COMMENTARY

New Biomarker Data Provide Even More Support for Exercise Against Cancer-Related Fatigue

Theodore Bosworth

Disclosures

August 31, 2017

The benefit of prescribing exercise for cancer-related fatigue (CRF) is making more sense, and some experts believe that it's time to prescribe exercise for most or all cancer patients.

In an effort to explain why patients with cancer paradoxically experience less rather than more fatigue following exercise, data presented at the 2017 annual meeting of the American Society of Clinical Oncology (ASCO) described some of the underlying mechanisms.

The body of data associating exercise with protection against CRF is large. One recently published meta-analysis compared pharmaceutical, psychological, and exercise treatments with data from 113 unique randomized trials with more than 11,000 participants.[1] Change in CRF with drug therapy did not reach significance, but the effect size with exercise was highly significant (P < .001). The new data presented at ASCO may explain why.

In this video from ASCO 2017, Ryan Nipp, MD, MPH, an oncologist and health services researcher at Massachusetts General Hospital Cancer Center who focuses on palliative care and geriatric oncology, discussed the growing body of evidence to support exercise in cancer care, as well as practical points to consider when discussing exercise with patients.

In one of the most compelling studies with a focus on CRF presented at ASCO 2017, the benefit of exercise correlated with a reduction in a molecular signal for muscle degradation.[2] In another, CRF was correlated with increasing circulating mitochondrial DNA (mtDNA), which is already a well-recognized signal of abnormal energy kinetics.[3] This suggests that mtDNA, like the molecular signal of muscle degradation, may be a clinically useful biomarker of CRF. A third study simply showed an improvement in quality of life (QOL) in older cancer patients with CRF when treated with exercise.[4] This study, like others, showed symptom improvement from modest amounts of exercise within weeks.

Overall, the CRF exercise data "are relatively consistent in showing a great return from going from nothing to something," said Tara B. Sanft, MD, medical director of Adult Survivorship at Yale Cancer Center in New Haven, Connecticut. An ASCO-invited discussant of these and other exercise studies, Dr Sanft is among those who believe that current data support exercise as a routine strategy to prevent or treat CRF. She emphasized that modest exercise goals are adequate and "it is never too late to start."

Modest exercise goals are adequate and it is never too late to start.

The study correlating exercise with a reduction in a marker of muscle degradation in patients with CRF was relatively large. Three hundred and fifty chemotherapy-naive cancer patients from 39 community oncology practices in the United States were enrolled and randomly assigned to two groups. One group initiated chemotherapy without exercise. The other initiated a 6-week standardized Exercise for Cancer Patients (EXCAP) program that includes aerobic and resistance components. Myosin light chain 5 (MYL5) and myosin heavy chain 8 (MYH8) proteins in the serum were measured over the course of the study.

"Upregulation of MYL5 and MYH8 are required for normal muscle regeneration in response to damage," said principal investigator Karen M. Mustian, PhD, MPH, an associate professor in the Departments of Surgery, Radiation Oncology, and Public Health Sciences at the Wilmot Cancer Institute at University of Rochester Medical Center in Rochester, New York. "Secretion of MYL5 and MYH8 proteins into the serum suggest degradation of muscle, which we hypothesize is a potentially useful marker for CRF."

The data are supportive. Serum levels of both proteins increased in those who did not receive exercise and remained stable in those who did. These differences were significant (P < .01). Separately, Pearson correlations demonstrated trends for increases in both MYL5 and MYH8 serum levels with CRF independent of exercise (P < .1).

"This is a measurable and consistent change, and it provides a plausible explanation of what we are seeing clinically," reported Dr Mustian, who said that corroborative studies are needed and ongoing. The promise is reproducible biomarkers for CRF. If biomarkers that link cancer and CRF on a molecular level are validated, they will strengthen objective evidence on top of subjective patient assessments that exercise or any other intervention is making a difference.

A second biomarker, mtDNA in the peripheral blood, was also shown to correlate with CRF, expanding the evidence that CRF is likely to be directly linked to cancer and its treatments. mtDNA was measured with polymerase chain reaction (PCR) prior to the initiation of chemotherapy and after 6 weeks of treatment in the blood of 91 women with breast cancer. CRF was assessed using the validated Multidimensional Fatigue Symptom Inventory–Short Form (MFSI-SF). When stratified by quartiles for worsening CRF, the reductions in mtDNA climbed in a stepwise fashion: 26.1%, 30.4%, 52.2%, and 59.1% for quartiles 1, 2, 3, and 4, respectively, for worsening CRF. Worsening CRF and a reduction in mtDNA remained correlated on multiple logistic regression.

While CRF has been associated with mitochondrial dysfunction by others, "this is the first study to show that reduction of mtDNA content in peripheral blood is associated with onset of CRF in patients receiving chemotherapy," said principal investigator Jung-Woo Chae, PhD, from the Department of Pharmacy at National University of Singapore. Like Dr Mustian, Dr Chae indicated that a CRF biomarker is valuable both for its ability to show CRF pathophysiology and as a tool for measuring treatment effects.

As suggested in a history of controlled trials dating back more than 20 years, the treatment effects of exercise for CRF are substantial, but it is important to recognize that relatively modest levels of exercise over relatively short periods reduce symptoms. In the study of exercise among older cancer patients, presented at ASCO and also from the University of Rochester, 198 cancer patients at least 60 years of age were randomly assigned to receive chemotherapy alone or chemotherapy with EXCAP. The mean age was 67 years. The primary outcome was QOL.

At the end of 6 weeks, the Functional Assessment of Cancer Therapy–General (FACT-G) scores showed significant improvement in social (P = .02), emotional (P = .04), and physical (P = .03) domains for those in the exercise group when compared with those on chemotherapy alone, according to Kah Poh Loh, MD, a research oncologist at the University of Rochester's Wilmot Cancer Institute.

Consistent with the theme that exercise has an impact at the molecular level on the pathophysiology of CRF, the improvement in social domain of QOL in this study was associated with a reduction (P = .03) in the proinflammatory cytokine interleukin-8 (IL-8), according to Dr Loh. Although not significantly correlated with other measures of QOL, the reduction in this signal of inflammation may be evidence of a fundamental effect of exercise on a driver mechanism of CRF.

We are at the point that we should be talking to every patient with cancer about the benefits of exercise.

Biomarkers are not essential to validate the benefits of exercise. The large body of evidence from randomized trials has already established efficacy. Still, the objective evidence of protection against signals of inflammation or deterioration in muscle strengthens the message that CRF is targetable.

"We are at the point that we should be talking to every patient with cancer about the benefits of exercise," Dr Sanft said.

On the basis of several surveys, Dr Sanft contended that most oncologists are at least aware that exercise is beneficial against CRF. One such survey, however, found that most clinicians who prescribe exercise refer patients. Dr Sanft speculated that this may be prompted by the limited time that oncologists are willing to devote to care not directly related to treatment of malignancy, or to concern that they are not equipped to identify appropriate exercise or to provide adequate motivation to follow a prescribed regimen. However, she cautioned that there is a rationale for urging oncologist to prescribe exercise.

"A study that evaluated how cancer patients feel about exercise found that about 80% wanted a home-based regimen, and most want the recommendation to come from their oncologist," Dr Sanft reported. While acknowledging that counseling patients about exercise is an extra step in care, Dr Sanft suggested that clinicians should not overcomplicate the task.

"Most patients can begin a walking program without an evaluation. The goal is 150 minutes per week, but it is reasonable to start low and slow. Patients do not need to go to the gym," Dr Sanft said. While there may be additional health benefits for those who can tolerate even greater levels of exercise, Dr Sanft said that the evidence makes clear that CRF can be reduced with modest effort.

Drs Sanft, Mustian, Loh, and Chae report that they have no relevant financial relationships to disclose.

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