Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial

BACKGROUND: The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer. METHODS: In this open-label, randomised, phase 3 trial, we randomly assigned patients (1:1 ratio) with advanced, measurable, non-resectable colorectal cancer and WHO performance status 0-2 to receive either first-line treatment with bolus (400 mg/m(2)) and infusional (2400 mg/m(2)) fluorouracil plus leucovorin (400 mg/m(2)) (simplified LV5FU2 regimen), second-line LV5FU2 plus oxaliplatin (100 mg/m(2)) (FOLFOX6), and third-line LV5FU2 plus irinotecan (180 mg/m(2)) (FOLFIRI) or first-line FOLFOX6 and second-line FOLFIRI. Chemotherapy was administered every 2 weeks. Randomisation was done centrally using minimisation (minimisation factors were WHO performance status, previous adjuvant chemotherapy, number of disease sites, and centre). The primary endpoint was progression-free survival after two lines of treatment. Analyses were by intention-to-treat. This trial is registered at ClinicalTrials.gov, NCT00126256. FINDINGS: 205 patients were randomly assigned to the sequential group and 205 to the combination group. 161 (79%) patients in the sequential group and 161 (79%) in the combination group died during the study. Median progression-free survival after two lines was 10·5 months (95% CI 9·6-11·5) in the sequential group and 10·3 months (9·0-11·9) in the combination group (hazard ratio 0·95, 95% CI 0·77-1·16; p=0·61). All six deaths caused by toxic effects of treatment occurred in the combination group. During first-line chemotherapy, significantly fewer severe (grade 3-4) haematological adverse events (12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group; p<0·0001) and non-haematological adverse events (26 events vs 186 events; p<0·0001) occurred in the sequential group than in the combination group. INTERPRETATION: Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced, non-resectable colorectal cancer. FUNDING: Sanofi-Aventis France

Individual participant data network meta-analysis of neoadjuvant chemotherapy or chemoradiotherapy in esophageal or gastroesophageal junction carcinoma

PURPOSEThe optimal neoadjuvant treatment for resectable carcinoma of the thoracic esophagus (TE) or gastroesophageal junction (GEJ) remains a matter of debate. We performed an individual participant data (IPD) network meta-analysis (NMA) of randomized controlled trials (RCTs) to study the effect of chemotherapy or chemoradiotherapy, with a focus on tumor location and histology subgroups.PATIENTS AND METHODSAll, published or unpublished, RCTs closed to accrual before December 31, 2015 and having compared at least two of the following strategies were eligible: upfront surgery (S), chemotherapy followed by surgery (CS), and chemoradiotherapy followed by surgery (CRS). All analyses were conducted on IPD obtained from investigators. The primary end point was overall survival (OS). The IPD-NMA was analyzed by a one-step mixed-effect Cox model adjusted for age, sex, tumor location, and histology. The NMA was registered in PROSPERO (CRD42018107158).RESULTSIPD were obtained for 26 of 35 RCTs (4,985 of 5,807 patients) corresponding to 12 comparisons for CS-S, 12 for CRS-S, and four for CRS-CS. CS and CRS led to increased OS when compared with S with hazard ratio (HR) = 0.86 (0.75 to 0.99), P = .03 and HR = 0.77 (0.68 to 0.87), P P = .27 (consistency P = .26, heterogeneity P = .0038). For CS versus S, a larger effect on OS was observed for GEJ versus TE tumors (P = .036). For the CRS versus S and CRS versus CS, a larger effect on OS was observed for women (P = .003, .012, respectively).CONCLUSIONNeoadjuvant chemotherapy and chemoradiotherapy were consistently better than S alone across histology, but with some variation in the magnitude of treatment effect by sex for CRS and tumor location for CS. A strong OS difference between CS and CRS was not identified.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Spatially heterogeneous ages in glassy dynamics

We construct a framework for the study of fluctuations in the nonequilibrium relaxation of glassy systems with and without quenched disorder. We study two types of two-time local correlators with the aim of characterizing the heterogeneous evolution: in one case we average the local correlators over histories of the thermal noise, in the other case we simply coarse-grain the local correlators. We explain why the former describe the fingerprint of quenched disorder when it exists, while the latter are linked to noise-induced mesoscopic fluctuations. We predict constraints on the pdfs of the fluctuations of the coarse-grained quantities. We show that locally defined correlations and responses are connected by a generalized local out-of-equilibrium fluctuation-dissipation relation. We argue that large-size heterogeneities in the age of the system survive in the long-time limit. The invariance of the theory under reparametrizations of time underlies these results. We relate the pdfs of local coarse-grained quantities and the theory of dynamic random manifolds. We define a two-time dependent correlation length from the spatial decay of the fluctuations in the two-time local functions. We present numerical tests performed on disordered spin models in finite and infinite dimensions. Finally, we explain how these ideas can be applied to the analysis of the dynamics of other glassy systems that can be either spin models without disorder or atomic and molecular glassy systems.Comment: 47 pages, 60 Fig

How individual participant data meta-analyses have influenced trial design, conduct, and analysis

To demonstrate how individual participant data (IPD) meta-analyses have impacted directly on the design and conduct of trials and highlight other advantages IPD might offer.Potential examples of the impact of IPD meta-analyses on trials were identified at an international workshop, attended by individuals with experience in the conduct of IPD meta-analyses and knowledge of trials in their respective clinical areas. Experts in the field who did not attend were asked to provide any further examples. We then examined relevant trial protocols, publications, and Web sites to verify the impacts of the IPD meta-analyses. A subgroup of workshop attendees sought further examples and identified other aspects of trial design and conduct that may inform IPD meta-analyses. We identified 52 examples of IPD meta-analyses thought to have had a direct impact on the design or conduct of trials. After screening relevant trial protocols and publications, we identified 28 instances where IPD meta-analyses had clearly impacted on trials. They have influenced the selection of comparators and participants, sample size calculations, analysis and interpretation of subsequent trials, and the conduct and analysis of ongoing trials, sometimes in ways that would not possible with systematic reviews of aggregate data. We identified additional potential ways that IPD meta-analyses could be used to influence trials. IPD meta-analysis could be better used to inform the design, conduct, analysis, and interpretation of trials

L'épidémie de fièvre jaune de l'Extrême Nord du Cameroun en 1990 : premier isolement du virus amaril au Cameroun

Une épidémie de fièvre jaune a éclaté dans le Nord du Cameroun de septembre à décembre 1990 dans une population immunologiquement réceptive. On connaît 182 cas, dont 125 décès, mais on estime que le nombre de cas réels se situe entre 5 et 20 000, avec un nombre de décès de 500 à 1000. La zone concernée est dans l'aire d'épidémicité. Elle est montagneuse avec un habitat rural dense, quoique dispersé. Une enquête menée en fin d'épidémie a permis l'isolement du virus et c'est la première souche isolée au Cameroun. L'étude de 107 sérums montre 20 % de porteurs d'IgM contre la fièvre jaune exclusivement. Les moins de 10 ans représentent 63 % des porteurs d'IgM. En IgG, il y a 98 % de réactions croisées avec des souches West-Nile et dengue 2. L'enquête entomologique a permis la capture de divers #Aedes, dont #A. aegypti, dont on reconnaît l'origine dans de très nombreux gîtes larvaires domestiques. C'est ce vecteur qui est considéré comme responsable de la transmission interhumaine. (Résumé d'auteur

Méta-analyses d'essais randomisés sur données individuelles dans le traitement des cancers ORL non métastatiques : principes, résultats, perspectives [Individual patient data meta-analyses of randomized trials for the treatment of non-metastatic head and neck squamous cell carcinomas: Principles, results and perspectives].

Meta-analyses are considered as an important pillar of evidence-based medicine. The aim of this review is to describe the main principles of a meta-analysis and to use examples of head and neck oncology to demonstrate their clinical impact and methodological interest. The major role of individual patient data is outlined, as well as the superiority of individual patient data over meta-analyses based on published summary data. The major clinical breakthrough of head and neck meta-analyses are summarized, regarding concomitant chemotherapy, altered fractionated chemotherapy, new regimens of induction chemotherapy or the use of radioprotectants. Recent methodological developments are described, including network meta-analyses, the validation of surrogate markers. Lastly, the future of meta-analyses is discussed in the context of personalized medicine

L'épidémie de fièvre jaune de l'Extrême Nord du Cameroun en 1990 : premier isolement du virus amaril au Cameroun

Une épidémie de fièvre jaune a éclaté dans le Nord du Cameroun de septembre à décembre 1990 dans une population immunologiquement réceptive. On connaît 182 cas, dont 125 décès, mais on estime que le nombre de cas réels se situe entre 5 et 20 000, avec un nombre de décès de 500 à 1000. La zone concernée est dans l'aire d'épidémicité. Elle est montagneuse avec un habitat rural dense, quoique dispersé. Une enquête menée en fin d'épidémie a permis l'isolement du virus et c'est la première souche isolée au Cameroun. L'étude de 107 sérums montre 20 % de porteurs d'IgM contre la fièvre jaune exclusivement. Les moins de 10 ans représentent 63 % des porteurs d'IgM. En IgG, il y a 98 % de réactions croisées avec des souches West-Nile et dengue 2. L'enquête entomologique a permis la capture de divers #Aedes, dont #A. aegypti, dont on reconnaît l'origine dans de très nombreux gîtes larvaires domestiques. C'est ce vecteur qui est considéré comme responsable de la transmission interhumaine. (Résumé d'auteur