Trial Information

Changes in Aerobic Capacity and Body Composition in Colon Cancer Patients Receiving Chemotherapy

Background Information: Recent evidence has suggested that the physical activity levels and
body composition of colorectal cancer survivors can impact the disease-free and overall
survival following diagnosis, with those individuals who are more overweight or obese and
less active at greater risk of a recurrence of or dying from colorectal cancer (Meyerhardt
et al, 2006a,b; Digman et al, 2006). Chemotherapy treatments have been shown to improve
survival in a number of cancer populations, but unfortunately they have also been shown to
negatively impact numerous physiological and psychological variables, including reduced
exercise capacity, self-reported physical functioning and activity levels, and negative
changes in body composition (Schmitz et al, 2005). This suggests that chemotherapy
treatments may negatively impact variables that have been associated with survival in
individuals diagnosed with colorectal cancer. However, this research has been conducted in
cancer populations other than colorectal cancer patients, hence the specific impact of the
chemotherapy treatments for colorectal cancer on these outcomes is not known.

Objectives: The primary objective of the study is to determine the effects of chemotherapy
treatments on the aerobic capacity and body composition of colon cancer patients. Secondary
objectives are to determine the effects of chemotherapy treatments on quality of life,
fatigue, performance status, self-reported and objectively measured physical functioning,
exercise behaviour, oxygen uptake kinetics, muscular strength, and anthropometric variables.

Study Design: The study parameters assessed will include descriptive information on
demographic, lifestyle and medical variables; a graded exercise test with metabolic
measurement to determine peak oxygen consumption (VO2peak); air-displacement plethysmography
(BOD POD) testing and anthropometric measurements (waist & hip circumferences, waist-to-hip
ratio, body mass index) to assess body composition; a questionnaire to determine
cancer-specific quality of life and fatigue (Functional Assessment of Cancer Treatment -
Colorectal and Fatigue); performance status assessment (Eastern Cooperative Oncology Group
performance status); self-reported (Medical Outcomes Study Short Form-36 Physical Function
Scale) and objectively measured (Physical Functional Performance-10 and Senior's Fitness
Tests) physical functioning; self-reported exercise behavior (Godin Leisure Time Exercise
Questionnaire); submaximal exercise test with metabolic measurement to determine oxygen
uptake kinetics; an 8-repetition maximum test to assess upper (bench press) and lower (leg
press) body muscular strength; and a fasted blood sample to be used for future biomarkers
assays. All of these assessments will be completed at baseline prior to the subject's first
chemotherapy infusion, and 1 and 6 months after the completion of all chemotherapy
infusions.

The following calculation was used to estimate the required sample size based on the primary
outcome of aerobic capacity (Peak Oxygen Consumption; VO2peak): n = 2 + C (s/d)2 (Snedecor
et al, 1989), where C is a constant equal to 7.85 for a power of 0.80 and alpha of 0.05, s
is the standard deviation of 6.0 ml/kg/min, and d is a 3.5 ml/kg/min difference between
groups. Therefore, a sample size of 25 subjects is required to detect a 1 Metabolic
Equivalent (MET) or 3.5 ml/kg/min reduction in VO2peak in colorectal cancer survivors
following the completion of chemotherapy treatment, with a standard deviation (SD) in oxygen
consumption of 6.0 ml/kg/min, a power of 0.80, and an alpha set at p<0.05 (two-tailed). Each
1 MET change in exercise capacity has been positively associated with a 12% difference in
overall survival in the general population (Myers et al, 2002). A sample of 30 subjects will
be recruited to account for any subjects lost to follow-up. To compare the effects of
chemotherapy treatment on the study assessments to colon cancer surgery alone, 10 subjects
will be recruited to complete all of the study assessments at the same 3 time points to
allow for a "surgery only" comparison group.

Inclusion/Exclusion Criteria: Inclusion criteria will include: 1)histologically confirmed
colon cancer (Stage III and those Stage II patients deemed high-risk 2) approval of the
treating oncologist 3) they will receive chemotherapy 4) able to understand and provide
written informed consent in English 5) 18+ years of age 6) no uncontrolled co-morbidities
(including hypertension, cardiac illness, psychiatric condition, etc.) negative ECG as
assessed during maximal graded exercise test *Ten patients meeting all eligibility
requirements except for criteria 3 will be recruited to the study to serve as "surgery only"
controls.

Exclusion criteria include 1) metastatic or recurrent colon cancer patients; 2) pregnancy;
3) any uncontrolled medical condition that would be a contraindication to exercise (assessed
by treating oncologist); 4) unwilling to attend, travel to, or participate in the
assessments at all 3 time points.

Recruitment: Patients will be recruited from outpatient colorectal clinics at the Cross
Cancer Institute. The project coordinator will be present at all clinics, and in conjunction
with the treating oncologist and clinic nurses will screen patient lists to determine
eligibility for that day. The treating medical oncologist will have final determination of
patient eligibility for the study and will introduce the trial to the patient if they are
deemed to meet all eligibility requirements. If the patient expresses interest, he or she
will be approached by the project coordinator who will discuss the study in further detail
and will also give the patient a study information package. The patient will be told that a
follow-up phone call will be made in the next few days to confirm if the patient is
interested in participating in the trial. If the patient is still interested, all baseline
testing appointments will be scheduled. Based on an estimate of 8 new colon cancer patients
eligible for the study in clinic per week and a 15% accrual rate, it should take
approximately 36 weeks to recruit the required number of subjects (n = 30).

Statistical Analysis: Data will be analyzed using SPSS version 15.0 software (SPSS, Inc.,
Evanston, IL). The principal analyses of end points will employ the last observation
carried forward approach. Independent t-tests will be used to test for variables
differentiating between patients accepting/declining participation and completing/dropping
out of study. Descriptive statistics will be used to summarize all study assessment data at
each time point. The changes in measured outcomes from baseline to post-chemotherapy (4
weeks post) to recovery (24 weeks post-chemotherapy) will be analysed using a one-way
analysis of variance for repeated measures. Any differences in study outcomes between
subjects receiving chemotherapy versus those who are receiving surgery alone will be
analysed using a two-way analysis of variance for repeated measures.

Stopping Rules: Subjects are free to withdraw from the study at any time, which includes
stopping at any point during any of the study assessments.

Data Safety Monitoring Committee: Ethical and scientific approval will be obtained from
Alberta Cancer Board and the Health Ethics Research Board at the University of Alberta. All
data will be number coded so that the identity of participants cannot be traced. All data
will be kept in a secure, locked cabinet in the Behavioral Medicine Laboratory and will only
be accessible to members of the research team. The local Institutional Research Ethics
Boards will oversee the validity and integrity of data by conducting periodic audits of
study records.

The safety of participants will be of primary concern at all times. Study investigators will
monitor participants during all study assessments. All adverse events, however minor, will
be recorded. All serious adverse events will be reported to the local Institutional Research
Ethics Boards, as well as each participant's treating oncologist. The project coordinator,
under the supervision of the principal investigator, will be responsible for reporting any
serious adverse events.

References:

Dignam JJ, Polite BN, Yothers G, Raich P, Colangelo L, O'Connell MJ, Wolmark N. (2006). Body
mass index and outcomes in patients who receive adjuvant chemotherapy for colon cancer.
Journal of the National Cancer Institute. 98:1647-1654.

Meyerhardt JA, Giovannucci EL, Holmes MD, Chan AT, Chan JA, Colditz GA, Fuchs CS. (2006a).
Physical activity and survival after colorectal cancer diagnosis. Journal of Clinical
Oncology. 24:3527-3534.

Meyerhardt JA, Heseltine D, Niedzwiecki D, Hollis D, Saltz LB, Mayer RJ, Thomas J, Nelson H,
Whitton R, Hantel A, Schilsky RL, Fuchs CS. (2006b). Impact of physical activity on cancer
recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803.
Journal of Clinical Oncology. 24:3535-3541.

Schmitz KH, Holtzman J, Courneya KS, Masse LC, Duval S, Kane R. (2005). Controlled physical
activity trials in cancer survivors: a systematic review and meta-analysis. Cancer
Epidemiology, Biomarkers & Prevention. 14:1588-1595.

Snedecor G, Cochran W, Cox D. (1989). Statistical Methods (8th ed). The Iowa State
University Press.