M.D Anne-Laure 1 Couderc
email: anne-laure.couderc@ap-hm.fr

MD, Ph.D Pascale Tomasini

Dominique Rey

Ph.D Emilie Nouguerède

Pharm.D. Ph.D Florian Correard

M.D Ph.D Fabrice Barlesi

M.D. Ph.D Pascal Thomas

M.D. Ph.D Patrick Villani

M.D. Ph.D Laurent Greillier

Octogenarians treated for thoracic and lung cancers: Impact of comprehensive geriatric assessment

Keywords: octogenarians, older adults, thoracic and lung cancers, comprehensive geriatric assessment, oncological treatment

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction:

Cancer, especially lung cancer, affects older adults. Half of all patients with lung cancer are aged 70 years or older at diagnosis [START_REF] Owonikoko | Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database[END_REF][START_REF] Howlader | SEER Cancer Statistics Review, 1975-2010[END_REF] and approximately 15% of cases are diagnosed in patients over 80 years [START_REF] Owonikoko | Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database[END_REF] . Lung cancer is the leading cause of death by cancer, in particular in the United States and Europe [START_REF] Ferlay | Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018[END_REF] . Initial symptoms at diagnosis are not significantly different between older and younger patients [START_REF] Giroux Leprieur | Delay between the initial symptoms, the diagnosis and the onset of specific treatment in elderly patients with lung cancer[END_REF] . The association between age and mortality is variable in the literature [START_REF] Owonikoko | Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database[END_REF][START_REF] Schulkes | Relevance of a Geriatric Assessment for Elderly Patients With Lung Cancer-A Systematic Review[END_REF][START_REF] Sterlacci | The elderly patient with surgically resected non-small cell lung cancer--a distinct situation?[END_REF][START_REF] Quoix | Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial[END_REF][START_REF] Rivera | Surgical management and outcomes of elderly patients with early stage non-small cell lung cancer: a nested casecontrol study[END_REF][START_REF] Driessen | Patterns of treatment and survival among older patients with stage III non-small cell lung cancer[END_REF] but the majority of studies show no differences between age groups, in particular when analyses were stratified by treatment.

Although older adults are the most affected by cancer, they are still under-represented in clinical trials, especially in an oncological setting [START_REF] Ruiter | Under-representation of elderly in clinical trials: An analysis of the initial approval documents in the Food and Drug Administration database[END_REF] . The Society for Geriatric Oncology (SIOG) and the European Organisation for Research and Treatment of Cancer (EORTC) [START_REF] Pallis | Management of elderly patients with NSCLC; updated expert's opinion paper: EORTC Elderly Task Force, Lung Cancer Group and International Society for Geriatric Oncology[END_REF] both propose guidelines of treatment in older adults; but for octogenarians, more data are needed to develop specific treatment recommendations. The development of Geriatric Oncology has greatly improved the management of older and older old adults with Comprehensive Geriatric Assessments (CGA) being conducted before and during cancer treatment [START_REF] Wildiers | International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer[END_REF][START_REF] Mohile | Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Chemotherapy: ASCO Guideline for Geriatric Oncology[END_REF] . The use of a CGA is essential to guide treatment decisions in older patients with cancer [START_REF] Mohile | Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Chemotherapy: ASCO Guideline for Geriatric Oncology[END_REF] and is now commonly used in lung and thoracic cancer management [START_REF] Schulkes | Relevance of a Geriatric Assessment for Elderly Patients With Lung Cancer-A Systematic Review[END_REF][START_REF] Quoix | Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial[END_REF][START_REF] Maione | Pretreatment quality of life and functional status assessment significantly predict survival of elderly patients with advanced non-small-cell lung cancer receiving chemotherapy: a prognostic analysis of the multicenter Italian lung cancer in the elderly study[END_REF][START_REF] Maestu | Assessment of functional status, symptoms and comorbidity in elderly patients with advanced non-small-cell lung cancer (NSCLC) treated with gemcitabine and vinorelbine[END_REF][START_REF] Biesma | Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study[END_REF][START_REF] Aliamus | Geriatric assessment contribution to treatment decision-making in thoracic oncology[END_REF][START_REF] Gironés | Comprehensive Geriatric Assessment (CGA) of elderly lung cancer patients: A singlecenter experience[END_REF][START_REF] Fiteni | Methodology of health-related quality of life analysis in phase III advanced non-small-cell lung cancer clinical trials: a critical review[END_REF][START_REF] Gridelli | Treatment of Elderly Patients With Non-Small-Cell Lung Cancer: Results of an International Expert Panel Meeting of the Italian Association of Thoracic Oncology[END_REF][START_REF] Corre | Use of a Comprehensive Geriatric Assessment for the Management of Elderly Patients With Advanced Non-Small-Cell Lung Cancer: The Phase III Randomized ESOGIA-GFPC-GECP 08-02 Study[END_REF][START_REF] Karampeazis | Docetaxel plus gemcitabine versus gemcitabine in elderly patients with advanced non-small cell lung cancer and use of a geriatric assessment: Lessons from a prematurely closed Hellenic Oncology Research Group randomized phase III study[END_REF][START_REF] Ruiz | Frailty assessment predicts toxicity during first cycle chemotherapy for advanced lung cancer regardless of chronologic age[END_REF] .

Schulkes et al showed that propositions of oncological treatment were more often based on the number of geriatric impairments than on the chronological age of the patients [START_REF] Schulkes | Lung Cancer in the Oldest Old: A Nation-Wide Study in The Netherlands[END_REF] .

We designed this study to compare geriatric characteristics, treatment decisions, unplanned hospitalizations, and overall survival (OS) between patients under 79 years (<80 years) and patients 80 years or more (≥80 years) treated for lung and thoracic cancers.

Methods

Study Design and Participants

This study was conducted between September 2015 and January 2019 at Marseille University Hospital (AP-HM) and was the result of a close collaboration between the geriatric unit and the thoracic surgery and oncological units of AP-HM. During this period, all consecutive older patients referred to the geriatric unit by the thoracic units for a CGA before initiation of thoracic and lung cancer treatment were included. Potentially frail patients were screened for a CGA by thoracic oncologists/surgeons using the G8 score according to French recommendations [START_REF] Soubeyran | Screening for vulnerability in older cancer patients: the ONCODAGE Prospective Multicenter Cohort Study[END_REF] . Oncologists also referred for a CGA all patients with an impaired G8 (G8 score of 14 or less out of 17) and all patients with a normal G8 score but with suspected frailties undetected by the G8 scale (i.e. depression, postural instability, or autonomy loss).

The CGA was performed by a geriatrician at AP-HM Geriatric Day Hospital. In this study, all the cancer patients were in an outpatient setting and all types of thoracic cancers and stages were included. Cancer treatment could be thoracic surgery, radiotherapy, chemo-radiotherapy, chemotherapy, targeted systemic therapy, immune checkpoint inhibitor therapy, or exclusive supportive care.

The study was approved by a local ethics committee. All the patients were registered at baseline in compliance with the French database and Privacy law (Commission Nationale de l'Informatique et Liberté CNIL registration number: 2017-33).

Data collection and baseline measurements

The different components of the CGA were collected by a geriatrician. Geriatric frailties and functional status were detected using the G8 screening tool (impaired ≤ 14/17) [START_REF] Soubeyran | Screening for vulnerability in older cancer patients: the ONCODAGE Prospective Multicenter Cohort Study[END_REF] , vulnerability score (ECOG-PS) (impaired ≥ 2) [START_REF] Oken | Toxicity and response criteria of the Eastern Cooperative Oncology Group[END_REF] , Activities of Daily Living (ADL) (impaired <6/6) [START_REF] Katz | Studies of Illness in the Aged. Index of ADL: A Standardized Measure of Biological and Psychosocial Function[END_REF] , and Instrumental Activities of Daily Living (IADL) scales (impaired < 4/4) [START_REF] Lawton | Assessment of older people: self-maintaining and instrumental activities of daily living[END_REF] .

Nutritional status was assessed using the Body Mass Index (BMI), albumin levels, and the Mini Nutritional Assessment scale (MNA) [START_REF] Guigoz | Mini Nutritional Assessment: a practical assessment tool for grading the nutritional state of elderly patients[END_REF] . The definition of malnutrition was taken from the recommendations issued by the French Department of Health (BMI < 21 and/or albumin levels < 35 g/l and/or MNA < 17). Cognitive disorders were assessed using the Mini Mental State Examination (MMSE) (impaired MMSE < 24) [START_REF] Folstein | Mini-mental state": A practical method for grading the cognitive state of patients for the clinician[END_REF] , and depression risk with the Geriatric Depression Scale (impaired GDS ≤ 1/4) [START_REF] Yesavage | Geriatric Depression Scale[END_REF] . Physical performance and mobility were assessed using gait speed (impaired ≤ 0.8 m/s) [START_REF] Friedman | A prospective trial of serial gait speed as a measure of rehabilitation in the elderly[END_REF] , the Timed Up and Go Test (TUG) (impaired TUG > 20 s) [START_REF] Podsiadlo | The timed « Up & Go »: a test of basic functional mobility for frail elderly persons[END_REF] , the One Leg Balance test (OLBT) (impaired OLBT < 5 s) [START_REF] Vellas | One-leg balance is an important predictor of injurious falls in older persons[END_REF] , and the history of falls in the three months prior to the CGA. Handgrip strength was measured three times for each hand using the Jamar Hydraulic Dynamometer according to the American Society of Hand Therapists recommendations [START_REF]Clinical Assessment recommendations -3 rd edition[END_REF] , and the cutoff values were those of the European Guidelines on Sarcopenia (EGSOP2) (impaired < 27 kg for men; < 16 kg for women) [START_REF] Bahat | Sarcopenia: revised European consensus on definition and diagnosis[END_REF] . Participants were asked about their demographic characteristics and lifestyle (age, living place, and presence of a caregiver). Severe comorbidities were identified using the geriatric Cumulative Illness Rating Scale (CIRS-G) [START_REF] Miller | Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale[END_REF] and polypharmacy (≥ 5 drugs per day) was assessed.

The main medical information was obtained from the medical records: type of thoracic and lung cancer, cancer stage, detailed treatment before and after a CGA, and biological data (plasma and serum chemistry). Albumin levels < 35 g/l were considered abnormal, lymphopenia was defined as a lymphocytes number < 1.26 G/l, vitamin B12 levels < 145 or > 569 pmol/l were considered abnormal, C-reactive protein (CRP) levels > 5 mg/l were considered abnormal, and patients with a BCI index > 40 000, which is the product of multiplying the CRP level with the vitamin B12 level (B12 X CRP) [START_REF] Geissbühler | Elevated serum vitamin B12 levels associated with CRP as a predictive factor of mortality in palliative care cancer patients: a prospective study over five years[END_REF] , were considered impaired.

Follow-up data and measurements

Data on cancer progression and treatment were obtained from the medical records.

Information about unplanned hospitalizations and the causes, as well as vital status (and causes of death) were collected in July 2019. Overall survival (OS) was defined as the time between the date of the CGA and the date of death or last known follow-up.

The oncological treatment proposed initially and the final oncological treatment chosen following the CGA were recorded.

Statistical analysis

A descriptive analysis was performed to describe the main demographic, oncologic, geriatric, and treatment characteristics of our population using headcounts and percentages for discrete data, as well as mean values plus or minus the standard error and minimum and maximum values for continuous data. A comparative analysis was performed between patients under 79 years (<80 years group) and patients 80 years and older (≥80 years group); the Pearson Chisquared test or Fischer exact test were used to analyze discrete data whereas Student's t-test was used to analyze continuous variables. To determine the differences between both populations, we performed a logistic regression analysis. Variables with a p-value ≤ 0.1 in the comparative analysis were added to the model, which was also adjusted by gender and tumor stage. Survival analysis was performed using a cumulative incidence curve with the Kaplan -Meier method. Survival was presented according to age groups (≥80 years vs <80 years) and cancer stages (stage IV vs other stages). A p-value ≤ 0.05 was considered statistically significant.

A comparative analysis was performed between octogenarians who underwent unplanned hospitalizations within three months after treatment initiation and those who did not; the same comparative analysis was performed among patients under 80 years old. The Chi-squared test was used to analyze discrete data. Survival analysis in the two age groups of patients (≥80 years and <80 years) was performed using a Cox regression analysis. For the patients in the ≥80 years group, we chose not to add albumin and the G8 into the model as they are are strongly correlated to malnutrition. All other variables with a p-value ≤ 0.1 in the univariate analysis were added to a stepwise model, which was adjusted on gender, and tumor stage. The same procedure was used for the survival model of the patients in the <80 years group. All the statistical analyses were performed using SPSS software (version 17.0).

Results

A total of 228 participants were recruited. The median age was 78.0±5 years (range 67 to 95 years) and 94 patients were 80 years or older. In this ≥80 years group, the majority of the patients were men (78.7%), adenocarcinoma was the most common histological type (42.6%), stage IV was diagnosed in 34 patients (36.2%) and the most common treatment was chemotherapy (43.6%). In the ≥80 years group, 32.3% of participants presented with an ECOG-PS score ≥ 2 and 94.6% had a G8 screening score ≤ 14/17. In our work, 21.3% of ≥80 years patients had their initial treatment proposal modified after the CGA; the geriatrician suggested less intensive treatment in almost all these patients.

In the <80 years group, 70.9% of the patients were men, adenocarcinoma was the most common histological type (43.3%), stage IV was diagnosed in 52.2% of patients, the most common treatment was chemotherapy (70.9%), 26.3% patients presented with an ECOG-PS score ≥ 2 and 90.2% had a G8 screening score ≤ 14/17. Finally, only 11.5 % of the <80 years patients had their initial treatment modified after the CGA.

Patient demographics, as well as the oncological and geriatric characteristics, are presented in Table 1.

Comparison of the patients according to their age group

Univariate and logistic regression analysis

Comparative univariate analysis (Table 1) showed that the ≥80 years group presented with less metastatic stage cancer (p=0.02), were more often treated by targeted therapy (p=0.009) or exclusive supportive care treatment (p=0.002), and less often by chemotherapy treatment (p<0.0001) compared to patients younger than 80. The initial treatment proposal was more frequently modified in the ≥80 years group (p=0.04); the geriatrician suggested less intensive treatment in almost all patients of the ≥80 years group (n=18/20 patients, 90 %). Concerning the CGA, ≥80 years patients were more likely to present with impairment in ADL (p=0.03), and/or in muscle strength (p=0.005) and to display sensory disorders (vision disorders p=0.005; hearing disorders p=0.03).

The logistic regression analysis comparing ≥80 years group and <80 years group is presented in Table 2. The logistic regression comparing ≥80 years and <80 years patients highlighted that <80 years group was more likely to present with stage IV (Odd Ratio (OR) 0.4; 95% CI; [0.2-0.8]; p = 0.005) and undergo chemotherapy treatment (OR 0.4; 95% CI [0.2-0.9]; p = 0.01), compared to patients older than 80 who were more likely to be treated by targeted therapy (OR 9.8; 95% CI [1.0-92.9]; p = 0.04) and more often presented with handgrip strength impairment (OR 2.3; 95% CI [1.3-4.3]; p = 0.008).

Overall survival

Median OS was 14.8 ± 2.6 months (95 % CI [9.7-19.8]) in ≥80 years patients and 15.3 ± 2.0 (95 % CI [11.5-19.2) in <80 years patients. Survival did not vary according to age groups (log rank=0,95) but was significantly reduced in patients with a stage IV disease (log rank <0,0001) (Figure 1). 3). In the Cox multivariate model, two characteristics remained significantly associated with the outcome: male gender and impaired handgrip strength (Table 4a).

Factors associated with unplanned hospitalizations and associated with worse OS in the ≥80

Unplanned hospitalization in the ≥80 years group

Factors associated with unplanned hospitalizations in univariate analysis are presented in Table 5. The only factors associated with unplanned hospitalizations within 3 months of treatment initiation in ≥80 years group were ADL impairment (OR 2.7; 95% CI [1.1-6.5]) and GDS impairment (OR 2.9; 95% CI [1.2-7.1]).

Factors associated with unplanned hospitalizations and associated with worse OS in the <80 years group

Overall survival in the <80 years group

In univariate analysis, the following factors were associated with worse OS in <80 years group: male gender (HR 1.8; 95% CI [1.0-3.2]), living alone (HR 1.8; 95% CI [1.0-3.0]), IADL impairment (HR 2.3; 95% CI [1.4-3.9]), albumin < 35g/l (HR 2.7; 95% CI [1.6-4.8]), abnormal TUG (HR 2.9; 95% CI [1.7-4.7]), abnormal OLBT (HR 1.9; 95% CI [1.1-3.2]), lymphopenia (HR 2. 3). In the Cox multivariate model, five characteristics remained significantly associated with the outcome: male gender, impaired IADL, stage IV cancer, lymphopenia and ECOG PS score ≥ 2 (Table 4b).

Unplanned hospitalization in the <80 years group

Factors associated with unplanned hospitalizations in univariate analysis are presented in Table 5. The factors associated with unplanned hospitalizations within 3 months of treatment initiation in <80 years group were living alone (OR 2.8; 95% CI [1.2-6.6]), malnutrition (OR 2.5; 95% CI [0.2-5.2]), and ECOG PS score ≥ 2 (OR 3.0; 95% CI [1.4-6.7]).

Discussion

This study shows no difference in OS between patients with lung or thoracic cancers whether they belong to ≥80 years or <80 years age group. This lack of association between age and mortality has already been reported in a few previous studies [START_REF] Biesma | Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study[END_REF][START_REF] Gironés | Comprehensive Geriatric Assessment (CGA) of elderly lung cancer patients: A singlecenter experience[END_REF] . In Quoix et al's study [START_REF] Quoix | Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial[END_REF] , comparison of doublet chemotherapy and monotherapy in older patients with non-small cell lung cancer, showed similar outcomes between ≥80 years and <80 years patients. This suggests that despite the absence of specific recommendations for this older old population, selected octogenarians can be treated as younger when taking health and geriatric status into account.

The ≥80 years patients are usually considered de facto as frail in oncology, even without objective frailty criteria. That is the reason why we chose to split our sample at the age of 80 years, as it corresponds to clinical reality. This may explain why, in our study, <80 years patients presented more often with metastatic disease at diagnosis compared to ≥80 years patients: many ≥80 years patients with metastatic thoracic cancer may have not been considered suitable for oncological treatment and therefore were not referred to oncologists or to a geriatrician for a CGA. This difference in the observed rates of cancer stage in the two age groups may partly explain the differences in treatment options; the <80 years patients were mostly managed with chemotherapy, while the ≥80 years participants were more often treated with targeted therapy and exclusive supportive care. Even if older old patients are still underrepresented in clinical trials, a limited number of studies have shown that octogenarians treated with targeted therapies had clinical outcomes and a toxicity profile comparable to younger patients [START_REF] Corre | Octogenarians with EGFR-mutated non-small cell lung cancer treated by tyrosine-kinase inhibitor: a multicentric real-world study assessing tolerance and efficacy (OCTOMUT study GFPC 07-15)[END_REF] .

In current guidelines [START_REF] Pallis | Management of elderly patients with NSCLC; updated expert's opinion paper: EORTC Elderly Task Force, Lung Cancer Group and International Society for Geriatric Oncology[END_REF] , there are no specific recommendations for octogenarians, and in the literature, older patients are often treated less aggressively than younger patients, with treatments of lower toxicity risk and/or better survival potential [START_REF] Hsu | Advanced non-small cell lung cancer in the elderly: the impact of age and comorbidities on treatment modalities and patient prognosis[END_REF][START_REF] Mellemgaard | Role of comorbidity on survival after radiotherapy and chemotherapy for nonsurgically treated lung cancer[END_REF] . However, Kale et al showed recently that octogenarians were as likely as patients aged 70-79 years to tolerate chemotherapy and radiotherapy for advanced non-small cell lung cancers [START_REF] Kale | Treatment Toxicity in Elderly Patients with Advanced Non-Small Cell Lung Cancer[END_REF] . Moreover, in thoracic surgery which is the gold standard of the treatment of early-stage disease, new studies showed older adults hadgood tolerance, in particular in infra-lobar thoracic surgery, even among octogenarians adults [START_REF] Altorki | Perioperative mortality and morbidity after sublobar versus lobar resection for early-stage non-small-cell lung cancer: post-hoc analysis of an international, randomised, phase 3 trial (CALGB/Alliance 140503)[END_REF][START_REF] Suzuki | Comparison of pulmonary segmentectomy and lobectomy: Safety results of a randomized trial[END_REF] . In our survey, the initial proposal of treatment was more often modified in octogenarians than in younger patients after taking into account the results of the geriatric assessment. However, these adaptations of treatment only occurred in one in five octogenarians. This highlights the importance of CGA before treatment initiation and confirms that age itself should not be a limitation to access to standard treatment.

In our study, handgrip strength was more often impaired among the octogenarians than in the younger group. Measurement of handgrip strength is usually used to assess sarcopenia [START_REF] Bahat | Sarcopenia: revised European consensus on definition and diagnosis[END_REF] , a muscle disorder characterized by loss of muscle strength and muscle mass with or without an increase in fat mass. In addition to aging, many factors may contribute to sarcopenia, such as malnutrition, inactivity, or cancer. Sarcopenia is known as a risk factor of early death, falls, and mobility impairment in older populations [START_REF] Bahat | Sarcopenia: revised European consensus on definition and diagnosis[END_REF] . Diagnosis is based on a combination of measurements of muscle mass and muscle strength including one-leg balance test, gait speed, and handgrip strength [START_REF] Bahat | Sarcopenia: revised European consensus on definition and diagnosis[END_REF] . Measurements of physical performance are used to appreciate the severity of the disease. Patients with thoracic cancer are more likely to be malnourished [START_REF] Marshall | Prevalence of malnutrition and impact on clinical outcomes in cancer services: A comparison of two time points[END_REF] and to develop sarcopenia, in particular patients with small cell lung cancer [START_REF] Pamoukdjian | Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: A systematic review[END_REF] and/or older old patients. Sarcopenia is associated with complications in surgery and chemotherapy, and is associated with worse OS during chemotherapy [START_REF] Pamoukdjian | Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: A systematic review[END_REF] .

In our survey, we only had information on handgrip strength impairment, which is not sufficient to suspect sarcopenia but has been shown to be a predictor of mortality in older adults [START_REF] Newman | Strength, but not muscle mass, is associated with mortality in the health, aging and body composition study cohort[END_REF] . We did not find any relation between mortality risk and handgrip strength in the <80 years group. But, interestingly, a decrease in handgrip strength was, with male gender, the only factors significantly associated with mortality risk in octogenarians. Among older old patients, geriatric deficits have more negative impacts on survival than the severity of cancer and type of treatments, contrary to what we found in <80 years group, and more generally to what has been observed among patients 70 years and older [START_REF] Couderc | Older Patients Treated for Lung and Thoracic Cancers: Unplanned Hospitalizations and Overall Survival[END_REF] . This result highlights the importance of measuring muscle strength and assessing physical performance on a systematic basis, in older old patients with lung or thoracic cancer.

Concerning geriatric deficits, we only found a significant association between IADL impairment and mortality risk in <80 years group, which may be related to the high frequency of cognitive disorders (26.7%) in this population. Cognitive disorders are known to negatively impact functional status, causing loss of instrumental autonomy [START_REF] Jekel | Mild cognitive impairment and deficits in instrumental activities of daily living: a systematic review[END_REF] . Finally, ECOG-PS which is also associated with mortality risk in the <80 years group is a performance scale not specific for older old patients [START_REF] Couderc | Functional status in a geriatric oncology setting: A review[END_REF] .

In the ≥80 years group, dysfunction in ADLs: the other part of functional status impairments, was a statistically significant risk factor for unplanned hospitalization within 3 months. Loss of functional capacity can increase the risk of treatment-related complications and the risk of poor outcomes in older patients with cancer [START_REF] Couderc | Functional status in a geriatric oncology setting: A review[END_REF] . Functional deficits assessed as part of the CGA include mobility disorders, cognitive impairment, depression, and sensorial disorders.

ADL score has been associated with OS in other studies with older patients with lung cancer [START_REF] Quoix | Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial[END_REF] but not with unplanned hospitalizations. This result is innovative in this octogenarian population especially since depression (GDS ≥1) is also a risk factor of unplanned hospitalizations. In the literature, depression has only been associated with OS in mixed cancer sites [START_REF] Kanesvaran | Analysis of prognostic factors of comprehensive geriatric assessment and development of a clinical scoring system in elderly Asian patients with cancer[END_REF] .

This study has some limitations. It was a monocentric survey that included a population of older and older old patients suffering from thoracic and lung cancer of various histological types, different clinical stages, and all types of treatment. Logistic regression was performed to compare patients according to their age group, but the small sample of octogenarians did not allow us to perform multivariate models for unplanned hospitalizations in the octogenarian population.

Conversely, our study has strengths. First, this work includes a rather large sample of older old outpatients with thoracic cancer (n=94) and a large set of data for each of them, which is rare in the oncologic literature. Moreover, our total sample size of older outpatients with thoracic cancer was also large (n=228 patients 70 years or older), and, as G8 screening is conducted routinely by the thoracic oncologists at our center, we were able to perform a CGA for all the patients with an impaired G8 in accordance with the international recommendations [START_REF] Mohile | Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Chemotherapy: ASCO Guideline for Geriatric Oncology[END_REF] . The role of the geriatrician, upstream of the therapeutic decision, is essential. Screening of frailties and management of deficits that can be improved can allow frail patients to benefit from standard treatments. This is the case in our university hospital where a multidisciplinary team including an oncologist, a geriatrician, a physical therapist, and a pharmacist has been set up since September 2013. More studies including large samples of older old patients are needed to determine the geriatric profile of older patients able to benefit from standard treatment with limited side effects. Moreover, improvements in patient follow-up are still needed. The role of the geriatrician should not be limited to the detection of geriatric impairments and the implementation of strategies to improve health status (i.e. physical activities with a therapist and dietary advice in case of muscle strength impairment).

It should also include a follow-up with regular reassessments of geriatric frailties during oncologic treatment to allow oncologists to adapt treatment on a more personalized basis.

Conclusion

Management of thoracic and lung cancer in octogenarian patients is challenging due to the heterogeneity of this population, the absence of specific recommendations, the large number of histological forms and treatments, and the under-representation of octogenarians in clinical trials. In our study, octogenarians were more often treated with targeted therapy and less often with chemotherapy. Consequently, it is of major importance to detect frailties, through geriatric screening and/or a CGA and allow personalized treatment adapted to patient specific profiles. In geriatric domains, muscle strength (handgrip strength), functional status (ADL) and mood evaluation (GDS) may be used in a clinical setting to help improve the management of octogenarians with thoracic and lung cancer by offering them more personalized care.

Conflict of interest:

  years group Overall survival in the ≥80 years group In univariate analysis, the following factors were associated with worse OS in ≥80 years group: male gender (HR 3.3; 95% CI [1.3-8.3]), stage IV disease (HR 2.1; 95% CI [1.1-3.7]), malnutrition (HR 2.0; 95% CI [1.1-3.6]), impairment in handgrip strength (HR 2.2; 95% CI [1.2-4.3]), abnormal BCI (HR 2.9; 95% CI [1.1-7.5]), surgery (HR 0.1; 95% CI [0.0-0.5]), chemotherapy (HR 1.9; 95% CI [1.0-3.4]), exclusive supportive care (HR 2.2; 95% CI [1.0-4.5]) and mesothelioma (HR 3.1; 95% CI [1.3-4.8]) (Table

  2; 95% CI [1.2-4.2]), epidermoid type (HR 2.0; 95% CI [1.2-3.6]) small cells (HR 4.4; 95% CI [1.9-10.1]), stage IV cancer (HR 2.3; 95% CI [1.4-3.9]), exclusive supportive care (HR 5.8; 95% CI [1.8-19.0]) and ECOG PS score ≥ 2 (HR 2.6; 95% CI [1.6-4.4]) (Table

  None of the authors have conflict of interest to declare. Author contributions: Study concepts and design: AL. Couderc. Study material or patients: AL. Couderc, P. Tomasini, L. Greillier. Quality control of data and algorithms: AL. Couderc, D. Rey, E Nouguerede. Data analysis and interpretation: AL. Couderc, D. Rey, E. Nouguerede, P. Tomasini, L. Greillier Statistical analysis: AL. Couderc, D. Rey, E. Nouguerede, L. Greillier. Manuscript preparation: AL. Couderc, D. Rey Manuscript editing: AL. Couderc and L. Greillier. Manuscript review: AL. Couderc, P. Tomasini, D. Rey, E. Nouguerede, F.Correard, F. Barlesi, P. Thomas, P. Villani, L. Greillier.

Table 1 :

 1 Demographic, geriatric and oncologic characteristics comparative analysis according age in ≥80 and <80 years Missing data n= 1; b Missing Data n=5; c Missing Data n=2; d Missing data n=6 ADL: activities of daily living; BCI: B12 X C reactive protein index; BMI: body mass index; ECOG-PS: eastern cooperative oncology group-performance status; G8: Oncodage; GDS: geriatric depression scale; IADL: instrumental activities of daily living; MMSE: mini mental state examination; SCLC: small cells lung cancer

	groups
	Characteristics	Total population (n=228)	<80 years group (n=134) ≥80 years group (n=94)	P value
		n or	(%) or	n or	(%) or	n or	(%) or
		Mean+ET	[min-max]	Mean+ET	[min-max]	Mean+ET	[min-max]
	Gender Men	169	(74.1)	95	(70.9)	74	(78.7)	0.19
	Age	78.7±5.0	[67-95]	75.3±2.8	[67-79]	83.7±3.0	[80-95]	NA
	Caregiver a	156	(68.7)	86	(64.7)	70	(74.5)	0.12
	Housing care facility (vs. home)°	19	(8.3)	11	(8.2)	8	(8.5)	0.94
	Living alone	39	(17.1)	28	(20.9)	11	(28.2)	0.07
	Fall History (in the past 3 months)	42	(18.4)	24	(17.9)	18	(19.1)	0.81
	Autonomy (ADL<6) a	73	(32.2)	35	(26.3)	38	(40.4)	0.03
	Instrumental autonomy (IALD <4)	124	(54.4)	71	(53.0)	53	(56.4)	0.61
	Cognitive disorders (MMSE<24) b	57	(25.6)	35	(26.7)	22	(23.9)	0.64
	Suspicion of depression (GDS ≥1) c	107	(47.3)	69	(51.9)	38	(40.9)	0.10
	Impaired handgrip strength (men <27kg, women <16kg) d	102	(45.9)	49	(38.0)	53	(57.0)	0.005
	Nutritional status BMI	24.0±4.4 [15.5-38.0] 23.7±4.3	[15.9-38.0]	24.3±4.5	[15.5-38.0]	0.35
	Albumin	38.3±5.2	[22-49]	38.4±5.3	[23-49]	38.0±4.9	[22-47]	0.61
	Malnutrition	102	(44.7)	64	(47.8)	38	(40.4)	0.27
	Mobility Timed up and go Test (>20s)	88	(38.6)	49	(36.6)	39	(41.5)	0.45
	One-leg balance test (< 5s)	139	(61.0)	78	(58.2)	61	(64.9)	0.31
	Gait speed (≤0.8m/s)	111	(48.7)	58	(43.3)	53	(56.4)	0.05
	Vision disorders	101	(44.3)	49	(36.6)	52	(55.3)	0.005
	Hearing disorders	85	(37.3)	42	(31.3)	43	(45.7)	0.03
	Number of comorbidities	4.1±2.3	[0-13]	4.0±2.3	[0-11]	4.2±2.4	[0-13]	0.55
	Severe comorbidities present	0.7±0.8	[0-4]	0.7±0.8	[0-4]	0.7±0.8	[0-4]	0.98
	Polypharmacy (≥5 drugs)	161	(70.6)	99	(61.5)	62	(66.0)	0.19
	Type of cancer Adenocarcinoma	98	(43.0)	58	(43.3)	40	(42.6)	0.91
	Epidermoid	89	(39.0)	54	(40.3)	35	(37.2)	0.64
	Mesothelioma°	18	(7..9)	9	(6.7)	9	(9.6)	0.46
	Small cells°	15	(6.6)	9	(6.7)	6	(6.4)	0.57
	Other°	8	(3.5)	4	(1.8)	4	(4.3)	0.72
	Stage IV (vs stage <IV)	104	(45.6)	70	(52.2)	34	(36.2)	0.02
	Treatments Surgery	51	(22.4)	30	(22.4)	21	(22.3)	0.99
	Chemotherapy	136	(59.6)	95	(70.9)	41	(43.6)	<0.0001
	Radiotherapy	69	(30.3)	41	(30.6)	28	(29.8)	0.89
	Targeted therapy°	8	(3.5)	1	(0.7)	7	(7.4)	0.009
	Immunotherapy°	10	(4.4)	8	(6.0)	2	(2.1)	0.20
	Exclusive supportive care°	20	(8.8)	5	(3.7)	15	(6.6)	0.002
	Final treatment modified from initial proposal	35	(15.6)	15	(11.5)	20	(21.5)	0.04
	Unplanned hospitalization	82	(36.0)	50	(37.3)	32	(34.0)	0.61

a

Table 2 :

 2 Logistic regression multivariable analysis of geriatric and oncological factors for <80 years patients compared to ≥80 years patients, adjusted on gender and presence or not of metastasis (included in the stepwise descending elimination analysis: Social isolation (n=228); chemotherapy (n=228), targeted therapy (n=228) or palliative care treatments (n=228), ADL score (n=227), handgrip strength and gait speed (n=224), final treatment modified from initial proposal (n=222) due to cumulative missing data, the analysis was done on 217 patients)

	Characteristics	N=217	aOR	IC 95%	P value
	Men	162	1.8	[0.9-3.8]	0.11
	Stage IV	96	0.4	[0.2-0.8]	0.005
	Chemotherapy	132	0.4	[0.2-0.9]	0.02
	Targeted therapy	7	9.8	[1.0-92.9]	0.04
	Exclusive supportive care	14	4.7	[0.9-24.4]	0.06
	Abnormal handgrip strength	120	2.3	[1.3-4.3]	0.008

aOR : adjusted odds ratio

Figure 1: Overall survival according to age and stage group, panel A shows Kaplan-Meier analysis according to stage and age group, panel B shows Kaplan-Meier analysis comparing ≥80 versus <80 group, panel, C shows Kaplan-Meier analysis for patients with stage IV tumor versus patients with stage I to III tumors.

Table 3 :

 3 Factors negatively associated with OS in old patients with thoracic cancers, according to age groups (univariates cox analysis)

	Characteristics		<80 years group (n=134)		≥80 years group (n=94)
		n	HR	IC 95%	P value	n	HR	IC 95%	P value
	Gender Men	95	1.8	[1.0-3.2]	0.04	74	3.3	[1.3-8.3]	0.01
	Caregiver	86	0.9	[0.5-1.5]	0.75	70	0.8	[0.4-1.5]	0.49
	Living alone	28	1.8	[1.0-3.0]	0.04	11	1.0	[0.3-2.7]	0.93
	Autonomy (ADL<6)	35	1.1	[0.7-2.0]	0.66	38	1.3	[0.7-2.3]	0.46
	Instrumental Activities of Daily Living (IALD <4)	71	2.3	[1.4-3.9]	0.002	53	1.5	[0.8-2.7]	0.19

Acknowledgments: This work has no funding.