Michel Soulie

Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial

BACKGROUND Early chemotherapy might improve the overall outcomes of patients with metastatic non-castrate (ie, hormone-sensitive) prostate cancer. We investigated the effects of the addition of docetaxel to androgen-deprivation therapy (ADT) for patients with metastatic non-castrate prostate cancer. METHODS In this randomised, open-label, phase 3 study, we enrolled patients in 29 centres in France and one in Belgium. Eligible patients were older than 18 years and had histologically confirmed adenocarcinoma of the prostate and radiologically proven metastatic disease; a Karnofsky score of at least 70%; a life expectancy of at least 3 months; and adequate hepatic, haematological, and renal function. They were randomly assigned to receive to ADT (orchiectomy or luteinising hormone-releasing hormone agonists, alone or combined with non-steroidal antiandrogens) alone or in combination with docetaxel (75 mg/m(2) intravenously on the first day of each 21-day cycle; up to nine cycles). Patients were randomised in a 1:1 ratio, with dynamic minimisation to minimise imbalances in previous systemic treatment with ADT, chemotherapy for local disease or isolated rising concentration of serum prostate-specific antigen, and Glass risk groups. Patients, physicians, and data analysts were not masked to treatment allocation. The primary endpoint was overall survival. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00104715. FINDINGS Between Oct 18, 2004, and Dec 31, 2008, 192 patients were randomly allocated to receive ADT plus docetaxel and 193 to receive ADT alone. Median follow-up was 50 months (IQR 39-63). Median overall survival was 58·9 months (95% CI 50·8-69·1) in the group given ADT plus docetaxel and 54·2 months (42·2-not reached) in that given ADT alone (hazard ratio 1·01, 95% CI 0·75-1·36). 72 serious adverse events were reported in the group given ADT plus docetaxel, of which the most frequent were neutropenia (40 [21%]), febrile neutropenia (six [3%]), abnormal liver function tests (three [2%]), and neutropenia with infection (two [1%]). Four treatment-related deaths occurred in the ADT plus docetaxel group (two of which were neutropenia-related), after which the data monitoring committee recommended treatment with granulocyte colony-stimulating factor. After this recommendation, no further treatment-related deaths occurred. No serious adverse events were reported in the ADT alone group. INTERPRETATION Docetaxel should not be used as part of first-line treatment for patients with non-castrate metastatic prostate cancer. FUNDING French Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, AstraZeneca, and Amgen.

Positive Surgical Margin Appears to Have Negligible Impact on Survival of Renal Cell Carcinomas Treated by Nephron-Sparing Surgery

BACKGROUND The occurrence of positive surgical margins (PSMs) after partial nephrectomy (PN) is rare, and little is known about their natural history. OBJECTIVE To identify predictive factors of cancer recurrence and related death in patients having a PSM following PN. DESIGN, SETTING, AND PARTICIPANTS Some 111 patients with a PSM were identified from a multicentre retrospective survey and were compared with 664 negative surgical margin (NSM) patients. A second cohort of NSM patients was created by matching NSM to PSM for indication, tumour size, and tumour grade. MEASUREMENTS PSM and NSM patients were compared using student t tests and chi-square tests on independent samples. A Cox proportional hazards regression model was used to test the independent effects of clinical and pathologic variables on survival. RESULTS AND LIMITATIONS Mean age at diagnosis was 61+/-12.5 yr. Mean tumour size was 3.5+/-2 cm. Imperative indications accounted for 39% (43 of 111) of the cases. Some 18 patients (16%) underwent a second surgery (partial or total nephrectomy). With a mean follow-up of 37 mo, 11 patients (10%) had recurrences and 12 patients (11%) died, including 6 patients (5.4%) who died of cancer progression. Some 91% (10 of 11) of the patients who had recurrences and 83% of the patients (10 of 12) who died belonged to the group with imperative surgical indications. Rates of recurrence-free survival, of cancer-specific survival, and of overall survival were the same among NSM patients and PSM patients. The multivariable Cox model showed that the two variables that could predict recurrence were the indication (p=0.017) and tumour location (p=0.02). No other variable, including PSM status, had any effect on recurrence. None of the studied parameters had any effect on the rate of cancer-specific survival. CONCLUSIONS PSM status occurs more frequently in cases in which surgery is imperative and is associated with an increased risk of recurrence, but PSM status does not appear to influence cancer-specific survival. Additional follow-up is needed.

EXTRAPERITONEAL LAPAROSCOPIC PYELOPLASTY: A MULTICENTER STUDY OF 55 PROCEDURES

PURPOSE We assessed the feasibility, reproducibility and morbidity of retroperitoneal laparoscopic pyeloplasty for ureteropelvic junction obstruction. MATERIALS AND METHODS A total of 55 retroperitoneal laparoscopic pyeloplasties were performed at 3 institutions between September 1996 and May 2000 in 33 women and 21 men. Results were analyzed in regard to radiological assessment by excretory urography at 3 months, complications and hospital stay. RESULTS We performed dismembered pyeloplasty in 48 cases and Fenger plasty in 7 cases. Crossing vessels were noted in 23 patients. The conversion rate was 5.4%. Mean operative time was 185 minutes (range 100 to 260), mean hospital stay was 4.5 days (range 1 to 14) and mean followup was 14.4 months (range 6 to 43.6). The overall complication rate was 12.7%. Complications in 7 patients included hematoma in 3, urinoma in 1, severe pyelonephritis in 1 and anastomotic stricture in 2 requiring open pyeloplasty at 3 weeks and delayed balloon incision at 13 months, respectively. Excretory urography in 50 patients and ultrasound in 4 showed decreased hydronephrosis in 88.9% at 3 months. Normal physical activity and absent pain were reported by 47 patients (87%) 1 month after surgery. CONCLUSIONS Retroperitoneal laparoscopic pyeloplasty seems to be a valuable alternative to open pyeloplasty for ureteropelvic junction obstruction. The long-term outcome must be assessed before this procedure may be definitively validated.

Androgen Deprivation Therapy (ADT) Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial

BACKGROUND The role of chemotherapy in metastatic non castrate prostate cancer (mNCPC) is debated. Survival benefits of docetaxel (D) added to androgen-deprivation therapy (ADT) were shown in the CHAARTED trial in patients with metastatic high-volume disease (HVD). OBJECTIVE To assess the impact of metastatic burden and to update overall survival (OS) data of the GETUG-AFU15 study. DESIGN, SETTING, AND PARTICIPANTS Randomized phase 3 trial of ADT plus D versus ADT alone in 385 mNCPC patients; median follow-up of 7 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary end point was OS. Secondary end points were biochemical progression-free survival (bPFS) and radiographic progression-free survival (rPFS). Retrospective analysis was by tumor volume. RESULTS AND LIMITATIONS After a median follow-up of 83.9 mo, median OS in the overall population was 62.1 mo (95% confidence interval [CI], 49.5-73.7) and 48.6 mo (95% CI, 40.9-60.6) for ADT plus D and ADT arms, respectively (hazard ratio [HR]: 0.88 [95% CI, 0.68-1.14]; p=0.3). Median OS in ADT plus D and ADT arms, respectively, was for HVD patients: 39.8 mo (95% CI, 28.0-53.4) versus 35.1 mo (95% CI, 29.9-43.6) (HR: 0.78 [95% CI, 0.56-1.09]; p=0.14), for low-volume disease (LVD) patients; median was not reached (NR; 95% CI, 69.5-NR) and 83.4 mo (95% CI, 61.8-NR) (HR: 1.02 [95% CI, 0.67-1.55]; p=0.9). For upfront metastatic patients, OS was 52.6 mo (95% CI, 43.3-66.8) and 41.5 mo (95% CI, 36.3-54.5), respectively (HR: 0.93 [95% CI, 0.69-1.25]; p=0.6). The bPFS (HR: 0.73 [95% CI, 0.56-0.94]; p=0.014) and rPFS (HR: 0.75 [95% CI, 0.58-0.97]; p=0.030) were significantly longer in the ADT plus D arm. Limitations included the retrospective analysis of metastatic extent and the lack of statistical power to detect a significant difference in subgroups. CONCLUSIONS The post hoc analyses of the GETUG-AFU15 study demonstrated a nonsignificant 20% reduction in the risk of death in the HVD subgroup. Patients with LVD had no survival improvement with early D. PATIENT SUMMARY In this study, docetaxel added to castration did not improve survival in patients with metastatic hormone-sensitive prostate cancer, partly due to methodological issues. However, early chemotherapy should be discussed with all patients, given the data of three randomized trials including GETUG-AFU15.

A MULTICENTER STUDY OF THE MORBIDITY OF RADICAL CYSTECTOMY IN SELECT ELDERLY PATIENTS WITH BLADDER CANCER

PURPOSE We evaluated the morbidity of radical cystectomy for invasive bladder cancer in select patients older than 75 years using recent data from 2 academic hospitals. MATERIALS AND METHODS We analyzed 73 radical cystectomies performed from January 1995 to June 2000 in patients 75 to 89 years old (median age 79.3). Cases were categorized according to the American Society of Anesthesiologists classification with a score of 2 in 41, 3 in 30 and 4 in 2. External urinary diversion was performed in 51 cases and an ileal neobladder was constructed in 22. We evaluated the incidence and type of complications, clinical outcome, and postoperative care unit and hospital stay. Statistical analysis was done using the chi-square and Student t tests. RESULTS Median operative time was 263 minutes (range 95 to 451). The perioperative mortality rate was 2.7%. The intraoperative, early and late postoperative complication rates were 38.4%, 46.5% and 16.4%, respectively. Three reoperations (4.1%) were necessary. The most common early complications were pyelonephritis in 12.3% of cases, disorientation in 10.9%, pneumonia in 8.2% and prolonged ileus in 12.3%. The most common late complications were ureteroileal anastomotic stenosis in 5 cases and hernia in 3. Median postoperative care unit and hospital stays were 12 and 34 days, respectively. At a median followup of 14.4 months (range 6 to 74) the overall mortality rate was 31.5%. Hospital stay was significantly higher in patients with complications. The incidence of complications was similar in the 2 groups. CONCLUSIONS These data support the aggressive surgical management of bladder cancer in select elderly patients. A rigorous multidisciplinary team approach can provide acceptable perioperative morbidity.

High-intensity focused ultrasound in prostate cancer; a systematic literature review of the French Association of Urology.

We discuss the efficacy and safety of high‐intensity focused ultrasound (HIFU) in patients with prostate cancer, to define the best indications for HIFU in daily clinical practice as primary therapy. We searched Medline and Embase for clinical studies evaluating the efficacy and safety of HIFU in prostate cancer (July 2007), and abstracts presented at the 2005–2007 annual meetings of the European Association of Urology and American Urological Association were screened. In all, 37 articles/abstracts were selected. As the data on HIFU as salvage therapy were limited, we focused on HIFU as primary therapy. Studies consisted of case series only. Included patients were ≈70 years old with T1‐T2 N0M0 disease, Gleason Score ≤7, a prostate‐specific antigen (PSA) level of ≤28 ng/mL and a prostate volume of ≤40 mL. Negative biopsy rates with the AblathermTM device (EDAP TMS S.A., Vaulx‐en‐Velin, France) were 64–93%, and a PSA nadir of ≤0.5 ng/mL was achieved in 55–84% of patients. The 5‐year actuarial disease‐free survival rates were 60–70%. The most common complications were stress urinary incontinence, urinary tract infection, urethral/bladder neck stenosis or strictures, and erectile dysfunction. For the Ablatherm device, the rate of complications has been significantly reduced over the years, due to technical improvements in the device and the use of transurethral resection of the prostate before HIFU. In conclusion, HIFU as primary therapy for prostate cancer is indicated in older patients (≥70 years) with T1‐T2 N0M0 disease, a Gleason score of <7, a PSA level of <15 ng/mL and a prostate volume of <40 mL. In these patients HIFU achieves short‐term cancer control, as shown by a high percentage of negative biopsies and significantly reduced PSA levels. The median‐term survival data also seem promising, but long‐term follow‐up studies are needed to further evaluate cancer‐specific and overall survival rates before the indications for primary therapy can be expanded.

Multi-institutional study of complications in 1085 laparoscopic urologic procedures

OBJECTIVES To assess the incidence of the complications in laparoscopic urologic procedures with regard to clinical presentation, etiology, and treatment. METHODS From January 1994 to December 2000, 1085 laparoscopic procedures were performed at three institutions in 1075 patients (702 men, 373 women). A referent surgeon for laparoscopy was at each institution. The major procedures were radical prostatectomy (n = 232), different types of nephrectomy (n = 171) and nephroureterectomy (n = 15), adrenalectomy (n = 130), pyeloplasty (n = 61), pelvic lymph node dissection (n = 130), genitourinary prolapse repair (n = 86), bladder neck suspension (n = 104), and treatment of benign kidney pathologic findings (lithiasis, cysts, and diverticula, n = 55). The complications were listed by incidence and etiology according to the procedure attempted. RESULTS A total of 75 complications (6.9%) occurred in this multi-institutional series. The mortality rate was 0.09%, and the conversion rate was 2.1%. Vascular (n = 7) and visceral injuries (n = 11) occurred in 24% of complications. Hematomas (n = 10), urinomas (n = 8), and wound infections (n = 7) at the trocar sites were the most frequent postoperative surgical complications. Pulmonary disorders (n = 9) and urinary infections (n = 9) were predominant in the postoperative medical problems. CONCLUSIONS Even though it appears to be minimally invasive, laparoscopy remains major surgery, with serious complications possible. These complications should be preventable with better mastery of the different steps of the procedures. Increased knowledge of the possible complications is essential for urologists in laparoscopic training and may help them improve their learning curve.

Cancer de la prostate

Mutations “ciblables” dans les cancers de la prostate métastatiques Fruit de la collaboration entre de grandes institutions américaines et européennes, un groupe de chercheurs international (1) a analysé, par séquençage systémique de l’exome entier et du transcriptome, les échantillons de 150 patients atteints d’un cancer de la prostate résistant à la castration métastatique (CPRCm). Près de 90 % des hommes testés présentaient au moins 1 mutation permettant de prédire une réponse ou une résistance à des thérapies connues. Des mutations au niveau du récepteur des androgènes (RA) ont été notées chez près du tiers des patients (63 %). Les autres anomalies génomiques retrouvées le plus fréquemment concernaient les gènes de fusion ETS, TP53 et PTEN (40 à 60 % des cas) avec, par rapport aux cancers de la prostate primaires, un enrichissement des altérations du RA et de TP53. De nouvelles altérations ont été identifiées : PI3K3CA/B, R-spondin , BRAF/RAF1, APC, β-caténine, ZBTB16/PLZF. Mais la découverte sans doute la plus importante est le fait, encore une fois par rapport aux tumeurs primaires, que de nombreux patients (23 %) présentaient des mutations des gènes de la réparation de l’ADN, comme BRCA2, BRCA1 et ATM, ouvrant des perspectives thérapeutiques particulières. Ces patients pourraient répondre à des inhibiteurs de PARP, comme l’olaparib (2) .

UROLOGICAL COMPLICATIONS OF LAPAROSCOPIC SURGERY: EXPERIENCE WITH 350 PROCEDURES AT A SINGLE CENTER

PURPOSE We assessed our experience with urological complications of laparoscopic surgery in regard to incidence, etiology, treatment and possible prevention. MATERIALS AND METHODS A total of 350 laparoscopic procedures were performed at our institution between June 1993 and December 1999 in 206 men and 139 women. These procedures included pelvic lymph node dissection in 102, bladder neck suspension in 99, adrenalectomy in 54, varicocelectomy in 23, pyeloplasty in 22, nephrectomy in 20, treatment of benign renal pathologies, including cyst, diverticula and calculi, in 13, genitourinary prolapse repair in 11 and miscellaneous procedures in 6 patients. Complications were evaluated according to the procedure attempted and were listed by incidence and etiology. RESULTS A total of 19 (5.4%) complications occurred in our series. The associated mortality rate was 0.3% and conversion rate was 1.1%. Most intraoperative complications (2.6%) were vascular (4) and visceral injuries (5), while postoperative complications (2.8%) were predominantly thromboembolism (3) and wound infection (2) at trocar sites. The complication rate decreased from 9% for the first 100 to 4% for the subsequent 250 procedures. CONCLUSIONS Critical documentation of complications of laparoscopic surgery is important for further development of the technique and information for urologists in training. Most of our serious complications should be preventable with better mastery of the different procedural steps. However, laparoscopy must be regarded as major surgery with a significant learning curve.

Retroperitoneal laparoscopic versus open pyeloplasty with a minimal incision: comparison of two surgical approaches

OBJECTIVES To compare the complications, hospital stay, and functional results of retroperitoneal laparoscopic (RL) pyeloplasty versus open pyeloplasty (OP) with a minimal subcostal incision. METHODS From October 1997 to January 2000, 53 consecutive nonrandomized patients underwent 26 RL pyeloplasties, of which 1 was bilateral (group 1), and 28 OP (group 2). The decision between the two techniques depended on the patients anesthetic ability to tolerate RL, previous ureteropelvic junction surgery, associated renal pathologic findings, and the surgeons laparoscopic experience. Subjective outcomes as to postoperative pain and convalescence and objective findings on intravenous urography were assessed at 3 months postoperatively in both groups. RESULTS The mean operating time (165 versus 145 minutes) and mean blood loss (92 versus 84 mL) were similar in both groups. No intraoperative complications occurred in either group; in group 1, 1 patient required open conversion. Postoperative complications occurred in 11.5% of group 1 and 14.3% of group 2. The mean hospital stay was 4.5 days for group 1 and 5.5 days for group 2. At 3 months, 23 patients (92%) in group 1 and 25 (89.2%) in group 2 were pain-free or improved. Intravenous urography showed a patent ureteropelvic junction in all cases and improvement of hydronephrosis in 88.5% of group 1 and 89.3% of group 2. CONCLUSIONS The incidence of complications, hospital stay, and functional results were equivalent for RL pyeloplasty and OP with a minimal incision, but the return to painless activity was more rapid with laparoscopy in younger patients.