This project is about the effect of a 12-week training therapy intervention in patients suffering from non-small cell and small-cell lung cancer. It has widely been accepted that exercise is preventive against certain types of cancer. Individuals following an active lifestyle have a significantly lower risk for several chronic diseases, including cancer, as compared to sedentary ones. However, evidence is still lacking for exercise as part of routine cancer treatment. It has widely been accepted that exercise strongly impacts immune response, and might influence antitumor immune response as well. In this study, patients suffering from lung cancer undergo either a 12-week training program consisting of moderate-intensity continuous exercise (MICE), or a 12-week program with high-intensity interval exercise. Both groups will be compared to a control group receiving standard exercise recommendations. The immunologic response, i.e. cytokine profiles and changes in peripheral blood mononuclear cell (PBMC) characteristics will be the main endpoint. Blood will be taken from the patients at different timepoints, and blood samples will be tested for these immunologic changes. FACS analysis will be used to assess the properties of immune cells and potential changes upon the exercise regimen. Mitochondrial function will be assessed via the Seahorse machine, and mass spectrometry (lipidomics) will be used for the analysis of lipid profile changes.
Lung cancer is the number one cause of cancer-related deaths worldwide. A few decades ago, the prognosis at lung cancer first diagnosis was generally poor with only a few months of median survival. New treatment regimens have markedly improved survival times - especially in certain histologic and molecular pathologic subtypes. The positive effect of exercise on the incidence of several cancer entities such as colorectal- or breast cancer, has been demonstrated previously. Physically active individuals are diagnosed with cancer significantly less often as compared to sedentary people. In oncologic follow-up care, a positive effect of exercise and training with an advantage in survival has also been proven, e.g. in breast cancer patients. In addition, existing data shows a positive effect of exercise on the immune system: active individuals show a different pattern of proinflammatory markers in the blood serum, with every exercise session generating an immune-stimulatory effect which changes the immunologic serum profile also at rest. Thus, regular exercise has an anti-inflammatory long-term effect. Hypothesis and Objectives: With this project the investigators seek to demonstrate distinct immunologic changes, assessing cytokine serum profiles and changes in peripheral blood mononuclear cell (PBMC) characteristics upon a medically guided training regimen. The investigators assume that the antitumor immune response is positively affected by the training therapy regimen. Setting and Methods. To exactly define "exercise" in this setting, as a first step the investigators will test two exercise types in healthy individuals. According to the individual exercise capacity as determined by spiroergometry, healthy subjects will either perform moderate-intensity continuous exercise (MICE), or a high-intensity interval training (HIIT). By means of venous blood sampling before and after training the investigators determine the respective changes of serum immune markers through exercise. The same two training types will then be performed by lung cancer patients upon immunotherapy, with one patient group doing MICE-sessions, one group doing the HIIT and a third group who will receive general exercise recommendations but otherwise will not undergo supervised training. Inflammatory serum parameters and PBMC characteristics will be compared between the groups. Moreover, the overall aerobic capacity (and respective changes before and after the training intervention), as well as quality of life will be analysed. Patients in the exercise groups will be advised to train once a week under medical supervision, and to walk briskly for 30 minutes every day of the week in addition. The investigators' hypothesis is, that exercise should be implemented as a complementary treatment strategy in the lung cancer treatment setting, possibly improving not only physical health and wellbeing but also treatment response. In addition to improving the patients' quality of life by a better physical capacity and fitness, helping the participants in everyday activities, the investigators propose that the implementation of exercise programs in various oncologic settings in future may improve the patients' outcome. Scientific Novelty. Standardization of exercise regimens in oncologic scenarios in the existing literature is generally poor. The investigators carry out one of the few studies where the type, duration, timing and intensity of exercise in both exercise groups is clearly defined according to the F.I.T.T. (frequency, intensity, type, time)-principle, comparing two different training modalities to sedentary control patients, respectively. Exercise needs to be seen as a drug, and like in any drug the optimum dose must be clearly outlined.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
50
1 study arm doing continuous type exercise will be compared to 1 study arm doing high-intensity interval exercise, over the course of 12 weeks, respectively. Both arms will be compared to sedentary control patients.
For patients in the control group, general exercise recommendations (e.g. recommendations by the CDC suitable for all adult individuals) will be given, however, no training therapy intervention is done and no home-based walking exercise is required either.
Medical University of Graz
Graz, Austria
RECRUITINGFACS analysis of PBMCs
The FACS panel comprises: CD4pos Helper T Cells, CD8pos Cytotoxic T Cells, Regulatory T Cells, Effector Memory T Cells, Naive/Memory Subsets, Activated/Exhausted T Cells, gamma-delta T Cells, Naive B Cells, Memory B Cells, Transitional B Cells, Classical Monocytes, Intermediate Monocytes, Non Classical Monocytes, NK CD16pos, NK CD16neg, Neutrophils, Basophils, Mast Cells, Viable vs. Dead Cells, Immune Checkpoint Subsets, Activation/Proliferation Markers. The total numbers and percentages of cells positive for the above listed markers are the primary outcome measures. The surface marker profile of PBMCs as a whole will define the outcome, showing differences between exercising and sedentary patients, e.g.: "In patients from the exercise group, XX% of naive B cells were found, and XX% of CD4pos Helper T Cells, and XX% CD8pos Cytotoxic T Cells were found. In patients from the control group, the proportion of naive B cells was XX...".
Time frame: Before and after the 12 week training therapy intervention, i.e. differences seen between 12 and 14 weeks
Cytokine analysis from peripheral blood sampling
IFN gamma, IL-13, GM-CSF, IL-1β, IL-5, sCD25 (IL-2Ra), IL-4, VEGF, IL-17A, IL-18, CCL4 (MIP-1β), IL-15, IL-12p70. The count of the above listed cytokines in pg/ml will be recorded in venous blood samples, with higher values after exercise indicating a more pronounced inflammatory response. Blood plasma samples from the patients will be collected at the beginning and after the 12 weeks exercise intervention for cytokine testing. Additionally, cytokine profiling will be done before and after one exercise bout to illustrate acute changes. Multiplex detecton kits (Legendplex) will be used for cytokine profiling. For every cytokine, differences will be recorded in one patient at enrollment and after completion of the 12 week training therapy. Differences between the exercising and non-exercising patients will be recorded as well. E.g. "IFNgamma levels were on average XX pg/ml before the intervention. After the intervention period of 12 weeks, IFNgamma levels were on average XX pg/ml."
Time frame: From enrollment to after the 12 week intervention, i.e. a period between 12-14 weeks
Number of participants with changes in mitochondrial function (Seahorse analysis)
Mitochondrial function parameters are combined to assess how well mitochondria work in a given patient. Oxygen Consumption Rate (OCR), Extracellular Acidification Rate (ECAR), Glycolytic Rate, Glycolytic Capacity, Basal Oxygen Consumption Rate, Maximal Respiration, and Spare Respiratory Rapacity are assessed by means of a Seahorse assay using a Seahorse XF Analyzer from Agilent, that measures the real-time metabolic activity of live cells by simultaneously assessing mitochondrial respiration and glycolysis. The number of patients with changes in oxygen consumption rate (OCR), which indicates mitochondrial respiration, and the extracellular acidification rate (ECAR), which is linked to glycolysis, is analysed. Aberrations in mitochondrial function as well as changes from before to after the intervention in % of patients / total number of patients is assessed.
Time frame: From enrollment to after completion of the exercise intervention, i.e. a period between 12-14 weeks
Mass spectrometry - Lipidomics
Marker Name (or m/z value), Retention Time and Intensity/Abundance of a given metabolite will be analysed in plasma samples. Markers comprise H4CH, H4A1, H4A2, TPA1, HDA1, IDPL, H4PL, Glutamine, L5CH, H3CH, TPA2, HDA2, L5PL, HDCH, H3A2, TPCH, L5PN, L5AB, V1FC, H3FC, L5FC, SPC, IDTG, V5FC, Glutamic acid, H4FC, Alanine, HDPL, V2PL, Glucose, LDCH, L4CH, H3A1, L4FC, V2TG. Lipidomics is used to describe the complete lipid profile within the patients' immune cells. It is a subset of the "metabolome". As opposed to classic analysis of carbohydrate metabolism, lipids are more stable, allowing for an analysis of frozen PBMCs. Our hypothesis is that upon the exercise program, lipidomics of the immune cells significantly change, allowing for a more favorable antitumor immune response. Total counts of each above-listed metabolite in the blood will be determined, e.g. in milligrams per deciliter and for every metabolite, changes between exercising and sedentary patients are recorded.
Time frame: From enrollment to after completion of the 12 week exercise intervention, i.e. a time period between 12 and 14 weeks
Aerobic capacity
With spiroergometry testing at the beginning of the exercise program and after completion of the program at 12 weeks, the investigators will assess potential changes in the patients' aerobic capacity. The normal range for womens' VO2max starts at 30 ml/kg/min and for men at 35 ml/kg/min with lower ranges expected in the usually elderly tumor patients. Improvements over the 12 week intervention period will be recorded.
Time frame: From enrollment to after completion of the 12 week training therapy intervention, i.e. a time period between 12 and 14 weeks
Quality of life - EORTC-QLQ C30 (German version)
The patient's quality of life will be assessed by two questionnaires, one for quality of life in cancer patients in general and one questionnaire specifically for lung cancer. The EORTC-QLQ C30 (German version) has a range from 0-100 with higher values representing a better quality of life. Minimal Important Difference (MID): A change of 5 to 10 points is generally considered clinically meaningful. Differences of 10 points are often used to indicate clinical relevance.
Time frame: From enrollment to after completion of the 12 week training therapy intervention, i.e. a period between 12 and 14 weeks
Quality of life - FACT-L scale (German version)
The FACT-L (Functional Assessment of Cancer Therapy-Lung) questionnaire has a maximum possible total score of 0 to 136, which includes the 27-item FACT-G (general) and the 9-item Lung Cancer Subscale (LCS). Higher scores indicate better quality of life.
Time frame: From enrollment to after 12 weeks, i.e. a period between 12 and 14 weeks
Bodycomposition / Bioimpedance measurement
Bioimpedance measurement will be used to determine body composition (and possible increments in muscle mass). The measures are given in % of total body mass. Higher values of muscle mass are generally considered better and indicate a good response to training, whist declines in muscle mass are often observed in inactive cancer patients.
Time frame: Enrollment to after 12 weeks, i.e. a period between 12 and 14 weeks
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