Peak oxygen uptake impairment in childhood cancer survivors treated with anthracycline-based chemotherapy: a systematic-review and meta-analysis

Background Exposure to cardiotoxic therapies such as anthracycline chemotherapy places childhood cancer survivors (CCS) at markedly increased risk of heart failure and cardiovascular mortality. Peak oxygen uptake (VO2peak) is an objective marker of cardiovascular function that is a strong predictor of incident heart failure and cardiovascular mortality. However, the degree of VO2peak impairment in CCS is yet to be definitively established. Purpose To perform a systematic review and meta-analysis comparing VO2peak and cardiac function in CCS treated with anthracycline chemotherapy versus age-matched non-cancer controls (CON). Methods A systematic search was performed using Embase, Scopus, MEDLINE, CINAHL and SPORTDiscus databases to identify cross-sectional studies comparing VO2peak (primary outcome) and resting cardiac function in CCS versus CON. Studies were included if i) participants were childhood cancer survivors (≤18 years old when cancer was diagnosed) exposed to anthracycline-based chemotherapy; ii) assessments were performed after completing adjuvant therapy; iii) reported VO2peak assessed from a maximal exercise test with expired gas analysis. Studies were excluded if they i) reported no original data; ii) did not include a healthy non-cancer control group; iii) reported duplicate data; iv) were not available in English. Values for CCS and CON were compared using a fixed-effects model, with results reported as weighted mean differences (WMD) with 95% confidence interval (95% CI) for the difference between CCS relative to CON. Heterogeneity was determined using the I2 statistic. Results 2026 studies were identified, of which 18 unique case-control studies reporting peak VO2 in CCS (n=786, 44% female, mean age: 16 yrs, mean time post-therapy: 2.7 yrs) and CON (n=1379, 50% female, mean age: 16 yrs) were included in the meta-analysis. Childhood cancer survivors had markedly lower VO2peak (WMD: -7.08 mL/kg/min; 95% CI: -7.75 to -6.42, I2: 79%). Resting left-ventricular ejection fraction (LVEF) was the only measure of cardiac function with a sufficient number of studies for meta-analysis (n=5 studies). In contrast to VO2peak, there was only a small decrement in resting LVEF (WMD: -1.6%; 95% CI: -2.6 to -0.6; I2: 49%), and the mean resting LVEF for CCS was in the normal range in all studies (Range: 61.4% to 72.0%). Conclusion Despite negligible differences in resting cardiac function, CCS have a marked reduction in VO2peak that may explain their increased risk of heart failure and cardiovascular mortality. Incorporating measures of VO2peak into cardiac surveillance may improve the identification of CCS at risk of future cardiovascular events who may benefit from therapies (eg. exercise-based cardiac rehabilitation) to address impairment in VO2peak. Figure 1Pooled results for VO2peak Figure 2Pooled results for resting LVEF