Cancer survivors are at increased risk for cardiovascular disease (CVD)–related morbidity and mortality as a result of underlying CVD risk factors combined with the direct effects of anti-cancer therapy (e.g. cardiomyocyte damage, myocardial and vascular ischemia) and effects of an unhealthy lifestyle (e.g. decreased physical activity) (1). Recent research has demonstrated that cancer survivors have reduced peak VO2 (1). The mechanism(s) responsible for the reduced peak VO2 are not well known, however it may be due to impaired peripheral vascular endothelial function, as measured by FMD in response to cuff ischemia, an endothelial dependent stimulus. Moreover, endothelial impairment precedes cardiovascular disease progression, therefore, FMD is a relevant clinical measure for evaluating cardiovascular risk profiles (2,3).
Exercise training is an effective therapy to increase peak VO2 in cancer patients and survivors (4,5). The underlying physiological mechanisms responsible for increased exercise capacity in patients with cancer are unknown, however it may be due to improved peripheral vascular endothelial function.
Methods: We performed a systematic review and meta-analysis of all randomized trials that examined the effects of exercise training on vascular function and exercise capacity in cancer survivors (including pre, during and post-treatment). Studies were identified via systematic searches of PubMed (1975 to June 2016), EMBASE CINAHL (1937 to June 2016), OVID MEDLINE (1948 to June 2016) and Cochrane Central Registry of Controlled Trials (1991 to June 2016) using the following subject headings: vascular function, endothelial function, reactive hyperemia, flow-mediated dilation, arterial stiffness, cancer and exercise, and related terms.
Results:
After screening 189 potentially relevant publications, we identified 4 eligible studies, including 82 survivors allocated to exercise training and 81 to non-exercise training controls (6-9). Three studies measured vascular endothelial function via brachial artery FMD and one measured endothelial function via EndoPat; while 3 studies measured peak VO2 and one measured treadmill walking time for assessment of exercise capacity. The four studies included in the final analysis included prostate (n=2) and breast cancer survivors (n=2).
Meta-analysis of 4 studies showed that vascular function was significantly improved across exercise training groups relative to the non-exercise training controls (standard mean difference [95% confidence interval (CI)]=0.65 [0.33, 0.96]) and the heterogeneity/inconsistency across studies was minimal (I2 = 0%). Among the three studies that reported FMD, flow-mediated dilation was increased by approximately 1.28% (weighted mean difference (WMD) [95% CI]=[0.22 2.34]; I2 = 23.2%) in exercise-trained subjects relative to non-exercise controls. Peak VO2 was improved in all three included studies relative to non-exercise training controls (WMD [95% CI]=2.22 [0.83, 3.61] ml/kg/min) with minimal heterogeneity (I2 = 0%).
Conclusion: Exercise training improved vascular function and peak VO2 in breast and prostate cancer survivors. Improvements in exercise capacity and vascular function have been correlated with decreases in cardiovascular risk and mortality. Specifically, a 3.5 ml/kg/min increase in peak VO2 is associated with a 12% and 17% decrease in mortality in men and women, respectively (10,11). Moreover, improving FMD by 1% is associated with an 8-13% decrease in cardiovascular risk (3,12). Accordingly, the improved exercise capacity and vascular function may be associated with reduced CVD-morbidity and mortality in cancer survivors.
Exercise training improves vascular function and peak VO2 in breast and prostate cancer survivors. Further research is required to elucidate the relationship between improved vascular function and exercise capacity, and if this improvement is associated with decreased CVD-related mortality, across a broader spectrum of cancer survivors.
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