“EXHALE”: exercise as a strategy for rehabilitation in advanced stage lung cancer patients: a randomized clinical trial comparing the effects of 12 weeks supervised exercise intervention versus usual care for advanced stage lung cancer patients

Eligible patients >18 years with a WHO performance status 0–2 with stage IIIb-IV NSCLC and SCLC-ED who are undergoing chemotherapy at the Department of Oncology are randomized to standard care or a 12 week physical and psycho-social intervention (Figure 1). Randomization is stratified for sex and lung cancer type (NSCLC or SCLC). Randomization is performed by the Copenhagen Trial Unit (CTU). Exclusion criteria are: brain or bone metastases; prolonged bone marrow suppression; anti-coagulant treatment; symptomatic heart disease, including congestive heart failure, arrhythmia or myocardial infarction diagnosed within the last three months; and inability to provide informed consent.

Patients who are randomized to the control group receive no training but are offered participation in the supervised training after completion of antineoplastic treatment, starting no earlier than twelve weeks after initiation of chemotherapy. Patients in early 2nd line treatment (“switch maintenance”) will be offered training after 12 weeks, although they have not necessarily completed chemotherapy.

The supervised training is carried out in groups of 12–16 patients and each session has a duration of 1.5 hours, is administered twice weekly and is supervised by a research physiotherapist. The training comprises warm up exercises, strength and fitness training as well as stretching. Warm up exercises consist of 10 minutes of light, stationery cycling, adjusted to 60-90% of the patient’s maximum HR. Strength training is carried out using 6 machines (Technogym: Leg press, chest press, lateral machine, leg extension, abdominal crunch, and lower back). The practical aim of strength training is to complete 3 series of 5–8 sets, with 70-90% of 1RM. The exercises are specifically selected to involve the largest possible number of muscle groups in the least number of exercises. To ensure progression in strength training, each patient is instructed in carrying out the 1RM test using each of the above-mentioned strength training machines once every second week, after which their program will be adjusted. Cardiovascular training is carried out as interval training on stationery bikes. Intensity is equivalent to 85-95% of each patient’s maximum HR and lasted approximately 10–15 minutes. After the training session, 5–10 minutes are dedicated to stretching the large muscle groups in order to increase agility. Following each training session, progressive relaxation of 15–20 minutes is performed.

Each patient is screened by a clinical nurse specialist prior to participating in each physical training session and before the physiological tests [35]. If one of the following criteria are met, the patient is prohibited from exercising/being tested on that day: diastolic blood pressure <45 or >95, heart rate (HR) at rest >115/min, temperature > 38°C, respiratory rate at rest >30/min, infection requiring treatment, fresh bleeding, total leucocyte count <1.0 10⁹/L or platelets <50 10⁹/L. Physical tests and HRQOL evaluation are performed at baseline and after six weeks of training.

Outcomes will be assessed at baseline (prior to randomization), 12 weeks and 12 months (Table 1). Baseline assessments involve a medical history; disease and treatment status is recorded from medical records and subjects will complete patient reported outcome (PRO) questionnaires, aerobic capacity (VO₂peak (Cardio-Pulmonary Exercise Test (C-PET)), muscle strength (1RM), Functional capacity (6 Minute Walk Test (6MWT)).

The primary endpoint will be VO₂ peak, as assessed with an aerobic capacity incremental C-PET on a cycle ergometer (Monark, ergomedic 839E). The C-PET is carried out by a physiotherapist who is blinded to the patient’s study group allocation. The test consists of a warm-up phase 2–4 minutes of cycling at a sub maximal load (10–50 watts). After the warm-up period the load increases after a short break (<2 minutes) by 5–10 watts every minute, until exhaustion or a possible symptom limitation (e.g. dizziness, sudden pain, vomiting sensation). Expired gases are analyzed continuously by a metabolic breath-by-breath analysis and calculated as an average over 15 seconds using the Oxycon Pro, Jaeger measurement system. During the C-PET, oxyhemoglobin saturation and heart rate is continuously monitored. After each test, maximum ventilation, respiratory exchange ratio (RER), possibly plateau in the increase in VO2, self-perceived exertion perception in the final seconds of the C-PET and maximal heart rate (Polar Team System 2, Polar, Finland) are recorded. Rating of perceived exertion is evaluated at the end of each workload using the modified Borg Scale. The primary outcome will be a comparison of VO₂ peak in the intervention and control arms at the conclusion of the intervention (i.e. at the 12-week assessment).

Muscle strength is measured by the one repetition maximum (1RM) [36] test using a Technogym™ that includes a leg press (lower extremity), chest press (pectoral muscles), lateral machine (latissimus dorsi), leg extension (quadriceps femoris), abdominal crunch (rectus abdominis) and lower back press (erector spinae). The 1RM test is the golden standard and has been found to be a reliable assessment to measure upper and lower extremity strength [36].

Functional capacity is measured by a 6 MWD test. The test is carried out over a pre-measured distance of 28 meters, in compliance with the American Thoracic Society (ATS) statement [37]. The 6MWD test has demonstrated good reliability and validity in COPD patients who are similar to patients with lung cancer with regard to disease patophysiology and symptomatology [38].

Lung capacity Forced Expiratory Volume in 1 second (FEV1) is measured using a standard spirometry in a standing position with the use of the Oxycon Pro, Jaeger measurement system.

Patient reported Outcomes (PRO’s): PRO’s include standard validated questionnaires assessing general wellbeing using the 36-Item Short Form Health Survey (MOS SF-36) [39], quality of life using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLG C-30 + LC13) [40] and the FACT instrument, comprising two parts, i.e. the general part (FACT-G) and the lung specific part (FACT-L) [41], social support and network using the Multidimensional Scale of Perceived Social Support (MSPSS) [42]. Furthermore sleep quality will be assessed using the Pittsburgh Sleep Quality Index [43], and levels of anxiety and depression will be assessed using the Hospital Anxiety and Depression Scale (HADS) [44]. Additional questionnaires will assess self-reported physical activity, labour market attachment, work ability and social reintegration. Demographic data is collected from self-developed questionnaires and training diaries.