Trial Information

Feasibility Study of Preoperative Exercise Intervention in the Resection of Colorectal Liver Metastasis.

Prehabilitation in Liver Surgery

Introduction Thirty per cent of patients with colorectal cancer have metastatic disease at
time of presentation, and a further 20% will develop liver metastases after the primary
colorectal malignancy has been resected. Liver resection offers the prospect of cure for a
proportion of these patients and, with the increasing use of effective neo-adjuvant
chemotherapy, this proportion is increasing. However, liver surgery is associated with
significant morbidity and mortality and this may be higher in patients with comorbidity,
poor cardiorespiratory fitness and in those who have received neo-adjuvant chemotherapy.

Cardiopulmonary exercise testing (CPET) is a non-invasive assessment of cardiovascular and
pulmonary function, which can be quantified by measures such as anaerobic threshold (AT) and
VO2peak. The anaerobic threshold is a measure of sustainable exercise, where the VO2peak is
a measure of maximal exercise capacity. The AT has been assessed in different surgical
groups and has been shown as a useful predictor of postoperative complications and survival.
Early work has demonstrated that short periods of preoperative exercise intervention can
improve AT and VO2peak. However, no work has to date been undertaken in patients prior to
liver surgery.

Hepatic glucose metabolism provides much of the energy requirements of the postoperative
period. Work has demonstrated that exercise training increases hepatic glucose production,
and that its inhibition has a marked effect on endurance capability. This may be
particularly relevant when surgical resections can involve resection of up to 80% of hepatic
tissue. However, a link between hepatic gluconeogenic capacity and fitness as assessed by
cardiopulmonary exercise testing has not been established.

A demonstrable link between gluconeogenic capacity and cardiopulmonary fitness and an
explanation of its underpinning physiology would help explain some of the systemic effects
of drug hepatotoxicity. It would also allow development of strategies to improve
gluconeogenic capacity that may reduce complications and improve tolerance of many hepatoxic
agents such as chemotherapy.

Hypothesis

1. A short exercise program can significantly improve the CPET defined anaerobic threshold
prior to liver surgery in a cancer population and this will be associated with reduced
post-operative morbidity and mortality.

2. Hepatic gluconeogenic capacity will be associated with cardiopulmonary fitness.

3. Gluconeogenic capacity will be associated with mitochondrial number and quantity of
enzymes which are integral to gluconeogenesis such as PEPCK

Methods Patients with colorectal liver metastases suitable for hepatic resection will
undergo a baseline CPET and then be randomised to either preoperative exercise intervention
or standard care. Patients within the intervention arm will undergo a 4 week exercise
program consisting of 3 interval sessions per week on a stationary bike. This will be
individually tailored according to their initial exercise test. In the week prior to surgery
all patients will then undergo a further CPET. At surgery liver tissue will be taken to
determine hepatic gluconeogenic capacity. CPET tests will then be performed where possible
in patients at 6 weeks and 3 months following surgery. Post-operative complications (Clavien
classification and Postoperative morbidity score (POMS)) and 30 and 90-day mortality will be
recorded. Quality of life assessments (EORTC/SF-36) will be taken at recruitment, the week
prior to surgery, 6 weeks after surgery and 3 months following surgery.

Laboratory Analysis Hepatic gluconeogenic capacity will be assessed by direct analysis of
fresh slices of hepatic tissue taken at the time of surgery. Slices will be taken using the
Krumdiek MD6000 tissue slicer. These will be weighed an incubated in a buffer containing
lactate. Glucose will be measured using the Glucose Oxidase assay, and calculated per mg
wet weight of hepatic tissue. Further analysis of mitochondrial number and ATP production,
and enzymatic levels will be conducted following initial results.

Statistical considerations This is a study of a continuous response variable from matched
pairs of study subjects and will need 38 patients to detect a true difference 1.5ml/min/kg,
with a probability 0.8 and Type I error 0.05). Anticipated recruitment period is 10 months
assuming a dropout rate of 20%. Randomisation is by computerised block randomisation, and
patients will be stratified by receipt of neo-adjuvant chemotherapy.