Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.

BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer.

PURPOSE: We have previously reported that radiotherapy (RT) added to androgen-deprivation therapy (ADT) improves survival in men with locally advanced prostate cancer. Here, we report the prespecified final analysis of this randomized trial. PATIENTS AND METHODS: NCIC Clinical Trials Group PR.3/Medical Research Council PR07/Intergroup T94-0110 was a randomized controlled trial of patients with locally advanced prostate cancer. Patients with T3-4, N0/Nx, M0 prostate cancer or T1-2 disease with either prostate-specific antigen (PSA) of more than 40 µg/L or PSA of 20 to 40 µg/L plus Gleason score of 8 to 10 were randomly assigned to lifelong ADT alone or to ADT+RT. The RT dose was 64 to 69 Gy in 35 to 39 fractions to the prostate and pelvis or prostate alone. Overall survival was compared using a log-rank test stratified for prespecified variables. RESULTS: One thousand two hundred five patients were randomly assigned between 1995 and 2005, 602 to ADT alone and 603 to ADT+RT. At a median follow-up time of 8 years, 465 patients had died, including 199 patients from prostate cancer. Overall survival was significantly improved in the patients allocated to ADT+RT (hazard ratio [HR], 0.70; 95% CI, 0.57 to 0.85; P < .001). Deaths from prostate cancer were significantly reduced by the addition of RT to ADT (HR, 0.46; 95% CI, 0.34 to 0.61; P < .001). Patients on ADT+RT reported a higher frequency of adverse events related to bowel toxicity, but only two of 589 patients had grade 3 or greater diarrhea at 24 months after RT. CONCLUSION: This analysis demonstrates that the previously reported benefit in survival is maintained at a median follow-up of 8 years and firmly establishes the role of RT in the treatment of men with locally advanced prostate cancer.

Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019).

BACKGROUND: Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa--the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)--includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort. OBJECTIVE: Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group. DESIGN, SETTING, AND PARTICIPANTS: STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models. RESULTS AND LIMITATIONS: A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow-up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n=574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2-yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68-76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population. CONCLUSIONS: Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse. PATIENT SUMMARY: Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body.

The cost of service quality improvements: tracking the flow of funds in social franchise networks in Myanmar.

INTRODUCTION: This paper examines the cost of quality improvements in Population Services International (PSI) Myanmar's social franchise operations from 2007 to 2009. METHODS: The social franchise commodities studied were products for reproductive health, malaria, STIs, pneumonia, and diarrhea. This project applied ingredients based costing for labor, supplies, transport, and overhead. Data were gathered seven during key informant interviews with staff in the central Yangon office, examination of 3 years of payroll data, examination of a time motion study conducted by PSI, and spreadsheets recording the costs of acquiring and transporting supplies. RESULTS: In 2009 PSI Myanmar's social franchise devoted $2.02 million towards a 94% reduction in commodity prices offered to its network of over 1700 primary care providers. These providers retained 1/3 of the subsidy as revenue and passed along the other 2/3 to their patients in the course of offering subsidized care for 1.5 million health episodes. In addition, PSI Myanmar devoted $2.09 million to support a team of franchise officers who conducted quality assurance for the private providers overseeing service quality and to distributing medical commodities. CONCLUSION: In Myanmar, the social franchise operated by PSI spends roughly $1.00 in quality management and retailing for every $1.00 spent subsidizing medical commodities. Some services are free, but patients also pay fees for other lines of service. Overall patients contribute 1/6 as much as PSI does. Unlike other NGO's, health services in social franchises like PSI are not all free to the patients, nor are the discounts uniformly applied. Discounts and subsidies evolve in response to public health concerns, market demand, providers' cost structures as well as strategic objectives in maintaining the network and its portfolio of services.

Reaching men who have sex with men in Myanmar: population characteristics, risk and preventive behavior, exposure to health programs.

To estimate risk behavior and HIV program reach among men who have sex with men (MSM) in Myanmar, we conducted cross-sectional surveys in four cities (Yangon, Mandalay, Pathein, Monywa) using respondent-driven sampling (RDS). Prevention response indicators across the cities ranged from 56 to 70 % testing for HIV and receiving results last year, 89-100 % identifying ways of preventing transmission, 50-95 % rejecting misconceptions about HIV, and 82-94 % using a condom at last anal sex. MSM in smaller cities had similar or higher use of programs compared those in larger cities. MSM classified as Ah Chawk Ma (broadly feminine gender presentation) reported having more sex partners, less consistent condom use, and more frequent history of sexually transmitted infections compared to those described as Tha Ngwe (broadly masculine gender presentation). Our behavioral survey data help advocate for appropriate services and form a baseline to gauge future impact of the HIV response for this marginalized population.

Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial.

BACKGROUND: Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer. METHODS: Patients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65-69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at controlledtrials.com as ISRCTN24991896 and Clinicaltrials.gov as NCT00002633. RESULTS: Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4-8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70-78 vs 66%, 60-70; hazard ratio [HR] 0·77, 95% CI 0·61-0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups). INTERPRETATION: The benefits of combined modality treatment--ADT and RT--should be discussed with all patients with locally advanced prostate cancer. FUNDING: Canadian Cancer Society Research Institute, US National Cancer Institute, and UK Medical Research Council.

Metronomic chemotherapy dosing-schedules with estramustine and temozolomide act synergistically with anti-VEGFR-2 antibody to cause inhibition of human umbilical venous endothelial cell growth.

UNLABELLED: The effects of 'metronomic' or extended chemotherapy dosing schedules (ECS) are mediated through poorly understood anti-angiogenic mechanisms. ECS combined with biological anti-angiogenic agents have produced promising pre-clinical results. MATERIALS AND METHODS: We have expanded the list of agents with an in vitro ECS profile to include the methylating agent temozolomide (Temodal) and the anti-mitotic agent estramustine (Estracyt). These agents were also combined with a specific anti-angiogenic inhibitor IMC-1C11 and a non-specific agent with anti-angiogenic properties, Compound 5h. The in vitro HUVEC ECS model system was optimised and cell proliferation assays undertaken. RESULTS: As a single agent, estramustine inhibited endothelial cell proliferation with an IC50 of 4.5 microM and was active at 10-33% of the maximum tolerated dose (MTD) from clinical schedules, whilst temozolomide had IC50 of 6.6 microM and was active at 1-6% of MTD. In combination, significant synergy was seen with IMC-1C11 in combination with either drug, whilst modest additive effects were observed with Compound 5h. None of the combinations resulted in significant cytotoxicity or apoptosis. DISCUSSION: The results show that ECS of temozolomide and estramustine can be significantly enhanced when combined with specific anti-angiogenic inhibitors in an in vitro HUVEC system.

From total empiricism to a rational design of metronomic chemotherapy phase I dosing trials.

'Metronomic chemotherapy' represents a novel anti-angiogenic strategy whereby low-dose chemotherapy is utilized in a continuous fashion in order to target tumor endothelium. There are many potential advantages of this strategy and clinical trials are already underway. However, although the scheduling of metronomic chemotherapy is relatively unequivocal, metronomic dosing principles are at present poorly defined. Arbitrarily, 10-33% of the maximum tolerated dose comprises 'the dose range'. We argue that this is too empirical and propose a set of phase I metronomic chemotherapy dosing strategies based on a principled approach which may help to reduce the problem of empiricism in dosing for metronomic chemotherapy trials.

Long-term follow-up of initially successful trabeculectomy with 5-fluorouracil injections.

PURPOSE: To study the long-term results (1-14 years) of trabeculectomies with 5-fluorouracil injections that were successful at 1 year. DESIGN: A retrospective noncomparative case series. INTERVENTION/PARTICIPANTS: We identified 87 patients (87 eyes) who had trabeculectomies with 5-fluorouracil injections from 1984 to 1989 that were successful at 1 year and had a follow-up range of 1.0 to 14.7 years (mean, 8.1, standard deviation of 4.4 years). All patients had previously failed glaucoma surgery (66.7%), cataract surgery (47.1%), or other diagnoses making them at high risk for failure. MAIN OUTCOME MEASURES: Successful control of intraocular pressure (IOP) was defined as IOP less than 21 mmHg or a reduction of 33% if preoperative pressure was less than 21 mmHg. Statistical analysis was performed using Kaplan-Meier life table analysis. RESULTS: If an eye is considered successful by IOP at 1 year, the probability of successful control is 61% at 5 years, 44% at 10 years, and 41% at 14 years. CONCLUSIONS: Despite successful IOP control at 1 year, trabeculectomies with 5-fluorouracil injections show a continual loss of IOP control over time.

The role of Acucise endopyelotomy in the treatment of ureteropelvic junction obstruction.

OBJECTIVE: Open surgical pyeloplasty has been the gold standard for the correction of ureteropelvic junction obstruction (UPJO). Endourological management of UPJO has gained increased acceptance, with reported success rates of 57-87%. It has been suggested that Acucise endopyelotomy (AE) should be the procedure of choice for patients with UPJO. The aim of this study was to assess the effectiveness of AE in the treatment of UPJO and the factors contributing to surgical outcome. MATERIALS AND METHODS: Forty-two patients (34 primary, 8 secondary UPJO) underwent AE between June 1995 and December 1999. Presenting symptoms were; pain 34 (80.9%), UTI 10 (23.8%) and haematuria 5 (11.9%). Preoperative evaluation included ultrasound and/or intravenous urogram with diuretic renography. Hydronephrosis was graded in 36 patients. Of these 4, 14, 9 and 9 had grade I, II, III and IV hydronephrosis, respectively. Twenty-four patients were stented prior to endopyelotomy and one required nephrostomy. Overall (true) success was defined as clinically pain free and radiologically no evidence of obstruction on diuretic scan. RESULTS: The average operating time was 45 min and mean hospital stay was 2.7 days. Mean follow-up was 27 months (range 6-55). The objective success rate was 52% and the subjective success rate was 64%. A total of 19 patients (45.2%) had long lasting clinical and radiographic treatment success. Three (7%) patients required nephrectomy and five (12%) underwent open pyeloplasty. Success rate for grade I/II hydronephrosis was 55.5% and only 27.7% with grade III/IV hydronephrosis. Normal renograms were found in 12 (48%) of those with perioperative extravasation compared to three (25%) without. Only one of the eight patients with secondary UPJO had a normal post-operative renogram. Size or type of stent used had no effect on surgical outcome. The substandard results were noted in patients with grade III/IV hydronephrosis, poor pre-operative renal function, secondary UPJO and without perioperative extravasation. CONCLUSIONS: Acucise endopyelotomy is a safe and minimally invasive procedure for the management of UPJO. Although the results of AE are suboptimal, its lower degree of invasiveness makes it reasonable choice for first-line treatment. Careful selection of patients will improve the results of AE, although multicentre randomized trials are needed to make a valued comparison with other techniques.

Patients with new onset haematuria: assessing the discriminant value of clinical information in relation to urological malignancies.

BACKGROUND: There is little information available to assist general practitioners (GPs) in deciding which patients with haematuria are likely to have a malignancy. AIM: To derive discriminant functions for specific items or clusters of clinical history information in relation to the categorisation of patients presenting to the 'open access' haematuria clinic in Hull. DESIGN OF STUDY: Recruitment of patients via an 'open-access' haematuria clinic. SETTING: A consecutive series of 363 patients aged between 18 and 80 years who attended the clinic. METHOD: Between February 1999 and October 1999 clinical history information derived from the participating patients was compared with the patients' diagnoses. Diagnoses were established by a combination of cystoscopy and radiological assessments and rechecked against the patient records and the hospital patient administration system two to three months later. RESULTS: A number of individual variables seemed to be particularly helpful in discriminating malignancies. However, when indicants were combined using regression shrinkage techniques, only the following variables were preserved: age, sex, type of haematuria, number of episodes of haematuria, hesitancy, poor urinary stream, smoking history, and history of urinary tract infections. CONCLUSION: It is possible to generate helpful discriminant information to assist GPs in making more appropriate decisions in a difficult area of clinical practice. However, it remains a matter of judgement as to how representative the study population is likely to be compared with all haematuria patients encountered in primary care. We have reasonable confidence in the general applicability of the rules for macroscopic haematuria: however, it seems likely that the prediction rules outlined for microscopic haematuria have their greatest relevance once a patient has been referred by a GP. In developing the work further and testing out the discriminators identified in this study, we propose that a primary care-based project now needs to be undertaken focusing on microscopic haematuria with a particular emphasis on addressing selection biases. In addition, there is a more general need to assess the reliability of all the suggested items of clinical discriminant information.