Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial.

BACKGROUND: Early risk-stratified chemotherapy is a standard treatment for breast, colorectal, and lung cancers, but not for high-risk localised prostate cancer. Combined docetaxel and estramustine improves survival in patients with castration-resistant prostate cancer. We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer. METHODS: We did this randomised phase 3 trial at 26 hospitals in France. We enrolled patients with treatment-naive prostate cancer and at least one risk factor (ie, stage T3-T4 disease, Gleason score of ≥8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive). All patients underwent a staging pelvic lymph node dissection. Patients were randomly assigned (1:1) to either androgen deprivation therapy (ADT; goserelin 10·8 mg every 3 months for 3 years) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m(2) and estramustine 10 mg/kg per day on days 1-5, every 3 weeks, or ADT only. The randomisation was done centrally by computer, stratified by risk factor. Local treatment was administered at 3 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was relapse-free survival in the intention-to-treat population. Follow-up for other endpoints is ongoing. This study is registered with ClinicalTrials.gov, number NCT00055731. FINDINGS: We randomly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group. Median follow-up was 8·8 years (IQR 8·1-9·7). 88 (43%) of 207 patients in the ADT plus docetaxel and estramustine group had an event (relapse or death) versus 111 (54%) of 206 in the ADT only group. 8-year relapse-free survival was 62% (95% CI 55-69) in the ADT plus docetaxel and estramustine group versus 50% (44-57) in the ADT only group (adjusted hazard ratio [HR] 0·71, 95% CI 0·54-0·94, p=0·017). Of patients who were treated with radiotherapy and had data available, 31 (21%) of 151 in the ADT plus docetaxel and estramustine group versus 26 (18%) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect (p=0·61). We recorded no excess second cancers (26 [13%] of 207 vs 22 [11%] of 206; p=0·57), and there were no treatment-related deaths. INTERPRETATION: Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer. Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival. FUNDING: Ligue Contre le Cancer, Sanofi-Aventis, AstraZeneca, Institut National du Cancer.

Quality of life of 1276 elderly patients with prostate cancer, starting treatment with a gonadotropin-releasing hormone agonist: results of a French observational study.

This French observational, longitudinal, prospective study described the health-related quality of life (HRQoL) of elderly men (≥75 years old) with prostate cancer after initiating gonadotropin-releasing hormone (GnRH) agonist therapy. At baseline and 3-6 months after baseline, European Organisation for Research and Treatment of Cancer quality of life questionnaire-core 30 (QLQ-C30) and prostate-specific (QLQ-PR25) questionnaires were completed by patients. Data from 1276 patients were analyzed. At baseline, mean (±SD) age was 80 (±4.1) years, 29.1% of patients had Gleason scores ≥8 and 24.9% had metastases. At baseline, increasing age, presence of metastasis and presence of comorbidity had a negative impact on QLQ-C30 and QLQ-PR25 scores. At follow-up, improvement in emotional-functioning (2.8; p < 0.001), social-functioning (1.7; p = 0.011), global HRQoL (1.6; p = 0.029), sleep-disturbance (-2.1; p = 0.011), appetite-loss (-4.0; p < 0.001) and pain (-4.1; p < 0.001) QLQ-C30 scores were observed. In addition, there was a worsening in treatment-related symptom (8.6; p < 0.001), sexual-activity (-5.5; p < 0.001) and sexual-functioning (-22.6; p < 0.001) QLQ-PR25 scores, and an improvement in urinary symptoms (-3.7; p < 0.001) and incontinence aid (-2.9; p = 0.023) QLQ-PR25 scores. This study shows that, apart from the expected impact on sexual functioning domains, HRQoL is not adversely affected by 3-6 months of GnRH agonist therapy in older men with prostate cancer.

[Management and complications of urinary diversions]. / Gestion et complications des néovessies et dérivations urinaires externs.

After cystectomy, the urine is eliminated by the uretra (orthotopic neobladder) or through a stoma. Orthotopic neobladder is done by priority when feasible. Practical aspects have to be managed very strictly by the urologist and the staff nurse. Side effects and complications are quite frequent (incontinence, retention, infection, diminished renal function, metabolic disorders, stoma complications) and need an adapted follow-up to propose adapted management if necessary.

Very Long-Term Complete Remission Can Be Achieved in Men With High-Risk Localized Prostate Cancer and a Very High PSA Value: An Analysis of the GETUG 12 Phase 3 Trial.

INTRODUCTION: Serum prostate specific antigen (PSA) is a well-known prognostic parameter in men with prostate cancer. The treatment of men with very high PSA values and apparently no detectable metastases is not fully established. PATIENTS AND METHODS: Ancillary analysis from the GETUG 12 phase 3 trial. Patients with non-metastatic high-risk prostate cancer by bone and computerized tomography (CT) scan were randomly assigned to receive androgen deprivation therapy (ADT) and docetaxel plus estramustine or ADT alone. Relapse-free survival (RFS), clinical RFS, metastases-free survival (MFS), overall survival (OS), and prostate cancer-specific survival (PCSS) were estimated using the Kaplan-Meier method for different levels of PSA (50 ng/mL, 75 ng/mL, and 100 ng/mL). The relationship between PSA and outcomes was studied using residual-based approaches and spline functions. RESULTS: The median follow-up was 12 years (range: 0-15.3). Baseline PSA (<50 ng/mL, n = 328; ≥50ng/mL, n = 85) was associated with improved RFS (P = .0005), cRFS (P = .0024), and MFS (P = .0068). The 12-year RFS rate was 46.33% (CI 40.59-51.86), 33.59% (CI 22.55-44.97), and 11.76% (1.96-31.20) in men with PSA values <50 ng/mL (n = 328), 50-100 ng/mL (n = 68), and ≥100 ng/mL (n = 17), respectively. Exploratory analyses revealed no deviation from the linear relationship assumption between PSA and the log hazard of events. CONCLUSIONS: Men with apparently localized prostate cancer and a high baseline PSA value have a reasonable chance of being long-term disease-free when treated with curative intent combining systemic and local therapy.

[Management of side-effects of targeted therapies in renal cancer: gastrointestinal side-effects]. / Gestion des effets secondaires des thérapies ciblées dans le cancer du rein: effets secondaires digestifs.

Several types of gastrointestinal complications can occur during treatment with targeted therapies: diarrhoea, nausea and vomiting, abnormalities in hepatic and pancreatic profiles, etc. Gastrointestinal problems in targeted therapy can have a significant impact on the general status of patients, their weight and their adherence to the treatment. The prevention, screening and rapid treatment of these side-effects are essential elements of patient care and can limit the associated dose reductions and loss of therapeutic benefit. In the case of diarrhoea, treatment must be started at the onset of grade 1 or 2 diarrhoea (four to six stools per day), with loperamide or racecadotril. Treatment with targeted therapy must be stopped if there is diarrhoea of grade 3 or 4 (more than six stools per day). In the case of nausea/vomiting or burning pain in the oesophagus, symptomatic treatment without stopping the targeted therapy is recommended. Biological assessment including transaminases, total and conjugated bilirubin should be prescribed before treatment initiation with targeted therapy. An elevation in alkaline phosphatases without elevation of transaminases suggests primarily the existence of hepatic metastases. In the event of worsening of the hepatic profile, if ALT greater than 5N, treatment must be stopped and specialist advice sought.

Oncological risk of laparoscopic surgery in urothelial carcinomas.

OBJECTIVE: To assess the oncological safety of laparoscopic procedures for the management of urothelial carcinomas of the urinary tract. METHODS: Data on laparoscopic management of urothelial carcinomas in the literature were analysed using MEDLINE and by matching the following keywords: urological malignancies, upper tract tumours, bladder carcinomas, laparoscopic approach, recurrence, follow-up and metastasis site. RESULTS: Minimally invasive techniques are being used increasingly in the management of these tumours and successfully achieving the benefits of lower blood loss and more rapid patient recovery. To date, no evidence level 1 information is available and published series of these technically challenging cases are small and follow-up limited. Short to medium term follow-up appears encouraging in terms of recurrence and survival rates, but long-term data are immature compared to the established open techniques these procedures seek to duplicate. Specific concerns in terms of the oncologic safety of laparoscopy, especially with regard to the pneumoperitoneum, tumour manipulation and specimen extraction are addressed. Port-site metastases and tumour seeding are rare events and appear to be mainly related to the grade and stage of the tumour. Specific precautions are required to minimise these risks. CONCLUSION: Oncological results of the laparoscopic approach are difficult to compare with those of open surgery. However, recent series have not reported unusual tumour dissemination or a higher rate of recurrence with this approach. Laparoscopic techniques are not yet standard of care in invasive urothelial carcinomas. Long-term assessment is ongoing and awaited.

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 approximately 70 years old with T1-T2 N0M0 disease, Gleason Score or=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.

[Surgical margins after radical prostatectomy: technical aspects and prognostic value]. / Marges après prostatectomie totale: aspects techniques et valeur pronostique.

The status of surgical margins after radical prostatectomy is a major prognostic factor. The role of several technical aspects of radical prostatectomy, such have surgical access, bladder neck preservation or neurovascular bundle sparing, in generating supplementary positive margins has been controversial for many years. Positive margins along with other poor prognostic factors are important elements in the decision to perform adjuvant therapy after radical prostatectomy. This review of the literature, based on a Medline search, was designed to update these various issues encountered by urologists in their everyday practice.

[The prostate: how to treat this symbol of male vulnerability? An Association Française d'Urologie (AFU)-IPSOS qualitative survey]. / La prostate: identification des attentes du médecin généraliste. Une enquête qualitative. Association Française d'Urologie (AFU)-IPSOS.

INTRODUCTION: Information on prostate diseases, including prostate cancer, has been promoted by the Association Française d'Urologie (AFU) for several years, but is developing slowly in France. In 2005, a first communication was targeted to the male public and identified the reasons for the fatalistic attitude of men, and paradoxically, why the prostate incarnates the vulnerability of their sexual capital. As part of a second phase, this article presents the results of a complementary study conducted among general practitioners to identify their expectations and the most appropriate levers to promote screening. MATERIAL AND METHOD: The Ipsos survey company developed a Krisis qualitative protocol in October 2005 (after the first French prostate day on 15 September 2005). Three groups of general practitioners were defined: doctors who are very active in terms of screening, doctors who are uncomfortable with this problem and doctors who systematically refer their patients to urologists. RESULTS: The management of prostate diseases often highlights the ageing process for the patient. The ability to discuss these problems during the consultation depended on the doctor's degree of comfort with this subject, which is related to his/her training and relationships with urologists. To initiate the question of screening, general practitioners involved in this process asked simple questions about everyday practices without being afraid of making jokes or basing their approach on mediatization of the disease. Digital rectal examination is one of the important clinical elements but is not always easy to perform. PSA was found to be an examination that is not always appropriate, characterized by a lack of information on the conditions for ordering this test, its usefulness and its relevance for screening. Ultrasound could be a way of alerting the patient without dramatizing the situation, letting the urologist perform digital rectal examination. Female general practitioners preferred PSA and ultrasound. The doctors surveyed relied on mediatization of prostate diseases, a high level of interactivity with urologists and documents and brochures to be placed in waiting rooms to relay screening messages. CONCLUSION: General practitioners need their authorities, specialists and public health institutions to develop and mediatize andrology in the same way as gynaecology. Urologists play a major supportive role by means of conferences, postgraduate training or AFU invitations.

[Intravesical BCG instillations for the treatment of superficial bladder tumours in renal transplant recipients]. / Utilisation des instillations intra-vésicales de bacille de Calmette et Guérin (BCG) pour le traitement des tumeurs superficielles de vessie chez les patients transplantés rénaux.

Superficial urothelial tumours of the bladder are more frequent and more often at higher risk of progression and recurrence in renal transplant recipients. When conservative treatment of these tumours is indicated, BCG instillations are recommended. However, immunosuppression of renal transplant recipients constitutes a classical contraindication to BCG therapy. Some authors have nevertheless used BCG instillations in renal transplant recipients. The authors reviewed the use of BCG in renal transplant recipients by studying the effects of immunosuppression on the mechanisms of action of BCG and the various clinical experiences reported in the international literature.

[Management of positive margins after total prostatectomy for localized prostate cancer]. / Prise en charge des marges positives après prostatectomie totale pour cancer localisé de la prostate.

Positive margins after total prostatectomy are frequently observed (10% to 40% of cases) in the everyday practice of urologists treating prostate cancer The presence of positive margins is correlated with the presence of residual tumour in about 50% of cases. It is difficult to clearly define optimal management in view of the marked heterogeneity of the published data concerning the significance and prognosis of positive margins. The objective of this review article was to analyse the various aspects of this situation and to propose practical management guidelines. This analysis was based on data of the literature derived from Medline. In practice, it is essential to more precisely define the concept of positive margins in histological terms by specifying the unifocal or multfocal nature, the total length of positive margins and their site. The decision to perform adjuvant or deferred therapy is based on these histopathological elements together with other prognostic criteria determined after total prostatectomy: pathological stage and Gleason score, tumour volume and postoperative PSA.

Outcome According to Elective Pelvic Radiation Therapy in Patients With High-Risk Localized Prostate Cancer: A Secondary Analysis of the GETUG 12 Phase 3 Randomized Trial.

PURPOSE: The role of pelvic elective nodal irradiation (ENI) in the management of prostate cancer is controversial. This study analyzed the role of pelvic radiation therapy (RT) on the outcome in high-risk localized prostate cancer patients included in the Groupe d'Etude des Tumeurs Uro-Genitales (GETUG) 12 trial. METHODS AND MATERIALS: Patients with a nonpretreated high-risk localized prostate cancer and a staging lymphadenectomy were randomly assigned to receive either goserelin every 3 months for 3 years and 4 cycles of docetaxel plus estramustine or goserelin alone. Local therapy was administered 3 months after the start of systemic treatment. Performance of pelvic ENI was left to the treating physician. Only patients treated with primary RT were included in this analysis. The primary endpoint was biochemical progression-free survival (bPFS). RESULTS: A total of 413 patients treated from 2002 to 2006 were included, of whom 358 were treated using primary RT. A total of 208 patients received pelvic RT and 150 prostate-only RT. Prostate-specific antigen (PSA) concentration, Gleason score, or T stage did not differ according to performance of pelvic RT; pN+ patients more frequently received pelvic RT than pN0 patients (P<.0001). Median follow-up was 8.8 years. In multivariate analysis, bPFS was negatively impacted by pN stage (hazard ratio [HR]: 2.52 [95% confidence interval [CI]: 1.78-3.54], P<.0001), Gleason score 8 or higher (HR: 1.41 [95% CI: 1.03-1.93], P=.033) and PSA higher than 20 ng/mL (HR: 1.41 [95% CI: 1.02-1.96], P=.038), and positively impacted by the use of chemotherapy (HR: 0.66 [95% CI: 0.48-0.9], P=.009). There was no association between bPFS and use of pelvic ENI in multivariate analysis (HR: 1.10 [95% CI: 0.78-1.55], P=.60), even when analysis was restricted to pN0 patients (HR: 0.88 [95% CI: 0.59-1.31], P=.53). Pelvic ENI was not associated with increased acute or late patient reported toxicity. CONCLUSIONS: This unplanned analysis of a randomized trial failed to demonstrate a benefit of pelvic ENI on bPFS in high-risk localized prostate cancer patients.

Transrectal high-intensity focused ultrasound in the treatment of localized prostate cancer.

The literature concerning the efficacy and safety of transrectal high-intensity focused ultrasound (HIFU) for the treatment of localized prostate cancer still comprises a relatively small number of articles. The main studies have been published by four teams using an apparatus available in Europe for several years. The recently presented results of the European Multicentre Study and the study by Gelet and associates based on 242 patients with a follow-up of more than 1 year show that HIFU is a valid alternative for the management of welldifferentiated and moderately differentiated localized prostate cancer with an initial PSA 10 years. In two studies, the combination of transurethral resection of the prostate and HIFU limited the risk of postoperative urinary retention without inducing a higher complication rate. In a series of patients presenting recurrence after external-beam radiotherapy, HIFU was found to be a useful therapy, with >80% negative biopsies. The best indications for HIFU are men over the age of 65, those who are not candidates for radical prostatectomy, obese patients, or patients with comorbidities likely to make surgery more difficult. The learning curve for this technique is relatively short, between 10 and 15 patients, for urologists experienced in transrectal ultrasonography. One of the advantages of HIFU is that it can be repeated in the case of recurrence or to re-treat a prostatic site, it involves no radiation, and patients do not suffer from long-term irritative urinary symptoms.

[Follow-up of renal cancer. Guidelines of the Comité de Cancérologie de l'Association Française d'Urologie]. / Suivi du cancer du rein.

The follow-up of renal cancer is essentially based on thoracoabdominal computed tomography (CT). The duration of this follow-up and the frequency of examinations depend on the patient's level of risk. Early detection of metastases has a limited therapeutic value at the present time, apart from tumours with a good prognosis or for the management of complications. Recent publications on targeted treatments raise new hopes and may lead to a modification of follow-up guidelines.

[Follow-up of urothelial tumours. Guidelines of the Comité de Cancérologie de l'Association Française d'Urologie]. / Suivi des tumeurs urothéliales.

The follow-up of urothelial tumours is designed to allow early detection of recurrence or progression, for which treatment is possible. Recent interesting points are: the more frequent and simpler use of the new classification into low grade and high grade, essentially applied to the management and surveillance of tumours involving the mucosa or lamina propria; and the limited place of urinary markers.

[Follow-up of testicular germ cell tumours. Guidelines of the Comité de Cancérologie de l'Association Française d'Urologie]. / Suivi des tumeurs germinales du testicule.

The follow-up of testicular tumours must be rigorous in view of the high cure rate in the case of recurrence. This follow-up is based on clinical examination, thoracoabdominopelvic CT and the tumour marker assays. The frequency of these examinations depends on the tumour stage.

[Follow-up of malignant tumours of the penis. Guidelines of the Comité de Cancérologie de l'Association Française d'Urologie]. / Suivi des tumeurs malignes du pénis.

Tumours of the penis are potentially serious tumours, but are uncommon in western countries. Follow-up is based on clinical examination and thoracoabdominopelvic CT scan.

[Follow-up of prostate cancer. Guidelines of the Comité de Cancérologie de l'Association Française d'Urologie]. / Suivi du cancer de la prostate.

The follow-up of prostate cancer is especially justified now that effective treatment options are available in the case of recurrence. Conditions of follow-up of patients with prostate cancer vary according to age, comorbidities, tumour stage, prognostic factors at diagnosis and the pervious treatment sequence.

[Update on screening, diagnosis and treatment of cancer of the prostate]. / Actualités sur le dépistage, le diagnostic et le traitement des cancers de prostate.

Recent progress in management of prostate cancer concern screening and treatment. The use of PSA and rectal examination advances the diagnosis by 5 to 10 years and shift the stage at the time of diagnosis toward curative localized intraprostatic disease. The impact of systematic screening remains controversial. However, individual screening explains, at least in part, the decrease of specific mortality due to prostatic cancer, recently observed in USA. PSA and lymphadenectomy have also contributed to a better selection of patients referred for local treatment by prostatectomy or radiotherapy. Radical prostatectomy is recommended for patients before 70 with T2 or less, Gleason score less than 8 and PSA less than 15 ng/ml. With that selection, disease-free survival reaches 75 to 80% at 10 years. Recently, dramatic improvement in radiotherapy techniques have been achieved, leading to a better local control by increasing the dose over 70 Gy without additional toxicity. Brachytherapy is also widely used for good prognosis localized disease. Limitant acute urinary side effects have been reported and results seem similar to those reported after prostatectomy or conformal radiotherapy. Recent randomized trials have demonstrated a benefit of early hormonal therapy concurrent with radiotherapy for patients with poor prognosis localized disease. For hormonoresistant metastatic disease, chemotherapy has been used with limited palliative benefit. New drugs are currently evaluated.