Impact of Resistance Training in Cancer Survivors

A Meta-analysis

Barbara Strasser; Karen Steindorf; Joachim Wiskemann; Cornelia M. Ulrich

Disclosures

Med Sci Sports Exerc. 2013;45(11):2080-2090. 

In This Article

Discussion

This meta-analysis was designed to investigate the effects of progressive RT on muscle strength and body composition in adult cancer patients. RT interventions resulted in a statistically significant improvement in muscle strength compared with controls. The increase of 14.6 kg for lower limb muscle strength (nine trials) and 6.9 kg for upper limb muscle strength (nine trials) was achieved during periods between 12 wk and 1 yr and compares well with reported improvements achieved in healthy elderly.[61] The clinical significance of muscle strength for healthy adult and cancer survivors can be gauged by evaluating cross-sectional and longitudinal studies examining direct measurement of muscle strength in association with morbidity[3,29] and mortality.[39,46] The Health, Aging, Body Composition Study study showed mortality to be associated with both lower limb and upper limb muscle strength, and this association remained significant even after adjustment for lean body mass.[39] For quadriceps strength (per SD of 3.8 kg), the crude hazard ratio for men was 1.51 (95% CI = 1.128–1.79) and 1.65 (95% CI = 1.19–2.30) for women.[29] Furthermore, the Aerobic Center Longitudinal Study noted that slightly higher levels of muscular strength (10.7 kg for leg press and 7.7 kg for bench press) were associated with 35% reduced cancer mortality in men, independent of body fat and cardiorespiratory fitness.[46] Thus, the significant gain in muscle strength achieved in our review may increase life expectancy in cancer patients considerably. Although we found no significant differences between the RT group and the control group in V·O2max (two trials), the improvement in the 12-min walk test with RT was statistically significant in two trials by Schwartz et al..[54,55] This may be in part due to an increase in muscle oxidative capacity and/or anaerobic muscle metabolism with RT.[23,32]

In addition to the increase in muscle strength, RT also resulted in a significant overall increase in lean body mass by 1.07 kg (six trials) compared with controls. This is in accordance with a recent meta-analysis by Peterson et al.[43] reporting a weighted pooled estimate of mean lean body mass change by 1.1 kg (95% CI = 0.9–1.2 kg) with RT (mean duration: 20.5 ± 9.1 wk) in healthy aging adults. Thus, RT twice a week increases muscle mass by 1–2 kg per 6 months and could prevent age-associated loss of muscle mass in both healthy adults[38] and patients with chronic disease.[62] In our meta-analysis, an RT intervention resulted in a significant lowering of percentage of body fat by 2.08% (eight trials) compared with the controls, but there was no significant difference between groups in body fat mass (-0.83 kg). The observed between-group effect sizes in body fat are similar to the effect sizes observed with aerobic training in adult patients after completion of main cancer treatment (-0.8%, -1.5 kg).[22] This result is not unimportant because already small reductions in body fat mass (1.5 kg) are associated with reductions in plasma lipid peroxidation.[68] Oxidative stress may be related to cancer prognosis and is closely associated with mitochondrial dysfunction, cytokine dysregulation, and disruptions in muscle metabolism, and all of them have been postulated as mechanistic underpinnings of cancer-related fatigue.[47] RT increases muscle protein synthesis,[45] improves cytokine response,[44] and diminishes atrophy.[21] Furthermore, reduced body fat may also impact cancer prognosis as there is some evidence for a positive association between body fat and increased cancer-related mortality or recurrence.[67]

On the basis of this meta-analysis, an RT intervention resulted in a significant reduction in FACT-Fatigue (four trials) compared with controls. The pooled results of the four studies examining the effect of RT on symptoms of fatigue showed a small effect; however, statistically significant improvements in symptoms of fatigue were reported in only two studies.[56,57] One study used the Schwartz cancer fatigue scale and noted no improvements in fatigue with RT.[73] The observed 1.9-point improvement in FACT-Fatigue with RT was lower than the 3.0-point threshold for minimal clinically important differences.[9] Only four meta-analyses have concluded that physical activity had significant effects on reducing fatigue in cancer survivors.[6,13,14,59] They reported at least small effects of physical activity. Cramp and Daniel[13] identified in their recent systematic review significant benefits of aerobic endurance training on cancer-related fatigue but RT failed to reach significance. Interestingly, Brown et al.[6] reported that RT had a positive, quadratic, and exercise intensity dose–response effect on cancer-related fatigue. Exercise reduced fatigue especially in programs that involved RT exercise among adult cancer survivors and that were of moderate to high intensity (60%–80% 1RM).[6] Thus, the intensity of exercise could play an important role in its effects. Fong et al.[22] reported significantly larger effects of aerobic plus RT than aerobic training alone on cancer-related fatigue that might indicate a potential benefit of higher intensity. In one study by Segal et al.,[57] improvements in fatigue were associated with improvements in upper-body strength, but not hemoglobin. This suggests that RT may improve fatigue by improving neuromuscular efficiency and reducing muscular fatigue.

How Much RT is Needed? Considering the benefits of RT on muscle function, body composition, and cancer-related fatigue, an important question is, how much RT (duration, intensity, and volume) is needed to confer such benefits? On the basis of this analysis, metaregression revealed no statistically significant dose–response relationship between the volume of RT and the effect size changes in assessed outcomes. For example, improvements in muscle strength were observed after low volume (4 S/MG/W),[35] moderate volume (6 S/MG/W),[12,57] and high volume (10 S/MG/W)[55] of RT. This is in accordance with data from a recent meta-analysis investigating the effectiveness of RT for strength improvement among adults >=50 yr.[42] However, we observed a significant negative impact on upper limb muscle strength with increasing intensity of RT intervention and a tendency toward a negative impact on upper limb muscle strength with increasing study duration. A possible reason might be a diminished increase in cross-sectional area per day with increasing length of the training period.[70] Muscle size shows significant changes after 8–12 wk of regular RT.[1] This adaptation appears to proceed in a linear manner during the first 6 months of training.[36] It is intuitive that the growth of skeletal muscle must slow or plateau eventually, and at some point, further RT would provide no additional benefit or treatment effect. On the basis of current data, it appears that to facilitate progressive adaptation in muscle mass and strength, it is necessary to increase the prescription dosage as individuals become more familiarized with training.[42] On the basis of our meta-analysis, prescription dosage (sets per muscle group per week) did not progressively increase over time in most studies. The only "progression" in training prescription was that of the absolute training load. It is therefore conceivable that the lack of increase in dosage may be the reason behind the negative impact on upper limb muscle strength with increasing study duration.

We observed a significant negative impact on upper limb muscle strength with increasing intensity. Metaregression revealed that low/moderate-intensity RT (<=75% 1RM) was associated with greater improvement than moderate/high-intensity RT (>75% 1RM). These data beg the question, how low can the RT intensity be and still produce a physiological adaptation and functional benefit? A recent study in healthy young adults showed that low-load high-volume leg RT to failure (30% 1RM) was more effective at increasing muscle protein synthesis than high-load low-volume RT to failure (90% 1RM).[7] Thus, RT-induced muscle protein synthesis may not necessarily be intensity dependent but may instead be determined by exercise volume. This would be important news for cancer patients who may be unable to sustain lifting weights at a relative high intensity due to sarcopenic comorbidities, such as connective tissue complications.

Although our metaregression suggests that moderate-intensity RT may be more effective than high-intensity for body fat loss, it is important to remember that the scientific evidence suggest only a modest effect of RT on body fatness and this may be influenced by whether the resistance exercise is accompanied by a concurrent reduction in energy intake.[19] RT without energy restriction does not show clinically significant decreases in body weight; however, data show that RT may be an effective alternative to improve body composition in the short-term and long-term (1–2 kg loss of body fat with 1–2 kg increase in lean body mass).[18]

On the basis of our review, an RT intervention resulted in a significant improvement in FACT-Fatigue in studies reporting muscle strength or body composition as primary outcome measure. However, there was no evidence for associations between total exercise volume or mean intensity and beneficial effects on cancer-related fatigue. Although a recent meta-analysis conducted by Brown et al. demonstrated the superiority of higher intensity RT for fatigue reduction,[6] no study has examined RT interventions greater than 80%1RM. It remains unknown whether more vigorous-intensity RT would provide greater or lesser reductions in cancer-related fatigue. For the current analysis, it is conceivable that the limited number of study groups and the overall lack of substantial variability in training regimens across intervention trials may have limited our analyses. Thus, further research is required to determine the optimal type and intensity of an exercise intervention on fatigue.

Strengths and Limitations Our study has several strengths. To our knowledge, this is the first systematic review to assess the association between dose of RT with changes in muscle strength, body composition, and fatigue both during and after cancer treatment. We included only published RCT in our meta-analysis. This is important because nonrandomized studies can overestimate treatment effects by 30%–41%.[53] We used the random-effects model to estimate WMD with 95% CI to consider heterogeneity. We excluded studies with a cointervention and where the RT was not either directly supervised or well documented.

Limitations of the present review include the limited number of studies and the heterogeneity in study design. Heterogeneity may be explained by the range of different RT intervention used (and protocols used) across studies.[64] Intervention differences included duration, frequency, intensity, and dose of exercise; diversity in the initial strength; and clinical status of participating individuals. The studies included had a broad array of populations: men and/or women; adults of any age; cancer survivors of any tumor type, tumor stage, and type of cancer treatment; and participants during treatment (radiotherapy, chemotherapy, and androgen deprivation therapy) or in long-term follow-up. Further, although the studies are expected to have internal validity, there may be limited generalizability because of differences between study participants and all cancer patients. Some studies did not provide information on the quality of the intervention such as randomization method, allocation concealment, and blinding of the study assignments to the persons performing the outcome measurements. However, the median quality score of 4 reflects high methodological quality of included trials.

Inspection of funnel plots suggests that publication bias cannot be excluded (see Figures, Supplemental Digital Content 3, http://links.lww.com/MSS/A279 and 4, http://links.lww.com/MSS/A280, which illustrate funnel plots showing study precision against the WMD effect estimate with 95% CI for lower- and upper-limb muscle strength, respectively). It appears that smaller studies with null results and larger SE may have been not published. The risk of publication bias might have been further increased by searching only three electronic databases and not contacting other experts for possible inclusion of more relevant studies as well as limiting this review to English-language publications.

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