Veterans Affairs Cooperative Studies Program Study #553: Chemotherapy After Prostatectomy for High-risk Prostate Carcinoma: A Phase III Randomized Study.

BACKGROUND: The Veterans Affairs Cooperative Studies Program study #553 was designed to evaluate the efficacy of adjuvant chemotherapy added to the standard of care (SOC) for patients who are at high risk for relapse after prostatectomy. OBJECTIVE: To test whether addition of chemotherapy to surgery for high-risk prostate cancer improves progression-free survival (PFS). DESIGN, SETTING, AND PARTICIPANTS: Eligible patients after prostatectomy were randomized to the SOC group with observation or to the chemotherapy group with docetaxel and prednisone administered every 3 wk for six cycles. Randomization was stratified for prostate-specific antigen, Gleason, tumor stage, and surgical margin status. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was PFS. Secondary endpoints included overall, prostate cancer-specific, and metastasis-free survival, and time to androgen deprivation therapy. RESULTS AND LIMITATIONS: A total of 298 of the planned 636 patients were randomized. The median follow-up was 59.1 mo (0.2-103.7 mo). For the primary endpoint, the two groups did not statistically differ in PFS (median 55.5 mo in the chemotherapy group and 42.2 mo in the SOC group; test adjusted for site via gamma frailty p=0.21; adjusted hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.58-1.11; p=0.18). Prespecified subgroup analyses showed benefit in PFS for patients with tumor stage ≥T3b (HR 0.54, 95% CI 0.32-0.92; p=0.022) and patients with Gleason score ≤7 (HR 0.65, 95% CI 0.43-0.99; p=0.046). Secondary endpoint analyses are hampered by low event rates. The most common adverse events (≥grade 3 related or possibly related to chemotherapy) included neutropenia (43%), hyperglycemia (20%), and fatigue (5%), with febrile neutropenia in 2%. CONCLUSIONS: Adjuvant chemotherapy in high-risk prostate cancer using docetaxel and prednisone did not lead to statistically significant improvement in PFS for the intention-to-treat population as a whole. The analysis was challenged by lower power due to accrual limitation. Subgroup analyses suggest potential benefit for patients with Gleason grade ≤7 and stage≥pT3b (ClinicalTrials.gov number NCT00132301). PATIENT SUMMARY: In this randomized trial, we tested whether addition of chemotherapy to surgery for high-risk prostate cancer decreased the risk of prostate-specific antigen rise after surgery. We found no benefit from docetaxel given after radical prostatectomy, although some subgroups of patients may benefit.

Prostate Cancer Screening and Mortality in Blacks and Whites: A Hospital-based Case-Control Study.

BACKGROUND: Prostate cancer incidence and mortality are substantially higher in Black than in white men. Prostate cancer screening remains controversial. This study was conducted to assess the impact of, and racial differences in, prostate cancer screening on prostate cancer mortality. METHODS: This was a case-control study of Black and White men in eight hospitals. Cases were deaths related to prostate cancer; controls were hospital-based subjects that were frequency-matched to cases based on age and race. Multivariable logistic regression was used to test the association between screening and prostate cancer mortality. RESULTS: Cases had fewer PSA (prostate-specific antigen) tests than controls (1.73 vs. 3.98, p<0.001). White controls had higher rates of PSA tests than other sub-groups. There was no difference in PSA testing between Black cases and controls. Mean co-morbidity was 10.3 in cases and 2.63 in controls. Prostate cancer mortality was 55 to 57% lower among the screened persons. Individuals who died of prostate cancer related causes were less likely to have received PSA testing (OR=0.65; 95% Cl 0.56-0.75). CONCLUSIONS: The odds of dying from prostate cancer were lower among white men receiving screening tests. Having less co-morbidity was associated with lower odds of mortality in both races. This study raises the possibility that screening for prostate cancer with the PSA test may be more effective in white than in Black men.

Musculoskeletal and prostate effects of combined testosterone and finasteride administration in older hypogonadal men: a randomized, controlled trial.

Testosterone acts directly at androgen receptors and also exerts potent actions following 5α-reduction to dihydrotestosterone (DHT). Finasteride (type II 5α-reductase inhibitor) lowers DHT and is used to treat benign prostatic hyperplasia. However, it is unknown whether elevated DHT mediates either beneficial musculoskeletal effects or prostate enlargement resulting from higher-than-replacement doses of testosterone. Our purpose was to determine whether administration of testosterone plus finasteride to older hypogonadal men could produce musculoskeletal benefits without prostate enlargement. Sixty men aged ≥60 yr with a serum testosterone concentration of ≤300 ng/dl or bioavailable testosterone ≤70 ng/dl received 52 wk of treatment with testosterone enanthate (TE; 125 mg/wk) vs. vehicle, paired with finasteride (5 mg/day) vs. placebo using a 2 × 2 factorial design. Over the course of 12 mo, TE increased upper and lower body muscle strength by 8-14% (P = 0.015 to <0.001), fat-free mass 4.04 kg (P = 0.032), lumbar spine bone mineral density (BMD) 4.19% (P < 0.001), and total hip BMD 1.96% (P = 0.024) while reducing total body fat -3.87 kg (P < 0.001) and trunk fat -1.88 kg (P = 0.0051). In the first 3 mo, testosterone increased hematocrit 4.13% (P < 0.001). Coadministration of finasteride did not alter any of these effects. Over 12 mo, testosterone also increased prostate volume 11.4 cm(3) (P = 0.0051), an effect that was completely prevented by finasteride (P = 0.0027). We conclude that a higher-than-replacement TE combined with finasteride significantly increases muscle strength and BMD and reduces body fat without causing prostate enlargement. These results demonstrate that elevated DHT mediates testosterone-induced prostate enlargement but is not required for benefits in musculoskeletal or adipose tissue.

A phase III, multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer.

PURPOSE: We compared hexaminolevulinate fluorescence cystoscopy with white light cystoscopy for detecting Ta and T1 papillary lesions in patients with bladder cancer. MATERIALS AND METHODS: A total of 311 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM HAL for 1 hour. The bladder was inspected using white light cystoscopy, followed by blue light (fluorescence) cystoscopy. Papillary lesions were mapped and resected for histological examination. RESULTS: Noninvasive pTa tumors were found in 108 of 196 evaluable patients (55.1%). In 31 patients (29%) at least 1 more tumor was detected by HAL than by white light cystoscopy (p<0.05). Six of these patients had no lesions detected by white light, 12 had 1 lesion detected by white light and more than 1 by HAL, and 13 had multiple Ta lesions detected by the 2 methods. Conversely at least 1 more tumor was detected by white light cystoscopy than by HAL cystoscopy in 10 patients (9%, 95% CI 5-16). Tumors invading the lamina propria (T1) were found in 20 patients (10.2%). At least 1 additional T1 tumor was detected by HAL but not by white light cystoscopy in 3 of these patients (15%), while at least 1 more T1 tumor was detected by white light cystoscopy than by HAL cystoscopy in 1 patient (5%, 95% CI 0-25). Detection rates for Ta tumors were 95% for HAL cystoscopy and 83% for white light cystoscopy (p=0.0001). Detection rates were 95% and 86%, respectively, for T1 tumors (p=0.3). HAL instillation was well tolerated with few local or systemic side effects. CONCLUSIONS: HAL fluorescence cystoscopy detected at least 1 more Ta and T1 papillary tumor than white light cystoscopy in approximately a third of the patients with such tumors. Whether this would translate to improved patient outcomes has yet to be determined.

Impact of prostate-specific antigen level and prostate volume as predictors of efficacy in photoselective vaporization prostatectomy: analysis and results of an ongoing prospective multicentre study at 3 years.

UNLABELLED: In a multicentre study from the USA, 3-year results of the high-power KTP laser prostatectomy are presented. The authors used preoperative PSA level as a marker of prostate volume and assessed its potential predictive value on the level of clinical efficacy for treating symptomatic BPH. They found that the overall results from the technique were positive and durable, and suggested that there was a significant difference in efficacy between patients presenting with a total PSA of <6 or >6 ng/mL. Many patients who have had a radical prostatectomy are followed for a prolonged period and several observations are presented from an Italian study of urinary incontinence. The authors present their detailed results, finding a considerable trend in incontinence and anastomotic stricture, which decreased over time. OBJECTIVE: To report the 3-year results and analyse whether total prostate-specific antigen (tPSA) levels and prostate volume before treatment can predict the level of clinical efficacy of photoselective vaporization prostatectomy (PVP) for treating obstructive benign prostatic disease, as high-power potassium-titanyl-phosphate (KTP) laser prostatectomy was previously shown to be safe and to efficiently vaporize prostatic adenoma secondary to benign prostatic hyperplasia (BPH), with minimal bleeding and morbidity. PATIENTS AND METHODS: From October 2001 to January 2003, 139 men (mean age 67.7 years, sd 8.7) diagnosed with obstructive lower urinary tract symptoms secondary to BPH, had PVP with an average 80 W of KTP laser energy, at six investigational centres. A subanalysis evaluating each patient for tPSA and prostate volume before PVP was conducted, with a long-term assessment of the primary efficacy outcomes at 3 years after PVP. Each patient was assigned to one of two subgroups according to the tPSA level (group 1, < or = 6.0 ng/mL; group 2 > or = 6.1 ng/mL) and evaluated separately. Each subgroup was assessed for changes from baseline in American Urological Symptom Index (AUA SI) score, quality of life (QoL) score, peak urinary flow rate (Q(max)), prostate volume, and postvoid residual urine volume (PVR) at 1, 2 and 3 years after PVP. RESULTS: All tPSA subgroups had a sustained improvement in all efficacy outcomes maintained through the 3 years. There was a statistically significant difference in the level of improvement between groups 1 and 2 (P < 0.05) in AUA SI and Q(max) at 1, 2 and 3 years. The mean (sd) prostate volume for group 1 was 48.3 (16.7) mL (87 men), and was 83.1 (30.6) mL (52 men) in group 2. The mean percentage improvement in the AUA SI at 1, 2 and 3 years in group 1 and 2, respectively, was 86%, 92% and 85%, and 69%, 74% and 76%; the corresponding percentage improvement in Q(max) was 194%, 185% and 179%, and 124%, 145% and 139%, respectively. Overall treatment efficacy in all patients evaluated showed a mean 83%, 79%, 71% and 165% improvement in AUA SI, QoL, PVR and Q(max), respectively. Adverse events were minimal and the re-treatment rate was 4.3%. CONCLUSIONS: These results suggest that there is a significant difference in efficacy in patients with a tPSA of < or = 6.0 ng/mL or > or = 6.1 ng/mL before PVP. However, the overall results achieved with PVP were very positive and durable to 3 years, irrespective of tPSA level and prostate volume.

The lipophilic extract of Hypericum perforatum exerts significant cytotoxic activity against T24 and NBT-II urinary bladder tumor cells.

Hypericum perforatum L. (St. John's wort) is a medicinal plant used for many pathologies, especially for the treatment of mild to moderate depression. In the present study we have investigated the cytotoxic activity of the locally collected (Epirus region) Hypericum perforatum L. against cultured T24 and NBT-II bladder cancer cell lines. The lipophilic extract of the herb, prepared using petroleum ether, induced apoptosis displaying LC(50) values at concentrations as low as 4 and 5 microg/mL. A fraction of this extract displayed 60 % cell growth inhibition at a concentration of 0.95 microg/mL. Evaluating the importance of various biologically active components of the extract, it was found that hypericins (hypericin, pseudohypericin, etc.) were identified only in the methanolic (lipophobic) extract of the herb, and not in the active lipophilic extract. In addition, hyperforin concentrations in the lipophilic extract and its most active fraction, were 0.94 microg/mL, and 0.17 microg/mL, respectively, while the active cytotoxic concentration of pure hyperforin appeared in the range of 1.8 microg/mL - 5.0 microg/mL. Therefore, pure hyperforin does not seem to contribute significantly to the cytotoxicity activity. Chlorophylls were identified in low, not significantly different, concentrations in all extracts and fractions and were not correlated to the biological activity. Owing to the combination of significant cytotoxic activity, natural abundance and low toxicity, the lipophilic extract of Hypericum perforatum holds the promise of being an interesting, new, antiproliferative agent against bladder cancer that deserves further investigation.

Photoselective vaporization of the prostate for the treatment of benign prostatic hyperplasia: 12-month results from the first United States multicenter prospective trial.

PURPOSE: We report the 1-year efficacy and safety of photoselective vaporization of the prostate (PVP) for symptomatic and obstructive benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A prospective clinical trial was performed in 139 men clinically diagnosed with symptomatic bladder outlet obstruction secondary to BPH who were enrolled and treated with a high power, 80 W, quasicontinuous wave potassium-titanyl-phosphate laser at 6 American medical centers across the country. Efficacy parameters were mean and percent changes from baseline in the American Urological Association Symptom Index (AUA-SI) score, quality of life score (QOL), peak urinary flow rate (Qmax), post-void residual urine volume (PVR) and transrectal ultrasound prostate volume measurement. Patients were evaluated 1, 3, 6 and 12 months following treatment. At each followup evaluation side effects were elicited. RESULTS: Significant improvements in AUA-SI score, QOL score, Qmax and PVR were noted as early as 1 month after PVP treatment. At 12 months the mean AUA-SI score decreased from 23.9 to 4.3 (p <0.0001) and the QOL score decreased from 4.3 to 1.1 (p <0.0001), while mean Qmax increased from 7.8 to 22.6 ml per second (p <0.0001). PVR decreased from 114.3 to 24.8 ml (p <0.0001), while the transrectal ultrasound volume reduction went from 54.6 ml at baseline to 34.4 ml. There was no significant blood loss or fluid absorption during or immediately after PVP. Complications consisted of transient hematuria, dysuria and urinary retention in 12 (8.6%), 13 (9.3%) and 7 (5%) patients, respectively. CONCLUSIONS: PVP is a unique, safe and effective outpatient modality that provides immediate symptomatic and urodynamic relief of bladder outlet obstruction secondary to BPH. Long-term followup is needed to validate further the maintenance of clinical efficacy beyond 1 year.

Mutagenic outcome of the urinary carcinogen 4-aminobiphenyl is increased in acidic pH.

One of the carcinogens from cigarette smoke, 4-aminobiphenyl, is excreted in urine as 4-N-hydroxyl aminobiphenyl metabolite conjugates that undergo pH mediated activation to nitreneum ions leading to bladder tumorigenesis via DNA adduct formation. We hypothesize that changing the pH of smokers' urine might impact the mutagenic outcome. 4-NOHABP was synthesized (∼98% purity), structure confirmed by TLC and NMR; mutagenic activity, assessed by the Ames test, was measured after pre-incubation in buffer solutions or human urine at pH 4, 6, 7 and 8. An inverse correlation was observed between number of histidine revertant colonies and pH (r(2)=0.89), 4-NOHABP exhibiting significant mutagenicity at pH 4.0 (P<0.05).