Recent systematic reviews and meta-analyses showed beneficial effects of exercise interventions on physical fitness, fatigue, and health-related quality of life (HRQoL) in cancer survivors (20,28,35). However, reported effect sizes were small to moderate. To improve the effectiveness of exercise, it is important to gain more insight into the mechanisms by which an exercise intervention achieves its effect. Mediators may help identify effective intervention components. By keeping effective intervention components and by removing ineffective ones, the cost-effectiveness and participant burden of the interventions can be improved (12). Furthermore, identification of mediators may support in the building and refining of intervention theory (27). It is hypothesized that physical inactivity induces muscle catabolism and causes further detraining, which may result in a self-perpetuating detraining state with easily induced fatigue. Physical exercise may break this self-perpetuating cycle by improving physical fitness, and consequently reducing fatigue and improving HRQoL (16,26).
Few previous studies investigated mediators of exercise effects on HRQoL in cancer survivors. They showed that the association between improved cardiorespiratory fitness and improved HRQoL was mediated by fatigue (8,10,11,33). In a randomized controlled trial (RCT) among 57 prostate cancer survivors, Buffart et al. (8) showed that upper body muscle strength and walking speed mediated the effects of a 12-wk combined resistance and endurance exercise intervention on physical health and that fatigue and walking speed mediated the effects on general health. Lower body muscle strength also mediated the effects of resistance and endurance exercise on global quality of life (QoL) and physical function in older long-term prostate cancer survivors. However, no mediating effects were found for cardiorespiratory fitness and fatigue (9).
To further build the knowledge of mechanisms underlying the exercise intervention effect on HRQoL, we tested the hypothesis that a combination of resistance and endurance exercise improves cardiorespiratory fitness and muscle strength, thereby reducing fatigue and improving global QoL and physical function (13). To test this hypothesis, we used data from the Resistance and Endurance exercise After ChemoTherapy (REACT) study (21,22), which was conducted in a large group of cancer survivors (n = 277) who had recently completed treatment with curative intent, including chemotherapy.
MATERIALS AND METHODS
Patient recruitment and allocation
The REACT study was a multicenter RCT that evaluated the effectiveness of a 12-wk high-intensity (HI) exercise program and a low- to moderate-intensity (LMI) exercise program compared with a wait list control (WLC) group on physical fitness, fatigue, and HRQoL (21,22). A detailed description of the study procedures has been published previously (21,22). The medical ethics committees of the VU University Medical Centre and the local ethical boards of the participating hospitals had approved the study, and written informed consent was obtained from all cancer survivors before participation (21,22).
Cancer survivors were eligible for the study if they were age ≥18 yr, were treated for histologically confirmed breast, colon, ovarian, lymphatic, cervical, or testicular cancer, had completed primary cancer treatment with curative intent including chemotherapy, and had no indication of recurrent or progressive disease (21,22). Cancer survivors were not eligible for the study if they were unable to perform basic activities of daily life, had cognitive disorders or severe emotional instability, had other serious diseases that might hamper the capacity of carrying out HI exercise (e.g., severe heart failure), or were unable to understand and read Dutch (21,22).
Cancer survivors were recruited between 2011 and 2013 from nine hospitals in The Netherlands. Baseline measurements were performed 4–6 wk after completion of primary cancer treatment. After baseline measurements, participants were stratified by cancer type and hospital and were randomly assigned into one of the three study arms. Both HI and LMI exercise groups started with their 12-wk exercise program. Participants from the WLC group were offered the intervention, wherein they were randomly allocated to, after 12 wk.
In total, 277 cancer survivors (response rate, 37%) participated in the study. We previously reported that both HI and LMI exercise were able to increase cardiorespiratory fitness, reduce fatigue, and improve QoL and physical function compared with WLC (22). The current analyses examine the mechanisms underlying the intervention effects on global QoL and physical function. Because we assumed that the intervention effects follow the same path as proposed in the hypothesized model, and to increase statistical power, we combined both intervention groups into one group. Therefore, 186 cancer survivors were allocated to the exercise intervention and 91 to the WLC group. Measurements were performed at baseline and after 12 wk.
A detailed description of the exercise interventions has been published elsewhere (21,22). In short, the exercise interventions took place twice a week for 12 wk and were identical with respect to exercise type, frequencies, and durations, and differed only in intensity. Resistance exercises included vertical row, leg press, bench press, pullover, abdominal crunch, and lunges, and these were performed at 70%–85% of one-repetition maximum (1RM) in the HI exercise group and at 40%–55% of 1RM in the LMI exercise group. Aerobic interval training aimed to improve cardiorespiratory endurance and included 8 min of cycling two times in the first 4 wk, with an alternating workload of 30% and 65% of the maximal short exercise capacity (estimated by the steep ramp test ) in the HI exercise group and 30% and 45% in the LMI exercise group. From the fifth week onward, an additional aerobic interval session was included in exchange for 8-min cycling. This interval session consisted of 5 min of cycling three times at constant workload, with 1-min rest between each bout. The constant workload was defined by means of heart rate reserve based on the Karvonen formula (23) and was at least 80% of the heart rate reserve for HI exercise and 40%–50% for LMI exercise. On average, 70% of the cancer survivors had high adherence rates, defined as attending 80% of the prescribed supervised exercise sessions (22).
HRQoL was measured with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (1), with higher scores representing a higher global QoL and better function. We used the global QoL and physical function scales for further analyses.
Cardiorespiratory fitness was measured with a maximal exercise test on an electronically braked cycle ergometer according to a ramp protocol in which the resistance gradually increased every 6 s, aiming to achieve the maximum peak oxygen uptake (peak V˙O2) within 8 to 12 min (4,19). Peak V˙O2 was defined as the highest V˙O2 value averaged over a 15-s interval within the last minute of exercise and was expressed in milliliters per kilogram per minute.
Hand-grip strength was assessed with a JAMAR hand-grip dynamometer (6) and was expressed in kilograms. The mean score of the three attempts with the dominant hand was used in the statistical analyses. We used the 30-s chair stand test as a measure for lower body muscle function (18). The total number of times participants raised to a full stand in 30 s was used in the statistical analyses.
Self-reported fatigue was measured with the Multidimensional Fatigue Inventory (34). We used the general and physical fatigue subscales for further analyses, with higher scores indicating higher levels of fatigue.
Demographic characteristics were collected at baseline with a self-reported questionnaire and included age, gender, education level, marital status, and smoking. We categorized education level into low (elementary and lower vocational education), medium (secondary and secondary vocational education), and high (higher vocational and university education). Clinical characteristics were collected from medical records and included cancer type, stage of disease, and treatment history (i.e., radiation therapy, immunotherapy, hormonal therapy, and/or surgery) (22).
Baseline characteristics and pre- and postintervention values of the outcome assessments are presented as means and SD, or as numbers and percentages. To test the hypothesis that exercise improves physical fitness (i.e., cardiorespiratory fitness, hand-grip strength, and lower body muscle function), which is associated with lower general and physical fatigue and higher global QoL and physical function (Fig. 1), we conducted path analyses using maximum likelihood estimation with MPlus. Path analysis allows the simultaneous assessment of multiple regression equations (38). Four separate path models were built using follow-up values of the mediators and outcome variables, adjusting for their baseline values, age, and gender: 1) physical fitness and general fatigue as mediators in the intervention effects on global QoL; 2) physical fitness and physical fatigue as mediators in the intervention effect on global QoL; 3) physical fitness and general fatigue as mediators in the intervention effects on physical function; and 4) physical fitness and physical fatigue as mediators in the intervention effect on physical function. Bootstrapping techniques were applied to calculate the 95% confidence interval (CI) around the estimates of the direct and indirect effects using 10,000 bootstrap samples. The model fit was evaluated using the root mean square error of approximation (RMSEA), with values below 0.05 for good fit (acceptable fit, 0.05–0.09), the comparative fit index (CFI), and the Tucker–Lewis index (TLI) with values above 0.95 as good fit (adequate fit, >0.90) (25). These tests were used because they are least sensitive to sample size and provide unbiased and consistent model specifications (17). The path analyses were based on complete cases.
Because we pooled data from the HI and LMI exercise groups including a heterogeneous group of cancer survivors, we conducted sensitivity analyses to test whether the mediator effects were similar between the two intervention groups and between survivors of breast cancer (n = 181) or other (n = 96) cancer types.
The mean age of the participants in the exercise group was 53.6 yr (SD = 11.1 yr), 81% was female, and 67% was diagnosed with breast cancer (Table 1). Participants in the WLC group were on average 53.5 yr (SD = 10.9 yr) old, 78% was female, and 63% was diagnosed with breast cancer. Descriptive values of all outcomes for the exercise and WLC groups at pre- and postintervention are presented in Table 2.
We found a significant beneficial effect of exercise on cardiorespiratory fitness, but not on hand-grip strength or lower body muscle function (Fig. 1 and Table 3). In addition, higher cardiorespiratory fitness was significantly associated with lower physical fatigue (Fig. 1B and D), but not with general fatigue (Fig. 1A and C). Better lower body muscle function test was significantly associated with lower general and physical fatigue. Higher hand-grip strength was significantly associated with lower physical fatigue (Fig. 1B and D). We also found a direct effect of the exercise on general and physical fatigue.
Both lower general fatigue and physical fatigue were significantly associated with higher global QoL and physical function. Higher cardiorespiratory fitness was significantly associated with higher physical function (Fig. 1C and D), but not with global QoL (Fig. 1A and B).
The paths explained 44%–61% of the total variance in global QoL or physical function, and the models had an adequate fit (RMSEA < 0.08, CFI > 0.98, TLI > 0.95; Fig. 1). Sensitivity analyses showed larger effects on global QoL for HI compared with LMI exercise and for survivors of breast cancer compared with survivors of other cancer types. Other paths were comparable across subgroups.
The current study found support for the hypothesis that a combined resistance and endurance exercise intervention improves cardiorespiratory fitness, which is associated with lower physical fatigue and higher global QoL and physical function. Furthermore, we found that higher hand-grip strength was significantly associated with lower physical fatigue and better lower body muscle function with lower general and physical fatigue.
We previously reported beneficial effects of the exercise intervention on cardiorespiratory fitness, fatigue, and HRQoL (22), which supports previous reviews and meta-analyses (14,20,28). The current study further elucidates these findings by providing insight into the mechanisms underlying the beneficial effects of resistance and endurance exercise on HRQoL.
Our finding that improved cardiorespiratory fitness mediated the exercise effects on physical fatigue, but not on general fatigue, indicates that improving cardiorespiratory fitness is an important intervention strategy to reduce physical fatigue. The lack of mediating effect of improved cardiorespiratory fitness on general fatigue is in line with previous findings in prostate (8) and breast cancer (30) survivors. This may be explained by the fact that general fatigue includes not only physical aspects but also mental aspects, which are perhaps more likely influenced by concepts other than or in addition to cardiorespiratory fitness. It is possible that psychological factors such as depression and anxiety may mediate exercise effects on general fatigue (30). Furthermore, exercise effects on fatigue could also be mediated by biological factors (e.g., improved body composition and increased pro-inflammatory cytokines) (31) or other psychosocial factors, such as reduced sleep quality, mastery, and self-efficacy (10,30). These factors may also explain the direct beneficial effect of exercise on general fatigue in the current study as well as in a previous study (10).
In line with findings from previous studies (8,29), we found that higher hand-grip strength and better lower body muscle function were significantly associated with lower fatigue. We further found that better lower body muscle function tended to be associated with higher physical function. This indicates that muscle strength and function might be important intervention targets when aiming to reduce fatigue and improving physical function. However, because of the lack of a significant intervention effect on hand-grip strength and 30-s chair stand test, we could not confirm that muscle strength and function mediated the exercise effects on fatigue and physical function. The lack of significant effects of exercise on muscle strength is in contrast with a previous meta-analysis (36) and a systematic review (24) summarizing the effects of exercise on muscle strength, and may be related to our choice of instruments used to assess the outcomes. Despite being valid and reliable measures of hand-grip strength (25) and lower body muscle function (5), they may have been less sensitive to detect exercise-induced changes. Future studies are needed to clarify the mediating role of muscle strength in the exercise intervention effect on fatigue and physical function.
We further found that the effects of exercise on global QoL can be explained by reduced fatigue, which supports findings from previous studies (8,10,11,33). In older long-term prostate cancer survivors, lower general fatigue was associated with higher global QoL (9). However, in this study, lower general fatigue was not a mediator of the exercise effect (9). Furthermore, our results demonstrate that the effects of exercise on physical function can be explained by reduced general and physical fatigue. This is in contrast to a study in prostate cancer survivors (8), which reported that general fatigue mediated the effects of exercise on global QoL but not on physical function. This lack of mediating effects of general fatigue on global QoL or physical function in these studies may be related to the lower baseline values of fatigue, leaving less room for improvement. In contrast, our study clearly suggests that reducing fatigue can be important to improve global QoL and physical function, and that exercise is an effective strategy to do so.
In addition to its effect via fatigue, we also found a direct association between improved cardiorespiratory fitness and improved physical function. The mediating role of cardiorespiratory fitness in the intervention effect on physical function was not found in studies among prostate cancer survivors (8,9). Differences in mediating effects may be related to differences in study population or to the type of instrument used to measure cardiorespiratory fitness (22). Instead of the submaximal exercise test, the current study used a gold standard maximum exercise test to assess cardiorespiratory fitness, which may be more sensitive to detect changes and less prone to measurement error (2). Baseline peak V˙O2 values of our population were low compared with normative values (32), which may interfere with daily life functioning (37). Our study showed that this can be (partially) counteracted by a training program of 12 wk that improves cardiorespiratory fitness.
The strengths of the present study are the examination of mediators in a well-designed RCT with a relatively large sample size, the use of valid and reliable instruments to assess outcome measures, and the use of path analyses enabling the simultaneous evaluation of multiple mediators (7). However, despite the use of an RCT design, one should still be cautious when making inferences about causality, because the mediator and outcome variables were measured at the same time (39). Consequently, we studied associations rather than temporal relationships between these variables, and the reverse—that higher global QoL and physical function were associated with lower levels of fatigue—may also be true. However, fatigue was found to be the strongest predictor of HRQoL and physical function (3), supporting the direction of the association studied. Another limitation is the use of indirect measures to assess muscle strength. Both hand-grip strength and 30-s chair stand test are valid and reliable measures to assess hand-grip strength (25) and lower body muscle function (5). In addition, the use of (indirect) 1RM tests would introduce learning bias in the intervention group because these tests were included as part of the intervention. However, hand-grip strength and 30-s chair stand test may not have been sensitive enough to detect exercise-induced changes. Finally, to increase statistical power, and because we hypothesized that the intervention effects had similar mechanisms underlying beneficial effects on global QoL and physical function, we pooled the data from both intervention groups. Our sensitivity analyses indicated that paths were comparable across subgroups, except for the intervention effect on global QoL, which was larger for HI than LMI exercise and for survivors of breast cancer compared with other cancer types (22). As a result of pooling, we were unable to distinguish differences in strengths of mediator effects between HI and LMI exercise.
Current results contribute to the understanding of the mechanisms by which a resistance and endurance exercise intervention achieves its effect on global QoL and physical function in cancer survivors. These results will help to further tailor interventions to the desired outcome. Supported by previous studies showing beneficial effects of exercise on cardiorespiratory fitness (20), it is recommended to improve cardiorespiratory fitness in order to reduce fatigue. Furthermore, reducing fatigue helps to improve the cancer survivors’ global QoL and physical function.
In conclusion, this study found support for the hypothesis that exercise increases cardiorespiratory fitness, and consequently reduces physical fatigue and improves global QoL and physical function in cancer survivors shortly after completion of primary cancer treatment. Improving cardiorespiratory fitness could therefore be an important intervention target to reduce fatigue and to improve cancer survivors’ global QoL and physical function.
This study is part of the A-CaRe Program, http://www.a-care.org. The authors acknowledge the A-CaRe Clinical Research Group and thank all cancer survivors who participated in the trial. In addition, the authors thank the oncologists, nurses, sports physicians and their laboratory staff, research assistants, rehabilitation specialists, and physical therapists for their support in conducting the trial.
The REACT study was supported by the Alpe d’HuZes/KWF Fund. The research grant is provided by the Dutch Cancer Society (grant number ALPE 2009-4619).
The contribution of J. Kalter and L. M. Buffart was further supported by the Bas Mulder Award, granted to L. M. Buffart by the Alpe d’HuZes/KWF fund, provided by the Dutch Cancer Society (grant number VU 2011-5054). The funders had no role in the study design, data collection and analyses, decision to publish, or preparation of the manuscript.
The authors declare no conflicts of interest.
The publication of this study does not constitute endorsement by the American College of Sports Medicine.
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Keywords:© 2016 American College of Sports Medicine
ONCOLOGY; MEDIATION ANALYSIS; GLOBAL QUALITY OF LIFE; PHYSICAL FUNCTION