Telehealth System: a Randomized Controlled Trial Evaluating the Impact of an

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1 Page 1 of 39 TITLE PAGE Manuscript title Telehealth System: a Randomized Controlled Trial Evaluating the Impact of an Internet-Based Exercise Intervention on Quality of Life, Pain, Muscle Strength and Fatigue in Breast Survivors Running title Telehealth system in breast cancer Authors list Noelia Galiano-Castillo, PhD a,b ; Irene Cantarero-Villanueva, PhD a,b,c ; Carolina Fernández-Lao, PhD a,b,c ; Angelica Ariza-García, MSc b,d ; Lourdes Díaz- Rodríguez, PhD a,c,e ; Rosario Del-Moral-Ávila, MD f ; Manuel Arroyo-Morales, MD a,b,c Affiliations list a Institute for Biomedical Research ibs.granada, University Hospital Complex of Granada/University of Granada, Granada, Spain. b Department of Physical Therapy, University of Granada, Granada, Spain. c Mixed University Sport and Health Institute (imuds), Granada, Spain. d Department of Physical Medicine and Rehabilitation, University Hospital San Cecilio, Granada, Spain. e Department of Nursing, University of Granada, Granada, Spain. f Radiotherapy Breast Oncology Unit, University Hospital Virgen de las Nieves, Granada, Spain. This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version record. Please cite this article as doi: /cncr

2 Page 2 of 39 Corresponding author Noelia Galiano-Castillo PhD, Department of Physical Therapy, Health Science Faculty, University of Granada Avda de la Ilustración 60, Granada (Spain) Tel: Fax: noeliagaliano@ugr.es Total number of each Text pages, including title page, references, and figure legends: 26 Tables: 2 Figures: 4 Funding support This work was supported by a research project grant (FIS PI10/ ) from the Health Institute Carlos III and PN I+D+I (FEDER funds); a grant (Program FPU AP ) from the Education Ministry, Madrid, Spanish Government; and a grant from the Andalusian Health Service, Junta de Andalucía (PI ). Conflict of Interest Disclosures The authors have declared no conflicts of interest. 2

3 Page 3 of 39 Author Contributions Conceptualization, methodology: All authors. Investigation, formal analysis: Noelia Galiano-Castillo, Irene Cantarero- Villanueva, Carolina Fernández-Lao, Lourdes Díaz-Rodríguez. Writing (original draft): Manuel Arroyo-Morales. Writing (review and editing): All authors. Resources: Carolina Fernández-Lao, Angélica Ariza-García, Lourdes Díaz- Rodríguez, Rosario Del-Moral-Ávila. Visualization: Noelia Galiano-Castillo. Supervision, project administration: Manuel Arroyo-Morales. Precis This is one of the most extensive randomized controlled trials to report effect sizes for telerehabilitation in breast cancer survivors using an adequate followup period. This non-face-to-face approach could help the growing number of cancer survivors using information and communications technology as delivery method. 3

4 Page 4 of 39 ABSTRACT Background: The chronicity status of breast cancer survivors suggests a growing need for cancer rehabilitation. Currently, technology use is a promising strategy for providing support, as reflected in the emergence of research interest in web-based interventions in cancer survivorship. Methods: A randomized controlled trial was conducted including a total of 81 participants who had completed adjuvant therapy (except hormonal treatment) for stage I to IIIA breast cancer. Participants were randomly assigned to an 8- week Internet-based tailored exercise program (n=40) or control group (n=41).the instruments used at baseline, 8 weeks and 6-month follow-up were European Organization for Research and Treatment of Quality of Life Questionnaire Core 30 and its breast cancer module, Brief Pain Inventory, handgrip dynamometer, isometric abdominal test, back dynamometer, Multiple sit-to-stand test and Piper Fatigue Scale. Results: After intervention, telerehabilitation group improved significantly global health status, physical, role, cognitive functioning and arm symptoms (all P<0.01) as well as pain severity (P=0.001) and pain interference (P=0.045) compared with the control group. Significant improvements were also observed favoring the telerehabilitation group for affected and non-affected side handgrip (both P=0.006), abdominal, back and lower body strength (all P<0.01), and total fatigue (P<0.001). These findings were maintained after 6-month follow-up, except for role functioning, pain severity and non-affected side handgrip. Analysis was based on intention-to-treat principle. 4

5 Page 5 of 39 Conclusions: This program may improve adverse effects and maintain benefits in breast cancer survivors. The results of this study have encouraging implications in cancer care. Keywords: telerehabilitation, telehealth, ehealth, exercise, Internet, breast cancer. 5

6 Page 6 of 39 MANUSCRIPT INTRODUCTION Breast cancer (BC) survival rates have improved, but patients have to cope with adverse effects related not only to the disease but also to treatment. For this reason, cancer patients suffer exercise intolerance 1 and consequently cardiorespiratory deconditioning, which affects their symptoms and functional level. Physical activity appears to provide health benefits in cancer survivors, suggesting that exercise-based rehabilitation programs should be performed within cancer care. 2 However, these programs are at risk for low adherence (remote location of the center, familial support, and previous physical activity habits). 3 Technological advancements may help to resolve barriers such as distance, time and cost. 4 Taking into account the negative impact of disease on the quality of life of breast cancer survivors (BCS), increasing access to programs by delivering them via telerehabilitation systems that are capable of assessing and treating their side effects might be a useful tool. 5,6 A recent review showed that telerehabilitation can be an effective part of cancer care. 7 In terms of quality of life, Ligibel et al. 8 found significant improvement only in physical functioning but did not demonstrate that intervention had a significant effect on other variables. This result could be because participants did not receive daily checkins to adjust each exercise according to their needs or because no audiovisual materials were used. Other similar systems delivered via telephone assessed variables such as fitness level, 5 pain, 9 fatigue 10 or upper body function. 11 However, only results related to fitness level were significant. 6

7 Page 7 of 39 Moreover, there is a lack of evidence for long-term maintenance of intervention effects that is described in the literature. 7,12 Because there is a growing interest in these non-face-to-face approaches, future randomized controlled trials should address weaknesses such as no reporting effect sizes (ES) and become stronger to shed light on their clinical effectiveness. This study aimed to investigate the effectiveness of a telehealth system for improving adverse effects after an 8-week intervention and its maintenance after 6-month follow-up in BCS. MATERIALS AND METHODS Study Design We conducted a two-arm, assessor-blinded, parallel, randomized controlled efficacy trial (ClinicalTrials.gov NCT ) to compare a telerehabilitation program to usual care. Members involved in delivering program were different from assessor member. Eighty-one BCS were randomly assigned to the telerehabilitation group or the control group using computer-generated random numbers (EPIDAT 3.1, Xunta de Galicia). These numbers were provided in numbered opaque envelopes by an external member to ensure that research member responsible for outcome assessments was blind to treatment group assignment. These envelopes were opened after baseline assessment. Baseline, after intervention (8 weeks) and follow-up at 6 months after intervention were the end points and were carried out at physical therapy laboratory in Health Science Faculty (Granada, Spain). The trial was approved by the Research Ethics Committee of The University of Granada (FIS 7

8 Page 8 of 39 PI10/ ) and performed according to the Helsinki Declaration and The Biomedical Research (14/2007). Written informed consent was obtained for all participants. Recruitment From March 2012 to November 2013, 99 BCS were recruited (Figure 1) from Oncology and Breast units at the Virgen de las Nieves Hospital (Granada, Spain). The oncologist involved in the management of each participant encouraged them to participate in this study. 13 Details of the trial protocol have been described elsewhere. 14 Eligibility criteria included: 1) diagnosis of stage I, II or IIIA BC; 2) medical clearance for participation; 3) no chronic disease or orthopedic concern that limited exercise training; 4) access to the Internet; 5) basic computer skills or living with someone with this ability; 6) completed adjuvant therapy except hormonal treatment; 7) no cancer recurrence; and 8) signed informed consent. Interventions E-CUIDATE system Telerehabilitation program was implemented using the e-cuidate system ( an online system that facilities the development of remote rehabilitation. The e-cuidate system consists of a public interface and a separate private interface. The public area is the homepage with updated information about BC. After completion of the baseline assessment, the patients received in-person instructions on how to access and use the private area on their own (usernames and passwords were provided). 8

9 Page 9 of 39 The CUIDATE research staff designed the most adequate tailored exercise program for each case. This was essential for enhancing adherence to the program. The intervention was managed by CUIDATE research staff using a control platform to assign and check different exercise programs. The schedule consisted of 3 sessions per week (nonconsecutive days) about 90 min each day. The intensity and volume of the physical exercise training were established following the recommendations of the American College of Sport Medicine for cancer survivors. 15 Each session was delivered online and contained a battery of specific exercises that were divided into three sections: 1) warm-up, 2) resistance and aerobic exercise training, and 3) cool-down. Participants had a space available to write questions or suggestions regarding their performance. Then, CUIDATE research staff could revise their comments and monitor the participant s performance remotely. The system allowed participants to send instant messages and set up videoconference sessions (3 times/week) using Wormhole Web Conference and Skype software (Microsoft Corporation, Redmond, Washington). Furthermore, participants received telephone calls from CUIDATE research staff if required. After the completion of the 8-week intervention, the participants were encouraged to continue with the exercise program self-sufficiently. Efforts were made to prevent the telerehabilitation group from receiving additional care apart from our intervention, including an attempt to convince the BCS of the importance of supervised intervention 16 to facilitate the success of the exercise program. 9

10 Page 10 of 39 Usual care The control group received basic recommendations (written format) for exercise. 15 These participants were asked to report any changes in their level of activity during the study. For ethical reasons, after completing the 6-month follow-up, the participants allocated to the control group had the opportunity to receive an intervention that was identical to that of the telerehabilitation group. These data were not analyzed. Sample size calculation It consisted of 72 participants (36 in each group), which provided 90% power (5% significance) for detecting differences of at least 5% in health-related quality of life, that is, global health status using The European Organization for Research and Treatment of Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). 17 In this questionnaire, a minimal important difference is 5 to 10 points. 18 In anticipation of possible losses, 80 participants were recruited to allow a maximum loss at follow-up of 10%. 19 The study was considered finished when it achieved the sample size. IBM SPSS Statistics 21 was used for all analyses. Outcomes Quality of life The Spanish version of the EORTC QLQ-C30 and its BC module were used to measure changes in quality of life in cancer patients and have shown an adequate reliability: Cronbach s α ranged between and , 20 respectively. 10

11 Page 11 of 39 Pain The Brief Pain Inventory (BPI) short form comprises four pain severity and seven pain interference items with daily activities. Mean scores were calculated. In this version, the ratings for pain were made for the previous 24 h. The reliability between dimensions was good (Cronbach s α ranged between ). 21 Isometric handgrip strength Handgrip strength was measured using a digital dynamometer with adjustable grip (TKK 5101 Grip-D; Takey, Tokyo, Japan). In standing position and elbow in complete extension. The test was performed three times per hand (alternating both hands), with a 1 min rest between trials. The average score for each hand was registered. This test has been shown to be valid and reliable. 22 Isometric abdominal strength Muscular endurance was measured while the participant lay supine with flexed knees and a distance of 0.30 m between heels-buttocks. The arms have to be lifted with the palms guided to level the knees, causing the inferior angle of the scapula to be barely lifted from the support platform. The participant was instructed to maintain this position as long as possible. The number of seconds was recorded. The reliability in terms of intraclass correlation coefficient (ICC) was

12 Page 12 of 39 Isometric back strength An analog back dynamometer (TKK 5002 Back-A; Takey, Tokyo, Japan) was used to measure muscle strength. From a standing position, the participant was required to maintain 30 lumbar flexion. This was performed three times with a 1-min interval between measures, and the average was recorded. The reliability has been acceptable to good (ICC ). 24 Lower body strength The multiple sit-to-stand test consisted of the participant sitting down and standing up from a chair with arms crossed over her chest ten times as fast as possible. The number of seconds was recorded. This test has shown good reliability (ICC=0.80). 25 Fatigue The Piper Fatigue Scale-revised (R-PFS) is a 22-item self-reported scale. A total score of fatigue was recorded. This tool has shown high reliability (Cronbach s α=0.97). 26 Statistical analysis Descriptive analyses were performed on all participants who were randomly assigned to either group. We analyzed between-group differences at baseline using t tests for continuous variables and X 2 tests for categorical variables. The Kolmogorov-Smirnov test was applied to test the hypothesis of normality for all variables. The main analysis was tested using analysis of covariance (ANCOVA) to assess the intervention effects as well as the maintenance of 12

13 Page 13 of 39 effects on study variables. The analysis was conducted according to the intention-to-treat principle for the N=76 patients (with the worst value carried forward in cases of missing data). Time since diagnosis, age, stage BC, type of surgery and menopause were used as covariates. Regarding the significance level, interaction effects were reported (time x group). Post hoc analyses were conducted if significant interaction effects were found in the main analysis. Additionally, ES were calculated as Cohen s d. RESULTS A total of 81 BCS were randomly assigned to the telerehabilitation group (n=40) or control group (n=41) (Figure 1). The sociodemographic and clinical characteristics were comparable between the groups, except for menopause (P=0.023) (Table 1). At the beginning of the study, there were no group differences in study variables except for lower body strength (P=0.012). Quality of life The results indicated significant effects for global health status (F=7.51;P=0.001), physical (F=7.45;P=0.001), role (F=6.13;P=0.003) and cognitive functioning (F=5.35;P=0.007) according to the EORTC QLQ-C30 and a significant effect for arm symptoms (F=6.13;P=0.003) according to its module. Post hoc ANCOVAS revealed that the telerehabilitation group improved significantly global health status, physical functioning (both P<0.001), role functioning (P=0.001), cognitive functioning and arm symptoms (both P=0.002) compared with the control group after the intervention. In addition, a significant 6-month maintenance of effects was found (all P<0.05) except for role 13

14 Page 14 of 39 functioning (P=0.169) (Table 2) (Figure 2a, Figure 2b, Figure 2c, and Figure 2d). We also reported the ES for significant between-group differences after intervention: global health status (d=0.89 CI95% -3.67;5.45), physical functioning (d=0.90 CI95% -1.84;3.64), role functioning (d=0.78 CI95% ;6.29), cognitive functioning (d=0.75 CI95% -3.95;5.44) and arm symptoms (d=-0.53 CI95% -4.25;3.20). The ES after follow-up were global health status (d=0.62 CI95% -3.28;4.53), physical (d=0.53 CI95% -2.15;3.22), cognitive functioning (d=0.62 CI95% -4.79;6.04) and arm symptoms (d=-0.40 CI95% ;3.69). Pain We found significant interaction effects for pain severity (F=6.30;P=0.003) and pain interference (F=3.70;P=0.03). Post hoc ANCOVAS revealed that after intervention, the telerehabilitation group reported significantly lower pain severity (P=0.001) and pain interference (P=0.045) than the control group. After the 6-month follow-up, significant results were maintained only for pain interference (P=0.008) (Supplemental Table 1). After intervention, the ES were: pain severity (d=-0.82 CI95% -1.23;-0.42) and pain interference (d=-0.47 CI95% -0.98;0.03). A moderate ES for pain interference was obtained after 6-month follow-up (d=-0.63 CI95% -1.08;-0.18). After including the different covariates, we found that menopause (F=2.74;P=0.071) affected the interaction effect of the pain interference. 14

15 Page 15 of 39 Static and dynamic muscle strength We found significant interaction effects for handgrip (affected: F=4.14;P=0.02; non-affected: F=5.90;P=0.004), isometric abdominal (F=9.43;P<0.001), isometric back (F=18.78;P<0.001) and lower body strength (F=6.87;P=0.002). Post hoc ANCOVAS revealed that the telerehabilitation group improved affected and non-affected side handgrip strength (both P=0.006) significantly compared with the control group after intervention. This improvement was only maintained after 6-month follow-up in the affected side (P=0.033) (Figure 3a and Figure 3b). Regarding the rest of the strength-related measures, after intervention, the telerehabilitation group significantly improved abdominal, back (both P<0.001) and lower body strength (P=0.001) compared with the control group. Similar findings were obtained as a result of the 6-month maintenance: abdominal (P=0.006), back (P=0.014) and lower body strength (P=0.001) (Supplemental Table 2). After intervention, the ES were large for abdominal (d=1.02 CI95% ;5.95), back (d=1.31 CI95% -0.82;3.44) and lower body strength (d=-0.81 CI95% -2.30;0.69), and moderate for affected side (d=0.66 CI95% -0.13;1.45) and non-affected side handgrip (d=0.66 CI95% 0.04;1.28). After the 6-month maintenance period, the ES were moderate for abdominal strength (d=0.66 CI95% -5.14;6.45), affected side handgrip (d=0.50 CI95% -0.48;1.48), back (d=0.58 CI95% -1.78;2.95) and body lower strength (d=-0.56 CI95% ;0.50). Fatigue A significant interaction effect was found for total fatigue (F=7.63;P=0.001). Post hoc ANCOVAS showed that after intervention, the telerehabilitation group 15

16 Page 16 of 39 improved total fatigue perception significantly (P<0.001) compared with the control group. This improvement was maintained after the 6-month follow-up (P=0.002) (Figure 4). The ES was large after intervention (d=-0.89 CI95% ;-0.48) and moderate after follow-up (d=-0.74 CI95% -1.19;-0.29). Adherence rate, adversity and acceptability The adherence rate was high (93.9%), at 22.5±1.7 out of 24 scheduled sessions, and no remarkable health problems or technical issues were recorded. Moreover, the participants allocated to the telerehabilitation group completed a satisfaction survey (Supplemental Table 3) during the 8-week end point. The mean percentage was 97.8% for global satisfaction. DISCUSSION The e-cuidate system improved quality of life, pain, muscle strength and fatigue significantly more than usual care. These findings were maintained after the 6-month follow-up period. Our results also demonstrate that there was high acceptance and adherence to the intervention, which is in line with other telerehabilitation systems that have been implemented in the acute stroke population 27 and BC patients. 5 If we focus on quality of life, our results are consistent with a meta-analysis that promoted exercise programs in BCS 28 and the maintenance of the effects after a 6-month period. 29 In the latter case, the ES associated with overall quality of life change score during the 6 month-follow up was compared with 0.62 which has been reported in our study and adds value to our results. Features such as tailored interventions 30 and audiovisual components, which are known 16

17 Page 17 of 39 to be essential to achieving both health-related behavioral changes 31 and cognitive improvements, 32 played important roles in the effects observed in the telerehabilitation group. The interventions delivered by Internet are a useful tool for motivating patients to make behavioral changes. 33 Our results related to pain and muscle strength are supported by prior studies. On the one hand, Tatham et al. 34 found that different face-to-face interventions were effective at reducing shoulder pain after intervention and follow-up in BC patients. Our pain-related results were similar to those reported by Tatham et al. 34 using a non-face-to-face intervention but targeting the same parameters in general terms. On the other hand, our findings that are related to static and dynamic muscle strength variables are in agreement with the literature describing traditional interventions in cancer survivors, with regard to both intervention effects 35 and also maintenance effects. 36 In this context, a tailored intervention that improves the strength level, continuous monitoring of each participant and previous experience of the CUIDATE research staff in supervised exercise programs, specifically in exercises for strength in BCS, 37 could have facilitated our findings. Regarding the maintenance effects, Rogers et al. 36 used a 3-month follow-up, so it should be emphasized that our favorable results were obtained with a longer follow-up period. According to the results related to fatigue, our findings are consistent with another telerehabilitation system. 12 However, in that study, the ES was small because only 10 sessions were assigned for physical activity. Regarding the maintenance of the effects, an on-site exercise program in BCS 38 obtained similar results, although their ES was better than ours. This result seems to be 17

18 Page 18 of 39 the result of the characteristics of their BC sample at baseline, which showed a moderate-high level of fatigue. In relation to the analysis of covariates, we found that menopause influenced pain interference. It has been shown that the side effects of hormonal treatment are related to estrogen deprivation. Arthralgia/myalgia syndromes have been reported in more than 40% of BC patients who received any hormonal treatment, being more frequent with aromatase inhibitor. 39 These musculoskeletal side effects affect their daily activities. Further studies should be performed to shed light on how estrogen deprivation could be related to a possible clinical model of pain. All of our findings support that non-face-to-face approaches could be an effective alternative to traditional cancer rehabilitation. These broad-reach modalities may minimize barriers such as distance, time and cost, and thereby increasing accessibility to non-urban cancer survivors, favoring quick feedback and reducing costs. 4,7 Several limitations of our trial should be noted. First, the eligibility criteria as well as the mean age of our sample may limit the generalization of our results. Second, multiple comparisons were made using a relatively small sample. Finally, the program in this study may not be sustainable because of the amount of staff time required. However, there were no technical limitations except that some participants experienced problems connecting to the Internet, which was solved the next day in all cases. In conclusion, our results indicate that the e-cuidate system may improve and maintain quality of life, pain, muscle strength and fatigue in BCS via the implementation of an Internet-based tailored exercise program. The 18

19 Page 19 of 39 improvements in muscle strength led to improvements in functionality related to daily activities, which could also have influenced the prominent effects on quality of life. 19

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26 Page 26 of 39 FIGURE LEGENDS Figure 1. Flow diagram of recruitment and randomization processes. Figure 2. Changes in post-intervention and follow-up on quality of life (EORTC QLQ-BR23). Figure 3. Changes in post-intervention and follow-up on handgrip strength. Figure 4. Changes in post-intervention and follow-up on fatigue. 26

27 Page 27 of 39 Table 1. Sociodemographic and clinical characteristics. Telerehabilitation group (n=40) Control group (n=41) P value Age (years). Mean (SD) 47.4 (9.6) 49.2 (7.9) Marital status. n (%) Single 8 (20) 5 (12.2) Married 26 (65) 30 (73.2) Divorced/widowed 6 (15) 6 (14.6) Time since surgery. n (%) months 29 (72.5) 22 (53.7) >12 months 11 (27.5) 19 (46.3) Educational level. n (%) Basic level 18 (45) 19 (46.3) Medium level 7 (17.5) 15 (36.6) High level 15 (37.5) 7 (17.1) Employment status. n (%) Housewife 15 (37.5) 14 (34.1) Employed 7 (17.5) 7 (17.1) Medical leave 13 (32.5) 12 (29.3) Unemployed (by illness) 5 (12.5) 8 (19.5) Stage BC. n (%) I 14 (35) 14 (34.1) II 18 (45) 24 (58.5) IIIA 8 (20) 3 (7.3) Type of surgery. n (%) Lumpectomy 15 (37.5) 19 (46.3) Quadrantectomy 16 (40) 12 (29.3) Mastectomy 9 (22.5) 10 (24.4) Medical treatment. n (%) Radiotherapy 1 (2.5) 3 (7.3) Chemotherapy 3 (7.5) 1 (2.4) Radiotherapy & chemotherapy 36 (90) 37 (90.2) Menopause. n (%) 0.023* Pre-menopause 7 (17.5) 1 (2.4) Post-menopause 33 (82.5) 40 (97.6) P values of between group differences using t test for independent samples (continuous variables) and X 2 analysis (categorical variables). SD: standard deviation; BC: breast cancer. *P<0.05.

28 Page 28 of 39 Table 2. Within and between group effects for the mean on quality of life (EORTC QLQ-C30) at baseline, 8-week intervention and 6-month follow-up. Outcomes measures Telerehabilitation group n=39 EORTC QLQ-C30 Global health status Baseline ± (52.38 to 66.00) 8-week intervention ± (66.77 to 80.23) 6-month follow-up ± (66.40 to 79.32) Control group n= ± (47.22 to 62.24) ± (43.52 to 57.38) ± (49.97 to 64.44) Between group effects Within group effects Baseline-8 weeks (6.03 to 22.60) ( to 4.22) (8.94 to 28.25)** Baseline-6months (6.56 to 20.79) 2.48 (-4.83 to 9.78) (2.90 to 19.49)* Physical functioning Baseline ± (71.62 to 82.56) 8-week intervention ± (82.76 to 90.91) 6-month follow-up ± ± (67.12 to 79.18) ± (65.75 to 77.31) ± (80.94 to 89.32) (68.03 to 81.15) Within group effects Baseline-8 weeks 9.75 (4.74 to 14.74) (-6.75 to 3.51) (5.54 to 17.19)** Baseline-6 months 8.04 (3.13 to 12.94) 1.44 (-3.60 to 6.48) 6.60 (0.87 to 12.31)* Role functioning Baseline ± (63.60 to 80.84) 8-week intervention ± (74.89 to 89.21) 6-month follow-up ± ± (58.81 to 77.22) ± (47.74 to 68.47) ± (74.08 to 90.02) (60.41 to 77.42) Within group effects Baseline-8 weeks 9.83 (-0.21 to 19.86) ( to 0.39) (8.04 to 31.44)* Baseline-6 months 9.83 (-1.17 to 20.82) 0.90 ( to 12.19) 8.93 (-3.89 to 21.75)

29 Page 29 of 39 Table 2. Within and between group effects for the mean on quality of life (EORTC QLQ-C30) at baseline, 8-week intervention and 6-month follow-up (continued). Emotional functioning Baseline ± (60.92 to 77.97) 8-week intervention ± (71.90 to 87.07) 6-month follow-up ± ± (47.93 to 68.28) ± (47.38 to 68.84) ± (69.77 to 85.36) (47.65 to 69.01) Within group effects Baseline-8 weeks (0.28 to 19.81) 0.00 ( to 10.02) (-1.34 to 21.43) Baseline-6 months 8.12 (0.09 to 16.14) 0.22 (-8.01 to 8.46) 7.90 (-1.46 to 17.25) Cognitive functioning Baseline ± (56.96 to 74.66) 8-week intervention ± (78.51 to 89.86) 6-month follow-up ± ± (54.75 to 73.18) ± (57.98 to 74.45) ± (71.18 to 85.23) (50.65 to 70.97) Within group effects Baseline-8 weeks (9.78 to 26.97) 2.26 (-6.57 to 11.08) (6.10 to 26.14)* Baseline-6 months (2.45 to 22.33) ( to 7.05) (3.96 to 27.14)* Social functioning Baseline ± (58.76 to 76.28) 8-week intervention ± (74.84 to 90.11) 6-month follow-up ± ± (52.37 to 70.15) ± (53.44 to 75.38) ± (77.67 to 91.56) (55.71 to 75.82) Within group effects Baseline-8 weeks (3.65 to 26.26) 3.15 (-8.45 to 14.76) (-1.37 to 24.98) Baseline-6 months (7.06 to 27.13) 4.50 (-5.80 to 14.80) (0.89 to 24.28) Data are shown as mean ± standard deviation (95% confidence interval for the mean) at baseline, 8-week intervention, 6-month follow-up and mean differences (95% confidence interval for the difference) for within and between group effects. EORTC QLQ-C30: European Organization for Research and Treatment of Quality of Life Questionnaire Core 30. The

30 Page 30 of 39 Table 2. Within and between group effects for the mean on quality of life (EORTC QLQ-C30) at baseline, 8-week intervention and 6-month follow-up (continued). pairwise comparisons were obtained with Bonferroni adjustment. Significant between group effect *P<0.05 **P<0.001.

31 Page 31 of 39 Figure 1. Flow diagram of recruitment and randomization processes. 57x81mm (600 x 600 DPI)

32 Page 32 of 39 Figure 1. Flow diagram of recruitment and randomization processes.

33 Page 33 of 39 Figure 2. Changes in post-intervention and follow-up on quality of life (EORTC QLQ-BR23). 28x20mm (600 x 600 DPI)

34 Page 34 of 39 Figure 2. Changes in post-intervention and follow-up on quality of life (EORTC QLQ-BR23). 28x20mm (600 x 600 DPI)

35 Page 35 of 39 Figure 2. Changes in post-intervention and follow-up on quality of life (EORTC QLQ-BR23). 28x20mm (600 x 600 DPI)

36 Page 36 of 39 Figure 2. Changes in post-intervention and follow-up on quality of life (EORTC QLQ-BR23). 28x20mm (600 x 600 DPI)

37 Page 37 of 39 Figure 3. Changes in post-intervention and follow-up on handgrip strength. 28x20mm (600 x 600 DPI)

38 Page 38 of 39 Figure 3. Changes in post-intervention and follow-up on handgrip strength. 28x20mm (600 x 600 DPI)

39 Page 39 of 39 Figure 4. Changes in post-intervention and follow-up on fatigue. 28x20mm (600 x 600 DPI)