# Are comorbidities associated with long-term survival of lung cancer? A population-based cohort study from French cancer registries

A. Seigneurin, P. Delafosse, B. Tretarre, A.S. Woronoff, M. Velten, P. Grosclaude, A.V. Guizard, B. Lapôtre-Ledoux, S. Bara, F. Molinié, et al.

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## To cite this version:

A. Seigneurin, P. Delafosse, B. Tretarre, A.S. Woronoff, M. Velten, et al.. Are comorbidities associated with long-term survival of lung cancer? A population-based cohort study from French cancer registries. BMC Cancer, 2018, 18 (1), 10.1186/s12885-018-5000-7. hal-02272374

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# Are comorbidities associated with long-term survival of lung cancer? A population-based cohort study from French cancer registries

A. Seigneurin<sup>1,2,3*</sup>, P. Delafosse<sup>1</sup>, B. Trétarre<sup>4</sup>, A. S. Woronoff<sup>5</sup>, M. Velten<sup>6</sup>, P. Grosclaude<sup>7,8</sup>, A. V. Guizard<sup>9</sup>, B. Lapôtre-Ledoux<sup>10</sup>, S. Bara<sup>11</sup>, F. Molinié<sup>12</sup> and M. Colonna<sup>1</sup>

## Abstract

**Background:** Survival rates of lung cancer remains poor and the impact of comorbidities on the prognosis is discussed. The objective of this study was to assess if the Charlson Comorbidity Index (CCI) was associated with 8-year survival rates by histological type.

**Methods:** A cohort study was conducted using randomly selected cases from 10 French cancer registries. Net survival rates were computed using the Pohar-Perme estimator of the net cumulative rate. Three Cox models were independently built for adenocarcinomas, squamous cell and small cell cancers to estimate prognostic factors including CCI grade.

**Results:** A total of 646 adenocarcinomas, 524 squamous cell and 233 small cell cancers were included in the analysis. The net 8-year survival rate ranged from 12.6% (95% CI: 9.8–15.4%) for adenocarcinomas and 13.4% (95% CI: 10.1–16.7%) for squamous cell carcinomas, to 3.7% (95% CI: 1.1–6.3%) for small cell cancers. Observed and net survival rates decreased for CCI grades ≥3 for all histological group considered. After adjustment for sex, age group, stage and diagnostic mode, CCI grades 1 (HR = 1.6 [95% CI: 1.1–2.3]), 2 (HR = 1.7 [95% CI: 1.1–2.7]) and ≥ 3 (HR = 2.7 [95% CI: 1.7–4.4]) were associated with lower survival rates only for small cell cancers.

**Conclusion:** After adjustment for age, sex, stage and diagnostic mode, the presence of comorbidity based on CCI grades 1–2 and ≥ 3 was associated with lower survival rates for small cell cancers whereas no differences were observed for adenocarcinomas and squamous cell cancers.

**Keywords:** Lung cancer, Prognostic factors, Net survival, Histological type, Population-based study

## Background

Lung cancer is the leading cause of cancer and cancer death worldwide with 1.82 million new cases by 2012, representing 12.9% of all new cancers, and 1.6 million deaths (19.5% of the total) [1]. In France, nearly 39,500 lung cancers were diagnosed and 30,000 individuals died from lung cancer in 2012, representing the 4th rank for incidence and the 1st rank for mortality [2]. Data from

cancer registries contributing to the International Agency for Research on Cancer (IARC) database showed that lung cancer incidence rates have peaked among men in many areas of the world, whereas rates among women continue to rise [3].

The prognosis of lung cancer remains poor and the improvement in survival that have been realized in other cancers have yet to be achieved in lung cancer. Indeed, the 5-year relative survival rate in US cancer registries for lung cancer diagnosed in 2008–2014 was 18.6% [4]. In France, the 5-year net survival rate for lung cancer diagnosed in 2005–2010 was 17% (95% CI: 16–17%) and the 10-year net survival was only 10% for the diagnoses

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BMC

© The Author(s). 2018 **Open Access** This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

<footnote>* Correspondence: aseigneurin@chu-grenoble.fr</footnote>

<footnote n="1">¹Isère Cancer Registry, CHU Grenoble, Grenoble, France</footnote>

<footnote n="2">²Grenoble Alpes University, Techniques de l'Ingénierie Médicale et de la Complexité – Informatique Mathématiques et Applications Grenoble, Unité Mixte de Recherche 5525, Grenoble, France</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
in the 1999–2004 period [5]. Several prognostic factors for non-small cell cancers have been identified [6, 7]. Stage at diagnosis remains one of the main factor [8] and other potential prognostic factors include perform- ance status [9, 10], increasing age [10, 11], male gender [12] and low socio economic status, [11] whereas the histological sub-type of non-small cell cancer remains controversial [13, 14]. For small cell cancers, disease ex- tent and performance status were identified as independ- ent prognostic factors [15].

The association of comorbidity based on the Charlson Comorbidity Index (CCI) with lung cancer prognosis re- mains discussed. Compared to an absence of comorbid- ity, lower survival was found for CCI grades 1–2 and ≥ 3 among non-small cell cancers who underwent curative surgery [10]. An analysis of a Spanish hospital database that included all histological types of lung cancers showed an impaired prognosis only for CCI grades ≥3 [16]. CCI grades 1–2 and ≥ 3 were associated with lower survival rates only for patients diagnosed with a low stage lung cancer (staged as 1 or 2) in a population-based study from the Danish Lung Cancer Registry [17]. On the other hand, Ganti et al. [18] did not find differences in survival for different CCI grades among all histological types of lung cancer treated in a US hospital. Few studies were conducted to estimate the association of CCI with long term survival rates using population-based data, separately for each histological type.

The objective of this study was to assess if CCI was as-
sociated with 8-year survival using population-based
data, separately for adenocarcinomas, squamous cell car-
cinomas and small cell cancers.

**Methods**

Study design and setting

A retrospective cohort study was conducted using cases
recruited from cancer registries. The original data from
9 cancer registries of the French network of cancer regis-
tries (FRANCIM) which covered 10 French administrative
entities (Départements of Calvados, Doubs, Hérault, Isère,
Loire-Atlantique, Manche, Bas-Rhin, Somme, Tarn,
Vendée) were analysed.

Participants

Participants were randomly selected from the databases
of cancer registries on the basis of the day and month of
birth of patients.

The total number of cases included in the analysis was
computed considering the comparison of survival rates
between two groups using the Log rank test. The pri-
mary objective was to assess if CCI was associated with
8-year survival among each histological type of lung can-
cer. Considering 4 groups of CCI grades, a total of 67 cases
per group corresponding to 268 cases per histological type

was necessary to detect a Hazard Ratio of 0.6 with a 8-year
survival rate of 10% in the reference group, a 80% statistical
power and a 5% alpha threshold. In a previous study, small
cell cancer was the less frequent histological group repre-
senting between 12 and 18% of all lung cancers, depending
on period of diagnosis and sex [19]. Consequently, the ne-
cessary number of lung cancers in the study was 1787 to
obtain at least 268 cases of small cell cancers (268/0.15).
As a result, the objective was to include 1800 cases corre-
sponding to 200 cases for each cancer registry.

Inclusion criteria were as follows: invasive lung can-
cers classified as C34 in the International Classification
of Disease for Oncology - 3 [20], diagnosed in 2004
among individuals who lived in one of the 10 adminis-
trative entities covered by the cancer registries. Only
adenocarcinomas, squamous cell cancers and small cell
cancers were considered for the analysis since other
histological types were less frequent and constituted an
heterogeneous group.

Data collection

Cancer registries routinely collected lung cancer cases
from different sources including histopathology labora-
tories, oncology departments, multidisciplinary meet-
ings, and computerized hospital discharge databases. For
this specific study, a supplementary collection of data in
medical files was carried out to follow-up participants
and to collect diagnostic mode, tobacco smoking, co-
morbidity, stage at diagnosis and treatment. Specific
training sessions were implemented to provide a consist-
ent collection of data among the cancer registries.

Stage for small-cell cancers was defined as limited (cancer remaining in one side of the chest including lung and lymph nodes on the same side of the chest) or extensive (cancer spreading widely throughout the lung, to the other lung, to lymph nodes on the other side of the chest, or to distant organs). Non-small cell cancers were categorized according to the TNM staging system [21] as stage 1 (T1-T2 N0 M0), stage 2 (T1-T2 N1 M0; T3 N0 M0), stage 3 (T1-T2-T3 N2 M0; T3 N1 M0; T1-T2-T3-T4 N3 M0; T4 N0-N1-N2-N3 M0) and stage 4 (T1-T2-T3-T4 N0-N1-N2-N3 M1).

The presence of comorbidities was collected using the
Charlson Comorbidity Index (CCI) [22]. Briefly, the CCI
is a simple and valid method of classifying comorbidity
based on a weighted index that takes into account the
number and the seriousness of comorbid condition. We
collected data on the presence of comorbid condition
at the time of diagnosis from hospitals and GP's med-
ical files. Performance status was not included consid-
ering the important proportion of missing values in
medical files.

An active search for the vital status at June 30, 2013
was carried out for all cases included in the study. The
information was collected for individuals with a birth-
place known by an electronic request to the Répertoire
National d'Identification des Personnes Physiques which
collects data on deaths in France. In case of missing
birthplace, other sources of information on the vital sta-
tus were used such as medical records.

Study outcomes

The main study endpoint was all cause of death during a
8-year follow-up period.

**Statistical analyses**

Observed and net survival rates, i.e. survival rates that would have been observed if lung cancer was the only cause of death in the population, were computed by histological type and CCI grades. Observed survival rates were obtained using the Kaplan-Meier method. Considering the unavailability and unreliability of causes of deaths, net survival rates were computed using the Pohar-Perme estimator of the net cumulative rate which did not require knowing causes of deaths [23]. Indeed, lung cancer mortality was deduced from the all-cause mortality of the study group and the “expected” mortality of a disease-free group. This expected mortality was assumed to reflect correctly the mortality due to other causes than lung cancer and was obtained from the general population life tables [24].

Three Cox models were independently built for adeno-
carcinomas, squamous cell cancers and small cell can-
cers to estimate the adjusted hazard ratio of death for
different CCI grades. The proportional-hazards assump-
tion was assessed graphically and tested on the basis of
Schoenfeld residuals. Time-varying variables were intro-
duced if the proportional hazard assumption was not
met to estimate different effects during the 0–1 year and
1–8 years period after diagnosis. For each histological
type, a full model was considered including sex, age
group, CCI, stage, and diagnostic mode since asymptom-
atic cancers could be associated with better survival
rates due to lead time, length bias and overdiagnosis.

Results

A total of 1751 lung cancer cases diagnosed in 2004 were collected. Adenocarcinoma was the most frequent histological type (36.9%), followed by squamous cell carcinoma (29.9%) and small cell carcinomas (13.3%). Other histological types represented 15.6% of cases and 4.2% had no cytological or histological diagnosis. Observed and net 8-year survival rates for all histological groups and stages combined were 9.7% (95% CI: 8.4–11.2%) and 11.2% (95% CI: 9.5–12.8%), respectively.

The present study focused on adenocarcinomas, squa-
mous cell and small cell cancers. The main characteris-
tics of the participants are summarized in Table 1. The

repartition of gender differed by histological type: the
proportion of men was 68.1% for adenocarcinomas,
90.5% for squamous cell cancers and 82.0% for small cell
cancers. For each histological type, the upper lobe was
the most frequent topography and pulmonary symptom
was the most frequent diagnostic mode. The most fre-
quent comorbid conditions were similar for the three
histological types of lung cancers considered with
chronic obstructive pulmonary disease, followed by per-
ipheral vascular disease, and congestive heart failure. By
June 30, 2013, less than 1.5% of individuals were lost to
follow-up (Table 2).

Net 8-year survival rates, reported in Table 2, remained
low for each histological group: 12.6% (95% CI: 9.8–
15.4%) for adenocarcinomas, 13.4% (95% CI: 10.1–16.7%)
for squamous cell cancers and 3.7% (95% CI: 1.1–6.3%)
for small cell cancers. Observed and net survival rates
were close for all histological types.

Observed and net survival rates decreased when the
CCI grade was ≥3 for all histological group (Table 3).
Univariate and multivariate prognostic factors obtained
from Cox models are reported in Table 4. After adjust-
ment for sex, age group, stage and diagnostic mode, CCI
grades 1, 2 and ≥ 3 were associated with lower survival
rates only for small cell cancers, whereas no differences
were observed for adenocarcinomas and squamous cell
cancers. Stage at diagnosis remains the main prognostic
factor for all histological types. Females were associated
with higher survival rates only for adenocarcinomas and
age at diagnosis ≥80 was associated with lower survival
rates for the 3 histological types. We did not include var-
iables related to treatments in our model due to a high
level of collinearity with stage. The proportion of pa-
tients who did not receive any curative treatments for
CCI grades 0, 1, 2 and ≥ 3 were 10.3, 13.1, 16.1 and
29.2% for small cell cancers, 11.9, 11.9, 11.9 and 16.1%
for adenocarcinomas, 12.3, 15.3, 20.2 and 21.3% for
squamous cell cancers, respectively.

**Discussion**

Eight-year net survival rates remained low for all histo-
logical types of lung cancers and CCI grades, ranging
from 0.0% (95% CI: 0.0–1.0%) for individuals with a CCI
grade ≥ 3 diagnosed with a small-cell carcinoma, to
14.1% (95% CI: 8.7–19.4%) for individuals with a CCI
grade 0 diagnosed with a squamous cell carcinoma. We
found lower survival rates for individuals with CCI
grades 1, 2 and ≥ 3 compared to individuals without co-
morbidity only for small cell cancers, after adjustment
for sex, age group, stage and diagnostic mode.

The main patient and cancer characteristics by histo-
logical types are consistent with data from literature, in-
cluding the high proportion of men among squamous
cell lung cancers [25, 26]. Since squamous cell cancer is
<table><caption>**Table 1** Characteristics of the 1403 individuals diagnosed with lung cancers in 2004 categorized as adenocarcinomas, squamous cell carcinomas and small cell cancers and recruited among 10 French cancer registries</caption><thead><tr><th></th><th>Adenocarcinomas<br>N = 646 (100.0%)</th><th>Squamous cell carcinomas<br>N = 524 (100.0%)</th><th>Small cell carcinomas<br>N = 233 (100.0%)</th></tr></thead><tbody><tr><td>Sex</td><td></td><td></td><td></td></tr><tr><td>Male</td><td>440 (68.1%)</td><td>474 (90.5%)</td><td>191 (82.0%)</td></tr><tr><td>Female</td><td>206 (31.9%)</td><td>50 (9.5%)</td><td>42 (18.0%)</td></tr><tr><td>Age group</td><td></td><td></td><td></td></tr><tr><td>&lt; 50</td><td>89 (13.8%)</td><td>21 (4.0%)</td><td>19 (8.1%)</td></tr><tr><td>50-59</td><td>186 (28.8%)</td><td>118 (22.5%)</td><td>68 (29.2%)</td></tr><tr><td>60-69</td><td>162 (25.1%)</td><td>142 (27.1%)</td><td>57 (24.5%)</td></tr><tr><td>70-79</td><td>163 (25.2%)</td><td>173 (33.0%)</td><td>70 (30.0%)</td></tr><tr><td>≥ 80</td><td>46 (7.1%)</td><td>70 (13.4%)</td><td>19 (8.1%)</td></tr><tr><td>Comorbid conditions<sup>a</sup></td><td></td><td></td><td></td></tr><tr><td>Chronic obstructive pulmonary disease</td><td>130 (20.1%)</td><td>161 (30.7%)</td><td>54 (23.2%)</td></tr><tr><td>Peripheral vascular disease</td><td>86 (13.3%)</td><td>77 (14.7%)</td><td>28 (12.0%)</td></tr><tr><td>Congestive heart failure</td><td>54 (8.4%)</td><td>75 (14.3%)</td><td>23 (9.9%)</td></tr><tr><td>Charlson Comorbidity Index</td><td></td><td></td><td></td></tr><tr><td>0</td><td>319 (49.4%)</td><td>195 (37.2%)</td><td>107 (45.9%)</td></tr><tr><td>1</td><td>159 (24.6%)</td><td>157 (30.0%)</td><td>61 (26.2%)</td></tr><tr><td>2</td><td>84 (13.0%)</td><td>79 (15.1%)</td><td>31 (13.3%)</td></tr><tr><td>≥ 3</td><td>62 (9.6%)</td><td>75 (14.3%)</td><td>24 (10.3%)</td></tr><tr><td>Unknown</td><td>22 (3.4%)</td><td>18 (3.4%)</td><td>10 (4.3%)</td></tr><tr><td>Topography</td><td></td><td></td><td></td></tr><tr><td>Main bronchus</td><td>22 (3.4%)</td><td>59 (11.3%)</td><td>24 (10.3%)</td></tr><tr><td>Upper lobe</td><td>341 (52.8%)</td><td>254 (48.5%)</td><td>109 (46.8%)</td></tr><tr><td>Middle lobe</td><td>26 (4.0%)</td><td>14 (2.7%)</td><td>12 (5.1%)</td></tr><tr><td>Lower lobe</td><td>153 (23.7%)</td><td>133 (25.4%)</td><td>43 (18.5%)</td></tr><tr><td>Overlapping lesion</td><td>33 (5.1%)</td><td>25 (4.8%)</td><td>26 (11.2%)</td></tr><tr><td>Not specified</td><td>71 (11.0%)</td><td>39 (7.4%)</td><td>19 (8.1%)</td></tr><tr><td>Stage</td><td></td><td></td><td></td></tr><tr><td>Non-small cell – Surgery</td><td></td><td></td><td></td></tr><tr><td>1</td><td>75 (41.0%)</td><td>52 (37.4%)</td><td>–</td></tr><tr><td>2</td><td>18 (9.8%)</td><td>39 (28.1%)</td><td>–</td></tr><tr><td>3</td><td>62 (33.9%)</td><td>45 (32.4%)</td><td>–</td></tr><tr><td>4</td><td>26 (14.2%)</td><td>2 (1.4%)</td><td>–</td></tr><tr><td>Unknown</td><td>2 (1.1%)</td><td>1 (0.7%)</td><td>–</td></tr><tr><td>Non-small cell – No surgery</td><td></td><td></td><td></td></tr><tr><td>1</td><td>8 (1.7%)</td><td>16 (4.2%)</td><td>–</td></tr><tr><td>2</td><td>2 (0.4%)</td><td>5 (1.3%)</td><td>–</td></tr><tr><td>3</td><td>87 (18.8%)</td><td>138 (36.0%)</td><td>–</td></tr><tr><td>4</td><td>354 (76.5%)</td><td>198 (51.7%)</td><td>–</td></tr><tr><td>Unknown</td><td>12 (2.6%)</td><td>26 (6.8%)</td><td>–</td></tr></tbody></table>
<table><caption>**Table 1** Characteristics of the 1403 individuals diagnosed with lung cancers in 2004 categorized as adenocarcinomas, squamous cell carcinomas and small cell cancers and recruited among 10 French cancer registries (Continued)</caption><thead><tr><th></th><th>Adenocarcinomas<br>N = 646 (100.0%)</th><th>Squamous cell carcinomas<br>N = 524 (100.0%)</th><th>Small cell carcinomas<br>N = 233 (100.0%)</th></tr></thead><tbody><tr><td><strong>Small cell – Surgery</strong></td><td></td><td></td><td></td></tr><tr><td>Limited</td><td>–</td><td>–</td><td>6 (85.7%)</td></tr><tr><td>Extensive</td><td>–</td><td>–</td><td>1 (14.3%)</td></tr><tr><td>Unknown</td><td>–</td><td>–</td><td>0 (0.0%)</td></tr><tr><td><strong>Small cell – No surgery</strong></td><td></td><td></td><td></td></tr><tr><td>Limited</td><td>–</td><td>–</td><td>61 (27.1%)</td></tr><tr><td>Extensive</td><td>–</td><td>–</td><td>155 (68.9%)</td></tr><tr><td>Unknown</td><td>–</td><td>–</td><td>9 (4.0%)</td></tr><tr><td><strong>Diagnostic mode</strong></td><td></td><td></td><td></td></tr><tr><td>Incidental diagnosis</td><td>76 (11.8%)</td><td>57 (10.9%)</td><td>19 (8.1%)</td></tr><tr><td>Pulmonary symptoms</td><td>360 (55.7%)</td><td>350 (66.8%)</td><td>143 (61.4%)</td></tr><tr><td>Other symptoms</td><td>169 (26.2%)</td><td>96 (18.3%)</td><td>63 (27.0%)</td></tr><tr><td>Surveillance of high-risk patients</td><td>29 (4.5%)</td><td>12 (2.3%)</td><td>2 (0.9%)</td></tr><tr><td>Unknown</td><td>12 (1.9%)</td><td>9 (1.7%)</td><td>6 (2.6%)</td></tr><tr><td><strong>Tobacco smoking</strong></td><td></td><td></td><td></td></tr><tr><td>Current smoker</td><td>274 (42.4%)</td><td>224 (42.7%)</td><td>123 (52.8%)</td></tr><tr><td>Former-smoker</td><td>227 (35.1%)</td><td>248 (47.3%)</td><td>89 (38.2%)</td></tr><tr><td>Never smoker</td><td>85 (13.2%)</td><td>15 (2.9%)</td><td>1 (0.4%)</td></tr><tr><td>Unknown</td><td>60 (9.3%)</td><td>37 (7.1%)</td><td>20 (8.6%)</td></tr><tr><td><strong>Absence of treatment</strong></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>78 (12.1%)</td><td>84 (16.0%)</td><td>34 (14.6%)</td></tr><tr><td>Unknown</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td></tr></tbody></table>

<table><caption>**Table 2** Observed and net survival rates (% (95% CI)) by histological types among lung cancers diagnosed in 2004 and recruited in 10 French cancer registries</caption><thead><tr><th></th><th>Adenocarcinoma<br>N = 646</th><th>Squamous cell carcinoma<br>N = 524</th><th>Small cell carcinoma<br>N = 233</th></tr></thead><tbody><tr><td>Number of person-years</td><td>1374.5</td><td>1020.7</td><td>264.8</td></tr><tr><td>Percentage of dead within 8 years</td><td>88.5%</td><td>88.7%</td><td>96.6%</td></tr><tr><td>Lost to follow-up at 8 years</td><td>1.4%</td><td>1.3%</td><td>0.4%</td></tr><tr><td><strong>1-year survival rate</strong></td><td></td><td></td><td></td></tr><tr><td>Observed</td><td>49.4% (45.5–53.2%)</td><td>43.3% (39.0–47.5%)</td><td>31.8% (25.9–37.8%)</td></tr><tr><td>Net</td><td>50.1% (46.2–54.0%)</td><td>44.5% (40.1–48.8%)</td><td>32.2% (26.2–38.3%)</td></tr><tr><td><strong>5-year survival rate</strong></td><td></td><td></td><td></td></tr><tr><td>Observed</td><td>15.8% (13.1–18.8%)</td><td>14.9% (12.0–18.1%)</td><td>3.9% (1.9–6.9%)</td></tr><tr><td>Net</td><td>17.1% (14.1–20.2%)</td><td>16.5% (13.1–19.9%)</td><td>4.1% (1.6–6.7%)</td></tr><tr><td><strong>8-year survival rate</strong></td><td></td><td></td><td></td></tr><tr><td>Observed</td><td>11.2% (8.9–13.8%)</td><td>11.2% (8.7–14.1%)</td><td>3.4% (1.6–6.4%)</td></tr><tr><td>Net</td><td>12.6% (9.8–15.4%)</td><td>13.4% (10.1–16.7%)</td><td>3.7% (1.1–6.3%)</td></tr></tbody></table>

<footnote><sup>a</sup>The three most frequent comorbid diseases were reported</footnote>
<table><caption>**Table 3** Observed and net 8-year survival rates (% (95% CI)) by histological type and Charlson Comorbidity Index (CCI) grade for adenocarcinomas, squamous cell carcinomas and small cell cancers diagnosed in 2004 and recruited among 10 French cancer registries</caption><thead><tr><th rowspan="2">CCI grade</th><th colspan="2">Adenocarcinomas (n = 646)</th><th colspan="2">Squamous cell cancers (n = 524)</th><th colspan="2">Small cell cancers (n = 233)</th></tr><tr><th>Observed survival</th><th>Net survival</th><th>Observed survival</th><th>Net survival</th><th>Observed survival</th><th>Net survival</th></tr></thead><tbody><tr><td>0</td><td>12.3% (9.0–16.2%)</td><td>13.7% (9.7–17.8%)</td><td>12.3% (8.2–17.3%)</td><td>14.1% (8.7–19.4%)</td><td>3.7% (1.2–8.6%)</td><td>4.1% (0.2–8.0%)</td></tr><tr><td>1</td><td>13.2% (8.5–19.0%)</td><td>15.1% (9.1–22.2%)</td><td>10.2% (6.1–15.5%)</td><td>12.6% (6.8–18.4%)</td><td>3.3% (0.6–10.1%)</td><td>3.5% (0.0–7.8%)</td></tr><tr><td>2</td><td>11.9% (6.1–19.8%)</td><td>14.0% (5.7–22.2%)</td><td>13.7% (7.2–22.3%)</td><td>17.4% (7.9–26.8%)</td><td>3.2% (0.2–14.1%)</td><td>3.3% (0.0–8.4%)</td></tr><tr><td>≥ 3</td><td>1.6% (0.1–7.6%)</td><td>1.7% (0.0–4.5%)</td><td>8.0% (3.3–15.5%)</td><td>10.1% (2.3–17.9%)</td><td>0.0% (0.0–0.0%)</td><td>0.0% (0.0–1.0%)</td></tr></tbody></table>

one of the histological types the most closely associated with smoking, the higher smoking rate among men could explain this finding.

Several hypotheses can be considered to explain the lower survival rates observed for patients with comorbidities. First, the presence of comorbidities could increase the delay of diagnosis of lung cancer implying a worst prognosis. We partly took into account the delay of diagnosis by including stage at diagnosis and diagnostic mode in our analyses but a residual effect could still be observed. Second, the use of sub optimal treatments when CCI grades increased could result in an increase of lung cancer-related deaths. For small cell cancers, the decrease of net survival rates from 3.3% for patients with CCI grade 2 to 0.0% for CCI grade ≥ 3 is consistent with this explanation, as well as the increase with CCI grades of the proportion of patients receiving no curative treatments. Less extensive treatments due to the presence of comorbid conditions could also be an explanation for the impaired survival rates. However, the precise type of treatment was not available in our database to verify this hypothesis. Søgaard et al. in a literature review found that patients with comorbidities were less likely to receive guideline-recommended treatments [27]. Third, lung cancer and its treatment could imply a sub optimal treatment of an active comorbidity as well as an unfavorable evolution of the comorbid condition, resulting in an increase of comorbidity-related deaths. Finally, differences in survival rates by CCI grade could reflect differences in socio-economic status [27] but this information was not available at an individual level in our study.

We found an association between the CCI grade at diagnosis and 8-year survival rates only for small cell cancers. The reason for this finding remains unclear. An increased delay of diagnosis, sub optimal treatments for the cancer and/or the comorbid condition and differences in socio-economic status could be observed more frequently for small cell cancers. Moreover, the effect on mortality of these factors might be more important for small cell lung cancer due to specificities in the natural history, the prognosis and the types of treatment performed compared to non-small cell cancers. In the literature, several authors also found lower survival rates

for increasing CCI grades for adenocarcinomas and squamous cell cancers when the analysis was restricted to sub groups of patients. Birim et al. [10] studied resected non-small cell lung cancers performed in an hospital and found that after adjusting for several confounders including age, sex, stage and individual comorbid conditions, survival was lower among patients with CCI grades 1–2 and ≥ 3 compared to patients with no comorbidity. A Danish population-based study found that CCI grade ≥ 3 was associated with lower survival among resected non-small lung cell cancers [28]. Few articles studied the effect of CCI grades on survival rates for small cell cancers. Dalton et al. [17] found that CCI grades 1–2 and ≥ 3 were associated with impaired survival only among lung cancers categorized as stage 1 and 2 in an analysis that included both small cell and non-small cell cancers.

Many studies reported prognostic factors of lung cancer [7, 29, 30]. Several studies reported an effect of sex on prognosis whereas we identified a better prognosis for women only among adenocarcinomas. The Surveillance, Epidemiology, and End Results database from 1975 to 1999 showed lower survival for men based on separate analyses by stage at diagnosis and after adjustment for histological type, treatment and age [12]. For small cell cancers, individual data pooled from first-line treatment trials showed a lower survival for men after adjustment for confounding factors [29]. On the other hand, no sex difference was found for resected non-small cell cancers diagnosed in the Medical University of Innsbruck, Austria [31]. Consistent with our results, several studies found lower survival rates for older patients [12, 29, 32].

The limits of our study should be acknowledged. First, the statistical power might have been too low to identify small effects on survival. Second, we could not exclude misclassification of the CCI related to differences in recording comorbidities in medical files [22]. Moreover, we considered comorbidities at the time of diagnosis in our analyses and we did not take into account the diagnosis of comorbid condition during the follow-up. The frequency of comorbidities increases with age, especially among the age group studied, and this increase of
<table><caption>**Table 4** Factors obtained from a cox model and associated with observed mortality for adenocarcinomas, squamous cell cancers and small cell cancers diagnosed in 2004 and recruited among 10 French cancer registries</caption><thead><tr><th rowspan="2"></th><th colspan="3">Adenocarcinomas (n = 646)</th><th colspan="3">Squamous cell cancers (n = 524)</th><th colspan="3">Small cell cancers (n = 233)</th></tr><tr><th>Time (years)<sup>a</sup></th><th>Unadjusted Hazard Ratios</th><th>Time (years)<sup>a</sup></th><th>Adjusted Hazard Ratios</th><th>Time (years)<sup>a</sup></th><th>Unadjusted Hazard Ratios</th><th>Time (years)<sup>a</sup></th><th>Adjusted Hazard Ratios</th><th>Time (years)<sup>a</sup></th><th>Adjusted Hazard Ratios</th></tr></thead><tbody><tr><td>Sex</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Male</td><td>0-8</td><td>0.8 (0.6-0.9)</td><td>0-8</td><td>0.7 (0.6-0.8)</td><td>0-8</td><td>1.1 (0.8-1.6)</td><td>0-8</td><td>1.3 (1.0-1.8)</td><td>0-8</td><td>0.8 (0.6-1.1)</td><td>0-8</td><td>0.7 (0.5-1.0)</td></tr><tr><td>Female</td><td>0-8</td><td></td><td>0-8</td><td></td><td>0-8</td><td></td><td>0-8</td><td></td><td>0-8</td><td></td><td>0-8</td><td></td></tr><tr><td>Age group</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 50</td><td>0-8</td><td>1.1 (0.9-1.5)</td><td>0-8</td><td>1.0 (0.7-1.3)</td><td>0-8</td><td>1.0 (0.6-1.6)</td><td>0-8</td><td>0.9 (0.6-1.5)</td><td>0-8</td><td>1.0 (0.6-1.8)</td><td>0-8</td><td>0.9 (0.5-1.6)</td></tr><tr><td>50-59</td><td>0-8</td><td>1.3 (1.0-1.7)</td><td>0-8</td><td>1.1 (0.8-1.4)</td><td>0-8</td><td>0.9 (0.5-1.4)</td><td>0-8</td><td>0.9 (0.5-1.5)</td><td>0-8</td><td>1.4 (0.8-2.4)</td><td>0-8</td><td>1.0 (0.6-1.7)</td></tr><tr><td>60-69</td><td>0-8</td><td>1.2 (0.9-1.6)</td><td>0-8</td><td>1.2 (0.9-1.6)</td><td>0-8</td><td>1.1 (0.7-1.8)</td><td>0-8</td><td>1.4 (0.8-2.3)</td><td>0-8</td><td>1.9 (1.1-3.2)</td><td>0-8</td><td>1.3 (0.8-2.3)</td></tr><tr><td>70-79</td><td>0-8</td><td>2.2 (1.5-3.2)</td><td>0-8</td><td>2.9 (2.0-4.3)</td><td>0-8</td><td>1.9 (1.1-3.2)</td><td>0-8</td><td>1.9 (1.1-3.2)</td><td>0-8</td><td>3.1 (1.6-6.1)</td><td>0-8</td><td>2.5 (1.3-4.9)</td></tr><tr><td>≥ 80</td><td>0-8</td><td></td><td>0-8</td><td></td><td>0-8</td><td></td><td>0-8</td><td></td><td>0-8</td><td></td><td>0-8</td><td></td></tr><tr><td>Charlson Comorbidity Index</td><td>0</td><td></td><td>1</td><td></td><td>1</td><td></td><td>1</td><td></td><td>1</td><td></td><td>1</td><td></td></tr><tr><td>1</td><td>0-8</td><td>1.0 (0.8-1.2)</td><td>0-8</td><td>1.0 (0.8-1.3)</td><td>0-8</td><td>1.0 (0.8-1.3)</td><td>0-8</td><td>1.0 (0.8-1.3)</td><td>0-8</td><td>1.3 (0.9-1.8)</td><td>0-8</td><td>1.6 (1.1-2.3)</td></tr><tr><td>2</td><td>0-8</td><td>0.9 (0.7-1.2)</td><td>0-8</td><td>0.8 (0.6-1.1)</td><td>0-8</td><td>0.9 (0.7-1.2)</td><td>0-8</td><td>0.9 (0.6-1.2)</td><td>0-8</td><td>1.4 (0.9-2.1)</td><td>0-8</td><td>1.7 (1.1-2.7)</td></tr><tr><td>≥ 3</td><td>0-8</td><td>1.3 (1.0-1.7)</td><td>0-8</td><td>1.2 (0.9-1.6)</td><td>0-8</td><td>1.1 (0.8-1.4)</td><td>0-8</td><td>0.9 (0.6-1.2)</td><td>0-8</td><td>2.4 (1.5-3.7)</td><td>0-8</td><td>2.7 (1.7-4.4)</td></tr><tr><td>Unknown</td><td>0-8</td><td>2.1 (1.4-3.3)</td><td>0-8</td><td>1.6 (1.0-2.6)</td><td>0-8</td><td>1.1 (0.7-1.9)</td><td>0-8</td><td>0.9 (0.6-1.6)</td><td>0-8</td><td>1.4 (0.7-2.8)</td><td>0-8</td><td>1.2 (0.6-2.5)</td></tr><tr><td>Stage (non-small cell cancers)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td>0-8</td><td>1.1 (0.6-2.2)</td><td>0-1</td><td>0.4 (0.1-3.3)</td><td>0-8</td><td>1.1 (0.7-1.7)</td><td>0-8</td><td>1.1 (0.7-1.8)</td><td>0-8</td><td>–</td><td>–</td><td>–</td></tr><tr><td>2</td><td>0-8</td><td></td><td>1-8</td><td>1.3 (0.0-90.3)</td><td>0-8</td><td></td><td>0-8</td><td></td><td>0-8</td><td></td><td>–</td><td>–</td></tr><tr><td>3</td><td>0-8</td><td>3.2 (2.2-4.5)</td><td>0-1</td><td>3.3 (1.6-6.7)</td><td>0-8</td><td>2.6 (1.8-3.7)</td><td>0-8</td><td>2.8 (2.0-4.0)</td><td>0-8</td><td>–</td><td>–</td><td>–</td></tr><tr><td>4</td><td>0-8</td><td>6.9 (5.0-9.6)</td><td>0-1</td><td>8.7 (4.4-17.1)</td><td>0-8</td><td>6.1 (4.3-8.7)</td><td>0-8</td><td>6.7 (4.6-9.6)</td><td>0-8</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Unknown</td><td>0-8</td><td>5.6 (3.0-10.5)</td><td>0-1</td><td>6.4 (1.5-27.5)</td><td>0-8</td><td>7.0 (4.3-11.4)</td><td>0-8</td><td>7.2 (4.4-11.7)</td><td>0-8</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Stage (small cell cancers)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Limited</td><td>–</td><td></td><td>–</td><td></td><td>–</td><td></td><td>–</td><td></td><td>1</td><td></td><td>1</td><td></td></tr><tr><td>Extensive</td><td>–</td><td></td><td>–</td><td></td><td>–</td><td></td><td>–</td><td></td><td>0-8</td><td></td><td>2.7 (1.9-3.6)</td><td>0-8</td><td>3.1 (2.2-4.4)</td></tr><tr><td>Unknown</td><td>–</td><td></td><td>–</td><td></td><td>–</td><td></td><td>–</td><td></td><td>0-8</td><td></td><td>6.2 (3.1-12.5)</td><td>0-8</td><td>4.7 (2.1-10.2)</td></tr></tbody></table>
<table><caption>**Table 4** Factors obtained from a Cox model and associated with observed mortality for adenocarcinomas, squamous cell cancers and small cell cancers diagnosed in 2004 and recruited among 10 French cancer registries (Continued)</caption><thead><tr><th rowspan="3">Diagnostic mode</th><th colspan="4">Adenocarcinomas (n = 646)</th><th colspan="4">Squamous cell cancers (n = 524)</th><th colspan="4">Small cell cancers (n = 233)</th></tr><tr><th>Time (years)<sup>a</sup></th><th>Unadjusted Hazard Ratios</th><th>Time (years)<sup>a</sup></th><th>Adjusted Hazard Ratios</th><th>Time (years)<sup>a</sup></th><th>Unadjusted Hazard Ratios</th><th>Time (years)<sup>a</sup></th><th>Adjusted Hazard Ratios</th><th>Time (years)<sup>a</sup></th><th>Unadjusted Hazard Ratios</th><th>Time (years)<sup>a</sup></th><th>Adjusted Hazard Ratios</th></tr><tr><th></th><th></th><th></th><th></th><th></th><th></th><th></th><th></th><th></th><th></th><th></th><th></th><th></th></tr></thead><tbody><tr><td>Pulmonary symptoms</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Incidental diagnosis</td><td>0-1</td><td>0.8 (0.6-1.0)</td><td>0-1</td><td>0.7 (0.5-1.1)</td><td>0-8</td><td>0.9 (0.7-1.3)</td><td>0-8</td><td>0.9 (0.7-1.2)</td><td>0-8</td><td>0.7 (0.4-1.1)</td><td>0-8</td><td>0.8 (0.4-1.3)</td></tr><tr><td>Non-pulmonary symptoms</td><td>0-1</td><td>1.3 (1.1-1.6)</td><td>0-1</td><td>1.1 (0.8-1.4)</td><td>0-8</td><td>1.8 (1.4-2.3)</td><td>0-8</td><td>1.5 (1.2-1.9)</td><td>0-8</td><td>1.2 (0.9-1.7)</td><td>0-8</td><td>1.1 (0.8-1.5)</td></tr><tr><td>Surveillance of high-risk patients</td><td>0-1</td><td>0.5 (0.3-0.7)</td><td>0-1</td><td>0.4 (0.2-1.1)</td><td>0-8</td><td>1.0 (0.6-1.8)</td><td>0-8</td><td>1.1 (0.6-2.0)</td><td>0-8</td><td>1.0 (0.2-4.1)</td><td>0-8</td><td>2.0 (0.5-8.7)</td></tr><tr><td>Unknown</td><td>0-1</td><td>1.4 (0.8-2.5)</td><td>0-1</td><td>1.0 (0.5-2.4)</td><td>0-8</td><td>1.3 (0.6-2.5)</td><td>0-8</td><td>1.6 (0.8-3.2)</td><td>0-8</td><td>2.3 (1.0-5.3)</td><td>0-8</td><td>1.6 (0.6-4.3)</td></tr><tr><td></td><td>1-8</td><td>3.4 (0.8-13.7)</td><td>1-8</td><td>1.9 (0.3-14.2)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

<footnote><sup>a</sup>Period of time since diagnosis considered to compute hazard ratios</footnote>
comorbidities could affect mortality. Third, we could not collect the cause of death and the multivariate analysis was based on all-cause mortality. As a result, we could not distinguish the effect of comorbidity on lung cancer deaths and comorbidity-related deaths. Fourth, perform- ance status was not introduced as a prognostic factor in our model since this information was not fully available in medical files. Finally, staging procedures have changed since 2004 including the widespread use of PET scan. However, the main objective was to assess the impact of comorbidities on survival adjusted for other prognosis factors. Stage was only used for adjustment purposes and the estimation of its precise effect on survival was not our main objective.

Our study present several strengths. First, we used population-based data from 10 cancer registries resulting in the absence of selection bias encountered in studies based on data obtained in specialized centres or ran- domized trials. Differences of cancer characteristics and practice patterns may exist among centres but the study reflects diagnosis of lung cancers and treatments in the general population. Second, we estimated the association of CCI grade and survival considering a long follow-up of 8 years. Third, the proportion of individuals lost to follow-up was low. Finally, we analysed the effect of CCI grades on survival separately for adenocarcinomas, squa- mous cell cancers and small cell cancers.

Conclusion

After adjustment for age, sex, stage and diagnostic mode, the presence of comorbidity based on CCI grades 1–2 and ≥ 3 was associated with lower 8-year survival rates for small cell cancers whereas no differences were found for adenocarcinomas and squamous cell cancers. Further studies should be conducted to assess differences of sur- vival by CCI grades among sub groups of adenocarcin- omas and squamous cell cancers and to elucidate the mechanisms explaining the lower survival associated with comorbid conditions among small cell lung cancers.

Acknowledgments

The authors thank the French Assurance Maladie and all participant cancer centres, hospitals, private clinics, and pathologists for case identification and data collection.

Funding

This work was supported by the Institut National du Cancer, Paris, France [grant number 0612-3D1514-14], and by the Ligue Nationale contre le Cancer, Paris, France. Funding bodies had no role in the design of the study, collection, analysis, and interpretation of data and in writing the manuscript.

Availability of data and materials

Data will not be shared since the datasets analyzed included identifying patient data.

Authors' contributions

AS, PD and MC designed the study and analyzed the data. AS wrote the manuscript and PD, BT, ASW, MV, PG, AVG, BLL, SB, FM, MC contributed to

writing of the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

This study is based on data from cancer registries gathered in the French network of cancer registries and a representative of each registry was involved in the study and approved the use of its data. Ethics approval and consent to participate were not required for this study.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author details

¹Isère Cancer Registry, CHU Grenoble, Grenoble, France. ²Grenoble Alpes University, Techniques de l'Ingénierie Médicale et de la Complexité – Informatique Mathématiques et Applications Grenoble, Unité Mixte de Recherche 5525, Grenoble, France. ³Medical evaluation unit, CHU Grenoble Alpes, Grenoble, France. ⁴Hérault Cancer Registry, Montpellier, France.

⁵Doubs Cancer Registry, CHU Besançon, Besançon, France. ⁶Bas-Rhin Cancer Registry, Université de Strasbourg, Strasbourg, France. ⁷Tarn Cancer Registry, Institut Claudius Regaud, IUCT-O, Registre des cancer du Tarn, Toulouse, France. ⁸LEASP - UMR 1027 Inserm-Université Toulouse III, Toulouse, France.

⁹Calvados Cancer Registry, CLCC François Baclesse, Caen, France. ¹⁰Somme Cancer Registry, CHU Amiens, Amiens, France. ¹¹Manche Cancer Registry, CH du Cotentin, Cherbourg en Cotentin, France. ¹²Loire-Atlantique and Vendée Cancer Registry, CHU Nantes, Nantes, France.

Received: 7 September 2017 Accepted: 28 October 2018

Published online: 12 November 2018

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