Guest Editor
Integrative Oncology is guest edited by Jun J. Mao, MD, MSCE, Laurance S. Rockefeller Chair in Integrative Medicine and Chief, Integrative Medicine Service, Memorial Sloan Kettering Cancer Center, New York.
The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on integrative and complementary therapies sometimes used by patients with cancer. Although physical activity is associated with many positive outcomes in the general population, patients with cancer often reduce physical activity because of surgical complications or treatment-related side effects such as fatigue and pain. As oncology physicians, what evidence can we communicate with patients to keep them physically active during treatment and beyond? In this article, Drs. Iyengar, Jones, and Scott summarize the current evidence of exercise research in patients with cancer and survivors of cancer.
Overview
National agencies (eg, the American College of Sports Medicine,1 American Cancer Society,2 National Comprehensive Cancer Network3) recommend avoidance of inactivity and adherence to regular physical activity consistent with national guidelines for healthy adults4 across the cancer continuum. Here we review the evidence for exercise therapy in the management of symptom burden (eg, poor health-related quality of life, fatigue) and tumor-related outcomes (eg, tumor biology, recurrence, cancer-specific mortality).
Exercise for Symptom Control
Several randomized controlled trials have assessed the efficacy of exercise therapy on various patient-reported outcomes during cancer therapy. For instance, in a meta-analysis of 32 studies with 2,626 women undergoing adjuvant therapy for breast cancer, Furmaniak et al found that exercise therapy reduced fatigue (standard mean difference [SMD] = –0.28, 95% confidence interval [CI] = –0.4 to –0.16) but resulted in no improvement in cancer-specific quality of life (SMD = 0.12, 95% CI = 0.00–0.25).5 Similarly, Yunfeng et al reported that exercise therapy reduced fatigue (SMD = 0.84, 95% CI = 1.43–3.10) in a meta-analysis of 15 studies involving 1,135 men undergoing androgen-deprivation therapy for prostate cancer.6
OF NOTE
The impact of exercise on cancer outcomes may be mediated by tumor subtype. For example, hormone receptor–positive breast cancers appear to be more responsive to exercise than HER2-amplified or triple-negative subtypes.
In patients receiving treatment for metastatic cancers, exercise has been shown to be feasible and to be associated with improvements in select patient-reported outcomes. Specifically, a systematic review of 21 studies reported that structured exercise is a feasible intervention that maintains or improves select patient-reported outcomes, although considerable heterogeneity in study methodology hampered data interpretation and cross-trial comparison.7
Two contemporary randomized controlled trials provided further insight into investigation of exercise in patients receiving treatment for advanced cancers. The METT study evaluated the tolerability and efficacy of a 16-week exercise program in 101 patients receiving any prior line and any therapy for metastatic breast cancer (42% were receiving concurrent chemotherapy at study entry).8 No significant differences were observed in quality-of-life measures.
In the second trial, Scott et al investigated the feasibility and safety of exercise in 65 patients with metastatic breast cancer (57% receiving chemotherapy; more than 40% having at least 2 lines of prior therapy).9 Intent-to-treat analyses indicated no differences in patient-reported outcomes. However, per-protocol analyses indicated improved functional capacity and cardiorespiratory fitness in patients receiving first- or second-line treatment for whom exercise was feasible. Thus, exercise may be beneficial for symptom management (eg, fatigue) in patients receiving cancer therapy.
In patients who have completed cancer therapy, treatment-related toxicities may persist for several years. Exercise improves patient-reported outcomes related to the chronic effects of prior cancer therapies. For example, in a Cochrane review evaluating the efficacy of exercise on overall quality of life among adult posttreatment cancer survivors, Mishra et al found that among 30 randomized controlled trials, exercise improved global quality of life compared with usual care (SMD = 0.48, 95% CI = 0.16–0.81).10 Similarly, in a meta-analysis of exercise trials among women with a history of breast cancer, Lahart et al reported that exercise training resulted in significant improvements in health-related quality of life (SMD = 0.39, 95% CI = 0.21–0.57), emotional function (SMD = 0.21, 95% CI = 0.10–0.32), and anxiety (SMD = –0.57, 95% CI = –0.95 to –0.19).11
Exercise for Cancer Treatment
A substantial body of epidemiologic data suggest that exposure to exercise following the diagnosis of certain solid tumors might decrease disease progression and reduce cancer-related mortality. Studies in this arena were launched by work that showed (self-reported) exercise was inversely associated with the risk for recurrence and cancer-specific mortality in primary breast cancer.
Neil M. Iyengar, MD
Lee W. Jones, PhD
Jessica M. Scott, PhD
In a seminal study by Holmes et al, 9 to 14.9 metabolic equivalent task (MET)-hrs·per wk−1 (ie, equivalent to approximately 150–250 minutes of moderate-intensity exercise per week) was associated with an adjusted 50% reduction in breast cancer death compared with less than 3 MET-hrs.wk-1 among 2,987 patients with primary breast cancer.12 In another systematic review, postdiagnosis exercise was associated with, on average, a 37% reduction (95% CI: 0.54–0.73) in the risk of cancer-specific mortality, comparing the most vs the least active patients.13
These data were corroborated in a meta-analysis of 10 studies examining the association between posttreatment physical activity and all-cause mortality in patients with early-stage colorectal (n = 6; 7,523 total patients) or breast (n = 4; 21,733 total patients) cancer. Comparing the highest vs lowest levels of physical activity, the overall relative risks of total mortality were 0.58 (95% CI: 0.48–0.70) and 0.52 (95% CI: 0.42–0.64) for colorectal and breast cancers, respectively.14 However, the “dose” of physical activity associated with benefit varied considerably across individual studies, ranging from as low as ~5 MET-hrs.wk-1 (~75 mins of moderate-intensity exercise/wk) to as high as ~21 MET-hrs.wk-1 (~400 mins of moderate-intensity exercise/wk).13,15
Furthermore, the impact of exercise on cancer outcomes may be mediated by tumor subtype. For example, hormone receptor–positive breast cancers appear to be more responsive to exercise than HER2-amplified or triple-negative subtypes.12,16-18 Collectively, observational data support the hypothesis that exercise improves disease-specific outcomes in several cancers.
Data from prospective randomized trials are not available; however, at least two trials are currently underway. The CHALLENGE trial is an international, multicenter phase III trial investigating the effects of structured exercise treatment on recurrence and cancer-specific mortality in 962 patients with resected stage III colorectal cancer.19 The INTERVAL trial is also an international, multicenter phase III study investigating the effects of high-intensity aerobic and resistance training with psychosocial support, compared with psychosocial support alone, on disease outcomes in 866 patients with metastatic prostate cancer (ClinicalTrials.gov identifier NCT02730338).
Summary and Recommendations
Meta-analyses and systematic reviews of the extant data conclude that exercise, particularly supervised exercise, improves quality of life in a broad array of patients with cancer both during and after treatment.1,20,21 In addition to conferring beneficial effects on symptomatology, emerging data suggest that exercise during these periods may lower the risk of death from cancer, although confirmatory data from adequately powered randomized trials are not yet available. Findings from ongoing and planned randomized controlled trials that will address the impact of exercise on cancer-related endpoints are needed to develop evidence-based clinical practice guidelines.
DISCLOSURE: This work is supported by research grants from the National Cancer Institute (to LWJ), AKTIV Against Cancer, the Kalvi Trust, the Breast Cancer Research Foundation (to NMI), Conquer Cancer the ASCO Foundation (to NMI), and the Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748). Dr. Iyengar has received consulting fees from Novartis and Puma Biotechnology. Dr. Jones has ownership of Exercise By Science and stock ownership of Pacylex, Inc. Dr. Scott reported no conflicts of interest.
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