Abstract
BackgroundIn 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.MethodsWe 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.ResultsMedian 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.ConclusionThe 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 RegistrationClinicaltrials.gov registration NCT01859442
Highlights
In the UK colorectal cancer is the third commonest cause of cancer death [1, 2]
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
We have previously demonstrated a significant reduction in objectively measured physical fitness with neoadjuvant chemotherapy in upper gastrointestinal cancer which was associated with reduced 1 year survival [20] and a similar reduction in fitness with neoadjuvant chemoradiotherapy in rectal cancer which was associated with in-hospital morbidity [21]
Summary
In the UK colorectal cancer is the third commonest cause of cancer death [1, 2]. In 2013, ,9000 patients were diagnosed with rectal cancer (35% aged .75 y), of whom ,4600 underwent major resection with a 90-day elective postoperative mortality of 2.5% [3]. 25% are locally advanced (Tumour, Node, Metastasis (TNM) stage - T3/T4N+) cancers (i.e. resection margin threatened) considered for neoadjuvant chemoradiotherapy (NACRT) to control local disease and to achieve tumour downsizing and negative resection margins [4,5,6,7,8]; external beam radiation and oral or intravenous fluoropyrimidines causes doselimiting toxicity, reaching Grade 3–5 in 20% (Common Terminology Criteria for Adverse Events, Version 3.0). We have previously demonstrated a significant reduction in objectively measured physical fitness with neoadjuvant chemotherapy in upper gastrointestinal cancer which was associated with reduced 1 year survival [20] and a similar reduction in fitness with neoadjuvant chemoradiotherapy in rectal cancer which was associated with in-hospital morbidity [21]. Whether and how this impaired physical fitness relates to changes in mitochondrial function is unknown. Primary variables of interest were the two physical fitness measures; oxygen uptake at estimated anaerobic threshold and oxygen
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