Effects of a 12-week home-based exercise program on the level of ...

Support Care Cancer (2013) 21:2537–2545 DOI 10.1007/s00520-013-1822-7

ORIGINAL ARTICLE

Effects of a 12-week home-based exercise program on the level of physical activity, insulin, and cytokines in colorectal cancer survivors: a pilot study Dong Hoon Lee & Ji Young Kim & Mi Kyung Lee & Choae Lee & Ji-Hee Min & Duck Hyoun Jeong & Ji-Won Lee & Sang Hui Chu & Jeffrey A. Meyerhardt & Jennifer Ligibel & Lee W. Jones & Nam Kyu Kim & Justin Y. Jeon

Received: 18 January 2013 / Accepted: 11 April 2013 / Published online: 2 May 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract Purpose The purposes of this study are to examine (1) the feasibility and efficacy of two different home-based exercise protocols on the level of physical activity (PA), and (2) the effect of increased PA via home-based exercise program on biomarkers of colorectal cancer. Methods Seventeen patients (age 55.18 ± 13.3 years) with stage II–III colorectal cancer completed the 12-week homeDong Hoon Lee and Ji Young Kim contributed equally to this work. D. H. Lee : J. Y. Kim : M. K. Lee : C. Lee : J.-H. Min : J. Y. Jeon Department of Sport and Leisure Studies, Yonsei University College of Education, Seoul, Korea D. H. Jeong : N. K. Kim Department of Surgery, Yonsei University College of Medicine, Seoul, Korea J.-W. Lee Department of Family Medicine, Yonsei University College of Medicine, Seoul, Korea S. H. Chu Department of Clinical Nursing Science, Nursing Policy and Research Institute, Biobehavioral Research Center, Yonsei University College of Nursing, Seoul, Korea J. A. Meyerhardt : J. Ligibel Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

based exercise program. Subjects were randomized into either casually intervened home-based exercise group (CIHE) or intensely intervened home-based exercise group (IIHE). The primary outcome was the level of PA. Furthermore, insulin, homeostasis model assessment of insulin resistance, insulinlike growth factor axis, and adipocytokines were measured. Results Both CIHE and IIHE program significantly increased the level of PA at 12 weeks compared to its level at baseline (CIHE, 10.00±8.49 vs. 46.07±45.59; IIHE, 12.08±11.04 vs. 35.42±27.42 MET hours per week). Since there was no difference in PA change between groups (p=0.511), the data was combined in analyzing the effects of increased PA on biomarkers. Increase in PA significantly reduced insulin (6.66± 4.58 vs. 4.86±3.48 μU/ml, p=0.006), HOMA-IR (1.66±1.23 vs. 1.25±1.04, p=0.017), and tumor necrosis alpha-α (TNF-α 4.85±7.88 vs. 2.95±5.38 pg/ml, p=0.004), and significantly increased IGF-1 (135.39±60.15 vs. 159.53 ng/ml, p=0.007), IGF binding protein (IGFBP)-3 (2.67 ± 1.48 vs. 3.48 ± 1.00 ng/ml, p=0.013), and adiponectin (6.73±3.07 vs. 7.54± 3.96 μg/ml, p=0.015). Conclusion CIHE program was as effective as IIHE program in increasing the level of PA, and the increase in PA resulted in significant change in HOMA-IR, IGF-1 axis, TNF-α, and adiponectin levels in stage II–III colorectal cancer survivors. Keywords Colorectal cancer . Exercise . Insulin resistance . IGFs . Cytokine

L. W. Jones Duke University Medical Center, Durham, NC, USA J. Y. Jeon (*) Department of Sport and Leisure Studies, Yonsei University, 134 Seodaemun-Gu, Shinchon-Dong, Seoul 120-749, Korea e-mail: [email protected]

Introduction Colorectal cancer is the third most common cancer in South Korea and the fourth common cancer worldwide [15, 33].

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Observational prospective studies have shown strong association between the level of physical activity and the risk and outcomes of colorectal cancer [11, 26–28]. In 2006, Meyerhardt et al. [28] reported two prospective studies that colorectal cancer patients who engaged in more than 18 metabolic equivalent task (MET) hours per week of physical activity had a 50 % higher disease-free survival (DFS) and approximately half lower cancer-specific mortality and overall mortality compared to patients whose level of physical activity was less than 3 MET hours per week in both males and females. Although prospective observation studies have demonstrated [12, 26–28] the association between physical activity and the prognosis of colorectal cancer patients, there has not been intervention studies or randomized controlled trials which demonstrated the beneficial effects of exercise on the prognosis of colorectal cancer or factors which may influence the prognosis of colorectal cancer. Studies have shown that insulin resistance, C-peptide, insulin growth factor (IGF)-1, IGF binding protein (IGFBP)-1 and -3, and some cytokines have been proposed as factors that may influence the prognosis of colorectal cancer patients [10, 35, 38, 40, 42]. In noncancer population, studies reported that exercise would change circulating levels of glucose, insulin, and IGF axis as well as cytokine such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and adiponectin which are associated with the risks of colorectal cancer [17–19, 31, 37]. Previous studies have also reported the effects of exercise or physical activity on insulin resistance, C-peptide, and IGF axis [7, 8, 14, 20] in breast cancer patients. However, the effects of exercise and physical activity on insulin resistance, IGF axis, and cytokines in colorectal cancer patients have not been studied. Recently, Ligibel et al. [23] have reported the feasibility and the effectiveness of telephone-based, home-based exercise intervention on the level of physical activity and functional capacity in breast and colorectal cancer patients, which might be a more cost-effective and feasible strategy to implement exercise on a large cohort of cancer patients [22, 24, 29]. Furthermore, Demark-Wahnefried et al. [6] also reported that home-based diet-exercise intervention was effective in increasing the level of physical activity as well as in promotion of healthier diet. However, these home-based exercise protocols vary between studies, and the impact of home-based exercise on biomarkers such as insulin and adipocytokines have not been fully studied in colorectal cancer patients. The primary objective of this pilot study is (1) to examine the effectiveness of two different home-based exercise protocols, Intensely Intervened Home-based Exercise (IIHE) protocol vs. Casually Intervened Home-based Exercise (CIHE) protocol, in increasing the level of physical activity in colorectal cancer survivors and (2) to test the efficacy of home-based exercise protocols on biomarkers of colorectal cancer prognosis including insulin, IGF-1, IGFBP-3, TNF-alpha, IL-6, leptin, and adiponectin in stage II–III colorectal cancer survivors.

Support Care Cancer (2013) 21:2537–2545

Methods Participants This pilot study was conducted at the Shinchon Severance Hospital at the Yonsei University in Seoul, Korea, from August 2011 to November 2011. The study and protocol were approved by the institutional review boards at the Yonsei University College of Medicine, and all participants signed a consent form prior to participation in the study. Colorectal cancer patients (18–75 years) who completed all standard surgery and chemotherapy (at least 1 month after the completion of adjuvant chemotherapy and within 2 years) were recruited for the study. The inclusion criteria for the study were as follows: (1) written informed consent prior to study procedures, (2) histologically confirmed stage II–III colon or rectal cancer with surgical resection and chemotherapy completed prior to the study, and (3) ECOG performance status of 0 or 1. Exclusion criteria for the study were as follows: (1) pregnant or planned to be pregnant within 6 months, (2) planned surgery anticipated during the 12-week intervention, and (3) any condition unsuitable for participation in the study. Study design The study which investigated the effect of two different home-based exercise protocols on the level of physical activity was a pilot randomized controlled trial. After informed consent was signed, participants were randomized into either an intensely intervened home-based exercise group or casually intervened home-based exercise group via minimization method. Randomization list was not set up in advance, and the first participant is randomly allocated and then in each subsequent participant the treatment allocation is identified (1:1 ratio). The intervention period was 12 weeks and assessments were conducted at baseline and at 12 weeks. The analysis of effects of increased physical activity on biomarkers of colorectal cancer was a single group pre- and post-intervention design. Intensely intervened home-based exercise (IIHE) protocols The goal of the home-based exercise was to increase the level of physical activity of the participants to 18 MET hours per week, as the beneficial effects proven by Meyerhardt et al. [27, 28] during the first 6 weeks. Then, the level of physical activity would be increased to 27 MET hours per week depending on individual health conditions over the course of the intervention period. We recommended brisk walking, hiking, stationary bike, or swimming for aerobic exercises. In addition, participants were provided with two types of exercise DVDs, which consisted of 30-min resistance training


using major and core muscles to be performed at home every day by participants (moderate, three sets of seven core and resistance exercises; vigorous, three sets of five aerobic and resistance combined exercises). Participants met with exercise trainers once a week at the clinic as a group for the first 3 weeks and again at the sixth week. The first exercise session was composed of both lecture and exercise session. During lecture time, they learned about the benefit of exercise for colorectal cancer survivors. After the lecture, participants were instructed about an exercise program which they were to follow at home (exercise DVDs). During six additional exercise sessions, the exercise trainer made sure that participants were performing exercises in proper technique. Other procedures to enhance adherence included (1) selfmonitoring with exercise logs and pedometers; (2) personalized feedback regarding baseline data with determination of individualized exercise program established from the baseline information; (3) individualized goals, updated on a regular basis; (4) initial use of individual in-person instruction to teach concepts and techniques; (5) weekly phone counsel or small group training sessions to facilitate overcoming barriers, to give positive reinforcement, to answer questions, and to inquire about and assess problems related to exercise; (6) monthly (4 week and 8 week) hiking on the mountain with physicians and exercise trainers; and (7) sending of routine daily text messages to check whether participants completed their daily exercise. Casually intervened home-based exercise (CIHE) protocol Participants in the CIHE group were provided written information that emphasized the importance of a healthy lifestyle and also the same exercise log and pedometers used in the IIHE group. However, unlike the IIHE group, the goal of physical activity was not set as either 18 or 27 MET hours per week. Participants in CIHE group only received one educational session, which addressed the benefit of physical activity on colorectal cancer treatment. At fourth week, participants in CIHE group participated in hiking on the mountain with physicians and exercise trainers. At sixth week, another session was provided to participants in CIHE group where their physical activity levels were checked and their questions on any topic of exercise study were answered by the physician and exercise trainer. Outcome measures Anthropometric measurement Height, weight, and waist circumference were measured by research staff at baseline and 12 weeks, blinded to the participants’ prior measurements. Participants’ height and weight were measured in standard manner wearing light indoor clothing, without shoes, rounding up to the nearest 0.1 kg. Waist circumference was measured at the midpoint between the lower border of

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the rib cage and the iliac crest. Participants underwent assessment of anthropometric measures and analysis of body composition with In-body (Biospace, Korea) at baseline and after the 12-week intervention. Physical activity assessment Participants underwent assessments of physical activity at baseline and 12 weeks to assess the efficacy of the intervention for physical activity. The International Physical Activity Questionnaire (IPAQ, short last 7 days self-administered format, Korean version) is a reliable assessment of physical activity, which provides data regarding the duration and intensity of the physical activity performed, and on sedentary activities [5]. The physical activity level measured by IPAQ was validated by 7-day physical activity recall (PAR), and the correlation analysis was performed and coefficient value of 0.497 (p=0.043) was observed. Biomarkers Blood samples were collected after overnight fasting (>12 h) and were analyzed for glucose metabolismrelated substances including fasting glucose (ADVIA 1650; Siemens, Tarrytown, NY, USA), fasting insulin (Roche, Indianapolis, IN, USA), and hemoglobin A1c (HbA1c) (HLC723GH; TOSOH, Siba, Minaoto-ku, Japan). Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR) index [insulin (μIU/ml) × fasting glucose (pmol/l)/22.5]. Lipid metabolite indices such as total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured using an ADVIA 1650 Chemistry system (Siemens). hs-CRP was measured using an ADVIA 1650 Chemistry system (Siemens). WBC and Hb levels were determined within 1 h after blood collection using the ADVIA 120 automated hematology analyzer (Siemens). CEA was measured by electrochemiluminescence immunoassay (Roche). TNF-a, IL-6, leptin, and osteopontin levels were measured using a commercially available enzyme-linked immunosorbent assay (R&D, Minneapolis, MN, USA); intraassay coefficients of variation (CV) were 5.3 %, 7.4 %, N/A, and 3.2 % and inter-assay CVs were 8.4 %, 7.8 %, N/A, and 5.9 %, respectively. Adiponectin was measured by enzymelinked immunosorbent assay (Mesdia, Seoul, Korea); intraassay CV and inter-assay CV were 4.5 % and 4.6 %, respectively. IGFBP-1 was measured using a commercially available enzyme-linked immunosorbent assay (Media diagnost, Reutlingen, Germany); intra-assay CV and inter-assay CV were 6.3 % and 6.4 %, respectively. IGF-1 and IGFBP-3 were assayed using an Immulite 2000 (Siemens). Statistical analyses Statistical analyses were performed with SPSS, Windows version 18.0. Baseline characteristics of the study participants

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and physical activity levels across the two intervention groups were compared with independent t test for continuous outcomes and χ2 test for categorical outcomes. Results of pre- and post-intervention values are presented as mean, standard deviation (SD). The normality of distribution was verified with Shapiro–Wilk test. To analyze the effect of the 12-week intervention, paired t test was used for normally distributed variables to compare the baseline and 12-week data within groups and Wilcoxon test was used for non-normally distributed variables. Comparisons of changes in physical activity level between an IIHE group and CIHE group were assessed with independent t test for normally distributed variables and Mann–Whitney test for non-normally distributed variables. If there is no difference in the level of physical activity increase during home-based exercise program, the data from two groups (IIHE and CIHE group) will be combined together in analyzing the effects of increase in physical activity on biomarkers of colorectal cancer with the same procedure above. A p value of less than 0.05 was considered statistically significant.

Results For subject recruitment, hospital data base was examined and identified 366 potential study participants. Among them, 186 met the study inclusion criteria, and mail package explaining the study was sent to them. Among them, 27 responded their interests in participating in the study and 23 agreed to participate in the study after the study was explained to them. A total of 23 signed the consent form and were randomized either to IIHE group (N=12) or CIHE (N=11) (Fig. 1). Of 23 participants, 19 of them completed the 12 weeks of intervention (82.6 %) and four of them dropped out of the study due to cancer recurrence (N=1) and were lost to follow-up (N=3). Of 19 participants who completed the intervention, two of them from the IIHE group had unintentional food intake in the morning of blood, thus a total of 17 participants (IIHE, 8; CIHE, 9) were included for the analyses. Baseline characteristics Baseline demographic and physiological data in the IIHE and CIHE groups were not different between groups. The average age of the study participants was 55±12.94 years and the average body mass index of the participants was 23.04 ± 3.25 kg/m 2 . All participants were diagnosed with stage II or III colorectal cancer, and the average time since diagnosis of the participants was 18.63 ± 2.96 months. Subject characteristics are summarized in Table 1.


The effect of two different home-based exercise programs on the level of physical activity Table 2 shows the level of physical activity at baseline and at 12 weeks of intervention in the CIHE and IIHE groups. The level of physical activity in MET hours per week was significantly increased in both CIHE and IIHE groups (CIHE, 10.00±8.49 vs. 46.07±45.59; IIHE, 12.08±11.04 vs. 35.42±27.42 MET hours per week). Vigorous physical activity (CIHE, 0 ±0 vs. 203.33 ± 252.69; IIHE, 22.50 ± 63.64 vs. 82.50±76.49 min per week) and total physical activity (CIHE, 150 ± 127.28 vs. 487.78 ± 453.48; IIHE, 158.75±114.20 vs. 448.75±418.58 min per week) were significantly increased only in the CIHE group. There was no significant difference in the level of physical activity changes during the period of study between the two groups. The impact of increase in physical activity via home-based exercise program on biomarkers of colorectal cancer survivors After the primary analysis, both data of CIHE and IIHE were combined and post-intervention data was compared with baseline data because there was no difference in the level of physical activity between the two groups. Homebased exercise participation significantly reduced body weight, fasting insulin, HOMA-IR, and TNF-alpha while it significantly increased IGF-1, IGFBP-3, and adiponectin levels (Table 3 and Fig. 2). IGF-1 levels at baseline and at 12 weeks were associated with lean mass at baseline (r=0.526, p=0.036) and at 12 weeks (r=0.637, p=0.008). Furthermore, increased physical activity significantly reduced TNF-α, but increased adiponectin levels without any changes in leptin and IL-6 levels (Fig. 2).

Discussion The primary hypothesis of the study was to test IIHE protocol which included daily text message, weekly exercise counseling, and exercise education classes in addition to pedometer and exercise log book would increase the level of physical activity more than CIHE protocol would. The result from the current study showed that the level of physical activity increment in the IIHE group was not significantly different from that of the CIHE group due to significantly increased level of physical activity in the CIHE group. Indeed, vigorous and total physical activity was only significantly increased in the CIHE group at 12 weeks of intervention compared with baseline physical activity level. Further analyses also showed that there was no difference between groups in anthropometric and physiological variables after the intervention. This study showed that CIHE


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Fig. 1 Flow of participants Hospital-based colorectal cancer registry (N=366) Stage 1 or 4 (N=180) Physician consent given (N=186)

Mail package was sent (N=186) No response (N=159) Attended orientation session (N=27) Too busy (N=2) No reason (N=1) Physical activity too high (N=1) Randomization (N=23)

Intensely intervened home-based protocol ¨ Received allocated intervention (N=12) 6 exercise sessions 2 mountain climbing with physicians Weekly phone call Daily text messages Exercise log Pedometer Exercise DVDs to follow

Lost to follow-up (N=2) Dropped out (N=2)

Lost to follow-up (N=2) Cancer recurrence (N=1) Dropped out (N=1)

Included in the analysis (N=8) ¨ Excluded from analysis for markers from blood analyses (N=2) Unintentional food intake before blood sampling (N=2)

was as effective as IIHE in increasing the level of physical activity in home-based exercise setting in colorectal cancer survivors. Although participants in the IIHE received intense exercise intervention compared to those of CIHE, interestingly, both groups increased the level of their physical activity levels well above 18 MET hours per week. Participants in the CIHE group increased the level of physical activity from 10.00±8.49 MET hours per week to 46.07±45.95 MET hours per week while the IIHE group increased the level of physical activity from 12.08±11.04 to 35.42±27.42 hours per week. Some studies have reported that providing exercise information and even pedometer does not significantly increase the level of physical activities in other population while other studies reported providing information on

Casually intervened home-based protocol ¨ Received allocated intervention (N=11) 1 health education session 1 mountain climbing with physicians Exercise log Pedometer

Analysed (N=9)

exercise itself was an effective tool to increase physical activity in cancer patients [39]. In our study, cancer survivors were highly motivated to exercise and only a small amount of encouragement and providence of pedometer and exercise diary were enough to increase the level of physical activity significantly. We have also provided one mountain climbing session with their surgeon and exercise physiologists so that we would prevent participants in CIHE group from dropping out of the study. Based on what was observed in our participants, CIHE protocol was as effective as IIHE protocol. This result is in agreement with Ligibel et al. [24] that this study also used a casual tool for exercise intervention (weekly telephone-based exercise program) and reported increased physical activity level from 13 min to 116 min after 12 weeks in early-stage breast cancer patients.

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Table 1 Baseline characteristics of the participants CIHE group (N=8)

IIHE group (N=9)

p value

Age (years) Male (%) Height (cm) Weight (kg) BMI (kg/m2) Colon cancer stage (%) Stage II Stage III Rectal cancer stage (%) Stage II Time since diagnosis (months) Married (%) Employment (%)

53.63±15.41 4 (50.0) 159.91±7.51 60.18±10.73 23.48±3.99

56.56±11.97 6 (66.7) 164.18±7.94 62.33±11.05 22.70±2.85

0.666 0.229 0.275 0.689 0.649

2 (25) 5 (62.5)

5 (55.6) 3 (33.3)

0.42

1 (12.5) 20.14±2.54 7 (87.5) 6 (66.7)

1 (11.1) 17.44±2.83 9 (100) 5 (62.5)

0.069 0.279 0.858

Completed college (%) Income