Study design and participants
The present study was a parallel, two-arm, single-center, open-labeled RCT conducted at the Breast Disease Diagnosis and Treatment Center, Shaanxi Provincial Tumor Hospital, from July 2017 to June 2019. The trial protocol was reviewed and approved by the Human Research Ethics Committee of Shaanxi Provincial Tumor Hospital (No.2017 − 148). This study was registered in the Chinese Clinical Trial Registry (ChiCTR2100042975).
The target population was female breast cancer patients who received chemotherapy about 10–15 days after a modified radical mastectomy or an extensive radical mastectomy. The chemotherapy regimens included docetaxel, epirubicin, and cyclophosphamide (TEC); dense adriamycin and cyclophosphamide (AC); sequential dense paclitaxel or docetaxel; AC; or docetaxel and cyclophosphamide (TC). The personalized doses of these drugs were calculated based on the patient’s weight and body surface area. All included patients received 6–8 complete treatment cycles, with each cycle consisting of 8 days of treatment followed by 21 days of no treatment.
The patients were recruited in this study by the convenient sampling method if they met the following inclusion criteria: (1) they were willing to join the study voluntarily; (2) aged 18 years or order; (3) they were diagnosed with breast cancer by tumor, lymph node, metastasis (TNM) staging based on the fast pathology slide and paraffin section; (4) they were undergoing chemotherapy after a radical mastectomy. By a detailed interview and assessment, patients with consciousness disorders; mental or neurological disorders; mental, hearing, or cognitive impairments; physical disabilities; or breast cancer with other cancers were excluded. Stage IV breast cancer patients were also excluded as their life expectancy was short. Before enrollment, the patients were given all related information about the study and signed the informed consent forms.
Randomization and blinding
Following baseline assessment, the patients were randomly allocated into the experimental group for music therapy combined with aerobic exercise and control group for routine nursing care. Based on the hospital identification number of each patient, all the patients were randomly allocated to two groups using a randomized code generated by computer software. The randomization was completed by independent research assistant who was not involved in recruitment, intervention, or data collection. The allocation of participants was conducted by using consecutive numbered, sealed, and opaque envelopes. Due to the intervention nature of this study, the patients and care providers were not blinded to the interventions. Besides, the data collectors and the outcome assessors were also not blinded to the intervention.
Intervention procedures
Music therapy combined with aerobic exercise
The intervention group completed music therapy combined with aerobic exercise from the first admission to the hospital for chemotherapy to the sixth admission to the hospital for chemotherapy and received routine nursing care. The researchers regularly visited the patients in the experimental group during the intervention period and supervised them to ensure that they adhered to the music therapy combined with aerobic exercise procedures. In addition, during the intermittent period of chemotherapy treatment, the patients in the intervention group were followed up by telephone and encouraged to stick to the intervention procedures. The detailed regimen of the treatment is described below.
The design of music therapy was based on previous studies, and the establishment of music media library was according to the characteristics of Pentameter Therapy Principle and different tonality [21, 22]. First, the patients gathered in a quiet and comfortable environment to relax their minds and bodies in the patient service center. Then, patients received the music therapy two times a day, 30min each time, continued until the 6th cycle of chemotherapy. They could also choose music according to their preference and wear headphones for the treatment. They could repeatedly listen to the music with the volume at 30–50 dB. The music media library consisted of Chinese classical folk music, world-famous music, a Music Therapy Association-recommended nature music series CD, and relaxing music; a total of 334 instrumental music pieces were included. Because of the interference effect of lyrics, songs and operas were not included. Instead, specific tracks such as “Yao Nationality Dance,” “Two Springs Reflect the Moon,” “Blue Danube River,” “Spring,” “Clouds Chasing the Moon,” and “Destiny Symphony” were included. After establishing the music library, it was copied into MP5 file format for use by the patients in the intervention group. The regimen was carried out twice a day for 30 min each time until the end of the sixth cycle of chemotherapy.
Along with music therapy, aerobic exercise was also implemented for the intervention. The design of aerobic exercise was based on the American College of Sports Medicine roundtable on exercise guidelines for cancer survivors [23] and a previous study [24]. First, the patients performed aerobic exercise for 15–20 min by exercising the upper extremity joints and the whole body, including head rotation, single shoulder exercises, arm exercises, forward bends, hip exercises, jump around a step, and step and swing arms. Then, the whole set of movements was repeated 2–3 times, for an additional 20–25 min. Cool-down activities were performed for another 10 min, including jogging in place, upper limb swing, and relaxation. The practical exercise intensity of the whole exercise session was controlled within the range of the target heart rate of the patients, with the target heart rate = (220 – age – resting heart rate) × (45–60%) + resting heart rate.
The patients were required to participate in group training aerobic exercise every Monday, Wednesday, and Friday afternoon, until the end of the sixth cycle of chemotherapy. Those who could not exercise at the specified time for special reasons participated in weekly supplementary training. In addition, intervention team members visited the patients regularly during the hospital stay, helped the patients adhere to the intervention, and conducted regular telephone follow-ups during the nontreatment interval to encourage the patients to continue the intervention.
Routine nursing care
The control group patients received the same perioperative and chemotherapy routine nursing care. Before chemotherapy, the responsible nurses explained post-radical mastectomy and chemotherapy to the patients. Then, in each chemotherapy cycle, the patient was instructed to perform rehabilitation exercises, including fist-clenching, wrist wrapping, elbow flexion, shoulder, and upper limb joint activities, 3 to 5 times a day for 5 to 10 minutes each time, until the end of the 6th chemotherapy cycle. However, they did not receive the intervention of music therapy combined with aerobic exercise.
Data collection
In this study, the social and demographic data as well as the disease-related conditions of the patients were collected by a general questionnaire. The questionnaire was designed by the Breast Disease Diagnosis and Treatment Center of Shaanxi Province Tumor Hospital and was completed under the guidance of relevant experts.
The sleep quality of the patients was evaluated by the Chinese version of the Pittsburgh Sleep Quality Index (PSQI)[25]. The PSQI was designed by Pittsburgh psychiatrist Buysse organically to evaluate the sleep quality and quantity simultaneously in one month [26]. The PSQI includes 19 self-rated and five peer-rated items, of which the 19th self-rated item and all five peer-rated items were not used for the score. The remaining 18 self-rated items were divided into seven components: subjective sleep quality, fall-asleep time, sleep duration, sleep efficiency, sleep disturbance, use of sleep medication, and daytime function, each of which was scored as 0–3. Based on the sum of the seven components with a global score range of 0–21, a higher global PSQI score indicated a worse sleep quality [26]. Therefore, this study set a global score of > 7 as the boundary value of overall sleep quality problems among participants [25]. Besides, we used a cut-off score of ≥ 2 to represent having sleep problems in each component.
Previous psychometric studies of the Chinses version of the PSQI have confirmed that it is a reliable and valid instrument for assessing subjective sleep quality in different populations, with a Cronbach alpha of 0.71 to 0.84 [25, 27, 28]. Therefore, in the present study, the Chinese version of the PSQI was assessed at four testing times to evaluate the sleep quality of the patients in the two groups: at the end of the 10th day after the radical mastectomy (baseline), after the first cycle of chemotherapy (first test), after the third cycle of chemotherapy (second test), and after the sixth cycle of chemotherapy (third test).
Outcomes
The primary outcome was the change in the global PSQI score from baseline. The secondary outcomes were the changes in each component of the PSQI score (i.e., sleep quality, fall-asleep time, sleep duration, sleep efficiency, sleep disturbance, use of sleep medication, and daytime function) from baseline.
Sample size
Using the G-power software (version 3.1.9.7), the sample size was estimated to be 90 (45 for each group) based on an assuming effect size of 0.6, power of 0.8, and significance level of 0.05. Considering a 20%-25% drop-out rate, we defined the target sample size as 110.
Statistical analysis
A linear mixed model accounting for repeated measurements was used to assess the effect of the intervention of music therapy combined with aerobic exercise on the sleep quality of the patients after controlling for all of the explanatory variables and the interaction between the intervention variable and the time variable.
In this study, the explanatory variables included the following: (i) age (20–39 years old, 40–59 years old, or ≥ 60 years old); (ii) marital status (unmarried, married, divorced, or widowed), (iii) education level (primary school or lower, junior school, high school, or college and above), (iv) household income per month (≤ 2000 RMB, 2000–5000 RMB, or ≥ 5000 RMB), (v) medical insurance (none, rural cooperation medical service, or other insurance), (vi) work status (unemployed, employed, or retired), (vii) clinical TNM stage (I stage, II stage, or III stage), (viii) chemotherapy regimen (AC sequential paclitaxel or docetaxel, TEC, or TC), and (ix) side effects of chemotherapy (mild, moderate, or severe). The intervention variable (intervention group and control group) and time variable (baseline, after the first, after the third, and after the sixth chemotherapy) were involved in this study.
Data were entered into Epidata, version 3.0 (Centers for Disease Control and Prevention, Atlanta, GA, USA), and all statistical analyses were performed using Statistics Analysis System software, version 9.4 (Cary, NC, USA). Categorical variables are expressed as the count and percentage/proportion. Continuous variables are expressed as the mean with standard deviation. The comparison of categorical variables was performed by Pearson’s chi-squared test or Fischer’s exact test. The statistical significance was achieved from statistical tests when P < 0.05.