All Methods of this study were performed in accordance with the relevant guidelines and regulations.
Study design and participants
This study utilized clinical trial with two arms, no blind, which was conducted at Breast Disease Diagnosis and Treatment Center, Shaanxi Provincial Tumor Hospital from July 2017 to June 2019.
The target population was female breast cancer patients who received chemotherapy about 10-15 days after modified radical mastectomy (MRM) or extensive radical mastectomy (ERM). Chemotherapy options include TEC, dense AC sequential dense Paclitaxel or Docetaxel, AC, TC, etc., that is, Paclitaxel or Docetaxel, Epirubicin or Adriamycin and Cyclophosphamide.
Personal controlled dose of these drugs were calculated based on patients’ weight and body surface area (BSA). The subjects received a total of 6-8 complete courses of treatments, which took 8 days with 21 days intervals in every complete course.
The sample size was determined by the levels of questionnaire dimensions. The calculation equation of sample size was presented on follows: Sample size=[Max(dimensions)×(10-20)]×(1+15％)
With Pittsburgh Sleep Quality Index table contains 7 dimensions, the minimum number of sample size of our study was approximately 80. Considering the situation of nonresponse, however, we expanded the sample size by 30% to 40%. The patients were recruited in this study by the convenient sampling method if they meet the following inclusion criteria: (1) they were willing to join the study voluntarily; (2) they must have normal cognitive state and ability to express clearly; (3) no physical disability; (4) they were clearly diagnosed with breast cancer of TNM staging based on fast pathology slide and paraffin section. Patients with consciousness disorders, mental or neurological disorders, mental, hearing or cognitive impairments, physical disabilities, and breast cancer with other cancers will be excluded. Stage IV breast cancer patients were also excluded. By the end, we expected to recruit 110 subjects. The patients were randomly allocated to two groups using a randomized code generally by computer software with 55 in each group.
The protocol was reviewed and approved by the Human Research Ethics Committee of Shaanxi Provincial Tumor Hospital. This study was registered in the Chinese Clinical Trial Registry (ChiCTR2100042975, 03/02/2021). Questionnaire survey method is adopted. The questionnaire is interpreted with unified guidance language, distributed and recovered on site. Based on identification numbers in hospital, all the patients are randomly allocated into the experimental and control group by random number table method. Before the study, all patients were given all related information about the study and signed "informed consent form". All patients were numbered according to the case number, Patients in the control group were cared with routine perioperative nursing and chemotherapy nursing. The intervention group accepted music therapy combined with aerobic exercise from the first admission to hospital for chemotherapy to the sixth admission to hospital for chemotherapy in addition to the routine nursing care, and implemented 30 min every time and 2 times every day. Patients were visited regularly during intervention by researchers, and supervised to adhere to music therapy combined with aerobic exercise procedures. During the intermittent period of chemotherapy treatment, moreover, patients in the intervention group were followed-up by telephone and encouraged to stick to intervention procedures. Control group patients received the same perioperative nursing care and chemotherapy, except for music therapy combined with aerobic exercise intervention.
Music therapy combined with aerobic exercise
First of all, patients gathered at the patient service center in a quiet and comfortable environment to relax their mind and body. They can also choose music according to their own preference and wear headphones after treatment. They can listen repeatedly with the volume of 30dB ~ 50dB.Music media library includes Chinese classical folk music, world famous music, music therapy association (AAMT) recommended nature music series CD and relaxing music, a total of 334 pieces of music, all instrumental music. Because of the interference effect of the lyrics, songs and operas are not included. Specific tracks such as 《Yao nationality dance》,《 Two springs reflect the moon》, 《Blue Danube river》, 《Spring》, 《Clouds chasing the moon》,《Destiny symphony》, etc. After the establishment of music library, it was copied into MP5 for use by patients in the intervention group twice a day for 30min each time until the end of the 6th cycle of chemotherapy .
Along with music therapy, in the meanwhile, aerobic exercise was also carried out in the intervention. Aerobic exercise for 15 ~ 20 min before the upper extremity joints and the whole body of each joint exercises, on the basis of aerobic exercise, including head, head rotation, single shoulders, shoulders, arm forward, lift on lateral flexion, left and right sides of, lift on forward bends, pendulum is before and after hip, hip, or jump around step, step swing arm, a total of 12 knots. Repeat the whole set of movements for 2-3 times, and the effective exercise time is 20 ~ 25 minutes. Finishing activities were performed for another 10 minutes, including treading in place, upper limb swing and relaxation, etc . The effective exercise intensity of the whole scheme was controlled within the range of the target rate of the patients, with target heart rate = (220-age-quiet heart rate) × (45% ~ 60%) + quiet heart rate.
Aerobic exercise requires the patients to have group training every Monday, Wednesday and Friday afternoon, lasting until the end of the 6th cycle of chemotherapy. Those who cannot exercise at the specified time due to special reasons should participate in weekly supplementary training. Intervention team members visited patients regularly during the hospital stay, helped patients adhere to the intervention, and conducted regular telephone follow-up during the treatment interval to encourage patients to continue the intervention.
Measurement of sleep quality
In this study, the social and demographic data and disease-related conditions of the patients were collected by general questionnaire, and the Sleep Quality of the patients was evaluated by Pittsburgh Sleep Quality Index (PSQI). The questionnaire of general situation was designed by the Breast Disease Diagnosis and Treatment Center of Shaanxi Province Tumor Hospital and completed under the guidance of relevant experts. It included demographic data and disease related conditions. PSQI was designed by Pittsburgh psychiatrist Buysse organically, which could evaluate sleep quality and sleep quantity simultaneously within one month.
19 self-rated and five peer-rated items are included in the PSQI, of which the 19th self-rated item and all five peer-rated items are not used for score. The rest of the 18 self-rated items are divided into seven dimensions, including subjective sleep quality, fall-asleep time, sleep duration, sleep efficiency, sleep disturbance, use of sleep medication, daytime function, each of which are weighted 0-3 scores. Based on the sum of the seven components with a range of 0-21, when the total score of PSQI is much higher, sleep quality is much worse. The PSQI should be completed in 5-10 minutes . In 1996, Liu Xianchen et al had translated the scale into Chinese, and also evaluated the reliability and validity. It was found a good internal consistency and reliability using the scale, which is suitable for Chinese patients. In the study, Pittsburgh sleep quality index greater than 7 was used as boundary value of sleep quality problem among adults in China . Pittsburgh sleep quality index (PSQI) was used to evaluate the sleep quality of patients in the two groups at the end of 10 days, the first cycle of chemotherapy, the third cycle of chemotherapy and the sixth cycle of chemotherapy, respectively.
In the study, random controlled trial study was applied. Before the study, a group was established to implements music therapy combined with aerobic exercise intervention, and all research staff was trained uniformly according to the detailed standard guidelines and training protocols developed in the pilot study. After the train, only the eligible research staff who passed the theory and practice examination, would be required to conduct this research. During the research, Subjects were also re-interviewed when errors and/or missing values were detected. For those absent patients within the prescribed time due to special reasons, they had to take part in additional training every week.
In the follow-up treatment, 4 patients in the intervention group were lost to follow-up, and 6 patients in the control group. Finally, 51 patients in the intervention group and 49 patients in the control group completed the study (Fig.1).
In this study, explanatory variables included: (i) age which was divided into 20-39, 40-59 and 60- group, (ii) marriage (unmarried, married, divorced, widowhood), (iii) education level (primary school or lower, junior school, high school and college and above), (iv) household income per month (≤2000, 2000-5000and ≥5000), (v) medical insurance (no, rural cooperation medical service, and other insurance), (vi) profession (unemployed, working at the job, retirement), (vii) clinical TNM stages (Ⅰ stage, Ⅱ stage, Ⅲ stage), (viii) Chemotherapy regimens (AC sequential Paclitaxel or Docetaxel, TEC or TC, Other) and (ix) side effects of chemotherapy (mild, moderate, severe). In the study, intervention variable (intervention group and control group) and time variable (baseline, the first, the third and the sixth chemotherapy) were involved.
The primary endpoint was the change in the score of PSQI-total from baseline with the secondary endpoints being the changes in the components of PSQI-total (sleep quality, fall-asleep time, sleep duration, sleep efficiency, sleep disturbance, use of sleep medication, daytime function) from baseline. A linear mixed model taking account of repeated measurements was used to assess the effect of music therapy combined with aerobic exercise intervention on the sleep quality after controlling for all the explanatory variables and the interaction of intervention variable and time variable.
Data was entered twice into Epidata Version 3.0 software (CDC, Atlanta, GA, USA) and all statistical analysis was performed using SAS 9.4 ((Statistics Analysis System, Inc. Cary, North Carolina, USA). The significance was achieved from statistical tests when P < 0.05.