Article Effects of Exercise on Biobehavioral Outcomes of Fatigue During Cancer Treatment: Results of a Feasibility Study Biological Research for Nursing 2015, Vol. 17(1) 40-48 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1099800414523489 brn.sagepub.com Sadeeka Al-Majid, RN, PhD1, Lori D. Wilson, PhD2, Cyril Rakovski, PhD3, and Jared W. Coburn, PhD4 Abstract Cancer treatment is associated with decreased hemoglobin (Hb) concentration and aerobic fitness (VO2 max), which may contribute to cancer-related fatigue (CRF) and decreased quality of life (QoL). Endurance exercise may attenuate CRF and improve QoL, but the mechanisms have not been thoroughly investigated. Objectives. To (a) determine the feasibility of conducting an exercise intervention among women receiving treatment for breast cancer; (b) examine the effects of exercise on Hb and VO2 max and determine their association with changes in CRF and QoL; and (c) investigate changes in selected inflammatory markers. Methods. Fourteen women receiving chemotherapy for Stages I–II breast cancer were randomly assigned to exercise (n ¼ 7) or usual care (n ¼ 7). Women in the exercise group performed supervised, individualized treadmill exercise 2–3 times/week for the duration of chemotherapy (9–12 weeks). Data were collected 4 times over 15–16 weeks. Results. Recruitment rate was 45.7%. Sixteen women consented and 14 completed the trial, for a retention rate of 87.5%. Adherence to exercise protocol was 95–97%, and completion of data collection was 87.5–100%. Exercise was well tolerated. VO2 max was maintained at prechemotherapy levels in exercisers but declined in the usual-care group (p < .05). Hb decreased (p < .001) in all participants as they progressed through chemotherapy. Exercise did not have significant effects on CRF or QoL. Changes in inflammatory markers favored the exercise group. Conclusions. Exercise during chemotherapy may protect against chemotherapy-induced decline in VO2 max but not Hb concentration. Keywords exercise, chemotherapy, biobehavioral, breast cancer Cancer-related fatigue (CRF) is the most frequently reported symptom by persons with cancer (Cheng & Yeung, 2013; Siefert, 2010), afflicting up to 94% of women receiving treatment for breast cancer (Li & Yuan, 2011). CRF interferes with a patient’s ability to fully engage in leisure and normal daily activities, leading to poor quality of life (QoL; Gupta, Lis, & Grutsch, 2007). Researchers have suggested the use of endurance exercise to decrease CRF and improve QoL in women undergoing chemotherapy for breast cancer (Ligibel et al., 2010). However, studies about the specific mechanisms through which exercise may mitigate CRF are scarce. Such studies might lead to the development of specific exercise programs that target these mechanisms. Although the mechanisms underlying CRF remain to be elucidated (McMillan & Newhouse, 2011), evidence suggests that CRF is a complex multifactorial phenomenon caused by a multitude of biobehavioral mechanisms (Al-Majid & Gray, 2009; McMillan & Newhouse, 2011; Ryan et al., 2007). Some of these mechanisms include decreased hemoglobin (Hb) concentration (Dolan et al., 2010), decreased aerobic fitness (VO2 max; Davis & Walsh, 2010), and upregulation of inflammatory mediators (Wang et al., 2012). Research has documented low Hb in patients receiving chemotherapy and revealed an association with CRF (Romito, Montanaro, Corvasce, Di Bisceglie, & Mattioli, 2008): higher Hb levels are associated with lower CRF and higher energy level and QoL (Boccia, Lillie, Tomita, & Balducci, 2007). Evidence about the effect of endurance exercise on Hb level during chemotherapy is inconclusive: some authors have reported a positive relationship (Drouin et al., 2006), while others have reported no relationship (Dolan et al., 2010). 1 School of Nursing, California State University, Fullerton, CA, USA Department of Kinesiology, California State University, Long Beach, Long Beach, CA, USA 3 Schmid College of Science & Technology, Chapman University, Orange, CA, USA 4 Kinesiology Department, California State University, Fullerton, Fullerton, CA, USA 2 Corresponding Author: Sadeeka Al-Majid, RN, PhD, School of Nursing, California State University, 800 N State College Blvd, Fullerton, CA 92831, USA. Email: sal-majid@fullerton.edu Al-Majid et al. 41 Table 1. Exercise Protocol. Program stage Week Exercise frequency (sessions/week) Exercise intensity (% HRR) Exercise duration (min) Initial 1 2–3 4–12 2 2–3 2–3 40–50 50–70 70–80 20 30 30–40 Improvement Note. % HRR ¼ percent heart rate reserve. VO2 max, an excellent indicator of aerobic capacity, is approximately 30% lower in cancer patients than in age- and sex-matched sedentary individuals who do not have a history of cancer (Haykowski, Mackey, Thompson, Jones, & Paterson, 2009; Jones et al., 2011). Decreased VO2 max reflects reduced exercise capacity, which may contribute to CRF (Vincent et al., 2013). Endurance exercise during chemotherapy may increase VO2 max (Dolan et al., 2010; Vincent et al., 2013). However, it is not clear if this increase in VO2 max is attributable to improvement in Hb level. Levels of the proinflammatory cytokine interleukin-6 (IL-6) increase during cancer treatment. Researchers have suggested that this increase contributes to CRF (Liu et al., 2012; Wang et al., 2012). In individuals without cancer, endurance exercise training lowers resting levels of IL-6 (Reyes-Gibby et al., 2013), possibly by increasing the level of the anti-inflammatory cytokine IL-10 (Walsh et al., 2011). It is not known whether endurance training has similar effects on IL-6 and IL-10 in patients receiving treatment for breast cancer. Additionally, the stress hormone cortisol is associated with chronic inflammatory diseases including cancer (Edwards, 2012). Compared to healthy individuals, patients receiving chemotherapy have higher levels of cortisol and lower levels of myeloperoxidase (MPO), a marker of oxidative stress (Limberaki et al., 2011). These findings suggest that chemotherapy might decrease antioxidant capacity. Endurance exercise training is thought to improve antioxidant status in healthy individuals (Finaud, Lac, & Filaire, 2006). Whether this response to endurance exercise occurs during chemotherapy is not known. Few studies have examined the effect of exercise on the mechanisms underlying CRF in patients receiving chemotherapy. Many of those who have focused on cancer survivors used home-based exercise protocols and/or did not use comparison groups. In the present study, we examined the feasibility and efficacy of a structured, supervised endurance exercise program in women undergoing chemotherapy for early-stage breast cancer. Our specific aims were to (a) determine the feasibility of the exercise intervention in terms of recruitment, retention, adherence to the exercise protocol, tolerance of exercise testing and completion of data collection; (b) examine the effects of the exercise program on Hb and VO2 max and determine their association with changes in CRF and QoL; and (c) investigate changes in selected inflammatory markers. Method Design, Sample, and Setting We used a prospective, repeated measures, randomized design. We recruited participants from two cancer centers in Central Virginia and Southern California, whose institutional review boards both approved the study. Patients eligible to participate included women aged 21 years or older diagnosed with Stage I or II breast cancer who were scheduled to receive chemotherapy, spoke and read English, and were willing to be randomly assigned to either group. Consistent with the exclusion criteria stipulated by the American College of Sports Medicine (Saxton, 2011), patients who had recent or uncontrolled cardiac conditions were excluded. Other exclusion criteria included self-reported history of unstable or severe clinical depression, activity-limiting arthritis, having had joint surgery within the previous 3 months, and having been engaged in regular exercise (5 days per week) in the past 3 months. Eligible patients were informed about the study by referring oncologists and were approached by study staff who invited them to participate. Women who consented were scheduled for baseline data collection (T1). Following T1, women were randomly assigned to the exercise (n ¼ 7) or usual care (n ¼ 7) group. The exercise sessions took place in the rehabilitation facility within the cancer center and were supervised by a qualified exercise physiologist or physical therapist familiarized with the exercise protocol. There was flexibility in scheduling exercise sessions to accommodate participant availability. Participants were allowed to make up missed exercise sessions. Exercise Protocol The exercise protocol (Table 1) consisted of supervised treadmill exercise with an individualized progressive increase in workload (speed, incline, and duration). All participants underwent baseline exercise testing to determine their initial VO2 max. Exercise started within 1 week of the first cycle of chemotherapy and ended with the completion of chemotherapy (9–12 weeks). During the first week, participants exercised for 20 min per session at a heart rate that corresponded to an intensity of 50–60% of maximal heart rate, which was determined via VO2 max measurement. As shown in Table 1, workload was increased progressively during subsequent weeks until participants achieved a heart rate that corresponded to an intensity of 70–80% of maximal heart rate. All exercisers were able to achieve target intensity by Week 5 (range 4–5 weeks). Each exercise session started with a 5-min warm-up and ended with a 5-min cooldown. While there were occasional fluctuations in the frequency, intensity, and duration of the exercise over the course of the study, all exercisers were able to exercise per protocol. Participants completed an average of 32 sessions (range 26–39) at an average incline of 7% (range 5–12%) and average speed of 3.4 mph (range 2.5–3.7). 42 Biological Research for Nursing 17(1) Table 2. Data Collection Timeline. Group Exercise T1 Exercise and chemo ! 4.5–6 weeks T2 Exercise and chemo ! 4.5–6 weeks T3 Chemo ! 4.5–6 weeks T2 chemo ! 4.5–6 weeks T3 ! 3–4 weeks T4 R Usual care T1 ! 3–4 weeks T4 Note. N ¼ 14. chemo ¼ chemotherapy; R ¼ randomization; T1 ¼ Time 1, baseline before chemotherapy and exercise; T2 ¼ Time 2, after second cycle of chemotherapy; T3 ¼ Time 3, at the completion of chemotherapy and exercise program; T4 ¼ Time 4, 3–4 weeks after completion of chemotherapy and exercise. Participants in the usual-care group received usual care, which did not involve exercise, and were instructed to document and report any exercise activities they engaged in while on the study. Similarly, we asked exercise-group participants to report engagement in nonprotocol exercise activities during the study. Outcome Measures and Data Collection Feasibility outcomes included recruitment, retention, adherence to exercise protocol, tolerance of exercise testing and completion of data collection. Recruitment rate was defined as the number of women consented divided by the number of those eligible to participate. Retention was defined as the number of women who completed the trial out of those consented. Adherence to exercise protocol was calculated as the number of exercise sessions completed as per protocol out of the total number of scheduled sessions. Tolerance of exercise testing was defined as ability to complete VO2 max testing. Completion of data collection was defined as the number of completed data collection time points divided by the total number of scheduled data collection time points. Efficacy outcomes included Hb concentration, VO2 max, CRF, QoL, and select inflammatory markers. We assessed all outcome measures, except inflammatory markers, in all participants (exercise and usual care) four times during the study (Table 2). Time 1 (T1) data (baseline) were collected at the time of enrollment in the study, prior to randomization and first chemotherapy cycle. Time 2 (T2) data were collected after patients completed two chemotherapy cycles. Time 3 (T3) data were collected within 1 week after patients completed chemotherapy. Postintervention data (T4) were collected 3–4 weeks following completion of the exercise program, which coincided with the completion of chemotherapy. Inflammatory markers were assessed in a subsample of six participants (three exercisers and three usual care) at baseline and within 1 week after the last cycle of chemotherapy. Aerobic fitness. Maximal oxygen (O2) consumption (VO2 max) was measured using a motorized treadmill (Trackmaster, TM500/S; JAS Fitness Systems, Carrollton, TX). Each participant wore a nose clip and breathed through a two-way valve (2700; Hans Rudolph, Kansas City, MO). Expired gas samples were continuously collected throughout the test and were analyzed using a calibrated TrueMax 2400 metabolic cart (Parvo Medics, Sandy, UT) with O2, carbon dioxide, and ventilatory parameters expressed as 20-s averages. Heart rate was monitored throughout the test with the Polar Heart Watch system (Polar Electro Inc., Lake Success, NY). A Bruce protocol was used for testing, with occasional modifications based on exercise tolerance. VO2 max was defined as the highest value recorded during the last 30 s of the test. The test was terminated if the participant met at least two of the following three criteria: (a) 90% of age-predicted heart rate (220—age); (b) Borg rating of 18; or (c) inability to maintain the exercise intensity despite verbal encouragement. Hb concentration. Hb concentration was measured in venous blood using a clinically performed complete blood count, which was conducted at the cancer center where chemotherapy treatment was administered. Blood samples were drawn in the morning of each data-collection visit. CRF. CRF was measured using the revised Piper Fatigue Scale (PFS). The PFS is a 22-item scale that measures four dimensions (behavioral/severity, sensory, cognitive, and affective meaning) of subjective fatigue on a scale of 0 (no fatigue) to10 (extreme fatigue), where participants circle the number that best describes their current fatigue experience. The PFS was validated in breast cancer patients with internal consistency (Cronbach’s a coefficients) ranging from .92 to .98 (Piper et al., 1998). QoL. QoL was measured using the Functional Assessment of Cancer Therapy–Breast (FACT-B) questionnaire-Version 4 (Brady et al. 1997). This 37-item self-reporting instrument consists of five subscales including 27 general QoL questions and 10 breast-cancer–specific questions. The general QoL questions are divided into four subscales: physical well-being, social well-being, emotional well-being, and functional wellbeing. The breast-cancer–specific scale asks how bothered participants are by symptoms such as pain, hair loss, weight change, and shortness of breath. Using a 5-point scale, participants rate how true each statement has been for them during the past 7 days. The FACT-B total score ranges from 0 to 144, with higher numbers indicating better QoL. Total score is calculated by summing all subscale scores. The a coefficient is .90 for the Al-Majid et al. 43 Table 3. Baseline Demographic Characteristics of Study Participants. Variable Age, years Cancer stage Ethnicity Hispanic Non-Hispanic Marital status Married Unmarried Education <High school High school Technical school College Postcollege Employment Employed Unemployed Exercise group (n ¼ 7) n (%) or M + SD Control group (n ¼ 7) n (%) or M + SD 47.9 + 10.4 2.0 + 0.5 52.7 + 10.7 1.6 + 0.6 2 (28.6) 5 (71.4) 2 (28.6) 5 (71.4) 5 (71.4) 2 (28.6) 3 (42.9) 4 (57.1) 1 (14.3) 1 (14.3) 0 (0.0) 2 (28.6) 3 (42.9) 0 (0.0) 3 (42.9) 3 (42.9) 0 (0.0) 1 (14.3) 4 (57.1) 3 (42.9) t p 0.9 1.2 — .41 .26 1.00a — .59a — .37a — .91a 5 (71.4) 2 (28.6) a p-values based on exact two-sample multinomial test. entire instrument and ranges from .63 to .86 for the subscales (Brady et al., 1997). Select inflammatory markers. Inflammatory markers were measured in plasma samples obtained at baseline (T1) and within a week of patients having completed chemotherapy (T3). Highsensitivity immunoassay quantification kits were used as follows: IL-6 and IL-10 were measured using kits by R&D Technologies (North Kingstown, Rhode Island, USA), cortisol was measured using IBL International (Toronto, Ontario, Canada), and MPO was measured using Northwest Life (Toronto, Ontario, Canada). The sensitivity of the tests were as follows: IL-6 (0.016 pg/ml), IL-10 (0.5 pg/ml), cortisol (2.5 ng/ml) and MPO (0.4 ng/ml). Due to known diurnal variations in some of the biomarkers, blood samples were collected at 9:00 a.m. via standard phlebotomy procedures. Participants were instructed not to exercise the morning of blood collection. Blood samples were centrifuged within 2 hr of acquisition and separated plasma was stored at 80 C for batch analysis. Plasma samples were thawed only once and run in duplicates. Data Analysis Analysis of group differences for demographic characteristics was performed using a two-sample t-test (for age) and the exact two-sample multinomial test for all categorical variables (ethnicity, marital status, education, and employment status). Twosample multinomial exact tests based on enumeration of all possible outcomes under the null and subsequent calculation of the exact p values were implemented. Group differences in VO2 max, Hb, CRF, and QoL were analyzed using repeated measures analysis of variance (RMANOVA). The small subsample of six participants (three exercisers and three usual care) that was used for examination of inflammatory markers precluded statistical analyses. These data are reported as percentage changes from baseline (T1) to end of chemotherapy (T3). We employed appropriately designed contrasts to test the global hypotheses of no group differences over all time points. In the cases of significant p values for the global hypothesis, we used corresponding contrast to test for differences between the exercise and the usual-care groups at all time points individually with Bonferonni adjustments for multiple comparisons. All calculations were carried out using the R statistical software package (http://www.r-project.org). Results Sample Characteristics Descriptive data on sample demographic characteristics are reported as frequencies, means, and standard deviations (Table 3). There were no group differences with respect to age, stage of cancer, ethnicity, or race. Age ranged between 32 and 67 years for the exercise group and between 37 and 73 years and for the usual-care group. The majority of participants were Caucasian and non-Hispanic. Feasibility Outcomes Participants’ flow through the trial is presented in Figure 1. We screened 52 women presenting with breast cancer for eligibility. Of the 35 women who met eligibility criteria, 19 (51%) declined participation. With 16 women consenting to participate, our recruitment rate was 45.7%. Of these, one withdrew consent before baseline data collection due to fear of commitment and one decided to discontinue chemotherapy after the first cycle and was no longer eligible, resulting in a retention rate of 87.5%. The remaining 14 women completed the trial. 44 Biological Research for Nursing 17(1) Screened (n = 52) Ineligible (n = 17) • Advanced cancer (n = 3) • Not receiving chemo (n = 10) • Prior chemo (n = 2) • Other reasons (n = 2) Eligible (n = 35) Declined (n = 19) Consented (n = 16) Randomized (N = 14) Exercise (n = 7) • Time commitment (n = 6) • Overwhelmed (n = 1) • Long commute (n = 7) • Work schedule (n = 3) • Too tired (n = 1) • Refused randomization (n = 1) Withdrew consent (n = 1) Discontinued chemotherapy, thus no longer eligible (n = 1) Control (n = 7) Completed T1 data collection (n = 7) Completed T2 data collection (n = 6) Completed T3 data collection (n = 6) Completed T4 data collection (n = 6) Completed T1 data collection (n = 7) Completed T2 data collection (n = 6) Completed T3 data collection (n = 6) Completed T4 data collection (n = 7) Figure 1. Participant flow through the study. Adherence to per-protocol exercise sessions was very high, ranging between 95% and 97%. Of the seven participants in the exercise group, two missed one and five missed two of the total number of scheduled exercise sessions. All participants completed remaining sessions per protocol. None of the women in either group reported participating in out-of-study exercise activities. All but 1 participant (n ¼ 13) tolerated and completed exercise testing (VO2 max measurement) without problems. The participant who did not complete it was from the usual-care group and was not able to continue exercise testing past the first 2 min on the second data-collection time point (T2) due to overwhelming tiredness. Completion of study measurements ranged between 85.7% and 100%. All participants (100%) completed measurements at T1, 12 (85.7%) completed them at T2 (85.7%), 3 completed them at T3 (85.7%), and 13 (92.8%) completed them at T4 data-collection time points. Efficacy Outcomes Aerobic fitness (VO2 max). The longitudinal changes in VO2 max for the exercise and usual-care groups are presented in Table 4. There were no group differences in baseline VO2 max (p ¼ 0.26). The exercise-group participants maintained VO2 max at prechemotherapy levels throughout chemotherapy, whereas the Table 4. Longitudinal Changes in Aerobic Fitness (VO2 max; ml/kg/min) and Hemoglobin Concentration (mg/dl) in the Exercise and Usual-Care Participants. Outcome Measure T1 T2 T3 T4 VO2 max (ml/kg/min) Exercise 26.1 (2.6) 24.8 (3.0) 24.7 (2.5) 26.0 (2.5) Usual care 23.8 (2.9) 20.4 (3.3)* 17.6 (2.8)* 17.5 (2.8)* Hemoglobin (mg/dl) Exercise 14.11 (1.02) 11.8 (1.32)* 12.4 (0.55)* 11.84 (0.60)* Usual care 13.23 (2.27) 11.5 (1.36)* 11.3 (0.88)* 11.03 (0.95)* Note. Data are presented as mean (SD). VO2 max ¼ maximal oxygen consumption; T1 ¼ Time 1 (baseline) data; T2 ¼ Time 2 data (after second cycle of chemotherapy); T3 ¼ Time 3 data (within a week of completion of chemotherapy and exercise); T4 ¼ Time 4 data (3–4 weeks after completion of chemotherapy and exercise). *Significant decrease from T1 (p < 0.5). usual-care group showed a significant decline of up to 6.3 ml/ kg/min (p < .05) that continued 3–4 weeks following the completion of chemotherapy. Hb concentration. Hb levels in the exercise and usual-care groups throughout the trial are also presented in Table 4. There Al-Majid et al. 45 Table 5. Longitudinal Changes in Cancer-Related Fatigue (CRF), Overall Quality of Life (QoL) and Subscales of QoL in the Exercise and Usual-Care Groups. Variable CRF Exercise Usual care FACT-B total (0–144) Exercise Usual care PWB scale (0–28) Exercise Usual care SWB scale (0–24) Exercise Usual care EWB scale (0–28) Exercise Usual care FWB scale (0–28) Exercise Usual care BCS (0–36) Exercise Usual care T1 Mean (SE) T2 Mean (SE) T3 Mean (SE) T4 Mean (SE) 3.0 (0.7) 0.8 (0.5) 3.9 (1.2) 3.3 (0.9) 3.0 (0.8) 4.6 (0.9) 2.9 (1.0) 4.3 (1.2) 116.4 (6.1) 115.5 (5.4) 110.1 (6.4) 107.0 (5.3) 108.0 (6.7) 96.4 (1.9) 113.3 (6.4) 97.5 (6.1) 23.9 (2.1) 25.3 (1.2) 19.9 (2.2) 19.2 (1.9) 19.3 (2.1) 16.2 (1.7) 21.9 (1.6) 17.3 (2.4) 25.6 (1.8) 24.7 (2.0) 24.1 (1.5) 24.0 (1.5) 23.1 (1.7) 24.8 (1.5) 25.6 (1.9) 24.0 (1.8) 18.4 (1.3) 19.2 (1.3) 18.7 (1.5) 22.2 (1.2) 19.4 (0.9) 17.2 (1.8) 20.3 (0.9) 17.0 (2.0) 22.9 (1.8) 22.7 (1.7) 22.7 (1.0) 18.6 (2.0) 21.4 (2.2) 16.6 (1.5) 22.4 (1.6) 16.8 (2.2) 23.8 (2.0) 23.7 (0.9) 24.9 (1.7) 23.0 (1.9) 24.7 (2.0) 21.6 (1.0) 24.0 (1.6) 22.3 (2.3) p .09 .52 .45 .81 .07 .45 .86 Note. SE ¼ standard error. BCS ¼ breast cancer scale; EWB ¼ emotional well-being; FACT-B total ¼ total quality of life; FWB ¼ functional well-being; PWB ¼ physical well-being; SWB ¼ social well-being; T1 ¼ Time 1 (baseline) data; T2 ¼ Time 2 data (after second cycle of chemotherapy); T3 ¼ Time 3 data (within a week of completion of chemotherapy and exercise); T4 ¼ Time 4 data (3–4 weeks after completion of chemotherapy and exercise). were no group differences in Hb concentration at any of the four data-collection time points. Hb levels decreased significantly (13.7 + 1.7 mg/dl to 11.0 + 0.9, p < .001) in all participants as they progressed through chemotherapy. In both groups, Hb decreased significantly by T2 (after the second cycle of chemotherapy) and remained low through T4 (3–4 weeks following the completion of chemotherapy). Relative to prechemotherapy, postchemotherapy cortisol levels dropped by 24% (from 92.7 to 70.2 mg/dl) in the exercise group but did not change in the usual-care group (69.2 and 70.6 mg/dl). Post-chemotherapy MPO was similar to the pre-chemotherapy level in the exercisers (11.8 and 11.9 mg/dl) but increased by 25% (from 11.7 to 14.7 mg/dl) in the usual-care group. CRF and QoL. The longitudinal changes in CRF and QoL in the exercise and usual-care participants as well as the p values for the global test for overall difference between the two groups across all time points are presented in Table 5. Changes in these variables favored the exercise group but did not reach statistical significance. Participants in both groups showed significant decrease in overall QoL as well as in physical and functional well-being (p ¼ .02, .005, and .01, respectively) as they progressed through chemotherapy. Discussion Select inflammatory markers. Prechemotherapy IL-6 level was higher in the usual-care group than in the exercise group (4.45 vs. 1.23 mg/dl). By the end of chemotherapy, IL-6 levels dropped slightly (2.96 mg/dl) in the usual-care group but did not change in the exercise group. Relative to prechemotherapy, postchemotherapy levels of IL-10 increased by 64% in the exercise group (from 0.58 to 1.22 pg/dl) and by only 30% in the usual-care group (from 0.81 to 1.11 pg/dl). This study provides information suggesting that a supervised, individualized treadmill exercise intervention performed during chemotherapy for early-stage breast cancer is both feasible and efficacious. Feasibility Outcomes Our 95–97% adherence to the exercise protocol is slightly higher than that reported in the literature. A recent metaanalysis of 17 randomized controlled trials that employed various types and doses of exercise during chemotherapy for breast cancer revealed adherence rates ranging between 26% and 93.8% (Carayol et al., 2012). However, Knobf, Thompson, Fennie, and Erdos (2013) reported a higher exercise adherence rate of up to 98% among cancer survivors. Our high adherence rate could be attributed to scheduling flexibility and permission to make up missed exercise sessions. 46 As with other exercise studies, particularly those that involved patients undergoing chemotherapy, it was difficult to recruit patients into the present study. Our recruitment rate of 45.7% is, however, within the range (33–54%) reported in the literature (Courneya et al., 2007; Dolan et al., 2010; Griffith et al., 2010; Payne, Held, Thorpe, & Shaw, 2008; Vincent et al., 2013). Several factors might have contributed to the low recruitment rate. First, baseline measures had to be obtained before initiation of chemotherapy, which meant that women had to make a decision about participating in the study at about the same time they were making decisions about their treatment options. Second, offering the exercise intervention in the cancer center entailed women making several trips per week to the center, which might have discouraged participation. Last, the mode of exercise (walking on a treadmill) might have deterred women with no prior treadmill experience from participating. However, this supervised exercise protocol allowed for quantification of exercise dose in terms of intensity, duration, and frequency. Efficacy Outcomes In this feasibility study, we demonstrated that a relatively shortduration endurance exercise program might protect against chemotherapy-associated decline in VO2 max. Exercise-group participants maintained their VO2 max, while those in the usual-care group showed a significant decline as they progressed through chemotherapy. This protective effect of exercise on VO2 max was independent of changes in Hb, suggesting that exercise might have improved O2 uptake/extraction at the tissue level, possibly by protecting against loss of skeletal muscle mitochondria, capillary density, and/or aerobic enzymes. Previous researchers have reported maintenance of prechemotherapy VO2 max level in women with breast cancer who exercised during chemotherapy (Dolan et al., 2010; Vincent et al., 2013). Similar to our findings, Dolan et al. (2010) reported no effect of endurance exercise on Hb during chemotherapy for breast cancer. The ability of these women to maintain their prechemotherapy VO2 max in the face of chemotherapy-induced decline in Hb provides evidence to support the beneficial role of exercise during chemotherapy. We found no significant effect of exercise on CRF. However, the exercise group participants maintained their baseline level of mild CRF (defined as 1–3 on PFS) throughout the study. Conversely, CRF in the usual-care group increased from less than mild at baseline to moderate (defined as 4–6 on PFS) by the end of chemotherapy and remained elevated 3–4 weeks after chemotherapy. Failure of exercise to significantly decrease CRF in this study could be due to low statistical power and low baseline levels of CRF in our sample. Other researchers also found no significant effect of exercise on mild to moderate CRF in breast cancer patients (Dodd et al., 2010; Payne et al., 2008; Vincent et al., 2013). However, Heim, Malsburg, and Niklas (2007) found that CRF decreased significantly in response to exercise in breast cancer patients who had higher levels of fatigue (>4 on an 11-point scale) at baseline. Future studies involving Biological Research for Nursing 17(1) interventions for CRF should consider a certain level of baseline fatigue as one of the inclusion criteria. Although exercisers maintained relatively higher QoL throughout the study compared to nonexercisers, there was no significant effect of exercise on QoL. This finding is consistent with those of Courneya et al. (2007) who found no effect of resistance or endurance exercise on QoL in women receiving chemotherapy for breast cancer. Similarly, Adamsen et al. (2009) found that a multimodal high-intensity exercise program did not have significant effects on QoL in patients undergoing chemotherapy for various cancers. There was a wide variability in longitudinal changes of QoL in our sample, as evidenced by the wide range of standard deviation (5–18). This variability, along with the small sample size, could have contributed to the failure to demonstrate a significant effect of exercise on overall QoL. Our preliminary findings regarding the effects of endurance exercise on IL-6 are consistent with those of Payne, Held, Thorpe, and Shaw (2008), suggesting that endurance exercise during chemotherapy for breast cancer does not affect IL-6 levels. However, increased levels of the anti-inflammatory cytokine IL-10 among the exercisers in the present study suggest that endurance exercise may attenuate some of the proinflammatory effects of chemotherapy. Our findings also show that MPO levels remained steady in the exercise group but increased by 25% in the usual-care group. This finding suggests that exercise during chemotherapy may contribute to increased antioxidant functioning. Additionally, our exercise group showed a greater drop in cortisol level compared to the usual-care group, suggesting that exercise may have positive effects on the stress response. Limitations The present study had several limitations. A major limitation is the small sample size, which reflects the limitations (budget and time) inherent in pilot and feasibility studies. The small sample size precludes us from drawing definitive conclusions regarding the effects of our endurance exercise protocol on the biobehavioral markers measured in this study. Another limitation is that participants had only mild baseline levels of CRF, which could have contributed to the failure to demonstrate a significant effect of exercise on CRF. Major strengths include the use of randomization, inclusion of a control group, and exploration of the effect of exercise on biological and behavioral factors concurrently. Implications The endurance exercise program used in this study appears to be feasible and potentially effective. Results from the study, despite the small sample size, support the role of exercise in preventing a decline in aerobic fitness during chemotherapy for breast cancer. Results for all outcome variables favored the exercise intervention, which supports the need for larger scale studies. Recruitment of eligible participants into the study was Al-Majid et al. challenging; for future studies, researchers should explore strategies to increase participant enrollment in randomized control trials involving exercise during cancer treatment. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funded by a grant from the Oncology Nursing Society. References Adamsen, L., Quist, M., Andersen, C., Moller, T., Herrsted, J., Krongborg, D., . . . Rorth, M. (2009). Effect of a multimodal high intensity exercise intervention in cancer patients undergoing chemotherapy: Randomised controlled trial. British Medical Journal, 339, b3410. doi:10.1136/bmj.b3410 Al-Majid, A., & Gray, D. P. (2009). A biobehavioral model for the study of exercise interventions in cancer-related fatigue. Biological Research for Nursing, 10, 381–391. doi:10.1177/109980 0408324431 Boccia, R., Lillie, T., Tomita, D., & Balducci, L. (2007). The effectiveness of Darbepoetin Alpha administered every 3 weeks on hematologic outcomes and quality of life in older patients with chemotherapy-induced anemia. The Oncologist, 12, 584–593. doi:10.1634/theoncologist.12-5-584 Brady, M. J., Cella, D. F., Mo, F., Bonomi, A. E., Tulsky, D. S., Lloyd, S. R., . . . Shiomoto, G. (1997). Reliability and validity of the functional assessment of cancer therapy breast quality-of-life instrument. Journal of Clinical Oncology, 15, 974–986. Carayol, M., Bernard, P, Boiche, J., Riou, F., Mercier, B, CoussonGellie, F., . . . Ninot, G. (2012). Psychological effect of exercise in women with breast cancer receiving adjuvant therapy: What is the optimal dose needed? Annals of Oncology, 24, 291–300. doi: 10.1093/annonc/mds342 Cheng, K. K., & Yeung, R. M. (2013). Impact of mood disturbance, sleep disturbance, fatigue and pain among patients receiving cancer therapy. European Journal of Cancer Care, 22, 70–78. doi: 10.1111/j.1365-2354.2012.01372.x Courneya, K. S., Segal, R. J., Mackey, J. R., Gelmon, K., Reid, R. D., Friedenreich, C. M., . . . McKenzie, D. C. (2007). Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: A multicenter randomized controlled trial. Journal of Clinical Oncology, 25, 4396–4404. doi:10.1200/JCO. 2006.08.2024 Davis, M. P., & Walsh, D. (2010). Mechanisms of fatigue. Journal of Supportive Oncology, 8, 164–174. Dodd, M. J., Cho, M. H., Miaskowski, C., Painter, P. L., Paul, S. M., Cooper, B. A., . . . Bank, K. A. (2010). A randomized controlled trial of home-based exercise for cancer-related fatigue in women during and after chemotherapy with or without radiation therapy. Cancer Nursing, 33, 245–257. doi:10.1097/NCC.0b013e3181ddc58c Dolan, L., Gelmon, K., Courneya, K., Mackey, J., Segal, R., Lane, K., . . . McKenzie, D. C. (2010). Hemoglobin and aerobic 47 fitness changes with supervised exercise training in breast cancer patients receiving chemotherapy. Cancer Epidemiology, Biomarkers and Prevention, 19, 2826–2832. doi:10.1158/ 1055-9965.EPI-10-0521 Drouin, J. S., Young, T. J., Beeler, J., Byrne, K., Birk, T. J., Hryniuk, W. M., & Hryniuk, L. E. (2006). Random control clinical trial on the effects of aerobic exercise training on erythrocyte levels during radiation treatment for breast cancer. Cancer, 107, 2490–2495. doi:10.1002/cncr.22267 Edwards, C. (2012). Sixty years after Hench—corticosteroids and chronic inflammatory disease. Journal of Clinical Endocrinology and Metabolism, 97, 1443–1451. doi:10.1210/jc.2011-2879 Finaud, J., Lac, G., & Filaire, E. (2006). Oxidative stress: Relationship with exercise and training. Sports Medicine, 36, 327–358. Griffith, K., Wenzel, J., Shang, J., Thompson, C., Stewart, K., & Mock, V. (2010). Impact of a walking intervention on cardiorespiratory fitness, self-reported physical function, and pain in patients undergoing treatment for solid tumors. Cancer, 115, 4874–4884. doi:10.1002/cncr.24551 Gupta, D., Lis, C. G, & Grutsch, J. F. (2007). The relationship between cancer-related fatigue and patient satisfaction with quality of life in cancer. Journal of Pain and Symptom Management, 34, 40–47. Haykowski, M. J., Mackey, J. R., Thompson, R. B., Jones, L., W., & Paterson, D. I. (2009). Adjuvant trastuzumab induces ventricular remodeling despite aerobic exercise training. Clinical Cancer Research, 15, 4963–4967. doi:10.1158/1078-0432.CCR-09-0628 Heim, M. E., Malsburg, M. L., & Niklas, A. (2007). Randomized controlled trial of a structured training program in breast cancer patients with tumor-related chronic fatigue. Onkologie, 30, 429–434. Jones, L. W., Liang, Y., Pituskin, E. N., Battaglini, C. L., Scott, J. M., Hornsby, W. E., & Haykowsky, M. (2011). Effect of exercise training on peak oxygen consumption in patients with cancer: A metaanalysis. The Oncologist, 16, 112–120. doi:10.1634/theoncologist. 2010-0197 Knobf, M. T., Thompson, A. S., Fennie, K., & Erdos, D. (2013). The effect of a community-based exercise intervention on symptoms and quality of life. Cancer Nursing. Advance online publication. doi:10.1097/NCC.0b013e318288d40e Li, Y., & Yuan, C. (2011). Levels of fatigue in Chinese women with breast cancer and its correlates: A cross-sectional questionnaire survey. Journal of the American Academy of Nurse Practitioners, 23, 153–160. Ligibel, J. A., Patridge, A., Giobbie-Hurder, A., Campbell, N., Shockro, L., Salinardi, T., & Winer, E. P. (2010). Physical and psychological outcomes among women in a telephone-based exercise intervention during adjuvant therapy for early-stage breast cancer. Journal of Women’s Health, 19, 1553–1559. doi:10.1089/jwh. 2009.1760 Limberaki, E., Eleftheriou1, P., Gasparis, G, Karalekos, E., Kostoglou, V., & Petrou, C. (2011). Cortisol levels and serum antioxidant status following chemotherapy. Health, 3, 512–517. doi:10. 4236/health.2011.38085 Liu, L., Mills, P. J., Rissling, M., Fiorentino, L., Natarajan, L., Dimsdale, J. E., . . . Ancoli-Israel, S. (2012). Fatigue and sleep quality are associated with changes in inflammatory markers in breast 48 cancer patients undergoing chemotherapy. Brain, Behavior, and Immunity, 26, 706–713. doi:10.1016/j.bbi.2012.02.001 McMillan, E. M., & Newhouse, I. J. (2011). Exercise is an effective treatment modality for reducing cancer-related fatigue and improving physical capacity in cancer patients and survivors: A metaanalysis. Applied Physiology, Nutrition, and Metabolism, 36, 892–903. doi:10.1139/h11-082 Payne, J. K., Held, J., Thorpe, J., & Shaw, H. (2008). Effect of exercise on biomarkers, fatigue, sleep disturbances, and depressive symptoms in older women with breast cancer receiving hormonal therapy. Oncology Nursing Forum, 35, 635–642. doi:10.1188/08.ONF. 635-642 Piper, B. F, Dibble, S. L., Dodd, M. J., Weiss, M. C, Slaughter, R. E., & Paul, S. M. (1998). The revised Piper fatigue scale: Psychometric evaluation in women with breast cancer. Oncology Nursing Forum, 25, 677–684. Reyes-Gibby, C. C., Wang, J., Spitz, M., Wu, X., Yennurajalingam, S., & Shete, S. (2013). Genetic variations in interleukin-8 and interleukin-10 are associated with pain, depressed mood, and fatigue in lung cancer patients. Journal of Pain and Symptom Management, 46, 161–172. doi:10.1016/j.jpainsymman.2012.07.019 Romito, F., Montanaro, R., Corvasce, C., Di Bisceglie, M., & Mattioli, V. (2008). Is cancer-related fatigue more strongly correlated to haematological or to psychological factors in cancer Biological Research for Nursing 17(1) patients? Supportive Care in Cancer, 16, 943–946. doi:10.1007/ s00520-007-0357-1 Ryan, J. L., Carroll, J. K., Ryan, E. P., Mustian, K. M., Fiscella, K., & Morrow, G. R. (2007). Mechanisms of cancer-related fatigue. Oncologist, 12, 22–34. doi:10.1634/theoncologist.12-S1-22 Saxton, J. (Ed.). (2011). Exercise and chronic disease: An evidencebased approach. London, England: Routledge. Siefert, M. L. (2010). Fatigue, pain, and functional status during outpatient chemotherapy. Oncology Nursing Forum, 37, E114–E123. doi:10.1188/10.ONF.114-123 Vincent, F., Labourey, J. L, Leobon, S., Anonini, M. T., Lavau-Denes, S., & Tubiana-Mathieu, N. (2013). Effects of a home-based walking training program on cardiorespiratory fitness in breast cancer patients receiving adjuvant chemotherapy: A pilot study. European Journal of Physical and Rehabilitation Medicine, 49, 1–11. Walsh, N. P., Gleeson, M., Shephard, R. J., Gleeson, M., Woods, J. A., Shephard, R. J., . . . Kajeniene, A. (2011). Position statement: Part one: Immune function and exercise. Exercise Immunology Review, 17, 6–61. Wang, X. S., Williams, L. A., Krishnan, S., Liao, Z., Liu, P., Mao, L., . . . Cleeland, C. S. (2012). Serum sTNF-R1, IL-6, and the development of fatigue in patients with gastrointestinal cancer undergoing chemoradiation therapy. Brain, Behavior, and Immunity, 26, 699–705. doi:10.1016/j.bbi.2011.12.007