| 1. |
- Ademuyiwa, Adesoji O., et al.
(författare)
-
Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
-
Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
|
|
| 2. |
- Beer, Tomasz M., et al.
(författare)
-
Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer : Extended Analysis of the Phase 3 PREVAIL Study
- 2017
-
Ingår i: European Urology. - : Elsevier BV. - 0302-2838. ; 71:2, s. 151-154
-
Tidskriftsartikel (refereegranskat)abstract
- Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the longer-term efficacy and safety of enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety. Enzalutamide reduced the risk of radiographic progression or death by 68% (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.28–0.37; p < 0.0001) and the risk of death by 23% (HR 0.77, 95% CI 0.67–0.88; p = 0.0002). Median investigator-assessed rPFS was 20.0 mo (95% CI 18.9–22.1) in the enzalutamide arm and 5.4 mo (95% CI 4.1–5.6) in the placebo arm. Median OS was 35.3 mo (95% CI 32.2–not yet reached) in the enzalutamide arm and 31.3 mo (95% CI 28.8–34.2) in the placebo arm. At the time of the OS analysis, 167 patients in the placebo arm had crossed over to receive enzalutamide. The most common adverse events in the enzalutamide arm were fatigue, back pain, constipation, and arthralgia. This final analysis of PREVAIL provides more complete assessment of the clinical benefit of enzalutamide. PREVAIL is registered on ClinicalTrials.gov as NCT01212991. Patient summary According to data from longer follow-up, enzalutamide continued to provide benefit over placebo in patients with metastatic castration-resistant prostate cancer.
|
|
| 3. |
- Beer, Tomasz M, et al.
(författare)
-
Enzalutamide in metastatic prostate cancer before chemotherapy
- 2014
-
Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 371:5, s. 33-424
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy.METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival.RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment.CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).
|
|
| 4. |
- Carducci, Michael A., et al.
(författare)
-
A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer
- 2007
-
Ingår i: Cancer. - : Wiley. - 1097-0142 .- 0008-543X. ; 110:9, s. 1959-1966
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. The objective of this study was to evaluate the efficacy and safety of atrasentan (Xinlay), a selective endothelin-A receptor antagonist, in patients with metastatic hormone- refractory prostate cancer (HRPC). METHODS. This multinational, double-blind, placebo-controlled trial enrolled 809 men with metastatic HRPC. Patients were randomized 1:1 to receive either atrasentan 10 mg per day or placebo. The primary endpoint was time to disease progression (TTP), which was determined according to radiographic and clinical measures. Analyses of overall survival and changes in biomarkers also were performed. RESULTS. Atrasentan did not reduce the risk of disease progression relative to placebo (hazards ratio, 0.89; 95% confidence interval, 0.76-1.04; P =.136). Most patients progressed radiographically at the first 12-week bone scan without concomitant clinical progression. In exploratory analyses, increases from baseline to final bone alkaline phosphatase (BAP) and prostate-specific antigen (PSA) levels were significantly lower with atrasentan treatment (P <.05 for each). The median time to BAP progression (> 50% increase from nadir) was twice as long with atrasentan treatment (505 days vs 254 days; P <.01). The delay in time to PSA progression did not reach statistical significance. Atrasentan generally was tolerated well, and the most common adverse events associated with treatment were headache, rhinitis, and peripheral edema, reflecting the vasodilatory and fluid-retention properties of endothelin-A receptor antagonism. CONCLUSIONS. Atrasentan did not delay disease progression in men with metastatic HRPC despite evidence of biologic effects on PSA and BAP as markers of disease burden.
|
|
| 5. |
- Chi, Kim N., et al.
(författare)
-
Castration-resistant Prostate Cancer: From New Pathophysiology to New Treatment Targets
- 2009
-
Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 56:4, s. 594-605
-
Tidskriftsartikel (refereegranskat)abstract
- Context: Castration-resistant prostate cancer (CRPC) refers to patients who no longer respond to surgical or medical castration. Standard treatment options are limited. Objective: To review the concepts and rationale behind targeted agents currently in late-stage clinical testing for patients with CRPC. Evidence acquisition: Novel targeted therapies in clinical trials were identified from registries. The MEDLINE database was searched for all relevant reports published from 1996 to October 2009. Bibliographies of the retrieved articles and major international meeting abstracts were hand-searched to identify additional studies. Evidence synthesis: Advances in our understanding of the molecular mechanisms underlying prostate cancer (PCa) progression has translated into a variety of treatment approaches. Agents targeting androgen receptor (AR) activation and local steroidogenesis, angiogenesis, immunotherapy, apoptosis, chaperone proteins, the insulin-like growth factor (IGF) pathway, RANK-ligand, endothelin receptors, and the Src family kinases are entering or have recently completed accrual to phase 3 trials for patients with CRPC. Conclusions: A number of new agents targeting mechanisms of PCa progression with early promising results are in clinical trials and have the potential to provide novel treatment options for CRPC in the near future. (C) 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.
|
|
| 6. |
- Ryan, Charles J, et al.
(författare)
-
Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302) : final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study
- 2015
-
Ingår i: The Lancet Oncology. - 1474-5488. ; 16:2, s. 60-152
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Abiraterone acetate plus prednisone significantly improved radiographic progression-free survival compared with placebo plus prednisone in men with chemotherapy-naive castration-resistant prostate cancer at the interim analyses of the COU-AA-302 trial. Here, we present the prespecified final analysis of the trial, assessing the effect of abiraterone acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent therapies.METHODS: In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 vs 1) were randomly assigned with a permuted block allocation scheme via a web response system in a 1:1 ratio to receive either abiraterone acetate (1000 mg once daily) plus prednisone (5 mg twice daily; abiraterone acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00887198.FINDINGS: At a median follow-up of 49.2 months (IQR 47.0-51.8), 741 (96%) of the prespecified 773 death events for the final analysis had been observed: 354 (65%) of 546 patients in the abiraterone acetate group and 387 (71%) of 542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received abiraterone acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall, 365 (67%) patients in the abiraterone acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. Median overall survival was significantly longer in the abiraterone acetate group than in the placebo group (34.7 months [95% CI 32.7-36.8] vs 30.3 months [28.7-33.3]; hazard ratio 0.81 [95% CI 0.70-0.93]; p=0.0033). The most common grade 3-4 adverse events of special interest were cardiac disorders (41 [8%] of 542 patients in the abiraterone acetate group vs 20 [4%] of 540 patients in the placebo group), increased alanine aminotransferase (32 [6%] vs four [<1%]), and hypertension (25 [5%] vs 17 [3%]).INTERPRETATION: In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of abiraterone acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer.FUNDING: Janssen Research & Development.
|
|
| 7. |
- Saad, Fred, et al.
(författare)
-
Preserving bone health in patients with hormone-sensitive prostate cancer: the role of bisphosphonates
- 2009
-
Ingår i: BJU International. - 1464-4096. ; 104:11, s. 1573-1579
-
Forskningsöversikt (refereegranskat)abstract
- Men with prostate cancer initiating androgen-deprivation therapy (ADT) may have multiple factors that threaten their skeletal health, including increased fracture risk from bone loss during ADT and the propensity to develop bone metastases, which may lead to skeletal-related events (SREs). Bisphosphonates have utility in oncology for patients with bone metastases to prevent bone loss during hormonal therapy and in the benign setting to treat osteoporosis. These agents have an emerging role in patients with hormone-sensitive prostate cancer (HSPC). Etidronate, alendronate, pamidronate, and zoledronic acid have all shown efficacy in preventing ADT-related bone loss. Alendronate and zoledronic acid have also been shown to increase bone mineral density vs baseline during ADT. Patients with bone metastases from HSPC who received 4 mg zoledronic acid every 3 or 4 weeks had a low incidence of skeletal complications, although controlled study data have not been reported. Bisphosphonate treatment in men with HSPC may be effective for the prevention of ADT-related bone loss, underscoring the importance of treating early to avoid SREs and potentially delay disease progression to metastatic bone disease.
|
|
| 8. |
- Smith, Matthew R, et al.
(författare)
-
Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.
- 2018
-
Ingår i: The New England journal of medicine. - 1533-4406. ; 378:15, s. 1408-1418
-
Tidskriftsartikel (refereegranskat)abstract
- Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis.We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death.A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%).Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204 .).
|
|
| 9. |
- Sternberg, Cora N., et al.
(författare)
-
Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer
- 2020
-
Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 382:23, s. 2197-2206
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Preliminary trial results showed that enzalutamide significantly improved metastasis-free survival among men who had nonmetastatic, castration-resistant prostate cancer and rapidly increasing prostate-specific antigen (PSA) levels while taking androgen-deprivation therapy. Results from the final analysis of overall survival have not yet been reported.Methods: In this double-blind, phase 3 trial, men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily. Overall survival was assessed with a group sequential testing procedure and an O’Brien–Fleming–type alpha-spending function.Results: As of October 15, 2019, a total of 288 of 933 patients (31%) in the enzalutamide group and 178 of 468 (38%) in the placebo group had died. Median overall survival was 67.0 months (95% confidence interval [CI], 64.0 to not reached) in the enzalutamide group and 56.3 months (95% CI, 54.4 to 63.0) in the placebo group (hazard ratio for death, 0.73; 95% CI, 0.61 to 0.89; P=0.001). The exposure-adjusted rate of adverse events of grade 3 or higher was 17 per 100 patient-years in the enzalutamide group and 20 per 100 patient-years in the placebo group. Adverse events in the enzalutamide group were consistent with those previously reported for enzalutamide; the most frequently reported events were fatigue and musculoskeletal events.Conclusions: Enzalutamide plus androgen-deprivation therapy resulted in longer median overall survival than placebo plus androgen-deprivation therapy among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. The risk of death associated with enzalutamide was 27% lower than with placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.)
|
|
