compared to no screening for reducing prostate cancer mortality. Currently, no robust evidence from randomised controlled trials is available regarding the impact of screening on quality of life, harms of screening, or its economic value. Results from two ongoing large scale multicentre randomised controlled trials that will be available in the next several years are required to make evidence-based decisions regarding prostate cancer screening.

Neo-adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer.

BACKGROUND: Hormone therapy for early prostate cancer has demonstrated an improvement in clinical and pathological variables, but not always an improvement in overall survival. We performed a systematic review of both adjuvant and neo-adjuvant hormone therapy combined with surgery or radiotherapy in localised or locally advanced prostate cancer. OBJECTIVES: The objective of this review was to undertake a systematic review and, if possible, a meta-analysis of neo-adjuvant and adjuvant hormone therapy in localised or locally advanced prostate cancer. SEARCH STRATEGY: We searched MEDLINE (1966-2006), EMBASE, The Cochrane Library, Science Citation Index, LILACS, and SIGLE for relevant randomised trials. Handsearching of appropriate publications was also undertaken. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of patients with localised or locally advanced prostate cancer, that is, stages T1-T4, any N, M0, comparing neo-adjuvant or adjuvant hormonal deprivation in combination with primary therapy (radical radiotherapy or radical prostatectomy) versus primary therapy alone were included in this review. DATA COLLECTION AND ANALYSIS: Data were extracted from eligible studies and assessed for quality, and included information on study design, participants, interventions, and outcomes. Comparable data were pooled together for meta-analysis with intention-to treat principle. MAIN RESULTS: Men with prostate cancer have different clinical outcomes based on their risk (T1-T2, T3-T4, PSA levels and Gleason score). However, the majority of studies included in this review did not report results by risk groups; therefore, it was not possible to perform sub-group analysis. Neo-adjuvant hormonal therapy prior to prostatectomy did not improve overall survival (OR 1.11, 95% CI 0.67 to 1.85, P = 0.69). However, there was a significant reduction in the positive surgical margin rate (OR 0.34, 95% CI 0.27 to 0.42, P < 0.00001) and a significant improvement in other pathological variables such as lymph node involvement, pathological staging and organ confined rates. There was a borderline significant reduction of disease recurrence rates (OR 0.74, 95% CI 0.55 to 1.0, P = 0.05), in favour of treatment. The use of longer duration of neo-adjuvant hormones, that is either 6 or 8 months prior to prostatectomy, was associated with a significant reduction in positive surgical margins (OR 0.56, 95% CI 0.39 to 0.80, P = 0.002). In one study, neo-adjuvant hormones prior to radiotherapy significantly improved overall survival for Gleason 2 to 6 patients; although, in two studies, there was no improvement in disease-specific survival (OR 0.99, 95% CI 0.75 to 1.32, P = 0.97). However, there was a significant improvement in both clinical disease-free survival (OR 1.86, 95% CI 1.93 to 2.40, P < 0.00001) and biochemical disease-free survival (OR 1.93, 95% CI 1.45 to 2.56, P < 0.00001). Adjuvant androgen deprivation following prostatectomy did not significantly improve overall survival at 5 years (OR 1.50, 95% CI 0.79 to 2.85, P = 0.2); although one study reported a significant disease-specific survival advantage with adjuvant therapy (P = 0.001). In addition, there was a significant improvement in disease-free survival at both 5 years (OR 3.73, 95%CI 2.30 to 6.03, P < 0.00001) and 10 years (OR 2.06, 95% CI 1.34 to 3.15, P = 0.0009). Adjuvant therapy following radiotherapy resulted in a significant overall survival gain apparent at 5 (OR 1.46, 95% CI 1.17 to 1.83, P = 0.0009) and 10 years (OR 1.44, 95% CI 1.13 to 1.84, P = 0.003); although there was significant heterogeneity (P = 0.09 and P = 0.07, respectively). There was also a significant improvement in disease-specific survival (OR 2.10, 95% CI 1.53 to 2.88, P = 0.00001) and disease-free survival (OR 2.53, 95% CI 2.05 to 3.12, P < 0.00001) at 5 years. AUTHORS' CONCLUSIONS: Hormone therapy combined with either prostatectomy or radiotherapy is associated with significant clinical benefits in patients with local or locally advanced prostate cancer. Significant local control may be achieved when given prior to prostatectomy or radiotherapy, which may improve patient's quality of life. When given adjuvant to these primary therapies, hormone therapy, not only provides a method for local control, but there is also evidence for a significant survival advantage. However, hormone therapy is associated with significant side effects, such as hot flushes and gynaecomastia, as well as cost implications. The decision to use hormone therapy should, therefore, be taken at a local level, between the patient, clinician and policy maker, taking into account the clinical benefits, toxicity and cost. More research is needed to guide the choice, the duration, and the schedule of hormonal deprivation therapy, and the impact of long-term hormone therapy with regard to toxicity and the patient's quality of life.

Bisphosphonates for advanced prostate cancer.

BACKGROUND: Prostate cancer is the most common cancer in men in many western countries. It is characterized by its propensity for bone metastases which occur in more than 80% of patients with advanced disease. Patients are at risk of complications including pain, hypercalcaemia, bone fracture and spinal cord compression. Hormonal treatment is the mainstay of treatment for these patients but most of them will then become hormone refractory. Bisphosphonates act by inhibiting osteoclast activities and are a potential therapeutic option for metastatic prostate cancer. In addition, they have been shown to reduce pain in patients with bone metastases as a consequence of multiple myeloma. Early uncontrolled studies of bisphosphonates in metastatic prostate cancer patients have shown encouraging results. OBJECTIVES: The objective of this review was to determine the effectiveness of bisphosphonates in relieving pain in patients with bone metastases from prostate cancer. SEARCH STRATEGY: Studies were identified by electronic search of bibliographic databases including MEDLINE, EMBASE, CancerLit and the Cochrane Controlled Trials Register. Handsearching included Proceedings of American Society of Clinical Oncology and reference lists of all eligible trials identified. SELECTION CRITERIA: Randomised controlled studies comparing the effectiveness of bisphosphonates with placebo or open control for pain relief in patients with bone metastases from prostate cancer. DATA COLLECTION AND ANALYSIS: Data were extracted from eligible studies and included study design, participants, interventions and outcomes. Comparable data were pooled together for meta-analysis with intention-to-treat principle. Outcomes included pain response, analgesic consumption, skeletal events (including pathological fractures, spinal cord compression, bone radiotherapy, bone surgery), prostate cancer death, disease progression, radiological response, PSA response, adverse events, performance status, quality of life and comparisons between different routes, doses and types of bisphosphonates. MAIN RESULTS: One thousand nine hundred and fifty-five patients from ten studies were included in this review. The pain response rates were 27.9% and 21.1% for the treatment group and the control group, respectively, with an absolute risk difference of 6.8%. The OR for pain response was 1.54 (95% CI 0.97 to 2.44, P = 0.07), showing a trend of improved pain relief in the bisphosphonate group, although this was not statistically significant. The rates for skeletal events were 37.8% and 43.0% for the treatment group and the control group, respectively, with an absolute risk difference of 5.2%. The OR for skeletal events was 0.79 (95% CI 0.62 to 1.00, P = 0.05). A significant increase in nausea was observed in patients who received bisphosphonates compared to placebo. No increase in other adverse events was observed. There was no statistically significant difference between the bisphosphonate group and the control group in terms of prostate cancer death, disease progression, radiological response and PSA response. There are insufficient data to guide the choice of bisphosphonates or the dose and the route of administration . AUTHORS' CONCLUSIONS: Bisphosphonates should be considered for patients with metastatic prostate cancer for the treatment of refractory bone pain and prevention of skeletal events. More research is needed to guide the choice of bisphosphonates, optimal treatment schedule as well as cost-benefit comparisons. Combining results from different studies is difficult because different tools were used to assess pain, and also, bisphosphonates vary considerably in potency. This review highlights the need for standardisation and co-ordination among researchers in cancer pain studies.

Immunotherapy for advanced renal cell cancer.

BACKGROUND: The course of advanced renal cell carcinoma is extremely variable, ranging from spontaneous remission to disease progression refractory to chemotherapy. Immunotherapy has held promise of improved outcomes based on uncontrolled studies and randomized controlled trials generally limited by small size and low power. OBJECTIVES: To evaluate immunotherapy for advanced renal cell carcinoma by comparing: (1) high dose interleukin-2 to other options and (2) interferon-alfa to other options. The primary outcome of interest was overall survival at one year, with remission as the main secondary outcome of interest. SEARCH STRATEGY: A systematic search of the CENTRAL, MEDLINE, and EMBASE databases was conducted for the period 1966 through end of December 2003. Handsearches were made of the proceedings of the periodic meetings of the American Urologic Association, the American Society of Clinical Oncology, ECCO - the European Cancer Conference, and the European Society of Medical Oncology for the period 1995 to June 2004. SELECTION CRITERIA: Randomized controlled trials that selected (or stratified) patients with advanced renal cell carcinoma, utilized an immunotherapeutic agent in at least one study arm, and reported remission or survival by allocation. Fifty-three identified studies involving 6117 patients were eligible and all but one reported remission; 32 of these studies reported the one-year survival outcome. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted each article by following a prospectively designed protocol. Dichotomous outcomes for treatment remission (partial plus complete) and for deaths at one year were used for the main comparisons. Survival hazard ratios were also used for studies of interferon-alfa versus controls, and for two randomized studies of the value of initial nephrectomy prior to interferon-alfa in fit patients with metastases detected at the time of diagnosis. MAIN RESULTS: Combined data for a variety of immunotherapies gave an overall chance of partial or complete remission of only 12.9% (99 study arms), compared to 2.5% in 10 non-immunotherapy control arms, and 4.3% in two placebo arms. Twenty-eight percent of these remissions were designated as complete (data from 45 studies). Median survival averaged 13.3 months (range by arm, 6 to 27+ months). The difference in remission rate between arms was poorly correlated with the difference in median survival so that remission rate is not a good surrogate or intermediate outcome for survival for advanced renal cancer. We were unable to identify any published randomized study of high-dose interleukin-2 versus a non-immunotherapy control, or of high-dose interleukin-2 versus interferon-alfa reporting survival. It has been established that reduced dose interleukin-2 given by intravenous bolus or by subcutaneous injection provides equivalent survival to high dose interleukin-2 with less toxicity. Results from four studies (644 patients) indicate that interferon-alfa is superior to controls (OR for death at one year = 0.56, 95% confidence interval 0.40 to 0.77). Using the method of Parmar 1998, the pooled overall hazard ratio for death was 0.74 (95% confidence interval 0.63 to 0.88). The weighted average median improvement in survival was 3.8 months. T he optimal dose and duration of interferon-alfa remains to be elucidated. The addition of a variety of enhancers, including lower dose intravenous or subcutaneous interleukin-2, has failed to improve survival compared to interferon-alfa alone. Two recent randomized studies have examined the role of initial nephrectomy prior to interferon-alfa therapy in highly selected fit patients with metastases at diagnosis and minimal symptoms: despite minimal improvement in the chance of remission, both studies of up-front nephrectomy improved median survival by 4.8 months over interferon-alfa alone. Recent studies have been examining anti-angiogenesis agents. A landmark study of bevacizumab, an anti-vascular endothelial growth factor antibody, was associated with significant prolongation of the time to progression of disease when given at high dose compared to low-dose or placebo therapy though frequency of remissions or survival were not improved. AUTHORS' CONCLUSIONS: interferon-alfa provides a modest survival benefit compared to other commonly used treatments and should be considered for the control arm of future studies of systemic agents. In fit patients with metastases at diagnosis and minimal symptoms, nephrectomy followed by interferon-alfa gives the best survival strategy for fully validated therapies. The need for more effective specific therapy for this condition is apparent.

Distribution of lipid phenotypes in community-living men with coronary heart disease. High prevalence of isolated low levels of high-density lipoprotein cholesterol.

BACKGROUND: Risk factor modification, including treatment of dyslipidemias, has been recommended for the prevention of future coronary events in patients with coronary heart disease (CHD). Since the prevalence of various dyslipidemias among outpatients with CHD has not been well documented, the purpose of this study was to determine the frequency of specific lipid phenotypes among ambulatory men with CHD. METHODS: Lipid profiles were obtained in 255 men (mean age, 65.5 +/- 9.1 years) with CHD in three Veterans Affairs medical centers. Desirable levels of lipids were defined according to National Cholesterol Education Program guidelines as follows: low-density lipoprotein cholesterol (LDL-C) levels less than 3.36 mmol/L (130 mg/dL); high-density lipoprotein cholesterol (HDL-C) levels equal to or greater than 0.90 mmol/L (35 mg/dL); and triglyceride levels less than 2.83 mmol/L. RESULTS: Seventy-six percent of the group had one or more abnormalities on lipid profile: 51% had high LDL-C levels with or without abnormalities of HDL-C and/or triglyceride levels; 22% had low HDL-C levels with desirable levels of LDL-C; and 3% had hypertriglyceridemia without any cholesterol abnormalities. Normal lipid profiles were significantly more prevalent in subjects over the age of 65 years than in younger patients (40% vs 14%). CONCLUSIONS: These data suggest that (1) a high proportion of men with CHD have dyslipidemia, including 50% with LDL-C level elevations. For these men, the potential benefits of therapeutic intervention have been documented in clinical trials, although the cost-efficiency of wide-scale treatment has not been determined; (2) isolated hypertriglyceridemia is rare in this population; and (3) low HDL-C levels in association with desirable LDL-C levels are present in more than one fifth of male patients with CHD. Clinical trials focusing on this large group are urgently needed to determine whether efforts to raise HDL-C levels result in reduced cardiac morbidity and/or mortality.

Correlates and consequences of diffuse atherosclerosis in men with coronary heart disease. Veterans Affairs High-Density Lipoprotein Intervention Trial Study Group.

BACKGROUND: Peripheral atherosclerosis is a strong and independent predictor of mortality even in patients with known coronary heart disease. However, the prevalence, correlates, and potential adverse effects on quality of life associated with combined coronary heart disease and clinically evident cerebrovascular or lower-extremity atherosclerosis are not known. Identification of patients with "diffuse atherosclerosis" may enhance treatment of modifiable risk factors and alter therapeutic strategies. METHODS: We conducted a cross-sectional analysis of 2531 men younger than 73 years with coronary heart disease, low-density lipoprotein cholesterol levels of 3.62 mmol/L (140 mg/dL) or less, and high-density lipoprotein cholesterol level of 1.03 mmol/L (40 mg/dL) or less who were participating in Department of Veterans Affairs Cooperative Study 363 (the Veterans Affairs High-Density Lipo-protein Intervention Trial. Baseline demographic, medication, comorbidity, and atherosclerotic risk factor data were assessed by means of a standardized questionnaire. All plasma lipid levels were determined after a 12-hour fast by a central standardized lipid laboratory. Health status was determined by baseline reported symptoms, medical comorbidities, and the Psychological General Well-being Index. Clinically evident diffuse atherosclerosis was defined as a documented history of lower-extremity atherosclerosis or cerebrovascular disease. RESULTS: The mean age of all participants was 63.5 years. The mean plasma lipid values were as follows: total cholesterol, 4,52 mmol/L (174.6 mg/dL); high-density lipo-protein cholesterol, 0.81 mmol/L (31.5 mg/dL); low-density lipoprotein cholesterol, 2.88 mmol/L (111.2 mg/dL); and triglycerides, 1.81 mmol/L (160.6 mg/dL). Diffuse atherosclerosis was present in 525 (21%). Lower-extremity atherosclerosis was reported in 10%, while cerebrovascular disease was present in 13%. After controlling for other variables, the following factors were associated with the presence of diffuse atherosclerosis: increased age, being unmarried, being retired, having less than a high school education, increased alcohol use, hypertension, cigarette smoking, and diabetes. There was no association between lipid levels and the presence of diffuse atherosclerosis. After adjustment for age, race, and comorbidities, men with diffuse disease still had a reduced quality of life compared with men without diffuse atherosclerosis, as defined by having a greater number of clinical symptoms, lower psychological well-being scores, and more advanced or complicated coronary heart disease. CONCLUSIONS: Clinically evident diffuse atherosclerosis is common in men with coronary heart disease and low levels of high-density lipoprotein cholesterol. Because diffuse atherosclerosis is associated with a reduced quality of life and several modifiable risk factors, early detection and aggressive risk factor intervention appear justified.

Pygeum africanum for the treatment of patients with benign prostatic hyperplasia: a systematic review and quantitative meta-analysis.

PURPOSE: To conduct a systematic review and quantitative meta-analysis of the therapeutic efficacy and tolerability of Pygeum africanum in men with symptomatic benign prostatic hyperplasia. METHODS: Studies were identified through the search of Medline (1966 to 2000), Embase, Phytodok, the Cochrane Library, bibliographies of identified trials and review articles, and contact with relevant authors and drug companies. Randomized trials were included if participants had symptomatic benign prostatic hyperplasia, the intervention was a preparation of P. africanum alone or in combination with other phytotherapeutic agents, a control group received placebo or other pharmacologic therapies for benign prostatic hyperplasia, and treatment duration was at least 30 days. Two investigators independently extracted key data on design features, subject characteristics, and therapy allocation. RESULTS: A total of 18 randomized controlled trials involving 1,562 men met the inclusion criteria and were analyzed. Many studies did not report results in a method that permitted meta-analysis. Only 1 of the studies reported a method of treatment allocation concealment, although 17 were double-blinded. The mean study duration was 64 days (range 30 to 122). Compared with placebo in 6 studies, P. africanum provided a moderately large improvement in the combined outcome of urologic symptoms and flow measures as assessed by an effect size defined by the difference of the mean change for each outcome divided by the pooled standard deviation for each outcome (-0.8 SD [95% confidence interval (CI): -1.4 to -0.3]). Summary estimates of individual outcomes were also improved by P. africanum. Men were more than twice as likely to report an improvement in overall symptoms (risk ratio = 2.1, 95% CI: 1.40 to 3.1). Nocturia was reduced by 19% and residual urine volume by 24%; peak urine flow was increased by 23%. Adverse effects due to P. africanum were mild and similar to placebo. The overall dropout rate was 12% and was similar for P. africanum (13%), placebo (11%), and other controls (8%; P = 0.4 versus placebo and P = 0.5 versus other controls). CONCLUSIONS: The literature on P. africanum for the treatment of benign prostatic hyperplasia is limited by the short duration of studies and the variability in study design, the use of phytotherapeutic preparations, and the types of reported outcomes. However, the evidence suggests that P. africanum modestly, but significantly, improves urologic symptoms and flow measures. Further research is needed using standardized preparations of P. africanum to determine its long-term effectiveness and ability to prevent complications associated with benign prostatic hyperplasia.

Distribution of lipids in 8,500 men with coronary artery disease. Department of Veterans Affairs HDL Intervention Trial Study Group.

In the present study we measured fasting lipid profiles in over 8,500 community-living men with coronary artery disease (CAD) to determine the distribution of lipid abnormalities in this population: 81% were white and 16% black; mean age 62.9 +/- 8 years; mean total cholesterol 214 +/- 41 mg/dl; low-density lipoprotein (LDL) cholesterol 140 +/- 37 mg/dl; high-density lipoprotein (HDL) cholesterol 39 +/- 11 mg/dl; and triglycerides 190 +/- 142 mg/dl. After adjusting for age, the only significant difference between blacks and whites was a higher HDL cholesterol in blacks (45 vs 38 mg/dl, p < 0.003). With use of cut points established by the National Cholesterol Education Program, 87% of subjects had high LDL cholesterol (> or = 100 mg/dl), 38% had low HDL cholesterol (< 35 mg/dl), and 33% had high triglycerides (> 200 mg/dl). We estimated that 42% of men with CAD would be definite candidates for cholesterol-lowering medication according to the National Cholesterol Education Program guidelines and that 41% of those in whom cholesterol-lowering medication would not be definitely indicated had low levels of HDL cholesterol. We conclude that (1) black men with CAD have substantially higher HDL cholesterol than white men, (2) almost 90% of male patients with CAD are candidates for dietary intervention and > 40% may need medications to lower LDL cholesterol, and (3) 40% of patients without a definite indication for cholesterol-lowering medications have low levels of HDL cholesterol.

Rationale and design of the Arterial Disease Multiple Intervention Trial (ADMIT) pilot study.

The primary objectives of the pilot study were to: (1) evaluate the feasibility of recruiting patients with peripheral arterial disease (PAD); (2) measure the efficacy and safety of high-density lipoprotein (HDL)-raising treatment, low-density lipoprotein (LDL)-lowering therapy, antioxidant therapy, antithrombotic therapy, and their combinations; and (3) assess adherence to a complex multiple drug regimen. Secondary objectives included measurement of the effect of the interventions on prespecified biochemical markers, maintenance of therapy masking (in particular with niacin), and measurement of the intervention's impact on functional status and on quality of life. To date, no secondary prevention trial has been conducted specifically among patients with PAD. Intermittent claudication affects about 0.5% to 1.0% of persons aged >35 years. There is a striking increase in incidence of PAD with age, particularly among those aged >50 years in both sexes, although men are twice as likely as women to develop PAD. The Arterial Disease Multiple Intervention Trial was a double-blind randomized pilot trial of 468 participants with documented PAD. A 2 x 2 x 2 factorial design was used to evaluate the effect of 3 interventions. The pilot incorporated several major novel design features: first, the use of a simple noninvasive method (measurement of ankle brachial index) to identify a population with either symptomatic or asymptomatic PAD; and second, a lipid modifying strategy to increase HDL with nicotinic acid in the intervention group while lowering LDL levels equally with an hydroxymethylglutaryl-coenzyme A reductase inhibitor as needed in the intervention and control group. Two other arms, the antioxidant arm (consisting of beta-carotene and vitamins E and C) and the antithrombotic arm (using warfarin) were also added. Adherence to therapy was measured by pill count, and success in treatment was measured by the proportion of values in target range for HDL, LDL, and the international normalized ratio.

Planning controlled clinical trials. Prostatic cancer.

OBJECTIVE: To address principles in the design and conduct of clinical trials on prostate cancer (PC) with special reference to localized disease. METHODS: In advance of and during the World Health Organization (WHO) conference on Prostate Cancer in Stockholm in September 1996, 6 members of a working group evaluated and reached consensus on key points for the planning and conduction of controlled clinical trials in PC. The key points discussed were 1) hypothesis formulation, 2) general methodological principles, 3) special problems of PC trials, 4) alternatives to randomization, and 5) trial organization. RESULTS: The hypothesis must be clearly formulated and also clinically relevant enough to justify the expenses (in a broad sense) of a randomized clinical trial. Patient selection, definition of endpoints, and sample size calculations must be carefully considered and correspond to the aims of the study. Stratification on important prognostic factors should be contemplated. Maintaining the accrual rate and ensuring compliance are critical for a quality study. Survival is the main endpoint and intention to treat analysis is the standard methodology. Secondary endpoints (eg, quality of life and costs) are important for the evaluation of many treatment modalities. The use of surrogate endpoints for survival, such as prostate-specific antigen (PSA) elevation, may be misleading. Surrogate endpoints require further validation. Special features, such as long natural history in localized disease and difficulties in assessing objective responses in advanced disease, need consideration in PC trials. The controlled randomized trial is the gold standard methodology. Nonrandomized trials are often hampered by severe methodological problems, such as selection bias and biased ascertainment of endpoints due to the doctor's or patient's preferences. For the organization of a successful trial, a well-constructed study protocol is essential. Good clinical practice as defined within the European Community helps define and solve practical problems. CONCLUSIONS: The past 30 years of poorly designed clinical research on PC has left us without reliable answers in key clinical issues regarding, for example, the efficacy of primary treatment of localized PC. It is a stimulating and important challenge to the urological scientific community to conduct well-organized controlled clinical trials.

Cholesterol awareness after case-finding: do patients really know their cholesterol numbers?

BACKGROUND: Patients who are informed of their cholesterol status have been shown to take steps subsequently to reduce their risks for coronary heart disease. Accordingly, as part of a population-based strategy to reduce disease burden due to high cholesterol, the National Cholesterol Education Program (NCEP) recommends that physicians tell all patients their cholesterol test results in a clear, understandable manner and encourage all patients, regardless of their risk factor status, to reduce their fat intake. OBJECTIVES: Our objective was to assess compliance with these NCEP recommendations at a 432-bed, Midwestern, university-affiliated VA Medical Center. METHODS: We surveyed, within a year of their cholesterol measurement, 250 randomly selected men and women who had had their cholesterol checked by physician order between January 1993 and 1994. Survey results were validated against laboratory data. RESULTS: Approximately one third of the men and women said their cholesterol had not been checked, and about one half said they had not been told their test results. Only 59% knew their cholesterol status, and only 19% accurately recalled their cholesterol number. More than half did not remember receiving dietary advice. Female gender and more years of education were correlated with cholesterol awareness on both bivariable and multivariable analyses (adjusted odds ratio [OR] = 2.00, 95% confidence intervals [CI] = 1.10, 3.67 and OR = 2.62, 95% CI = 1.43, 4.78, respectively). Respondents were more likely to accurately recall their cholesterol number if they remembered being told their test results or remembered receiving dietary advice (OR = 7.70, 95% CI = 2.04, 29.0 and OR = 2.65, 95% CI = 1.15, 6.07, respectively). CONCLUSIONS: We conclude that compliance with the NCEP population-based guidelines is poor. Physicians should endeavor to improve patients' awareness of their cholesterol status and be more diligent in prescribing dietary therapy.

The Prostate Cancer Intervention Versus Observation Trial (PIVOT).

The Prostate Cancer Intervention Versus Observation Trial (PIVOT) is a randomized trial designed to determine whether radical prostatectomy or expectant management provides superior length and quality of life for men with clinically localized prostate cancer. Conducted at Department of Veterans Affairs and National Cancer Institute medical centers, PIVOT will enroll over 1,000 individuals < 75 years of age. The primary study end point is all-cause mortality. Secondary outcomes include prostate cancer- and treatment-specific morbidity and mortality, health status, predictors of disease-specific outcomes, and cost-effectiveness. Within the first 3 years of enrollment, over 400 men have been randomized. Early analysis of participants' baseline characteristics indicate that enrollees are representative of men diagnosed with clinically localized prostate cancer throughout the United States. Therefore, results of PIVOT will be generalizable. These results are necessary in order to determine the preferred therapy for clinically localized prostate cancer.

Effect of written and computerized decision support aids for the U.S. Agency for Health Care Policy and Research depression guidelines on the evaluation of hypothetical clinical scenarios.

OBJECTIVE: The objective of this study was to compare the effects of written and computerized decision support aids (DSAs) based on U.S. Agency for Health Care Policy and Research depression guidelines. METHODS: Fifty-six internal medicine residents were randomized to evaluate clinical scenarios using either a written or a computerized DSA after first assessing scenarios without a DSA. The paired difference between aided and unaided scores was determined for diagnostic accuracy, treatment selection, severity and subtype classification, antipsychotic use, and mental health consultations. RESULTS: Diagnostic accuracy with the written DSA increased from 64% to 73%, and with the computerized DSA decreased from 67% to 64% (P=0.0065). Residents using the computerized DSA (vs. no DSA) requested fewer consultations (65% vs. 52%, P=0.028). In post hoc analysis, the written DSA increased sensitivity (66% to 89%, P<0.001) and the computerized DSA improved specificity (66% to 86%, P=0.0020) but reduced sensitivity (67% to 49%, P = 0.011). CONCLUSIONS: A written DSA improved diagnostic accuracy, whereas a computerized DSA did not. However, the computerized DSA improved specificity and reduced mental health consultations.

Allopurinol for chronic prostatitis.

BACKGROUND: Chronic prostatitis is a condition that causes men substantial morbidity through the associated constellation of urinary symptoms, sexual dysfunction, and pelvic pain. The etiology of chronic prostatitis is unknown, and the many and varied treatments for chronic prostatitis reflect in part this knowledge gap. One novel etiologic theory is that the reflux of urine into prostatic ducts causes prostatic inflammation via high concentrations of purine and pyrimidine base-containing metabolites in prostatic secretions. This theory has led to the use of allopurinol for treatment of chronic prostatitis in hopes of lowering prostatic levels of uric acid and improving symptoms. OBJECTIVES: To determine the effects of allopurinol in the treatment of chronic prostatitis SEARCH STRATEGY: Trials were searched in computerized general and specialized databases (MEDLINE, Cochrane Library, Cochrane Prostate Group database), bibliographies of obtained articles, and direct contact with authors. SELECTION CRITERIA: All randomized trials of allopurinol versus placebo used to treat patients with chronic prostatitis. Acute prostatitis, bacterial prostatitis, and asymptomatic prostatitis were excluded. The main outcome measure was the change in patient-reported discomfort. DATA COLLECTION AND ANALYSIS: The reviewers extracted the data independently for the outcomes of change in patient-reported discomfort, investigator graded prostate pain, leukocyte counts, and biochemical indices. MAIN RESULTS: In this update, no new trials were identified (08/2002). Only one trial with 54 men lasting 240 days (with 330 days of follow-up) met study inclusion criteria. There was a statistically significant change favoring allopurinol in patient-reported discomfort between the study and control groups at follow-up. Between days 45-225, the mean score was -0.95 (s.d. 0.19) for the allopurinol group (7 men), compared with -0.47 (s.d. 0.21) for the placebo group (7 men). The weighted mean difference (WMD) was -0.48 (95%CI -0.690, -0.270). The mean score between days 45-135 was -1.08 (s.d. 1.29) for the 25 men in the allopurinol group, compared with -0.21 (sd 0.97) for the 14 men in the control group. The WMD was -0.87 (95%CI -1.587, -0.153). The allopurinol group had significantly less investigator graded prostate pain and had lower levels of serum urate, urine urate, and expressed prostatic secretion urate and xanthine. No significant differences between the two groups regarding leukocyte counts were found. No patient receiving allopurinol had any significant side effects. Three patients in the placebo group dropped out because of side effects. REVIEWER'S CONCLUSIONS: One small trial of allopurinol for treating chronic prostatitis showed improvements in patient-reported symptom improvement, investigator-graded prostate pain, and biochemical parameters. However, the data provided, the measures used, and the statistics presented do not make these findings convincing that changes in urine and prostatic secretion composition regarding purine and pyrimidine bases resulted in the relief of symptoms. Further studies of allopurinol treatment using standardized and validated outcomes measures and analyses are necessary to determine whether allopurinol is effective.