Molecular profiling of advanced soft-tissue sarcomas: the MULTISARC randomized trial.

BACKGROUND: Soft-tissue sarcomas (STS) represent a heterogeneous group of rare tumors including more than 70 different histological subtypes. High throughput molecular analysis (next generation sequencing exome [NGS]) is a unique opportunity to identify driver mutations that can change the usual one-size-fits-all treatment paradigm to a patient-driven therapeutic strategy. The primary objective of the MULTISARC trial is to assess whether NGS can be conducted for a large proportion of metastatic STS participants within a reasonable time, and, secondarily to determine whether a NGS-guided therapeutic strategy improves participant's outcome. METHODS: This is a randomized, multicentre, phase II/III trial inspired by the design of umbrella and biomarker-driven trials. The setting plans up to 17 investigational centres across France and the recruitment of 960 participants. Participants aged at least 18 years, with unresectable locally advanced and/or metastatic STS confirmed by the French sarcoma pathological reference network, are randomized according to 1:1 allocation ratio between the experimental arm "NGS" and the standard "No NGS". NGS will be considered feasible if (i) NGS results are available and interpretable, and (ii) a report of exome sequencing including a clinical recommendation from a multidisciplinary tumor board is provided to investigators within 7 weeks from reception of the samples on the biopathological platform. A feasibility rate of more than 70% is expected (null hypothesis: 70% versus alternative hypothesis: 80%). In terms of care, participants randomized in "No NGS" arm and who fail treatment will be able to switch to the NGS arm at the request of the investigator. DISCUSSION: The MULTISARC trial is a prospective study designed to provide high-level evidence to support the implementation of NGS in routine clinical practice for advanced STS participants, on a large scale. TRIAL REGISTRATION: clinicaltrial.gov NCT03784014 .

Determinants of the access to remote specialised services provided by national sarcoma reference centres.

BACKGROUND: Spatial inequalities in cancer management have been evidenced by studies reporting lower quality of care or/and lower survival for patients living in remote or socially deprived areas. NETSARC+ is a national reference network implemented to improve the outcome of sarcoma patients in France since 2010, providing remote access to specialized diagnosis and Multidisciplinary Tumour Board (MTB). The IGéAS research program aims to assess the potential of this innovative organization, with remote management of cancers including rare tumours, to go through geographical barriers usually impeding the optimal management of cancer patients. METHODS: Using the nationwide NETSARC+ databases, the individual, clinical and geographical determinants of the access to sarcoma-specialized diagnosis and MTB were analysed. The IGéAS cohort (n = 20,590) includes all patients living in France with first sarcoma diagnosis between 2011 and 2014. Early access was defined as specialised review performed before 30 days of sampling and as first sarcoma MTB discussion performed before the first surgery. RESULTS: Some clinical populations are at highest risk of initial management without access to sarcoma specialized services, such as patients with non-GIST visceral sarcoma for diagnosis [OR 1.96, 95% CI 1.78 to 2.15] and MTB discussion [OR 3.56, 95% CI 3.16 to 4.01]. Social deprivation of the municipality is not associated with early access on NETSARC+ remote services. The quintile of patients furthest away from reference centres have lower chances of early access to specialized diagnosis [OR 1.18, 95% CI 1.06 to 1.31] and MTB discussion [OR 1.24, 95% CI 1.10 to 1.40] but this influence of the distance is slight in comparison with clinical factors and previous studies on the access to cancer-specialized facilities. CONCLUSIONS: In the context of national organization driven by reference network, distance to reference centres slightly alters the early access to sarcoma specialized services and social deprivation has no impact on it. The reference networks' organization, designed to improve the access to specialized services and the quality of cancer management, can be considered as an interesting device to reduce social and spatial inequalities in cancer management. The potential of this organization must be confirmed by further studies, including survival analysis.

Contemporary outcomes of metastatic breast cancer among 22,000 women from the multicentre ESME cohort 2008-2016.

AIM: Real-world data inform the outcome comparisons and help the development of new therapeutic strategies. To this end, we aimed to describe the full characteristics and outcomes in the Epidemiological Strategy and Medical Economics (ESME) cohort, a large national contemporary observational database of patients with metastatic breast cancer (MBC). METHODS: Women aged ≥18 years with newly diagnosed MBC and who initiated MBC treatment between January 2008 and December 2016 in one of the 18 French Comprehensive Cancer Centers (N = 22,109) were included. We assessed the full patients' characteristics, first-line treatments, overall survival (OS) and first-line progression-free survival, as well as updated prognostic factors in the whole cohort and among the 3 major subtypes: hormone receptor positive and HER2-negative (HR+/HER2-, n = 13,656), HER2-positive (HER2+, n = 4017) and triple-negative (n = 2963) tumours. RESULTS: The median OS of the whole cohort was 39.5 months (95% confidence interval [CI], 38.7-40.3). Five-year OS was 33.8%. OS differed significantly between the 3 subtypes (p < 0.0001) with a median OS of 43.3 (95% CI, 42.5-44.5) in HR+/HER2-; 50.1 (95% CI, 47.6-53.1) in HER2+; and 14.8 months (95% CI, 14.1-15.5) in triple-negative subgroups, respectively. Beyond performance status, the following variables had a constant significant negative prognostic impact on OS in the whole cohort and among subtypes: older age at diagnosis of metastases (except for the triple-negative subtype), metastasis-free interval between 6 and 24 months, presence of visceral metastases and number of metastatic sites ≥ 3. CONCLUSIONS: The ESME program represents a unique large-scale real-life cohort on MBC. This study highlights important situations of high medical need within MBC patients. DATABASE REGISTRATION: clinicaltrials.gov Identifier NCT032753.

Management and outcome of male metastatic breast cancer in the national multicenter observational research program Epidemiological Strategy and Medical Economics (ESME).

BACKGROUND AND AIMS: Because of its low prevalence, metastatic breast cancer (MBC) in males is managed based on clinical experience with women. Using a real-life database, we aim to provide a comprehensive analysis of male MBC characteristics, management and outcome. METHODS: The Epidemiological Strategy and Medical Economics Data Platform collected data for all men and women ⩾18 years with MBC in 18 participating French Comprehensive Cancer Centers from January 2008 to November 2016. Demographic, clinical, and pathological characteristics were retrieved, as was treatment modality. Men were matched 1:1 to women with similar characteristics. RESULTS: Of 16,701 evaluable patients, 149 (0.89%) men were identified. These men were older (median age 69 years) and predominantly had hormone receptor HR+/HER2- disease (78.3%). Median overall survival (OS) was 41.8 months [95% confidence interval (CI: 26.9-49.7)] and similar to women. Median progression-free survival (PFS) with first-line therapy was 9.3 months [95% CI (7.4-11.5)]. In the HR+/HER2- subpopulation, endocrine therapy (ET) alone was the frontline treatment for 43% of patients, including antiestrogens (n = 19), aromatase inhibitors (n = 15) with luteinizing hormone-releasing hormone (LHRH) analogs (n = 3), and various sequential treatments. Median PFS achieved by frontline ET alone was similar in men [9.8 months, 95% CI (6.9-17.4)] and in women [13 months, 95% CI (8.4-30.9)] (p = 0.80). PFS was similar for HR+/HER2- men receiving upfront ET or chemotherapy: 9.8 months [95% CI (6.9-17.4)] versus 9.5 months [95% CI (7.4-11.7)] (p = 0.22), respectively. CONCLUSION: MBC management in men and women leads to similar outcomes, especially in HR+/HER2- patients for whom ET should also be a cornerstone. Unsolved questions remain and successfully recruiting trials for men are still lacking.

Study protocol for the assessment of nurses internal contamination by antineoplastic drugs in hospital centres: a cross-sectional multicentre descriptive study.

INTRODUCTION: Antineoplastic drugs (AD) are potentially carcinogenic and/or reprotoxic molecules. Healthcare professionals are increasingly exposed to these drugs and can be potentially contaminated by them. Internal contamination of professionals is a key concern for occupational physicians in the assessment and management of occupational risks in healthcare settings. Objectives of this study are to report AD internal contamination rate in nursing staff and to identify factors associated with internal contamination. METHODS AND ANALYSIS: This trial will be conducted in two French hospital centres: University Hospital of Bordeaux and IUCT-Oncopole of Toulouse. The target population is nurses practicing in one of the fifteen selected care departments where at least one of the five studied AD is handled (5-fluorouracil, cyclophosphamide, doxorubicin, ifosfamide, methotrexate). The trial will be conducted with the following steps: (1) development of analytical methods to quantify AD urine biomarkers, (2) study of the workplace and organization around AD in each care department (transport and handling, professional practices, personal and collective protection equipments available) (3) development of a self-questionnaire detailing professional activities during the day of inclusion, (4) nurses inclusion (urine samples and self-questionnaire collection), (5) urine assays, (6) data analysis. ETHICS AND DISSEMINATION: The study protocol has been approved by the French Advisory Committee on the Treatment of Information in Health Research (CCTIRS) and by the French Data Protection Authority (CNIL). Following the opinion of the Regional Committee for the Protection of Persons, this study is outside the scope of the provisions governing biomedical research and routine care (n°2014/87). The results will be submitted to peer-reviewed journals and reported at suitable national and international meetings. TRIAL REGISTRATION NUMBER: NCT03137641.

The ongoing French metastatic breast cancer (MBC) cohort: the example-based methodology of the Epidemiological Strategy and Medical Economics (ESME).

PURPOSE: The currently ongoing Epidemiological Strategy and Medical Economics (ESME) research programme aims at centralising real-life data on oncology care for epidemiological research purposes. We draw on results from the metastatic breast cancer (MBC) cohort to illustrate the methodology used for data collection in the ESME research programme. PARTICIPANTS: All consecutive ≥18 years patients with MBC treatment initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres were selected. Diagnostic, therapeutic and follow-up data (demographics, primary tumour, metastatic disease, treatment patterns and vital status) were collected through the course of the disease. Data collection is updated annually. FINDING TO DATE: With a recruitment target of 30 000 patients with MBC by 2019, we currently screened a total of 45 329 patients, and >16 700 patients with a metastatic disease treatment initiated after 2008 have been selected. 20.7% of patients had an hormone receptor (HR)-negative MBC, 73.7% had a HER2-negative MBC and 13.9% were classified as triple-negative BC (ie, HER2 and HR status both negative). Median follow-up duration from MBC diagnosis was 48.55 months for the whole cohort. FUTURE PLANS: These real-world data will help standardise the management of MBC and improve patient care. A dozen of ancillary research projects have been conducted and some of them are already accepted for publication or ready to be issued. The ESME research programme is expanding to ovarian cancer and advanced/metastatic lung cancer. Our ultimate goal is to achieve a continuous link to the data of the cohort to the French national Health Data System for centralising data on healthcare reimbursement (drugs, medical procedures), inpatient/outpatient stays and visits in primary/secondary care settings. TRIAL REGISTRATION NUMBER: NCT03275311; Pre-results.

Sociodemographic, socioeconomic, and clinical determinants of survival in patients with cancer: A systematic review of the literature focused on the elderly.

Studies on cancer survival have revealed disparities not only between the elderly and their younger counterparts, but also among the elderly themselves. The aim of this work was to identify sociodemographic, socioeconomic, clinical, and care-related determinants of survival or mortality in older patients with cancer by a systematic synthesis of the literature. Understanding these factors is of great value for guiding health policies and programs aimed at reducing cancer survival disparities. We conducted a search of MEDLINE and SCOPUS databases under PRISMA guidelines. Results were limited to articles published in English and French from 2005 to 2015, and focused on elderly patients with cancer. The article selection was performed in a stepwise fashion: title, abstract, and full-text selection. Studied determinants and results of each article were synthesized. Forty-five articles were eligible and included in the study. We observed different ways of measuring socioeconomic status, comorbidities, and treatment among studies. Cancer-specific and overall survival were the main studied outcomes. Advanced age, low income, low socioeconomic status, presence of comorbidities, advanced stage, and poor tumor grade were found to be associated with lower survival or higher mortality. On the other hand, female gender and being married were predictive of increased survival or lower mortality. The next logical step is to carry out studies on elderly patients from different countries and to incorporate pertinent factors in a unique model. Moreover, specific geriatric health impairments should be taken into account in further research because of their association with survival.

Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials).

BACKGROUND: Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer. METHODS: Time-to-event end-points currently used were identified from a literature review of pancreatic RCT trials (2006-2009). Academic research groups were contacted for participation in order to select clinicians and methodologists to participate in the pilot and scoring groups (>30 experts). A consensus was built after 2 rounds of the modified Delphi formal consensus approach with the Rand scoring methodology (range: 1-9). RESULTS: For pancreatic cancer, 14 time to event end-points and 25 distinct event types applied to two settings (detectable disease and/or no detectable disease) were considered relevant and included in the questionnaire sent to 52 selected experts. Thirty experts answered both scoring rounds. A total of 204 events distributed over the 14 end-points were scored. After the first round, consensus was reached for 25 items; after the second consensus was reached for 156 items; and after the face-to-face meeting for 203 items. CONCLUSION: The formal consensus approach reached the elaboration of guidelines for standardised definitions of time-to-event end-points allowing cross-comparison of RCTs in pancreatic cancer.

Protocol of the Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) project: formal consensus method for the development of guidelines for standardised time-to-event endpoints' definitions in cancer clinical trials.

INTRODUCTION: In randomised phase III cancer clinical trials, the most objectively defined and only validated time-to-event endpoint is overall survival (OS). The appearance of new types of treatments and the multiplication of lines of treatment have resulted in the use of surrogate endpoints for overall survival such as progression-free survival (PFS), or time-to-treatment failure. Their development is strongly influenced by the necessity of reducing clinical trial duration, cost and number of patients. However, while these endpoints are frequently used, they are often poorly defined and definitions can differ between trials which may limit their use as primary endpoints. Moreover, this variability of definitions can impact on the trial's results by affecting estimation of treatments' effects. The aim of the Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) project is to provide recommendations for standardised definitions of time-to-event endpoints in randomised cancer clinical trials. METHODS: We will use a formal consensus methodology based on experts' opinions which will be obtained in a systematic manner. RESULTS: Definitions will be independently developed for several cancer sites, including pancreatic, breast, head and neck and colon cancer, as well as sarcomas and gastrointestinal stromal tumours (GISTs). DISCUSSION: The DATECAN project should lead to the elaboration of recommendations that can then be used as guidelines by researchers participating in clinical trials. This process should lead to a standardisation of the definitions of commonly used time-to-event endpoints, enabling appropriate comparisons of future trials' results.

Direct costs of cervical cancer management in Morocco.

BACKGROUND: For cervical cancer the epidemiological profile is poorly known in Morocco and no data is available concerning the direct medical costs. The purpose of this work is to estimate the direct cost of medical management of invasive cervical cancer during the first year after diagnosis in Morocco. METHODS: The estimation of direct costs of medical management of invasive cervical cancer during the first year after diagnosis in Morocco is based on the estimation of individual cost in each stage which covers diagnosis, treatment and follow-up during first year. The cost was estimated per patient and whole cycle-set using the costs for each drug and procedure as indicated by the Moroccan National Agency for Health Insurance. Extrapolation of the results to the whole country was used to calculate the total annual cost of cervical cancer treatments in Morocco. RESULTS: Overall approximately 1,978 new cases of cervical cancer occur each year in Morocco. The majority (82.96%) of these cases were diagnosed at a late stage (stage II or more). The cost of one case of cervical cancer depends on stage of diagnosis, the lowest cost is $382 for stage Cis followed by the cost of stage IA1 for young women (<40 years) which is $2,952. The highest cost is for stage IV, which is $7,827. The total cost of cervical cancer care for one year after diagnosis is estimated at $13,589,360. The share allocated to treatment is the most important part of the global care budget with an annual sum of $13,027,609 whereas other cost components are represented as follows: $435,694 for annual follow-up activity and $126,057 for diagnosis and preclinical staging. CONCLUSION: This study provides health decision-makers with a first estimate of costs and the opportunity to achieve the optimal use of available data to estimate the needs of health facilities in Morocco.

[Impact of pathological review by an expert on the diagnosis and management of patients with cancer in Aquitania]. / Impacts des avis diagnostiques de cancérologie en Aquitaine. Etude quantitative, qualitative et médicoéconomique rétrospective sur une année.

AIMS: The goal of this work was to evaluate the impact of expert pathological second opinion on the diagnosis and management of patients with cancer, in a French region (Aquitaine) and with an economic point of view. MATERIAL AND METHODS: The study was first quantitative, performed retrospectively on all cases of cancer, voluntary sent for a second opinion to an expert pathologist of two centers. Secondly, we restricted the study to lymphoid, melanocytic and soft tissue tumors sent for second opinion. We considered that the expert review had an important diagnostic impact either when the initial pathologist sent the specimen to identify or classify malignant tumor or hesitated between benign and malignant tumor or had no hypothesis, or if there were discordant diagnoses (malignant/benign) between the two pathologists. We considered that the expert review had a high therapeutic impact if the disagreement between initial and expert diagnoses induced a complete modification in therapy. We evaluated the cost of second opinion for the expert centers and the cost of care management. RESULTS: Over the year 2006, the expert centers received 5077 lesions for consultation: 3769 specimens were sent by a pathologist for a second review, 1324 by pathologists of Aquitania and of these, 751 samples were submitted for lymphoid (55%), soft tissues (30%) or melanocytic tumors (15%). There was an important diagnostic impact for 75% of the samples; the impact of the expert review on patient management was considered high for 46% of specimens and the expert pathological diagnosis modified the clinical prognosis for 40% of the specimens. We estimated that for 53 discordant diagnoses (malignant/benign), second opinion allowed an economy of 500,000 euro. CONCLUSION: Expert second opinion is very important not only for diagnosis and management for patient with cancer but also for economic reasons.

Cost-effectiveness of testing for human immunodeficiency virus and hepatitis C virus among blood transfusion recipients.

OBJECTIVE: To choose the most cost-effective option for detecting human immunodeficiency virus (HIV-1) and hepatitis C virus (HCV) among blood transfusion recipients. DESIGN: Cost-effectiveness analysis. Effectiveness was expressed as the number of HIV-1 or HCV infections detected, regardless of whether they were related to transfusion. To estimate costs, we assumed hospital insurance would cover costs related to detection and compensation, when granted. SETTING: A 2,890-bed acute care teaching hospital in Bordeaux, France. METHODS: Eight options were defined, from the simplest, which would be to do nothing, to a maximal approach, which would be to keep a serum sample in a serum library for a lookback and perform tests for antibody to HIV-1 and to HCV before and 3 months after transfusion. Data on probabilities and costs were taken from the literature and experiences of French hospitals. RESULTS: The most cost-effective option was to perform viral antibody testing before transfusions (option 3), which would detect 27 infections per 1,000 patients, for an expenditure of US $1,260 per detected patient Option 6, obtaining a serum sample before transfusion and performing tests for antibody to HIV-1 and to HCV 3 months after transfusion, had a similar cost-effectiveness ratio but detected only 16 infections per 1,000 patients. Performing tests before and 3 months after transfusion (option 4), compared with option 3, would detect 1 additional infection for an additional cost of US $8,322. CONCLUSION: The most cost-effective options are not specific to blood transfusion recipients and might be more suited to all hospitalized patients.