Approximately 40% of non–small cell lung cancer (NSCLC) patients are diagnosed with metastatic disease. These patients suffer from a high symptom load (dyspnea, cough, pain, cachexia, and fatigue) and existential distress (median survival 10–12 months) caused by anticancer treatment, the disease itself, and psychological distress in the forms of resignation, anxiety, and depression ([2,7,13]).
Physical activity has been shown to improve physical as well as psychological conditions of cancer patients in several studies. For example, in breast cancer, it was shown that combined endurance and resistance training, even during the treatment period, improves body composition, aerobic fitness, and quality of life (QoL) and mitigates fatigue (18). Even in patients receiving very intensive treatment (e.g., allogeneic hematopoietic stem cell transplantation), exercise improved physical function and reduced fatigue, global stress, anxiety, and pain (25). Exercise interventions in NSCLC patients have been conducted in the context of locoregional treatment (surgery, radiotherapy, and chemo- or radiotherapy), showing safety, feasibility, and improvement of exercise capacity (11). At least two studies focused on patients with advanced or metastatic NSCLC. Temel et al. (23) observed no improvement of muscle strength but a significant reduction of lung cancer symptoms (FACT-L) in a 12-wk hospital-based combined endurance and muscle strength training intervention (NSCLC stage III/IV). Training was performed in 90- to 120-min group-based supervised sessions and included treadmill/bicycle endurance as well as machine-based resistance exercises. A 6-wk-long combined endurance and resistance training intervention along with relaxation sessions (five times per week) in patients with stage III/IV NSCLC and extensive disease-SCLC showed a significant improvement of endurance capacity, muscle strength, and the emotional well-being subscale of the FACT-L questionnaire (20). Training/relaxation sessions were supervised and carried out in groups two times per week in the hospital, whereas the other three sessions were conducted at home. Supervised in-hospital sessions consisted of endurance training on stationary bikes and machine-based resistance exercises lasting 90 min. The home-based program included walking exercises for approximately 30 min.
In advanced and metastatic NSCLC, systemic therapy is the primary treatment approach. With respect to chemotherapy, patients have short clinic stays of less than 5 d in 3- to 4-wk periods. We investigated the feasibility, adherence, and effect of an 8-wk exercise program fitting into this setting. The program consisted of combined endurance and resistance training, with home-based as well as in-hospital components.
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 [10]) 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−2 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 (9). The 6MWT is considered to be a simple, economical, feasible, and reliable measurement (8,21) and is also well established in cancer patients (26). 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 ([3,16,19]).
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 (6). 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 (24). 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 (22). 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) (4). 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−1, and hemoglobin ≤8 g·dL−1. 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 (25).
Statistical analysis
Standard methods were used for data analysis (12,17). 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 (5) 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).
RESULTS
Patient flow and baseline characteristics
Between April and June 2011, 81 patients were asked to give informed consent. Forty patients (49%) were enrolled and completed the baseline measurement (see Fig. 2). Thirty-one patients completed the intervention by participating in the postinterventional assessment (T1). Reasons for premature dropout were exhaustion (n = 4) as well as pneumonia (n = 1), death (n = 1), pain (n = 1), infection (n = 1), and stroke (n = 1). No adverse event relating to the exercise intervention program occurred. Twenty-two patients took part in the follow-up measurement (T2). Nine patients did not complete T2 assessment. The most common reason for dropout was lack of time (e.g., caring for household, family, and social contacts, n = 4).
FIGURE 2:
Consort diagram. T1, postinterventional assessment; T2, follow-up.
The baseline characteristics of the enrolled patients are shown in Table 1. Majority of the patients (67%) were diagnosed with NSCLC, stage IV. Of the patients, 82.5% received chemotherapy only, whereas the remainder underwent combined radio- and chemotherapy. Most of the patients (77.5%) received first-line chemotherapy. Mean BMI was 25 kg·m−2. Ninety percent of the study participants reported former smoking.
TABLE 1:
Sociodemographic and clinical characteristics at baseline (T0).
Adherence and feasibility
The overall adherence rate to the exercise program was 82% for those patients who completed T1 (n = 31). With respect to the different intervention settings, the adherence rates were 95% for the inpatient period and 77% for the home-based period. Fifty percent of the performed sessions in the inpatient setting consisted of resistance training elements only and 27% consisted of endurance training only; the remaining 23% were a combination of both. In the outpatient setting, 29% of the sessions were resistance training and 47% were endurance training. A combination of both was performed in 24% of in-home sessions.
As mentioned earlier, feasibility was defined as the ability of an individual to perform at least two training sessions per week in six of the eight intervention weeks. Only 22 (55%) of the 40 patients fulfilled the criterion of feasibility. The group meeting feasibility criterion performed an average of 33 training sessions during the intervention period. The remaining patients completed an average of 23 training sessions, but with insufficient regularity. The duration of the outpatient period was comparable between both groups (50 ± 6 vs 50 ± 9 d).
Functional capacity
Table 2 shows the results of the muscle strength and endurance assessment during study time. For the 31 patients who completed the intervention, a statistically significant improvement in elbow-extensor strength was observed. In the lower limb, significant muscle strength increases were seen in knee extension and flexion (P < 0.01). Hip abduction also improved significantly (P < 0.01). In terms of endurance, a statistically significant gain (28 m; P < 0.01) of the walked distance (6-min walk distance, 6MWD) was observed. At the follow-up measurement (8 wk after termination of the intervention), muscle strength in knee flexion as well as in extension improved significantly, with a mean change of 40 and 114 N, respectively (P < 0.01).
TABLE 2:
Mean pre-, post-, and follow-up scores for muscle strength and functional capacity.
Patients who met the feasibility criteria showed improved muscle strength during the intervention period; for instance, the elbow flexors (mean change: 12 ± 28 vs −3 ± 40 N) and knee extensors (mean change: 80 ± 76 vs 56 ± 110 N) both improved significantly. With respect to 6MWD, the mean improvement of the group meeting feasibility criteria was not as pronounced as for the group not meeting feasibility criteria (23 ± 45 m vs 41 ± 27 m).
Patient-reported outcomes
The results of the patient-reported outcomes (PRO) are represented in Table 3. At the T1 assessment, no statistically significant changes were detected. Most scores of the FACT-L decreased slightly, whereas the total score of PHQ-9 and the subscale scores of the MFI increased marginally. However, most of the FACT-L values deteriorated at T2. The change in the FACT-L total score was statistically significant (P = 0.03). Fatigue scores (MFI) also decreased further at T2.
TABLE 3:
Mean pre-, post-, and follow-up scores for QoL.
Participants who met the feasibility criteria fared better in nearly all PRO. For example, the FACT-L total score changed by 0.7 ± 10.9 in patients meeting the feasibility criteria compared with −2.8 ± 3.4 among those who did not. Similar results were observed for fatigue measures (mean change in general fatigue: −0.6 ± 12.4 vs 2.2 ± 7.7). No difference, however, was observed in the total score of the PHQ-9 (mean change: 2.2 ± 9.1 vs 2.2 ± 5.4).
DISCUSSION
The present study shows that a hospital- and home-based exercise program is feasible for patients with NSCLC while undergoing anticancer treatment. Furthermore, significant improvements were observed in endurance and isometric muscle strength (knee flexion and extension, elbow extension, and hip abduction) after 8 wk of training.
Given the challenging situation of advanced NSCLC patients, defining the feasibility of an adjuvant exercise therapy approach is an important first step; knowledge regarding the feasibility of such exercise interventions in this patient group, however, is limited (1,20,23). Temel et al. (23) included patients with NSCLC stage IIIB and IV and defined feasibility as the ability of an individual to perform 16 supervised training sessions within the 12 wk of intervention. This goal was achieved by 44% of the study population (23). The feasibility rate, according our definition of feasibility (the ability of each individual to exercise at least two times per week in 6 of 8 wk of intervention), was 55%. Taking into account that most the patients of the present study were stage IV and were undergoing radio- and/or chemotherapy, a feasibility rate of 55% can be considered as success. Furthermore, we did not observe any exercise-related adverse events even in the unsupervised home-based training situation. Because of the safety concerns of this setting, proper patient contact management is required; this has been guaranteed by the regular phone calls and by defining clear contraindications for exercising. The successful implementation of the exercise program might reflect the advantageous training concept being adaptable for each individual. The value of an individually adaptable training concept was also discussed by Temel et al. (23), who advised initiating an intervention of training sessions of lesser intensity/duration lasting less than 2 h. Other comparable studies explored only adherence (14,20). One of these studies enrolled 20 NSCLC patients after lung resection of stages I–IIIB of the disease (14). The study measured adherence as a percentage of the number of training sessions performed by a study participant divided by the total number of possible training sessions (n = 42). The adherence rate was 85% (range = 29%–100%) with a mean of 36 training sessions during 14 wk (14). Our patients were advanced stage patients and reached an overall adherence rate of 82%. Quist et al. (20), who offered supervised training for patients with NSCLC and SCLC two times per week for 6 wk, recorded an adherence rate of 73% for hospital-based sessions. In their parallel home-based setting (three times per week), however, patients achieved an adherence rate of only 9% (20). Compared with these findings, our intervention concept was more successful with a home-based training adherence of 77%. Reasons for this rather successful adherence may be due to regular phone calls and detailed information about how to overcome training barriers.
We reported a dropout rate of 23%, which appears acceptable compared with similar studies that report 26% and 56% dropout rates, respectively, (20,23). The main reasons for dropout in the present study were exhaustion (n = 4) as well as pneumonia, death, pain, infection, and stroke (n = 1 each). Dropout reasons in other studies were similar (23), with the addition of loss of motivation by Quist et al. (20).
With respect to training outcomes, our pilot study showed significant increases in the 6MWD, which increased on average from 493 to 525 m. Similar studies have either used the 6MWT (20,23), and the Incremental and Endurance Shuttle Walk Test (ISWT and ESWT) (1) or measured the functional capacity with the V˙O2max (14). A significant increase has been reported in only one study (20). The significant improvement of the 6MWD during treatment in predominantly advanced NSCLC in the present study (increase of 28 m on average; P < 0.01) can be interpreted as a success of the training program. Given some evidence that 6MWD distance is a predictor of survival in NSCLC patients (15), the improvement of the 6MWD by our intervention may be of important clinical relevance.
We observed a significant increase in multiple measures of isometric muscle strength (maximal voluntary isometric contraction) measured via HHDM, which may be attributable to the individually adaptable training. In other studies, mostly the one repetition maximum (1RM) was used (20,23), and no changes in muscle strength were reported.
We observed that most scores of the FACT-L decreased slightly, indicating minor deterioration in QoL over the course of study participation. Also MFI subscales were reduced, indicating a slight deterioration of fatigue. The total score of PHQ-9 increased subtly, suggesting a higher level of a depressive mood. All changes in our PRO reached no statistical significance. In comparison, Quist et al. (20) reported a significant increase of emotional well-being (FACT-L) and attributed this to the relaxation training they offered in addition to the endurance and muscle strength training. Jones et al. (14) as well as Temel et al. (23) also noted significant improvements in the functional well-being and lung cancer subscales of the FACT-L. Andersen et al. (1), who enrolled patients with NSCLC and SCLC for a 7-wk inpatient exercise study, could not detect significant improvements in QoL. Nevertheless, the above-mentioned results should be interpreted with caution due to the lack of a control group and the relatively small sample size.
Our 8-wk follow-up measurement showed that muscle strength in knee flexion and extension continued to increase significantly, as did the walked distance, although not with statistical significance. The remaining muscle groups did not show a substantial improvement. These findings may indicate that the intervention resulted in a continued, more active lifestyle. However, as patients were not asked to document their physical activity in the follow-up period, and especially in the absence of a control group, it is difficult to say what actually led to the improvements in that time point. Nevertheless, all patients were still under treatment during the follow-up period, and therefore, an increase or maintained level is a positive result.
Compared with other studies in this field, our study has several strengths. It extends on the work by Temel et al. (23) by including a larger patient group (n = 40). Furthermore, this is one of the first studies investigating the feasibility and the effects of a hospital- and home-based exercise program adjuvant to anticancer treatment protocols among patients experiencing advanced NSCLC. Most patients received palliative anticancer treatment while participating in the intervention. Including patients with histologically confirmed NSCLC only (no other subtypes like for example SCLC) and exclusively those undergoing radio- and/or chemotherapy, resulted in greater homogeneity in our study population. In addition, the follow-up measurement indicating sustainability of the intervention program is a novelty in this field.
Our study also has some limitations. The lack of a control group is a weakness of the study design. Alternatively, demonstrating the feasibility of the program as well as first effects of the training on relevant end points is a necessary first step before the initiation of randomized controlled trials. Moreover, five patients were included, who were of lower stage (stage IIa/IIIa based on the International Association for the Study of Lung Cancer) than the rest of the participants; however, results did not differ substantially between the patients of differing stages. Only a subset of patients were willing to participate in the intervention, which may have resulted in a selectively, more strongly motivated group. We also only considered patients in the analysis who completed at least two of the three assessment points. Furthermore, patients were asked to document their training sessions on their own, which may have resulted in reporting inaccuracies. Lastly, it must be considered that the German health care system may differ from that of other countries, which may limit the generalizability of this study; however, considering that the intervention was designed for inpatient and home-based settings, results from the study may still be applicable to diverse settings.
In conclusion, to date, only few studies have focused on the effects of physical exercise in patients with advanced NSCLC undergoing radio- and/or chemotherapy. Our study showed significant improvements in both endurance and isometric muscle strength. Fifty-five percent of the participants were able to perform two or more training units per week (feasibility criteria), and no adverse events related to the training were observed. This study reveals that physical function remained at higher levels toward the follow-up; at the same time, QoL declined nonsignificantly. Despite the nonsignificant decrease in QoL measures, the increased physical function levels may suggest longer-term sustainability of the intervention. Our study results are encouraging given that the period of cancer treatment is commonly accompanied with physical impairment through side-effects as well as deterioration of QoL. On the basis of these promising results, we are planning to investigate the impact of a structured, combined endurance and resistance training in patients with NSCLC undergoing cancer treatment on functional capacity and QoL within a randomized controlled trial.
The authors would like to thank TOGU–Gebr. Obermaier oHG for providing exercise materials. Furthermore, the authors appreciate the intense proofreading efforts of Michael Paskow.
The authors declare no conflict of interest.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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