The effect of neoadjuvant chemotherapy on physical fitness and survival in patients undergoing oesophagogastric cancer surgery
Introduction
Worldwide, oesophageal cancer is the eighth most common cancer and the sixth most common cause of cancer-death, while gastric cancer is the fifth most common cancer and third most common cause of cancer-death.1 In England and Wales, approximately 11,500 patients were diagnosed in 2013, of which 35% underwent planned curative resection.2 Although potentially curative, surgical resection has a significant morbidity and mortality3, 4; recent national audit data report 90-day mortality for oesophagectomy and gastrectomy as 3.2% and 2.8% respectively, with 1-year survival rates between 76.1% and 78.0% depending on the site of the primary tumour.2
A recent meta-analysis provides evidence that for operable, early stage disease neoadjuvant chemotherapy improves survival over surgery alone5 and in the UK the MAGIC trial has resulted in practice change in favour of NAC.6 However treatment with NAC carries the risk of toxicity and in clinical practice this may be associated with an increased risk of surgical morbidity.5 Physiological toxicity includes down-regulated muscle proteasome dependent proteolysis leading to skeletal muscle wasting,7 oxidative stress8 and mitochondrial death.9 Although not statistically significant, sub-group analysis from the MAGIC study6 demonstrated efficacy of NAC before upper gastrointestinal (UGI) surgery and suggests that less fit patients benefit less from NAC than fitter patients.
Traditionally ‘fitness’ has been measured using crude tools (Eastern Cooperative Oncology Group Performance Status), the assessment of which often varies significantly between clinicians.10 An objective measure of physical fitness is therefore of significant clinical interest, provided the assessment can be undertaken non-invasively and reproducibly.
Oxygen consumption increases after major surgery and a greater physiological reserve may allow patients to better tolerate this metabolic stress.11 Cardiopulmonary exercise testing (CPET) provides an objective assessment of cardio-respiratory function under the stress of exercise. Lower levels of physical fitness, as defined by oxygen uptake at estimated lactate threshold and at peak exercise (peak) assessed by CPET, are associated with worse outcome following general8, 9, 10, 11 and UGI surgery.11, 12, 13, 14, 15 A systematic review14 concluded that CPET derived variables outperform alternative methods of preoperative risk stratification: 11 of 12 studies reported a significant association between at and postoperative outcome and 7/12 studies for at peak.
In this study we set out to quantify CPET derived physiological parameters with the aim of assessing, whether the change of these variables over the course of NAC can be used to identify patients whose outcome is adversely affected by NAC.
Section snippets
Methods and materials
We conducted a single-centre, prospective, observational cohort study to test the hypothesis that NAC prior to UGI cancer surgery has a harmful effect on physical fitness. We used at , assessed using CPET as a tool to measure physiological fitness. The ultimate aim was to assess whether changes in at have an effect on overall survival. Research Ethics Committee approval (08/H1001/137; 08/H1001/139) and written informed consent were obtained. This study is registered with //ClinicalTrials.gov
Discussion
This study is the first to report the effect of NAC prior to surgery on objectively measured physical fitness using CPET and identifies a reduction in at and peak following NAC. Our data support that CPET is a predictive biomarker, which identifies patients whose outcome may be adversely affected by NAC. Using a physiologically robust method we have shown a significant impact of NAC on physical fitness, in contrast to a recent study using self paced exercise tests only.23
Acknowledgements
The authors would like to acknowledge the Upper Gastrointestinal Multidisciplinary team at Aintree University Hospitals NHS Foundation Trust for their patient input and Dr. A Bateman, Consultant Clinical Oncologist and Senior Lecturer at the University of Southampton for the oncological input.
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