METHODS

Study design and patient selection

A pre–post, single-arm study was designed to test the feasibility of exercising patients with incurable metastatic cancer on chemotherapy. Participants were recruited from the Chemotherapy Clinic at Rouge Valley Centenary Hospital (as of December 1, 2016, Scarborough and Rouge Hospital—Centenary Site) in Toronto, between February 2014 and August 2016. Only patients under the care of one medical oncologist (JAC) were eligible. All such patients with incurable metastatic malignancy receiving chemotherapy were candidates. There were no formal exclusion criteria. The study was approved by the Research Ethics Board at the Rouge Valley Health System. All participants provided written informed consent for this study.


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Kinesiologists experienced in exercise therapy in cardiac rehabilitation supervised participants on a dedicated track with access to resistance and aerobic training machines within the Rouge Valley Centenary Hospital. Basic first-aid, CPR, and an emergency response team were available. Parking was free on the day of the group exercise.

Assessments

A kinesiologist discussed exercise history, limitations, and addressed any concerns. A 6-minute walk test determined baseline aerobic capacity. Changes were tracked every 3 months. The Functional Assessment of Chronic Illness Therapy (FACIT) and Piper Fatigue Scale (PFS) questionnaires were administered at baseline and at 30 weeks. FACIT is a quality-of-life questionnaire tested for reliability and validity in a general cancer population9 (FACT-G) with a tumor-site specific form (FACT-Specific). The PFS measures a cancer patient’s fatigue tested for reliability and validity in a general cancer population.10

Exercise intervention

The intervention was a supervised, weekly, group, strength and aerobic exercise program. One 75-minute time block was allocated during the week. Two kinesiologists case managed and supervised all exercise participants. For strength training, participants used free weights or resistance bands targeting the five major muscle groups that included arms, legs, shoulders, back, and core. Five to seven total exercises were performed in each session for two sets of 10 repetitions at each group exercise session. For aerobic training, participants were encouraged to walk or cycle as a part of their aerobic training routine for up to 45 minutes. Participants were encouraged to perform their strength and aerobic exercises throughout the remainder of the week. The exercise intervention was indefinite and lasted as long as the patient wished to participate. Scheduling of the exercise sessions was just before a clinic visit or chemotherapy treatment, which continued uninterrupted according to the cancer treatment plan. 

Participants submitted weekly written diaries at each exercise session to monitor home exercise. They were then given a new diary for the week as well as an exercise prescription based on their individual capacity, including aerobic and strengthening exercises. 

Measurements

Demographic data and primary cancer site and chemotherapy treatment information were available for all patients treated with palliative intent by the medical oncologist during the time the study was active. Attendance for group sessions was recorded by the kinesiologist. 

Prognostic factors collected at baseline for patients with metastatic CRC consisted of patient performance status measured using the Eastern Cooperative Oncology Group scale, and white blood count, absolute neutrophil count, alkaline phosphatase, number of metastatic sites, right vs left side of primary cancer, K-ras status, and number of lines of chemotherapy11,12 with previous adjuvant chemotherapy also included.

Attrition typically looks at the rate of withdrawal from an exercise program with a fixed duration, comparing the number of participants at the beginning and conclusion.13 This pilot did not have a fixed duration of exercise participation. These were patients with incurable cancer with a chance of dying while in the pilot study. Additionally, many completed their course of palliative treatment, with no obligation to continue in the pilot study. Attrition was defined as withdrawal from the pilot earlier than 90 days before death or later than 30 days after completion of palliative chemotherapy.

The compliance rate was defined as the number of group exercise attendances divided by the number of available group exercise sessions between the first and last attended exercise sessions for each participant.

Survival for CRC patients was calculated as the time elapsed between the diagnostic biopsy and death.

Paraffin-embedded tissue blocks were collected for every patient with metastatic colon or rectal cancer treated by the medical oncologist, while the exercise pilot was active, regardless of participation in the pilot. The sample was always from a pretreatment specimen: a surgical section (n=14) or biopsy (n=3) for colon cancer or a biopsy for rectal cancer (Table 1). This was stained for β-catenin with normal colonic epithelial cells serving as internal controls. A team of five pathologists graded the nuclear staining as weak (0, +1, +2), indicating intact regulation of the WNT-CTNNB1 pathway, or strong (+3 or +4), indicating aberrant upregulation of the WNT–CTNNB1 pathway.

Immunohistochemical analysis for β-catenin

β-Catenin is a ready-to-use/predilute antibody (catalog # IR702; Dako/Agilent, Santa Clara, CA, USA). Dako Envision Flex+ kits (catalog #K8002) were used for detection. The slides were cut at 3 μm and dried in the oven at 60°C for 30 minutes, then dewaxed with xylene and hydrated, and then put into a high pH retrieval buffer for 20 minutes at 98°C. The slides were rinsed with buffer and then loaded onto Dako Autostainers where they underwent the staining process (peroxidase block, β-catenin antibody [20 minutes incubation], horseradish peroxidase polymer, and diaminobenzidine substrate–chromogen). The slides were counterstained with hematoxylin manually and coverslipped for review.

Data analysis

To assess the impact of exercise on cancer treatment delivery, chemotherapy DI was determined for all patients involved in the trial with CRC and myeloma patients being compared to age- and sex-matched nonparticipants. 

Demographic and clinical data were presented as mean, median, or proportion with 95% confidence intervals (CIs). Given the exploratory nature of the study, no formal sample size or power analysis was undertaken. Therefore, the most relevant outcomes from the statistical analysis were 95% CI. P-values should be viewed as being of secondary importance. Furthermore, the findings of this pilot study should be seen as exploratory and hypothesis generating. The paired t-test was used to compare changes in the 6-minute walk test relative to baseline. The association between participation in the exercise program, nuclear staining for β-catenin, and overall survival was assessed using Cox proportional hazard regression. Survival curves were generated with the method of Kaplan–Meier and compared with the log-rank test. 

All of the statistical analyses were performed using Stata, release 14.0 (StataCorp LP, College Station, TX, USA).