Quality of Life and Sexual Function Benefits of Long-Term Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME).

BACKGROUND: The benefits and risks of long-term testosterone administration have been a topic of much scientific and regulatory interest in recent years. AIM: To assess long-term quality of life (QOL) and sexual function benefits of testosterone replacement therapy (TRT) prospectively in a diverse, multinational cohort of men with hypogonadism. METHODS: A multinational patient registry was used to assess long-term changes associated with TRT in middle-age and older men with hypogonadism. Comprehensive evaluations were conducted at 6, 12, 24, and 36 months after enrollment into the registry. OUTCOMES: QOL and sexual function were evaluated by validated measures, including the Aging Males' Symptom (AMS) Scale and the International Index of Erectile Function (IIEF). RESULTS: A total of 999 previously untreated men with hypogonadism were enrolled at 25 European centers, 750 of whom received TRT at at least one visit during the period of observation. Patients on TRT reported rapid and sustained improvements in QOL, with fewer sexual, psychological, and somatic symptoms. Modest improvements in QOL and sexual function, including erectile function, also were noted in RHYME patients not on TRT, although treated patients showed consistently greater benefit over time in all symptom domains compared with untreated patients. AMS total scores for patients on TRT were 32.8 (95% confidence interval = 31.3-34.4) compared with 36.6 (95% confidence interval = 34.8-38.5) for untreated patients (P < .001). Small but significant improvements in IIEF scores over time also were noted with TRT. Approximately 25% of treated and untreated men also used phosphodiesterase type 5 inhibitors, with notable differences in the frequency of phosphodiesterase type 5 inhibitor prescription use according to physician specialty and geographic site location. CLINICAL IMPLICATIONS: TRT-related benefits in QOL and sexual function are well maintained for up to 36 months after initiation of treatment. STRENGTHS AND LIMITATIONS: The major strengths are the large, diverse patient population being treated in multidisciplinary clinical settings. The major limitation is the frequency of switching from one formulation to another. CONCLUSION: Overall, we confirmed the broad and sustained benefits of TRT across major QOL dimensions, including sexual, somatic, and psychological health, which were sustained over 36 months in our treatment cohort. Rosen RC, Wu F, Behre H, et al. Quality of Life and Sexual Function Benefits Effects of Long-Term Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME). J Sex Med 2017;14:1104-1115.

Multiparametric Magnetic Resonance Imaging for the Detection of Clinically Significant Prostate Cancer: What Urologists Need to Know. Part 4: Transperineal Magnetic Resonance-Ultrasound Fusion Guided Biopsy Using Local Anesthesia.

BACKGROUND: Transperineal magnetic resonance imaging-transrectal ultrasound fusion guided biopsy (MFGB) is an increasingly popular technique due to increasing rates of biopsy-related infections. However, its widespread implementation has been hampered by the supposed necessity of epidural or general anesthesia. OBJECTIVE: To demonstrate the technique, feasibility, and results of transperineal MFGB under local anesthesia, in an ambulatory setting without the administration of prophylactic antibiotics. DESIGN, SETTING, AND PARTICIPANTS: This single-center study enrolled consecutive biopsy-naïve men with a clinical suspicion of prostate cancer into a prospective database between November 2015 and November 2020. Men with Prostate Imaging Reporting and Data System (PI-RADS) version 2 scores 3-5 underwent transperineal MFGB. SURGICAL PROCEDURE: Transperineal MFGB was performed in an ambulatory setting under local anesthesia by a single operator. MEASUREMENTS: Procedure-associated adverse events were recorded. Patient discomfort during both the local anesthesia and the biopsy procedure was determined using a visual analogic scale (0-10). Detection rates of grade group (GG) ≥2 prostate cancer and the proportion of men with GG 1 cancer were assessed. RESULTS AND LIMITATIONS: A total of 1097 eligible men underwent transperineal MFGB. The complication rate was 0.73% (8/1097); complications comprised five (0.46%) urinary tract infections including one hospitalization and three (0.27%) urinary retentions. In 735 men, the median pain scores were 2 (interquartile range [IQR] 2-3) for the local anesthesia procedure and 1 (IQR 0-2) for the biopsy. Prostate cancer was detected in 84% (926/1097) of men; 66% (723/1097) had GG ≥2 and 19% (203/1097) GG 1. CONCLUSIONS: Transperineal MFGB can safely be performed as an outpatient procedure under local anesthesia in an ambulatory setting. The detection rate of clinically significant prostate cancer is high, and biopsy is well tolerated. Although no antibiotic prophylaxis was used, the rate of infectious complications is practicably negligible. PATIENT SUMMARY: This article shows how tissue samples (biopsies) can accurately be obtained from suspicious regions seen on prostate magnetic resonance imaging via needles inserted in the perineum (skin between the scrotum and the anus) in men with suspected prostate cancer. This technique appears to be very well tolerated under local anesthesia and has a lower risk of infection without antibiotic prophylaxis than the more common biopsy route through the rectum, with antibiotics.

Identification of circulating prostate cancer cells: a challenge to the clinical implementation of molecular biology (review).

Conventional diagnosis of prostate cancer does not appear to be sensitive enough to differentiate pre-operatively between organ-confined and extracapsular disease. New technologies, arising from the field of molecular biology, have been introduced to improve diagnosis and their implementation into the clinical practice is nowadays extensively explored. In 1992, focusing on prostate cancer, the application of the highly sensitive and specific reverse transcription-polymerase chain reaction (RT-PCR) technology which amplifies predefined mRNA species was introduced. Assuming haematogenous prostate tissue-specific mRNA species to be representative for the presence of circulating prostate cancer cells, an impressive series of clinical studies, for the greater part addressing mRNA encoding for prostate-specific antigen (PSA), were performed to improve pre-operative staging (molecular staging) and prognosis of prostate cancer, and to study iatrogenic cell dissemination. In this review we summarize the efforts, concentrating on the RT-PCR methodology, to identify extracapsular prostate cancer cells in easy accessible body fluids. The substantial amount of available biological and clinical data allow an in depth illustration of the advantages, disadvantages and clinical future of this technology. The intrinsic limitations of the technology, technical as well as biological, will be addressed since these may well explain the controversies associated with its general acceptance in the clinical practice. Together with considerable improvements of the methodology to be expected in the near future, new avenues for the detection of disseminated prostate cancer cells will be subject of discussion.

Changes in health-related quality of life of men with prostate cancer 3 months after diagnosis: the role of psychosocial factors and comparisment with benign prostate hyperplasia patients.

The objective of the pilot study is to measure the changes in health-related quality of life (HRQOL, general and prostate specific) 3 months after the disease has been diagnosed in men with prostate cancer. The results are compared with benign prostate hyperplasia (BPH) patients. Also the influence of psychosocial factors (distress, coping and social support) on the experienced changes in health-related quality of life is studied for both patient groups. The sample consists of 61 patients who filled in the questionnaire before the diagnosis was know to them and after 3 months (38 benign prostate hyperplasia and 23 prostate cancer patients). The measures consist of: quality of life, micturation symptoms, sexual functioning, coping style, psychological distress, life events, social support, social desirability, and health behavior. The results show a decrease in quality of life for prostate cancer patient after three moments, while the quality of life measure for BPH patients are stable over time. For both patient groups, the psychosocial factors do not change after 3 months. The psychosocial factors contribute only marginal to the changes in quality of life. Conclusions are drawn concerning the need and the content of psychosocial support and education for prostate cancer patients.

Early versus delayed endocrine treatment of T2-T3 pN1-3 M0 prostate cancer without local treatment of the primary tumour: final results of European Organisation for the Research and Treatment of Cancer protocol 30846 after 13 years of follow-up (a randomised controlled trial).

BACKGROUND: The timing of endocrine treatment (ET) for prostate cancer (PCa) remains controversial. The issue is addressed in European Organisation for the Research and Treatment of Cancer (EORTC) protocol 30846 for patients with lymph node-positive (pN1-3) cancer without local treatment of the primary tumour. OBJECTIVE: To evaluate the effect of early versus delayed treatment in pN1-3 PCa. DESIGN, SETTING, AND PARTICIPANTS: Two hundred thirty-four patients with histologically proven PCa and nodal metastases (pN1-3) were randomized to immediate versus delayed ET without treatment of the primary tumour. ET consisted of a depot luteinising hormone-releasing hormone (LHRH) agonist and 1 mo of an anti-androgen or surgical castration. The trial's main objective was to show non-inferiority of delayed ET to immediate ET by ruling out a hazard ratio (HR) of 1.50 for overall survival (OS), with 85% power at one-sided alpha=5%. MEASUREMENTS: All but three patients were treated as randomized. The median follow-up is 13 yr. The median protocol treatment duration was 2.7 yr in the delayed and 3.2 yr in the immediate ET groups. RESULTS AND LIMITATIONS: Overall, 193 patients (82.5%) have died (97 on delayed ET and 96 on immediate ET), 59.4% of them as a result of PCa. The intention-to-treat analysis shows a 22% increase in the hazard of death of those randomized to delayed treatment (HR=1.22, 95% confidence interval [CI]: 0.92, 1.62). The difference is not statistically significant, but non-inferiority is also not proved. The median OS on immediate ET is 7.6 yr (95% CI, 6.3-8.3 yr) versus 6.1 yr (95% CI, 5.7-7.3 yr) in the delayed ET group. The 10-yr cumulative incidence of death resulting from PCa was 55.6% in the delayed ET group versus 52.1% with immediate ET group. Similar conclusions hold for PCa-specific survival. CONCLUSIONS: After 13 years of follow-up, survival or PCa-specific survival between immediate and delayed ET appear similar, but the trial is underpowered to reach its goal of showing non-inferiority.

Bone resorption and renal calcium reabsorption in renal cell carcinoma-bearing mice: the effects of bisphosphonate.

OBJECTIVE: To examine the contribution of the skeleton and the kidney to the development of humoral hypercalcaemia of malignancy (HHM) in a mouse model of HHM treated with a potent bisphosphonate. MATERIALS AND METHODS: Mice bearing the human RCC cell line RC-9 were treated with bisphosphonate (subcutaneous, 0.25 mg/kg body weight olpadronate) or saline solution. Treatment was initiated at a tumour volume (TV) of approximately 100 mm(3) and 500 mm(3), and the mice were monitored for approximately 4 weeks. Serum calcium and phosphate concentrations and trabecular bone volume (TBV) were assessed during and/or after treatment. RESULTS: Athymic mice implanted with the RCC RC-9, developed severe hypercalcaemia and bone resorption. During tumour growth the mean (sd) serum calcium concentration increased to 4.1 (0.3) mmol/L, and phosphate decreased to 1.6 (0.3) mmol/L, vs 2.3 (0.1) and 2.9 (0.4) mmol/L in controls, respectively. TBV decreased from 8.7 (1.8)% in mice with no tumour, to 5.3 (2.7)% in RC-9-bearing mice. Olpadronate initiated at a Tv of 100 mm(3) prevented the loss of bone induced by RCC RC-9 cells, with a TBV of 12.8 (2.1)%, but the development of hypercalcaemia was unaffected. Olpadronate treatment at a TV of 500 mm(3) did not influence the development of hypercalcaemia and did not protect against bone resorption. Kinetic monitoring showed an identical rate of tumour growth in the presence or absence of bisphosphonate, while under both conditions there was a tumour load-dependent increase in calcium concentration. CONCLUSIONS: Bisphosphonate can prevent parathyroid hormone-related peptide (PTHrP)-mediated bone resorption when administered during the early phase of renal tumour growth, but has no effect on the tumour-induced development of hypercalcaemia, indicating a primary role for renal tubular reabsorption of calcium in the kidney by PTHrP in HHM.

BCG dose reduction by decreasing the instillation frequency: effects on local Th1/Th2 cytokine responses in a mouse model.

OBJECTIVES: Based on the requirement of a Th1 immune response for clinical efficacy, and incited by the arbitrary induction scheme, frequent side effects and the empirical approach in improving BCG immunotherapy for superficial bladder cancer, an alternative intravesical BCG treatment schedule for dose reduction was investigated without compromising Th1 cytokine induction in the bladder in a mouse model. METHODS: Mice were submitted to 6 weekly BCG instillations and treatment schedules omitting intermediate instillations during this standard scheme. Th1 (IFN-gamma, IL-2, IL-12p40), and Th2 (IL-10, IL-4) cytokine responses in individual mouse bladders were measured by a semiquantitative RT-PCR based method. RESULTS: A schedule of only two BCG instillations, administered in week 1 and week 6, resulted in induction of at least the same levels of IFN-gamma, IL-2 and IL-12p40 Th1 cytokine mRNA compared to 6 weekly instillations, whereas significantly lower levels of Th2 cytokines IL-10 and IL-4 mRNA were observed. CONCLUSIONS: During the 6-week period the intermediate weekly BCG instillations 2, 3, 4, and 5 do not contribute to Th1 cytokine upregulation in the bladder, provided that the BCG dose is sufficient. Whether such a reduced BCG frequency schedule has immune stimulating capacity and therapeutic efficacy associated with less side effects in patients remains to be investigated.

High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder.

We sought to review the definition, diagnosis, prognosis, and treatment of high-grade Ta urothelioma carcinoma and carcinomas in situ (CIS) in order to provide evidence-based guidelines for their diagnosis and treatment. The English-language literature on high-grade Ta urothelial carcinoma and CIS was identified and critically reviewed by a panel of 9 international experts. The panel then met at a consensus conference to present their conclusions. Levels of evidence and grades of recommendation were assessed. Findings from approximately 100 publications appearing prior to February 2005 were reviewed and summarized. High-grade Ta urothelial carcinoma and CIS are relatively rare tumors; thus results are often based on small nonrandomized studies. Their assessment is made more difficult owing to inaccuracies in staging and grading. Although there were similar numbers of level 1, level 2, and level 3 evidence citations, guidelines have been developed based only on levels of evidence supporting grade A and grade B recommendations. These evidence-based guidelines have been developed to aid clinicians in the diagnosis and treatment of patients with high-grade Ta urothelial carcinoma and CIS.

Improved detection and treatment of bladder cancer using hexaminolevulinate imaging: a prospective, phase III multicenter study.

PURPOSE: We determined if improved tumor detection using hexaminolevulinate (HAL) fluorescence cystoscopy could lead to improved treatment in patients with bladder cancer. MATERIALS AND METHODS: A total of 146 patients with known or suspected bladder cancer were assessed in this open, comparative, within patient, controlled phase III study. Patients received intravesical HAL for 1 hour and were assessed with standard white light cystoscopy and blue light fluorescence cystoscopy. All lesions were mapped onto a bladder chart and biopsies were taken from suspicious areas for assessment by an independent pathologist. An independent urologist blinded to the detection method used recommended treatment plans based on biopsy results and medical history according to European Association of Urology bladder cancer guidelines. Any differences in recommended treatment plans arising from the 2 cystoscopy methods were recorded. RESULTS: HAL imaging improved overall tumor detection. Of all tumors 96% were detected with HAL imaging compared with 77% using standard cystoscopy. This difference was particularly noticeable for dysplasia (93% vs 48%), carcinoma in situ (95% vs 68%) and superficial papillary tumors (96% vs 85%). As a result of improved detection, additional postoperative procedures were recommended in 15 patients (10%) and more extensive treatment was done intraoperatively in a further 10. Overall 17% of patients received more appropriate treatment at the time of the study following blue light fluorescence cystoscopy, that is 22% or 1 of 5 if patients without tumors were excluded. CONCLUSIONS: HAL imaging is more effective than standard white light cystoscopy for detecting bladder tumors and lesions. This leads to improved treatment in a significant number of patients (p <0.0001).

Bacillus Calmette-Guerin versus epirubicin for primary, secondary or concurrent carcinoma in situ of the bladder: results of a European Organization for the Research and Treatment of Cancer--Genito-Urinary Group Phase III Trial (30906).

PURPOSE: We compared the efficacy and side effects of intravesical instillations of bacillus Calmette-Guerin (BCG) and epirubicin in patients with carcinoma in situ (CIS) of the bladder. MATERIALS AND METHODS: Patients with primary, secondary or concurrent CIS of the bladder were randomized to 81 mg BCG-Connaught (6 weekly instillations) or 50 mg epirubicin (8 weekly instillations). When a complete response (CR), defined as no Ta/T1 or CIS on biopsy and negative cytology, was obtained, patients in the 2 groups received maintenance instillations at months 3, 6, 12, 18, 24, 30 and 36. When no complete response was observed, the original treatment was repeated, followed again by cystoscopy and biopsies plus cytology. RESULTS: A total of 168 patients were randomized between March 1993 and April 1999 to receive BCG (84) or epirubicin (84), while 4 on epirubicin and 3 on BCG were ineligible. The majority (52%) had concurrent CIS. Primary and secondary CIS was found in 23% and 24% of cases, respectively. The overall CR rate was 56% for epirubicin and 65% for BCG (p = 0.21, 90% CI 21.5 to -2.9). When tumor was found following 2 instillation courses, further treatment was left to the investigator (BCG in 29 cases and epirubicin in 37). Time to bladder tumor recurrence after CR was longer in patients treated with BCG vs epirubicin (median 5.1 vs 1.4 years). CIS recurrences were more frequently observed in complete responders to epirubicin (45% vs 16%). No differences in time to progression or duration of survival were observed. Side effects were more frequently seen in patients on BCG with 26 on BCG and 8 on epirubicin stopping treatment due to side effects. CONCLUSIONS: No significant difference in CR rates could be demonstrated with intravesical instillations of epirubicin or BCG. Time to recurrence was significantly longer in patients treated with BCG after having achieved a CR. More CIS recurrences were found in patients treated with epirubicin. For time to progression and survival longer followup is warranted. Side effects were more frequent in patients on BCG.

Cytokine gene expression in a mouse model: the first instillations with viable bacillus Calmette-Guerin determine the succeeding Th1 response.

PURPOSE: Bacillus Calmette-Guerin (BCG) therapy for superficial bladder cancer is immune dependent and activation of a Th1 immune response is probably required for clinical efficacy. Given the empirical approach to improving BCG therapy we investigated in a mouse model the consequences of modifications in BCG therapy with regard to Th1 and Th2 cytokine responses in the bladder. These studies may provide a rationale for possible modifications of the established clinical treatment protocol. MATERIALS AND METHODS: The dynamics of Th1 (interferon-gamma, interleukin [IL]-2, IL-12p40 and tumor necrosis factor-alpha) and Th2 (IL-10 and IL-4) cytokine responses during and after 6 once weekly intravesical BCG instillations in mice was determined by a semiquantitative reverse transcriptase-polymerase chain reaction based method. RESULTS: During 6 weekly BCG instillations a dose and time dependent induction of the various Th1 as well as Th2 cytokines was observed. The response pattern was comparable to urinary cytokine induction patterns in patients. Electrocauterization prior to BCG instillations led to lower and more variable levels of cytokine polymerase chain reaction products compared with noncauterization. Lowering the dose of BCG seemed to affect the Th1 cytokine response most, whereas the Th2 response was less influenced by dilution of the BCG preparation. Six instillations with nonviable BCG induced Th2 but failed to induce Th1 cytokines, which may explain the necessity of BCG viability for antitumor activity. However, when mice were first treated 3 times with viable BCG and subsequently received 3 instillations with killed BCG, the Th1 and Th2 cytokine pattern was comparable to the standard 6-week regimen with viable BCG. CONCLUSIONS: The model seems an appropriate one in which to investigate changes in Th1 and Th2 cytokine gene expression levels in bladders resulting from modifications in intravesical BCG treatment. It was possible to induce a local Th1 cytokine response with nonviable BCG provided that local sensitization to BCG antigens had occurred during preceding instillations with a viable BCG preparation. Whether such an approach could decrease BCG therapy toxicity, while maintaining antitumor efficacy, remains to be further investigated in patients.

Numeric definition of the clinical performance of the nested reverse transcription-PCR for detection of hematogenous epithelial cells and correction for specific mRNA of non-target cell origin as evaluated for prostate cancer cells.

BACKGROUND: Inappropriate quality management of reverse transcription-PCR (RT-PCR) assays for the detection of blood-borne prostate cancer (PCa) cells hampers clinical conclusions. Improvement of the RT-PCR methodology for prostate-specific antigen (PSA) mRNA should focus on an appropriate numeric definition of the performance of the assay and correction for PSA mRNA that is not associated with PCa cells. METHODS AND RESULTS: Repeated (RT-)PCR tests for PSA mRNA in single blood specimens from PCa patients and PCa-free controls, performed by four international institutions, showed a large percentage (approximately equal to 50%) of divergent test results. The best estimates of the mean, lambda (SD), of the expected Poisson frequency distributions of the number of positive tests among five replicate assays of samples from PCa-free individuals were 1.0 (0.2) for 2 x 35 PCR cycles and 0.2 (0.1) for 2 x 25 PCR cycles. Assessment of the numeric value of the mean can be considered as a new indicator of the performance of a RT-PCR assay for PSA mRNA under clinical conditions. Moreover, it determines the required number of positive test repetitions to differentiate between true and false positives for circulating prostate cells. At a predefined diagnostic specificity of > or = 98%, repeated PCRs with lambda of either 1.0 or 0.2 require, respectively, more than three or more than one positive tests to support the conclusion that PSA mRNA-containing cells are present. CONCLUSIONS: Repeated nested PCR tests for PSA and appropriate handling of the data allow numeric quantification of the performance of the assay and differentiation between analytical false and true positives at a predefined accuracy. This new approach may contribute to introduction of PSA RT-PCR assays in clinical practice.

Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial.

BACKGROUND: Recombinant activated factor VII (factor VIIa) has prohaemostatic effects in bleeding patients with coagulation abnormalities. We aimed to test the hypothesis that recombinant factor VIIa could reduce perioperative blood loss in patients with normal coagulation systems. Therefore, we assessed safety and efficacy of this drug in patients undergoing retropubic prostatectomy, which is often associated with major blood loss and need for transfusion. METHODS: In a double-blind, randomised placebo-controlled trial, we recorded blood loss and transfusion requirements in 36 patients undergoing retropubic prostatectomy, who were randomised to receive an intravenous bolus of recombinant factor VIIa (20 microg/kg or 40 microg/kg) or placebo in the early operative phase. FINDINGS: Median perioperative blood loss was 1235 mL (IQR 1025-1407) and 1089 mL (928-1320) in groups given recombinant factor VIIa 20 microg/kg and 40 microg/kg, respectively, compared with 2688 mL (1707-3565) in the placebo group (p=0.001). Seven of twelve placebo-treated patients were transfused, whereas no patients who received 40 microg/kg recombinant factor VIIa needed transfusion. The odds ratio for receiving any blood product in patients treated with recombinant factor VIIa compared with control patients was 0 (95% CI 0.00-0.33) No adverse events arose. INTERPRETATION: An injection of recombinant factor VIIa can reduce perioperative blood loss and eliminate the need for transfusion in patients undergoing major surgery.

Metastatic prostate cancer treated by flutamide versus cyproterone acetate. Final analysis of the "European Organization for Research and Treatment of Cancer" (EORTC) Protocol 30892.

OBJECTIVES: This trial was designed to compare the efficacy of Flutamide (FLU) versus Cyproterone acetate (CPA) in men with metastatic prostate cancer and favourable prognostic factors. The primary endpoint of the trial was overall survival, disease specific survival, time to progression and side effects were secondary endpoints. The results pertaining to sexual function were already reported [Br J Cancer 82(2) (2000) 283]. MATERIAL AND METHODS: The trial was designed to detect a 50% improvement in median overall survival with 80% power. At the time of the present report, the trial provides 88% power to detect the planned difference of 50% with a 2-sided Logrank test and 80% power to detect a difference of 43% in median survival. RESULTS: 310 patients were randomized to treatment by FLU (250 mg t.i.d. p.o.) or CPA (100 mg t.i.d. p.o.). Of the 310 patients, 12 (3.9%) were ineligible. The baseline characteristics of the two groups were similar except for age which was significantly younger in the CPA group and for the presence of soft tissue metastases which were absent in the FLU group and present in 6 patients in the CPA group. The median follow-up was 8.6 years, 245 patients died, 158 (64.5%) of prostate cancer. There was no significant difference between the treatment arms with respect to overall survival, specific survival nor time to progression. Side effect profiles were studied and found to be more favourable for CPA overall and in particular with respect to gynecomastia, diarrhea and nausea. CONCLUSIONS: The trial shows no significant differences in efficacy between Flutamide and CPA monotherapy. The number of patients who died of prostate cancer up to this time is insufficient for a definitive analysis of specific survival. Erectile function and sexual activity are not preserved with FLU but decay slowly with both antiandrogens, toxicity is more pronounced with FLU.

Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846--a phase III study.

PURPOSE: The timing of endocrine treatment for prostate cancer remains controversial. The issue is addressed in protocol 30846 of the European Organisation for Research and Treatment of Cancer for patients with lymph node positive cancer without local treatment of the primary tumor. MATERIALS AND METHODS: A total of 302 patients with metastatic regional lymph nodes who had not received local treatment for the primary tumor were included in the trial, of whom 234 were randomized to immediate vs delayed endocrine treatment. Endocrine treatment consisted of an luteinizing hormone-releasing hormone agonist and 1 month of antiandrogen treatment or surgical castration. The main end point of the trial was overall survival. Analysis followed the intent to treat principle. RESULTS: At a median followup of 9.6 years (8.7 in the randomized sample) 190 patients (62.9%) had died, including 76% of prostate cancer. In the randomized sample the HR for survival on delayed vs immediate treatment was 1.23 (95% CI 0.88 to 1.71), indicating a 23% nonsignificant trend in favor of early treatment. However, the wide CI showed that results remained compatible with true effects, ranging from a 12% benefit in favor of delayed treatment to a 71% detriment for the same treatment approach. CONCLUSIONS: While this study suggests an advantage for early treatment, it is under powered to show equivalence or superiority for the early or delayed approach. When dealing with individual patients, the potential survival advantage on early treatment must be balanced against potential advantages in quality of life on delayed treatment.