Clinical trial NCT03670927: Etiosarc: Environmental Aetiology of Sarcomas From a Multicenter French Population-based Case-control Study Among Adults
Official title: Etiosarc: Study of the Environmental Aetiology (Environment, Occupations and Lifestyle) of Sarcomas (Soft Tissue, Visceral and Bone) From a Multicenter French Population-based Case-control Study Among Adults.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Sarcoma
Environmental Exposure
Occupational Exposure
Life Style
Lead sponsor: Institut National de la Santé Et de la Recherche Médicale, France
Sponsor class: OTHER_GOV
First posted: 2018-09-14
Enrollment: 2237
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Cases are defined as all incident patients with a diagnosis of primary sarcoma and histologically confirmed by an expert pathologist of the RRePS or ResOs networks in the 15 districts of France participating to this study.

Two control subjects per case will be randomly selected from the French general population using electoral rolls and individually matched to case by age (by 5-year age group), sex and residential area.

Brief summary: Introduction: Sarcomas are rare tumors of connective tissue. The exact overall incidence of sarcomas is unknown due to diagnostic difficulties and the various histological subtypes (over 80 subtypes). However, the apparent increasing incidence of sarcomas suggests environmental causes such as pesticides. Except for some specific factors (i.e. ionizing radiation, vinyl chloride, dioxin, and genetic predispositions) the scientific knowledge on the aetiology of sarcomas is sparse and inconsistent. France is a particularly appropriate country to set up a study investigating the causes of sarcoma occurrence due to the French organization in treatment and care of sarcoma patients, which is highly structured and revolved around national expert networks. The main objective of the ETIOSARC project is to study the role of lifestyle, environmental and occupational factors in the occurrence of sarcomas among adults from a multicentric population-based case-control study.

Methods and analysis: Cases will be all incident cases (older than 18 years old) identified in 15 districts of France covered by a cancer registry and/or a reference center in sarcoma's patient care over a three-year period with an inclusion start date ranging from the 1st October 2018 to the 1st January 2020 and histologically confirmed by a second review of the diagnosis. Two controls will be individually-matched by sex, age (5-years group), and districts of residence and randomly selected from electoral list. A standardized questionnaire will be administered by a trained interviewer in order to gather information about occupational and residential history, demographic and socioeconomic characteristics and lifestyle factors. At the end of the interview, a saliva sample will be systematically proposed.

This study will permit to validate or not already suspected risk factors for sarcomas such as phenoxyherbicides, chlorophenol and to generate new hypothesis to increase our understanding about the genetic and environmental contributions in the carcinogenicity process.

Detailed description: The main objective of the ETIOSARC study is to assess the role of lifestyle, environmental and occupational factors in the occurrence of sarcomas among adults from a multicenter population-based case-control study.

Specific objectives are:

* To identify environmental risk factors for sarcomas as a whole and for the most frequent subtypes;
* To investigate the interactions between gene polymorphisms and environmental exposures in sarcoma susceptibility;
* To assess whether some specific genetic characteristics of sarcoma' tumors are associated with environmental exposures; We will also explore the feasibility of classifying sarcomas by genetics types (simple vs complex genomic profile) as part of the objective of identifying environmental risk factors.

Study design

The ETIOSARC study is a prospective multicenter population-based case-control study. This study is restricted to French geographical areas (further called districts) that meet at least one of these four criteria:

* Criteria 1: Districts covered by both a general cancer registry and a French Sarcoma Group (GSF-GETO) expert center from either the network of reference for soft-tissue sarcoma pathology (RRePS), the network of reference for bone sarcoma pathology (ResOs) or the clinical sarcoma network (NetSarc);
* Criteria 2: Districts including a coordinator center of any of the RRePS / NetSarc networks;
* Criteria 3: Districts covered by a general cancer registry that is expected to register more than 50 cases per year;
* Criteria 4: Districts adjacent to districts meeting criteria 1 and covered by a general cancer registry.

In total, 15 districts meet one of the four criteria, which represent approximatively 24% of the French population (2015 estimations from the national institute of statistics and economic studies, Insee). Nine districts meet criteria 1 (Gironde, Hérault, Haute-Vienne, Loire Atlantique, Calvados, Nord, Bas-Rhin and Doubs, Poitou-Charentes), two districts meet criteria 2 (Rhône and Val-de-Marne); two districts meet criteria 3 (Isère and Haut-Rhin) et two districts meet criteria 4 (Manche, Vendée).

Study population

Cases recruitment modalities

Patients will be recruited by specifically trained clinical research associate (CRA). In districts where a general cancer registry is active, the process of identifying incident sarcoma patients is well defined, which warrants the efficiency and exhaustiveness of the recruitment. However, poor survival for some cancer cases will not allow to rely on routine inclusion procedure and the registries will implement a rapid case ascertainment procedure to minimize the delay between diagnosis and enrollment and interview. Cases will be identified from pathology laboratories and multidisciplinary sarcoma tumor board (including sarcoma, gynecological, digestive, skin and bone tumor board). CRA will regularly contact laboratories and hospitals (within a three months window) to identify newly diagnosed sarcoma cases and to collect associated reports. The CRA will retrieve the clinical file in order to check inclusion and non inclusion criteria and to collect names and addresses of eligible patients and their physicians. Then, the CRA will contact the case's physicians in order to gather their clinical advice to include their patients in the study. In case of agreement, the CRA will contact the patients and ask them to participate. In case of oral agreement, he/she will arrange an interview to collect written consent and administer detailed questionnaire.

In Rhône and Val de Marne where no general cancer registry exists, the process of identifying incident sarcoma patients will largely rely on the existence of a RRePS/ResOS/NetSarc coordination center to facilitate the identification of new cases.

Regardless of the district, the diagnosis of all included cases will be systematically ascertained by an expert pathologist within the RRePS and ResOs networks following a standard procedure.

On a regular basis (at least once a month), the list of incident cases included in the RRePS/ResOS/NetSarc networks will be extracted from the shared databases. The list of cases identified by registries will be merged with the list of cases included in the RRePS/ResOS/NetSarc networks by the pathology sample reference number in order to collect diagnosis confirmation and to identify new but missed incident cases.

Controls selection

The selection of controls and the recruitment of cases will take place simultaneously. Every time a case will be diagnosed and identified, two controls will be randomly selected at that time from the electoral rolls of the same district as the case district of residence. For each case, a list of 20 potential controls with the same age (within a 5-year age group) and sex as the cases will be constituted in order to account for potential refusal. Calls to contact potential controls will be centralized and will be made by an investigator specifically trained to better understand the objectives of the study. First, this investigator will try to retrieve the phone number of the first potential control on the list and will contact him/her in order to gather his/her agreement to participate in this study. After five calls made at different schedules (e.g. in the evening on weekdays), if the potential control couldn't be reached, the investigator will send an information letter containing a reply coupon indicating phone number and schedule at which the person could be reach. If the reply coupon is not returned, or after 10 calls made at the phone number and the schedule indicated on the reply coupon, the first potential control will be considered as unreachable and then, the same procedure will be applied for the second potential controls on the list and so on until two controls per case agreed to participate to the study.

For each control agreeing to participate, an appointment will be made to collect written consent and to administer detailed questionnaire by a CRA.

All participants will give their informed written consent to participation, in line with French ethical guidelines.

Data collection

Data will be collected from self-questionnaire supplemented by a specific questionnaire. The self-questionnaire will permit to gather the complete occupational history (for each job held for at least 6 months) and residential history (for each place occupied for at least 6 months). During a face-to-face interview, the trained interviewer will check (complete if necessary) and supplement the self-administered questionnaire by a specific questionnaire with questions about demographic and socioeconomic characteristics, occupations of spouse and parents, leisure-time activities, reproduction, medical history, family history of cancer, diet, lifestyle factors such as tobacco smoking and alcohol consumption. The specific questionnaire will also collect additional occupational and residential information such as work tasks, work places, materials handled for each job held for at least 6 months and description of the environment of each residence places.

At the end of the interview, subjects (both cases and controls) will be invited to provide a saliva sample in order to obtain germline DNA.

In case of refusal to participate and if the subject agreed, data on demographic and socioeconomic characteristics will be collected in order to assess the potential selection bias that might occur due to the specific profile of non-respondent subjects.

Biological sampling and storage

Each participant will be asked to provide a salivary sample in order to obtain germline DNA. Salivary samples will be collected by the subjects themselves under instructions from the CRA, using DNA Genotek Oragene 575 collection kit. After collection, samples will be sent at the Biological Resources Center of the Bordeaux hospital university center "Bordeaux Biothèque Santé" for storage.

Determination of the sample size

Since our definition of environmental exposures is very broad, the sample size calculation has been based on various scenarios of exposure prevalence, from 5% (relevant for domestic, environmental but also some occupational exposures such as farmer in the general population) to 20% (relevant for some occupational exposures such as fibers). For a total sample size of 2000 cases and a 1:2 individually-matched design, considering a statistical power of 80% at a significance level of 5%, the minimum detectable odds ratio will be 1.39 and 1.21 under a exposure prevalence of 5% and 20%, respectively. Considering sub-types analyses, the four main histological types are GIST, liposarcoma, leiomyosarcoma and unclassified sarcoma, which account for 18%, 15%, 11% and 16% of sarcomas, respectively. Considering a sample size of 300 cases, the minimum detectable odds ratio will be 2.21 and 1.61 under an exposure prevalence of 5% and 20%, respectively. Typically in environmental epidemiology, the relative increases in disease risks due to environmental exposures are usually low around 1.5, thus, it is essential to recruit a minimum of 2000 cases in order to be able to perform sub-type analyses.

Statistical analysis

Relationship between case/control status and each exposure variable and 95% confidence intervals will be individually estimated using conditional logistic regression models. If necessary, a multilevel logistic model will be implemented in order to take into account the data variability due to the multicenter design and the various CRA that will administer the questionnaires.

Stratified histological sub-types analyses are also planned. Moreover, since sarcomas may be classified into four groups on a molecular basis (i.e. sarcomas with recurrent translocation, sarcomas with specific activating or inactivating mutations, sarcomas with MDM2 amplifications, and sarcomas with a complex genomic profile), the feasibility of classifying sarcomas by genetic types instead of by histological subtypes for the objective of identifying environmental risk factors will be explore. The underlying hypothesis is that the aetiology among these four molecular groups may be homogeneous.

Methods for coordinating the project and for quality control

This study is organized around three different centers or committees: a national coordination center, a steering committee, and local centers.

The national coordination center will be in charge of running routine operations, assisting participating local centers, guaranteeing the quality of the data collection, centralizing data, supervising the data coding and exposure assessment.

The steering committee's principal role will be to establish research priorities based on the availability of the data and the current scientific knowledge.

Local centers will be in charge of determining identification sources of cases in their districts and of collecting data. They will also transmit the collected data to the national coordination center.

Standardized procedures are written in a procedure manual to guarantee the quality of the collected data. Besides, a completion guide of the standardized questionnaire has been developed to assist CRA during interviews. A data manager will ensure that the study is conducted in compliance with the protocol. On a regular basis and as frequently as necessary, he/she will assess the quality of the collected data using several indicators: the average time spent by the CRA at the subject's home, the degree of completeness of the questionnaires by CRA, the ratio of included cases to expected cases, the average elapsed time between the identification of a case and the interview, the average elapsed time between case and control interviews, etc.

All collected data will be centralized in a single location, the University of Bordeaux (CREDIM, centre de Recherche et de Développement en Informatique Médicale).

Eligibility criteria: Inclusion Criteria:

* Cases

  * Patients diagnosed in the previous 6 months from identification with a primary and histologically confirmed malignant sarcoma including soft-tissue, visceral and bone sarcomas as defined by the WHO classification of bones and soft tissue sarcoma, fourth edition, 2013;
  * Diagnosed over a three-year period with an inclusion start date ranging from the 1st October 2018 to the 1st January 2020;
  * Living in the 15 districts participating to the study at the time of diagnosis
  * French nationality (due to control selection within electoral lists);
  * At least 18 years old at diagnosis;
  * Agreed to participate to the study with a signed informed consent;
* Controls

  * Subjects registered within the electoral rolls;
  * At least 18 years old at interview;
  * Living in the 15 districts participating to the study at the time of interview;
  * Agreed to participate to the study with a signed informed consent;

Exclusion Criteria:

* Cases

  * Patients with a known genetic predisposition to sarcoma such as Li-Fraumeni syndrome, Retinoblastoma syndrome, neurofibromatosis;
  * Kaposi's' sarcoma;
  * Protected adults' patients (aged of at least 18 years old) under guardianship by court order.
* Controls

  * Subject previously diagnosed with a primary and histologically confirmed malignant sarcoma including soft-tissue, visceral and bone sarcomas as defined by the WHO classification of bones and soft tissue sarcoma, fourth edition, 2013;
  * Protected adults' patients (aged of at least 18 years old) under guardianship by court order.

Primary outcomes:
measure: Odds ratios measuring the association between environmental exposures under study (environmental, occupational and lifestyle exposures) and sarcoma occurence
timeFrame: 1 year
Secondary outcomes:
Other outcomes:
Locations:
city: Besançon
country: France
facility: CHRU
city: Bordeaux
country: France
facility: Institut Bergonié
city: Caen
country: France
facility: Centre François Baclesse
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: CHU Dupuytren
city: Lyon
country: France
facility: Centre Léon Bérard
city: Montpellier
country: France
facility: Institut régional du Cancer Montpellier
city: Nantes
country: France
facility: CHU
city: Strasbourg
country: France
facility: CHRU
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: French National Institute of Health and Medical Research
name: Aude Lacourt, PhD
role: PRINCIPAL_INVESTIGATOR
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