Improving aerobic capacity in patients with advanced non-small cell lung cancer: study protocol of the 3-armed randomized controlled BREATH trial

Improving aerobic capacity in patients with advanced non-small cell lung cancer: study protocol of the 3-armed randomized controlled BREATH trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Improving aerobic capacity in patients with advanced non-small cell lung cancer: study protocol of the 3-armed randomized controlled BREATH trial Nico De Lazzari, Marcel Wiesweg, Miriam Götte, Jan Franco, Raluca Ileana Mincu, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7271256/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Jan, 2026 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background: Lung cancer is one of the most common cancers in Germany, with around 56,000 new cases diagnosed in 2020. Approximately 65% are diagnosed at advanced stages, where symptoms such as fatigue, pain, dyspnea, and weight loss are prevalent. These patients often suffer from cardiovascular and pulmonary comorbidities, which interact with treatment toxicity, outcome and increase treatment costs. Although exercise therapy is proven to alleviate cancer-related symptoms and to improve quality of life, current lung cancer treatment guidelines fail to adequately prioritize its crucial role. Methods: The Better symptom contRol with Exercise in pAtients wiTH advanced non-small cell lung cancer (BREATH) study is a prospective, three-arm randomized controlled trial (RCT) designed to assess the impact of exercise therapy on patients with advanced NSCLC (stage IIIB-IV) who are receiving first- or second-line systemic therapy) in the palliative setting. Patients are randomized in a 2:1:1 ratio into a control group (receiving exercise recommendations) or one of two intervention arms: endurance training and breathing exercise or combined endurance and resistance training. The intervention groups will exercise twice a week for 12 weeks. The control group participants will be randomized again in a 1:1 ratio into one of the two intervention arms after completion of the control period. The study will assess outcomes at baseline, 12 weeks, and 24 weeks. The primary outcome is improvement of aerobic capacity (VO 2 peak). Secondary outcomes include quality of life, fatigue, adherence to exercise and adverse events. Patient representatives were involved in all stages of protocol development. Discussion: The BREATH study addresses a significant gap in the current management of advanced lung cancer treatment by evaluating the impact of different exercise treatment protocols to reduce symptoms and improve clinical outcome. The study design and exercise program aim to enhance adherence and optimize patient related outcomes. The results of the BREATH study have the potential to influence future guidelines and improve the management of patients with advanced NSCLC. Trial registration ClinicalTrials.gov NCT registered on the 18. April 2024 (NCT06374160) advanced lung cancer NSCL exercise palliative treatment VO2 peak Figures Figure 1 Background With approximately 56,000 new cases in 2020, lung cancer is one of the most common cancer entities in Germany [ 1 ]. Approximately 65% are diagnosed in advanced stages [ 2 , 3 , 4 ]. Prominent symptoms during the cancer trajectory include tumor-related fatigue [ 5 , 6 ], pain [ 7 ], depression [ 8 ], cough [ 9 ], dyspnea (shortness of breath) [ 10 ], weight loss/appetite loss [ 11 ], and sleep problems [ 12 , 13 ]. In addition to these cancer-related symptoms, patients with advanced lung cancer typically present with comorbidities, with the common causal root in nicotine consumption. Cardiovascular diseases and chronic obstructive pulmonary disease (COPD) form the most common and relevant comorbidities [ 14 ]. Besides a significantly adverse effect on treatment outcome [ 15 ], patients with multiple comorbid conditions require more outpatient and inpatient treatments, leading to higher treatment costs [ 16 , 17 ]. To support these multimorbid patients, multimodal strategies need to be developed. The Roundtable Report of the American College of Sports Medicine recommends that cancer patients engage in moderate physical activity for 150–300 minutes per week [ 18 ]. However, in the current German S3 guidelines for the diagnosis and treatment of lung cancer, exercise interventions are only marginally addressed [ 2 ], and in the real-world setting, oncologists rarely recommend exercise [ 19 ]. Additionally, many barriers exist for patients to self-implement exercise as a routine. Over 700 studies involving 50,000 cancer patients have evaluated the impact of exercise therapy in oncological patients [ 20 ]. Exercise therapy demonstrates improvements in cancer-related side effects such as fatigue, pain, quality of life [ 21 ], dyspnea [ 22 – 24 ], cardiologic performance [ 25 ] or physical fitness, and prevents muscle loss during active systematic treatment [ 26 – 31 ]. In addition to improving cancer-specific symptoms, exercise therapy interventions show a positive impact on patients with COPD or cardiovascular disease [ 32 – 34 ]. Since comorbidities have been proven to worsen the quality of life and prognosis of therapy, exercise therapy can offer relief from symptom burden in addition to oncological systematic therapy [ 35 – 37 ]. Advanced metastatic lung cancer patients exhibit a significantly increased symptom burden along with a low quality of life compared to other tumor entities [ 38 ]. The feasibility of exercise and potential barriers in patients with advanced cancer have been studied in recent years [ 39 – 41 ]. Published exercise studies specifically targeting patients with advanced lung cancer have limited evidence: Sample sizes in clinical trials were insufficient to evaluate the effect of exercise therapy. Almost all randomized controlled trials included fewer than 50 subjects [ 42 – 55 ]. Recruitment rates range from 25–70%, with significantly higher drop-out rates (15%-42%) compared to other patient cohorts with advanced tumor diseases. Only half of the published studies report the rate of adherence to the exercise intervention. First-line treatment of metastatic non-small lung cancer (NSCLC) is molecularly stratified. After molecular diagnostics, eligible patients (EGFR, ALK, ROS1, RET) receive targeted treatment, while the majority of patients receives (chemo)immunotherapy. Standard-of-care platinum-base chemo-immunotherapy typically consists of four cycles of platinum-contained chemotherapy combined with immunotherapy, followed by immunotherapy maintenance. The addition of immunotherapy in the last decade led to a significant improvement with 5-year overall survival rates of 20%, or 30% in selected subgroups [ 56 , 57 ]. Despite this improvement in therapy, there are currently no studies combining standard-of-care immunotherapy-based systemic therapy for advanced lung tumors with exercise intervention. Of note, immune checkpoint inhibitors (ICI) targeting programmed Cell Death Protein 1 (PD-1), programmed Cell Death Protein ligand 1 (PD-L1) or cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) have the potential to induce rare but severe toxicity such as pneumonitis, hepatitis or ICI-related myocarditis, heart failure and arrhythmias other various cardiologic diseases or major cardiac events (MACE) [ 58 – 64 ]. Initial preclinical studies show a positive synergistic effect between exercise therapy and immunotherapy [ 65 – 69 ]. Considering the current literature, it is evident that a successful exercise therapy concept has not yet been implemented for advanced lung cancer patients. Methods and Design BREATH is a prospective 3-arm randomized controlled trial (RCT) including histologically confirmed advanced NSCLC (UICC stages IIIB, IIIC and IV) patients during palliative anti-cancer treatment. Patients in stage IIIB and IIIC will only be enrolled if potentially curative treatment options were excluded. Enrollment started in June 2024 and is estimated to be open for 2.5 years (Fig. 1 ). Study participants will be divided into study arms using a 2:1:1 randomization, with one control group and two exercise therapy groups. Participants in the two intervention arms will undergo exercise therapy, with one group receiving individual endurance training with additional breathing exercise and the other group receiving a combination of endurance and resistance training. Both intervention groups will exercise supervised twice a week for 12 weeks. The control group will initially undergo standard of care for 12 weeks. Afterwards, the patients in the control group will be randomized into one of the two intervention arms and will also receive treatment twice a week for 12 weeks. This approach has the advantage of providing a sufficiently large sample for both comparing overall exercise therapy with the control group and comparing the two types of exercise therapy. In addition, this design allows all participating patients to receive exercise therapy. By individually measuring the hypothetical One-Repetition Maximum (h1-RM) and conducting a cardiopulmonary exercise testing (CPET) on a cycle ergometer, a tailored individual training program based on current performance will be offered to the patient. BREATH exercise begins with moderate exertion and is progressively increased during the course of the study participation (see chapter interventions for a detailed description). Outcome measurement will be at baseline (t 0 ), after 12 weeks (t 1 ) and after 24 weeks (t 2 ) leading to a maximum study participation of six months (Fig. 1 ). The Ethics Committee of the Medical Faculty University of Duisburg-Essen approved this study (22-10522-BO) in December 2023. Table 1 Inclusion criteria of the BREATH Study Inclusion criteria Exclusion criteria • Patients with histologically confirmed non-small cell lung carcinoma in UICC stages IIIB, IIIC and IV • First- or second-line therapy (inclusion up to 28 days after the first cycle) in palliative intention • Age ≥ 18 years • Signed informed consent • Severe cardiopulmonary disease (EF < 30%) • Newly occurring or progressive uncontrolled CNS (central nervous system) metastases • Expected life expectancy 2 • Acute pulmonary embolism • Acute myocardial infarction • Requiring surgery for aortic aneurysm • Tension pneumothorax • Lack of proficiency in the German language • Active infection Patients with NSCLC at the West German Cancer Center (University Hospital Essen and University Medicine Essen – Ruhrlandklinik) will be identified by the treating physicians, specialist nurses, by screening patients presented at the multidisciplinary tumor board, or by systematically screening patients receiving routine follow-up scans during first-line treatment. Informed consent will be obtained by the treating physician. After study inclusion, exercise assessment (baseline) followed by randomization will be performed. Objectives The primary objective is to achieve an improvement in aerobic capacity (VO 2 peak) from t0 to t1 through exercise therapy compared to standard of care. As a secondary objective, we aim to examine whether there is a difference between the two exercise therapies regarding the performance improvement (VO 2 peak) from the beginning of the therapy to the end of the therapy (either t2 compared to t1 or t1 compared to t0, depending on the randomization arm). Other secondary objectives are to assess changes in quality of life, fatigue, dyspnea during the study participation and evaluation adherence to the intervention, dropout rates, adverse events, and tumor therapy response. Variables and Data Collection The full variables of the BREATH study are displayed in Table 2 . Anthropometric and medical data includes the following variables: Age, weight, highest education, marital status, date of first cancer diagnosis, tumor diagnosis, tumor stage, TNM classification, first-line or second-line treatment, histology, metastasis and location, PD-L1 expression and molecular pathology based on sequence analyses. Tobacco use plays a major role in the development of lung tumors and poorer cardiopulmonary performance. To fully understand this variable, the following items are asked: pack years and current smoking status (current smoker, non-smoker and former smoker). A former smoker is defined as a person who has quit smoking for longer than the last 12 months. To capture this category, the abstinence date is also queried. The dose of cigarettes smoked is categorized as light smoker (persons who smoke a low number of cigarettes per day, typically less than 10 cigarettes), moderate smoker (persons who smoke a moderate number of cigarettes per day, typically between 10 and 20 cigarettes) and heavy smoker (persons who smoke a high number of cigarettes per day, typically more than 20 cigarettes). In general, a comparison for or all primary and secondary outcomes will be conducted between both exercise arms and the control arm and additionally between the two exercise arms (either t 2 compared to t 1 or t 1 compared to t 0 , depending on the randomization arm). Table 2 Spirit figure of the trial data collection points Enrollment Allocation Post-allocation TIMEPOINT -t 1 t 0 inclusion week 0 t 1 (12 weeks) t 2 (24 weeks) Enrollment: Eligibility screen 1 X Informed consent X Allocation 2 X INTERVENTIONS : Arm A (aerobic exercise+ strength training) Study End Arm A Arm B (aerobic exercise) Study End Arm B Arm C (Usual Care) Crossover 3 Study End ASSESSMENTS : Anthropometric data and medical history X Smoker status X Tumor stage and histology X Molecular pathology X Anti-tumor therapy X X Blood sampling 4 X X X Urin sampling 5 X X X CPET Maximum oxygen uptake (VO2 peak [ml/min/kg]) 6 X X X Patient related outcomes measurements 7 X X X Arterial blood pressure (mmHg) X X X Change in ECG (PQ, QRS, and QTc intervals) X X X Feasibility of exercise X X X Adverse Events and SAE 7 X X X Treatment scheme (change of dose or frequency) X X 1 Check Table 1 for inclusion criteria 2 Allocation to intervention groups will be done after completion of baseline assessment. Following randomization strata will be used: 1. Histological stratification (non-squamous vs squamous) 2. Forced expiratory Volume in 1 second (FEV1) > 50 and under < 50 3 Randomization of the control group based on the same strata used for the first randomization. 4 Blood sampling will be done at every visit for anti-cancer treatment mostly every 3 weeks until study ends. Cisplatin based treatments 1 + 8 day followed by 3 weeks. Carboplatin and Docetaxel d1 q3w. Blood sampling consists of BNP, high-sensitive troponin T/I as heart markers, Hemoglobin [g/dl], Erythrocytes [count/pl], Leukocytes [count/nl], Lymphocytes [count/nl], Neutrophils [count/nl], C-reactive protein [mg/dl], Cytokeratin-19 Fragment, CYFRA 21 − 1 [ng/ml] 5 Urine (3 mL) and blood (1.5 mL) (EDTA anti-coagulated) will be collected for Nuclear Magnetic Resonance (NMR)-based metabolome analysis 6 Full variable of CPET consisting of: Forced vital capacity [L], maximal voluntary ventilation [L/min], forced expiratory volume in 1 second, one-second capacity [L], relative one-second capacity, tiffeneau index [ %] pmax [Watt], HR [Beats/minute], BP [mmHg], O2-Saturation in [%], Breathing reserve [%], Ventilatory Threshold 1 [ml/min], Ventilatory Threshold 2 [ml/min] max O2-Pulse [ml/beat], Ventilatory Equivalent for Carbon Dioxide Slope, partial pressure in the arterial blood [mmHg], O2 partial pressure in the arterial blood [mmHg], Dead Space Volume/Tidal volume, P(A-a)O2, Oxygen Consumption/work load, respitory exchange ratio (RER), pH value, PAO2 [mmHg], SaO2 [%], PCO2 [mmHg], BE [mmol/l], HCO3 [mmol/l], SBCe [mmol/l] 7 To be filled out by patient: EORTC-QLQ-C30 - lung cancer specific LC13 and Functional Assessment of Cancer Therapy-Fatigue-Scale 8 Adverse Events/Serious Adverse Events related to exercise will be documented weekly by the exercise therapist in combination with the study nurse after the manual of Common Terminology Criteria for Adverse Events (CTCAE) v5.0. and CTCAE after the cardio-oncology guidelines Randomization Patients will be randomized into one of three study arms (Arm A: endurance + resistance training, Arm B: endurance training + breathing exercises, Arm C: control group = usual care + exercise recommendation (following the guidelines of the American College of Sports Medicine) using a web-based tool ( https://randomizer.at ). The allocation ratio is 2:1:1 for the first randomization into the control arm and two exercise arms followed by a 1:1 randomization of the original control group. Randomization is conducted after baseline assessment and is stratified based on the following two criteria to ensure balanced distribution of prognostic factors across all groups: Histological stratification (non-squamous vs squamous) Squamous and non-squamous lung cancer differs by underlying biology, molecular characteristics, and response patterns to systemic therapy. Forced expiratory Volume in 1 second (FEV1) FEV1 is a crucial measurement of lung function and is highly associated with VO 2 peak. In advanced lung cancer patients, impairment of pulmonary function is common. FEV1 will be divided into two classifications: Mild to moderate COPD - FEV1 is equal or greater than 50% of predicted value; and severe to very severe COPD - FEV1 lower than 50% of predicted value. The minimization method is used for stratified sampling [ 70 ]. Due to the nature of the intervention, participant blinding and concealment of randomization is not feasible. However, the assessors of functional testing for VO2 peak will not be aware of the treatment allocation. Cardiopulmonary exercise testing CPET will be carried out to assess the patient's cardiopulmonary performance using the cycle ergometer in a semi-recumbent position. Through a breathing mask, inhaled and exhaled air can be analyzed, enabling a precise calculation of oxygen uptake (VO 2 ) and carbon dioxide output (VCO 2 ). To assess participants peak oxygen uptake (V0 2 peak), a ramp protocol will be utilized. This diagnostic procedure is characterized by high precision in determining the anaerobic threshold through the ratio of VO 2 to VCO 2 . The V0 2 peak is considered a crucial factor in aerobic performance. Cardiopulmonary exercise testing also proves to be a safe diagnostic tool for advanced lung cancer patients [ 71 ]. Physical function based on the hypothetical 1-Repition maximum (h1-Rm) The one-repetition maximum (1RM) is a test to determine the maximum weight that the patient can move within a predefined range of motion. The test procedure for measurement of maximum strength is characterized by high reliability. As the one-repetition maximum represents an increased risk of injury in patients, there is the possibility of calculating the hypothetical one-repetition maximum (h1-Rm). For this purpose, the Brzycki formula is used and the maximum force can be calculated from this after the exercise and reduce the risk of injury or other adverse events [ 72 ]. Questionnaires The Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-Fatigue) questionnaire comprises 13 questions aimed at assessing self-reported fatigue and its impact on daily activities and physical function [ 73 , 74 ]. The EORTC QLQ-C30/LC13 is a tumor entity-specific questionnaire designed to assess the quality of life in patients with lung cancer. The EORTC QLQ-C30/LC13 captures functional parameters (physical functioning, role functioning, cognitive functioning, emotional functioning), symptom scales (pain, fatigue, nausea and vomiting), Global Quality of Life, and Global Health Status. Additionally, patients can indicate individual items that were symptomatic in the past week [ 75 , 76 ]. The questionnaires are self-administered by patients at each time point, if study personnel need to assist it will be documented in the trials management. Exercise Adherence Feasibility parameters include recruitment rate, drop-out rate and adherence to the training will be measured and documented by the responsible exercise therapist. All withdrawals will be considered as dropouts, with reasons noted and compared between each study arm. This provides a straightforward comparison of the raw dropout counts between groups. The percentage of participants who dropped out will also be calculated for each study arm relative to the total number of participants initially assigned to that arm. Adherence based on the absolute numbers of scheduled exercise sessions, both absolute and percentage-based adherence can be calculated and compared between study arms. Adherence to the protocol is defined as completing at least 75% of the possible training sessions. Interventions Intervention (Arm A) is a supervised exercise program combining endurance training and resistance training. Participants conduct two exercise sessions each week, with each session lasting 60 minutes. The breakdown of these sessions involves 20 minutes dedicated to endurance training and 40 minutes to resistance training. Aerobic interval training is characterized by an intensity set at 50% of the participants' maximal workload, determined through CPET. This approach aims to optimize cardiovascular fitness through controlled and targeted aerobic exercises. Resistance training targeting major muscle groups during each session. The exercise protocol prescribes two sets of each resistance exercise, with participants completing 8–12 repetitions per set. The training intensity for resistance exercises is progressive increased within a range of 50–80% of the participants' h1-RM. This tailored approach allows for a progressive and adaptive response, ensuring that participants are appropriately challenged while minimizing the risk of overexertion. The initiation phase, scheduled for week one, is characterized by an intentional starting point at 30% of participants' maximum capacity. The primary objective during this initial phase is to prepare the muscles for subsequent exertion while concurrently fostering an increased awareness of the body's responses to the introduced exercise stimuli. Arm B focuses exclusively on supervised aerobic exercise followed by breathing exercise. Participants in Arm B engage in exercise twice per week, with each session lasting 30 minutes intensity interval training. The endurance training in Arm B adopts an interval-based method to strike a balance between exertion and recovery. The training intensity is set at 50% of the participants' maximal workload and is increasing during the intervention to 80% of maximal workload. The structured intervals involve 10 sets of two minutes of exertion alternated with 10 sets of one minute for recovery, resulting in a total exercise time of 30 minutes per session. This design aims to challenge participants' aerobic capacity while providing adequate recovery intervals. A pulse oximeter is employed for measuring heart rate and oxygen saturation to ensure safety. Additionally, the Borg-CR scale is utilized to assess subjective dyspnea after every second interval, providing a qualitative measure of perceived exertion and discomfort. Termination criteria are established to guide the conditions for stopping exercise within treatment arms: oxygen saturation < 85% without increase during recovery and subjective increase in Borg-CR scale indicating severe dyspnea. The control group receives a one-time physical activity consultation with general information about daily activities and exercise participation, as well as individual training recommendations. After 12 weeks, the control group will be randomized into one of the exercise groups. Metabolic fingerprinting Venous blood (EDTA) and urine samples from all participants are collected at the onset of the first session and subsequently every 12 weeks until the conclusion of the study. Both sample types are subjected to centrifugation at 900 xg at 4°C for 10 minutes, and the resulting supernatant is stored at -80°C for future analysis. For metabolomic analysis, the samples are diluted with specific urine and plasma diluents, and sodium trimethylsilylpropanesulfonate is added as an NMR standard. Evaluation of the intervention and patient centered interviews Quantitative and qualitative data are collected as part of the evaluation process [ 77 ]. The quantitative component focuses on participants’ satisfaction with various aspects of the exercise intervention. A self-developed online questionnaire assesses elements such as the structure and delivery of the intervention, organizational aspects, and support provided by the trainer team. Responses are recorded on a five-point Likert scale (“strongly disagree” to “strongly agree”), and sociodemographic information is also collected. Open-ended items allow participants to elaborate on their responses and provide detailed feedback. The survey is distributed to all participants, and data are analyzed descriptively. Frequency distributions, means, medians, standard deviations, and modes describe satisfaction levels and variability. Subgroup comparisons (e.g., age, intervention format) help identify potential differences. Free-text responses are analyzed using qualitative content analysis [ 78 , 79 ], enabling systematic coding and inductive category development. The qualitative component consists of episodic interviews with a purposive sample of approximately fifteen participants. While participants are comparable in terms of their underlying medical condition, the sample is deliberately selected to reflect diversity in other relevant characteristics. Selection is based on factors such as age, gender, and symptom burden to capture a broad range of experiences. The number of interviews is guided by data saturation and may be adjusted as needed. The interviews explore perceived changes in quality of life, physical well-being, self-efficacy, and sustained physical activity. The episodic format captures both specific experiences and broader reflections. Transcripts are analyzed using qualitative content analysis according to Kuckartz [ 78 ], a method well suited to identifying thematic patterns in narrative data. Findings from both components are expected to inform the development and refinement of future exercise interventions. Combining structured satisfaction data with personal narratives supports improvements that are both evidence-informed and participant-centered [ 80 , 81 ]. Sample size calculation The sample size calculation is based on the primary endpoint of the improvement in VO 2 peak after 12 weeks (t 1 ) compared to baseline (t 0 ). Using a study by Quist et al. [ 82 ], where VO 2 peak was measured in patients with advanced lung cancer before and after a 6-week exercise therapy, an assumed mean difference of 0.1 is considered between the exercise therapy groups and the control group. Additionally, a standard deviation of 0.18 is assumed [ 81 ]. With a one-sided t-test assuming equal variances at a significance level of 0.05 and a power of 0.80, 41 patients are required in the control group and 41 patients in the exercise therapy groups. Considering that approximately 15% of deaths are expected after 24 weeks due to disease progression [ 83 ], a dropout rate of 20% is assumed, resulting in the inclusion of 52 patients per group (52 patients in the control group, 26 patients in Arm A, and 26 patients in Arm B). Data Analysis Statistical analyses of the primary and secondary endpoints will be conducted on the Intention-To-Treat (ITT) population. As a sensitivity analysis, the analyses will also be performed on the Per-Protocol (PP) population. The primary endpoint of the improvement in VO 2 peak after 12 weeks (t 1 ) compared to baseline (t 0 ) will be assessed using a one-sided two-sample t-test assuming equal variances at a significance level of α = 0.05. In addition, a linear regression will be applied, adjusting for age, sex, non-squamous vs squamous and FEV1. All secondary analyses will be exploratory, meaning without adjustment of the significance level for multiplicity, and will be conducted using standard methods of statistical inference. Quantitative variables (including test scores) will be analyzed using univariable and multivariable linear regression to detect differences between the groups. Dichotomous variables will be analyzed using a univariable and a multivariable generalized linear model with identity link in order to estimate absolute risk differences. Event times will be analyzed using univariable and multivariable Cox regression, and Kaplan-Meier curves will be illustrated for event times. Subgroup analyses will be conducted based on age, gender, and first or second-line treatment. Adverse events will be documented and reported to the responsible physician during the study. Details of the statistical analyses will be specified in a Statistical Analysis Plan (SAP) prior to the start of analysis. The processing of NMR-based metabolomic data will be performed using an adapted version of the AlpsNMR package in R, which includes baseline correction, spectra alignment based on sodium trimethylsilylpropanesulfonate (DSS), and total intensity normalization [ 84 ]. The statistical analyses will include principal component analysis (PCA) with robust outlier detection. Loadings between |0.7| and |1| will be employed to identify the main determinants of the observed changes in the blood metabolome. The identification of the underlying substances in the PCA will be conducted using the Human Metabolome Database ( https://hmdb.ca/ ). Furthermore, partial least squares (PLS) analysis will be used to correlate these changes in the metabolome with other clinical and biochemical parameters, thereby identifying the main drivers of plasma metabolome changes. Pearson correlation will be employed for numeric data with a linear relationship and normal distribution, while Spearman correlation will be used for rank data or non-linear relationships. Correlations between 0.7 and 1.0 (or -0.7 and − 1.0) are generally considered strong, while correlations between 0.4 and 0.7 (or -0.4 and − 0.7) are moderate. Correlations with a p-value less than 0.05 are considered statistically significant. Metabolic data analysis utilizing the R package ALPs was modified by researchers at the Children’s Hospital 2, University Hospital Essen, to meet the particular requirements of this study. Patient and public involvement A patient representative from the patient advisory board Essen was involved in the development of the BREATH study. To disseminate results, they will be published and presented on expert conferences. In addition, patient support groups will receive all the necessary information created by BREATH. Data Management The BREATH study team will work closely with the Institute for Medical Informatics, Biometry and Epidemiology (IMIBE) and the Centre for Clinical Trials Essen (ZKSE). All study data will be documented on standardized case report forms and recorded with a good clinical practice (GCP)-compliant clinical data management system. The data will be checked for completeness and plausibility during the entire study period in order to guarantee a high data quality. The study database created for this purpose minimizes invalid data by performing automatic plausibility checks and highlighting missing values. Discussion The BREATH trial addresses the unmet need for targeted exercise therapy interventions for advanced NSCLC patients, considering the challenges posed by the disease and its treatment. The proposed trial design and patient involvement strategies aim to address existing gaps in the literature and enhance the understanding of the potential cardiopulmonary benefits of exercise therapy in this specific patient population. Furthermore, our study design offers the benefits of having a control group while all patients will be receiving exercise therapy. Especially lung cancer patients are not aware of the potential benefits of exercise and maintaining physical activity during palliative treatment [ 85 , 86 ]. In palliative treatment settings, longer or more intensive training sessions can be a barrier for patients. Therefore, it needs to be assessed whether a shorter exercise intervention focusing on endurance parameters can generate improved adherence or even have more positive influence on patient-relevant endpoints, enhancing both quality of life and maximum oxygen uptake through combined endurance and strength training. BREATH can spread awareness based on the results in this specific population of advanced NSCLC patients. In addition the high amount of comorbidities can be directly linked with shorter survival time and increased costs for therapies. Furthermore, the BREATH study offers insights of exercise therapy during active immunotherapy treatment with a sufficient sample size. Several theoretical and mouse model studies have highlighted the potential of combining exercise therapy with immunotherapy, although there's a lack of evidence from clinical trials [ 84 – 85 ]. Currently, multiple trial protocols are listed on clinicaltrials.gov aiming to investigate the impact of exercise therapy during immunotherapy, including NCT06026111 [ 89 ], NCT04866810 [ 90 ], NCT06152926 [ 91 ], NCT04645680 [ 92 ] and NCT04263467 [ 93 ]. The ERICA study currently investigates the effects of aerobic exercise within one hour prior to immunotherapy (pembrolizumab) in combination with chemoptherapy (platinum-based) in metastatic NSCLC patients. ERICA study will investigate the impact of aerobic exercise on immune biomarkers (NK cells, B lymphocytes, T lymphocytes, monocytes, subpopulations of dendritic cells on frozen PBMC, plasma biomarkers of sarcopenia and inflammation [ 94 ]. To complement clinical and physiological outcomes, the BREATH trial also includes a structured evaluation of the intervention from the patient perspective. By combining quantitative satisfaction surveys and qualitative interviews, the evaluation provides important insights into feasibility, acceptance, and individual experiences with the intervention. These findings will help refine future exercise programs for this vulnerable population. Consequently, BREATH has the potential to contribute evidence to the emerging field of immunotherapy combined with exercise therapy in a vulnerable patient cohort defined by high symptom burden and low quality of life. Trial status Recruitment did start on 1. June 2024.The first patient was enrolled on June 12, 2024. As of the current date (August 27, 2025), a total of 25 patients have been enrolled in the BREATH study. Estimated end of enrollment/recruitment is planned for December 2026. Protocol Version 1.1 date: 27.08.2025 Abbreviations COPD chronic obstructive pulmonary disease NSCLC Non-small-cell lung cancer UICC Union for International Cancer Control ICI Immune checkpoint inhibitors PD-1 Programmed Cell Death Protein 1 CTLA-4 Cytotoxic T-Lymphocyte-Associated Protein 4 NMR Nuclear Magnetic Resonance BNP Brain natriuretic peptide MACE major adverse cardiac event h1-RM hypothetical one repetition maximum CPET Cardiopulmonary exercise testing ITT Intention-To-Treat PP Per-Protocol DSS Sodium trimethylsilylpropanesulfonate PCA Principal component analysis PLS partial least squares IMIBE Institute for Medical Informatics, Biometry and Epidemiology ZKSE Centre for Clinical Trials Essen GCP Good clinical practice Declarations Consent for publication Not applicable. Ethics approval and consent to participate Ethical approval for the study was obtained from the Ethics Committee of the Medical Faculty University of Duisburg-Essen under the following number: 22-10522-BO. Competing interests The authors declare no competing interests within the BREATH study. Funding: BREATH is funded by the German Cancer Aid (Deutsche Krebshilfe). The funders had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit result. Authors’ contributions MT is the principal investigator of the BREATH trial. She conceived the study, leads all study activities. EMH, NK, and AS are the study biostatisticians and co-investigators. They contributed to the study design, managed statistical analyses. MTz and RM are the study cardiology co-investigators. They contributed to the design and interpretation of cardiology assessments, oversaw participant evaluations in cardiology. MW is the lead for study recruitment. He coordinated participant enrollment across clinical sites and the oncology expert in lung cancer. NDL and MG are the study exercise scientists and co-investigators. They contributed to the conception and implementation of the physical activity components of the trial. JJ is responsible for the metabolomic sub-study. He coordinated biosample processing and analysis, including NMR-based metabolic fingerprinting of blood and urine samples. All Authors read, edited and approved the final manuscript. Acknowledgement We acknowledge support by the Open Access Publication Fund of the University of Duisburg-Essen. Availability of data and materials Not available at this point. References Robert Koch-Institut, Herausgeber, Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V, Herausgeber. Krebs in Deutschland für 2019/2020. 14. Ausgabe. Berlin: Robert Koch-Institut; 2023. Lung Oncology. Prävention, Diagnostik. Therapie und Nachsorge des Lungenkarzinoms. Langversion, 1; 2018. Morgensztern D, Ng SH, Gao F, Govindan R. Trends in Stage Distribution for Patients with Non-small Cell Lung Cancer: A National Cancer Database Survey. 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16:34:53","extension":"html","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":211331,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7271256/v1/96d77ac4288196c063af17ee.html"},{"id":96652514,"identity":"5372973f-85de-4a1e-ae9a-6badc7ddc46e","added_by":"auto","created_at":"2025-11-24 16:34:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":16903,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design of the BREATH study\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7271256/v1/b36af3d0d1c0a863b749838b.png"},{"id":100614802,"identity":"ff63733b-198c-426c-996c-1cd599b25a1e","added_by":"auto","created_at":"2026-01-19 17:25:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":962913,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7271256/v1/2c786c7c-b183-4875-944b-9b38cadfbc88.pdf"},{"id":96710179,"identity":"dc6d9a64-9f4c-44c6-9d50-a5332f5fcc2d","added_by":"auto","created_at":"2025-11-25 10:10:16","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":40623,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITchecklistBREATHStudy.docx","url":"https://assets-eu.researchsquare.com/files/rs-7271256/v1/95a9cc685a128def784d2137.docx"}],"financialInterests":"","formattedTitle":"Improving aerobic capacity in patients with advanced non-small cell lung cancer: study protocol of the 3-armed randomized controlled BREATH trial","fulltext":[{"header":"Background","content":"\u003cp\u003eWith approximately 56,000 new cases in 2020, lung cancer is one of the most common cancer entities in Germany [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Approximately 65% are diagnosed in advanced stages [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Prominent symptoms during the cancer trajectory include tumor-related fatigue [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], pain [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], depression [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], cough [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], dyspnea (shortness of breath) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], weight loss/appetite loss [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and sleep problems [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In addition to these cancer-related symptoms, patients with advanced lung cancer typically present with comorbidities, with the common causal root in nicotine consumption. Cardiovascular diseases and chronic obstructive pulmonary disease (COPD) form the most common and relevant comorbidities [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Besides a significantly adverse effect on treatment outcome [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], patients with multiple comorbid conditions require more outpatient and inpatient treatments, leading to higher treatment costs [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. To support these multimorbid patients, multimodal strategies need to be developed. The Roundtable Report of the American College of Sports Medicine recommends that cancer patients engage in moderate physical activity for 150\u0026ndash;300 minutes per week [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, in the current German S3 guidelines for the diagnosis and treatment of lung cancer, exercise interventions are only marginally addressed [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], and in the real-world setting, oncologists rarely recommend exercise [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Additionally, many barriers exist for patients to self-implement exercise as a routine. Over 700 studies involving 50,000 cancer patients have evaluated the impact of exercise therapy in oncological patients [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Exercise therapy demonstrates improvements in cancer-related side effects such as fatigue, pain, quality of life [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], dyspnea [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], cardiologic performance [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] or physical fitness, and prevents muscle loss during active systematic treatment [\u003cspan additionalcitationids=\"CR27 CR28 CR29 CR30\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In addition to improving cancer-specific symptoms, exercise therapy interventions show a positive impact on patients with COPD or cardiovascular disease [\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Since comorbidities have been proven to worsen the quality of life and prognosis of therapy, exercise therapy can offer relief from symptom burden in addition to oncological systematic therapy [\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Advanced metastatic lung cancer patients exhibit a significantly increased symptom burden along with a low quality of life compared to other tumor entities [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The feasibility of exercise and potential barriers in patients with advanced cancer have been studied in recent years [\u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Published exercise studies specifically targeting patients with advanced lung cancer have limited evidence: Sample sizes in clinical trials were insufficient to evaluate the effect of exercise therapy. Almost all randomized controlled trials included fewer than 50 subjects [\u003cspan additionalcitationids=\"CR43 CR44 CR45 CR46 CR47 CR48 CR49 CR50 CR51 CR52 CR53 CR54\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. Recruitment rates range from 25\u0026ndash;70%, with significantly higher drop-out rates (15%-42%) compared to other patient cohorts with advanced tumor diseases. Only half of the published studies report the rate of adherence to the exercise intervention.\u003c/p\u003e\u003cp\u003eFirst-line treatment of metastatic non-small lung cancer (NSCLC) is molecularly stratified. After molecular diagnostics, eligible patients (EGFR, ALK, ROS1, RET) receive targeted treatment, while the majority of patients receives (chemo)immunotherapy. Standard-of-care platinum-base chemo-immunotherapy typically consists of four cycles of platinum-contained chemotherapy combined with immunotherapy, followed by immunotherapy maintenance. The addition of immunotherapy in the last decade led to a significant improvement with 5-year overall survival rates of 20%, or 30% in selected subgroups [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. Despite this improvement in therapy, there are currently no studies combining standard-of-care immunotherapy-based systemic therapy for advanced lung tumors with exercise intervention. Of note, immune checkpoint inhibitors (ICI) targeting programmed Cell Death Protein 1 (PD-1), programmed Cell Death Protein ligand 1 (PD-L1) or cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) have the potential to induce rare but severe toxicity such as pneumonitis, hepatitis or ICI-related myocarditis, heart failure and arrhythmias other various cardiologic diseases or major cardiac events (MACE) [\u003cspan additionalcitationids=\"CR59 CR60 CR61 CR62 CR63\" citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. Initial preclinical studies show a positive synergistic effect between exercise therapy and immunotherapy [\u003cspan additionalcitationids=\"CR66 CR67 CR68\" citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e]. Considering the current literature, it is evident that a successful exercise therapy concept has not yet been implemented for advanced lung cancer patients.\u003c/p\u003e"},{"header":"Methods and Design","content":"\u003cp\u003eBREATH is a prospective 3-arm randomized controlled trial (RCT) including histologically confirmed advanced NSCLC (UICC stages IIIB, IIIC and IV) patients during palliative anti-cancer treatment. Patients in stage IIIB and IIIC will only be enrolled if potentially curative treatment options were excluded. Enrollment started in June 2024 and is estimated to be open for 2.5 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Study participants will be divided into study arms using a 2:1:1 randomization, with one control group and two exercise therapy groups. Participants in the two intervention arms will undergo exercise therapy, with one group receiving individual endurance training with additional breathing exercise and the other group receiving a combination of endurance and resistance training. Both intervention groups will exercise supervised twice a week for 12 weeks. The control group will initially undergo standard of care for 12 weeks. Afterwards, the patients in the control group will be randomized into one of the two intervention arms and will also receive treatment twice a week for 12 weeks. This approach has the advantage of providing a sufficiently large sample for both comparing overall exercise therapy with the control group and comparing the two types of exercise therapy. In addition, this design allows all participating patients to receive exercise therapy. By individually measuring the hypothetical One-Repetition Maximum (h1-RM) and conducting a cardiopulmonary exercise testing (CPET) on a cycle ergometer, a tailored individual training program based on current performance will be offered to the patient. BREATH exercise begins with moderate exertion and is progressively increased during the course of the study participation (see chapter interventions for a detailed description). Outcome measurement will be at baseline (t\u003csub\u003e0\u003c/sub\u003e), after 12 weeks (t\u003csub\u003e1\u003c/sub\u003e) and after 24 weeks (t\u003csub\u003e2\u003c/sub\u003e) leading to a maximum study participation of six months (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The Ethics Committee of the Medical Faculty University of Duisburg-Essen approved this study (22-10522-BO) in December 2023.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eInclusion criteria of the BREATH Study\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInclusion criteria\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExclusion criteria\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026bull; Patients with histologically confirmed non-small cell lung carcinoma in UICC stages IIIB, IIIC and IV\u003c/p\u003e\u003cp\u003e\u0026bull; First- or second-line therapy (inclusion up to 28 days after the first cycle) in palliative intention\u003c/p\u003e\u003cp\u003e\u0026bull; Age\u0026thinsp;\u0026ge;\u0026thinsp;18 years\u003c/p\u003e\u003cp\u003e\u0026bull; Signed informed consent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026bull; Severe cardiopulmonary disease (EF\u0026thinsp;\u0026lt;\u0026thinsp;30%)\u003c/p\u003e\u003cp\u003e\u0026bull; Newly occurring or progressive uncontrolled CNS (central nervous system) metastases\u003c/p\u003e\u003cp\u003e\u0026bull; Expected life expectancy\u0026thinsp;\u0026lt;\u0026thinsp;3 months\u003c/p\u003e\u003cp\u003e\u0026bull; Bone metastases with acute risk of fracture\u003c/p\u003e\u003cp\u003e\u0026bull; ECOG (Eastern Cooperative Oncology Group) performance status\u0026thinsp;\u0026gt;\u0026thinsp;2\u003c/p\u003e\u003cp\u003e\u0026bull; Acute pulmonary embolism\u003c/p\u003e\u003cp\u003e\u0026bull; Acute myocardial infarction\u003c/p\u003e\u003cp\u003e\u0026bull; Requiring surgery for aortic aneurysm\u003c/p\u003e\u003cp\u003e\u0026bull; Tension pneumothorax\u003c/p\u003e\u003cp\u003e\u0026bull; Lack of proficiency in the German language\u003c/p\u003e\u003cp\u003e\u0026bull; Active infection\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e Patients with NSCLC at the West German Cancer Center (University Hospital Essen and University Medicine Essen \u0026ndash; Ruhrlandklinik) will be identified by the treating physicians, specialist nurses, by screening patients presented at the multidisciplinary tumor board, or by systematically screening patients receiving routine follow-up scans during first-line treatment. Informed consent will be obtained by the treating physician. After study inclusion, exercise assessment (baseline) followed by randomization will be performed.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eObjectives\u003c/h2\u003e\u003cp\u003eThe primary objective is to achieve an improvement in aerobic capacity (VO\u003csub\u003e2\u003c/sub\u003e peak) from t0 to t1 through exercise therapy compared to standard of care. As a secondary objective, we aim to examine whether there is a difference between the two exercise therapies regarding the performance improvement (VO\u003csub\u003e2\u003c/sub\u003e peak) from the beginning of the therapy to the end of the therapy (either t2 compared to t1 or t1 compared to t0, depending on the randomization arm). Other secondary objectives are to assess changes in quality of life, fatigue, dyspnea during the study participation and evaluation adherence to the intervention, dropout rates, adverse events, and tumor therapy response.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eVariables and Data Collection\u003c/h3\u003e\n\u003cp\u003eThe full variables of the BREATH study are displayed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Anthropometric and medical data includes the following variables: Age, weight, highest education, marital status, date of first cancer diagnosis, tumor diagnosis, tumor stage, TNM classification, first-line or second-line treatment, histology, metastasis and location, PD-L1 expression and molecular pathology based on sequence analyses.\u003c/p\u003e\u003cp\u003eTobacco use plays a major role in the development of lung tumors and poorer cardiopulmonary performance. To fully understand this variable, the following items are asked: pack years and current smoking status (current smoker, non-smoker and former smoker). A former smoker is defined as a person who has quit smoking for longer than the last 12 months. To capture this category, the abstinence date is also queried. The dose of cigarettes smoked is categorized as light smoker (persons who smoke a low number of cigarettes per day, typically less than 10 cigarettes), moderate smoker (persons who smoke a moderate number of cigarettes per day, typically between 10 and 20 cigarettes) and heavy smoker (persons who smoke a high number of cigarettes per day, typically more than 20 cigarettes).\u003c/p\u003e\u003cp\u003eIn general, a comparison for or all primary and secondary outcomes will be conducted between both exercise arms and the control arm and additionally between the two exercise arms (either t\u003csub\u003e2\u003c/sub\u003e compared to t\u003csub\u003e1\u003c/sub\u003e or t\u003csub\u003e1\u003c/sub\u003e compared to t\u003csub\u003e0\u003c/sub\u003e, depending on the randomization arm).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSpirit figure of the trial data collection points\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEnrollment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAllocation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003ePost-allocation\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTIMEPOINT\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003e-t\u003c/em\u003e\u003csub\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sub\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003et\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\u003cp\u003e\u003csub\u003e\u003cem\u003einclusion week 0\u003c/em\u003e\u003c/sub\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003et\u003c/em\u003e\u003csub\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sub\u003e\u003c/p\u003e\u003cp\u003e\u003csub\u003e\u003cem\u003e(12 weeks)\u003c/em\u003e\u003c/sub\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003et\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003c/p\u003e\u003cp\u003e\u003csub\u003e\u003cem\u003e(24 weeks)\u003c/em\u003e\u003c/sub\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEnrollment:\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEligibility screen\u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInformed consent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAllocation\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eINTERVENTIONS\u003c/b\u003e:\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eArm A (aerobic exercise+\u003c/p\u003e\u003cp\u003estrength training)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStudy End\u003c/p\u003e\u003cp\u003eArm A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eArm B (aerobic exercise)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStudy End\u003c/p\u003e\u003cp\u003eArm B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eArm C (Usual Care)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCrossover\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eStudy End\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eASSESSMENTS\u003c/b\u003e:\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eAnthropometric data and medical history\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eSmoker status\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eTumor stage and histology\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eMolecular pathology\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eAnti-tumor therapy\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eBlood sampling\u003c/em\u003e\u003csup\u003e\u003cb\u003e4\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eUrin sampling\u003c/em\u003e\u003csup\u003e\u003cem\u003e5\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eCPET Maximum oxygen uptake (VO2 peak [ml/min/kg])\u003c/em\u003e\u003csup\u003e\u003cem\u003e6\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ePatient related outcomes measurements\u003c/em\u003e\u003csup\u003e\u003cb\u003e7\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eArterial blood pressure (mmHg)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eChange in ECG (PQ, QRS, and QTc intervals)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eFeasibility of exercise\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eAdverse Events and SAE\u003c/em\u003e\u003csup\u003e\u003cb\u003e7\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eTreatment scheme (change of dose or frequency)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e1\u003c/sup\u003eCheck Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e for inclusion criteria\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e2\u003c/sup\u003eAllocation to intervention groups will be done after completion of baseline assessment. Following randomization strata will be used: 1. Histological stratification (non-squamous vs squamous) 2. Forced expiratory Volume in 1 second (FEV1)\u0026thinsp;\u0026gt;\u0026thinsp;50 and under \u0026lt;\u0026thinsp;50\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003csup\u003e3\u003c/sup\u003eRandomization of the control group based on the same strata used for the first randomization.\u003c/p\u003e\u003cp\u003e\u003csup\u003e4\u003c/sup\u003eBlood sampling will be done at every visit for anti-cancer treatment mostly every 3 weeks until study ends. Cisplatin based treatments 1\u0026thinsp;+\u0026thinsp;8 day followed by 3 weeks. Carboplatin and Docetaxel d1 q3w.\u003c/p\u003e\u003cp\u003eBlood sampling consists of BNP, high-sensitive troponin T/I as heart markers, Hemoglobin [g/dl], Erythrocytes [count/pl], Leukocytes [count/nl], Lymphocytes [count/nl], Neutrophils [count/nl], C-reactive protein [mg/dl], Cytokeratin-19 Fragment, CYFRA 21\u0026thinsp;\u0026minus;\u0026thinsp;1 [ng/ml]\u003c/p\u003e\u003cp\u003e\u003csup\u003e5\u003c/sup\u003e Urine (3 mL) and blood (1.5 mL) (EDTA anti-coagulated) will be collected for Nuclear Magnetic Resonance (NMR)-based metabolome analysis\u003c/p\u003e\u003cp\u003e\u003csup\u003e6\u003c/sup\u003eFull variable of CPET consisting of: Forced vital capacity [L], maximal voluntary ventilation [L/min], forced expiratory volume in 1 second, one-second capacity [L], relative one-second capacity, tiffeneau index [ %]\u003c/p\u003e\u003cp\u003epmax [Watt], HR [Beats/minute], BP [mmHg], O2-Saturation in [%], Breathing reserve [%], Ventilatory Threshold 1 [ml/min], Ventilatory Threshold 2 [ml/min] max O2-Pulse [ml/beat], Ventilatory Equivalent for Carbon Dioxide Slope, partial pressure in the arterial blood [mmHg], O2 partial pressure in the arterial blood [mmHg], Dead Space Volume/Tidal volume, P(A-a)O2, Oxygen Consumption/work load, respitory exchange ratio (RER), pH value, PAO2 [mmHg], SaO2 [%], PCO2 [mmHg], BE [mmol/l], HCO3 [mmol/l], SBCe [mmol/l]\u003c/p\u003e\u003cp\u003e\u003csup\u003e7\u003c/sup\u003e To be filled out by patient: EORTC-QLQ-C30 - lung cancer specific LC13 and Functional Assessment of Cancer Therapy-Fatigue-Scale\u003c/p\u003e\u003cp\u003e\u003csup\u003e8\u003c/sup\u003eAdverse Events/Serious Adverse Events related to exercise will be documented weekly by the exercise therapist in combination with the study nurse after the manual of Common Terminology Criteria for Adverse Events (CTCAE) v5.0. and CTCAE after the cardio-oncology guidelines\u003c/p\u003e\n\u003ch3\u003eRandomization\u003c/h3\u003e\n\u003cp\u003ePatients will be randomized into one of three study arms (Arm A: endurance\u0026thinsp;+\u0026thinsp;resistance training, Arm B: endurance training\u0026thinsp;+\u0026thinsp;breathing exercises, Arm C: control group\u0026thinsp;=\u0026thinsp;usual care\u0026thinsp;+\u0026thinsp;exercise recommendation (following the guidelines of the American College of Sports Medicine) using a web-based tool (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://randomizer.at\u003c/span\u003e\u003cspan address=\"https://randomizer.at\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The allocation ratio is 2:1:1 for the first randomization into the control arm and two exercise arms followed by a 1:1 randomization of the original control group. Randomization is conducted after baseline assessment and is stratified based on the following two criteria to ensure balanced distribution of prognostic factors across all groups:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eHistological stratification (non-squamous vs squamous)\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eSquamous and non-squamous lung cancer differs by underlying biology, molecular characteristics, and response patterns to systemic therapy.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eForced expiratory Volume in 1 second (FEV1)\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eFEV1 is a crucial measurement of lung function and is highly associated with VO\u003csub\u003e2\u003c/sub\u003e peak. In advanced lung cancer patients, impairment of pulmonary function is common. FEV1 will be divided into two classifications: Mild to moderate COPD - FEV1 is equal or greater than 50% of predicted value; and severe to very severe COPD - FEV1 lower than 50% of predicted value.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe minimization method is used for stratified sampling [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]. Due to the nature of the intervention, participant blinding and concealment of randomization is not feasible. However, the assessors of functional testing for VO2 peak will not be aware of the treatment allocation.\u003c/p\u003e\n\u003ch3\u003eCardiopulmonary exercise testing\u003c/h3\u003e\n\u003cp\u003eCPET will be carried out to assess the patient's cardiopulmonary performance using the cycle ergometer in a semi-recumbent position. Through a breathing mask, inhaled and exhaled air can be analyzed, enabling a precise calculation of oxygen uptake (VO\u003csub\u003e2\u003c/sub\u003e) and carbon dioxide output (VCO\u003csub\u003e2\u003c/sub\u003e). To assess participants peak oxygen uptake (V0\u003csub\u003e2\u003c/sub\u003e peak), a ramp protocol will be utilized. This diagnostic procedure is characterized by high precision in determining the anaerobic threshold through the ratio of VO\u003csub\u003e2\u003c/sub\u003e to VCO\u003csub\u003e2\u003c/sub\u003e. The V0\u003csub\u003e2\u003c/sub\u003e peak is considered a crucial factor in aerobic performance. Cardiopulmonary exercise testing also proves to be a safe diagnostic tool for advanced lung cancer patients [\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003ePhysical function based on the hypothetical 1-Repition maximum (h1-Rm)\u003c/h3\u003e\n\u003cp\u003eThe one-repetition maximum (1RM) is a test to determine the maximum weight that the patient can move within a predefined range of motion. The test procedure for measurement of maximum strength is characterized by high reliability. As the one-repetition maximum represents an increased risk of injury in patients, there is the possibility of calculating the hypothetical one-repetition maximum (h1-Rm). For this purpose, the Brzycki formula is used and the maximum force can be calculated from this after the exercise and reduce the risk of injury or other adverse events [\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e].\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eQuestionnaires\u003c/h2\u003e\u003cp\u003eThe Functional Assessment of Chronic Illness Therapy \u0026ndash; Fatigue (FACIT-Fatigue) questionnaire comprises 13 questions aimed at assessing self-reported fatigue and its impact on daily activities and physical function [\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e, \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e]. The EORTC QLQ-C30/LC13 is a tumor entity-specific questionnaire designed to assess the quality of life in patients with lung cancer. The EORTC QLQ-C30/LC13 captures functional parameters (physical functioning, role functioning, cognitive functioning, emotional functioning), symptom scales (pain, fatigue, nausea and vomiting), Global Quality of Life, and Global Health Status. Additionally, patients can indicate individual items that were symptomatic in the past week [\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e, \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e]. The questionnaires are self-administered by patients at each time point, if study personnel need to assist it will be documented in the trials management.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eExercise Adherence\u003c/h3\u003e\n\u003cp\u003eFeasibility parameters include recruitment rate, drop-out rate and adherence to the training will be measured and documented by the responsible exercise therapist. All withdrawals will be considered as dropouts, with reasons noted and compared between each study arm. This provides a straightforward comparison of the raw dropout counts between groups. The percentage of participants who dropped out will also be calculated for each study arm relative to the total number of participants initially assigned to that arm. Adherence based on the absolute numbers of scheduled exercise sessions, both absolute and percentage-based adherence can be calculated and compared between study arms. Adherence to the protocol is defined as completing at least 75% of the possible training sessions.\u003c/p\u003e\n\u003ch3\u003eInterventions\u003c/h3\u003e\n\u003cp\u003eIntervention (Arm A) is a supervised exercise program combining endurance training and resistance training. Participants conduct two exercise sessions each week, with each session lasting 60 minutes. The breakdown of these sessions involves 20 minutes dedicated to endurance training and 40 minutes to resistance training. Aerobic interval training is characterized by an intensity set at 50% of the participants' maximal workload, determined through CPET. This approach aims to optimize cardiovascular fitness through controlled and targeted aerobic exercises. Resistance training targeting major muscle groups during each session. The exercise protocol prescribes two sets of each resistance exercise, with participants completing 8\u0026ndash;12 repetitions per set. The training intensity for resistance exercises is progressive increased within a range of 50\u0026ndash;80% of the participants' h1-RM. This tailored approach allows for a progressive and adaptive response, ensuring that participants are appropriately challenged while minimizing the risk of overexertion. The initiation phase, scheduled for week one, is characterized by an intentional starting point at 30% of participants' maximum capacity. The primary objective during this initial phase is to prepare the muscles for subsequent exertion while concurrently fostering an increased awareness of the body's responses to the introduced exercise stimuli.\u003c/p\u003e\u003cp\u003eArm B focuses exclusively on supervised aerobic exercise followed by breathing exercise. Participants in Arm B engage in exercise twice per week, with each session lasting 30 minutes intensity interval training. The endurance training in Arm B adopts an interval-based method to strike a balance between exertion and recovery. The training intensity is set at 50% of the participants' maximal workload and is increasing during the intervention to 80% of maximal workload. The structured intervals involve 10 sets of two minutes of exertion alternated with 10 sets of one minute for recovery, resulting in a total exercise time of 30 minutes per session. This design aims to challenge participants' aerobic capacity while providing adequate recovery intervals.\u003c/p\u003e\u003cp\u003eA pulse oximeter is employed for measuring heart rate and oxygen saturation to ensure safety. Additionally, the Borg-CR scale is utilized to assess subjective dyspnea after every second interval, providing a qualitative measure of perceived exertion and discomfort. Termination criteria are established to guide the conditions for stopping exercise within treatment arms: oxygen saturation\u0026thinsp;\u0026lt;\u0026thinsp;85% without increase during recovery and subjective increase in Borg-CR scale indicating severe dyspnea.\u003c/p\u003e\u003cp\u003eThe control group receives a one-time physical activity consultation with general information about daily activities and exercise participation, as well as individual training recommendations. After 12 weeks, the control group will be randomized into one of the exercise groups.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eMetabolic fingerprinting\u003c/h2\u003e\u003cp\u003eVenous blood (EDTA) and urine samples from all participants are collected at the onset of the first session and subsequently every 12 weeks until the conclusion of the study. Both sample types are subjected to centrifugation at 900 xg at 4\u0026deg;C for 10 minutes, and the resulting supernatant is stored at -80\u0026deg;C for future analysis.\u003c/p\u003e\u003cp\u003eFor metabolomic analysis, the samples are diluted with specific urine and plasma diluents, and sodium trimethylsilylpropanesulfonate is added as an NMR standard.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eEvaluation of the intervention and patient centered interviews\u003c/h2\u003e\u003cp\u003eQuantitative and qualitative data are collected as part of the evaluation process [\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e]. The quantitative component focuses on participants\u0026rsquo; satisfaction with various aspects of the exercise intervention. A self-developed online questionnaire assesses elements such as the structure and delivery of the intervention, organizational aspects, and support provided by the trainer team. Responses are recorded on a five-point Likert scale (\u0026ldquo;strongly disagree\u0026rdquo; to \u0026ldquo;strongly agree\u0026rdquo;), and sociodemographic information is also collected. Open-ended items allow participants to elaborate on their responses and provide detailed feedback. The survey is distributed to all participants, and data are analyzed descriptively. Frequency distributions, means, medians, standard deviations, and modes describe satisfaction levels and variability. Subgroup comparisons (e.g., age, intervention format) help identify potential differences. Free-text responses are analyzed using qualitative content analysis [\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e, \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e], enabling systematic coding and inductive category development.\u003c/p\u003e\u003cp\u003eThe qualitative component consists of episodic interviews with a purposive sample of approximately fifteen participants. While participants are comparable in terms of their underlying medical condition, the sample is deliberately selected to reflect diversity in other relevant characteristics. Selection is based on factors such as age, gender, and symptom burden to capture a broad range of experiences.\u003c/p\u003e\u003cp\u003eThe number of interviews is guided by data saturation and may be adjusted as needed. The interviews explore perceived changes in quality of life, physical well-being, self-efficacy, and sustained physical activity. The episodic format captures both specific experiences and broader reflections. Transcripts are analyzed using qualitative content analysis according to Kuckartz [\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e], a method well suited to identifying thematic patterns in narrative data.\u003c/p\u003e\u003cp\u003eFindings from both components are expected to inform the development and refinement of future exercise interventions. Combining structured satisfaction data with personal narratives supports improvements that are both evidence-informed and participant-centered [\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eSample size calculation\u003c/h2\u003e\u003cp\u003eThe sample size calculation is based on the primary endpoint of the improvement in VO\u003csub\u003e2\u003c/sub\u003e peak after 12 weeks (t\u003csub\u003e1\u003c/sub\u003e) compared to baseline (t\u003csub\u003e0\u003c/sub\u003e). Using a study by Quist et al. [\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e], where VO\u003csub\u003e2\u003c/sub\u003e peak was measured in patients with advanced lung cancer before and after a 6-week exercise therapy, an assumed mean difference of 0.1 is considered between the exercise therapy groups and the control group. Additionally, a standard deviation of 0.18 is assumed [\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e]. With a one-sided t-test assuming equal variances at a significance level of 0.05 and a power of 0.80, 41 patients are required in the control group and 41 patients in the exercise therapy groups. Considering that approximately 15% of deaths are expected after 24 weeks due to disease progression [\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e], a dropout rate of 20% is assumed, resulting in the inclusion of 52 patients per group (52 patients in the control group, 26 patients in Arm A, and 26 patients in Arm B).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eData Analysis\u003c/h2\u003e\u003cp\u003eStatistical analyses of the primary and secondary endpoints will be conducted on the Intention-To-Treat (ITT) population. As a sensitivity analysis, the analyses will also be performed on the Per-Protocol (PP) population. The primary endpoint of the improvement in VO\u003csub\u003e2\u003c/sub\u003e peak after 12 weeks (t\u003csub\u003e1\u003c/sub\u003e) compared to baseline (t\u003csub\u003e0\u003c/sub\u003e) will be assessed using a one-sided two-sample t-test assuming equal variances at a significance level of α\u0026thinsp;=\u0026thinsp;0.05. In addition, a linear regression will be applied, adjusting for age, sex, non-squamous vs squamous and FEV1. All secondary analyses will be exploratory, meaning without adjustment of the significance level for multiplicity, and will be conducted using standard methods of statistical inference. Quantitative variables (including test scores) will be analyzed using univariable and multivariable linear regression to detect differences between the groups. Dichotomous variables will be analyzed using a univariable and a multivariable generalized linear model with identity link in order to estimate absolute risk differences. Event times will be analyzed using univariable and multivariable Cox regression, and Kaplan-Meier curves will be illustrated for event times. Subgroup analyses will be conducted based on age, gender, and first or second-line treatment. Adverse events will be documented and reported to the responsible physician during the study. Details of the statistical analyses will be specified in a Statistical Analysis Plan (SAP) prior to the start of analysis.\u003c/p\u003e\u003cp\u003eThe processing of NMR-based metabolomic data will be performed using an adapted version of the AlpsNMR package in R, which includes baseline correction, spectra alignment based on sodium trimethylsilylpropanesulfonate (DSS), and total intensity normalization [\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e]. The statistical analyses will include principal component analysis (PCA) with robust outlier detection. Loadings between |0.7| and |1| will be employed to identify the main determinants of the observed changes in the blood metabolome. The identification of the underlying substances in the PCA will be conducted using the Human Metabolome Database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://hmdb.ca/\u003c/span\u003e\u003cspan address=\"https://hmdb.ca/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Furthermore, partial least squares (PLS) analysis will be used to correlate these changes in the metabolome with other clinical and biochemical parameters, thereby identifying the main drivers of plasma metabolome changes. Pearson correlation will be employed for numeric data with a linear relationship and normal distribution, while Spearman correlation will be used for rank data or non-linear relationships. Correlations between 0.7 and 1.0 (or -0.7 and \u0026minus;\u0026thinsp;1.0) are generally considered strong, while correlations between 0.4 and 0.7 (or -0.4 and \u0026minus;\u0026thinsp;0.7) are moderate. Correlations with a p-value less than 0.05 are considered statistically significant.\u003c/p\u003e\u003cp\u003eMetabolic data analysis utilizing the R package ALPs was modified by researchers at the Children\u0026rsquo;s Hospital 2, University Hospital Essen, to meet the particular requirements of this study.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003ePatient and public involvement\u003c/h2\u003e\u003cp\u003e A patient representative from the patient advisory board Essen was involved in the development of the BREATH study. To disseminate results, they will be published and presented on expert conferences. In addition, patient support groups will receive all the necessary information created by BREATH.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eData Management\u003c/h2\u003e\u003cp\u003eThe BREATH study team will work closely with the Institute for Medical Informatics, Biometry and Epidemiology (IMIBE) and the Centre for Clinical Trials Essen (ZKSE). All study data will be documented on standardized case report forms and recorded with a good clinical practice (GCP)-compliant clinical data management system. The data will be checked for completeness and plausibility during the entire study period in order to guarantee a high data quality. The study database created for this purpose minimizes invalid data by performing automatic plausibility checks and highlighting missing values.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe BREATH trial addresses the unmet need for targeted exercise therapy interventions for advanced NSCLC patients, considering the challenges posed by the disease and its treatment. The proposed trial design and patient involvement strategies aim to address existing gaps in the literature and enhance the understanding of the potential cardiopulmonary benefits of exercise therapy in this specific patient population. Furthermore, our study design offers the benefits of having a control group while all patients will be receiving exercise therapy. Especially lung cancer patients are not aware of the potential benefits of exercise and maintaining physical activity during palliative treatment [\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e, \u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e]. In palliative treatment settings, longer or more intensive training sessions can be a barrier for patients. Therefore, it needs to be assessed whether a shorter exercise intervention focusing on endurance parameters can generate improved adherence or even have more positive influence on patient-relevant endpoints, enhancing both quality of life and maximum oxygen uptake through combined endurance and strength training. BREATH can spread awareness based on the results in this specific population of advanced NSCLC patients. In addition the high amount of comorbidities can be directly linked with shorter survival time and increased costs for therapies. Furthermore, the BREATH study offers insights of exercise therapy during active immunotherapy treatment with a sufficient sample size. Several theoretical and mouse model studies have highlighted the potential of combining exercise therapy with immunotherapy, although there's a lack of evidence from clinical trials [\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e]. Currently, multiple trial protocols are listed on clinicaltrials.gov aiming to investigate the impact of exercise therapy during immunotherapy, including NCT06026111 [\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e], NCT04866810 [\u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e], NCT06152926 [\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e], NCT04645680 [\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e] and NCT04263467 [\u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e]. The ERICA study currently investigates the effects of aerobic exercise within one hour prior to immunotherapy (pembrolizumab) in combination with chemoptherapy (platinum-based) in metastatic NSCLC patients. ERICA study will investigate the impact of aerobic exercise on immune biomarkers (NK cells, B lymphocytes, T lymphocytes, monocytes, subpopulations of dendritic cells on frozen PBMC, plasma biomarkers of sarcopenia and inflammation [\u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo complement clinical and physiological outcomes, the BREATH trial also includes a structured evaluation of the intervention from the patient perspective. By combining quantitative satisfaction surveys and qualitative interviews, the evaluation provides important insights into feasibility, acceptance, and individual experiences with the intervention. These findings will help refine future exercise programs for this vulnerable population.\u003c/p\u003e\u003cp\u003eConsequently, BREATH has the potential to contribute evidence to the emerging field of immunotherapy combined with exercise therapy in a vulnerable patient cohort defined by high symptom burden and low quality of life.\u003c/p\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eTrial status\u003c/h2\u003e\u003cp\u003eRecruitment did start on 1. June 2024.The first patient was enrolled on June 12, 2024. As of the current date (August 27, 2025), a total of 25 patients have been enrolled in the BREATH study. Estimated end of enrollment/recruitment is planned for December 2026. Protocol Version 1.1 date: 27.08.2025\u003c/p\u003e\u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003cp\u003eCOPD chronic obstructive pulmonary disease\u003c/p\u003e\u003cp\u003eNSCLC Non-small-cell lung cancer\u003c/p\u003e\u003cp\u003eUICC Union for International Cancer Control\u003c/p\u003e\u003cp\u003eICI Immune checkpoint inhibitors\u003c/p\u003e\u003cp\u003ePD-1 Programmed Cell Death Protein 1\u003c/p\u003e\u003cp\u003eCTLA-4 Cytotoxic T-Lymphocyte-Associated Protein 4\u003c/p\u003e\u003cp\u003eNMR Nuclear Magnetic Resonance\u003c/p\u003e\u003cp\u003eBNP Brain natriuretic peptide\u003c/p\u003e\u003cp\u003eMACE major adverse cardiac event\u003c/p\u003e\u003cp\u003eh1-RM hypothetical one repetition maximum\u003c/p\u003e\u003cp\u003eCPET Cardiopulmonary exercise testing\u003c/p\u003e\u003cp\u003eITT Intention-To-Treat\u003c/p\u003e\u003cp\u003ePP Per-Protocol\u003c/p\u003e\u003cp\u003eDSS Sodium trimethylsilylpropanesulfonate\u003c/p\u003e\u003cp\u003ePCA Principal component analysis\u003c/p\u003e\u003cp\u003ePLS partial least squares\u003c/p\u003e\u003cp\u003eIMIBE Institute for Medical Informatics, Biometry and Epidemiology\u003c/p\u003e\u003cp\u003eZKSE Centre for Clinical Trials Essen\u003c/p\u003e\u003cp\u003eGCP Good clinical practice\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eConsent for publication\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\u003cp\u003e Ethical approval for the study was obtained from the Ethics Committee of the Medical Faculty University of Duisburg-Essen under the following number: 22-10522-BO.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cp\u003eThe authors declare no competing interests within the BREATH study.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eBREATH is funded by the German Cancer Aid (Deutsche Krebshilfe). The funders had no role in\u003c/p\u003e\u003cp\u003ethe design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit result.\u003c/p\u003e\u003ch2\u003eAuthors\u0026rsquo; contributions\u003c/h2\u003e\u003cp\u003eMT is the principal investigator of the BREATH trial. She conceived the study, leads all study activities. EMH, NK, and AS are the study biostatisticians and co-investigators. They contributed to the study design, managed statistical analyses. MTz and RM are the study cardiology co-investigators. They contributed to the design and interpretation of cardiology assessments, oversaw participant evaluations in cardiology. MW is the lead for study recruitment. He coordinated participant enrollment across clinical sites and the oncology expert in lung cancer. NDL and MG are the study exercise scientists and co-investigators. They contributed to the conception and implementation of the physical activity components of the trial. JJ is responsible for the metabolomic sub-study. He coordinated biosample processing and analysis, including NMR-based metabolic fingerprinting of blood and urine samples. All Authors read, edited and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe acknowledge support by the Open Access Publication Fund of the University of Duisburg-Essen.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\u003cp\u003eNot available at this point.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRobert Koch-Institut, Herausgeber, Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V, Herausgeber. Krebs in Deutschland f\u0026uuml;r 2019/2020. 14. Ausgabe. 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Front Immunol. 2023;14:849502.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGustafson MP, Wheatley-Guy CM, Rosenthal AC, Gastineau DA, Katsanis E, Johnson BD et al. Exercise and the immune system: taking steps to improve responses to cancer immunotherapy. J Immunother Cancer. 2021;9(7).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDieli-Conwright C, Dana-Farber Cancer Institute. Feasibility and Preliminary Efficacy of Exercise During Immunotherapy in Patients With Lung Cancer: The INHALE Trial [Internet]. ClinicalTrials.gov. 2024 [cited 2024 Apr 15]. 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Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://classic.clinicaltrials.gov/ct2/show/NCT04263467\u003c/span\u003e\u003cspan address=\"https://classic.clinicaltrials.gov/ct2/show/NCT04263467\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGouez M, P\u0026eacute;rol O, P\u0026eacute;rol M, Caux C, M\u0026eacute;n\u0026eacute;trier-Caux C, Villard M, Walzer T, Delrieu L, Saintigny P, Marijnen P, Pialoux V, Fervers B. Effect of acute aerobic exercise before immunotherapy and chemotherapy infusion in patients with metastatic non-small-cell lung cancer: protocol for the ERICA feasibility trial. BMJ Open. 2022;12(4).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"advanced lung cancer, NSCL, exercise, palliative treatment, VO2 peak","lastPublishedDoi":"10.21203/rs.3.rs-7271256/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7271256/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Lung cancer is one of the most common cancers in Germany, with around 56,000 new cases diagnosed in 2020. Approximately 65% are diagnosed at advanced stages, where symptoms such as fatigue, pain, dyspnea, and weight loss are prevalent. These patients often suffer from cardiovascular and pulmonary comorbidities, which interact with treatment toxicity, outcome and increase treatment costs. Although exercise therapy is proven to alleviate cancer-related symptoms and to improve quality of life, current lung cancer treatment guidelines fail to adequately prioritize its crucial role.\u003c/p\u003e\u003cp\u003eMethods: The Better symptom contRol with Exercise in pAtients wiTH advanced non-small cell lung cancer (BREATH) study is a prospective, three-arm randomized controlled trial (RCT) designed to assess the impact of exercise therapy on patients with advanced NSCLC (stage IIIB-IV) who are receiving first- or second-line systemic therapy) in the palliative setting. Patients are randomized in a 2:1:1 ratio into a control group (receiving exercise recommendations) or one of two intervention arms: endurance training and breathing exercise or combined endurance and resistance training. The intervention groups will exercise twice a week for 12 weeks. The control group participants will be randomized again in a 1:1 ratio into one of the two intervention arms after completion of the control period. The study will assess outcomes at baseline, 12 weeks, and 24 weeks. The primary outcome is improvement of aerobic capacity (VO\u003csub\u003e2\u003c/sub\u003e peak). Secondary outcomes include quality of life, fatigue, adherence to exercise and adverse events. Patient representatives were involved in all stages of protocol development.\u003c/p\u003e\u003cp\u003eDiscussion: The BREATH study addresses a significant gap in the current management of advanced lung cancer treatment by evaluating the impact of different exercise treatment protocols to reduce symptoms and improve clinical outcome. The study design and exercise program aim to enhance adherence and optimize patient related outcomes. The results of the BREATH study have the potential to influence future guidelines and improve the management of patients with advanced NSCLC.\u003c/p\u003e\u003cp\u003eTrial registration ClinicalTrials.gov NCT registered on the 18. April 2024 (NCT06374160)\u003c/p\u003e","manuscriptTitle":"Improving aerobic capacity in patients with advanced non-small cell lung cancer: study protocol of the 3-armed randomized controlled BREATH trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-24 16:34:48","doi":"10.21203/rs.3.rs-7271256/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-11-12T09:37:08+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-12T09:36:35+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-01T12:08:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-08-29T07:39:17+00:00","index":"","fulltext":""},{"type":"decision","content":"Major revision","date":"2025-08-21T04:14:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"883d6a53-8f46-44ec-84b9-68921c49c0b0","owner":[],"postedDate":"November 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T16:48:46+00:00","versionOfRecord":{"articleIdentity":"rs-7271256","link":"https://doi.org/10.1186/s13063-025-09416-2","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2026-01-17 16:30:15","publishedOnDateReadable":"January 17th, 2026"},"versionCreatedAt":"2025-11-24 16:34:48","video":"","vorDoi":"10.1186/s13063-025-09416-2","vorDoiUrl":"https://doi.org/10.1186/s13063-025-09416-2","workflowStages":[]},"version":"v1","identity":"rs-7271256","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7271256","identity":"rs-7271256","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}