How may exercise reduce fatigue in patients with cancer. A pilot study examining the role of muscular, immune and endocrine systems.

Survival after cancer has substantially improved due to advances in early
detection and treatment. In the Netherlands, the current 5-year survival rate
of patients with colon cancer is 94% for patients with stage I, 78% for stage
II and 59% for stage III. For stage IV, 5-year survival rates are only 7%.
Cancer and its treatment are often associated with prolonged adverse
psychosocial and physical symptoms, including decreased physical fitness,
reduced lean body mass, bone loss, increased risk for anxiety and depression
and fatigue. Particularly fatigue has been identified as one of the most common
and distressing symptoms of patients with cancer affecting quality of life
(QoL). Approximately 70% of patients with cancer report fatigue complaints
during chemotherapy and/or radiotherapy. Even years after the end of treatment,
fatigue is still a major problem for at least 30% of cancer survivors. In a
previous study in a large group of colorectal cancer (CRC) survivors (n= 1371)
we showed that fatigue was present in 42%. This number is considerably higher
than in the general population; results from the Maastricht Cohort Study showed
that prolonged fatigue is present in 22% of the general Dutch working
population.
Reducing fatigue is a key component in optimising daily functioning and
QoL of patients with cancer and survivors. However, a main barrier to effective
management of fatigue is the inadequate understanding of its aetiology. To
date, specific mechanisms that cause and maintain fatigue are not yet known.
Fatigue is a multidimensional concept covering physiological,
biological and psychological aspects. Psychological aspects of fatigue include
anxiety and depressive symptoms. In addition perceived fatigue may be
influenced by concentration, physical activity, and social functioning.
Physiological fatigue is usually defined as the loss of voluntary
force-producing capacity during exercise, and can both (and simultaneously)
have a peripheral and central origin. Peripheral fatigue refers to the loss of
force in the muscle tissue after constant activation. Central fatigue refers to
a decrease of voluntary activation of the muscle by the nervous system, leading
to a suboptimal input from the nervous system to the muscle. As a consequence,
the muscle is not able to develop its maximal force capacity. Central and
peripheral fatigue can be assessed by measuring contractile muscle properties
(e.g. force production, speed of force development and speed of relaxation),
and muscle fatigability after/during repeated contractions.
The muscular system is the body*s largest metabolic organ system, and
therefore has an important role in human functioning. Interestingly, skeletal
muscle has been shown to have great adaptability with appropriate training
stimuli even in cases of severe muscle atrophy and fatigue. Exercise in
patients with cancer, and particularly resistance training can counteract the
reduced muscle mass and strength, and bone mass. Previous studies showed that
exercise may improve muscle mass and strength, reduce fatigue and improve the
QoL in cancer patients during and after treatment. Epidemiological studies
further showed that physical activity after the diagnosis of stages I to III
CRC may reduce the risk of CRC-specific and overall mortality. In patients with
metastatic breast cancer treated with capecetabine, Prado et al. showed that
sarcopenia (severe atrophy of skeletal muscle) was an important predictor of
toxicity and time to tumour progression. Therefore, exercise may even be more
important in patients with metastatic disease in which sarcopenia and fatigue
is more present. So far, little is known about the effects of exercise on
health outcomes and survival in patients with stage III CRC.

Biological aspects include the function of the immune and endocrine systems.
Cancer and its treatments may alter immune system function. C-reactive protein
(CRP) is a sensitive marker of low-grade systemic inflammation. In cancer
survivors, elevated concentrations of CRP have been found to be associated with
fatigue and reduced overall and disease-free survival. Exercise can have a
beneficial effect on the immune system of cancer survivors. Reductions in CRP
after exercise were found in an observational study among breast cancer
survivors and randomised controlled trials (RCTs) among survivors of breast,
lung, and prostate cancer.
Pro-inflammatory cytokines (e.g. tumour necrosis factor-alpha (TNF-*)
and Interleukin (IL)-6) may be released in response to the tumour or cancer
treatment, and may promote tumour growth and angiogenesis. TNF-* and IL-6 have
been associated with cancer-related anaemia, cachexia, loss of muscle mass, and
cancer-related fatigue. Exercise may have an anti-inflammatory effect in cancer
survivors, as cytokines may be expressed and released by muscle fibres.
However, no change in IL-6 levels after exercise was found in 20 patients with
breast cancer. Comparably, a study in 10 patients with prostate cancer did not
find changes in resting serum concentrations of IL-6 and TNF-* after a 20-week
resistance exercise program, but increased IL-6 levels were found after acute
resistance exercise. Exercise has been shown to improve Natural Killer cell
cytotoxity among cancer survivors, indicating improved immune function. Other
beneficial effects included increased lymphocyte proliferation and granulocyte
cell counts. Although evidence is still preliminary, exercise may be associated
with beneficial changes in inflammation and immunity. However, the effect of
chemotherapy on the immune system responses, and the potential preventive
effect of exercise in patients with colon cancer, and the mediating role in
reducing fatigue, improving QoL and survival is unclear.
Insulin, Insulin-like growth factor (IGF), and IGF binding proteins
(IGFBP) are important regulators of energy metabolism and growth, and may also
be involved in tumour development and progression. High insulin levels have
been associated with increased risk of tumour recurrence or death in survivors
of breast and colon cancer. In addition, there is increasing evidence
suggesting that insulin, IGF and IGFBP may have an important mediating role in
the effect of exercise on cancer risk and prognosis. Recently, Ballard-Barbash
et al. systematically reviewed studies among cancer survivors examining
associations between exercise and biomarkers. One observational study and four
RCTs evaluated effects of exercise on insulin, IGF and IGFBP among breast
cancer survivors. Higher levels of exercise were found to be associated with
lower levels of C-peptide (marker of insulin secretion) and leptin, and higher
levels of IGF-1, but no association was found for IGFBP-III. Results from RCTs
provide preliminary evidence that exercise may result in beneficial changes in
the circulating levels of insulin and insulin-related pathways, which may be
more pronounced for obese or sedentary women who generally have higher serum
insulin levels at baseline, and for women who are not taking Tamoxifen.
Weighted-mean effect size of the effect of post-treatment exercise on IGF-1 was
found to be significant but small-to-moderate. No changes were reported for
insulin and IGFBP-III, and evidence was insufficient for IGF-II and IGFBP-I.
The number of studies on the effects of exercise on insulin, IGF and IGFBPs
during treatment was too small to draw conclusions. Therefore, more insight in
the effect of cancer treatment on the endocrine system function and the
potential beneficial effects of exercise is necessary.

More insight into the mechanisms through which exercise exerts its
effect on fatigue should provide information for more potent and effective
interventions. Exercise during chemotherapy may prevent deterioration or
improve function of the muscular, immune and endocrine systems.

Primary Objective(s):
1. To obtain preliminary data on whether (and to which extend) adjuvant
chemotherapy for colon cancer results in (a) deterioration of contractile
muscle properties and increased muscle fatigability, (b) increased
inflammation, (c) deterioration of the insulin pathway (within group
differences in group A).
2. To obtain preliminary data on whether (and to which extend) resistance and
endurance exercise can prevent adjuvant chemotherapy-induced deterioration of
or improve (a) contractile muscle properties and muscle fatigability, (b)
immune system function (i.e. reduced inflammation), (c) endocrine system
function (i.e. improved insulin pathway) in patients after surgery for colon
cancer (differences between group A and B).

Secondary Objective(s):
1. To obtain preliminary data on whether improvement in function of the
muscular, immune and endocrine systems are associated with:
a. Reduced perceived fatigue
b. Improved health-related quality of life (HRQoL)

This prospective pilot randomized controlled trial (RCT) will compare a nine or
twelve weeks resistance and endurance exercise program to a usual care control
group. All potentially eligible patients will be identified and informed of the
study by their treating medical oncologist. They will receive written
information of the study to take home. If the patient decides to participate in
the study, he or she will sign the informed consent.
Following consent, the baseline measurements will take place. Subsequently, the
participating patients will be randomized into one of the two study groups and
will be informed of the result of randomization. Prior to randomization,
patients will be stratified by gender.
Group A will receive a 9 or 12-week (depending on the duration of chemotherapy
treatment) resistance and endurance exercise intervention in the first half of
chemotherapy treatment. Group B will receive usual care in the first half of
chemotherapy treatment. Current usual care does not contain a structured
exercise training. However, since usual care for patients with cancer is
rapidly changing towards the inclusion of physical activity and exercise
programs, we will also offer the same exercise intervention to group B, but
starting mid-chemotherapy treatment (after 9 or 12 weeks). This allows us to
examine the effects of chemotherapy on muscular, immune and endocrine systems
and the potential beneficial effects of exercise.
Function of the muscular, immune and endocrine system, as well as perceived
fatigue and QoL are measured at baseline (T0), mid-chemotherapy treatment (T1),
and after chemotherapy treatment (T2).

Resistance and endurance exercise: the CytoFys program.
Patients will participate in a 9 or 12-week resistance and endurance exercise
intervention during chemotherapy. They will be randomly assigned into two
groups. Patients in the first group (group A) will start the exercise program
immediately, e.g. at start of the chemotherapy, and patients in the second
group (group B) will start 9 or 12 weeks after they started chemotherapy
(mid-chemotherapy treatment). In the CytoFys program, resistance and endurance
exercise and will be performed twice a week under supervision of a
physiotherapist.

Laboratory visits: measurement of contractile properties and fatigability of
muscles and blood samples
Patients will visit the laboratory on three occasions (see figure 1): at
baseline (T0), mid-chemotherapy treatment (T1) and after completing
chemotherapy treatment (T2).
During these visits, contractile properties of the muscle and fatigability will
be determined, using electro stimulation of the muscles of the upper leg (m.
quadriceps) (see methods). In addition, during each visit patients will fill
out questionnaires to assess perceived fatigue and HRQoL, and their physical
activity and fitness levels will be assessed. At the start of each visit, a
venous blood sample (ca 43 ml) will be drawn. Each visit will last
approximately 120 minutes.
Participants are requested to avoid any moderate and/or vigorous intensity
activity or to consume any alcohol for at least 48 hours prior to the
laboratory visits, and to refrain from eating or drinking sugar-containing
beverages 2 hours prior to the visit.

We expect the risk associated with participation to be negligible. The only
burden for the patients is the time investment, and not being able to consume
alcohol or conduct vigorous exercise 48 hours prior to the measurement and
eating or drinking suger-containing beverages 2 hours prior to the measurements.
In clinical practice, it has been shown that CytoFys is feasible for cancer
patients. At baseline, mid-chemotherapy treatment and after chemotherapy
treatment, patients will visit the laboratory (VU University, Faculty of Human
Movement Sciences) for approximately 120 minutes. During these sessions, muscle
properties and fatigability will be assessed, and venous blood samples will be
drawn to assess inflammation and insulin-pathway. Both measurements of muscle
properties and fatigue have been shown to be feasible in various groups of
patients.
The effect of physical exercise on muscle properties, inflammation and the
insulin-pathway, and the relationship with fatigue and HRQoL in CRC and breast
cancer patients stage II/III is still unclear. We expect exercise to have
beneficial effects on these outcomes.