This is a multi-center, randomized, three-arm, controlled trial. Subjects from 5 clinical research centers in China are to be recruited by the trial. Yueyang Hospital affiliated to Shanghai university of TCM, Shanghai Chest Hospital affiliated to Shanghai Jiao Tong University, Shanghai Pulmonary Hospital affiliated to Shanghai Tong Ji University, Shanghai Cancer Hospital affiliated to Shanghai FuDan University, Huadong hospital affiliated to Shanghai Fudan university. Eligible participants are to be randomized into 3 groups at a ratio of 1:1:1, namely intervention group A (IGA), intervention group B (IGB) and controlled group (CG). Each group received adjuvant platinum-based doublet chemotherapy for 4 cycles. IGA participants receive chemotherapy combined with CHM and LZJ exercise, IGB participants receive chemotherapy combined with CHM and rehabilitation education, and CG participants receive chemotherapy combined with placebo and rehabilitation education. 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 Traditional Chinese Medicine (No.2016-059), will follow the Declaration of Helsinki. The study design is based on SPIRIT 2013 statement. 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 of this study are NSCLC postoperative patients who will complete adjuvant chemotherapy after complete resection with confirmed pathological diagnosis of stage Ib-IIIa; TCM syndromes include Yin deficiency, Qi deficiency, Qi and Yin deficiency. Recruitment is mainly through doctors’ referrals and recruitment posters and brochures.
In accordance with "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), meet the diagnostic criteria of primary bronchial lung cancer, and pathologically or cytologically confirmed of NSCLC patients, which include squamous carcinoma, adenocarcinoma, adenosquamous carcinoma and large cell carcinoma. TNM staging of primary bronchogenic carcinoma: following the 2009 International Anti-Cancer Alliance (UICC) staging system, version 7.
Syndrome differentiation criteria
Syndrome differentiation criteria 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), lung cancer symptoms are stratified into 3 basic TCM syndromes and are judged by 2 senior physician/deputy chief physicians before treatment.
- Qi deficiency syndrome
Major symptoms: cough, lots of sputum, loss of appetite, fatigue and weakness, pale and bulgy tongue. Secondary symptoms: spontaneous perspiration, loose stool, thin superficial as well as smooth pulse.
- Yin deficiency syndrome
Major symptoms: cough, less sputum, dry mouth, red tongue. Secondary symptoms: night sweat, insomnia, low fever, thready pulse as well as rapid pulse.
- Qi and Yin deficiency syndrome
Major symptoms: cough, less sputum, fatigue and weakness, as well as dry mouth without polydipsia. Secondary symptoms: spontaneous perspiration, night sweat, reddish tongue or tongue with teeth imprints, thready and weak pulse.
Patients with at least 2 main symptoms and 1 secondary symptom can be diagnosed.
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; aged between 18 and 74 years; 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 sign informed consent.
Exclusion criteria are as follows: Indefinite pathological diagnosis; expected survival time＜6 months; with heart, liver, kidney and hematopoietic system and other serious diseases; treated with antibiotics or infected one week before the test; Pregnant or child breast feeding women; Mental or cognitive disorders.
Sample size calculation
The primary outcome of the study will be the change of the QoL score assessed by QLQ-C30 scale. According to the results of JRB.10 study, 27% lung cancer patients at stage Ib to IIIa after 3-month adjuvant chemotherapy had lower QoL scores than baseline. Based on the validity assumptions and clinical experience of the past, it is estimated that 15% of patients had no deterioration in QoL combined with comprehensive rehabilitation program compared with treatment without comprehensive rehabilitation program for patients receiving 3-month postoperative adjuvant chemotherapy. Inspection level α= 0.05, 1-β= 0.90, the QoL score after 3 months in the intervention group decreased by 10% while by 27% in the control group compared with the baseline, 98 cases of sample size were obtained in each group and 20% off rate is considered, 354 cases (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.
The stratified and randomized methods are to be employed to randomize the patients enrolled here. Stratified Block randomization is designed and implemented by Shanghai Clinical Research Center, Shanghai, China) via the internet. A block size of 6 and patients are stratified in line with clinic stages and the center.
Researchers will conduct a one-day training course for this trial, covering the study of the protocol, the recording methods for clinical record forms (CRF), basic information about clinical research, researcher responsibility as well as research monitoring. All eligible participants are to be randomly divided into 3 groups at 1:1:1 ratio (IGA, IGB and CG). Each group will be assessed at baseline and before each cycles of chemotherapy. The treatment lasted for 3 months.
Platinum-doublet chemotherapy regimen will be recommended for patients at stage Ib to IIIa in 6 weeks after surgery, and one of the following five regimens is available:
- Cisplatin 75-80mg/m2 day 1 or carboplatin AUC 5 day 1; Vinorelbine 25-30mg/m2 days 1, 8, per 21 days for 4 cycles
- Cisplatin 75-80mg/m2 day 1 or carboplatin AUC 5 day 1; Gemcitabine 1250mg/m2 days 1, 8, per 21 days for 4 cycles
- Cisplatin 75-80mg/m2 day 1 or carboplatin AUC 5 day 1; Docetaxel 75mg/m2 day 1 per 21 days for 4 cycles
- Cisplatin 75-80mg/m2 day 1 or carboplatin AUC 5 day 1; Pemetrexed 500mg/m2 day 1 for non-squamous per 21 days for 4 cycles
- Cisplatin 75-80mg/m2 day 1 or carboplatin AUC 5 day 1; Paclitaxel 135-175mg/m2 day 1 per 21 days for 4 cycles
For patients having received fewer than the intended number of cycles of chemotherapy, the study duration is to be calculated by the basis of the projected interval.
Chinese herbal medicine and placebo
1.Chinese herbal medicine (CHM)
Prescriptions are formulated into granules provided by Professor Ling Xu. Package of granules is to be made into 5 types with functions (e.g. regulating stomach granules, Qi granules, nourishing Yin granules, supplementing Qi and nourishing Yin granules, regulating stomach granules, and detoxifying and resolving masses granules). Each package contained water-soluble herbal granules manufactured at a Good Manufacture Practice (GMP) standard facility (Tian Jiang Ltd, Jiangyin, China). Each package is labeled by a serial number. The prescription form comprised the stock list with both the name and serial number. Participant will take regulating stomach granules in the first week after chemotherapy and started to take TCM syndrome differentiation prescriptions in the second week after chemotherapy (Fig.3).
The TCM syndrome differentiation prescriptions are employed based on the following regimens (Table1):
The raw materials for the placebo including edible pigment and artificial flavors without CHM are compromised. Placebo and therapeutic packages are stored in different cabinets, and only the dispensing technician knew the contents of the packages.
Liuzijue exercise and rehabilitation education
Participant in IGA will learn LZJ exercise 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 receive LZJ exercise 4 times a week at home during adjuvant chemotherapy.
The program of LZJ exercise include: 1) Warm-up: patients perform 5 min joint activities; 2) LZJ exercise: patients exhale through 6 different mouth forms to breathe and pronounce the "XU, HE, HU, SI, CHUI, and XI" exercises in turn with corresponding actions for about 30mins at all; 3) relaxation: patients adjust the breathing and relax the muscles for 5 minutes.
Participant in IGB and CG are to be instructed to do 30 min exercises 4 times a week, which could satisfy their physical strength (e.g. deep breathing training, slow walking and jogging) during the chemotherapy.
Information (e.g. sex, age, pathological type and stage) will be extracted from baseline questionnaires.
Quality of life
Quality of Life Scale: QLQ-LC30 and QLQ-LC13 scales produced by EORTC is used to assess the QoL of patients. The scoring method is used to determine the results based on the score changes. Before and after the intervention, the international quality scoring system is used to calculate the scores of general QoL and various fields. The physical condition of the patient is to be assessed following the ECOG PS standard before and after treatment.
2-year disease-free survival rate
It refers to the percentage of patients without recurrence and metastasis within 2 years after surgery.
Disease-free survival (DFS)
It refers to the interval time either from date of randomization to the date of first documented progression or date of death from any cause, whichever comes first. Response evaluation criteria in solid tumors (RECIST version 1.1) is to be applied for the assessment of tumor response.
TCM symptoms changes
The TCM symptoms scores are to be recorded and calculated based on 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 the State Drug Administration. The changes before and after each treatment are to be applied for the assessment of efficacy.
Tumor markers would be measured before and after treatment which include CEA, CA-125 and CYFRA21-1.
Safety and adverse events
According to Common Terminology Criteria for Adverse Events V4.0 (CTCAE) issued by 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 function, urine and stool routine tests and electrocardiogram 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.
The data will be accessed and saved into the project database of Shanghai Clinical Research Center. SAS software is to be applied for statistical analysis after the access. The methods of statistical analysis are as follows:
A paired t-test is to be performed to compare the average score before and after treatment in each group, and an independent-sample t-test is to be performed to compare the scores between the two groups. According to the homogeneity of variance test, a rank sum test between two groups is performed for those whose P value is not consistent with normal distribution. A chi-square test is used for variable data (baseline, medicine for adjuvant chemotherapy). A rank sum test is performed to analyze Ordered hierarchical data (NCI-CTC graded adverse events). The Kaplan-Meier method is employed to analyze the median survival time of the 2 groups. The Log-Rank is used to test the median survival time. There exists a statistical significance, when P＜0.05 occur with two-sided test.
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 is required to have an "Investigator's Brochure" for easy access. All data quality control should be carried out every three months, and the problems of supervision and inspection should be corrected within 48 hours after the end of quality control.
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.