POSITIVE - Study (Part III) Heidelberg

Study Overview
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Brief Summary
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The investigators plan to evaluate, in a randomized, controlled phase III trial in patients with advanced non-small cell lung cancer (NSCLC), the effects of a 24-week exercise intervention program (EIP) on quality of life, physical functioning and immune function parameters. Eligible patients (n=250) will be enrolled in the Clinic for Thoracic Diseases, Heidelberg, over a time period of two years and followed up for a total of 12 months. Patients will be randomized either to EIP plus Care Management Phone Calls (CMPC) versus CMPC alone (besides a proper symptom and side effect management CMPC ensures the potential influence of social contacts that can be anticipated for the patients in the intervention group). Our primary aims are to investigate whether a combination of a partly supervised (in- and outpatient) and partly home-based endurance and resistance training improves quality of life (QoL) and lowers levels of fatigue (evaluation via the standardized and validated questionnaires FACT-L and MFI). In addition we propose to evaluate the effects of EIP on tumor specific immune responses. Biomarkers of immune function will be measured by cellular immunity and cytokine and chemokine panels. Further secondary outcomes include measurement of anxiety, depression and demoralization, physical performance parameters (e.g. improvement in walk distance, muscle strength), as well as overall and progression free survival analyses. The study builds on a previous feasibility study of a 8 weeks exercise intervention trial in patients with advanced NSCLC with the results being utilized in the design of the here proposed trial. The investigators hypothesize that patients randomized in the exercise intervention group will show improved QoL and reduced fatigue, as well as improved physical functioning and increased tumor specific immune responses.

Official Title
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Physical Exercise Program in Lung Cancer Patients With Non-operable Disease Undergoing Palliative Treatment

Conditions
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Advanced NSCLC, First Line Treatment

Intervention / Treatment
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* Behavioral: Exercise Intervention
* Other: Care-Management-Phone-Calls


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: NSCLC stage IIIB/IV receiving systemic treatment (palliative radiotherapy accepted) BMI > 18 ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2 signed informed consent Exclusion Criteria: serious active infection (i.e. requiring an iv antibiotic, antifungal or antiviral agent) inability to walk immobility (more than two days) previously untreated (non-irradiated or non-resected) symptomatic brain metastases;permitted are: (1) previously treated brain metastases [radiotherapy, surgery, dexamethasone dosage 8 mg per day, anti-epileptic therapy]; (2) asymptomatic brain metastases without additional therapy requirement severe neurologic impairment (e.g. apoplectic insult, Morbus Parkinson, pareses of extremities) severe cardiac impairment (e.g. cardiac insufficiency NYHA (New York Heart Association) > III, myocardial infarction within the last three months, unexplained syncopal events, severe cardiac arrhythmias, high grade aortic stenosis) severe respiratory insufficiency uncontrolled pain abuse of alcohol or drugs reducing compliance to the study bone metastasis inducing skeletal fragility any circumstance that would impede ability to give informed consent or adherence to study requirements.

Ages Eligible for Study
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Minimum Age: 18 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 Intervention Program (EIP)<br>Inpatient periods: The combined resistance and endurance program consist of free weight and rubber band training for major upper and lower body muscle groups respectively of cycling/walking on an ergometer/treadmill 3x/week. Outpatient periods (3x/week at least two/one supervised training sessions): Supervised training sessions in the local outpatient training center will comprise of resistance exercise on machines and endurance training on an ergometer/treadmill. For non-supervised training session during the outpatient period participants will receive an exercise manual for individualized home-based exercising. In weekly phone calls, the advanced practice nurse will review adherence to the intervention and identify problems. Furthermore, the patients will also be asked the same questions as in the CMPC group. | Behavioral: Exercise Intervention<br> <br> Other: Care-Management-Phone-Calls<br> <br> |
| Active Comparator: Care-Management-Phone-Calls (CMPC)<br>Patients in this arm will receive a weekly care-management-phone-call (CMPC), performed by an advanced practice nurse (APN). The CMPCs are based on a structured questionnaire, reflecting pain, shortness of breath, disturbed sleep, exhaustion and distress and potentially treatment related side effects (e.g. infections, polyneuropathy, etc.). In case of demanding management of symptoms or complaints (e.g. uncontrolled pain or breathlessness) the treating physician is contacted by the APN to facilitate improvement. | Other: Care-Management-Phone-Calls<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| QoL: Physical Well-Being (FACT-L) | The FACT-L (Functional Assessment of Cancer Therapy-Lung) questionnaire comprises of 36 items and deter-mines the quality of life in patients with lung cancer. It is separated in the subcategories physical well-being (PRIMARY OUTCOME), emotional well-being, social well-being, functional well-being and disease-specific items. It is widely used in clinical studies and was already applied in exercise intervention studies in lung cancer patients | assessed after 12 weeks of enrolement | 
| General Fatigue (MFI) | The MFI (Multidimensional Fatigue Inventory) questionnaire (20 items) evaluates the extent of chronic fatigue and is divided into the 5 subscales general fatigue, physical fatigue, mental fatigue, reduced motivation and reduced activity. The MFI questionnaire is widely used in oncological studies and an adequate number of comparative samples exists. | assessed after 12 weeks of enrolement | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physical Performance (endurance and strength capacity) | 6-Minute Walk Test (endurance capacity) The 6 minute walk test is feasible and safe to determine patients physical capacity. Patients are instructed to walk in 6 min. as many meters as possible with oxygen saturation and pulse rate being measured concomitantly. Hand-held Dynamometry (isometric strength capacity) The hand-held dynamometry is a standardized instrument to measure muscular strength. In the study 6 major muscle groups of upper and lower extremities will be assessed for their isometric power. | assessed every 3 month after enrolement until month 12 | 
| Psychosocial Parameters (e.g. depression, anxiety, demoralization) | PHQ(Ultra-Brief Patient Health Questionnaire)-4 : The PHQ-4 (Ultra-Brief Patient Health Questionnaire) questionnaire is a short instrument comprising of 4 items to detect the extent of depression and anxiety. It provides sufficient diagnostic accuracy for major depression and can be used as a screening instrument in cancer populations. DS (Demoralization Scale) The demoralization scale (DS) is a relatively new developed questionnaire to detect the extent of existential distress in cancer patients. The German version was validated in 2011 and comprises of 24 questions. The results of the validation showed that the concept of demoralization is a useful instrument to describe the different states of existential distress and the individual incapacity to cope effectively with stressful situations. | assessed every 3 month after enrolement until month 12 | 
| Overall survival |  | for the period of 1 year after enrolement | 
| progression-free survival |  | for the period of 1 year after enrolement | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exercise, Physical Activity, Palliative Care, Lung Cancer, NSCLC