A Longitudinal Study of a Multicomponent Exercise Intervention with Remote Guidance among Breast Cancer Patients

Purpose: Breast cancer patients in treatment suffer from long-term side effects that seriously influence their physical and mental health. The aim of this study was to examine effectiveness of a 12-week multicomponent exercise (ME) with remote guidance intervention on health-related outcomes after one year among breast cancer patients. Methods: In phases I–III, 60 patients (51.2 ± 7.9 years) with breast cancer (BC) who completed chemotherapy/postoperative radiotherapy within the previous four months to two years were randomly assigned to (1) multicomponent exercise with remote guidance (ME) and (2) usual care (UC). Eligible participants were approached to assess cancer-related quality of life (QOL), muscle strength, cardiorespiratory endurance, and physical activity (PA) barriers after one year. Results: The results demonstrated that, after one year, the ME group reported higher vitality-related QOL (5.776, 95% confidence interval [CI] 0.987, 10.565, effect size [ES] = 0.360), mental health-related QOL (9.938, 95% CI 4.146, 15.729, ES = 0.512), leg strength and endurance (2.880, CI 1.337, 4.423, ES = 0.557), and strength and endurance of upper extremities (2.745, 95% CI 1.076, 4.415, ES = 0.491) and lower physical activity (PA) hindrance (5.120, 95% CI 1.976, 8.264, ES = 0.486) than the UC group. Conclusions: The ME group observed significant differences from the UC group in QOL, muscle strength, cardiopulmonary endurance, and PA participation. These findings suggested that the multicomponent exercise intervention with remote guidance produced long-term health benefits for breast cancer patients.


Introduction
Breast cancer ranks as the fifth leading cause of cancer mortality among women around the world [1,2]. With advances in screening, diagnosis, and treatment of breast cancer, survival rates for breast cancer survivors have improved and the population of survivors has increased dramatically [3].
Committee of the Second Hospital of Shandong University (registration numbers: KYLL-2017(KJ) P-0003). The trial was registered with Chinese Clinical Trial Registry (ChiCTR-IPR-17012368). All individual participants signed an informed consent form in the study. After a 12-week intervention, eligible participants were recalled for evaluation to complete an in-clinic physical fitness test and an online self-reported questionnaire.

Designed Intervention Program
The randomized controlled trial (RCT) protocol [19] and health outcomes of the 12-week exercise intervention [16] have been published elsewhere. Further, the 12-week internet-based multicomponent exercise intervention has been reported previously [18]. Remote exercise rehabilitation guidance included resistance training, cardiorespiratory endurance training, and rehabilitation knowledge. The intervention program in the ME group consisted of the following: (1) resistance training, including muscle strength, endurance, and function training: each session was 30 min, three times per week, including a five-min warm up, 20 min of training, and five-minutes of relaxation. Participants were asked to do 8-12 repetitions at an intensity of 70-80% of their estimated one repetition maximum (1-RM); (2) cardiorespiratory endurance training, including remote aerobic exercise, performed four times per week and measured by rate of perceived exertion (RPE [13][14][15][16]; and (3) rehabilitation knowledge, special exercise, and health knowledge for BC rehabilitation transmitted by social media apps each day in order to encourage consistency of exercise. Patients were not allowed to participate in any other type of exercises or sports physical activity training program except for the intervention program. The intervention rehabilitation program was directed by professional physiotherapists within the hospital. Various symptoms and performance of patients were recorded and reported to the research coordinator, who determined whether further measures were necessary for patients.
Patients in the UC group were administered general treatment and rehabilitation in terms of treatment requirements. We did not restrict their voluntary movement or general physical activity. The treatment and rehabilitation were directed from the National Institute for Health and Care Excellence Clinical Guidance (NG101) [20].

Follow-Up Period
After completion of the 12-week intervention program, exercise prescriptions consisting of aerobic and resistance exercises were provided to participants in the ME group and simple PA equipment (e.g., elastic bands and dumbbells) was also provided, free of charge. The exercise and health knowledge of BC rehabilitation were delivered by social media apps during the 1-year follow-up period (2018 to 2019).

Outcome Measures
Patient characteristics were reported at baseline, including clinical records and demographic characteristics: age, hemodynamics, blood pressure (blood pressure systolic [BPS] and blood pressure diastolic [BPD]), stage of illness, phase of treatment (observation, chemotherapy, radiation therapy, and radio-chemotherapy). Outcomes were measured at baseline (0 week), postintervention (12 weeks postbaseline), and one-year follow-up. Cancer-related QOL was assessed using the Short Form Health Survey (SF-36) [21,22]. Upper and lower body strength were evaluated by the curl-up test or arm-lifting test (30 s dumbbell of 5 pounds or 2.3 kg lifting test) and the chair stand test, respectively [19]. Cardiorespiratory endurance was measured by maximal oxygen uptake, which was evaluated by the modified Bruce treadmill protocol [23]. The participants' PA estimates were assessed by a standard self-report questionnaire [24].

Statistical Analysis
The original power calculation was based on our preliminary trial. The vitality score was the primary outcome measure in the 12-week intervention. According to the previous study, we calculated that thirty participants were enrolled in each group for an 80% power to detect a difference in vitality of 8 between the groups with standard deviation (SD) of 10, α level of 0.05, and allowing for a 25% loss to follow-up. Quality of life, PA estimates, muscle strength and cardiopulmonary endurance at 12 weeks of data are available at: www.mdpi.com/xxx/s1 (see Supplementary Materials).
Baseline characteristics were analyzed with analysis of variance (for continuous measures) and the chi-square test (for nominal data) to assess for differences among the two groups. Analysis of linear mixed models was performed for the comparison of health outcomes between groups. Mean differences and 95% confidence intervals (CIs) were accompanied by standardized effect size (ES) (p < 0.05 represents significant difference). Effect sizes (Cohen's d) were categorized as small if d > 0.2, as medium if d > 0.5, and as large if d > 0.8 [25]. Data analysis was performed using SPSS software version 25.0 (IBM Corp., Armonk, NY, USA). All significances were set at 0.05 in this study.

Participant Characteristics
The flow chart for the intervention process is illustrated ( Figure 1). During the period of the 1-year follow-up, seven participants withdrew from the intervention group and nine participants withdrew from the control group. The total dropout rate was 23% in the intervention group and 30% in the control group. The main reasons for dropouts in the intervention group were quitting exercise (n = 1), health issues (n = 4), or too busy (n = 2), whereas the terminated participants in the control group were too busy (n = 2), health issues (n = 5), or uninterested in continuing (n = 2) (i.e., no specific reason given). Table 1 shows the characteristics of participants. The ranges of the age and BMI of the participants were 44-61 years old and 21-28.5 body mass index (BMI). Participant characteristics reveal no significant differences between the two groups at baseline and between the two groups for those who completed the 1-year follow-up.

Health Outcome
Quality of life (QOL): To examine the differences of QOL between the ME and UC, linear mixed models were performed to verify whether QOL was better in participants with ME. The results showed significant differences between the ME and UC, favoring ME for vitality-related QOL (5.776, 95% CI 0.987−10.565, ES = 0.360) and mental health-related QOL (9.938, CI 4.146, 15.729, ES = 0.512) after the one-year intervention. There were no other significant differences found for both the ME and UC ( Table 2).  Muscle strength: the linear mixed models were performed (Table 3) and observed significant differences between the ME and UC, favoring ME for leg strength and endurance (2.  Cardiorespiratory endurance: Table 3 presents the differences of cardiorespiratory endurance between the ME and UC. However, there were no significant differences between the groups for cardiorespiratory capacity. Physical activity estimates: Table 3 shows the differences of PA estimates between the ME and UC groups. Significant differences were found in both the ME and UC, favoring ME for PA hindrance (5.120, 95% CI 1.976, 8.264, ES = 0.486). Other significant differences were not found between the ME and UC.

Discussion
This study focused on the long-term effects of diversified combination exercises with remote guidance (e.g., resistance training, aerobic exercises, and psychological guidance) on breast-cancer patients' QOL, muscle strength, cardiopulmonary endurance, and participation of PA in China. The results demonstrated that, after one year, the experimental group showed some favorable differences in QOL, muscle strength, cardiopulmonary endurance, and participation of PAs, and especially improvement of physical capability and mental health QOL, significantly raised muscle strength of the upper and lower limbs and reduced obstruction in PAs, but no significant difference between groups in cardiopulmonary endurance was observed.
According to the analysis of QOL, some indices between groups were of no statistical significance, but the experimental group had a more significant improvement in quality of life than the control group. It is worth noting that quality of life for the experimental group was markedly enhanced based on energy and mental health statistics compared with the UC group. Previous studies have indicated that the main cause of fatigue in breast cancer patients is due to surgery and chemotherapy during treatment [26]. Fatigue is almost universal among the breast cancer patients [27,28], which continues long after treatment, even after 10 years of treatment [29][30][31]. The persistent fatigue not only severely interferes with patients' normal physical function [32] but also has a significant correlation with the occurrence of depression and anxiety in later stages [33], which greatly affects the QOL of breast cancer patients [34]. Therefore, the improvement of physical energy and endurance are critical for breast cancer patients because undergoing surgery or chemotherapy during treatment may cause many mental health problems which heavily influence daily life [35,36]. The results of the study illustrated that combination exercises with remote guidance for breast cancer patients yields a certain improvement in the QOL after one year. In addition, the functional limitations caused by physiological problems were also reduced in the experimental group.
Regarding strength, the significant differences in strength of the upper and lower limbs between the experimental and the control groups remained and the participants in the experimental group improved greatly. As far as we know, there have been fewer studies exploring the longitudinal effects of exercise interventions on strength for breast cancer patients. This study investigated the longitudinal effect of internet-based combination exercise programs on muscle strength among breast cancer patients after one year. The results showed that combination exercises with remote guidance have long-term and significant effects on fatigue and strength of the upper and lower limbs of breast cancer patients after surgery. Findings of this study are consistent with previous studies in that general fatigue is associated with muscle strength in breast cancer patients [37] and that muscle strength is a predictor of death for older adults [38]. In addition, some studies have found that muscle atrophy can cause physical impairment [39,40], disability [41,42], fall risk [43], loss of independence [44], and decreased QOL [45] among older people and is a major determinant of muscle atrophy. During the one-year follow-up, lymphedema was not reported among participants in the experimental group, which is consistent with previous studies showing that resistance training does not result in lymphedema-a condition common in breast cancer patients [46][47][48]. We speculate that the difference may be due to the improvement of muscle strength and QOL in the experimental group so that they can gradually take care of themselves and even return to work normally. Then, they may become conscious of the benefits of exercise and may therefore adhere to exercise actively for a long time such that physical capability may be rehabilitated significantly after one year.
Cardiopulmonary function is an important predictor of cardiovascular events and mortality [49,50]. The treatment of breast cancer leads to decreases in cardiopulmonary function [51], but regular PA can offset such a decrease and even improve cardiopulmonary functions [52][53][54]. However, after the one year of follow-up, improvement of patients in the experimental group was higher than in the control group, but statistical analysis demonstrated that there was no significant difference between two groups and that the effect size was small. We speculate that, during the follow-up, the experimental group may have engaged in more PA than the control group, but there may have been nuances of exercise regularity and intensity between groups, which warrants further study in the future.
Physical inactivity is a predictor of death both for breast cancer patients and healthy women [49,50]. Some studies have demonstrated that PA can improve physical fitness and QOL in women [55][56][57][58][59], with clinical significance for breast cancer patients [60]. In the present study, the experimental group participating in PA had a certain improvement over the control group with obstruction factors of PA observing a significant difference between groups. The experimental group showed that PA barriers were reduced greatly and that the level of PA increased appropriately. Previous studies have indicated that PA can improve health, symptoms control, QOL, and complications after treatment among breast cancer patients [55,56].
Our findings suggest that taking part in planned remote exercise guidance intervention after breast cancer surgery may provide long-term benefits for some physical and psychological conditions. Both rehabilitation professionals and breast cancer patients should be acutely aware of the benefits of combined exercises [61]. Considering the lack of physical activity in breast cancer patients, it is necessary to formulate corresponding exercise prescriptions and behavioral intervention strategies [62,63] during the whole recovery process to guarantee or improve the level of physical activity.

Strengths and Limitation
First, it is one of the only longitudinal studies to date that has evaluated the long-term beneficial effects of remotely guided combination exercises (including anti-resistance training, aerobic exercises, and psychological guidance) on postsurgical breast cancer patients. From this perspective, the study is significant because it provides a reference for the implementation of postoperative rehabilitation programs for breast cancer patients in the future. Second, at the one-year follow-up, although about one-fifth of the participants dropped out, the dropout rate was lower than the maximum rate recommended by long-term follow-up studies (30%) [64]. The limitation is that the follow-up time of this study was only one year and thus observation time needs to be extended for further verification.

Conclusions
After one year, the experimental group improved significantly in energy, mental health, PA, and muscle strength of the upper and lower limbs, but cardiopulmonary endurance was not significantly different between the two groups. The present study suggests that combination exercises with remote guidance leads to long-term enhancement of the QOL and muscle strength among breast cancer patients. A longitudinal study is needed to further explore the long-term impact of remotely guided multicomponent exercise intervention on breast cancer patients after surgery.