Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial.

BACKGROUND: Androgen-deprivation therapy is offered to men with prostate cancer who have a rising prostate-specific antigen after curative therapy (PSA relapse) or who are considered not suitable for curative treatment; however, the optimal timing for its introduction is uncertain. We aimed to assess whether immediate androgen-deprivation therapy improves overall survival compared with delayed therapy. METHODS: In this randomised, multicentre, phase 3, non-blinded trial, we recruited men through 29 oncology centres in Australia, New Zealand, and Canada. Men with prostate cancer were eligible if they had a PSA relapse after previous attempted curative therapy (radiotherapy or surgery, with or without postoperative radiotherapy) or if they were not considered suitable for curative treatment (because of age, comorbidity, or locally advanced disease). We used a database-embedded, dynamically balanced, randomisation algorithm, coordinated by the Cancer Council Victoria, to randomly assign participants (1:1) to immediate androgen-deprivation therapy (immediate therapy arm) or to delayed androgen-deprivation therapy (delayed therapy arm) with a recommended interval of at least 2 years unless clinically contraindicated. Randomisation for participants with PSA relapse was stratified by type of previous therapy, relapse-free interval, and PSA doubling time; randomisation for those with non-curative disease was stratified by metastatic status; and randomisation in both groups was stratified by planned treatment schedule (continuous or intermittent) and treatment centre. Clinicians could prescribe any form and schedule of androgen-deprivation therapy and group assignment was not masked. The primary outcome was overall survival in the intention-to-treat population. The trial closed to accrual in 2012 after review by the independent data monitoring committee, but data collection continued for 18 months until Feb 26, 2014. It is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000301561) and ClinicalTrials.gov (NCT00110162). FINDINGS: Between Sept 3, 2004, and July 13, 2012, we recruited 293 men (261 with PSA relapse and 32 with non-curable disease). We randomly assigned 142 men to the immediate therapy arm and 151 to the delayed therapy arm. Median follow-up was 5 years (IQR 3·3-6·2) from the date of randomisation. 16 (11%) men died in the immediate therapy arm and 30 (20%) died in the delayed therapy arm. 5-year overall survival was 86·4% (95% CI 78·5-91·5) in the delayed therapy arm versus 91·2% (84·2-95·2) in the immediate therapy arm (log-rank p=0·047). After Cox regression, the unadjusted HR for overall survival for immediate versus delayed arm assignment was 0·55 (95% CI 0·30-1·00; p=0·050). 23 patients had grade 3 treatment-related adverse events. 105 (36%) men had adverse events requiring hospital admission; none of these events were attributable to treatment or differed between treatment-timing groups. The most common serious adverse events were cardiovascular, which occurred in nine (6%) patients in the delayed therapy arm and 13 (9%) in the immediate therapy arm. INTERPRETATION: Immediate receipt of androgen-deprivation therapy significantly improved overall survival compared with delayed intervention in men with PSA-relapsed or non-curable prostate cancer. The results provide benchmark evidence of survival rates and morbidity to discuss with men when considering their treatment options. FUNDING: Australian National Health and Medical Research Council and Cancer Councils, The Royal Australian and New Zealand College of Radiologists, Mayne Pharma Australia.

Predictors of prostate cancer specific mortality after radical prostatectomy: 10 year oncologic outcomes from the Victorian Radical Prostatectomy Registry.

PURPOSE: To identify the ability of multiple variables to predict prostate cancer specific mortality (PCSM) in a whole of population series of all radical prostatectomies (RP) performed in Victoria, Australia. MATERIALS & METHODS: A total of 2154 open RPs were performed in Victoria between July 1995 and December 2000. Subjects without follow up data, Gleason grade, pathological stage were excluded as were those who had pT4 disease or received neoadjuvant treatment. 1967 cases (91.3% of total) met the inclusion criteria for this study. Tumour characteristics were collated via a central registry. We used competing hazards regression models to investigate associations. RESULTS: At median follow up of 10.3 years pT stage of RP (P < 0.001) and high Gleason score of the RP specimen (P < 0.001 for ≥8 [Subhazard ratio (SHR) 11.19] and 4 + 3 = 7 [SHR 7.10]) compared with Gleason score 6 disease were strong predictors of progression to PCSM. Gleason score 3 + 4 = 7 was not at this time a significant predictor of PCSM (P = 0.08, SHR 1.84). Predictors of PCSM, independent of stage and grade, included rural residency (P = 0.003), primary surgeon contributing less than 40 cases (low-volume) to the VRPR (P = 0.025) and the involvement of a trainee surgeon in the operation (P = 0.031). CONCLUSION: The significant prediction of PCSM by pT cancer stage, Gleason score and primary Gleason pattern at RP in this whole of population study suggests a need to avoid understaging/grading in the process of cancer diagnosis and active surveillance protocols. Multi-modality therapy is likely to have a greater impact on PCSM in higher stage and Gleason grade disease. Identification of increased PCSM with rural residency and with involvement of a trainee urologist, and reduction in PCSM with higher surgeon volume all suggest potential for improved PC outcomes to be achieved with changes to surgical training and service delivery.

Necessity to palliate pain and suffering as a defence to medical homicide.

The courts, in applying the criminal law in relation to homicide, rely heavily on determining the cause of death, and the existence of intention to cause death. The inadequacy of such processes in relation to prosecutions for medical actions at the end of life is discussed. The principle that there is no "special defence" for doctors is refuted. The legal and ethical obligation of doctors to respect their patients' autonomy, and maximally relieve their pain and suffering, creates a special and exposed position for doctors treating patients near life's end. The result is a quasi-legal practice in which doctors achieve such relief, even though it may commonly hasten death. This medical and legal position has its basis in hypocrisy and obfuscation. The astonishing rarity of prosecution of doctors indicates a "benign conspiracy" on the part of prosecutorial authorities in this regard. It is argued that a transparent and objectively sustainable defence to medical homicide would be a defence based on the necessity to palliate pain and suffering, combined with documented consent by the sufferer to the provision of such palliation.

Management of muscle-invasive bladder cancer in Victoria, 1990-1995.

BACKGROUND: The management and outcomes of muscle-invasive bladder cancer are described in this article. METHODS: A retrospective survey of medical practitioners involved in the management of bladder cancer was conducted. The survey obtained at least 5 years of follow-up data on all patients. The sample was taken from the public and private health sectors in Victoria. All were cases of muscle-invasive bladder cancer diagnosed between 1990 and 1995. The main outcome measures included reported management by staging, treatment and survival. RESULTS: Completed questionnaires were returned for 743 (89.6%) of 829 cases. Of these, 523 (70.4%) were men, and the mean age was 72.7 years. More than 75% of the cases (560) presented with macroscopic haematuria. The majority (696, 94%) had transitional cell carcinoma. A variety of treatments were given in various sequences, with 231 cases (31.1%) having initial surveillance. Eventually, 303 cases (40.8%) proceeded to 'definitive' management with either radiotherapy (132, 17.8%) or cystectomy (171, 23.0%). In addition, chemotherapy was given to 254 patients (34.2%) at some time. Most patients (613, 82.5%) have subsequently died; 402 (54%) died from bladder cancer. Crude 5-year survival was 13.0%, and disease-specific survival was 27.7%. Multivariate analysis identified the following predictors of greater disease-specific survival: grade 1 or 2 histopathology (P = 0.0003), T2 primary (P < 0.0001), N0 disease (P = 0.04), M0 disease (P < 0.0001), radiation dose in BED(10) >70 Gy and cystectomy (P < 0.0001). CONCLUSION: Muscle-invasive bladder cancer in Victoria typically occurs in elderly patients, and a notable proportion of these patients do not proceed onto 'definitive' treatment. Disease stage, cystectomy and the use of high doses of radiation are associated with better outcomes. Chemotherapy was given to approximately one-third of patients at some point in their disease management. Our data are similar to population-based data from North America, and provide a baseline against which potential changes in management of bladder cancer can be compared.

Supervisor volume affects oncological outcomes of trainees performing open radical prostatectomy.

BACKGROUND: The relationship between biochemical failure (BF) rate and surgeon experience following open radical prostatectomy (ORP) has been well established, but BF when ORP is performed by urology trainees who are supervised by urologists of differing volume has not. We aimed to compare the oncological outcomes from ORP when a urology trainee as primary operator and is supervised by a high- or low-volume consultant urologist. METHODS: Using a centralized whole of population dataset, created through the Victorian Radical Prostatectomy Registry, patients were classified as either those where a consultant was the primary operator, a urology trainee was the primary operator and supervised by a high-volume consultant or those where a urology trainee was supervised by a low-volume consultant. BF- and prostate cancer (PCa)-specific mortality was compared between these latter two groups and the consultant-only group. RESULTS: We found BF- and PCa-specific mortality rate to be poorer when ORP was performed by a urology trainee supervised by a low-volume consultant compared with consultant-led surgery (hazard ratio (HR) = 1.33, P = 0.022; subhazard ratio (SHR) = 2.31, P = 0.010, respectively). When a urology trainee, as primary operator, was supervised by a high-volume consultant, there was no statistical difference in BF- or PCa-specific mortality rate following ORP compared with consultant-led surgery (HR = 1.19, P = 0.234; SHR = 1.53, P = 0.346, respectively). There was a trend evident with decreasing supervisor volume leading to worse oncological and mortality outcomes for trainee-led cases. CONCLUSION: This study demonstrates the value of high-volume and fellowship-trained urologists in performing and teaching ORP. As outcomes are increasingly scrutinized with audits, the best strategy for clinicians to maintain standards and optimal patient outcomes is to understand these elements and direct trainees to appropriate centres for training and fellowships.

Management of superficial bladder cancer in Victoria: 1990 and 1995.

BACKGROUND: A retrospective survey of medical practitioners was undertaken to describe the tumour characteristics, management and outcomes of all superficial bladder cancers newly diagnosed in 1990 and in 1995 in Victoria. METHODS: Cases were identified from the population cancer registry. The survey was conducted in 1999 and the cohort followed up until 2000 to obtain at least 5 years of follow-up data on all patients, in particular to identify recurrence of tumour as assessed at surveillance cystoscopy and progression to muscle invasive cancer. RESULTS: Tumour recurrence was observed in 390/610 patients (63.9%), of whom 56.9% had their recurrence noted at the first check cystoscopy. Ultimately 43 (6.3%) of patients progressed to invasive disease, with this subgroup demonstrating 5-year overall survival of 35% (95% confidence interval (CI) 21-49%). Ultimately survival was proportional to the extent of tumour invasion, being greater in low-risk patients (76%, 95% CI 72-80%, mucosal disease only) than in high-risk patients (46%, 95% CI 36-56%, lamina propria invasion noted at diagnosis). CONCLUSIONS: In low-risk subgroups of patients with superficial transitional cell carcinoma, the frequency of surveillance cystoscopy may be able to be reduced to levels in accordance with established European guidelines without a likely impact on patient survival. Where progression to muscle invasive disease does ensue, more aggressive management may be warranted in order to try to improve survival.

Increased prostate cancer specific mortality following radical prostatectomy in men presenting with voiding symptoms-A whole of population study.

BACKGROUND: Whole of population studies reporting long-term outcomes following radical prostatectomy (RP) are scarce. We aimed to evaluate the long-term outcomes in men with prostate cancer (PC) treated with RP in a whole of population cohort. A secondary objective was to evaluate the influence of mode of presentation on PC specific mortality (PCSM). METHODS: A prospective database of all cases of RP performed in Victoria, Australia between 1995 and 2000 was established within the Victorian Cancer Registry. Specimen histopathology reports and prostate-specific antigen (PSA) values were obtained by record linkage to pathology laboratories. Mode of presentation was recorded as either PSA screened (PSA testing offered in absence of voiding symptoms) or symptomatic (diagnosis of PC following presentation with voiding symptoms). Multivariate Cox and competing risk regression models were fitted to analyze all-cause mortality, biochemical recurrence, and PCSM. RESULTS: Between 1995 and 2000, 2,154 men underwent RP in Victoria. During median follow up of 10.2 years (range 0.26-13.5 years), 74 men died from PC. In addition to Gleason score and pathological stage, symptomatic presentation was associated with PCSM. After adjusting for stage and PSA, no difference in PCSM was found between men with Gleason score ≤ 6 and Gleason score 3 + 4 = 7. Men with Gleason score 4 + 3 had significantly greater cumulative incidence of PCSM compared with men with Gleason score 3 + 4. CONCLUSIONS: Primary Gleason pattern in Gleason 7 PC is an important prognosticator of survival. Our findings suggest that concomitant voiding symptoms should be considered in the work-up and treatment of PC.

Rural residency and prostate cancer specific mortality: results from the Victorian Radical Prostatectomy Register.

OBJECTIVE: To present long-term survival data from the Victorian Radical Prostatectomy Register (VRPR), 1995-2000, and analyse the effect of rural residence on survival. METHODS: Men who underwent open radical prostatectomy (RP) in Victoria from 1995 to 2000 were recorded in a population register co-ordinated by the Victorian Cancer Registry and Cancer Council Victoria. Baseline clinical, pathological and demographic information such as location were recorded and linked to mortality and recurrence data. Men who had neoadjuvant therapy or missing data for socioeconomic status (SES), tumour grade and stage were excluded leaving 1984 patients in the analyses (92.1% of total register). RESULTS: Follow-up concluded in 2009 with 238 deaths observed, of which 77 were prostate cancer (PCa) specific. Cox and competing risk regressions were used for analysis. Living in a rural area was associated with higher odds of PCa specific mortality after RP (trend p<0.001) and a higher hazard of PCa death, the discrepancy rising up to four-fold (SHR=4.09, p=0.004) with increasing remoteness of residence. This effect is apparent after adjustment for SES, age, private or public hospital treatment, PSA level and tumour-specific factors. CONCLUSION: Rural men in Victoria have a shorter time to PCa death following definitive treatment, even after adjustment for SES and adverse tumour characteristics. IMPLICATION: Rural men are faring worse than their urban counterparts following the same cancer treatment.

A whole of population-based series of radical prostatectomy in Victoria, 1995 to 2000.

OBJECTIVE: Radical prostatectomy (RP) as a first line treatment of prostate cancer was rare prior to the advent of prostate specific antigen (PSA) testing, yet little is known of its use and outcomes in a population setting. We described baseline characteristics of cases in the Victorian Radical Prostatectomy Register (VRPR), investigated possible associations between demographic characteristics and characteristics at diagnosis and at surgery and trends over time. METHODS: The VRPR is a population-based series of all RPs performed in Victoria from July 1995 to December 2000 (n=2,154). RESULTS: On average, socio-economic status for cases was higher than for the general Victorian population (34% vs 20% in the highest quintile respectively, p<0.0001). The proportion of PSA-detected cases increased from 53% in 1995 to 79% in 2000 (p for linear trend=0.0004). Age at surgery and PSA levels at diagnosis decreased over time (p=0.006 and p=0.04 respectively). The proportion of cases with Gleason score < or =5 from RP decreased from 35% in 1995 to 14% in 2000, while cases with Gleason score 6-7 increased from 60% to 79%. Similar trends were observed for Gleason score from biopsy. We found little evidence of significant trends over time in other pathological characteristics relevant to prognosis. CONCLUSION AND IMPLICATIONS: The VRPR provides a unique whole of population based description of radical prostatectomy in Victoria, confirms findings previously reported in single institution clinical series overseas such as migration to younger age at surgery and to Gleason scores 6 to 7, and provides a resource for evaluating RP outcomes in the future.

Deviation of the Ureters due to Giant Bladder Diverticula.

Vesical diverticula may on occasion reach very large size, containing more urine than the bladder proper. Depending on its position, a diverticulum may cause displacement of the lower ureter. Medial deviation of the pelvic ureter, by which a non-visualized diverticulum may be diagnosed, is not rare. The case to be described is exceptional in that both medial and lateral deviation of the ureters was present in the same patient, due to giant bilateral diverticula.