Study design
This is a multi-center, randomized, controlled trial. Subjects from 5 clinical research centers in China will be recruited for the trial: Yueyang Hospital affiliated with Shanghai University of TCM, Shanghai Chest Hospital affiliated with Shanghai Jiao Tong University, Shanghai Pulmonary Hospital affiliated with Shanghai Tong Ji University, Shanghai Cancer Hospital affiliated with Shanghai FuDan University, and Huadong hospital affiliated with Shanghai Fudan University. This study protocol has been approved by the Regional Ethics Review Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine affiliated with Shanghai University of TCM (No. 2016-059) and follows the Declaration of Helsinki. The study design is based on SPIRIT 2013 statement[29]. Eligible participants will be randomized into 3 groups at a ratio of 1:1:1: intervention group A (IGA), intervention group B (IGB) and control group (CG). A flow diagram of the study is given in Fig. 1, and the schedule of enrolment, intervention, and assessments is presented in Fig. 2.
Study participants and recruitment
Participants in this study are NSCLC postoperative patients who will complete adjuvant chemotherapy after complete resection with a confirmed pathological diagnosis of stage Ib-IIIa; TCM syndromes include Yin deficiency, Qi deficiency, Qi and Yin deficiency. Patients will obtain information about the study from their surgeons or recruitment brochures. The investigator will make an appointment for the clinic to assess whether the subject meets the inclusion exclusion criteria. Eligible patients will be required to sign a written informed consent form before starting the intervention.
Diagnostic criteria
Histologically or cytologically confirmed NSCLC, including squamous carcinoma, adenocarcinoma, adenosquamous carcinoma and large cell carcinoma, according to "Standards for the diagnosis and treatment of primary lung cancer (2015 version) in China" (National Health and Family Planning Commission of the People’s Republic of China, 2015). TNM staging of primary bronchogenic carcinoma will follow the 2009 International Anti-Cancer Alliance (UICC) staging system, version 7.
Syndrome differentiation criteria
The syndrome differentiation criteria will follow "Clinical Practice Guidelines of Chinese Medicine in Oncology" (published by People's Medical Publishing House, National Health and Family Planning Commission of the People’s Republic of China, 2014). Symptoms will be stratified into 3 basic TCM syndromes and judged by 2 senior deputy chief physicians before treatment.
- Qi deficiency syndrome
Major symptoms: cough, a large amount of sputum, loss of appetite, fatigue and weakness, and a pale and bulgy tongue. Secondary symptoms: spontaneous perspiration, loose stool, and a thin superficial and smooth pulse.
- Yin deficiency syndrome
Major symptoms: cough, a small amount of sputum, dry mouth, and red tongue. Secondary symptoms: night sweats, insomnia, low heat, and a thready and rapid pulse.
- Qi and Yin deficiency syndrome
Major symptoms: cough, a small amount of sputum, fatigue and weakness, and dry mouth without polydipsia. Secondary symptoms: spontaneous perspiration, night sweats, a reddish tongue or tongue with teeth imprints, and a thready and weak pulse.
Patients with at least 2 main symptoms and 1 secondary symptom can be diagnosed.
Inclusion criteria
The inclusion criteria are as follows: patients with completely resected stage Ib-IIIa NSCLC who will receive adjuvant chemotherapy for the first time in 6 weeks after surgery; patients aged between 18 and 74 years; patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) scale of 0-2; without major organ dysfunction: hemoglobin ≥10 g/dL, absolute neutrophil count (ANC) ≥1.5*10^9/L, platelets ≥100 *10^9/L; with normal hepatic and renal functions; voluntary participation in clinical study; and signed informed consent.
Exclusion criteria
The exclusion criteria are as follows: indefinite pathological diagnosis; expected survival time<6 months; heart, liver, kidney and hematopoietic system and other serious diseases; treated with antibiotics or infected one week before the test; pregnant or breastfeeding women; and mental or cognitive disorders.
Sample size calculation
The primary outcome of the study will be the change in the QoL score assessed by the QLQ-C30 scale. According to the results of the JRB.10 study, 27% of lung cancer patients at stage Ib to IIIa after 3 months of adjuvant chemotherapy had lower QoL scores than at baseline[9]. Based on the validity assumptions and clinical experience of the past, it is estimated that 15% of patients had no deterioration in the QoL combined with a comprehensive rehabilitation program compared with treatment without a comprehensive rehabilitation program for patients receiving 3-month postoperative adjuvant chemotherapy. At the inspection level α= 0.05 and 1-β= 0.90, the QoL score after 3 months in the intervention group decreased by 10% and by 27% in the control group compared with the baseline. A sample size of 98 patients was obtained for each group, and a 20% cut off rate was considered; therefore, 354 patients (n=118) will be observed in 3 years. It is suggested that comprehensive rehabilitation combined with chemotherapy can improve the QoL of NSCLC postoperative patients compared with chemotherapy alone.
Randomization
Stratified blocked randomization will be designed and performed by Subject Randomization and Drug Blindness/Distribution Management System (RBS) V1.0 of Shanghai Clinical Research Center (SCRC). There will be a block size of 6, and patients will be stratified in line with the clinical stages and the center. The researcher will be able to obtain random numbers and group allocation immediately in the form of a short message service. Patients will be randomly divided into three groups at a ratio of 1:1:1.
Blinding
This is a partially patient-blind trial. It is unavoidable that patients will know whether they are undergoing LZJ exercises or rehabilitation education. The placebo granules are indistinguishable from the CHM granules in terms of smell, color, taste and packaging. Thus, all participants will be blinded for the medication section. A third-party independent evaluation method will be used to evaluate the outcomes. All the outcome analyzers will be blinded to the allocation.
Intervention
All participants will be permitted to continue their regular medications except for Chinese patent drugs. Each group will receive adjuvant platinum-based doublet chemotherapy for 4 cycles. IGA participants will receive chemotherapy combined with CHM and LZJ exercises, IGB participants will receive chemotherapy combined with CHM and rehabilitation education, and CG participants will receive chemotherapy combined with placebo and rehabilitation education.
Herbal treatment, CHM or placebo, will be given as granules daily for 12 weeks until the end of chemotherapy. IGA participants will perform LZJ exercises 4 times a week for 12 weeks. IGB and CG participants will be instructed to perform 30 min exercises 4 times a week for 12 weeks. The groups are as follows:
- IGA: Chemotherapy + CHM + LZJ exercises
- IGB: Chemotherapy + CHM + rehabilitation education
- CG: Chemotherapy + placebo + rehabilitation education
Chemotherapy
A platinum-doublet chemotherapy regimen will be recommended for patients at stage Ib to IIIa 6 weeks after surgery. The chemotherapy will be given as four cycles in total, with every 21 days making up one cycle. One of the following five regimens will be available:
- Cisplatin 75-80mg/m2 on day 1 or carboplatin AUC 5 on day 1; Vinorelbine 25-30mg/m2 on days 1 and 8
- Cisplatin 75-80mg/m2 on day 1 or carboplatin AUC 5 on day 1; Gemcitabine 1250mg/m2 on days 1 and 8
- Cisplatin 75-80mg/m2 on day 1 or carboplatin AUC 5 on day 1; Docetaxel 75mg/m2 on day 1
- Cisplatin 75-80mg/m2 on day 1 or carboplatin AUC 5 on day 1; Pemetrexed 500mg/m2 on day 1 for non-squamous
- Cisplatin 75-80mg/m2 on day 1 or carboplatin AUC 5 on day 1; Paclitaxel 135-175mg/m2 on day 1
For patients who received fewer than the intended number of cycles of chemotherapy, the study duration will be calculated on the basis of the projected interval.
Chinese herbal medicine and placebo
1.Chinese herbal medicine (CHM)
Prescriptions will be formulated into granules provided by Professor Ling Xu. Packages of granules will be made into 5 types of functions (e.g., stomach-regulating granules, supplementing Qi granules, nourishing Yin granules, supplementing Qi and nourishing Yin granules, and detoxifying and resolving mass granules). Each package will contain water-soluble herbal granules manufactured at a Good Manufacture Practice (GMP) standard facility (Tian Jiang Ltd, Jiangyin, China). The prescription form will comprise the stock list with both the name and serial number. Participants will take stomach-regulating granules in the first week after chemotherapy and will start to take TCM syndrome differentiation medications in the second week after chemotherapy (Fig.3).
The TCM syndrome differentiation medications will be employed based on the following regimens (Table 1):
2.Placebo
The placebo granules will be composed of edible pigment and artificial flavors without CHM, to look and taste similar to therapeutic granules.. Placebo and therapeutic packages will be stored in different cabinets, and only the dispensing technician will know the contents of the packages.
Liu Zi Jue exercises and rehabilitation education
1.Liu Zi Jue (LZJ)exercises
IGA Participants will learn LZJ exercises within 1 month after surgery under the leadership of a specialist at the Yue-Yang Integrative Medicine Hospital of the Shanghai University of Traditional Chinese Medicine and will perform LZJ exercises 4 times a week at home during adjuvant chemotherapy.
The program of LZJ exercises includes the following: 1) warm-up: patients will perform 5 min of joint activities; 2) LZJ exercises: patients will exhale through 6 different mouth forms to breathe and pronounce the sounds “XU”, “HE”, “HU”, “SI”, “CHUI”, and “XI” in turn with corresponding actions for approximately 30 mins in total; and 3) relaxation: patients will adjust their breathing and relax their muscles for 5 mins.
2.Rehabilitation education
IGB and CG participants will be instructed to perform 30 min of exercises 4 times a week that could maintain their physical strength (e.g., deep breathing training, slow walking and jogging) during chemotherapy.
Outcome measurement
Primary outcome
- Quality of life: assessed with EORTC QOL- LC43. The scoring method will be used to determine the results based on the score changes. Before and after the intervention, the international quality scoring system will be used to calculate the scores of general QoL and various fields.
Secondary outcome
- 2-year disease-free survival rate: this rate refers to the percentage of patients without recurrence and metastasis within 2 years after surgery.
- Disease-free survival (DFS): DFS refers to the interval time either from the date of randomization to the date of the first documented progression or the date of death from any cause, whichever comes first.
- TCM symptom changes: TCM symptom scores will be recorded and calculated based on the grading scale of lung cancer symptoms required in "The Guiding Principles of Clinical Research of New Chinese Medicine treating Primary Bronchial Lung Cancer" (2002) issued by National Medical Products Administration. The changes before and after each treatment will be applied for the assessment of efficacy.
- Physical condition: The physical condition of the patient will be assessed following the ECOG PS standard before and after treatment.
- Tumor markers: Tumor markers, which include CEA, CA-125 and CYFRA21-1, will be measured before and after treatment.
- Safety and adverse events: According to the Common Terminology Criteria for Adverse Events (CTCAE) V4.0 issued by the National Cancer Institute (NCI)(https://ctep.cancer.gov), all the patients will be assessed before and after treatment. The evaluation includes hematological and non-hematological adverse events. Complete blood count, hepatic and renal functions, urine and stool routine tests and electrocardiograms will be measured to assess hematological toxicity. Other adverse events, including toxicity and side effects, of each group will also be recorded and reported during treatment. If there is a serious adverse event (SAE), the treatment will be stopped immediately, and appropriate treatment will be provided. The types and frequencies of adverse events in each group will be reported.
Data collection and monitoring
The researchers from each center will collect their data with the use of a Case Report Form (CRF). The SCRC will be responsible for establishing a special database for data entry and management. Two data managers will independently input and proofread the data. Specialists will check the data of each center every month. Relevant researchers will need to verify and correct the problems found within one week.
Statistical analysis
The data will be accessed and saved into the project database of Shanghai Clinical Research Center. SAS software will be applied for statistical analysis after access. The methods of statistical analysis are as follows:
A paired t-test will be performed to compare the average score before and after treatment in each group, and an independent-sample t-test will be performed to compare the scores between the two groups. According to the homogeneity of variance test, a rank sum test between two groups will be performed for those whose P value is not consistent with a normal distribution. A chi-squared test will be used for variable data (baseline, medicine for adjuvant chemotherapy). A rank sum test will be performed to analyze ordered hierarchical data (NCI-CTC graded adverse events). The Kaplan-Meier method will be employed to analyze the median survival time of the 2 groups. The Log-Rank will be used to test the median survival time. Statistical significance will be defined as when P<0.05 occurs with a two-sided test.
Quality control
Researchers must be trained in Good Clinical Practice for those who have the expertise, qualifications and competence to participate in clinical trials. All medical staff will be uniformly trained before the start of the project so that they have a full understanding of the clinical trial. Each researcher will be required to have an "Investigator's Brochure" for easy access. All data quality control will be carried out every three months, and the problems of supervision and inspection will be corrected within 48 hours after the end of the quality control.
Confidentiality
Only researchers involved in clinical trials may be exposed to and confidential to the subject's personal medical records. The personal information of the identifiable subject will be omitted anonymously during data processing.