An Explorative Study on Physiological and Neurophysiological Determinants of Fatigue in Cancer Survivors
Fatigue after curative treatment for cancer is a severe and invalidating problem. 20-40% of
disease-free cancer patients mention fatigue as a frequent complaint, impairing quality of
life. In search for (neuro)physiological factors determining fatigue, our centre has
recently demonstrated the presence of morphological differences in the brains of non-cancer
patients with the chronic fatigue syndrome (CFS) compared with healthy volunteers. Both in
patients with CFS and in fatigued patients with neuromuscular diseases we showed that
fatigue has a central neurophysiological component (so-called central activation failure).
Others have shown that chronic fatigue is associated with altered brain metabolism. Studies
with proton MR spectroscopy (1H MRS) have demonstrated a higher choline to creatine ratio in
the brains of chronically fatigued patients. This suggests increased cell membrane turnover.
Also reduced levels of N-acetylaspartate-creatine ratio (NAA/Cr) in the right hippocampus
have been observed in these patients, which suggests a decrease in functional axons.
Finally, elevated ventricular lactate was observed, which suggests changes in brain glucose
metabolism. Actigraphy has shown that actual physical activity in fatigued cancer survivors
is decreased compared to healthy controls. It is not known whether physical deconditioning
originated during the actual cancer treatment is the reason why these patients are still
less active. Until now no other (neuro)physiological factors have been identified explaining
fatigue in cancer survivors. Recently we have shown that Cognitive Behaviour Therapy (CBT)
especially designed for fatigued cancer patients is an effective treatment.
Aim: To identify and measure (neuro)physiological factors of fatigue in fatigued cancer
survivors and to determine the role of these factors in the maintaining of fatigue. The
identification of (neuro)physiological factors of persistent fatigue can help to improve the
diagnostics of fatigue, predict therapy outcome and facilitate other treatment options.
Finally, if (neuro)physiological characteristics of fatigue can be influenced by CBT it will
enhance our understanding of the mechanism causing fatigue.
Research questions: 1) What are characteristic (neuro)physiological factors of fatigue in
disease-free cancer patients? 2) To which degree can these factors be influenced by
Cognitive Behaviour Therapy?
Design: In this explorative study fatigued disease-free cancer patients (n=57), who finished
treatment for cancer at least one year and maximally ten years ago, will be approached for
this study and asked for informed consent. They will be compared to age and sex matched
non-fatigued patients (n=21). First, a base-line assessment will take place, which includes
magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to assess brain
morphology and brain metabolites, respectively. To assess peripheral and central fatigue a
two-minute endurance test will be administered at maximal voluntary (isometric) contraction
(MVC). During the test changes in EMG and force indicate peripheral fatigue, while central
fatigue is studied by the twitch interpolation technique. A maximal exercise test will be
performed to assess physical fitness and deconditioning. At baseline patients will also be
given an actometer which will register daily activity during two weeks. Further, the
actometer will register daily activity up to five days after the maximal exercise test.
Finally, at baseline patients will fill out a standardized questionnaire, including the
Checklist Individual Strength and a self-observation list to assess fatigue severity. Then,
the fatigued patients start immediately with Cognitive Behaviour Therapy (CBT). At the end
of the therapy, after 6 months, a second assessment will take place in this group of
patients. The assessment consists of the same measurements as at baseline. The results will
be compared with the baseline situation to analyze the effect of CBT on the
Relevance of this study: Fatigue long after treatment for cancer is a frequently occurring
problem, which has important consequences for quality of life in these patients.
Identification of characteristic (neuro)physiological factors of fatigue in disease-free
cancer patients may not only serve a theoretical understanding of this invalidating
condition, but may also provide an objective biological marker that could support the
diagnosis and follow-up of treatment. The identification of (neuro)physiological factors
which play a role in fatigue after cancer may aid in the early recognition of patients who
are at risk for developing fatigue and may lead to early intervention and/or different
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Possible (neuro)physiological determinants of postcancer fatigue
MRI to assess brain morphology; MRS to assess brain metabolite concentrations; sEMG and force registration to assess central and peripheral muscle fatigue; maximal exercise test to assess physical condition; actometer measurements and self-observation list to assess daily activity and symptoms; standardized questionnaires to assess fatigue severity and general health; neurological tests to assess information processing and motor speed; screening of blood and urine to find possible explanations for postcancer fatigue.
The measurements will be performed at baseline and comparable measurements will be performed 6 months later (after 6 months cognitive behavior therapy or 6 months waiting list condition)
H.W.M. van Laarhoven, Md
University Medical Centre Nijmegen
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)