The effect of colon cancer on muscle gene expression, body composition, muscle function, and muscle metabolism

Cachexia is a complex metabolic syndrome characterized by clinically relevant
loss of muscle mass with or without loss of fat mass. Progression of this
condition can severely impact therapy, quality of life and prognosis. In many
patients cachexia is associated with reduced treatment efficacy and quality of
life. Moreover, animal work has shown that not only skeletal muscles but also
the heart is affected in cancer cachexia.

According to the definition of cachexia focusing on loss of muscle mass
and function, a cachectic person not necessarily has to have a low BMI.
According to this definition a patient is cachectic if there has been 5% weight
loss up to the preceding 12 months or if the BMI of the patient is below 20,
plus a combination of three out of five of the following phenomena: a decreased
muscle strength, fatigue, anorexia, a low fat-free mass index or an abnormal
biochemistry.

Cachexia has been estimated to be responsible for approximately 20% of
deaths in cancer and in the western world about 30% of all individuals with
cachexia, are cancer cachexia patients (US >1.3 million people). Although the
condition is frequently seen in various types of cancers, the highest
incidences are observed in lung cancer and tumors of the GI tract. Colon cancer
(CC) is the third most common cancer worldwide. About 30% of CC patients
exhibit cachexia at diagnosis and response to treatment (either surgical or
chemotherapy) is hampered by the presence of cachexia in these patients.
Moreover, surgery further adds to the muscle mass loss. Next to that it has
been described that patient do not gain muscle after surgery, even though the
muscle is no longer resistant to anabolic triggers after removal of the tumor
(surgery). This absence of regaining muscle mass after removal of the tumor
could be due to a combination of an inadequate protein intake and a reduction
in daily activity.
Due to the multi-factorial nature of the disease (both anabolism and
catabolism are affected), treatment should consist of a combination of
interventions (i.e. pharmacology, nutrition and training). To determine how
treatment methods can be most effective, full mechanistic insight in changes in
body composition, gene expression, muscle metabolism and muscle function are of
great importance.

Primary Objective:
Main aim of the study is to investigate in detail the differences in gene
expression, body composition, muscle function and muscle metabolism in colon
cancer patients compared to controls.

Secondary objectives:
Secondary aim of the study is to investigate whether there are differences
between colon cancer patients in different stages of cachexia and how these
factors are inter-related.

• Before the surgery (D-1) patients will come to the hospital (measurement
duration: +/- 1.5 hours). This visit will be combined with the regular care as
much as possible (physiotherapy visit of colon cancer patients or the visit to
the anesthesiologist in the control patients).
The following measurements will be done:
(1) questionnaire on physical and functional wellbeing and anorexia/cachexia
(three subscales of the FAACT)
(2) a muscle function test (hand grip strength).

• On the day of the surgery (D0) patients come in fasted for regular care
procedures.
Fasted blood samples (total 55 mL) will be collected after inserting an
intravenous cannula in the holding area (regular care), to identify levels of
CRP, IL-6, Hb and albumin, cytokine levels and micronutrient status.
During the surgery a biopsy (1 cm3) of the rectus abdominis muscle will be
taken and immediately aliquoted and frozen for 1) transcriptomics, 2) protein
metabolism parameters, 3) histology and 4) single fiber measurements. For
clarification of the cachexia process also biopsies from the subcutaneous and
visceral fat will be taken (0.5 cm3 ¬each). Biopsies are taken as early as
possible during the operation to minimize influence of anesthetics.
• One year after tumor removal (Y1) patients will be asked to come fasted to
the hospital (measurement duration +/- 15 minutes). Blood samples (total 55 mL)
will be collected to identify basal levels of CRP, IL-6, Hb and albumin,
cytokine levels and micronutrient status. In vivo muscle function (hand grip
strength) will be measured. Patients will fill out a questionnaire on physical
and functional wellbeing and anorexia/cachexia (three subscales of the FAACT).

Benefits and risks assessment, group relatedness

Potential value of research
The current study will give insights into relation between body composition,
immune reaction, muscle function and gene expression. With these insights,
indications can be found for targets for pharmacological, nutritional and/or
exercise intervention.

Benefits and risk participants
Since the proposed study is an observational study that comprises no
intervention, no benefits for the participants are expected. Risks for the
patients are also considered minor. Research visits to the hospital will be
combined with visits for regular care. Time consumption for the patients is
minor +/- 3 hours. In total 110 mL of blood will be collected.

Study procedures with possible risks are described shortly below:

Muscle and fat biopsies
Because all surgery involved a surgical procedure of the abdomen, the abdomen
will be opened during all procedures. This means that the biopsies of muscle
and fat taken will be of very less extra burden to the patient.