Randomized phase II study investigating pazopanib versus weekly paclitaxel in relapsed or progressive urothelial cancer

Purpose: Two previous single-arm trials have drawn conflicting conclusions regarding the activity of pazopanib in urothelial cancers after failure of platinum-based chemotherapy. Patients and Methods: This randomized (1:1) open-label phase II trial compared the efficacy of pazopanib 800 mg orally with paclitaxel (80 mg/m2 days 1, 8, and 15 every 28 days) in the second-line setting. The primary end point was overall survival (OS). Results: Between August 2012 and October 2014, 131 patients, out of 140 planned, were randomly assigned. The study was terminated early on the recommendation of the independent data monitoring committee because of futility. Final analysis after the preplanned number of deaths (n = 110) occurred after a median follow-up of 18 months. One hundred fifteen deaths had occurred at the final data extract presented here. Median OS was 8.0 months for paclitaxel (80% CI, 6.9 to 9.7 months) and 4.7 months for pazopanib (80% CI, 4.2 to 6.4 months). The hazard ratio (HR) adjusted for baseline stratification factors was 1.28 (80% CI, 0.99 to 1.67; one-sided P = .89). Median progression-free survival was 4.1 months for paclitaxel (80% CI, 3.0 to 5.6 months) and 3.1 months for pazopanib (80% CI, 2.7 to 4.6 months; HR, 1.09; 80% CI, 0.85 to 1.40; one-sided P = .67). Discontinuations for toxicity occurred in 7.8% and 23.1% for paclitaxel and pazopanib, respectively. Conclusion: Pazopanib did not have greater efficacy than paclitaxel in the second-line treatment of urothelial cancers. There was a trend toward superior OS for paclitaxel

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

Addition of Docetaxel to First-line Long-term Hormone Therapy in Prostate Cancer (STAMPEDE) : Modelling to Estimate Long-term Survival, Quality-adjusted Survival, and Cost-effectiveness

Background Results from large randomised controlled trials have shown that adding docetaxel to the standard of care (SOC) for men initiating hormone therapy for prostate cancer (PC) prolongs survival for those with metastatic disease and prolongs failure-free survival for those without. To date there has been no formal assessment of whether funding docetaxel in this setting represents an appropriate use of UK National Health Service (NHS) resources. Objective To assess whether administering docetaxel to men with PC starting long-term hormone therapy is cost-effective in a UK setting. Design, setting, and participants We modelled health outcomes and costs in the UK NHS using data collected within the STAMPEDE trial, which enrolled men with high-risk, locally advanced metastatic or recurrent PC starting first-line hormone therapy. Intervention SOC was hormone therapy for ≥2 yr and radiotherapy in some patients. Docetaxel (75 mg/m2) was administered alongside SOC for six three-weekly cycles. Outcome measurements and statistical analysis The model generated lifetime predictions of costs, changes in survival duration, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Results and limitations The model predicted that docetaxel would extend survival (discounted quality-adjusted survival) by 0.89 yr (0.51) for metastatic PC and 0.78 yr (0.39) for nonmetastatic PC, and would be cost-effective in metastatic PC (ICER £5514/QALY vs SOC) and nonmetastatic PC (higher QALYs, lower costs vs SOC). Docetaxel remained cost-effective in nonmetastatic PC when the assumption of no survival advantage was modelled. Conclusions Docetaxel is cost-effective among patients with nonmetastatic and metastatic PC in a UK setting. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in patients with nonmetastatic PC, as the opportunity to offer docetaxel at hormone therapy initiation will be missed for some patients by the time more mature survival data are available. Patient summary Starting docetaxel chemotherapy alongside hormone therapy represents a good use of UK National Health Service resources for patients with prostate cancer that is high risk or has spread to other parts of the body.This study was supported by the UK Medical Research Council (delegation to Swiss Group for Cancer Clinical Research [SAKK] in Switzerland) grant number MRC_MC_UU_12023/25 and the following funders: Cancer Research UK (grant number CRUK_A12459), Medical Research Council, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis. The sponsors played no direct role in the study

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy

BACKGROUND Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. METHODS We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). RESULTS A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). CONCLUSIONS Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476, and Current Controlled Trials number, ISRCTN78818544.

Evaluation of some mangrove species on the nature of their reproduction along the coastal belt of the Indian Sunderbans

Reproductive biology of three dominating mangrove species Rhizophora mucronata, Ceriops decandra and Avicennia marina from the Indian Sunderbans were studied. A comparative account on all floral parts revealed that as the bud progresses to completely open, the length of androecium surpassed the length of gynoecium and the anther matured first thus showing protandrous nature and favouring cross-fertilization. A study of pollen grain viability revealed that all of them produces fairly good amounts of viable pollen grains in their natural condition. The pollens showed their maximum viability late in the morning till early noon. The stigma showed peak receptivity after three days of flower opening in C. decandra and four days of flower opening in R. mucronata and A. marina. All the species showed out-breeding mechanism of pollination. The fruit setting percentage obtained by xenogamy was the highest and autogamy failed to show any result in all the three genera. Although Ceriops decandra and Avicennia marina showed very limited fruit set with geitonogamy, these two species can be called facultative out-crossers, while Rhizophora was obligate outcrosser in nature. The study on floral structure, pollen viability along with stigma receptivity of the investigated taxa guided to maximum exploitation of reproductive behavior for rising artificial and natural plant population in addition to build up a future research strategy in ecosystem conservation

Synthetic studies toward complex diterpenoids. Stereocontrolled total synthesis of some gibbane synthons and degradation products of gibberellins

This article does not have an abstract

Condensed cyclic and bridged-ring systems. Part III. Regioselectivity and stereoselectivity in the acid-catalysed cyclisations of substituted benzylcyclohexanols. Stereocontrolled synthesis of some gem-carboxy-methyl-substituted hexahydrofluorene and hexahydro-5,9-methanobenzocyclo-octene derivatives

Treatment of ethyl 2-benzyl-2-hydroxy-1,3-dimethylcyclohexanecarboxylate (8) with polyphosphoric acid produced either (±)-c-2-benzyl-1,3-dimethylcyclohexane-r-1,c-3-carbolactone (6) or a mixture from which (1RS,4aRS,9aRS)2,3,4,4a,9,9a-hexahydro-1,4a-dimethyl-1H-fluorene-1-carboxylic acid (5a) was isolated in a moderate yield, depending upon the reaction temperature. Whereas aluminium chloride-catalysed cyclisation of the lactone (6) resulted in the stereospecific formation of (5SR,8RS,9SR,11RS)-5,6,7,8,9,10-hexahydro-8,11-dimethyl-5,9-methanobenzocyclo-octene-8-carboxylic acid (9), the epimeric t-2-benzyl lactone (7) produced a mixture of the hexahydrofluorene acid (5a) and the epimeric (8SR)-hexahydromethanobenzocyclo-octene acid (12), in high yields. By a similar process (±)-methyl t-2-benzyl-t-3-hydroxy-1,3-dimethylcyclohexane-r-1-carboxylate (4) gave the acid (9) and a mixture of hexahydrofluorene ester (5b) and (8SR)-hexahydromethanobenzocyclo-octene (13). Structures and configurations of the bridged-ring compounds were determined from chemical and n.m.r. spectral studies. Ready alkaline hydrolysis of the tertiary ester group in (5SR,8RS,9SR,11SR)-methyl 5,6,7,8,9,10-hexahydro-8,11-dimethyl-10-oxo-5,9-methanobenzocyclo-octene-8-carboxylate (11), through intramolecular oxo-group participation, revealed the stereochemistry of the ester group. The observed differences in the nature of products in polyphosphoric acid-catalysed cyclisation of (8) and the behavioural differences shown by the diastereoisomeric lactones (6) and (7) and the hydroxy-ester (4) in aluminium chloride-induced cyclisations are rationalised on the basis of steric and stereoelectronic factors in the intermediate cations as well as the thermodynamic stability of the products under reversible reaction conditions

Condensed cyclic and bridged-ring systems. Part IV. Stereochemically controlled synthesis of some endo-2-aryl-6-oxobicyclo[3.2.1]octanes and related compounds through intramolecular alkylations of &#947;<SUP>&#948;</SUP>-unsaturated &#945;'-diazomethyl ketones

The 4-arylcyclohex-3-enecarboxylic acids (4a-d), prepared through a modified Diels-Alder reaction, have been converted via the corresponding diazomethyl ketones (5a-d) into cyclopropyl ketones (6a-d) and the 2-aryl-6-oxobicyclo[3.2.1]oct-2-ene derivatives (7a-d), by oxo-carbenoid addition and boron trifluoride-ether-catalysed cyclisation, respectively, in excellent yields. In addition to the unsaturated ketones (7a and c), the hydroxy-ketones (10a and c) were also obtained in the aqueous tetrafluoroboric acid-catalysed cyclisation of the diazoketones (5a and c). Catalytic reduction of the cyclopropyl ketones and the unsaturated ketones produced the endo-2-aryl-6-oxobicyclo[3.2.1]octane derivatives (8a-d) exclusively

(±)-des-N-morphinan: a unique bridged hydrocarbon attractant for the rhinoceros beetle, Oryctes rhinoceros; and development of an olfactometer

An olfactometer designed for Oryctes rhinoceros (L.) is described and its effectiveness demonstrated by a comparison of results with field tested chemicals. Using the olfactometer, (±)-Des-N-morphinan, but not its stereoisomer was found to be a strong attractant for adult rhinoceros beetles. This is the 1st synthetic bridged hydrocarbon found to be an insect attractant