Colorectal Cancer Clinical Trial
Official title:
I-Walk-CRC - Feasibility and Efficacy of Interval Walking in Patients With Colorectal Cancer
Background: The level physical exercise is strongly associated with colorectal cancer risk in
the general population, and recent data shows that physical activity after a colorectal
cancer diagnosis is inversely associated with mortality risk, indication the physical
exercise can protect against disease progression. However, few studies have successfully
performed exercise interventions in patients with colorectal cancer, and the potential
mechanisms responsible for the tumor suppressing effects of exercise remain poorly explored.
Purpose: To investigate interval-walking, delivered by the InterWalk smart phone application
as exercise-modality in patients with colorectal cancer. Specifically it is the aim to
explore if InterWalk is safe and feasible as well as effective to improve cardio-metabolic
health profile.
Subjects: Colorectal cancer patients, stage I-III, who are at least one month post-surgery
and have concluded any adjuvant chemotherapy treatment, are eligible for inclusion. Exclusion
criteria are: age <18; any major surgical procedure planned within 6 months after inclusion;
pregnancy; ongoing treatment for any known malignancy; performance status > 1; unable to read
and understand Danish
Methods: 40 colorectal cancer patients are included and randomized to I) InterWalk or II)
waiting list control for 24 weeks. Patients are evaluated at baseline, week 12 and week 24 by
assessment measures to determine cardio-metabolic health profile and other relevant study
outcomes, including: cardiopulmonary exercise test (VO2peak); anthropometrics; blood
pressure; resting heart rate; body composition; health related quality of life
questionnaires; plasma concentration levels of cholesterol, triglycerides, insulin, glucose
and inflammatory cytokines; insulin sensitivity; and cognitive function.
INTRODUCTION More than 30.000 individuals are living with a colorectal cancer (CRC) diagnosis
in Denmark today. Due to marked advances in surgical and medical treatment, as well as novel
screening programs, this number is expected to increase over the coming years. Numerous
studies have shown that physical activity is inversely associated with colorectal cancer
risk. A meta-analysis of 52 studies found that regular participation in physical activity
reduced disease risk by 24% (HR: 0.76 , 95%Confidence Interval [95%CI]: 0.72 - 0.81). Recent
evidence furthermore shows that physical activity after a CRC diagnosis is a strong
independent predictor for overall survival, CRC-specific survival, and survival after disease
relapse. CRC patients who adhere to the current recommendation of at least 150 min moderate
intensity physical activity per week have an estimated 10-40% lower CRC-specific and 20-50%
lower overall mortality risk in comparison to sedentary counterparts. The causative
mechanisms responsible for this protective effect are not fully elucidated, but several
studies have shown that metabolic health factors, i.e. overweight/adiposity, systemic levels
of glucose, insulin, Insulin-like Growth Factor (IGF)-1, leptin, adiponectin and inflammatory
cytokines (TNF-α, CRP) are associated with CRC prognosis. These factors are, under normal
circumstances modifiable through physical activity and exercise, which may constitute a
plausible mode of action, through which, exercise may reduce risk of disease progression as
well as development and/or progression of cardio-metabolic co-morbid disorders.
BACKGROUND Over the last decade, more than 70 studies have explored the capacity of physical
exercise to improve physiological (fitness, muscle strength, body composition) and
psychosocial (fatigue, depression, emotional well-being) outcomes in patients with cancer
during and after anti-neoplastic therapy and although CRC is among the most prevalent
malignancies, few exercise-trials have been performed in this patient group. The reason for
this notable low number of studies, relative to other common cancers in particular breast and
prostate cancer, may be a number of disease and treatment specific phenomena, e.g. high
prevalence of co-morbidities, stoma, late-effects from surgery or adjuvants therapies etc.,
which may complicate participation in traditional hospital-based exercise-programs, which is
often comprised of fitness- and strength-training. A recent meta-analysis included just 3
randomized trials investigating exercise in CRC patients, and found positive effects exercise
vs control on cardiovascular fitness; standardized mean difference: 0.59 [95%CI 0.25-0.93],
P<0.01. A recent pilot study furthermore showed that home-based exercise improved several
metabolic factors including reduction in body weight, plasma insulin levels and improved
insulin sensitivity. Thus, these data indicate that CRC patients can improve cardio-metabolic
health profile by physical exercise; however, the present body of research have included a
total of less than 200 patients; explored various exercise-modalities, and applied
inconsistent and/or indirect assessment-methods. To this end, there is a remaining need for
high quality evidence describing effective exercise-interventions in CRC patients,
particularly interventions aimed to be successfully implemented in clinical practice in case
of positive results.
Interval training, as characterized by inter-changing cycles of high and low intensity
exercise, have long been recognized as the most effective exercise-modality to improve
cardiopulmonary fitness, and can furthermore induce equal or greater metabolic effects than
continuous exercise over longer duration. Considerable challenges exists however, when
performing high intensity interval exercise-training in clinical settings. This type of
exercise often needs to be performed on ergometer bicycles or treadmills and organized as
supervised, hospital-based training to ensure proper monitoring and feedback to participants
for optimal exercise intensity and progression, which limits the dissemination potential
beyond the trial period.
Center for Physical Activity Research (CFAS) have performed a number of trials showing that
interval training can be performed as free-living interval-walking, consisting of repeating
cycles of 3 minutes fast walking followed by 3 minutes slow walking with significant positive
effects in cardio-metabolic health profile. Our studies show, that 16 weeks of
interval-walking improved VO2peak (+4ml /kg/min) reduced bodyweight (-4 kg) and fat mass (-3
kg) in patients with type 2 diabetes. Moreover, interval-walking improved plasma
lipid-profile, glucose metabolism and insulin sensitivity, in contrast to continuous walking,
which was matched for training-volume and energy expenditure. In parallel with these
intervention-studies, a smart-phone application, called InterWalk (www.InterWalk.dk), has
been developed, which can deliver this training program of repeating cycles: 3 minutes fast
walking followed by 3 minutes slow walking. The exercise-program is based on an
individualized test-function with live-feedback, ensuring proper exercise-intensities
(walking-speed), and can simultaneously store test- and training data (exercise-time,
walking-speed, distance etc.) to an external server for research purposes. Preliminary data
shows that three months home-based interval-walking using the InterWalk-application can
improve fitness by ~10%. Thus, our preliminary data shows InterWalk can deliver an
un-supervised, yet individualized, structured and objectively monitored exercise-program
which can effectively improve cardio-metabolic health, and may be more applicable and
feasible, compared to traditional hospital-based programs in stigmatized patient groups with
major co-morbid complications.
The investigators therefore propose this intervention can have a great health promoting
potential in patients with CRC; however previous work have found considerable barriers and
complications associated with successful participation in exercise-programs for this patient
group. Thus, the investigators intend to explore whether interval-walking, delivered by the
InterWalk-app, is safe and feasible, and furthermore the investigatorsintend to explore if
the intervention can cause similar positive effects as the investigators have seen previously
in other clinical populations.
PURPOSE AND HYPOTHESES Based on promising results from studies in type 2 diabetes, it is the
primary purpose of this study to investigate interval-walking via InterWalk-app as health
promoting exercise-intervention in patients with CRC. Specifically it is the aim of this
pilot study to determine the safety, feasibility, adherence and compliance of InterWalk; as
well as evaluating effects on cardio-metabolic health profile, compared to a waiting-list
control group.
RESEARCH PLAN This is a prospective, randomized controlled pilot-study in 40 CRC patients.
The study is a collaboration between Center for Physical Activity Research, Rigshospitalet,
Institut for Folkesundhedsvidenskab, Copenhagen University, Oncology Clinic, Rigshospitalet,
Abdominalcenter K, Bispebjerg Hospital, Gastroenheden Hvidovre Hospital, and
Patientforeningen for Tarmkræft.
Recruitment and Randomization CRC patients will be recruited from the oncology clinic,
Rigshospitalet and the gastro-intestinal surgical ward at Hvidovre Hospital. Patients, who
have undergone adjuvant chemotherapy, will be informed of the study during their final visit
at the oncology clinic. Patients in active surveillance will be informed of the study at the
first clinical visit, at least one month after surgery. The responsible clinicians and nurses
in the clinical department will present patients with the written information of the study
and gather contact information for interested participants to the study coordinator for more
information of the study. Before any study related test-procedures are initiated, patients
will sign informed consent, and undergo medical screening including former and present
medication, physical examination including resting EKG by a study physician to determine if
the patient can be included in the trial and subsequently scheduled for baseline assessment.
Following baseline-assessment patients will be allocated to one of two experimental arms I)
InterWalk or II) waiting-list control. To account for potential bias, patients will be
stratified by prior treatment (adjuvant chemotherapy/no adjuvant chemotherapy), which may
have significant impact on study outcomes. A random allocation sequence of treatment
assignments for each stratification group will be created by the trial biostatistician and
concealed from the study personal. The study coordinator will inform the patient of the
treatment assignment and the patient will remain in this group for the full study period.
Study Outcomes and Procedures
The test procedures involve a number of assessments which will be conducted 3 times during
the study; at baseline, week 12 and week 24:
1. Body composition by DXA scan
2. Fasting blood sample for analyses of plasma biochemistry (cholesterol, triglycerides,
inflammatory markers, HbA1C)
3. Oral Glucose Tolerance Test (OGTT) with repeated measures of plasma glucose, insulin and
c-peptide
4. Health related Quality of Life questionnaires
5. Cognitive function
6. Cardio Pulmonary Exercise Test (VO2peak)
Statistical Considerations The primary analysis will compare difference in changes in study
outcomes from 0 to 12 weeks between the two treatment arms InterWalk vs control. For the
primary outcome, VO2peak, assuming a standard deviation of 2 ml/kg/min, 16 patients in each
group will provide 80% power to detect a between group difference of +2 ml/kg/min in. To
account for a potential attrition-rate of up to 20%, 20 patients will be included in each
group.
The primary analysis is performed as a random effect model using study outcomes as dependent
variables, the covariates "group", "time" and their interaction as fixed effects, and a
random effect of "patient".
Dropouts and Missing Observations Patients who wish to drop-out of the study during the
intervention-periods will be offered to remain in the study with regard to test-assessments.
All analyses are performed as 'intention-to-treat' analyses, thus all patients will remain in
the originally allocated treatment arms regardless of compliance to the intervention.
Potential drop-outs and missing observations are handled by the "missing at random"
principle.
Ethical Considerations This study, as described, is expected to include limited risks,
adverse effects and discomfort for subjects. During all assessment procedures, a medical
doctor will be present in case of discomfort or other medical problems. Should patients
report discomfort or adverse reactions during interval-walking, the study coordinator in
collaboration with the responsible clinicians, will determine if the programs needs to be
adapted or terminated.
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