The effect of radiotherapy on glucose metabolism in patients with rectal cancer; a feasibility study

Insulin resistance is a state of insensitivity of tissues for action of insulin
leading to hyperglycemia, a situation similar to non-insulin dependent diabetes
mellitus. It is well known that insulin resistance occurs after surgery and is
related to the severity of the procedure performed. The negative correlation
between insulin resistance and postoperative recovery, either by prolonging the
capacity of the body to regain normal function, or by increasing the metabolic
stress and the risk for complications, has already been confirmed (1,2). The
precise mechanism underlying the occurrence of perioperative insulin resistance
is unknown, but the latest insights point to an important role for oxidative
stress. Oxidative stress is the consequence of an imbalance between the
production of oxidant species and their neutralization by antioxidants.

Radiotherapy induces oxidative stress in tissues, an important mechanism of
inducing tumor cell apoptosis. However, the oxidative effects of radiotherapy
are not limited to the site of radiation but also induce systemic effect as
identified by peroxidation of plasma lipids (3, 4). Lipid peroxidation occurs
mainly through formation of free radicals and causes membrane damage as well as
oxidative modification of critical targets (5). The relationship between
radiotherapy and insulin resistance has been described before. Chemaitilly et
al. observed frequently insulin resistance in adult survivors of haematopoietic
stamcelltransplantation treated with total body irradiation in childhood in
their study (6). Furthermore, in 1997 Cicognani already described an impaired
insulin response in some patients treated for Wilms* tumour in childhood,
mainly in male patients who received abdominal radiotherapy (7). To our
knowledge there are no data on the effect of radiotherapy in adults.

Preoperative radiotherapy in combination with total mesorectal excision is the
treatment of choice in rectal cancer reducing local recurrence rate < 5%. Most
of the patients with rectal cancer receive short-term preoperative
radiotherapy for 5 days (5 x 5 Gy) and some with more extensive tumours
receive this dose during 5 weeks.
Insulin resistance is considered a risk factor in the development of
complications.

The hypothesis of the present study is that insulin resistance is induced by
preoperative radiotherapy in rectal cancer patients and mediated by oxidative
stress.
The effects of radiotherapy on the induction of insulin resistance are unknown
therefore a feasibility study will be performed using the oral glucose
tolerance test (OGTT) before and during the course of radiotherapy. Plasma
samples will be taken to measure oxidative stress parameters.

Primary objective:
Effect of preoperative radiotherapy on insulin resistance in rectal cancer
patients.

Secondary objectives:
Effect of preoperative radiotherapy on plasma oxidative stress parameters.

Study description
Glucose metabolism of 10 patients, scheduled for radiotherapy as preoperative
therapy in rectal cancer, will be studied using the oral glucose tolerance test
(OGTT). Oral glucose tolerance testing is a sensitive technique that can detect
sub clinical glucose metabolism disorders and discern between increased
resistance and impaired insulin production. The test will be performed in the
morning after an overnight fast both before and after radiotherapy. Glucose
(0.5 g/kg body weight, maximum 75 g glucose) will be administered orally for 4
minutes. Blood samples for measurement of whole blood glucose, C-peptide and
insulin will be taken from the opposite arm at t= -15, 0, 5, 10, 15, 20, 30,
40, 50, 60 min.
Insulin resistance will be estimated by the homeostatic model assessment
(HOMA-IR), insulin sensitivity by the ratio of fasting glucose (GF) to fasting
insulin (IF) (GF/IF), and the quantitative insulin sensitivity check index
(QUICKI) (7,8). The calculations are as follows: HOMA-IR=(fasting insulin
(mU/ml) X fasting glucose (mmol/l) / 22.5); insulin resistance will be defined
as HOMA-IR>2; GF/IF in mg/dl for glucose and mU/ml for insulin; QUICKI=1/[log
(fasting insulin (mU/ ml)) + log (fasting glucose (mg/dl))]; impaired insulin
sensitivity was defined as QUICKI<0.339.
To determine oxidative status, plasma samples will be drawn three times during
a 5 days session of a 5 X 5 Gy radiotherapy course as preoperative therapy in
rectal cancer patients. Plasma samples will be drawn before the start of
radiotherapy, on day 3 and day 5 during the radiotherapy course. Samples will
be taken after an overnight fast.
The parameters we are interested in are glucose, insulin, C reactive protein,
Malondialdehyde, oxidative LDL and HbA1c.
In addition a bio-impedance measurements will be performed to study body
composition and monitor fluid shift during radiotherapy.

The patients have to undergo 3 times an OGTT. At these moments, some blood will
be taken for further analysis.