The Effect of Neoadjuvant Chemoradiotherapy on Whole-Body Physical Fitness and Skeletal Muscle Mitochondrial Oxidative Phosphorylation <i>In Vivo</i> in Locally Advanced Rectal Cancer Patients – An Observational Pilot Study

Background In the United Kingdom, patients with locally advanced rectal cancer routinely receive neoadjuvant chemoradiotherapy. However, the effects of this on physical fitness are unclear. This pilot study is aimed to investigate the effect of neoadjuvant chemoradiotherapy on objectively measured in vivo muscle mitochondrial function and whole-body physical fitness. Methods We prospectively studied 12 patients with rectal cancer who completed standardized neoadjuvant chemoradiotherapy, recruited from a large tertiary cancer centre, between October 2012 and July 2013. All patients underwent a cardiopulmonary exercise test and a phosphorus magnetic resonance spectroscopy quadriceps muscle exercise-recovery study before and after neoadjuvant chemoradiotherapy. Data were analysed and reported blind to patient identity and clinical course. Primary variables of interest were the two physical fitness measures; oxygen uptake at estimated anaerobic threshold and oxygen uptake at Peak exercise (ml.kg−1.min−1), and the post-exercise phosphocreatine recovery rate constant (min−1), a measure of muscle mitochondrial capacity in vivo. Results Median age was 67 years (IQR 64–75). Differences (95%CI) in all three primary variables were significantly negative post-NACRT: Oxygen uptake at estimated anaerobic threshold −2.4 ml.kg−1.min−1 (−3.8, −0.9), p = 0.004; Oxygen uptake at Peak −4.0 ml.kg−1.min−1 (−6.8, −1.1), p = 0.011; and post-exercise phosphocreatine recovery rate constant −0.34 min−1 (−0.51, −0.17), p<0.001. Conclusion The significant decrease in both whole-body physical fitness and in vivo muscle mitochondrial function raises the possibility that muscle mitochondrial mechanisms, no doubt multifactorial, may be important in deterioration of physical fitness following neoadjuvant chemoradiotherapy. This may have implications for targeted interventions to improve physical fitness pre-surgery. Trial Registration Clinicaltrials.gov registration NCT01859442背景 在英国，局部晚期直肠癌（locally advanced rectal cancer）患者常规接受新辅助放化疗（neoadjuvant chemoradiotherapy），但该治疗对患者体适能的影响尚不明确。本预试验旨在探究新辅助放化疗对客观检测的体内肌肉线粒体功能及全身体适能的影响。 方法 本研究于2012年10月至2013年7月间，从某大型三级肿瘤中心招募了12名完成标准化新辅助放化疗的直肠癌患者并进行前瞻性研究。所有患者在新辅助放化疗前后均接受了心肺运动试验（cardiopulmonary exercise test）及股四头肌（quadriceps muscle）运动-恢复磷磁共振波谱（phosphorus magnetic resonance spectroscopy）检查。数据分析及报告过程对患者身份与临床病程设盲。本研究关注的主要变量为两项体适能指标：估算无氧阈值（anaerobic threshold）时的摄氧量、极量运动（peak exercise）时的摄氧量（单位：ml·kg⁻¹·min⁻¹），以及代表体内肌肉线粒体容量的指标——运动后磷酸肌酸恢复速率常数（phosphocreatine recovery rate constant，单位：min⁻¹）。 结果 受试者中位年龄为67岁（四分位数间距Interquartile Range，IQR：64~75）。新辅助放化疗后，三项主要变量均出现显著负向变化：估算无氧阈值时的摄氧量下降2.4 ml·kg⁻¹·min⁻¹（95%置信区间confidence interval，CI：-3.8，-0.9，p=0.004）；极量运动时的摄氧量下降4.0 ml·kg⁻¹·min⁻¹（95%CI：-6.8，-1.1，p=0.011）；运动后磷酸肌酸恢复速率常数下降0.34 min⁻¹（95%CI：-0.51，-0.17，p<0.001）。 结论 全身体适能与体内肌肉线粒体功能均出现显著下降，提示尽管涉及多因素机制，肌肉线粒体相关通路可能在新辅助放化疗后体适能恶化过程中发挥重要作用。该结果可为术前改善体适能的靶向干预措施提供参考依据。 试验注册 Clinicaltrials.gov注册号：NCT01859442