Feasibility of an Acute Physical Exercise Before Treatment Infusion for Metastatic Lung Cancer Patients

Study Overview
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Brief Summary
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Because of metastatic Non-Small Cell Lung Cancer (mNSCLC) and its treatments, patients suffer from numerous symptoms such as dyspnea, muscle atrophy, pain, fatigue, loss of appetite, altered physical condition and lung function, which may further impair the patient's overall condition. Nevertheless, it has been suggested that physical exercise could improve response to treatment at the clinical level due to its known effects on the immune system. Moreover, preclinical studies have shown that exercise performed during chemotherapy administration could result in physiological benefits such as improved intra-tumoral infusion and drug delivery. The ERICA study aims to assess the feasibility of an acute physical exercise immediately before immunotherapy and chemotherapy administration in patients with mNSCLC.

Official Title
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Feasibility of an Acute Physical Exercise Before Immunotherapy and Chemotherapy Infusion for Metastatic Non-small-cell Lung Cancer Patients: Protocol ERICA Study

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Other: Exercise arm :


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 80 years old, Having a newly metastatic non-small-cell lung cancer (NSCLC) without an EGFR/ALK alteration diagnosis, Being scheduled to receive a 1st line intravenous chemotherapy (Cisplatin and Pemetrexed or Carboplatin and Pemetrexed or Taxol and Carboplatin), and immunotherapy (monoclonal anti-PD-1 and anti-PD-L1 antibodies : Pembrolizumab) treatment NB : patients who have previously received one or more treatments other than chemotherapy (e.g. targeted therapy) and must start their first chemotherapy are eligible, Treated in Centre Leon Berard, Having an Eastern Co-operative Oncology Group (ECOG) performance status ≤ 2, Being voluntary and available to get involved throughout the study duration, Being able to engage in Physical Activity with a medical certificate attested by one of the investigators clinical oncologist or the referring oncologist, Affiliated with a social security scheme, Having dated and signed an informed consent. Able to read, write and understand French Exclusion Criteria: Patient with unstable bone metastases or unconsolidated pathologic fractures, Having a central nervous system impairment with neurological disorder avoids the physical exercise practice on a cycle ergometry, Personal history or co-existence of another primary cancer (except of in situ cancer regardless of the site and/or basal cell skin cancer and/or cancer in complete remission for more than 5 years), Having severe undernutrition defined according to the Haute Autorité de Santé (i.e. , for an adult aged ≥18 years and < 70 : BIM ≤ 17 or weight loss ≥ 10% in 1 month or ≥15% in 6 months or ≥ 15% compared to the usual weight before the disease diagnosis or albuminemia < 30 g/l ; for an adult aged ≥70 years : BIM < 18 or weight loss ≥ 10% in 1 month or ≥15% in 6 months or an albuminemia < 30 g/l), Having a severe amenia (hemoglobin ≤ 8 g/dl) during the 30 last days prior inclusion, Presenting cardiovascular history or any cardiovascular risk: chronic coronary (or poorly balanced), artery disease, cardiac arrhythmia, symptomatic heart disease, uncontrolled or untreated hypertension, heart attack diagnosed within the last 6 months, coronary angioplasty with or without stent less than 6 months old, coronary artery bypass surgery less than 12 months old, history of poorly balanced type 2 diabetes, In case of diabetes: Glycated hemoglobin (HbA1c) > 7% (in the last 3 months), Stage IV Chronic Obstructive Pulmonary Disease (FEV1 < 30%), Patient with a contraindication to the proposed physical exercise in the study (orthopedic disorder likely to impede walking and pedaling such as disabling coxarthrosis or gonarthrosis, operated or not), Already included in a PA study, Cannot be followed for medical, social, family, geographical or psychological reasons, for the duration of the intervention (3 months) and then for the duration of the post-intervention follow-up (3 months), Patient under legal protection measure (under guardianship, curatorship, safeguard of justice), Deprived of liberty by judicial or administrative decision, Pregnant patient.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exercise arm :<br>Patient randomized to the Exercise arm will receive physical activity recommendations at inclusion and nutritional assessment will be carried out during the first and last treatment cure. Patients will receive an acute physical exercise just before immunotherapy and chemotherapy infusion.They will have a home walking program and will have to wear an activity tracker during the 3 months of intervention. 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place before exercise (1), after exercise (2) and 12 hours after the start of treatment (3). | Other: Exercise arm :<br>* Patients will receive physical activity recommendations at inclusion. At each treatment cure, patients will receive pre-exercise nutritional recommendations and an acute physical exercise prior to immunotherapy and chemotherapy. The acute physical exercise will last 35 minutes and will be intermittent and individualized based on the results obtained by the patient during an endurance test on a ergocyle performed prior to treatment. 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place before exercise (1), after exercise (2) and 12 hours after the start of treatment (3). A nutritional assessment will be carried out during the first and last treatment cure. They will also benefit a home walking program. These patients will have to wear an activity tracker tracker during all intervention (3 months). They will have a phone follow-up every 10 days (± 3 days) after each treatment cure for the study duration.<br>|
| No Intervention: Control arm<br>Patients will receive physical activity recommendations at inclusion and a nutritional assessment will be carried out during the first and last treatment cure. They will receive the usual care and standard treatment protocol (immunotherapy and chemotherapy). 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment (3). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigate the feasibility of an acute physical exercise during the immunotherapy/chemotherapy preinfusion | Ratio of the number of acute physical exercise sessions immunotherapy/chemotherapy preinfusion performed byexercise group patient / number of acute physical exercise sessions planned | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigate the physical activity fitness (sub-maximum endurance test) | Sub-maximum endurance test on an ergocycle | Baseline, 3 months | 
| Investigate the lower strength muscular function change | Maximum isometric force of the knee extensors | Baseline, 3 months, 6 months | 
| Investigate the maximum isometric upper limb strength change | Hand dynamometer | Baseline, 3 months, 6 months | 
| Investigate the Physical Activity level change | The PA level will be measured by the Godin Leisure-Time Physical Activity Questionnaire (GLTAPQ). The GLTAPQ is a 4-item self-administered questionnaire with the first three questions designed to obtain information on the number of times an individual engages in light, moderate and intense leisure-time PA periods of at least 15 minutes during a typical week. The scoring of the GSLTPAQ is the LSI (Leisure Score Index) is obtained using the following formula: (light PA frequency × 3) + (moderate PA frequency × 5) + (vigorous PA frequency × 9). People with a moderate to high LSI ≥ 24 are classified as active, while people reporting a moderate to high LSI ≤ 23 are classified as insufficiently active (estimated energy expenditure < 14 Kcal/kg/week). | Baseline, 3 months, 6 months | 
| Investigate the patient anthropometrics change | Weight in kilograms | Baseline, 3 months, 6 months | 
| Investigate the patient anthropometrics change | Hip circumference in centimeters | Baseline, 3 months, 6 months | 
| Investigate the patient anthropometrics change | Waist circumference in centimeters | Baseline, 3 months, 6 months | 
| Investigate the patient anthropometrics change | BMI (weight/height²) | Baseline, 3 months, 6 months | 
| Investigate the patient health-related quality of life change | Quality of life will be measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality Of Life Questionnaire (QLQ-C30). Quality of life specific to lung cancer will be assessed by the 13-item module: The Quality Of Life Questionnaire - Lung Cancer 13 (QLQ-LC13). The QLQ-LC13 self-questionnaire is an additional measure of the symptoms and side effects experienced by lung cancer patients who receive non-surgical treatment. | Baseline, 3 months, 6 months | 
| Investigate the patient health-related quality of life specific to lung cancer change | Quality of life specific to lung cancer will be assessed by the 13-item module: The Quality Of Life Questionnaire - Lung Cancer 13 (QLQ-LC13). The QLQ-LC13 self-questionnaire is an additional measure of the symptoms and side effects experienced by lung cancer patients who receive non-surgical treatment. | Baseline, 3 months, 6 months | 
| Investigate the fatigue change | Fatigue will be assessed by the EORTC-QLQ module measuring cancer-related fatigue (EORTC QLQ-FA12). This self-questionnaire includes 12 items that assess physical, cognitive and emotional fatigue related to cancer. Participants will respond on a Likert scale ranging from not at all to a lot. All scores will be transformed into a scale from 0 to 100, with a higher score indicating a higher degree of fatigue. | Baseline, 3 months, 6 months | 
| Investigate the sleep quality change | The perceived quality of sleep is assessed by the Insomnia Severity Index (ISI) which measures the severity of insomnia. The questionnaire consists of 7 items rated on a 5-point scale ranging from 0 (none) to 4 (very severe). This self-questionnaire makes it possible to evaluate the severity of the patient's sleep difficulties (initial, maintenance, morning insomnia), the degree of sleep dissatisfaction, the level of interference with daily functioning, the degree of appearance of sleep difficulties and the level of anxiety related to insomnia. The total score of the items varies between 0 and 28. A high score indicates greater sleep difficulties. | Baseline, 3 months, 6 months | 
| Investigate the impact of social vulnerability | Social vulnerability will be assessed by the EPICES score (Evaluation de la Précarité et des Inégalités de santé dans les Centres d'Examens de Santé). By adding up the points of the 11 binary questions (Yes/No) of the self-questionnaire we obtain the so-called EPICES score. This quantitative score varies from 0 no precariousness to 100 highest precariousness. | Baseline | 
| Investigate the muscle mass and sarcopenia | CT scans | Baseline, 3 months, 6 months | 
| Investigate the immune biomarkers change | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). The following immune biomarkers will be assay : Natural Killer cells, B lymphocytes, T lymphocytes, monocytes, sub-populations of dendritic cells on frozen PBMC | Baseline and 3 months | 
| Investigate the Activin change (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the TNF-alpha change (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the IL-1béta change (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the IL-6 change (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the Follistatin (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the GDF5 (BMP14) (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the GDF15 (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the IL-10 (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the IL-15 (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the NH3 (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the Aminogramme (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the CRP (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the IFN-gamma change (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the Cortisol change (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the Myostatin change (inflammation biomarkers) | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the Advanced oxidation protein products (AOPP) change | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the Superoxide dismutase (SOD) change | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the catalase (CAT) change | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the malondialdehyde (MDA) change | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). The following biomarkers will be assay : Advanced oxidation protein products (AOPP), malondialdehyde (MDA), Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), Xanthine oxidase (XO), and Myeloperoxidase (MPO). | Baseline and 3 months | 
| Investigate the glutathione peroxidase (GPX) change | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). The following biomarkers will be assay : Advanced oxidation protein products (AOPP), malondialdehyde (MDA), Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), Xanthine oxidase (XO), and Myeloperoxidase (MPO). | Baseline and 3 months | 
| Investigate the Xanthine Myeloperoxidase (MPO) change | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). The following biomarkers will be assay : Advanced oxidation protein products (AOPP), malondialdehyde (MDA), Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), Xanthine oxidase (XO), and Myeloperoxidase (MPO). | Baseline and 3 months | 
| Investigate the Xanthine oxidase (XO) change | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). The following biomarkers will be assay : Advanced oxidation protein products (AOPP), malondialdehyde (MDA), Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), Xanthine oxidase (XO), and Myeloperoxidase (MPO). | Baseline and 3 months | 
| Proportion of patients who have severe toxicity (grade >2) | Occurence of severe toxicity (grade > 2) according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE). Number of delayed or cancelled treatment sessions and relative dose-intensity (RDI) for patients with grade ≥ 3 chemotherapy-related toxicities, calculated as the ratio of the delivered dose-intensity to the expected dose-intensity. | Up to 3 months | 
| Progression free survival | Period from the date of randomization to the date of event defined as disease progression or death from any cause | 6 months | 
| Acceptability of the study | Ratio of the number of patients included / number of eligible patients | 3 months | 
| Tracker activity acceptability | Number of days the activity tracker is worn / number of days in the programme | 3 months | 
| Safety of the intervention | Number, type and timing of adverse events due to program | 3 months | 
| Adherence of the intervention | number of steps at home realized / number of steps at home prescribed (only in the intervention arm) | 3 months and 6 months | 
| Investigate the Physical Activity level change | Daily number of step prescription (only in the intervention arm) | Baseline, 3 months and 6 months | 
| Investigate the glucose change | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the insulin change | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the lactat change | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the PCR change | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 
| Investigate the HIF-1 change | 3 blood sampling times (2 EDTAsx10 mL) will be specially added to the study and will take place: for the exercise group: before exercise (1), after exercise (2) and 12 hours after the start of treatment (3); and for the control group: 40 min before the administration of treatments (1), just before the administration of treatments (2) and 12 hours after the start of treatment(3). | Baseline and 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung Cancer, Lung Neoplasm, Metastasis, Acute exercise, Immunotherapy, Connected devices