Méta-analyses sur données individuelles d'essais randomisés dans les cancers des voies aéro-digestives supérieures. Développements méthodologiques et cliniques

Les cancers des voies aérodigestives supérieures (VADS) représentent la 5e cause de cancer en France. Ils sont fréquemment découverts à un stade avancé, et leur mauvais pronostic a conduit à l élaboration de traitements intensifiés. De nombreux essais randomisés ont évalué l apport de la chimiothérapie et de modifications du fractionnement de la radiothérapie. Leurs résultats ont été synthétisés dans deux méta-analyses sur données individuelles coordonnées par l Institut Gustave Roussy. Cependant ces méta-analyses génèrent des questions cliniques et méthodologiques, qui constituent le socle de cette thèse. Ainsi nous avons exploré par différents moyens l étude de l interaction entre des covariables de niveau individuel, le site tumoral, et l effet du traitement. Nous avons adapté la méthodologie des méta-analyses en réseau pour les données de survie afin réaliser une analyse globale de l ensemble de ces essais randomisés et classer les traitements selon leur efficacité sur la survie. Certains de ces traitements n avaient pas fait l objet de comparaison directe, et nos résultats se sont vérifiés dans des essais publiés ultérieurement. Nous avons passé en revue les avantages et les limites de la méta-analyse en réseau. Nous avons enfin engagé la mise à jour de ce corpus de méta-analyses pour produire des résultats en accord avec les pratiques actuelles, avec un suivi long, et en explorant des problématiques variées, telles que l efficacité, la toxicité et l adhérence au protocole thérapeutique. Les résultats finaux de la méta-analyse sur la chimiothérapie d induction avec taxanes sont présentés dans cette thèse.Head and neck cancers represent the fifth cause of death from cancer in France. They are often diagnosed at an advanced stage. The poor prognosis of these diseases has led to the introduction of intensified treatments. Numerous randomized trials have evaluated the benefits of the addition of chemotherapy to locoregional treatment and of the modification of radiotherapy fractionation. The results of these trials have been synthesized in two individual patient data meta-analyses coordinated by the Meta-Analysis Unit of Gustave Roussy Cancer Center. However these meta-analyses bring up clinical and methodological questions, some of which are dealt with in this thesis. First we have studied by different means the interaction between patient level covariate, tumor site and treatment effect. We have also adapted the methodology of network meta-analyses to survival data to perform a global analysis of the entire meta-analysis database, and to rank treatments according to their efficacy, including some treatments that had not been directly compared. Some of these results were eventually confirmed by subsequently published randomized trials. We have reviewed the advantages and limits of network meta-analysis. We have also launched the update of all these meta-analyses in order to produce results consistent with actual clinical practice, update patient follow-up, and collect additional data regarding treatment efficacy, toxicity and compliance. The final results of the taxane induction meta-analysis are presented in this manuscript.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Cost Effectiveness of Modified Fractionation Radiotherapy versus Conventional Radiotherapy for Unresected Non–Small-Cell Lung Cancer Patients

IntroductionModified fractionation radiotherapy (RT), delivering multiple fractions per day or shortening the overall treatment time, improves overall survival for non -small-cell lung cancer (NSCLC) patients compared with conventional fractionation RT (CRT). However, its cost effectiveness is unknown. Therefore, we aimed to examine and compare the cost effectiveness of different modified RT schemes and CRT in the curative treatment of unresected NSCLC patients.MethodsA probabilistic Markov model was developed based on individual patient data from the meta-analysis of radiotherapy in lung cancer (N = 2000). Dutch health care costs, quality-adjusted life years (QALYs), and net monetary benefits (NMBs) were compared between two accelerated schemes (very accelerated RT [VART] and moderately accelerated RT [MART]), two hyperfractionated schemes (using an identical (HRTI) or higher (HRTH) total treatment dose than CRT) and CRT.ResultsAll modified fractionations were more effective and costlier than CRT (1.12 QALYs, €24,360). VART and MART were most effective (1.30 and 1.32 QALYs) and cost €25,746 and €26,208, respectively. HRTI and HRTH yielded less QALYs than the accelerated schemes (1.27 and 1.14 QALYs), and cost €26,199 and €29,683, respectively. MART had the highest NMB (€79,322; 95% confidence interval [CI], €35,478-€133,648) and was the most cost-effective treatment followed by VART (€78,347; 95% CI, €64,635-€92,526). CRT had an NMB of €65,125 (95% CI, €54,663-€75,537). MART had the highest probability of being cost effective (43%), followed by VART (31%), HRTI (24%), HRTH (2%), and CRT (0%).ConclusionImplementing accelerated RT is almost certainly more efficient than current practice CRT and should be recommended as standard RT for the curative treatment of unresected NSCLC patients not receiving concurrent chemo-radiotherapy

Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05

L’objectif de ce travail était la recherche de biomarqueurs moléculaires prédictifs de la tolérance et de l’efficacité des chimio– thérapies utilisées dans le colorectal (CCR) métastatique. Nous avons effectué le génotypage de 20 polymorphismes présents au sein de 9 gènes connus ou suspectés d’être impliqués dans la voie du 5FU, de l’oxaliplatine, ou de l’irinotécan, à partir de l’ADN extrait du sang de 346 patients traités dans le cadre d’un essai de phase III. Cet essai comparait une chimiothérapie séquentielle par 5FU (schéma LV5FU2) suivie d’une association 5FU plus oxali– platine (schéma FOLFOX) à une chimiothérapie combinée de type FOLFOX d’emblée en première ligne de traitement. Nous avons trouvé un risque de toxicité hématologique sévère sous FOLFOX significativement augmenté chez les patients porteurs de l’allèle ERCC2-K751QC. La présence de l’allèle TS-5’UTR3RG du gène de la thymidylate synthase était associée à un taux de réponse significativement plus élevé sous LV5FU2. Le taux de réponse au FOLFOX en 2e ligne était significativement supérieur chez les patients porteurs de l’allèle ERCC1-IVS3+74G, et chez ceux ayant au moins un allèle de GSTT1 présent. L’analyse prédictive a montré un effet dépendant du traitement de certains polymorphismes. En effet, une survie sans progression significativement allongée par l’ajout de l’oxaliplatine en 1re ligne a été observée uniquement chez les patients ayant un génotype TS-5’UTR2R/2R ou 2R/3R, suggérant l’absence de bénéfice d’une bithérapie par FOLFOX d’emblée en première ligne chez les patients TS-5’UTR3R/3R. Ces résultats montrent que l’étude des polymorphismes constitutionnels permettent de prédire non seulement la toxicité mais aussi l’efficacité des chimiothérapies antitumorales du cancer colorectal, et ainsi (sous réserve d’une validation sur une population indépendante) d’orienter la stratégie thérapeutique à l’échelle de l’individu

Individual patient data meta-analysis of neoadjuvant chemotherapy followed by surgery versus upfront surgery for carcinoma of the oesophagus or the gastro- oesophageal junction

Introduction Which neoadjuvant treatment for locally advanced thoracic oesophagus (TE) or gastro-oesophageal junction carcinoma is best remains an open question. Randomised controlled trials variously accrued patients with adenocarcinoma and squamous cell carcinoma, making strong conclusions hard to obtain. The primary objective of this individual participant data meta-analysis was to investigate the effect of neoadjuvant chemotherapy on overall survival (OS). Patients and methods Eligible trials should have closed to accrual before 2016 and compared neoadjuvant chemotherapy and surgery (CS) to surgery alone. All relevant published and unpublished trials were identified via searches of electronic databases, conference proceedings and clinical trial registers. The main end-point was OS. Investigators were contacted to obtain the individual patient data, which was recorded, harmonised and checked. A random-effects Cox model, stratified by trial, was used for meta-analysis and subgroup analyses were preplanned. Results 16 trials were identified as eligible. Individual patient data were obtained from 12 trial and 2478 patients. CS was associated with an improved OS versus surgery, hazard ratio (HR) = 0.83 [0.72–0.96], p < 0.0001, translating to an absolute benefit of 5.7% at 5-years from 16.8% to 22.5%. Treatment effects did not vary substantially between adenocarcinoma (HR = 0.73 [0.62–0.87]) and squamous cell carcinoma (HR = 0.91 [0.76–1.08], interaction p = 0.26). A somewhat more pronounced effect was observed in gastro-oesophageal junction (HR = 0.68 [0.50–0.93]) versus TE (HR = 0.87 [0.75–1.00], interaction p = 0.07). CS was also associated with a greater disease-free survival (HR = 0.74 [0.64–0.85], p < 0.001). Conclusions Neoadjuvant chemotherapy conferred a better OS than surgery alone and should be considered in all anatomical location and histological subtypes

ANtiangiogenic Second-line Lung cancer Meta-Analysis on individual patient data in non-small cell lung cancer:ANSELMA

BACKGROUND: Now that immunotherapy plus chemotherapy (CT) is one standard option in first-line treatment of advanced non-small cell lung cancer (NSCLC), there exists a medical need to assess the efficacy of second-line treatments (2LT) with antiangiogenics (AA). We performed an individual patient data meta-analysis to validate the efficacy of these combinations as 2LT. METHODS: Randomised trials of AA plus standard 2LT compared to 2LT alone that ended accrual before 2015 were eligible. Fixed-effect models were used to compute pooled hazard ratios (HRs) for overall survival (OS, main end-point), progression-free survival (PFS) and subgroup analyses. RESULTS: Sixteen trials were available (8,629 patients, 64% adenocarcinoma). AA significantly prolonged OS (HR = 0.93 [95% confidence interval {CI}: 0.89; 0.98], p = 0.005) and PFS (0.80 [0.77; 0.84], p < 0.0001) compared with 2LT alone. Absolute 1-year OS and PFS benefit for AA were +1.8% [-0.4; +4.0] and +3.5% [+1.9; +5.1], respectively. The OS benefit of AA was higher in younger patients (HR = 0.87 [95% CI: 0.76; 1.00], 0.89 [0.81; 0.97], 0.94 [0.87; 1.02] and 1,04 [0.93; 1.17] for patients <50, 50-59, 60-69 and ≥ 70 years old, respectively; trend test: p = 0.02) and in patients who started AA within 9 months after starting the first-line therapy (0.88 [0.82; 0.99]) than in patients who started AA later (0.99 [0.91; 1.08]) (interaction: p = 0.03). Results were similar for PFS. AA increased the risk of hypertension (p < 0.0001), but not the risk of pulmonary thromboembolic events (p = 0.21). CONCLUSIONS: In the 2LT of advanced NSCLC, adding AA significantly prolongs OS and PFS, but the benefit is clinically limited, mainly observed in younger patients and after shorter time since the start of first-line therapy

Urban Climate, Human behavior & Energy consumption: from LCZ mapping to simulation and urban planning (the MapUCE project)

International audienceThe MApUCE project aims to integrate in urban policies and most relevant legal documents quantitative data from urban microclimate, climate and energy.The primary objective of this project is to obtain climate and energy quantitative data from numerical simulations, focusing on urban microclimate and building energy consumption in the residential and service sectors, which represents in France 41% of the final energy consumption. Both aspects are coupled as building energy consumption is highly meteorologically dependent (e.g. domestic heating, air-conditioning) and heat waste impact the Urban Heat Island. We propose to develop, using national databases, a generic and automated method for generating Local Climate Zones (LCZ) for all cities in France, including the urban architectural, geographical and sociological parameters necessary for energy and microclimate simulations.As will be presented, previous projects on adaptation of cities to climate change have shown that human behavior is a very potent level to address energy consumption reduction, as much as urban forms or architectural technologies. Therefore, in order to further refine the coupled urban climate and energy consumption calculations, we will develop within TEB (and its Building Energy Module) a model of energy consumer behavior.The second objective of the project is to propose a methodology to integrate quantitative data in urban policies. Lawyers analyze the potential levers in legal and planning documents. A few “best cases” are also studied, in order to evaluate their performances. Finally, based on urban planning agencies requirements, we will define vectors to include quantified energy-climate data to legal urban planning documents. These vectors have to be understandable by urban planners and contain the relevant information.To meet these challenges, the project is organized around strongly interdisciplinary partners in the following fields: law, urban climate, building energetics, architecture, sociology, geography and meteorology, as well as the national federation of urban planning agencies.In terms of results, the cross-analysis of input urban parameters and urban micro-climate-energy simulated data will be available on-line as standardized maps for each of the studied cities. The urban parameter production tool as well as the models will be available as open-source. LCZ and associated urban (and social!) indicators may be integrated within the WUDAPT database