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 All relevant published and unpublished trials were identified via searches of electronic databases, conference proceedings and clinical trial registers.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

Individual Participant Data Network Meta-Analysis of Neoadjuvant Chemotherapy or Chemoradiotherapy in Esophageal or Gastroesophageal Junction Carcinoma

PURPOSE: The 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 METHODS: All, 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). RESULTS: IPD 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 &lt; .001 respectively. The NMA comparison of CRS versus CS for OS gave a HR of 0.90 (0.74 to 1.09), 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). CONCLUSION:Neoadjuvant 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.</p

Meta-analyse des traitements néoadjuvants des cancers de l’œsophage et de la jonction oesogastrique

Esophagus cancer still carries a dismal prognosis. Multimodal treatment strategies usually combine surgery (S), chemotherapy (C) and radiotherapy (R) to obtain better survival. Esophagus cancer is also a heterogeneous entity with two histological subtypes (adenocarcinoma and squamous cell carcinoma) and two anatomical locations (thoracic esophagus and gastroesophageal junction). This is a problem of studying the interaction between the treatment effect and modifiers in a clinical situation where more than two treatments are available. Individual participant data network meta-analysis was therefore the optimal methodology.The first part of the thesis focused on studying the performance of a model for one step individual participant data network meta-analysis for a time to event outcome under the frequentist paradigm. A special emphasis was made on situation where an interaction between the treatment effect and a modifier is present.The second part of the thesis was the analysis of the individual participant data of all the available studie. Three pairwise meta-analysis comparing the three most frequent therapeutic sequences were done : S vs. CS, S vs. CRS and CS vs. CRS. These analyses were completed by a network meta-analysis combining all the available information in a one-step design. Primary outcome was overall survival. Secondary outcomes were disease-free survival, type of recurrence (local or distant or death without recurrence with competing risks), cause of death, quality of the surgical resection and postoperative morbidity and mortality. For each analyses an interaction between the treatment effects and the histological subtypes or the anatomical location were seeked.Les cancers de l’œsophage restent grevés d’un pronostic à long terme sombre. Des stratégies multimodales associant différemment chirurgie (S), chimiothérapie (C) et radiothérapie (R) ont été développé afin d’améliorer ce pronostic. Ce cancer est également hétérogène en raison de la présence de deux histologies différentes (adénocarcinomes et carcinomes épidermoïdes) et deux localisations anatomiques (œsophage thoracique et jonction œsogastrique). La problématique était donc l’étude de l’interaction entre l’effet traitement et des modificateurs dans une situation clinique comportant plus de deux traitements. La méta-analyse en réseau sur données individuelles d’essais randomisé était donc la méthodologie la plus appropriée.La première partie de la thèse a permis l’étude des performances d’un modèle permettant d’évaluer une méta-analyse en réseau sur données individuelles en une étape à critère de jugement de type survie sous paradigme fréquentiste. L’accent était porté sur une situation où de l’interaction avec un modificateur était présente.La seconde partie de la thèse portait sur la réalisation d’une analyse sur données individuelles. Trois méta-analyse par paire comparant les trois stratégies actuelles S contre CS, S contre CRS et CS contre CRS ont été réalisé. Cette analyse a été complété par une méta-analyse en réseau utilisant toute l’information disponible. Le critère de jugement principal était la survie globale. Les critères secondaires étaient la survie sans récidive, le mode de récidive (sous forme de risques compétitifs) les causes de décès, la qualité de la résection et la morbi-mortalité postopératoire. Pour chaque analyse une recherche d’interaction entre l’effet traitement et le type histologique ou la localisation tumorale était recherché

Meta-analysis of neoadjuvant treatment of esophageal and gastroesophageal junction carcinoma

Les cancers de l’œsophage restent grevés d’un pronostic à long terme sombre. Des stratégies multimodales associant différemment chirurgie (S), chimiothérapie (C) et radiothérapie (R) ont été développé afin d’améliorer ce pronostic. Ce cancer est également hétérogène en raison de la présence de deux histologies différentes (adénocarcinomes et carcinomes épidermoïdes) et deux localisations anatomiques (œsophage thoracique et jonction œsogastrique). La problématique était donc l’étude de l’interaction entre l’effet traitement et des modificateurs dans une situation clinique comportant plus de deux traitements. La méta-analyse en réseau sur données individuelles d’essais randomisé était donc la méthodologie la plus appropriée.La première partie de la thèse a permis l’étude des performances d’un modèle permettant d’évaluer une méta-analyse en réseau sur données individuelles en une étape à critère de jugement de type survie sous paradigme fréquentiste. L’accent était porté sur une situation où de l’interaction avec un modificateur était présente.La seconde partie de la thèse portait sur la réalisation d’une analyse sur données individuelles. Trois méta-analyse par paire comparant les trois stratégies actuelles S contre CS, S contre CRS et CS contre CRS ont été réalisé. Cette analyse a été complété par une méta-analyse en réseau utilisant toute l’information disponible. Le critère de jugement principal était la survie globale. Les critères secondaires étaient la survie sans récidive, le mode de récidive (sous forme de risques compétitifs) les causes de décès, la qualité de la résection et la morbi-mortalité postopératoire. Pour chaque analyse une recherche d’interaction entre l’effet traitement et le type histologique ou la localisation tumorale était recherché.Esophagus cancer still carries a dismal prognosis. Multimodal treatment strategies usually combine surgery (S), chemotherapy (C) and radiotherapy (R) to obtain better survival. Esophagus cancer is also a heterogeneous entity with two histological subtypes (adenocarcinoma and squamous cell carcinoma) and two anatomical locations (thoracic esophagus and gastroesophageal junction). This is a problem of studying the interaction between the treatment effect and modifiers in a clinical situation where more than two treatments are available. Individual participant data network meta-analysis was therefore the optimal methodology.The first part of the thesis focused on studying the performance of a model for one step individual participant data network meta-analysis for a time to event outcome under the frequentist paradigm. A special emphasis was made on situation where an interaction between the treatment effect and a modifier is present.The second part of the thesis was the analysis of the individual participant data of all the available studie. Three pairwise meta-analysis comparing the three most frequent therapeutic sequences were done : S vs. CS, S vs. CRS and CS vs. CRS. These analyses were completed by a network meta-analysis combining all the available information in a one-step design. Primary outcome was overall survival. Secondary outcomes were disease-free survival, type of recurrence (local or distant or death without recurrence with competing risks), cause of death, quality of the surgical resection and postoperative morbidity and mortality. For each analyses an interaction between the treatment effects and the histological subtypes or the anatomical location were seeked

Meta-analyse des traitements néoadjuvants des cancers de l’œsophage et de la jonction oesogastrique

Esophagus cancer still carries a dismal prognosis. Multimodal treatment strategies usually combine surgery (S), chemotherapy (C) and radiotherapy (R) to obtain better survival. Esophagus cancer is also a heterogeneous entity with two histological subtypes (adenocarcinoma and squamous cell carcinoma) and two anatomical locations (thoracic esophagus and gastroesophageal junction). This is a problem of studying the interaction between the treatment effect and modifiers in a clinical situation where more than two treatments are available. Individual participant data network meta-analysis was therefore the optimal methodology.The first part of the thesis focused on studying the performance of a model for one step individual participant data network meta-analysis for a time to event outcome under the frequentist paradigm. A special emphasis was made on situation where an interaction between the treatment effect and a modifier is present.The second part of the thesis was the analysis of the individual participant data of all the available studie. Three pairwise meta-analysis comparing the three most frequent therapeutic sequences were done : S vs. CS, S vs. CRS and CS vs. CRS. These analyses were completed by a network meta-analysis combining all the available information in a one-step design. Primary outcome was overall survival. Secondary outcomes were disease-free survival, type of recurrence (local or distant or death without recurrence with competing risks), cause of death, quality of the surgical resection and postoperative morbidity and mortality. For each analyses an interaction between the treatment effects and the histological subtypes or the anatomical location were seeked.Les cancers de l’œsophage restent grevés d’un pronostic à long terme sombre. Des stratégies multimodales associant différemment chirurgie (S), chimiothérapie (C) et radiothérapie (R) ont été développé afin d’améliorer ce pronostic. Ce cancer est également hétérogène en raison de la présence de deux histologies différentes (adénocarcinomes et carcinomes épidermoïdes) et deux localisations anatomiques (œsophage thoracique et jonction œsogastrique). La problématique était donc l’étude de l’interaction entre l’effet traitement et des modificateurs dans une situation clinique comportant plus de deux traitements. La méta-analyse en réseau sur données individuelles d’essais randomisé était donc la méthodologie la plus appropriée.La première partie de la thèse a permis l’étude des performances d’un modèle permettant d’évaluer une méta-analyse en réseau sur données individuelles en une étape à critère de jugement de type survie sous paradigme fréquentiste. L’accent était porté sur une situation où de l’interaction avec un modificateur était présente.La seconde partie de la thèse portait sur la réalisation d’une analyse sur données individuelles. Trois méta-analyse par paire comparant les trois stratégies actuelles S contre CS, S contre CRS et CS contre CRS ont été réalisé. Cette analyse a été complété par une méta-analyse en réseau utilisant toute l’information disponible. Le critère de jugement principal était la survie globale. Les critères secondaires étaient la survie sans récidive, le mode de récidive (sous forme de risques compétitifs) les causes de décès, la qualité de la résection et la morbi-mortalité postopératoire. Pour chaque analyse une recherche d’interaction entre l’effet traitement et le type histologique ou la localisation tumorale était recherché

La recherche de ganglion sentinelle a-t-elle des indications dans les cancers digestifs ?

International audienceDespite being a standard of care in several cancers, sentinel lymph node (SLN) is not widespread in digestive cancers. European guidelines do not recommend its use for any digestive cancers. Particularity of the lymphatic vessel, intimately linked to blood vessel, may explain part of this phenomenon. Nevertheless, more indication could arise in the near future with the early diagnosis of tumor induced by cancer screening. Ruling out the lymphatic invasion could allow preserving the organ currently resected because of risk of lymph node positivity. This procedure is well studied in early gastric cancer in Korea and Japan. Several study have demonstrated that, a dual-tracer (isotopic and dye) allows to accurately identify the SLN. A randomized phase 3 trial is currently active in Korea to evaluate the oncological results of the procedure. Similar indication could arise for T1 tumor of the low-rectum, but currently available data are insufficient to recommend its use outside of a study. SLN may also be used to detect aberrant lymphatic drainage (rectum, ileum) but have been tested so far only in a few dozen of patients. Finally, SLN is disappointing in colon cancer, due to its low sensitivity and the absence of modification of the surgical procedure induced

Intérêts respectifs des chimiothérapies pré et postopératoires chez les patients présentant des métastases hépatiques d'origine colorectale résecables d'emblée

La présence de métastases hépatiques au cours de la prise en charge d un cancer colorectal est une situation fréquente. Les progrès des thérapies multimodales, associant chirurgie et chimiothérapie, permettent d obtenir des survies prolongées mais l enchainement optimal de celles-ci fait encore débat. Le but de cette étude était l estimation des bénéfices apportés respectivement par les chimiothérapies pré (CTPRE) et postopératoires (CTPOST). Nous avons identifié de façon rétrospective tous les patients ayant été opérés de métastases hépatiques d origine colorectale. Ceux présentant une maladie extra-hépatique, ou non résécables d emblée, ou ayant été traités par d autres molécules que le FOLFOX ont été exclus. L efficacité sur les survies globale (SG) et sans récidive (SSR) a été évaluée par un modèle de Cox ajusté sur les variables de confusion.Cent soixante-dix-neuf patients ont été inclus. Parmi eux, 24 (13%) n avaient reçu aucune chimiothérapie, 84 (47%) avaient eu de la CTPRE, 128 (72%) de la CTPOST, dont 57 (32%) avaient eu les deux à la fois. La CTPOST était un facteur indépendant de meilleure SG (HR=0,55[0,35-0,87], p=0,01) et SSR (HR=0,54[0,36-0,82], p=0,004). La CTPRE n était associée de façon indépendante ni à la SG (HR=0,96 [0,57-1,60], p=0,87), ni à la SSR (1,05 [0,66-1,66], p=0,83).Dans cette étude, la CTPOST a confirmé son bénéfice en termes de SG et SSR. A l inverse, la CTPRE n était pas associée à des gains de survie statistiquement significatifs. Un essai randomisé est souhaitable pour évaluer précisément l intérêt de cette dernière.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Predicting the propagation of COVID-19 at an international scale: extension of an SIR model

International audienceObjectives Several epidemiological models have been published to forecast the spread of the COVID-19 pandemic, yet many of them have proven inaccurate for reasons that remain to be fully determined. We aimed to develop a novel model and implement it in a freely accessible web application.Design We built an SIR-type compartmental model with two additional compartments: D (deceased patients); L (individuals who will die but who will not infect anybody due to social or medical isolation) and integration of a time-dependent transmission rate and a periodical weekly component linked to the way in which cases and deaths are reported.Results The model was implemented in a web application (as of 2 June 2020). It was shown to be able to accurately capture the changes in the dynamics of the pandemic for 20 countries whatever the type of pandemic spread or containment measures: for instance, the model explains 97% of the variance of US data (daily cases) and predicts the number of deaths at a 2-week horizon with an error of 1%.Conclusions In early performance evaluation, our model showed a high level of accuracy between prediction and observed data. Such a tool might be used by the global community to follow the spread of the pandemic

Extension of a SIR model for modelling the propagation of Covid-19 in several countries.

Background Several epidemiologic models have been published to forecast the spread of the COVID-19 pandemic yet there are still uncertainties regarding their accuracy. We report the main features of the development of a novel freely accessible model intended to urgently help researchers and decision makers to predict the evolution of the pandemic in their country. Methods and findings We built a SIR-type compartmental model with additional compartments and features. We made the hypothesis that the number of contagious individuals in the population was negligible as compared to the population size. We introduced a compartment D corresponding to the deceased patients and a compartment L representing the group of individuals who will die but who will not infect anybody (due to social or medical isolation). Our model integrated a time-dependent transmission rate, whose variations can be thought to be related to the public measures taken by each country and a cosine function to incorporate a periodic weekly component linked to the way in which numbers of cases and deaths are counted and reported, which can change from day to day. The model was able to accurately capture the different changes in the dynamics of the pandemic for nine different countries whatever the type of pandemic spread or containment measures. The model provided very accurate forecasts in the relatively short term (10 days). Conclusions In early evaluation of the performance of our model, we found a high level of accuracy between prediction and observed data, regardless of the country. The model should be used by the community to help public health decisions as we will refine it over time and further investigate its performance

Health as an independent predictor of the 2017 French presidential voting behaviour: a cross-sectional analysis

International audienceBACKGROUND : It has been suggested that poor health has influenced vote for Brexit and the US presidential election. No such research has been published regarding the 2017 French presidential election.METHODS : We performed a cross-sectional analysis using a comprehensive set of socioeconomic and health indicators, to be compared with voting outcome at the first round of the 2017 French presidential election. The 95 French departments were selected as the unit of analysis. Data were obtained from publicly available sources. The linear model was used for both univariate and multivariate analysis to investigate the relation between voting patterns and predictors. Sensitivity analyses were done using the elastic-net regularisation.RESULTS : Emmanuel Macron and Marine Le Pen arrived ahead. When projected on the first factorial plane (~ 60% of the total inertia), Emmanuel Macron and Marine Le Pen tended to be in opposite directions regarding both socioeconomic and health factors. In the respective multivariate analyses of the two candidates, both socio-economic and health variables were significantly associated with voting patterns, with wealthier and healthier departments more likely to vote for Emmanuel Macron, and opposite departments more likely to vote for Marine Le Pen. Mortality (p = 0.03), severe chronic conditions (p = 0.014), and diabetes mellitus (p < 0.0001) were among the strongest predictors of voting pattern for Marine Le Pen. Sensitivity analyses did not substantially change those findings.CONCLUSIONS : We found that areas associated with poorer health status were significantly more likely to vote for the far-right candidate at the French presidential election, even after adjustment on socioeconomic criteria