Fizazi K.,University Paris - Sud |
Scher H.I.,Sloan Kettering Cancer Center |
Molina A.,Janssen Research and Development |
Logothetis C.J.,University of Texas M. D. Anderson Cancer Center |
And 14 more authors.
The Lancet Oncology | Year: 2012
Background: Abiraterone acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study. Here, we present the final analysis of the study before crossover from placebo to abiraterone acetate (after 775 of the prespecified 797 death events). Methods: Between May 8, 2008, and July 28, 2009, this study enrolled 1195 patients at 147 sites in 13 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status, worst pain over the past 24 h on the Brief Pain Inventory-Short Form, number of previous chemotherapy regimens, and type of progression. Patients were randomly assigned (ratio 2:1) to receive either abiraterone acetate (1000 mg, once daily and orally) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone with a permuted block method via an interactive web response system. The primary endpoint was overall survival, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00091442. Findings: Of the 1195 eligible patients, 797 were randomly assigned to receive abiraterone acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20·2 months (IQR 18·4-22·1), median overall survival for the abiraterone group was longer than in the placebo group (15·8 months [95% CI 14·8-17·0] vs 11·2 months [10·4-13·1]; hazard ratio [HR] 0·74, 95% CI 0·64-0·86; p<0·0001). Median time to PSA progression (8·5 months, 95% CI 8·3-11·1, in the abiraterone group vs 6·6 months, 5·6-8·3, in the placebo group; HR 0·63, 0·52-0·78; p<0·0001), median radiologic progression-free survival (5·6 months, 5·6-6·5, vs 3·6 months, 2·9-5·5; HR 0·66, 0·58-0·76; p<0·0001), and proportion of patients who had a PSA response (235 [29·5%] of 797 patients vs 22 [5·5%] of 398; p<0·0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3-4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]). Interpretation: This final analysis confirms that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up. Funding: Janssen Research & Development. © 2012 Elsevier Ltd.
McCall P.,University of Glasgow |
Bennett L.,University of Glasgow |
Ahmad I.,Institute of Cancer science |
MacKenzie L.M.,University of Glasgow |
And 8 more authors.
British Journal of Cancer | Year: 2012
Background: Cell line models suggest that activation of NFκB is associated with progression of prostate cancer. This pathway may be a therapeutic target if these observations translate to clinical specimens. Methods: Immunohistochemistry measured NFκBp65 (p65), NFκBp65 nuclear localisation signal (NLS), NFκBp65 phosphorylated at ser 276 (p65 ser276), NFκBp65 phosphorylated at ser 536 (p65 ser536), IκBα phosphorylated at ser 32/36 (pIκBα ser32/36) and MMP-9 protein expression in 61 matched hormone naive prostate cancer (HNPC) and castrate-resistant prostate cancer (CRPC) tumours. Animal and cell models were used to investigate the role of NFκB inhibition in prostate carcinogenesis. Results: In HNPC tumours, NLS expression significantly associated with a shorter time to disease recurrence and disease-specific death. In CRPC tumours p65, pIκBα ser32/36 and MMP-9 expression significantly associated with shorter time to death from disease recurrence and shorter disease-specific death. MMP-9 and pIκBα ser32/36 expression significantly associated with metastases at recurrence and were independent of Gleason sum and prostate-specific antigen at recurrence. Expression of phosphorylated Akt was associated with increased p65 activation in mouse models and inhibition of NFκB in LNCaP cells significantly reduced cellular proliferation and induced apoptosis. Conclusion: These results provide further evidence that the NFκB pathway could be exploited as a target for CRPC. © 2012 Cancer Research UK All rights reserved.
Bernstein J.M.,Royal Infirmary |
Bernstein J.M.,Institute of Cancer science |
Andrews T.D.,University of Liverpool |
Slevin N.J.,Institute of Cancer science |
And 4 more authors.
Laryngoscope | Year: 2015
Objectives/Hypothesis: To determine the prognostic value of hypoxia-Associated markers carbonic anhydrase-9 (CA-9) and hypoxia-inducible factor-1α (HIF-1α) in advanced larynx and hypopharynx squamous cell carcinoma (SCCa) treated by organ preservation strategies.Study Design: Retrospective cohort study.Methods: Pretreatment CA-9 and HIF-1α expression, clinicopathologic data, and tumor volume were analyzed in a series of 114 patients with T3-4 SCCa larynx or hypopharynx treated by (chemo)radiation.Results: Adverse prognostic factors for locoregional control were T4 classification (P50.008), and for disease-specific survival were CA-9 positivity (P 5 0.039), T4 classification (P 5 0.001), larger tumor volume (P 5 0.004), N1-3 classification (P 5 0.002), and pretreatment hemoglobin<13.0 g/dl (P 5 0.014). With increasing CA-9 expression, there was a trend to increasing tumor recurrence (Ptrend50.009) and decreasing survival (Ptrend50.002). On multivariate analysis, independent variables were T4 classification (hazard ratio [HR] 13.54, P 5 0.01) for locoregional failure, and CA-9 positivity (HR58.02, P 5 0.042) and higher tumor volume (HR53.33, P 5 0.007) for disease-specific mortality.Conclusion: This is the first study to look specifically at T3 and T4 SCCa larynx and hypopharynx for a relationship between hypoxia-Associated marker expression and clinical outcome. Pretreatment immunohistochemical CA-9 expression is an adverse prognostic factor for disease-specific survival, indicating that CA-9 expression may confer a more aggressive tumor phenotype. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.
De Bono J.S.,Royal Marsden Hospital |
Logothetis C.J.,University of Texas M. D. Anderson Cancer Center |
Molina A.,Ortho Biotech Oncology Research and Development a Unit of Cougar Biotechnology |
Fizazi K.,Institute Gustave Roussy |
And 28 more authors.
New England Journal of Medicine | Year: 2011
BACKGROUND: Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. METHODS: We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. RESULTS: After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo - prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo - prednisone group. CONCLUSIONS: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 Clinical Trials. gov number, NCT00638690.) Copyright © 2011 Massachusetts Medical Society.
Tait C.,Christie NHS Foundation Trust |
Tait C.,Salford Royal NHS Foundation Trust |
Moore D.,University of Manchester |
Hodgson C.,University of Manchester |
And 9 more authors.
BJU International | Year: 2014
Results Patients with a higher metastasis number had a shorter PFS and OS (hazard ratio [HR] 2.0, 95% confidence interval [CI] 1.7-2.4; P < 0.001). Patients with 1-4 metastases had much better PFS and OS than those with 5-20 metastases. The median PFS and OS in the latter was 10.9 (95% CI 8.4-12.8) and 22.1 (95% CI: 18.5-24.5) months, respectively. PFS and OS for patients with >20 metastases were shorter still [median 5.3 (95% CI 3.4-6.9) months and 13.3 (95% CI 11.3-17.6) months, respectively]. Dichotomising into cohorts with 1-4 and ≥5 metastases, the latter group had considerably poorer PFS [8.4 (95% CI 6.8-10.3) months; P < 0.001) and OS [18.7 (95% CI 17.5-22.1) months; P < 0.001].Conclusions Dichotomising patients with CRPC into cohorts with 1-4 or ≥5 skeletal metastases identifies a better and a worse cohort in a manner that is easy and clinically accessible. This simple method facilitates disease stratification and patient management, enabling clinicians to counsel patients more effectively about long-term outcomes and to help select intervention therapies more effectively.Objective To report a simplified and effective method for substratification of M1 castrate-resistant prostate cancer (CRPC) by correlating progression-free (PFS) and overall survival (OS) with simple quantification of skeletal metastases.Patients and Methods In all, 561 men with M1 CRPC were studied longitudinally. Individual bone scan disease burden, quantified by counting bone metastasis number, was correlated with clinical outcome using specific threshold points of 1-4, 5-20 and >20 detectable lesions. © 2014 The Authors.
Cassidy J.,Institute of Cancer science |
Clarke S.,University of Sydney |
Diaz-Rubio E.,Hospital Clinico San Carlos |
Scheithauer W.,Medical University of Vienna |
And 6 more authors.
British Journal of Cancer | Year: 2011
Background:We report updated overall survival (OS) data from study NO16966, which compared capecitabine plus oxaliplatin (XELOX) vs 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX4) as first-line therapy in metastatic colorectal cancer.Methods:NO16966 was a randomised, two-arm, non-inferiority, phase III comparison of XELOX vs FOLFOX4, which was subsequently amended to a 2 × 2 factorial design with further randomisation to bevacizumab or placebo. A planned follow-up exploratory analysis of OS was performed.Results:The intent-to-treat (ITT) population comprised 2034 patients (two-arm portion, n634; 2 × 2 factorial portion, n1400). For the whole NO16966 study population, median OS was 19.8 months in the pooled XELOX/XELOX-placebo/XELOX-bevacizumab arms vs 19.5 months in the pooled FOLFOX4/FOLFOX4-placebo/FOLFOX4-bevacizumab arms (hazard ratio 0.95 (97.5% CI 0.85-1.06)). In the pooled XELOX/XELOX-placebo arms, median OS was 19.0 vs 18.9 months in the pooled FOLFOX4/FOLFOX4-placebo arms (hazard ratio 0.95 (97.5% CI 0.83-1.09)). FOLFOX4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhoea and grade 3 hand-foot syndrome than FOLFOX4.Conclusion: Updated survival data from study NO16966 show that XELOX is similar to FOLFOX4, confirming the primary analysis of progression-free survival. XELOX can be considered as a routine first-line treatment option for patients with metastatic colorectal cancer. © 2011 Cancer Research UK All rights reserved.
Makin G.,Institute of Cancer science |
Makin G.,Royal Manchester Childrens Hospital
Paediatrics and Child Health (United Kingdom) | Year: 2014
Combination chemotherapy is the mainstay of treatment for most childhood cancer, either alone or in combination with surgery and radiotherapy. Sequential national and international studies of combinations of mostly well established cytotoxic drugs, with careful attention paid to the maintenance of dose intensity and the optimization of supportive care to manage acute toxicity, have resulted in dramatic improvements in the outcome for childhood cancer. Increased understanding of the molecular basis of childhood cancer will lead to the introduction of more targeted anti-cancer drugs, probably in combination with existing conventional agents. This will allow the remaining stubbornly drug-resistant childhood cancers to be treated more effectively, but will also allow does reduction of conventional agents in sensitive tumour types, reducing both acute and chronic toxicity. Increasing understanding of both pharmacokinetics and pharmacogenomics offers the opportunity for more personalized anti-cancer treatment, to optimize drug dosing for an individual, and to reduce their toxicity. © 2013 Elsevier Ltd.
Andreassen C.N.,Aarhus University Hospital |
Dikomey E.,University of Hamburg |
Parliament M.,Cross Cancer Institute |
West C.M.L.,Institute of Cancer science
Radiotherapy and Oncology | Year: 2012
The ability to predict individual risk of radiation-induced normal tissue complications is a long sought goal in radiobiology. The last decade saw increasing interest in identifying associations between single nucleotide polymorphisms (SNPs) and normal tissue complication risk. Nevertheless, it remains controversial whether SNPs will be useful predictors of normal tissue radiosensitivity. This paper provides a summary of a scientific debate held at the 31st ESTRO conference in which four scientists argued in favor or against the motion that SNPs will be useful predictors of normal tissue radiosensitivity in the future. © 2012 Elsevier Ireland Ltd. All rights reserved.
Ioannidou K.,University of Glasgow |
Anderson K.I.,Institute of Cancer science |
Strachan D.,Institute of Cancer science |
Edgar J.M.,University of Glasgow |
Barnett S.C.,University of Glasgow
PLoS ONE | Year: 2012
Background: Myelination is an exquisite and dynamic example of heterologous cell-cell interaction, which consists of the concentric wrapping of multiple layers of oligodendrocyte membrane around neuronal axons. Understanding the mechanism by which oligodendrocytes ensheath axons may bring us closer to designing strategies to promote remyelination in demyelinating diseases. The main aim of this study was to follow glial-axonal interactions over time both in vitro and ex vivo to visualize the various stages of myelination. Methodology/Principal Findings: We took two approaches to follow myelination over time: i) time-lapse imaging of mixed CNS myelinating cultures generated from mouse spinal cord to which exogenous GFP-labelled murine cells were added, and ii) ex vivo imaging of the spinal cord of shiverer (Mbp mutant) mice, transplanted with GFP-labelled murine neurospheres. We demonstrate that oligodendrocyte-axonal interactions are dynamic events with continuous retraction and extension of oligodendroglial processes. Using cytoplasmic and membrane-GFP labelled cells to examine different components of the myelin-like sheath, we provide evidence from time-lapse fluorescence microscopy and confocal microscopy that the oligodendrocytes' cytoplasm-filled processes initially spiral around the axon in a corkscrew-like manner. This is followed subsequently by focal expansion of the corkscrew process to form short cuffs, which then extend longitudinally along the axons. We predict from this model that these spiral cuffs must extend over each other first before extending to form internodes of myelin. Conclusion: These experiments show the feasibility of visualizing the dynamics of glial-axonal interaction during myelination over time. Moreover, these approaches complement each other with the in vitro approach allowing visualization of an entire internodal length of myelin and the ex vivo approach validating the in vitro data. © 2012 Ioannidou et al.
Watson C.J.,University of Cambridge |
Gusterson B.A.,Institute of Cancer science
Breast Cancer Research | Year: 2010
Cancer vaccines are the Holy Grail for patients and clinicians alike. The possibility that we can be vaccinated against common cancers is very appealing and the socioeconomic consequences are significant. A recent paper published in the journal Nature Medicine suggests a new approach for the development of a prophylactic vaccine for breast cancer. Their strategy was to induce mammary gland failure in mice by immunisation with an antibody specific to a milk protein that resulted in autoimmunity during lactation. This also showed some efficacy as a therapeutic vaccine. Can we look forward to the elimination of breast cancer? © 2010 BioMed Central Ltd.