Major changes in lung cancer over the last ten years in France: The KBP-CPHG studies

Lung Cancer 81 (2013) 32–38

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Major changes in lung cancer over the last ten years in France: The KBP-CPHG studies Chrystèle Locher a,∗ , Didier Debieuvre b , Daniel Coëtmeur c , Franc¸ois Goupil d , Olivier Molinier d , Thierry Collon e , Charles Dayen f , Jacques Le Treut g , Bernard Asselain h , Francis Martin i , Franc¸ois Blanchon a , Michel Grivaux a a

Respiratory Medicine Department, General Hospital, 6-8 Rue Saint Fiacre, BP 218, 77104 Meaux CEDEX, France Respiratory Medicine Department, Emile Muller General Hospital, 20 Avenue du Docteur René Laennec, BP 1370, 68070 Mulhouse, France c Respiratory Medicine Department, Yves Le Foll General Hospital, 10 Rue Marcel Proust, 22027 Saint-Brieuc CEDEX 1, France d Respiratory Medicine Department, General Hospital, 194 Avenue Rubillard, 72037 Le Mans CEDEX 9, France e Respiratory Medicine Department, Le Raincy-Montfermeil Intermunicipal Hospital, 10 Rue du Général Leclerc, 93370 Montfermeil, France f Respiratory Medicine Department, General Hospital, 1 Avenue Michel de l’Hospital, BP 608, 02321 Saint-Quentin CEDEX, France g Respiratory Medicine Department, Pays d’Aix General Hospital, Avenue des Tamaris, 13616 Aix-en-Provence CEDEX 1, France h Biostatistics Department, Curie Institute, 26 Rue d’Ulm, 75005 Paris, France i Respiratory Medicine Department, Compiègne-Noyon, General Hospital, 8 avenue Henri Adnot, ZAC de Mercières 3, BP 50029, 60321 Compiègne CEDEX, France b

a r t i c l e

i n f o

Article history: Received 22 November 2012 Received in revised form 22 February 2013 Accepted 5 March 2013 Keywords: Adenocarcinoma Epidemiology France Hospitals General Lung cancer

a b s t r a c t The incidence of lung cancer has dramatically increased in ten years, being now the most commonly diagnosed cancer in males and the fourth most commonly diagnosed cancer in females. Considering social and scientific evolution, the aim of the present study conducted by the French College of General Hospital Respiratory Physicians (CPHG) was to compare patient and lung cancer characteristics at a ten-year interval. Two epidemiological studies, KBP-2000-CPHG and KBP-2010-CPHG, were conducted at a ten-year interval. These prospective multicentre studies included all patients ≥18 years of age with primary lung cancer diagnosed between 1st January and 31st December 2000 or 2010, and managed in the respiratory departments of one of the participating general hospitals. A standardised form was completed for each patient. A steering committee checked recruitment exhaustiveness. Respectively, in 2000 and 2010, 137 and 104 centres included 5667 and 7051 patients. Compared to 2000, patients in 2010 were significantly older (65.5 ± 11.3 vs. 64.3 ± 11.5 years, p < 0.0001), more frequently women (24.3% vs. 16.0%, p < 0.0001) and never-smokers (10.9% vs. 7.2%, p < 0.0001). In 2010, adenocarcinoma was the most common tumour (45.4%, vs. 29.0% in 2000, p < 0.0001). The adenocarcinoma rate increased irrespective of sex, age, or smoking status (relative risk [RR] before and after adjustment, RR = 2.07 [1.92–2.24], p < 0.0001 and 2.06 [1.90–2.23], p < 0.0001). In ten years, lung cancer characteristics have therefore changed: more women, more never-smokers, and more adenocarcinomas. The particular high increase in adenocarcinoma rate deserves further analysis. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Lung cancer is a major public health issue all over the world. It is the most commonly diagnosed cancer and leading cause of cancer deaths in males, and the fourth most commonly diagnosed and second leading cause in females [1]. In the European Union, in 2008, 253,000 deaths (20.5% of cancer deaths) were due to lung cancer [2].

∗ Corresponding author at: Service de Pneumologie, Hôpital de Meaux, 6-8 Rue Saint Fiacre, BP 218, 77104 Meaux CEDEX, France. Tel.: +33 1 64 35 38 56; fax: +33 1 64 35 37 28. E-mail address: [email protected] (C. Locher). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.03.001

In France, in 2010, the number of new diagnoses was estimated at 39,500 (27,500 men and 12,000 women), and an estimated 28,100 people (21,000 men and 7100 women) died of lung cancer [3]. In ten years, the incidence of lung cancer has increased: the estimated number of new diagnoses rose from 28,000 [4] to 39,500 [3]. At the same time, several social and scientific changes have occurred. Due to anti-smoking campaigns, smoking rates have significantly decreased in the French population [5]. Diagnosis of lung cancer has improved, with routine use of PET-CT in clinical practice for staging and the development of immunochemistry and molecular biology methods to detect gene mutations and improve tumour characterisation [6]. Treatment has evolved, with the emergence of new drugs targeting specific pathways and new treatment strategies such as maintenance chemotherapy [7]. Finally, since 2010,

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a revised TNM classification (seventh edition) has been routinely used to classify lung cancer [8–10]. To evaluate the impact of these changes on patient characteristics and tumour features, the French College of General Hospital Respiratory Physicians (CPHG) conducted two prospective multicentre epidemiological studies at a ten year interval: KBP2000-CPHG and KBP-2010-CPHG.

2. Material and methods Study design: French prospective multicentre observational studies [11–13]. Study centres: The members of the CPHG which gathers the chest physicians of the respiratory departments of the French general hospitals (overseas départements and territories included) were contacted. Those agreeing to participate became study investigators and their departments study centres. Participation in one study was independent of participation in the other study. Inclusion criteria: All consecutive patients aged over 18 years with primary lung cancer histologically or cytologically diagnosed between 1st January and 31st December 2000 (KBP-2000-CPHG) or 2010 (KBP-2010-CPHG) (date of sampling), and managed by a chest physician in one of the study centres were included in the study on condition that they agreed to participate. Data collection: For each included patient, the investigators filled out an anonymous questionnaire comprising items on age, sex, smoking, performance status, histologic tumour type, tumour stage according to the sixth (KBP-2000-CPHG) or seventh (KBP-2010CPHG) TNM classification, and first-line therapy (Supplementary Fig. 1). Study exhaustiveness: A steering committee assessed study completeness. For each centre, the committee checked the regularity of inclusions throughout the year for all centres individually and taken together. It also checked the coherence of the data between 2000 and 2010 for the centres that participated in both studies. Clinical research associates checked the completion of the questionnaires and contributed to the exhaustiveness of the recruitment. Ethical considerations: The study protocols were approved by French Information technology and freedoms commission (CNIL) on 2 August 2000 (900019) and 11 January 2010 (909479). The KBP2010-CPHG protocol was also approved by the advisory committee on research information processing in the health field (CCTIRS) on

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19 November 2009. The ethics committee of the French Society of Pneumology confirmed the observational nature of the study on 23 April 2010 (No. 2010–008). All patients were duly informed of the study objectives and requirements and gave oral consent before inclusion. Statistical analysis: Standard SAS® procedures (SAS Institute, Cary, NC, USA) were used for univariate and multivariate analysis. The population was described in terms of the questionnaire variables. Results were expressed as mean ± standard deviation (SD) or percentage. Univariate analysis used the Chi2 -test to assess association between categorical variables, and the Student t test or analysis of variance (ANOVA) (for normal distributions) or non-parametric tests (for non-normal distributions) to analyse quantitative variables. Adenocarcinoma risk was assessed on multivariate analysis using a logistic regression model. Adjustments were made for age, sex and smoking status. Statistical test results were considered significant at p < 0.05 (two-sided).

3. Results In 2000, 148 centres agreed to participate and included 5870 patients. Eleven centres and a total of 203 questionnaires (3.5% of the questionnaires) were excluded because of major deviation or lack of exhaustiveness. Finally, analysis was done on 137 centres and 5667 patients (Fig. 1). Each active centre included between 1 and 110 patients (mean ± SD: 41 ± 26 patients). In 2010, among the 132 centres which agreed to participate, 119 centres actually participated and included 7610 patients. Fifteen centres and a total of 559 questionnaires (7.3% of the questionnaires) were excluded. Finally, analysis was done on 104 centres and 7051 patients (Fig. 1). Each active centre included between 3 and 193 patients (68 ± 37 patients). Both in 2000 and 2010, active centres were distributed across France as a whole (including the overseas départements and territories); 80 centres participated in both studies (Fig. 2). Compared to 2000, patients in 2010 were significantly older (65.5 ± 11.3 vs. 64.3 ± 11.5 years, p < 0.0001), more frequently women (24.3% vs. 16.0%, p < 0.0001), and more frequently neversmokers (10.9% vs. 7.2%, p < 0.0001). Performance status (PS) 0 and 1 at diagnosis were more frequent in 2010 than in 2000 (68.9% vs. 64.1%, p < 0.0001) (Table 1). Compared to 2000, non-small-cell lung cancers (NSCLCs) in 2010 were more frequently diagnosed at an advanced stage (stage

Fig. 1. Flow chart of study populations. (*) Questionnaire in duplicate, no histological or cytological sample, sampling date outside of the recommended window, follow-up outside of the general hospital.

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Fig. 2. Geographical representation of (a) the KBP-2000-CPHG and (b) KBP-2010-CPHG study centres. In grey, centres in KBP-2010-CPHG not previously involved in KBP2000-CPHG.

IV): 58.3% vs. 42.6% (p < 0.0001) (Table 2). In 2000, the main histologic type was squamous cell carcinoma (38.8%) followed by adenocarcinoma (29.0%); conversely, in 2010 there were 3200 (45.4%) adenocarcinomas and 1854 (26.3%) squamous cell carcinomas. In all subgroups defined according to patient characteristics (sex, age, and smoking status), the percentage of NSCLC patients with adenocarcinoma was significantly higher in 2010 than 2000 (Fig. 3). Adenocarcinoma risk in NSCLC patients was significantly higher in 2010 than in 2000 (relative risk: RR = 2.07 [1.92–2.24], p < 0.0001). This increased risk of adenocarcinoma persisted after adjustment on age, sex, and smoking status (RR = 2.06 [1.90–2.23], p < 0.0001) (Table 3).

4. Discussion The KBP-CPHG studies demonstrated an increase over the ten-year period in the proportion of women and never-smokers presenting with primary lung cancer and that adenocarcinoma had become the most frequent histologic type. It also demonstrated an increase in patient age at diagnosis and that lung cancer continued to be frequently diagnosed only at advanced stages. The originality of these findings is that the histologic change observed over the ten-year period was not solely due to the changes in patient characteristics: adenocarcinoma risk increased irrespective of age, gender, or smoking status (relative risk: RR = 2.06 [1.90–2.23]; p < 0.0001).

4.1. Study strengths and weaknesses Evolution in lung cancer characteristics over a ten-year period was highlighted via the performance of two large-scale prospective epidemiological studies of similar design: identical inclusion criteria, virtually identical study centres, and data collection. Other epidemiological studies recently showing evolution in lung cancer have been retrospective, with longer recruitment periods and/or a lesser degree of exhaustiveness (single-centre design, limited to one lung-cancer subtype) [14,15]. The size and composition of the two cohorts enabled a description and representative comparison to be made of lung cancer in France. In France, lung cancer is managed approximately equally by three kinds of facility: state-sector general hospitals, teaching hospitals, and private-sector hospitals. In general hospitals, there are about 200 respiratory medicine departments treating lung cancer. In the 2000 and 2010 studies, about 50% of the French general hospital respiratory medicine departments included nearly 20% of the new diagnoses in France and more than half of the new cases diagnosed in the general hospitals [2,11]. The geographic distribution of the study centres (Fig. 2) suggest that recruitment was representative of general hospital respiratory medicine departments as a whole in France (including the overseas départements and territories). The exhaustiveness of inclusion and data collection was checked by the study’s steering committee. The study design ensured good

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Table 1 Comparison of main patient characteristics between the KBP-2000-CPHG and KBP-2010-CPHG studies.

Sex: N (%) - Male - Female Age - Mean ± SD (years) - N (%) ≤50 years 51–60 years 61–70 years 71–80 years >80 years Smoking - Smoking status: N (%) - Never-smoker Former smoker Smoker Current and former-smokers Number of packet-years Mean ± SD Duration of smoking Mean ± SD (years) Former-smokers Smoking cessation/lung cancer time Mean ± SD (years) Performance status at diagnosis: N (%) 0 – Fully active 1 – Restricted in heavy physical work 2 – Up and about more than half the day 3 – In bed or sitting in a chair more than half the day 4 – In bed or in a chair all the time Occupational exposure* : N (%) - No - Possible - Certain *

2000 N = 5667

2010 N = 7051

p-value

n = 5667 4763 (84.0) 904 (16.0) n = 5664 64.3 ± 11.5

n = 7051 5340 (75.7) 1711 (24.3) n = 7051 65.5 ± 11.3

<0.0001

783 (13.8) 1270 (22.4) 1743 (30.8) 1530 (27.0) 338 (6.0)

615 (8.7) 1899 (26.9) 2066 (29.3) 1732 (24.6) 739 (10.5)

n = 5586 402 (7.2) 2253 (40.3) 2931 (52.5)

n = 7008 762 (10.9) 2795 (39.9) 3451 (49.2)

<0.0001

n = 5112 44.4 ± 21.4 n = 4926 37.3 ± 11.5

n = 5945 43.0 ± 21.4 n = 5268 37.5 ± 11.6

0.0006

n = 2177 11.3 ± 9.8 n = 5656 1518 (26.8) 2131 (37.7) 1004 (17.8) 817 (14.4) 186 (3.3) n = 5623 5051 (89.8) 495 (8.8) 77 (1.4)

n = 2647 14.8 ± 11.6 n = 6976 1902 (27.3) 2904 (41.6) 1284 (18.4) 693 (9.9) 193 (2.8) n = 6800 5461 (80.3) 1128 (16.0) 253 (3.7)

<0.0001

<0.0001

0.43

<0.0001

<0.0001

According to the investigator.

data collection quality, with a single form to be completed at diagnosis, comprising a manageable number of items. In 2010, the most frequently neglected item (cancer stage) was missing in only 46 of the 7051 questionnaires analysed (0.7%). Data collection quality was further enhanced by the experience of the investigators, 80 centres had been involved in both studies. Several methods

were used to check the exhaustiveness of the recruitment. First, the study’s steering committee checked the regularity of inclusion throughout the study period for all centres individually and taken together (see Supplementary Fig. 2). It also checked the coherence of the recruitment with respect to the 2000 data in the 80 centres involved in both studies. Then, in 2010, 26 centres were visited

Fig. 3. Adenocarcinoma rate according to patient characteristics (i.e., sex, age, and smoking status) – NSCLC patients. NSCLC: non-small-cell lung cancer.

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Table 2 Comparison of main tumour characteristics between the KBP-2000-CPHG and KBP2010-CPHG studies.

Histology* N (%) Small cell lung cancer Squamous cell carcinoma Adenocarcinoma Large-cell carcinoma Bronchiolo-alveolar Other Combination of several subtypes Stage (NSCLC only): N (%) 0 IA IB IIA IIB IIIA IIIB IV

2000 N = 5667

2010 N = 7051

n = 5650 930 (16.5) 2193 (38.8) 1640 (29.0) 667 (11.8) 44 (0.8) 88 (1.6) 88 (1.6) n = 4411† 22 (0.5) 210 (4.8) 432 (9.8) 35 (0.8) 311 (7.1) 623 (14.1) 899 (20.4) 1879 (42.6)

n = 7051 950 (13.5) 1852 (26.3) 3199 (45.4) 754 (10.7) 59 (0.8) 148 (2.1) 89 (1.3) n = 6046‡ 11 (0.2) 355 (5.9) 252 (4.2) 253 (4.2) 230 (3.8) 846 (14.0) 574 (9.5) 3524 (58.3)

p-value

<0.0001

<0.0001

NSCLC: non-small-cell lung cancer. * Only one variable † Former TNM classification. ‡ New TNM classification.

Table 3 Risk of adenocarcinoma in NSCLC patients.

Univariate model KBP-2000-CPHG KBP-2010-CPHG Multivariate model* KBP-2000-CPHG KBP-2010-CPHG *

Relative risk

95% CI

p

1 2.07

[1.92–2.24]

<0.0001

1 2.06

[1.90–2.23]

<0.0001

Adjustment on age, sex and smoking status.

by an independent clinical research associate who helped study investigators and checked the exhaustiveness of their recruitment. Finally, each investigator (or designee) was to check his/her inclusions against data from the pathology department record, and/or the hospital computerised medical record (PMSI), and/or the hospital record of multidisciplinary team meetings in cancerology. In 2010, 63% of the active centres complied with this request. Data from 11 centres in 2000 and 15 centres in 2010 suspected of deficient exhaustiveness were excluded from analysis so as to ensure against any associated bias. Centres suspected of deficient exhaustiveness could be identified using several methods: in 2010, one investigator claimed that his/her centre was non-exhaustive, and the clinical research associates and the steering committee identified 6 and 15 centres, respectively. 4.2. Epidemiologic and histologic evolution over the ten-year period Lung-cancer patients were on average older in 2010 than in 2000: mean age at diagnosis, 65.5 vs. 64.3 years respectively (p < 0.0001). This change reflected both a lower proportion of young patients (≤50 years: 8.7% vs. 13.8% respectively) and a higher proportion of very elderly patients (>80 years: 10.5% vs. 6%). The increase in the number of elderly patients can be explained partly by increasing life expectancy and consequently increased percentage of elderly persons in the general French population. It was also due to improved management of elderly patients, who are increasingly demanding with regard to diagnosis, care, and treatment and for whom clinical trials are on-going (IFTC-0501, ESOGIA-GFPC 0802 and RACCOSA GFPC 08-06 trials) [16–18].

The proportion of women followed for lung cancer increased from 16.0% in 2000 to 24.3% in 2010 (p < 0 0001), confirming a trend observed for several years in France, Europe, and most countries worldwide [14,19,20] In France, since the 1990s, lung-cancer incidence has stabilised for men (52 per 100,000 person-years, world-standard rate) but almost doubled in women (9.7 per 100,000 person-years in 2000 vs. 17·8 in 2010) [2,21]. This difference is probably due to differential change in smoking habits between men and women. In men, it decreased from 1995, whereas in women it began to fall only in 2005 [22]. Montesinos and al. [14] attributed the increased proportion of women among the NSCLC patients (6% for the period 1990–1997 vs. 10.3% for 2003–2005; p = 0·01) exclusively to increased smoking in women and decreased smoking in men, in Spain. Population aging, however, and the greater life expectancy of women than men may also have contributed to this increased rate in women. The percentage of never-smokers, likewise, increased from 7.2% in 2000 to 10.9% in 2010 (p < 0.0001). These figures reflect an increased percentage of never-smokers among men, whereas the percentage for women has remained constant. Smoking is the prime cause of lung cancer. It is well-admitted that someone who has smoked all his life has a lung-cancer risk at least 20 times greater than a never-smoker [23]. Even so, 10% to 25% of lung cancers are in never-smokers [24], in whom it is now considered as an entity in itself [25]. It predominates in women, and generally takes the form of adenocarcinoma. Several factors are involved in this increasing risk of lung cancer in never-smokers: passive smoking; environmental factors, notably including radon exposure in industrialised countries; indoor pollution due to coal or biomass combustion or cooking-oil smoke in poor countries; occupational exposure to asbestos, arsenic, silica or pesticides; outdoor pollution (motor-vehicle exhaust-fume microparticles) [26]; and pre-existing lung disease such as tuberculosis [27] or emphysema, with or without associated chronic obstructive pulmonary disease [28]. Diet-related factors such as obesity, or the protective action of fruit and vegetables, have also been mentioned. In the present study, 158 of the 762 never-smoking patients (20.7%) declared exposure to passive smoking (data not shown). Lung cancer diagnosis continues to be late. Stage IV rate increases from 42.6% in 2000 to 58.3% in 2010. This increase is probably the result of a bias. Indeed, a new TNM classification of lung cancers is implemented since January 2010: in this seventh edition, pleural and pericardial malignancies are categorised as M1a and stage IV, whereas they had been T4 and stage IIIB in the previous edition. In addition, although no information on the staging procedures was collected during the studies, the increase in stage IV rate can also be a consequence of a routine use of PET-CT, which improves metastasis detection [29]; French recommendations on the use of PET-CT were published between 2000 and 2010 [30]. Moreover, change in histologic characteristics may also lead to a later onset of first symptoms, a greater aggressiveness of the disease with a faster course. Finally, the unequal geographic spread of physicians reported in recent years in France may have led to later consultation [31]. The most remarkable change found between 2000 and 2010 was the increased percentage of adenocarcinoma (29.0% vs. 45.4%, respectively; p < 0.0001) compared to squamous cell carcinoma (38.8% vs. 26.3%). This histological evolution in lung cancer has already been reported in several countries (Table 4) [14,20,32]. Adenocarcinoma is the histologically most frequent form in smoking and never-smoking women and in never-smoking men [26]. The increase in the percentage of adenocarcinoma between 2000 and 2010, however, is not solely due to increase in the proportions of women and male never-smokers: the present results show an increased adenocarcinoma risk independently of gender, smoking

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Table 4 Histological changes in lung cancer according to the literature and in the KBP-CPHG studies. Reference KBP-CPHG studies

Country

Years

Gender

Adenocarcinoma

Squamous cell carcinoma

France

2000 2010 1950s 1990s 1990–1997 2003–2005 2005–2007 vs. 1988–1990

All

29% 45% 1 1 31% 51.1% −5% +51%

39% 26% 18 1.2–1.4 51.3% 32.5% −51% −13%

Wynder, 1995

[32]

USA

Montesinos, 2011

[14]

Spain

Jiang, 2012

[20]

Canada

status or age (OR = 2.06 [1.90–2.23]; p < 0.0001). Other factors are thus involved in this histological evolution. Some authors point to changes in cigarette manufacture (use of filters and changes in composition) and thus in the inhaled smoke: nicotine and tare rate fell whereas nitrate concentrations have been made stronger [33]. Reduced nicotine strength may lead to deeper inhalation, increasing oncogene exposure in the peripheral lung [34] and thus onset of adenocarcinoma. The reduction in cigarette consumption observed in smokers and former-smokers over the ten-year period and the increased of the interval between the smoking cessation and the onset of the lung cancer suggest that other oncogenes may be implicated with a longer time of action. The decrease of the age at first smoking (especially in women) may also affect the type of cancer. Finally, the use of more specific immunohistochemical markers (TTF1, P63, CK5-6) by pathologists could partly explain the increased percentage of adenocarcinoma in 2010 [35–37]. 5. Conclusion In France, over the last ten years, the characteristics of patients and of lung cancers have changed: the percentages of female patients, never-smoking patients, stage IV lung cancer, and adenocarcinoma have all increased. The increased adenocarcinoma risk is independent of gender, age, and smoking status. These findings should improve lung cancer management: targeting women in anti-smoking campaigns, researching possible new oncogenic substances that could explain the increased incidence of adenocarcinoma, and continuing to assess screening methods to enable early-stage detection of lung cancer. Conflict of interest statement This study was promoted by the Collège des Pneumologues des Hôpitaux Généraux (CPHG) with the help of the Recherche en Santé Respiratoire endowment fund. It was funded by AstraZeneca, Boehringer Ingelheim, Chugai, GlaxoSmithKline, Lilly France, Pierre Fabre Oncologie, Pfizer, Pneumologie Développement, Roche, and Sanofi-Aventis. The study sponsors were not involved in the study design, data collection, data analysis, data interpretation, report writing, or decision to submit for publication. The authors have no financial and personal relationship with other people or organizations that could inappropriately bias this work. Steering committee Michel Grivaux, Chrystèle Locher, Didier Debieuvre, Bernard Asselain, Franc¸ois Blanchon, Daniel Coëtmeur, Thierry Collon, Charles Dayen, Franc¸ois Goupil, Francis Martin, Olivier Molinier, Jacques Le Treut.

Men All Men Women

Investigators Drs Caroline Clarot, Olivier Leleu, Abbeville; Jacques Le Treut, Aix-en-Provence; Bernard Borrel, Albi; Marie-Pierre Lafourcade, Michel Martin, Angoulême-Saint-Michel; Stephane Hominal, Annecy; Christine Mouroux-Rotomondo, Antibes-Juan-Les-Pins; Catherine Dubos-Arvis, Argentan; Hubert De Cremoux, Argenteuil; Yves Lierman, Arras; Michèle Gay, Aubagne; Patrick Dion, Aubenas; Jérôme Virally, Aulnay-sous-Bois; Hubert Barbieux, Khaldoun Hakim, Christine Lemonnier, Auxerre; Philippe Tagu, Bar-le-Duc; Jean-Claude Mouries, Bastia-Furiani; JeanPierre Mathieu, Cecilia Nocent-Ejnaini, Bayonne; Didier Debieuvre, Belfort-Montbéliard; Laurent Portel, Bergerac; Frédéric Goutorbe, Béziers; Pascale Beynel, Marie-Laure Braud, Marielle Perrichon, Bourg-en-Bresse; Gilles Adam, Yves-Marie Allain, Zafer Khayat, Antoine Lévy, Bourges; Béatrice Gentil le Pecq, Anne-Claire Ravel, Bourgoin-Jallieu; Bruno Remignon, Briey; Jean-Yves Le Tinier, Briis-sous-Forges-Bligny; Patricia Barre, Michel Farny, Cahors; Yannick Duval, Christophe Perrin, Cannes; Gérard Berthiot, Chalons-en-Champagne; Violaine Frappat, Eric Kelkel, Chambéry; Marguerite Le Poulain-Doubliez, Charleville-Mézières; Florence Lamotte, Chateauroux; Bernard Simon, Chaumont; Patrick Dumont, Chauny; Katy De Luca, Chevilly-Larue; Philippe Masson, Cholet; Valérie Hammerer, Didier Levy, Pierre Désiré Meyer, Lionel Moreau, Jean-Philippe Oster, Colmar; Antoine Belle, Stéphanie Dehette, Sandrine Loutski, Compiègne; Abderhamane Belmekki, Philippe Ménager, Odile Salmon, Corbeil-Essonnes; Jacky Crequit, Pierre Le Lann, Creil; Cyril Bernier, Dinan; Edith Maëtz, Jean-Yves Tavernier, Douai; Jean-Renaud Barrière, Draguignan; Franc¸ois Martin, Dreux; Frederic Deniel, Eaubonne; Pierre-Alexandre Hauss, ElbeufLouviers-Val-de-Reuil; Michel Carbonnelle, Epernay; Jean-Louis Collignon, Jean-Pierre Pontier, Epinal; Habeeb Mahmoud, Evreux; Ahmed Merzoug, Fougères; Djilalli Boudoumi, Béatrice DesurmontSalasc, Fréjus-Saint-Raphaël; Pascal Thomas, Gap; Véronique Tizon-Couetil, Granville-Avranches; Micheline Figueredo, Grasse; Kheder Badour, Guingamp; Eric Fournier, Hénin-Beaumont; Alexandra Bedossa, Lagny-sur-Marne; David Lemerre, La Rochelle; Jacques Berruchon, La-Roche-sur-Yon; Cécile Dujon, Le-ChesnayVersailles; Olivier Raffy, Marc Zaegel, Le-Coudray-Chartres; Marc Peureux, Le-Havre; Franc¸ois Goupil, Olivier Molinier, Le-Mans; Dragos Ciobanu, Lens; Oana Florea, Lens; Jean-Michel Marcos, Libourne; Gerard Oliviero, Longjumeau; Marielle Perrichon, LonsLe-Saunier; Jean-Paul Vabre, Lourdes; Jean-Marc Dot, Jean-Michel Peloni, Lyon-Desgenettes; Anne-Sophie Blanchet-Legens, Sylvie Vuillermoz-Blas, Lyon-St-Joseph-St-Luc; Sébastien Larive, Mâcon; Jean-Bernard Auliac, Mantes-la-Jolie; Mokrane Belkaïd, Martigues; Michel Grivaux, Chrystèle Locher, Meaux; Jean-Pierre Di Mercurio, Melun; Nadine Paillot, Metz; Etienne Leroy-Terquem, Meulan-lesMureaux; Tayeb Benaicha, Montargis; Bernard Duvert, Montélimar; Thierry Collon, Jacques Piquet, Montfermeil-Le-Raincy; Ravin Rangasamy, Mont-Saint-Martin; David Renault, Morlaix; Hamid Belhadj, André Marcuccilli, Moulins; Pierre Bombaron, Didier Debieuvre, Anne-Catherine Neidhardt, Mulhouse; Marie Saillour, Nanterre; Geoffroy De Faverges, Dominique Herman, Nevers;

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Isabelle Bourlaud, Michel D’Arlhac, Niort; Guillaume Fesq, NouméaNouvelle-Calédonie; Eric De Groote, Oloron-Sainte-Marie; Adrien Dixmier, Bertrand Lemaire, Orléans; Geneviève Perrus, Paimpol; Pablo Ferrer-Lopez, Papeete-Tahiti; Camille Genety, Paray-leMonial; Patrick-Aldo Renault, Pau; Serge Lacroix, Périgueux; Didier Choma, Perpignan; Gislaine Fraboulet, Pontoise; Hubert Galloux, Quimper; Sylvie Julien, Rodez; Nathalie Bautin, Florence Bolard, Anne Brichet-Martin, Béatrice Cavestri, Nicolas Just, Juliette Lelong, Fabienne Salez, Franc¸ois Steenhouwer, Roubaix; Daniel Coëtmeur, Guillaume Leveiller, Saint-Brieuc; Habib Benothman, Stéphane Jouveshomme, Saint-Germain-en-Laye-Poissy; Eric Goarant, SaintMalo; Clothilde Marty, Daniel Sandron, Saint-Nazaire; Eric Huchot, Fabrice Paganin, Saint-Pierre-Réunion; Marie Boutemy, Charles Dayen, Emmanuelle Lecuyer, Saint-Quentin; Bendela KasseyetKalume, Salon-de-Provence; Franc¸ois Brolly, Saverne; Serge Jeandeau, Sainte-Feyre; Ghassan-Jacques Kassem, Sedan; MarieGermaine Legrand-Hougnon, Soissons; Pierre Botrus, Thionville; Philippe Romand, Thonon-Les-Bains; Bertrand Delclaux, Troyes; Philippe Brun, Robert Riou, Valence; Didier Debieuvre, Jean Pierre Gury, Vesoul; Jacques Boyer, Catherine Marichy, Vienne; Lionel Falchero, Villefranche-sur-Saône; Alain Cuguilliere, Villenaved’Ornon; Andriamampionoma Razafindramboa, Villeneuve sur lot; Catherine Fouret, Villeneuve-Saint-Georges. Acknowledgments The authors would like to thank all the members of the steering committee and all the chest physicians who have actively participated in this study (see list hereafter). They also thank Fabienne Péretz ([email protected]) for her help in preparing this article. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.lungcan.2013.03.001. References [1] Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69–90. [2] INCa. [The cancer situation in France in 2010]. Collections rapports & syntheses. Boulogne-Billancourt; November 2010 [in French]. [3] InVS, INCa, Francim, Hôpitaux de Lyon, CépiDc, Inserm. Projection of incidence and cancer mortality in France in 2010. Technical Report; April 2010 [in French]. [4] Molinié F, Velten M, Remontet L, Bercelli P, et le réseau FRANCIM. The progression of lung cancer in France (1978–2000). Rev Mal Resp 2006;23:127–34 [in French]. [5] Institut national du cancer (INCa). Actions against smoking. http://lesdonnees. e-cancer.fr/les-fiches-de-synthese/3-facteurs-risque/41-tabac/69-actionslutte-contre-tabagisme.html. Date last accessed: July 18, 2012. [6] Zalcman G, Bergot E. Lechapt. Update on nonsmall cell lung cancer. Eur Respir Rev 2010;19:173–85. [7] Pérol M, Odier L, Arpin D. The maintenance strategies in first line treatment of advanced non-small cell lung cancers. La lettre du cancérologue 2010;13:102–11 [in French]. [8] Rami-Porta R, Ball D, Crowley J, Giroux DJ, Jett J, Travis WD, et al. Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2007;2:593–602. [9] Rusch VW, Crowley J, Giroux DJ, Goldstraw P, Im JG, Tsuboi M, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2007;2:603–12. [10] Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM Stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2007;2:706–14. [11] Blanchon F, Grivaux M, Collon T, Zureik M, Barbieux H, Bénichou-Flurin M, et al. Epidemiologic of primary bronchial carcinoma management in the general French hospital centers. Rev Mal Respir 2002;19:727–34 [in French].

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