Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study.

BACKGROUND: The optimal perioperative chemotherapy for patients with muscle-invasive bladder cancer is not defined. The VESPER (French Genito-Urinary Tumor Group and French Association of Urology V05) trial reported improved 3-year progression-free survival with dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) versus gemcitabine and cisplatin (GC) in patients who received neoadjuvant therapy, but not in the overall perioperative setting. In this Article, we report on the secondary endpoints of overall survival and time to death due to bladder cancer at 5-year follow-up. METHODS: VESPER was an open-label, randomised, phase 3 trial done at 28 university hospitals or comprehensive cancer centres in France, in which adults (age ≤18 years and ≤80 years) with primary bladder cancer and histologically confirmed muscle-invasive urothelial carcinoma were randomly allocated (1:1; block size four) to treatment with dd-MVAC (every 2 weeks for a total of six cycles) or GC (every 3 weeks for a total of four cycles). Overall survival and time to death due to bladder cancer (presented as 5-year cumulative incidence of death due to bladder cancer) was analysed by intention to treat (ITT) in all randomly assigned patients. Overall survival was assessed by the Kaplan-Meier method with the treatment groups compared with log-rank test stratified for mode of administration of chemotherapy (neoadjuvant or adjuvant) and lymph node involvement. Time to death due to bladder cancer was analysed with an Aalen model for competing risks and a Fine and Gray regression model stratified for the same two covariates. Results were presented for the total perioperative population and for the neoadjuvant and adjuvant subgroups. The trial is registered with ClinicalTrials.gov, NCT01812369, and is complete. FINDINGS: From Feb 25, 2013, to March 1, 2018, 500 patients were randomly assigned, of whom 493 were included in the final ITT population (245 [50%] in the GC group and 248 [50%] in the dd-MVAC group; 408 [83%] male and 85 [17%] female). 437 (89%) patients received neoadjuvant chemotherapy. Median follow-up was 5·3 years (IQR 5·1-5·4); 190 deaths at the 5-year cutoff were reported. In the perioperative setting (total ITT population), we found no evidence of association of overall survival at 5 years with dd-MVAC treatment versus GC treatment (64% [95% CI 58-70] vs 56% [50-63], stratified hazard ratio [HRstrat] 0·79 [95% CI 0·59-1·05]). Time to death due to bladder cancer was increased in the dd-MVAC group compared with in the GC group (5-year cumulative incidence of death: 27% [95% CI 21-32] vs 40% [34-46], HRstrat 0·61 [95% CI 0·45-0·84]). In the neoadjuvant subgroup, overall survival at 5 years was improved in the dd-MVAC group versus the GC group (66% [95% CI 60-73] vs 57% [50-64], HR 0·71 [95% CI 0·52-0·97]), as was time to death due to bladder cancer (5-year cumulative incidence: 24% [18-30] vs 38% [32-45], HR 0·55 [0·39-0·78]). In the adjuvant subgroup, the results were not conclusive due to the small sample size. Bladder cancer progression was the cause of death for 157 (83%) of the 190 deaths; other causes of death included cardiovascular events (eight [4%] deaths), deaths related to chemotherapy toxicity (four [2%]), and secondary cancers (four [2%]). INTERPRETATION: Our results on overall survival at 5 years were in accordance with the primary endpoint analysis (3-year progression-free survival). We found no evidence of improved overall survival with dd-MVAC over GC in the perioperative setting, but the data support the use of six cycles of dd-MVAC over four cycles of GC in the neoadjuvant setting. These results should impact practice and future trials of immunotherapy in bladder cancer. FUNDING: French National Cancer Institute.

Transforming growth factor ß-receptor II protein expression in benign prostatic hyperplasia is associated with prostate volume and inflammation.

OBJECTIVE: To assess transforming growth factor ß-receptor II (TGFBRII) protein expression in benign prostatic hyperplasia (BPH) using immunohistochemistry analysis, and to compare the analysis with phenotypic properties. METHODS: TGFBRII protein expression was profiled using three clinical outcome tissue microarrays (TMAs), sampled from 231 patients who underwent surgery for BPH. Using these TMAs, five inflammatory cell markers were also assessed, including CD3, CD4, CD8, CD20, and CD163. The surgical procedure was open prostatectomy in 95 patients and transurethral resection of the prostate in 136 patients. RESULTS: TGFBRII protein expression was found in BPH epithelium cells for both basal and secretory cells, as well as in fibromuscular stromal cells. TGFBRII staining was also strong in most of the lymphocytes infiltrating the prostate. TGFBRII stromal staining was found to be significantly associated with prostate volume (P = 0.04), whereas TGFBRII epithelial staining was found to be significantly associated with 5-α-reductase-inhibitor medical therapy received by patients before surgery (P = 0.004). Both stromal and epithelial TGFBRII staining were found to be associated with CD4 T-lymphocyte infiltrate, independently of prostate volume (P < 0.001 and P = 0.002). CONCLUSIONS: TGFBRII protein expression in BPH is associated with prostate gland volume and with CD4 T-lymphocyte prostatitis. TGFBRII might be a promising therapeutic target to prevent prostate enlargement or even to decrease prostate volume.

Extensive biopsies and transurethral prostate resection in men with previous negative biopsies and high or increasing prostate specific antigen.

PURPOSE: We determined the diagnostic role of an extensive biopsy protocol associated with transurethral prostate resection in patients with persistently increased or increasing prostate specific antigen without evidence of prostate cancer after 2 or more extended negative sets of biopsies. MATERIALS AND METHODS: A new set of 21-core biopsies was done in 113 patients under general anesthesia in association with transurethral prostate resection. Demographics, clinical and biological data, operative parameters, pathological results and followup were recorded prospectively. RESULTS: Extended biopsies provided an 18.6% detection rate and detected 77.8% of prostate cancers. Transurethral prostate resection significantly increased the detection rate by 28.5% for an overall 23.9% prostate cancer detection rate (p = 0.035). Most prostate cancer detected on chips and/or biopsy was clinically significant and 30% were scored as Gleason 7 or greater. Of prostatectomy specimens 19% showed pT3a-pT4 cancer with a median Gleason score of 7. In patients with no cancer mean prostate specific antigen 1 year after transurethral prostate resection was 4.5 ng/ml (range 0.3 to 16.3), which remained stable during followup. A third of these patients underwent repeat biopsy with a 16.7% prostate cancer detection rate. CONCLUSIONS: About a fourth of patients with at least 2 extended negative sets of prostate biopsies remain at risk for prostate cancer and most tumors missed on initial procedures are clinically significant. Repeat biopsy using general anesthesia detects three-fourths of these prostate cancers. However, the diagnostic yield of transurethral prostate resection appears significant and may provide additional data of clinical importance in select, informed patients.

Laparoscopic radical prostatectomy after transurethral resection of the prostate: surgical and functional outcomes.

OBJECTIVES: To compare the morbidity and functional results after laparoscopic radical prostatectomy with and without previous transurethral resection of the prostate (TURP). METHODS: From May 1998 to January 2005, 640 patients underwent laparoscopic radical prostatectomy, of whom 46 (7.2%) had previously undergone TURP. The perioperative and postoperative data were compared between group 1 (with previous TURP) and group 2 (without previous TURP). The functional results were assessed by self-administered questionnaires at 12 and 24 months after surgery. RESULTS: In group 1, the operative time, hospital stay, and bladder catheterization duration was increased by 31 minutes, 1.9 days, and 2.9 days, respectively. The positive margin rate was not significantly different statistically between the two groups (P = .62). The 5-year actuarial freedom from biochemical recurrence rate was similar between the two groups (P = .86). Surgical complications occurred in 15.2% of group 1 and 5.7% of group 2 (P = .02). The risk of anastomotic stricture was 6.5% and 1.2% in groups 1 and 2, respectively (P = .02). Two years after surgery, the continence rate was 86.9% in group 1 and 95.8% in group 2 (P = .77), and the potency rate was 63.8% and 70.9%, respectively, after bilateral neurovascular bundle preservation (P = .61). However, neurovascular bundle preservation was performed after previous TURP in only 56.5% of group 1 vs 78.9% in group 2 (P = .02). The median follow-up was 50.8 months (range 30-107). CONCLUSIONS: Laparoscopic radical prostatectomy can be performed after TURP without compromising the oncologic results. However, patients should be informed that the procedure is associated with worse intraoperative and postoperative outcomes. Although the urinary continence rate was not hampered by previous TURP, neurovascular bundle preservation is technically more difficult and compromises postoperative erectile function.