Inclusion of Older Patients with Cancer in Randomized Controlled Trials with Patient-Reported Outcomes:a Systematic Review

Objectives: Inclusion of patient-reported outcomes (PROs) in cancer randomised controlled trials (RCTs) may be particularly important for older patients. The objectives of this systematic review were to quantify the frequency with which older patients are included in RCTs with PROs and to evaluate the quality of PRO reporting in those trials. Methods: All RCTs with PRO endpoints, published between January 2004 and February 2019, which included a patient sample with a mean/median age ≥70 years, were considered for this systematic review. The following cancer malignancies were considered: breast, colorectal, lung, prostate, gynaecological and bladder cancer. Quality of PRO reporting was evaluated using the International Society for Quality of Life Research-PRO standards. Studies meeting at least two-thirds of these criteria were considered to have high-quality PRO reporting. Results: Of 649 RCTs identified with a PRO endpoint, only 72 (11.1%) included older patients. Of these, 35 trials (48.6%) were conducted in patients with metastatic/advanced disease. PROs were primary endpoints in 20 RCTs (27.8%). Overall survival was the most frequently reported clinical outcome in studies of patients with metastatic/advanced cancer (n=28, 80%). One-third of the RCTs (n=24, 33.3%) were considered to have high-quality PRO reporting. Overall, the largest prevalence of RCTs with high-quality PRO reporting was observed in prostate and colorectal cancers. Conclusions: Our review indicates not only that PRO-RCT-based studies in oncology rarely include older patients but also that completeness of PRO reporting of many of them is often suboptimal

Longitudinal analysis of health-related quality of life data in oncology : towards a standardization of the time to deterioration method

Cette thèse a pour but d’apporter une contribution à l’analyse et la comparaison des données de PROs (« patient-reported outcomes » ou « résultats rapportés par le patient ») dans les essais cliniques en cancérologie, dont l’interprétation reste complexe et non standardisée. Parmi les nombreuses méthodes proposées pour l’analyse longitudinale des données de PROs, figure l’approche du temps jusqu’à détérioration (TJD). Dans le cadre de ce projet, des travaux menés ont fait l’état des définitions du TJD utilisées et mettent en évidence que certaines recommandations n’ont pas été suivies. De plus, la variabilité des définitions utilisées compromet la comparaison des résultats entre les essais cliniques. L’approche du TJD nécessite une définition claire de ce qui est considéré comme une « détérioration », et cela dépendra à la fois de la localisation cancéreuse, de la situation thérapeutique, du score de référence, de la différence minimale cliniquement importante perçue par le patient, ainsi que des règles de censure. Dans l’optique d’optimiser et d’harmoniser les définitions utilisées du TJD, afin d’avoir des résultats comparables, deux macros SAS ont été créées sur la méthode du TJD afin de standardiser les définitions utilisées par la communauté. S’inscrivant dans cette trajectoire, une étude menée sur une cohorte de patientes atteintes d’un cancer du sein en situation adjuvante a conduit à s’intéresser à la première détérioration du patient et à la gestion de l’absence de randomisation à l’inclusion. En parallèle, cette méthode a également été appliquée dans un essai de phase II randomisé chez des patients atteints d’un cancer du pancréas métastatique. L’impact de l’occurrence des données manquantes à l’inclusion dans cet essai a été traité en appliquant une imputation multiple utilisant la méthode de Monte-Carlo par chaînes de Markov. Ces travaux soulignent le besoin de continuer la création de consensus pour l’analyse longitudinale des données de PROs dans les essais cliniques en cancérologie.The purpose/aim of this thesis is to contribute to the analysis and comparison of PROs (« patient-reported outcomes ») data in oncology clinical trials. The interpretation of such results remains complex and unstandardized. One of the many ways to carry out a longitudinal analysis of PRO data is the time to deterioration (TTD) approach. Within of the scope of this project, some of the research examined which definitions of TTD are used and pointed out that some recommendations have not been followed. Moreover, due to the variability of the definitions in use, the comparison of various results from clinical trials is compromised. A clear definition of what is considered to be a « deterioration » is required for the TTD approach. It will depend on many criteria such as the location of the cancer, the therapeutic setting, the reference score, the minimal important difference perceived by the patient, as well as on censoring rules. Two SAS macros were developed on the TTD method as a way to optimize and harmonize the TTD definitions that are being used, as well as to be able to have comparable results and consequently a way to help standardize those definitions. In this perspective, a study conducted on a cohort of adjuvant breast cancer patients led to more focus on the first deterioration of the patient and the management of non-randomization at baseline. In parallel, this method was also implemented for a randomized phase II trial on patients with metastatic pancreatic cancer. During this trial, the impact of the occurrence of missing data at baseline was handled by applying a multiple imputation based on the Markov Chain Monte Carlo method. These works highlight the need to continue developing a consensus for the longitudinal analysis of PROs data in oncology clinical trials

Analyse longitudinale des données de qualité de vie relative à la santé en cancérologie : vers une standardisation de la méthode du temps jusqu’à détérioration

The purpose/aim of this thesis is to contribute to the analysis and comparison of PROs (« patient-reported outcomes ») data in oncology clinical trials. The interpretation of such results remains complex and unstandardized. One of the many ways to carry out a longitudinal analysis of PRO data is the time to deterioration (TTD) approach. Within of the scope of this project, some of the research examined which definitions of TTD are used and pointed out that some recommendations have not been followed. Moreover, due to the variability of the definitions in use, the comparison of various results from clinical trials is compromised. A clear definition of what is considered to be a « deterioration » is required for the TTD approach. It will depend on many criteria such as the location of the cancer, the therapeutic setting, the reference score, the minimal important difference perceived by the patient, as well as on censoring rules. Two SAS macros were developed on the TTD method as a way to optimize and harmonize the TTD definitions that are being used, as well as to be able to have comparable results and consequently a way to help standardize those definitions. In this perspective, a study conducted on a cohort of adjuvant breast cancer patients led to more focus on the first deterioration of the patient and the management of non-randomization at baseline. In parallel, this method was also implemented for a randomized phase II trial on patients with metastatic pancreatic cancer. During this trial, the impact of the occurrence of missing data at baseline was handled by applying a multiple imputation based on the Markov Chain Monte Carlo method. These works highlight the need to continue developing a consensus for the longitudinal analysis of PROs data in oncology clinical trials.Cette thèse a pour but d’apporter une contribution à l’analyse et la comparaison des données de PROs (« patient-reported outcomes » ou « résultats rapportés par le patient ») dans les essais cliniques en cancérologie, dont l’interprétation reste complexe et non standardisée. Parmi les nombreuses méthodes proposées pour l’analyse longitudinale des données de PROs, figure l’approche du temps jusqu’à détérioration (TJD). Dans le cadre de ce projet, des travaux menés ont fait l’état des définitions du TJD utilisées et mettent en évidence que certaines recommandations n’ont pas été suivies. De plus, la variabilité des définitions utilisées compromet la comparaison des résultats entre les essais cliniques. L’approche du TJD nécessite une définition claire de ce qui est considéré comme une « détérioration », et cela dépendra à la fois de la localisation cancéreuse, de la situation thérapeutique, du score de référence, de la différence minimale cliniquement importante perçue par le patient, ainsi que des règles de censure. Dans l’optique d’optimiser et d’harmoniser les définitions utilisées du TJD, afin d’avoir des résultats comparables, deux macros SAS ont été créées sur la méthode du TJD afin de standardiser les définitions utilisées par la communauté. S’inscrivant dans cette trajectoire, une étude menée sur une cohorte de patientes atteintes d’un cancer du sein en situation adjuvante a conduit à s’intéresser à la première détérioration du patient et à la gestion de l’absence de randomisation à l’inclusion. En parallèle, cette méthode a également été appliquée dans un essai de phase II randomisé chez des patients atteints d’un cancer du pancréas métastatique. L’impact de l’occurrence des données manquantes à l’inclusion dans cet essai a été traité en appliquant une imputation multiple utilisant la méthode de Monte-Carlo par chaînes de Markov. Ces travaux soulignent le besoin de continuer la création de consensus pour l’analyse longitudinale des données de PROs dans les essais cliniques en cancérologie

Médecine de précision et inégalités sociales d’accès aux essais précoces en cancérologie

Depuis dix ans, le développement de la médecine de précision bouscule la prise en charge du cancer. Pour autant, ces nouveaux traitements restent essentiellement disponibles via la participation à des essais cliniques. Cet article s’intéresse donc aux inégalités sociales d’accès aux essais précoces en cancérologie, question jusque-là peu investiguée. Ce travail s’appuie sur une méthodologie mixte associant données qualitatives (entretiens semi-directifs et observations) et quantitatives (enquête nationale auprès de 1 355 patients inclus). L’analyse croisée de ces données met au jour l’existence d’inégalités d’ordre social (genre), organisationnel (parcours de soin) et géographique. Ces inégalités s’illustrent dès les premières étapes de la prise en charge autour de trois mécanismes : l’organisation des filières d’accès aux essais, le tri des patients en amont de l’inclusion et les contraintes liées à la participation à un protocole de recherche

Farnesoid X Receptor Activation in Brain Alters Brown Adipose Tissue Function via the Sympathetic System

International audienceThe nuclear bile acid (BA) receptor farnesoid X receptor (FXR) is a major regulator of metabolic/energy homeostasis in peripheral organs. Indeed, enterohepatic-expressed FXR controls metabolic processes (BA, glucose and lipid metabolism, fat mass, body weight). The central nervous system (CNS) regulates energy homeostasis in close interaction with peripheral organs. While FXR has been reported to be expressed in the brain, its function has not been studied so far. We studied the role of FXR in brain control of energy homeostasis by treating wild-type and FXR-deficient mice by intracerebroventricular (ICV) injection with the reference FXR agonist GW4064. Here we show that pharmacological activation of brain FXR modifies energy homeostasis by affecting brown adipose tissue (BAT) function. Brain FXR activation decreases the rate-limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), and consequently the sympathetic tone. FXR activation acts by inhibiting hypothalamic PKA-CREB induction of TH expression. These findings identify a function of brain FXR in the control of energy homeostasis and shed new light on the complex control of energy homeostasis by BA through FXR

The impact of urban contamination on antibioresistance in microbial communities from periphyton and sediments

International audienceSince the early 20's antibiotics have been massively produced and consumed for the benefit of bothhuman and animal health. Nevertheless, antibiotics have also reached the aquatic environmentthrough diffuse sources (e.g. veterinary treatment, contaminated manure application...) and throughwastewater. Consequently, antibiotics concentrations between the ng/L and μg/L range are regularlydetected in surface water and those molecules have also been found in sediments and aquatic biota.The ubiquitous presence of antibiotics exerts a selective pressure on microbial communities leading tothe acquisition and dissemination of antibioresistance in the environment. While both antibiotics andantibioresistance have been found in different aquatic compartments, more investigation is requiredto better understand their distribution and to identify hot spots of accumulation.In this context, we investigated the repartition of antibiotics and antibioresistance in different aquaticcompartments on 4 stations belonging to regional observatories and presenting contrasting levels ofpharmaceuticals: 2 on the Arve river belonging to Sipibel observatory and 2 on Lake Geneva belongingto the Observatory on Lakes. On the Arve river, the 2 stations were located up- and down- stream thedischarge place of a wastewater treatment plant (WWTP) collecting both urban and hospitalwastewaters. On Lake Geneva, one station was located in a relatively pristine area while the secondwas close to the discharge of an urban WWTP. To better identify a potential temporal dynamic ofantibiotics and antibioresistances over seasons, 6 samplings were conducted during 1.5 year. On eachsampling campaign, the following parameters were determined: (i) antibiotics levels in water,sediments and periphyton; (ii) antibioresistance in periphyton and sediments using various techniques:detection of resistance genes, integrons quantification, detection of tolerance acquisition via a PICT(Pollution Induced Community Tolerance) approach; (iii) antibiotics biodegradation potential ofmicrobial community from sediments (by radiorespirometric measurement); (iv) diversity of bacteriaand diatoms in periphyton and sediments; (v) physico-chemical parameters and (vi) metalliccontamination in sediments.While microbial resistance to antibiotics is commonly assessed by quantifying resistance genes orisolating antibiotic resistant bacteria, antibiotic resistance can also be estimated by measuring theacquisition of antibiotics tolerance at community level, following a PICT approach. In our study,periphytic microbial communities from the Arve river were found to have a higher tolerance to thetested antibiotics (ciprofloxacin, ofloxacin, sulfamethazine and erythromycin) than communities fromLake Geneva, in agreement with the expected levels of contamination. In addition, in some cases, ahigher tolerance was also found at stations close to WWTP effluents than in upstream/protectedstations. For example, periphytic microbial communities collected downstream the WWTP on the Arveriver were generally found to have a higher tolerance to ciprofloxacin than the upstream communities.Comparing whole community tolerance to other classical indicators of antibioresistance and toantibiotics levels in the aquatic ecosystems allows us to better understand the interconnectionbetween pharmaceutical exposure, in situ tolerance and genetic potential for antibioresistance

Multiple tools for antibiotics and AMR characterisation in aquatic ecosystems a 2-years monitoring study

International audienc

Multiple tools for antibiotics and AMR characterisation in aquatic ecosystems a 2-years monitoring study

International audienc

Multiple tools for antibiotics and AMR characterisation in aquatic ecosystems a 2-years monitoring study

International audienc