Methods
The study was a prospective 8-wk exercise intervention pilot study for adult patients with histologically confirmed NSCLC (stages IIa–IV based on the International Association for the Study of Lung Cancer undergoing radio- and/or chemotherapy. The study was conducted in the Thoracic Oncology Department in the Clinic of Thoracic Diseases of the University Hospital Heidelberg. The study protocol was approved by the ethics committee of the medical faculty of Heidelberg, registered at clinicaltrials.gov (NCT01581346), and all patients signed informed consent.
Eligible participants were enrolled by the oncologists caring for the patients. Patients were approached before the initiation of chemotherapy (in metastatic disease not beyond third line) or radiotherapy. Aside from histologically confirmed NSCLC, inclusion criteria were body mass index (BMI) >18 kg·m and ability to follow the German study instructions and questionnaires. Exclusion criteria were as follows: suffering from acute infectious diseases, inability to stand or walk, immobility lasting longer than 2 d, bone metastasis in the spine, and severe neurologic disorders. Furthermore, serious cardiovascular diseases, grave pulmonary or renal insufficiency, and an addiction to alcohol and drugs or substance abuse in general were also grounds for exclusion from the study.
End point assessment was performed at baseline (T0, wk 0), after the conclusion of the exercise intervention (T1, week 9), and 8 wk after the conclusion of the intervention (T2, week 17). The primary outcome was feasibility (adequate adherence), defined as completing at least two training sessions per week in six of the eight intervention weeks. As an additional outcome, adherence was defined as the ability to train according to the study guidelines by performing five sessions in the inpatient and three sessions in the home-based setting each week. Additional secondary outcomes included endurance and strength capacity, QoL, fatigue, and depression.
Sociodemographic Data and Medical History
Information about sociodemographic status (e.g., educational status and smoking history) was collected at baseline by questionnaire. Medical information (e.g., stage of disease and treatment) was recorded from the patients' medical records.
Functional Capacity
Functional capacity was assessed by the 6-min walk test (6MWT) and handheld dynamometry (HHDM). In each testing situation, patients started with the 6MWT; because of leg muscle fatigue caused by the 6MWT, the subsequent HHDM testing began with upper extremities.
The 6MWT was performed according to the protocol of the American Thoracic Society. The 6MWT is considered to be a simple, economical, feasible, and reliable measurement and is also well established in cancer patients. The test was conducted on a ward floor (60 m) where patients were asked to walk as many meters as possible within 6 min. Oxygen saturation and heart rate were controlled before, during, and after testing by pulse oximetry.
The HHDM measured maximal voluntary isometric contraction in newton-meters in various muscle groups (device from CITEC, Haren, the Netherlands). Within our study, knee flexors and extensors, hip flexors and abductors, and elbow flexors and extensors were assessed in precisely defined testing positions. Each measurement was repeated three times and averaged. The reliability and the validity of HHDM testing were found to be acceptable in both healthy persons and patients.]
Patient-reported Outcomes
The questionnaires used to assess the psychosocial status of the patients were the Functional Assessment of Cancer Therapy–Lung (FACT-L), the Multidimensional Fatigue Inventory (MFI), and the Patient Health Questionnaire (PHQ-9).
The QoL questionnaire, FACT-L, consists of 36 items grouped into five different categories: physical, social, emotional, and functional well-being, as well as a scale listing symptoms typical for lung cancer, such as coughing and dyspnea. Higher scores indicate a higher QoL.
The PHQ-9 is composed of nine items evaluating psychological impairment, with a focus on depression. This questionnaire is often applied within oncology research. Higher scores indicate greater depression.
The MFI is composed of 20 items divided into five different subscales (general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue), representing the multidimensionality of the fatigue syndrome. The MFI is also commonly used in oncologic research. Higher scores correspond to stronger manifestations of fatigue.
Exercise Program
The intervention consisted of an 8-wk consecutive hospital- and home-based combined endurance and resistance training program. All enrolled patients started the exercise program with a guided practical introduction provided by an exercise specialist during their inpatient stay. Patients obtained exercise materials (stretch bands and dumbbells) and a training manual.
During the inpatient setting, study participants were asked to exercise five times per week. They were supervised by an exercise specialist three times per week. It was an important goal of this study to enable patients to train independently; thus, patients were encouraged to exercise two times per week on their own. In the outpatient setting, patients' exercise goal was three times per week. Participants received a weekly phone call by the study team inquiring about possible problems and difficulties, as well as to provide advice with regard to the exercise program (see Fig. 1). Patients recorded their exercise program status (duration, intensity and type of exercise) in a standardized diary.
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Figure 1.
Exercise intervention scheme.
Training options regarding endurance training were brisk walks outside or inside the clinic with the possibility to use a treadmill or a cycle ergometer during the inpatient stay. For the resistance training, patients were provided with a training manual illustrating different gymnastic exercises conducted with or without dumbbells and a set of color-coded stretch bands with different levels of resistance.
Training intensity was adapted using the Borg scale (target scores = 12–14 for endurance and 14–16 for resistance exercises). Furthermore, patients were asked to rate their current pain, fatigue, emotional status, and nausea on a visual analog scale (0–10) each training day. This assessment was used to self-rate patients' well-being and group them into three different categories (red, yellow, and green) for tailoring the exercise intervention. Green coded for subjective good or normal health status and included the most challenging exercise recommendations. Yellow and red corresponded to medium or bad health status (respectively), resulting in less challenging exercises.
Contraindications for starting a training session were infections (body temperature ≥38°C), severe pain, nausea and dizziness, platelet counts ≥10,000 L, and hemoglobin ≤8 g·dL. The exercise sessions were stopped if pain, dizziness, or other contraindications occurred.
The training program has been implemented successfully in an RCT with patients undergoing an allogeneic stem cell transplantation.
Statistical Analysis
Standard methods were used for data analysis. The Wilcoxon rank sum test and the Fisher exact test were used for comparing independent samples of quantitative and binary data, respectively. Paired data, originating from variables measured at different time points, were analyzed by using the rank version of the t-test for dependent samples and by calculating rank correlation coefficients (Kendall's tau). All statistical tests were two-tailed, using a nominal significance level of 5%. As this was a feasibility study, statistical analyses were exploratory in nature. Thus, although hypothesis tests were performed, statistical significance was understood to be interpretable as a signal rather than a formal probability. Accordingly, no adjustment for multiple testing was performed. All analyses were carried out using the SAS statistical software package, version 9.1 (SAS Institute, Inc. Cary, NC).