Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma.

BACKGROUND: Sorafenib is an orally available kinase inhibitor with activity at Raf, PDGFß and VEGF receptors that is licensed for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Current evidence-based post-nephrectomy management of individuals with localized RCC consists of surveillance-based follow up. The SORCE trial is designed to investigate whether treatment with adjuvant sorafenib can reduce recurrence rates in this cohort. CASE PRESENTATION: Here we report an idiosyncratic reaction to sorafenib resulting in fatal hepatotoxicity and associated renal failure in a 62 year-old man treated with sorafenib within the SORCE trial. CONCLUSION: This is the first reported case of sorafenib exposure associated fatal toxicity in the adjuvant setting and highlights the unpredictable adverse effects of novel adjuvant therapies.

National and international variation in the registration of bladder cancer.

OBJECTIVE: To determine whether variations exist in the methods by which different cancer registries record information on bladder cancers. METHODS: The registration practices of the various cancer registries within the UK, Europe and the USA were investigated by consulting the available publications and by correspondence with registry staff. In addition, a telephone survey was carried out within the UK to determine whether the national guidelines on bladder cancer coding were being followed. RESULTS: There is variation in the registration of bladder cancers both among regions within the UK and between the UK and other regions. The telephone survey showed that only four of the 11 UK regional registries were correctly following the national bladder cancer coding guidelines. Bladder cancer registration also varies between the cancer registries within mainland Europe. When comparing registration practices in the UK and the USA the major difference is that cases of bladder carcinoma in situ and pTa transitional cell carcinoma are included in the North American cancer statistics but not in the British cancer statistics. CONCLUSION: Much needs to be done before it can be claimed that the registration of bladder cancers has been standardized either nationally or internationally. In particular, the differences in registration practices between the UK and the USA will tend to give a falsely low impression of British incidence and survival rates compared with the equivalent North American figures. This confounding factor must be considered if these incidence and survival values are to be compared.

The influence of histological diagnosis on the postoperative complication rate following trans-urethral resection of prostate (TURP).

BACKGROUND: A number of studies have shown that the early mortality following TURP is higher for patients with prostate cancer than those with benign disease. This study examines the effect of the histological diagnosis on the predischarge complication rate following TURP. METHODS: Information on the postoperative, predischarge complications of 3036 patients, who underwent TURP over the last decade at our institution, was collated from the urology department database (AuditBase for Windows). The information on this database is collected prospectively, at the point of care and validated at monthly audit meetings. Statistical analyses were performed using chi2 and difference of proportion where n > 60. Statistical significance was taken as P < 0.05. RESULTS: The postoperative, predischarge major complication rate for patients with benign disease was 2.1%. This was not statistically different from the 2.3% complication rate seen in patients with malignant disease. Patients suffering a postoperative complication stayed in hospital significantly longer than those who had a straightforward postoperative course (P < 0.001); however, patients with malignant histology suffering a postoperative complication did not stay statistically significantly longer than those with benign histology suffering a postoperative complication (P < 0.1). CONCLUSIONS: Patients undergoing TURP for prostate cancer do not suffer more postoperative, predischarge complications or stay in hospital longer than patients undergoing TURP for benign disease.

Phosphine generation by mixed- and monoseptic-cultures of anaerobic bacteria.

A microbial basis for bioreductive generation of phosphine is proposed, which could account at least in part for the presence of this toxic gas in natural anaerobic environments and in sewage and landfill gases. Phosphine generation under anaerobic growth conditions was dependent upon both the culture inoculum source (animal faeces) and enrichment culture conditions. Phosphine was detected in headspace gases from mixed cultures under conditions promoting fermentative growth of mixed acid and butyric acid bacteria, either in the presence or absence of methane generation. Monoseptic cultures of certain mixed acid fermentors (Escherichia coli, Salmonella gallinarum, and Salmonella arizonae) and solvent fermentors (Clostridium sporogenes, Clostridium acetobutyricum and Clostridium cochliarium) also generated phosphine. Such fermentative bacteria participate in the multi-stage process of methanogenesis in nature. Generation of phosphine by these bacteria, rather than by methanoarchaea themselves, could explain the apparent correlation between methanogenesis and the formation of phosphine in nature.

An audit of positive findings in flexible and rigid check cystoscopy.

Both flexible and rigid cysto-urethroscopy are routinely used in the surveillance of transitional cell bladder tumours. This study addressed the issue of patient selection for either rigid or flexible cystoscopy. What proportion of positive findings at flexible cystoscopy and negative findings at rigid cystoscopy are acceptable? Standards were set of 10% for the former and 50% for the latter and our practice was then audited. A retrospective analysis of 800 patients undergoing check cystoscopy revealed a positive finding rate of 8.3% using the flexible instrument and 48.1% using the rigid instrument.

NATALI--a model for National Computer Databases in the investigation of new therapeutic techniques.

New medical treatments are often introduced without the benefit of randomized trials. We describe how a national computerized database was produced, by the Thrombolysis Study Group, for monitoring one such new treatment: peripheral arterial thrombolysis. A novel method for transferring angiograms to computer generated arterial maps that can help in the classification and analysis of the outcome of thrombolysis is also described. Data provided by prospective collection from 14 hospitals within the UK was entered onto the database (Auditbase for Windows), to give contributing members a continual audit of their own results and complications that can be compared with that of the group as a whole. This system may be an appropriate model for other forms of multi-centre audit and the monitoring of new treatments.

Computerized angiographic analysis of the outcome of peripheral thrombolysis.

BACKGROUND: Catheter-directed peripheral thrombolysis is used increasingly for the management of acute limb ischemia. The comparison of different agents and techniques has proven difficult because of the variations in patient presentation, vessel involvement, and treatment methods. METHODS: A computerized database in which angiographic information is stored on computerized arterial maps has been designed to record details of thrombolysis. RESULTS: A total of 201 patients who presented with rest pain were recorded on the database, and their angiograms were analyzed. There were 123 native-vessel and 78 graft occlusions. Immediate success of lysis and 30-day outcome were not dependent on the site of the occlusion. If an underlying stenosis was revealed, limb salvage rates were significantly greater than when none was found (82% versus 58%, P < 0.01). The presence of at least 1 run-off vessel increased limb salvage rates by 30% (P < 0.001). If more than 5 arterial segments were occluded on the prelysis angiogram, limb salvage was worse than if there were fewer than 5 (57% versus 85%, P < 0.0001). For grafts, less than 5 segments of occlusion led to limb salvage rates of 90%, and more than 5 segments of occlusion led to rates of 72% (P = 0.07). CONCLUSIONS: This simple and user-friendly system of computerized angiographic analysis will enable detailed examination of thrombolytic practice and assist in the prediction of success.

Mechanisms responsible for diminished fragmentation of ureteral calculi: an experimental and clinical study.

We molded 24 synthetic stones (mean weight 680 mg., range 641 to 715) from a commercial mixture of gypsum, silica, cellulose and polyvinyl acetate. Each stone was subjected to 400 shocks on a Wolf 2300 Piezolith and groups of 6 stones were treated in 4 different modes. Mean amounts fragmented were 243 +/- 18 mg. in a free environment, 62 +/- 18 mg. confined loosely in a latex tube, 22 +/- 8 mg. impacted in the tube and 30 +/- 8 mg. impacted alongside a 7F stent. During a 30-month period 118 patients received in situ extracorporeal shock wave lithotripsy for ureteral calculi using the same lithotriptor. The mean stone burden was 11.4 mm. (range 4 to 29). Success was greater for patients with calculi 10 mm. or less than for those with stones greater than 10 mm. (71% versus 51%, p less than 0.05), despite the former group receiving less shocks (5,404 versus 7,491). The influence of size was then excluded by studying the number of shocks delivered per mm. of calculus. Patients receiving 500 to 699 shocks per mm. showed a higher success rate than those receiving a smaller number of shocks per mm. Treatment with a greater number of shocks per mm. did not improve success rate. The experimental study demonstrated that confinement and impaction significantly diminish the rate of fragmentation of calculi. However, the clinical study suggested that there may be an optimum number of shocks per mm. that should be delivered. Treatment beyond this point fails to improve results. The 28% failure rate even in those receiving the highest number of shocks per mm. suggests that large, impacted calculi are unsuitable for treatment with in situ shock wave lithotripsy on this machine.

J-wire facilitates retrograde manipulation of ureteric calculi prior to extracorporeal shock wave lithotripsy.

During a 13-month period, 55 patients underwent attempted retrograde manipulation for ureteric lying above the pelvic brim. The mean stone burden was 11 mm (range 5-21); 41 stones (75%) were primary ureteric calculi and 14 (25%) were fragments resulting from extracorporeal shock wave lithotripsy to renal calculi. The method of retrograde manipulation was recorded prospectively. Retrograde flushing through an 8F angiography catheter with a mixture of saline and lignocaine gel was successful in 27 patients (49%). The insertion of a J-wire through the angiocath allowed for successful manipulation in a further 17 patients (31%). Retrograde manipulation was impossible in 11 patients (20%). There were 4 complications (7%), none attributable to the use of a J-wire.

An investigation of factors influencing the in vitro induction of LAK activity against a variety of human bladder cancer cell lines.

We investigated the sensitivity of transitional cell carcinoma cells, derived from the human bladder, to lymphokine activated killer cells. Recombinant interleukin-2 activated peripheral blood mononuclear cells were studied for their ability to mediate the cytolysis of a panel of four established human bladder transitional cell carcinoma cell lines. Lymphokine activated killer activity was assessed using a standard four hour chromium release assay. All four bladder cancer cell lines proved to be susceptible to lymphokine activated killer mediated cytolysis. This was found to be dependent upon the dose of cytokine and upon the duration of the activation period. The four cell lines were differentially susceptible to lysis (specific cytotoxicity at effector to target ratio of 40:1; RT112 = 22.9%, RT4 = 49.2%, MGH-U1 = 49.1%, EJ18 = 62.3%). The varying susceptibility of lymphokine activated killer mediated cytotoxicity was found to be independent of the histological grade of the parent tumour or the donor of effector cells. Both interferon-alpha and tumour necrosis factor-alpha also elicited lymphokine activated killer cell activity, although the maximum specific cytotoxicity achieved was considerably lower than that obtained with interleukin-2 alone. Interleukin-2, at optimal concentration, and tumour necrosis factor-alpha were found to behave synergistically in the generation of lymphokine activated killer effectors. However, concentrations of tumour necrosis factor-alpha higher than 100 Uml.-1 resulted in a decrease in specific cytotoxicity. These findings suggest a possible use of adoptive immunotherapy in human bladder cancer and indicate the optimum conditions for the generation of such effector cells.

Does further extracorporeal lithotripsy promote clearance of small residual fragments?

Small persistent fragments (less than or equal to 4 mm) following extracorporeal shock wave lithotripsy have been termed clinically insignificant residual fragments (CIRF), but their presence may be associated with an increased rate of development of recurrent symptomatic renal calculi. We have adopted a policy of further extracorporeal piezoelectric shock wave lithotripsy (EPL) for patients with CIRF in an attempt to promote complete clearance. A series of 22 patients with a mean initial stone burden of 16 mm (range 7-48) developed CIRF after a median of 2 EPL treatment sessions (range 1-9). CIRF were in the lower calices (n = 20), middle calices (n = 1) and upper calices (n = 1). These calices were normal (n = 6), slightly dilated (n = 9), moderately dilated (n = 2) or grossly dilated (n = 5). After 6 to 14 months, patients underwent a further session of EPL. One month later, 3 patients with normal calices showed a considerable reduction in CIRF, but all other patients showed no change. When CIRF form in normal calices a further session of EPL may promote clearance. However, when calices containing CIRF are significantly dilated, further EPL is of no value.