March 9, 2016

Exercise During Cancer Treatment Lessens Fatigue

Combating the most common side effect of cancer treatment
Could exercise be even more important than diet and supplements in an integrative cancer treatment plan?


van Vulpen JK, Peeters PHM, Velthuis MJ, van der Wall E, May AM. Effects of physical exercise during adjuvant breast cancer treatment on physical and psychosocial dimensions of cancer-related fatigue: A meta-analysis. Maturitas. 2016;85:104-111. 


Two arm, randomized controlled trial


Women undergoing, or scheduled to undergo, treatment with chemotherapy for newly diagnosed breast cancer. Recruitment took place at 7 facilities throughout the Netherlands between January 2010 and December 2012. 
Participants were randomly assigned to either the exercise group or to “usual care.” All participants began the study within 6 weeks of diagnosis. A total of 204 participants were recruited: 102 in the exercise group and 102 in the “usual care” group. There were 15 participants lost to follow-up in the intervention group and 25 in the control group, leaving 87 and 77 evaluable women in each group, respectively, at week 36.


An 18-week, individualized exercise program versus “usual care,” where the patients were asked explicitly not to partake in more exercise than their usual activities of daily living. Those in the intervention group underwent a personalized assessment and individualized exercise sessions twice weekly with a physiotherapist at the treating institution. Each session was 60 minutes total and included 5 minutes of warm-up, 25 minutes each of aerobic and resistive exercise, and 5 minutes of cool down. Each session also included cognitive behavioral therapy as part of the visit. Those in the intervention group were also asked to engage in a minimum of 30 minutes of unsupervised exercise 3 days per week in addition to the formal sessions.
The control group was asked to maintain usual physical activity levels from the start of the study through week 18. At week 18, those in the usual care group were allowed to participate in exercise programs that are part of “usual care” for everyone who has gone through cancer treatment in the Netherlands.

Outcome Measures

Fatigue was the primary outcome measure. Assessments for fatigue were made at baseline, 18 weeks, and 36 weeks. The Multidimensional Fatigue Inventory (MFI), which includes a 20-item questionnaire measuring general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue was used. The Fatigue Quality List (FQL), which consists of 28 adjectives in 4 subscales, was used to further assess perception of fatigue. 
Quality of life (QoL) was measured using the 30-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and the 36-item Short Form Health Survey (SF-36). Anxiety and depression were assessed using the 20-item Hospital Anxiety and Depression Scale.
Physical activity outside the study setting was evaluated with the Short Questionnaire to ASess Health enhancing physical activity (SQUASH) form. 
Aerobic capacity was assessed using cardiopulmonary exercise test with continuous breathing gas analysis. Thigh muscle and handgrip strength were measured using dynamometers. Body height and weight were measured.

Key Findings

Baseline: The study group characteristics were comparable by most measures, except women in the intervention group were more highly educated (46.1% vs 35.3%), had more triple-negative breast cancers (23.5% vs 11.8%), and were more likely to be postmenopausal (44.1% vs 32.4%). 
18-week assessment: The study found that exercise that began within 6 weeks of diagnosis significantly reduced the amount of physical fatigue developed during conventional cancer treatment. General and mental fatigue also trended toward less severe in the intervention group but did not reach statistical significance. Submaximal cardiorespiratory fitness and muscle strength (leg extension and flexion) were also significantly better with exercise intervention. 
36-week assessment: There was no difference between groups in any parameters measured at 36 weeks. Most of the control group began to exercise posttreatment as part of the “usual care” offered by the healthcare system in the Netherlands.
Body weight was increased at 18 weeks and 36 weeks for both groups with no difference between groups. There was no difference at 18 or 36 weeks in overall quality of life, anxiety, or depression.


Fatigue is the most common side effect reported by those receiving conventional cancer treatments (chemotherapy and/or radiation).1 Several reviews and meta-analyses have suggested exercise during and after treatment results in fewer fatigue symptoms.2-4 It is passé to suggest to patients with breast cancer undergoing chemotherapy to “just take it easy and rest.” The evidence clearly suggests that movement/exercise during treatment is beneficial.
There are, however, questions about how much and what types of exercise are best. While ongoing studies will more precisely define these details, we have enough data to date to give some solid guidance to our patients.
A Cochrane review published in 2012 determined that aerobic exercise during and after treatment for solid tumors lessened fatigue, but there was insufficient evidence to determine whether resistive exercise was helpful.5 Note that the review did not conclude resistive exercise is not helpful, merely that there was insufficient evidence to make any conclusion. 
A Cochrane review is the most rigorous in today’s evidence-based medical paradigm. It is safe to say there is little doubt that partaking in aerobic exercise during and after treatment leads to improvements in quality of life for those undergoing treatment for breast cancer. 
Resistive exercise has only recently garnered attention in clinical research. Since the 2012 Cochrane review, several studies have suggested resistive exercise during treatment may be beneficial. 6-8 Most of these trials have been well designed to minimize the psychosocial influences inherent to group activities such as exercise classes. In some fashion, the trials divided participants into 2 groups and used a supervised group activity, such as relaxation, as the control. This allows some mitigation of the confounder of social support, which may be therapeutic in itself. This design is not relevant to the study reviewed here, since participants were seen 1-on-1 with a physiotherapist. 
Clinical trials of resistive exercise in women undergoing radiation and/or chemotherapy for breast cancer are ongoing.7 This is happening at a time when there is a growing understanding of how muscle itself influences systemic physiology. No longer is muscle just a mechanical contributor to overall health. In nonobese adults, muscle is the largest endocrine organ.9 In obese adults, adipose can be the largest endocrine organ.10 By definition, endocrine organs are those that produce and secrete molecules that have effects on distant organs/systems. Muscle cells produce and secrete myokines. 
The secretion of myokines is highest during the act of muscle contraction. Myokines then act locally (autocrine/paracrine) or systemically (endocrine). The endocrine effects of myokines appear to be at the crux of how exercise ultimately lowers the risk of many chronic diseases. The discovery and continuing elucidation of myokines offers a new paradigm for understanding how exercise in general, and muscle contraction specifically, can influence overall physiology so profoundly. 
Myokines include well-known molecules such as interleukins (eg, IL-6, IL-4, IL-15), insulin-like growth factor-1( IGF-1), fibroblast growth factor, and many others.11 In addition, the muscle produces some more unique molecules such as irisin. Irisin is partly responsible for the simulation of cortical bone growth with exercise.12 Such factoids have practical use for us as clinicians as means of motivating our female patients, especially those on aromatase inhibitors, to stimulate bone growth with exercise. 
It appears that a combination of aerobic and resistive exercise, as was used in the study currently under review, is optimal for those undergoing treatment for breast cancer. However, the optimal exercise intensity may vary depending on whether the patient is in active treatment (chemo/radiation) or posttreatment. A pooled analysis of 17 studies of breast cancer patients undergoing conventional treatment showed that low- to moderate-intensity exercise during treatment was more beneficial than higher-intensity exercise.13 In contrast, the opposite has been found true posttreatment: Greater intensity reaps greater the benefit.14 This is not surprising given the physical stress the body is under during chemotherapy/radiation. Treatment induces a higher oxidative and inflammatory state. High-intensity exercise is itself a mild stressor on the body, also creating oxidation and transient inflammation, so it stands to reason that during treatment the additive effects of high-intensity exercise may be excessive.
A final consideration: Exercise during and after treatment may also lessen the risk of recurrence. A meta-analysis published in 2012 that culled the medical literature from 1950 to 2011 determined that exercise not only improved quality of life, but also was associated with a 25% to 75% reduction in risk of death from breast cancer specifically.15 Such information can be highly motivating for patients and can lead to better compliance than blanket statements about the overall benefits of exercise.
There seems to be little if any down side risk to exercising within one’s physiological limits during treatment. We, as clinicians, should motivate patients to prioritize exercise above nutritional supplements and above adopting a pristine diet. Adding a structured resistive exercise program to the aerobic component will likely lessen fatigue during treatment and lead to overall improvements in quality of life.

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