key: cord-0020134-xr2y5p05 authors: Zhang, Tong; Fei, Yu-tong; Xu, Yun; Sun, Ling-yun; He, Bin; Yan, Shao-hua; Tang, Mo; Yan, Yun-zi; Mao, Jun; Yang, Yu-fei title: Effect of Jianpi Bushen Sequential Formula on Adjuvant Chemotherapy of Colon Cancer: Study Protocol for a Randomized Controlled Trial date: 2021-08-25 journal: Chin J Integr Med DOI: 10.1007/s11655-021-3448-9 sha: 1be6ab73bfa77e9a97484e5d7e48758d06333263 doc_id: 20134 cord_uid: xr2y5p05 BACKGROUND: The side effects of chemotherapy-induced nausea and vomiting (CINV) and myelosuppression reduce the cancer patients’ adherence to chemotherapy. Many Chinese patients choose Chinese medicine (CM) during chemotherapy to reduce side effects; however, the evidence is lacking. The efficacy of a CM herbal treatment protocol, Jianpi Bushen Sequential Formula (健脾补肾续贯方, JBSF) will be evaluated on chemotherapy completion rate among patients with colon cancer. METHODS: A multi-center double-blind randomized controlled trial (RCT) will be conducted on 400 patients with colon cancer who will receive 8 cycles of adjuvant chemotherapy with oxaliplatin and capecitabine (CAPEOX). Patients will be randomized 1:1 to receive the JBSF or placebo formula. The primary outcome is the overall chemotherapy completion rate. The secondary outcomes include individual chemotherapy completion rate, 4-cycle completion rate of chemotherapy, time to treatment failure, relative dose intensity and treatment toxicity. Follow-up visits will be scheduled before every and after last chemotherapy. DISCUSSION: This study will provide evidence on whether JBSF can improve the chemotherapy completion rate and reduce side effects among patients with colon cancer. (Trial registration: ClinicalTrials.gov, No. NCT03716518) Colorectal cancer is one of the most common malignant tumors of the human digestive system, (1) with the third incidence rate and second mortality rate in China. (2) After radical resection of colonic cancer, patients of stage Ⅲ and high-risk stage Ⅱ should receive adjuvant chemotherapy according to the "National Comprehensive Cancer Network (NCCN) clinical practice guidelines in colon cancer (version 2. 2018)" and the "Colon cancer diagnosis and treatment guidelines (2018.v1)" of the Chinese Society of Clinical Oncology (CSCO). Standard adjuvant chemotherapy regimens include CAPEOX and FOLFOX, which are composed of oxaliplatin and 5-fluorouracil, respectively. (3, 4) Of these two regimes, CAPEOX is more favored by patients and clinicians because of its simpler medication and longer hospitalization interval. Chemotherapy-induced nausea and vomiting (CINV) and myelosuppression are common side effects. There is a moderate risk of CINV in regimen including oxaliplatin of 30% to 90%. (5, 6) Even though there are recognized routine preventive measures such as glucocorticoids and 5-hydroxytryptamine inhibitors, some patients refuse chemotherapy due to an intolerance of CINV. Myelosuppression is another common side effect and recovery time of bone marrow determines when the next chemotherapy cycle can be carried. (7) In China, more than 80% of cancer patients used Chinese medicine (CM), which is often used for symptom control. It has been found that CM could control and alleviate CINV and myelosuppression. In previous research based on the theory of CM, side effi cacy of a CM herbal treatment protocol, Jianpi Bushen Sequential Formula (健脾补肾续贯方, JBSF) will be effi cacy of a CM herbal treatment protocol, Jianpi Bushen Sequential Formula (健脾补肾续贯方, JBSF) will be evaluated on chemotherapy completion rate among patients with colon cancer. evaluated on chemotherapy completion rate among patients with colon cancer. Methods Methods: A multi-center double-: A multi-center doubleblind randomized controlled trial (RCT) will be conducted on 400 patients with colon cancer who will receive 8 blind randomized controlled trial (RCT) will be conducted on 400 patients with colon cancer who will receive 8 cycles of adjuvant chemotherapy with oxaliplatin and capecitabine (CAPEOX). Patients will be randomized 1:1 cycles of adjuvant chemotherapy with oxaliplatin and capecitabine (CAPEOX). Patients will be randomized 1:1 to receive the JBSF or placebo formula. The primary outcome is the overall chemotherapy completion rate. The to receive the JBSF or placebo formula. The primary outcome is the overall chemotherapy completion rate. The secondary outcomes include individual chemotherapy completion rate, 4-cycle completion rate of chemotherapy, secondary outcomes include individual chemotherapy completion rate, 4-cycle completion rate of chemotherapy, time to treatment failure, relative dose intensity and treatment toxicity. Follow-up visits will be scheduled before time to treatment failure, relative dose intensity and treatment toxicity. Follow-up visits will be scheduled before every and after last chemotherapy. every and after last chemotherapy. Discussion Discussion: This study will provide evidence on whether JBSF can improve : This study will provide evidence on whether JBSF can improve the chemotherapy completion rate and reduce side effects among patients with colon cancer. (Trial registration: the chemotherapy completion rate and reduce side effects among patients with colon cancer. (Trial registration: effects of chemotherapy were addressed using the 'two steps of CM treatment' and the newly created Jianpi Bushen Sequential Formula (健脾补肾续贯方, JBSF), which achieved good therapeutic effects in controling the effects of CINV and myelosuppression. (8) The first step is to treat Pi (Spleen) and Wei (Stomach), using Liujun Anwei Formula (六君安胃 方, LAF) to alleviate any CINV after chemotherapy by strengthening Pi and Wei. The second step is to treat Pi and Shen (Kidney), using Qitu Erzhi Formula (芪 菟二至方, QEF) to protect the hematopoietic function of bone marrow and reduce the myelosuppression after chemotherapy by warming Pi and Shen. Based on the National Key Research and Development Plan (2017YFC1700604), this study will provide evidence whether JBSF can reduce the side reactions of adjuvant chemotherapy for colonic cancer. The inclusion criteria include the following: (1) patients who have completed radical surgery for colon cancer and will be given adjuvant chemotherapy with CAPEOX; (2) all patients will be over 18 and up to 75 years old; (3) no chemotherapy within 6 weeks after radical operation; (4) Eastern Cooperative Oncology Group Performance Score (ECOG-PS) of 0 to 2; (5) definite pathological diagnosis and negative pathological margin; (6) stage Ⅲ and high risk in stage Ⅱ according to TNM (American Joint Committee on Cancer, 8th edition). According to "NCCN clinical practice guidelines in colon cancer (version 2. 2018)", high risk factors for recurrence include poorly differentiated histology (exclusive of those cancers that are MSI-H), lymphatic or vascular invasion, bowel obstruction, less than 12 lymph nodes examined, perineural invasion, localized perforation and close, indeterminate, or positive margins. Exclusion criteria include the following: (1) patients judged by the physician not to need CAPEOX chemotherapy; (2) with severe cardiovascular system complications, cerebrovascular system complications, active hepatitis, or severe liver or kidney dysfunctions; (3) patients who are known or suspected to be allergic to the known ingredients in the study drug; (4) with intestinal obstruction that can not be treated by oral medicine and need intravenous high energy nutrition; (5) with severe malabsorption or other diseases affecting gastrointestinal absorption and colostomy. This double-blind multi-center randomized controlled study will be performed by the Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing Cancer Hospital, Tianjin Renmin Hospital, Affiliated Hospital of Nanjing University of Chinese Medicine, Guangdong Hospital of Chinese Medicine and the Beijing University of Chinese Medicine. The subjects will be recruited from Beijing, Tianjin, Shanghai, Nanjing, Guangzhou and other sub centers. All sub centers are Grade-A general hospitals or tumor specialized hospitals. They are able to follow NCCN clinical guidelines for colon cancer treatment in a high level of tumor diagnosis and treatment and have a high degree of consistency in treatment. Ethics approval has been obtained from the Medical Ethical Committee of Xiyuan Hospital (approval No. 2018XLA048-2). This study will conducted according to the principles of the Declaration of Helsinki (64th version, October 2013) and in accordance with the Medical Research Involving Human Subjects Act (WMO, 1-3-2006). In this study, a stratified block design will be used. Each site will be used as a stratification factor. Statisticians generate a random sequence by SAS (proc plan) statistical software. The selected 400 subjects will be divided into the treatment group and the control group at a 1:1 ratio. The random seed and sequences will be sealed in opaque envelopes as confi dential data and the emergency envelopes will be securely stored by the Institute of Clinical Pharmacology of Xiyuan Hospital (separate department from the PI) to ensure adequate masking of patients, researchers and outcome evaluators. According to "NCCN clinical practice guidelines in colon cancer (Version 2. 2018)", the adjuvant chemotherapy regimen is CAPEOX, consisting of oxaliplatin 130 mg/m 2 on day 1 and capecitabine 1000 mg/m 2 , given twice daily on day 1-14 and repeated every 21 d. Patients assigned to the treatment group will receive JBSF, which included two prescriptions: LAF granules, composed of Radix pseudostellariae, stir fried Atractylodes macrocephala, Poria cocos, Rhizoma Pinelliae, will be given twice daily on day 0 to 6 in each cycle; QEF granules, composed of raw astragalus, dodder, Ligustrum lucidum, Angelica, will be given twice daily on day 7-20 in each chemotherapy cycle. Patients assigned to the control group will receive placebo granules of LAF and QEF granules, which are prepared with 2% of the test drugs and 5% of balsam pear extract. The appearance, dosage form, weight, color and smell of placebo granules are consistent with those of the test drugs. All the granules are produced by Beijing Kang Ren Tang Pharmaceutical Co., Ltd., China. If patients were given a different chemotherapy regimen due to the researcher or were affected by the side effects of chemotherapy, or were unwilling to continue chemotherapy for other reasons, the outcomes will be assessed in the interview after the last chemotherapy. Figure 1 shows a study fl owchart and Table 1 gives an overview of all outcome measures. Patient and treatment characteristics and demographic variables like age, gender and living situation will be obtained from the medical records and a baseline questionnaire. Medical data will be extracted from medical records. The overall chemotherapy completion rate is defined as: patients who completed 8 cycles of chemotherapy/total number of patients×100%, when completion is defined as the progression of chemotherapy for a patient to the end of 24 weeks, when the 8th cycle of chemotherapy is started. If the last chemotherapy is in progress, it will be regarded as completed. If the patient suspends chemotherapy due to side effects, such as myelosuppression and could continue to receive chemotherapy after treatment, the total number of chemotherapy cycles at the end of 24 weeks will be calculated. Patients who reach the clinical end point will continue to receive treatment according to the guidelines. This study will use some medical evaluation scales, such as Edmonton Symptom Assessment System (ESAS), (9) Functional Assessment of Cancer Therapy-Colorectal (FACT-C), (10) to evaluate the quality of life of patients during chemotherapy. This study will also use some self-made CM scales such as Pi (Spleen) defi ciency scale of CM, Shen (Kidney) deficiency scale of CM, symptom scale of CM, to evaluate the degree of Pi and/or Shen deficiency Follow-up visits will be scheduled before and after last chemotherapy and the improvement of CM symptoms during chemotherapy. Analysis of intestinal fl ora, function of immunity and cytokine detection will be carried out according to the specified schedule as exploratory outcomes. Sample size was calculated according to the primary outcome-overall chemotherapy completion rate. The proportion in the treatment group is assumed to be 78%. The proportion in the control group is 64%. (11) SPSS (22.0, IBM Corp. Armonk, NY) software was used for the calculation. The significance level of the test was targeted at 0.05. Group sample sizes of 164 in each group will achieve 80% power to detect a difference between the group proportions of 0.14. Therefore, we plan to recruit a total of 200 patients per group to account for loss to follow-up (18%). The statistical analysis will be completed by the Evidence-based Medicine Center of Beijing University of Chinese Medicine. Data will be analyzed using SPSS (22.0, IBM Corp. Armonk, NY, USA) for descriptive and statistical analyses. All analyses will be performed according to the intention-totreat principle. For quantitative data, descriptive statistical analysis will be made by case number, mean±standard deviation or median, upper quartile and lower quartile, according to data distribution type. Descriptive statistical analysis of qualitative data will be shown by frequency table, percentage or composition ratio after treatment. The quantitative data will be tested by t test or rank sum test, while the qualitative data will be tested by chi square or rank sum test. Survival probabilities will be estimated using the Kaplan-Meier method. C h e m o t h e r a p y c a u s e s a s e r i e s o f s i d e effects, affects the compliance and quality of life of patients, affects the efficacy of chemotherapy and the survival time of patients. The efficacy and tolerance of chemotherapy in postoperative adjuvant chemotherapy for colorectal cancer patients has been reported. (12) Some researchers found that the tolerance of Chinese people to adjuvant chemotherapy with oxaliplatin containing regimens was worse than that of Western patients. (13) Of the 111 patients who received the 3 week regimen, only 54% completed 6 cycles of chemotherapy. Intolerance of side reactions was the main reason for early termination of treatment. Nausea (88.8%), peripheral neurotoxicity (71.2%), thrombocytopenia (55.6%), vomit (45.6%), and neutropenia (38.0%) were the most common side reactions. (13) More attention should be paid to the control of side effects of chemotherapy and to improve the quality of life during chemotherapy. This study is designed to provide evidence-based medicine evidence for whether JBSF can reduce the side effects of adjuvant chemotherapy for colon cancer. During chemotherapy, nausea, vomiting, anorexia and other side effects of the digestive tract and myelosuppression symptoms are usually summarized as disharmony of Spleen and Stomach and insuffi ciency of Pi and Shen in CM. The disease is caused by the damage of Spleen and Wei (Stomach) qi caused by chemotherapy drugs, and the main treatment principle is to strengthen these organs. It has been shown that CM has an auxiliary when combined with chemotherapy, to improve immune function, protect hematopoiesis function, reverse multidrug resistance of tumors and better reduce the toxic side effects caused by the interaction of chemotherapy drugs. (14, 15) According to the theory of syndrome differentiation and treatment of CM, Prof. YANG Yu-fei invented JBSF to target the effects of chemotherapy on the gastrointestinal system and bone marrow suppression. The fi rst step is to treat Pi and Wei, using LAF granules to alleviate the digestive tract reaction after chemotherapy by strengthening Pi and Wei. The second step is to treat Pi and Shen, using QEF granules to protect the hematopoietic function of bone marrow and reduce the myelosuppression after chemotherapy by warming Pi and Shen. There are still some limitations in this study, which was designed and funded in 2017. In 2018, the American Society of Clinical Oncology proposed as the main conclusion of IDEA research, that the period of postoperative adjuvant chemotherapy for colorectal cancer should be adjusted to 3 to 6 months according to the different stages and risk factors after radical resection. For patients with low risk factors, postoperative adjuvant chemotherapy for 3 months could be selected. (11) This meant that this study needed to screen more patients with high risk factors, put forward higher requirements for the recruitment and enrollment of the subjects and this indirectly affected the enrollment speed. This study cannot test the intestinal fl ora distribution of all subjects during chemotherapy due to limited research funding, research progress and other factors, but it can still test the intestinal fl ora of subjects in the fi rst two chemotherapy cycles, which provides a certain basis for further research. Limited by the research conditions, the whole process dynamic monitoring of T, B lymphocyte subsets and cytokines of all subjects could not be realized in this study, only in the sub centers with the examination conditions. I n J a n u a r y 2 0 2 0 , t h e o u t b r e a k o f 2 0 1 9 coronavirus disease (COVID-19) has been having extensive infl uence on the society and people's daily life in China. (16, 17) During this period, treatments for cancer patients will be impacted to a certain extent and this will affect the management of the study and the recruitment of the subjects, which is likely to lead to the postponement of the study. The authors declare that there is no conflict of interest regarding the publication of this paper. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries Analysis of cancer incidence and death in different regions of China Chinese society of Clinical Oncology (CSCO) colorectal cancer diagnosis and treatment guidelines NCCN guidelines insights: colon cancer, version 2 Expert Committee on Rational Drug Use of National Health and Family Planning Commission. 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