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Analysis of Existing Guidelines and Controlled Clinical Trials for Development of [Guideline of Clinical Trials with Herbal Medicinal Products for Colorectal Cancer]

Article information

J Korean Med. 2019;40(1):124-152
Eunjoo Park1,2orcid_icon, Sin Seong1orcid_icon, Sungsu Kim1orcid_icon, Jinsung Kim3orcid_icon, Jae-Woo Park3orcid_icon, Seok-Jae Ko3orcid_icon, Gajin Han1,2,orcid_icon
1Soram Hospital of Korean Medicine
2Soram Korean Medicine Research Institute
3Department of Gastroenterology, College of Korean Medicine, Kyung Hee University
Correspondence to: 한가진 (Gajin Han), 서울 강남구 봉은사로 462, 소람한의약연구소, Tel: +82-70-4803-6648, Fax: +82-70-8282-7001, E-mail: kmdhgj@soram.kr
Received 2019 February 26; Revised 2019 March 14; Accepted 2019 March 14.

Abstract

Objectives

This study aimed to ascertain what should be considered in the “Guideline for Clinical Trials with Herbal Medicinal Products for Colorectal Cancer” by analyzing the existing guidelines and clinical trials.

Methods

The development committee searched guidelines for herbal medicinal products for colorectal cancer that have already been developed. Then, clinical trials for colorectal cancer using herbal medicine were searched. The searched trials were analyzed in terms of inclusion and exclusion of participants, intervention, comparator, outcomes and trial design. Then, we compared the results of our analysis with the regulations and guidelines of the Ministry of Food and Drug Safety in order to identify the issues we will have to consider when making the “Guideline for Clinical Trials with Herbal Medicinal Products for Colorectal Cancer”. Several guidelines for anti-tumor agents and clinical trials with herbal medicinal products were searched on the national institution homepage. In addition, 12 articles were searched using a combination of the following search terms: ‘colorectal neoplasms’, ‘herbal medicine’, ‘Medicine, Korean traditional’, ‘Medicine, Chinese Traditional’, ‘medicine, East Asian medicine’, ‘medicine, Kampo’, etc.

Results

The characteristics of participants were various, such as people with medical histories of surgeries or recurrent cancers or who complained of chemotherapy-induced side effects. The types of interventions were also various and included decoctions, powders, intravenous fluids, intraperitoneal injections and gargles. Comparators used included placebos and conventional treatments. The outcome measurements used in the studies were quality of life, symptom score, tumor response, and survival duration, etc. Safety was evaluated by recording adverse events.

Conclusions

Findings were made by reviewing existing guidelines and comparing them with clinical trials for colorectal cancer and herbal medicinal products. These results will be utilized in the development of the “Guideline for Clinical Trials with Herbal Medicinal Products for Colorectal Cancer”.

Keywords: Colorectal neoplasms; herbal medicinal product; Clinical trial; Guidelines
Fig. 1

Flow chart of the study selection process

Search Strategy used in PubMed

The List of Searched Guidelines related to Colorectal Cancer, Clinical Trial for Herbal Medicinal Product

The Characteristics of Included Study

The Characteristics of Participants in the Included Studies

The Inclusion and Exclusion Criteria of the Selected Studies

The Characteristics of Intervention in the Included Studies

The Characteristics of Comparator and Outcomes in the Included Studies

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Article information Continued

Copyright © 2019 The Society of Korean Medicine all rights reserved

Fig. 1

Fig. 1

Flow chart of the study selection process

Table 1

Search Strategy used in PubMed

No. Search items
1 colorectal neoplasms[MeSH Terms]
2 colon neoplasms[MeSH Terms]
3 rectal Neoplasms[MeSH Terms]
4 #1 OR #2 OR #3
5 medicine, Korean traditional[MeSH Terms]
6 medicine, Chinese traditional[MeSH Terms]
7 medicine, East Asian medicine[MeSH Terms]
8 medicine, Kampo[MeSH Terms]
9 integrative medicine[MeSH Terms]
10 complementary therapies[MeSH Terms]
11 traditional Japan medicine[Text Words]
12 alternative medicine[Text Words]
13 #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12
14 #4 AND #13
15 herbal medicine[MeSH Terms]
16 herb*[Text Words]
17 tang[Text Words]
18 san[Text Words]
19 decoction[ALL]
20 #15 OR #16 OR #17 OR #18 OR #19
21 #4 AND #20
22 #14 OR #21
Filter Text availability: full text, Publication dates: 10 years, Languages: English

Table 2

The List of Searched Guidelines related to Colorectal Cancer, Clinical Trial for Herbal Medicinal Product

Publisher Year Title Characteristics
Kim JY, 2014 A preliminary study for development of clinical practice guidelines of Korean medicine in colorectal cancer19 1. clinical practice guideline of Korean traditional medicine
2. related to colorectal cancer
3. a research report
Korea Institute of Oriental Medicine, 2005 A study on the clinical trial guidelines of herbal medicinal drug21 1. related to general herbal medicinal drug
2. a research report
Korea Institute of Oriental Medicine, 2005 A study on the clinical trial guideline of herbal medical drug(II)22 1. analysis of guidelines for clinical research of new medication in Chinese medicine
2. related to general herbal medicinal drug
Industry-Academia Collaboration Foundation, Kyung Hee University, 2006 Research on outcome indicators for clinical trials of herbal medicinal products23 1. related to assessment tool
2. related to cough, phlegm, asthma
3. a research report
SH Kim, 2006 Study on development of assessment guideline and endpoints for clinical trial with antitumor natural product24 1. specific to assessment tool for clinical trial
2. related to antitumor natural product
3. a research report
Korea Food & Drug Administration, 2006 Guideline for evaluation of clinical trial of anticancer drug25 1. related to anticancer agents which have toxicity against cancer cell or function of inhibition of cancer cell growth
Korea Food & Drug Administration, 2007 General considerations for clinical trials in herbal medicine26 1. related to general herbal medicine
2. general principles and methods of clinical trials
3. a research report
Korea Food & Drug Administration, 2010 Guidelines for the review of nonclinical test data for approval of anti-cancer drug’s clinical trial plan and item authorization27 1. description of the minimum considerations for clinical testing of anticancer drugs aimed at treating progressive cancer patients based on the type and timing of nonclinical studies
National Institute of food and drug safety evaluation, 2015 Guidelines for clinical trial of anti-cancer drugs28 1. related to anticancer agents which have toxicity against cancer cell or function of inhibition of cancer cell growth
National Institute of food and drug safety evaluation, 2015 Guidelines for non-clinical trial of anti-cancer drugs29 1. recommendations for nonclinical evaluation to support clinical trials in the development of anticancer drugs
National Institute of food and drug safety evaluation, 2015 Guidelines for exemption of anti-cancer drug data in Korean population30 1. guidelines for exemption from submission of clinical trial data about Koreans
National Institute of food and drug safety evaluation, 2017 Quality guidelines of herbal medicine for clinical trial31 1. recommendations for chemistry, manufacturing and control information on herbal medicines used in clinical trials
Ministry of Food and Drug Safety, 2018 Guideline for the use of clinical trial medicines for therapeutic purposes32 1. guideline for the use of clinical trial medicines to patients with life-threatening conditions without other treatment
Korean Academy of Medical Sciences 2012 Korean Clilnical Practice Guideline for Colon and Rectal Cancer v1.04 1. clinical practice guideline of conventional medicine
2. related to colorectal cancer
3. multidisciplinary clinical guideline in Korea
Lee BI 2012 Korean Guidelines for Colorectal Cancer Screening and Polyp Detection33 1. guideline for optimal screening methods for colorectal cancer and dection of adenomas

Table 3

The Characteristics of Included Study

Title Author Journal, Year Nation Design Group
Randomized controlled trial
A phase I study of the chinese herbal medicine PHY906 as a modulator of irinotecan-based chemotherapy in patients with advanced colorectal cancer34) Kummar Clin Colorectal Cancer. 2011 USA multicenter, double-blind, randomized, placebo-controlled, dose escalation, cross-over phase I study cohort 1
chemotherapy of ILF(irinotecan/5-flurouracil/leukovori n) + (sequence 1) half the patients: PHY906 1.2g/day during the first cycle of chemotherapy and placebo with the second cycle
(sequence 2) the other half of patients: placebo with the first cycle and PHY906 1.2g/day with the second cycle
cohort 2
chemotherapy of ILF(irinotecan/5-flurouracil/leukovori n) + (sequence 1) half the patients: PHY906 2.4g/day during the first cycle of chemotherapy and placebo with the second cycle
(sequence 2) the other half of patients: placebo with the first cycle and PHY906 2.4g/day with the second cycle
Yiqi zhuyu decoction combined with FOLFOX-4 as first-line therapy in metastatic colorectal cancer35) Cao Chin J Integr Med. 2011 China multicenter, randomized, 2-armed, controlled study A: FOLFOX-4 (oxaliplatin/5-flurouracil/leucovorin) + Yiqi Zhuyu Decoction
B: FOLFOX-4 (oxaliplatin/5-flurouracil/leucovorin) + placebo
The Kampo medicine, Goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen36) Nishioka Int J Clin Oncol. 2011 Japan single center, randomized, 2-armed, controlled study A: modified FOLFOX6 (oxaliplatin/5-flurouracil/leucovorin) +Goshajinkigan
B: modofied FOLFOX6 (oxaliplatin/5-flurouracil/leucovorin)
The effects of the Kampo medicine (Japanese herbal medicine)
“Daikenchuto” on the surgical inflammatory response following laparoscopic colorectal resection37) 		Yoshikawa Surg Today. 2012 Japan single center, randomized, 2-armed, controlled study A: daikenchuto
B: control group, did not take any drugs or placebo
Effectiveness of a novel herbal agent MB-6 as a potential adjunct to 5-fluoracil-based chemotherapy in colorectal cancer38) Chen Nutr Res. 2014 China multicenter, parallel, double-blind, randomized, 2-armed, placebo-controlled study A: FOLFOX-4 (oxaliplatin/5-flurouracil/leucovorin) + MB-6
B: FOLFOX-4 (oxaliplatin/5-flurouracil/leucovorin) + placebo
Double-blind, placebo-controlled, randomized phase II study of TJ-14 (Hangeshashinto) for infusional fluorinated-pyrimidine-based colorectal cancer chemotherapy-induced oral mucositis39) Matsuda Cancer Chemother Pharmacol. 2015 Japan multi-center, double-blind, randomized, 2-armed, placebo-controlled phase II trial A: second cycle of chemotherapy + TJ-14 (Hangeshashinto)
B: second cycle of chemotherapy + placebo
Preventive effect of Goshajinkigan on peripheral neurotoxicity of FOLFOX therapy (GENIUS trial): a placebo-controlled, double-blind, randomized phase III study40) Oki Int J Clin Oncol. 2015 Japan multicenter, randomized, double-blind, 2-armed, placebo-controlled, phase III trial A: modified FOLFOX6 (oxaliplatin/5-flurouracil/leucovorin) +Goshajinkigan(GJG)
B: modified FOLFOX6(oxaliplatin/5-flurouracil/leucovorin) +placebo
Clinical efficacy of Daikenchuto for gastrointestinal dysfunction following colon surgery: a randomized, double-blind, multicenter, placebo-controlled study41) Katsuno Jpn J Clin Oncol. 2015 Japan multicenter, randomized, double-blind, 2-armed, placebo-controlled, phase III trial A: Daikenchuto
B: placebo
Efficacy, Safety, and Cost of Therapy of the Traditional Chinese Medicine, Catalpol, in Patients Following Surgical Resection for Locally Advanced Colon Cancer42) Fei Med Sci Monit. 2018 China multicenter, randomized, parallel, 3-armed, controlled study A: placebo-treated group (patients who did not receive chemotherapy of any kind during the next two years of survival)
B: intraperitoneal injection of 10 mg/kg catalpol twice a day for 12 weeks
C: two-hour intravenous infusion of 5 mg/kg bevacizumab, twice in a week for 12 weeks
Non-randomized controlled trial
Clinical observation on treatment of colonic cancer with combined treatment of chemotherapy and Chinese herbal medicine43) Zhou Chin J Integr Med. 2009 China singlecenter, non-randomized, 2-armed, controlled clinical trial A: Zhao’s Weitiao No. 3 (赵氏微调 3号方,ZW3)
B: OLF protocol (oxaliplatin (L-OHP)+leukovorin(LV)+5-fluorour acil(5-FU))
A clinical study on safety and efficacy of Aidi injection combined with chemotherapy44) Xu Asian Pac J Cancer Prev. 2011 China singlecenter, non-randomized, 2-armed, controlled clinical trial A: FOLFOX4(leucovorin calcium/5-fluorouracil/oxaliplatin) + Aidi injection
B: FOLFOX4(leucovorin calcium/5-fluorouracil/oxaliplatin)
Therapeutic efficacy of Traditional Chinese medicine, “Kuan-Sin-Yin”, in patients undergoing chemotherapy for advanced colon cancer - A controlled trial45) Chien Complement Ther Med. 2016 Taiwan singlecenter, non-randomized, 2-armed, controlled clinical trial A: Kuan-Sin-Yin(KSY) between the interval of 2 times chemotherapy
B: no special drug during the interval of 2 times chemotherapy

Table 4

The Characteristics of Participants in the Included Studies

Study Age Sample size Patients
Kummar, 201134) cohort 1: 44–74
cohort 2: 46–64		 cohort 1: 13
cohort 2: 4
total 17		 patients with advanced, metastatic colorectal cancer
Cao, 201135) A: 55.2±13.3
B: 58.8±13.7		 A: 60
B: 60
total 120		 patients with histologically confirmed metastatic colorectal cancer, one or more unidimensionally measurable lesions, who were not amenable to curative resection
Nishioka, 201136) A: 67(48–77)
B: 65(52–80)		 A: 22
B: 23
total 45		 nonresectable or recurrent colorectal cancer who received modified FOLFOX6 (mFOLFOX6) therapy at Tokushima University Hospital
Yoshikawa, 201237) A: 62±12
B: 70±5		 A: 15
B: 15
total 30		 patients who underwent laparoscopic colectomy for colorectal carcinoma in the Department of Digestive Surgery of Tokushima University
Chen, 201438) A: 63.4±13.66
B: 63.9±13.25		 A: 34
B: 38
total 72		 patients had histologically confirmed CRC and/or clinical evidence of metastasis and at least one measurable lesion, either by computed tomography or magnetic resonance imaging
Matsuda, 20539) A: 67(49–84)
B: 67(29–85)		 A: 43
B: 47
total 90		 patients with colorectal cancer who developed moderate-to-severe chemotherapy-induced oral mucositis(COM) (WHO grade ≧1) during any cycle of chemotherapy using FOLFOX, FOLFIRI, and/or XELOX treatment
Oki, 201540) A: 62.4±10.6
B: 60.4±11.5		 A: 89
B: 93
total 182		 patients who had histologically confirmed adenocarcinoma of colorectal cancer, with the lower edge of the tumor located at a site above the pouch of Douglas
Katsuno, 201541) A: 68(28–88)
B: 69(35–91)		 A: 174
B: 162
total: 336		 patients undergoing open colectomy for colon cancer
Fei, 201842) A: 52.2±4.46
B: 52.32±4.45
C: 52.6 ± 4.3		 A: 115
B: 115
C: 115
total 345		 patients who had undergone surgical resection for locally advanced colon adenocarcinoma
Zhou, 200943) A: 63.07±12.23 (36–85)
B: 58.62±12.00 (36–78)		 A: 105
B: 58
total 163		 patients with colonic cancer confirmed by histopathologic or cytologic examination and who refused to receive surgical operation or were unsuitable to have it, or had tumor relapse after excision and showed no indication of re-operation
Xu, 201144) 18–75 100 patients pathologically diagnosed as colorectal cancer
Chien, 201645) A: 62.5
B: 50.1		 A: 30
B: 31
total 61		 patients with advanced colon cancer

Table 5

The Inclusion and Exclusion Criteria of the Selected Studies

Study Inclusion Criteria Exclusion Criteria
Kummar, 201134) 1. Eastern Cooperative Oncology Group performance status of 0 or 1
2. adequate organ function, defined as absolute neutrophil count ≥1.5 × 109/L, platelets≥100 × 109/L, hemoglobin ≥9.0g/dL, creatinine ≤3.0mg/dL, serum bilirubin ≤1.5mg/dL, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤5		 1. patients with known hypersensitivity to the study medication
2. patients with active infections
3. active/progressive central nervous system metastases
4. amilial, nonhemolytic, acholuric jaundice (Gilbert syndrome)
5. patients who received an investigational agent within 4 weeks prior to study entry
6. pregnant and/or lactating women
7. patients with a permanent colostomy in whom evaluation of diarrhea
Cao, 201135) 1. Eastern Cooperative Oncology Group performance status ≤1
2. age ≥18 years
3. life expectancy longer than 3 months		 1. prior systemic therapy for metastatic colorectal cancer or previous treatment with oxaliplatin or Yiqi zhuyu decoction
2. radiotherapy or surgery for metastatic colorectal cancer completed≤4 weeks before random assignment
3. pregnant or breast-feeding women
4. clinically significant cardiovascular disease; clinically detectable ascites; use of full-dose anticoagulants or thrombolytics; known central nervous system metastasis; serious nonhealing wound, ulcer, or bone fracture; clinically significant bleeding diathesis or coagulopathy; and proteinuria≥500mg/24 h
Nishioka, 201136) 1. Eastern Cooperative Oncology Group performance status 0–2
2. normal bone marrow function (white blood count ≥4000/m2, platelet count ≥100000/m2)
3. liver function (serum total bilirubin<1.5 mg/dl)
4. renal function (creatinine<1.5mg/dl)
5. heart function (stable cardiac rhythm, no active angina, no clinical evidence of congestive heart failure)		 1. who had clinical neuropathy, diabetes mellitus, alcoholic disease, or brain involvement
2. who recieved vitamin B, magnesium or calcium therapy
Yoshikawa, 201237) 1. histologically confirmed adenocarcinoma of the colorectum, no involvement of other organs
2. performance status of 0 or 1
3. no prior abdominal surgery, and no prior chemotherapy or radiotherapy for any malignancy		 1. unstable anemia
2. myocardial infarction within 6 months before registration
3. uncontrolled hypertension or diabetes mellitus
4. severe respiratory disease
5. intestinal leakage or obstruction
Chen, 201438) 1. Eastern Cooperative Oncology Group performance status less than or equal to 2
2. adequate bone marrow reserve (hemoglobin level at least 9 g/dL, absolute neutrophil count at least 1.5×109/L, and platelets at least 100×109/L) and hepatorenal function (total bilirubin less than or equal to 1.25 creatinine less than or equal to 1.25, and alanine aminotransferase or aspartate aminotransferase less than 2.5 upper normal limits)		 1. pregnant or lactating
2. did not practice adequate contraceptive measures
3. showed evidence of central nervous system metastasis
4. presented with active infection that required systemic antimicrobial treatment
5. current chronic diarrhea and/or other serious comorbidities (ie, angina, myocardial infarction, congestive heart failure, epilepsy, or other significant medical conditions as judged by the investigators)
6. history of second primary malignancies (except for adequately treated basal cell skin carcinoma or cervical carcinoma in situ) or were undergoing concurrent treatment with any other anticancer therapy
7. another investigational drug treatment within the previous 4 weeks
Matsuda, 201539) patients who developed WHO grade≥1 oral mucositis during the first screening cycle of chemotherapy were eligible no explanation of exclusion criteria
Oki, 201540) 1. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1
2. cancer status was pathological stage III (based on the 7th edition of the Japanese Classification of Colorectal Carcinoma)
3. who had undergone complete radical resection (R0)
4. surgery had taken place within 8 weeks
5. who had adequate hepatic, renal, respiratory and bone marrow function		 who had pre-existing peripheral neuropathy of any grade
Katsuno, 201541) 1. qualified for curative colonic open resection for colon cancer(including cancer of rectosigmoid) that had been diagnosed pre-operatively according to the disease staging (I, II, IIIa, IIIb, TNM category distribution: T =1–3, N=0–2, M=0)
2. diagnosed with a performance status (PS) of 0–1
3. able to tolerate oral administration of Daikenchuto(DKT)
4. aged 20 years or older
5. able to stay in hospital during the entire length of study period
6. able to provide written informed consent		 1. scheduled for endoscopic or laparoscopic surgery
2. having complicated inflammatory bowel disease (ulcerative colitis and Crohns disease)
3. requiring emergency surgery
4. diagnosed with double cancer, serious liver disorder or serious renal disorder
5. history of laparotomy and peritonitis (excluding surgery for appendicitis)
6. taking other Kampo medicines
7. pregnant, possibly pregnant, lactating or considering pregnancy
8. unfit for the study as determined by the attending physician.
Fei, 201842) 1. aged between 18–70 years
2. no previous exposure to chemotherapy or immunotherapy in the previous two years
3. had adequate renal, liver, bone marrow, and hepatic function and histopathologically proven colon cancer		 1. confirmed metastasis, or primary malignancy of other organs
2. refused to provide written informed consent
3. did not attend regular post-treatment follow-up
Zhou, 200943) 1. who refused to receive surgical operation or were unsuitable to have it, or had tumor relapse after excision and showed no indication of re-operation
2. who had lesions with measurable bi-radiuses, showing a size by CT of ≥10mm×10mm, with initial examination performed 20 days before the first medication in this trial
3. aged from 36 to 85 years of any sex
4. Karnofsky score≥30 scores and predicted survival time≥3 months
5. The results of laboratory examination matched the following criteria: WBC count ≥4.0×109/L; hemoglobin≥60 g/L; urea nitrogen(mmol/L)≤1.25-fold of the upper limit of the normal range; creatinine(μ mol/L)≤1.25-fold of the upper limit of the normal range; alanine transaminase(ALT) and aspartate aminotransferase (AST)≤2.5-fold of the upper limit of the normal range, with the initial examination performed 8 days before the first medication
6. who had signed on the written informed consent for participating in the trial of their own will		 1. tumor metastasis to brain or cerebral maninges
2. history of other complicated malignant tumors
3. severe cardiovascular disease, hepatopathy, nephropathy; complicated with severe diseases or events, including uncontrolled active infection, severe electrolyte disorder, active disseminated intravascular coagulation, or with obvious tendency of bleeding
4. target lesion having already received radiation
5. in the process of receiving treatment by other Chinese herbal medicines
Xu, 201144) 1. karnofsky performance status ≥ 70
2. adequate bone marrow (white blood cell count>3.0×109 and platelet count >150×109), liver function(bilirubin and transaminases <1.5 times the upper limit of normal) and renal function (creatinine <1.5 upper limit of normal)
3. no evidence of metastatic disease
4. age between 18 and 75 years
5. signed an informed consent before chemotherapy		 1. active cardiac disease (LVEF <50%)
2. significant arrhythmia
3. any serious medical or psychiatric condition
4. other malignancy
5. pregnant or lactating women
Chien, 201645) 1. advanced colon cancer confirmed by an oncologist
2. Eastern Cooperative Oncology Group (ECOG) performance scores < = 2
3. age 20 to 80 years
4. current treatment under chemotherapy course with an 5FU-based regimen
5. ability to understand the purpose and methods of this study		 1. terminal disease or life expectancy <6 months
2. presence of psychiatric problems
3. completion of the chemotherapy treatment course
4. development of a major event (including surgical intervention, acute myocardial infarction, severe infection such as pneumonia, or ventilator use) causing withdrawal from the study
5. presence of any other condition the physician in charge deemed would make the patient unsuitable for the study

Table 6

The Characteristics of Intervention in the Included Studies

Study Intervention Contents & Dose Period
Kummar, 201134) chemotherapy +chinese herbal medicine (PHY 906) 1. chemotherapy:
ILF(irinotecan/5-flurouracil/leukovorin). irinotecan at a weekly dose of 125 mg/m2, followed by leucovorin at 20 mg/m2 and 5-FU at a dose of 500 mg/m2. Chemotherapy was administered weekly for 4 weeks, followed by a 2-week rest period. Cycles were repeated every 6 weeks, grade 2 or higher toxicity (NCI-CTC version 2.0) occurred during the first course of treatment, the dose of chemotherapy was modified
2. PHY906 is a novel Chinese herbal preparation that is composed of 4 main herbs, Scutelleria baicalensis Georgi, Paeonia lactiflora Pall., Glycyrrhiza uralensis Fisch., and Ziziphus jujuba Mill, in a ratio of 3:2:2:2, respectively. Patients in cohort I received either 1.2 g of PHY906 or placebo. Patients in Cohort II received 2.4 g of PHY906 or placebo. If constipation occurred, study medication was to be temporarily discontinued for any remaining days of the 4days of dosing during the week that the constipation occurred. The median total dose of PHY906 in cohort I was 19.2 g (range, 5.2–19.2 g) and in cohort II was 30.2 g (range, 8.0–38.4 g).		 12 weeks
Cao, 201135) chemotherapy +Chinese herbal medicine (Yiqi zhuyu decoction) 1. chemotherapy : FOLFOX-4 (oxaliplatin/5-flurouracil/leucovorin). The FOLFOX-4 regimen was a 2-h LV (Lingnan Pharmaceutical Ltd.) infusion of LV [200 mg/(m2·d)] followed by a 5-FU bolus [400 mg/(m2·d), Tianjin Jinyao Anjisuan Co., Ltd., China] and 22-h infusion[600 mg/(m2·d)] for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin (Nanjing Pharmaceutical Factory Co., Ltd., China) 85 mg/m2 as a 2-h infusion on day 1.
2. The prescription of Yiqi zhuyu decoction(YZD) was composed of Radix Ginseng 10 g, Radix Sophorae Flavescentis 10 g, Rhizoma chuanxiong 10 g, Stephania Tetrandra 10 g, Rhizoma Curcumae 12 g, Radix Codonopsis 15 g, Radix astragali 30 g, Rhizoma Atractylodes 10 g, Radix Angelicae sinensis 10 g, Rhizoma Curcumae Longae 10 g, Radix Paeoniae 10 g, Rhizoma Sparganii 12 g, Herba Hedyotis diffusae 30 g, and Herba Scutellariae Barbatae 30 g.
YZD or placebo (Ringer’s solution) was administered as an oral liquid medicine before oxaliplatin at a dose of 5 mL/kg on day 1 of a 2-week cycle.		 continued until disease progression(PD) or for 48 weeks (i.e., up to 24 cycles of FOLFOX-4)
Nishioka, 201136) chemotherapy +Kampo medicine (Goshajinkigan) 1. chemotherapy : modified FOLFOX6 chemotherapeutic regimen consisted of a 2-h intravenous infusion of oxaliplatin (85 mg/m2) combined with 1-LV(100 mg/m2), followed by a rapid intravenous infusion of 5-FU (400 mg/m2), and then a 46-h continuous infusion of 5-FU (2400 mg/m2), this regimen comprised one course of therapy and was repeated once every 2 weeks
2. Goshajinkigan (GJG), a traditional Japanese herbal medicine (Kampo), is composed of 10 crude herbs: Rehmanniag lutinosa, Achyranthes spp. root, Cornus officinalis, Dioscorea spp. rhizome, Plantago spp. seed, Alisma orientale, Porica cocos, Moutan cortex, Cinnamomum cassia, and aconite tuber.(7.5 g/day divided into 2–3 doses) (Tsumura and Co., Japan)		 1. primary end point was the incidence of grade 3 peripheral neuropathy
2. secondary end points were the percentage of grade 2 and 3 peripheral neuropathy in each course, adverse effects except for neuropathy, and tumor response to mFOLFOX6 →The median number of cycles per patient
A: GJG group was 13 (range 4–32)
B: control group was 12 (range 4–28)
Yoshikawa, 201237) Daikenchuto Daikenchuto(DKT), from Tsumura & Co., Tokyo, Japan, is a traditional Japanese herbal medicine, containing 1.25 g of DKT extract powder, 10 g of malt sugar and 3.75 g of vehicle in a total amount of 15 g. DKT extract powder is a mixture of dried ginger root, ginseng and zanthoxylum fruit at a ratio of 5:3:2, respectively. A group took 7.5 g/day of DKT. from the day after surgery to the 7th postoperative day
Chen, 201438) chemotherapy +chinese herbal medicine(MB-6) 1. chemotherapy: FOLFOX4. on the first day, 2-hour infusion of leucovorin (LV) (200 mg/m2) and oxaliplatin (85 mg/m2), followed by a 22-hour infusion of 400 mg/m2 5-fluorouracil bolus and 600 mg/m2. on the second day, a 2-hour infusion of LV 200mg/m2, followed by a 22-hour infusion of 400 mg/m2 5-fluorouracil bolus and 600mg/m2.
2. MB-6 is a botanical preparation composed of fermented soybean extract (MicrSoy-20), green tea extract (Camellia sinensis O), Antrodia camphorata mycelia, spirulina (Arthrospira platensis), grape seed extract (Vitis vinifera), and curcumin extract (Curcuma longa L). MB-6 dosage included 6 capsules of 320 mg each administered 3 times daily with meals.		 16weeks
Matsuda, 201539) chemotherapy +Kampo medicine (Hangeshashinto) 1. chemotherapy: FOLFOX (40 %), FOLFIRI(30 %), XELOX (7.8 %), others(22.2%)
2. TJ-14 (Hangeshashinto) is one of the Kampo formulas in Japanese traditional herbal medicine, is the mixture of seven herbs including pinellia tuber, scutellaria root, glycyrrhiza, jujube, ginseng, processed ginger, and Coptis rhizome. 2.5 g X3 times per day for a total daily dose of 7.5 g, dissolve 2.5 g of TJ-14 in 50 ml of drinking water, divided it into twice or three times in an oral cavity, rinsed their oral cavity with it three times daily		 2 weeks (from the first day of chemotherapy to before the next course of chemotherapy began)
Oki, 201540) chemotherapy +Kampo medicine (Goshajinkigan) 1. The mFOLFOX6 chemotherapy regimen consisted of a 2-h intravenous infusion of oxaliplatin(85 mg/m2) combined with 1-LV (100 mg/m2) followed by a rapid intravenous infusion of 5-FU (400 mg/m2) and then a 46-hour continuous infusion of 5-FU (2400 mg/m2). This regimen comprised one course of therapy and was repeated once every 2 weeks. Dose reduction of oxaliplatin to 75 mg/m2 was allowed for patients who experienced persistent grade2 sensory neurotoxicity.
Patients were allocated randomly to a 12-course mFOLFOX6 regimen with GJG at 7.5 g/day (Tsumura and Co., Akasaka, Japan) or an identical placebo. The average cycle of chemotherapy was 9.0 in the A(GJG group) and 8.3 in the B(placebo group).
2. Goshajinkigan(GJG) at 7.5 g/day (Tsumura and Co., Akasaka, Japan), from the first day of mFOLFOX6 therapy continued to be administered orally before meals or between meals on a daily basis until the end of the 12 courses		 The primary endpoint was the time to the onset of grade2 or greater sensory neurotoxicity [i.e., time to neuropathy(TTN)] during therapy. The secondary endpoints were of the proportions of patients who reported adverse events and the dose intensity of oxaliplatin. Goshajinkigan did not prevent oxaliplatin associated peripheral neuropathy in this clinical trial. The clinical study was therefore terminated.
Katsuno, 201541) Kampo medicine (Daikenchuto) Daikenchuto(DKT)and placebo were manufactured by Tsumura & Co. (Tokyo, Japan) and patients were received either oral doses of 15 g/day (5g t.i.d) of DKT or placebo. post operative day 2 to 8
Fei, 201842) 1. chinese herbal medicine extract(catalpol) injection (group B)
2. chemotherapy (group C)		 1. Catalpol is an iridoid glucoside extracted from Rehmannia glutinosa(Chinese name: Di Huang). intraperitoneal injection of 10 mg/kg catalpol twice a day for 12 weeks
2. 5 mg/kg intravenous bevacizumab(Avastin®) twice a week for 12 weeks		 12 weeks
Zhou, 200943) 1. chinese herbal medicine(Zhao’s Weitiao No. 3) (group A)
2. chemotherapy (group B)		 1. Zhao’s Weitiao No. 3 (赵氏微调 3号方, ZW3) : asiabell root 10 g, grifola 30 g, prepared white atractylodes tuber 10 g, Indian bread 10 g, coix seed 15 g, pinellia tuber 6 g, tangerine peel 6 g, and loquat leaf 10 g.
decoction of 80mL, taken in two portions every day, 40 mL each time. 30 days as one cycle 6 cycles in total administered to all patients.
2. chemotherapy of OLF : Oxaliplatin (L-OHP) 130 mg/(m2·d) through intravenous drip on day 1, LV 200 mg/(m2·d) and 5-fluorouracil(5-FU) 300 mg/(m2·d) through intravenous drip per day from day 1 to day 5, 3 weeks as one cycle, 4–6 cycles in total.		 A: 180days
B: 12–18 weeks
Xu, 201144) chemotherapy+chi nese herbal preparation (Aidi injection) 1. chemotherapy: intravenous(iv) leucovorin calcium at a dose of 200 mg/m2, iv bolus Fluorouracil (5-FU) at a dose of 400 mg/m2 and continuous iv 5-FU at a dose of 600 mg/m2 on day 1, day2, Oxaliplatin 85 mg/m2 repeated every 2weeks.
2. Aidi Injection® has been developed and manufactured by Guizhou Ebay Pharmaceutical Co., Ltd in China. Its main components include Ban Mao (Mylabri), Ci Wu Jia (Radix Acantropanacis Senticosi), Huang Qi (Radix Astragali) and Ren Shen (Radix Ginsheng). 60–80ml intravenous infusion on iv, once daily, for 7 days.		 Treatment was biweekly administered until progressive disease(PD) or unacceptable toxicity, withdrawal of consent, and physicians decision or treatment interruption for >2 weeks. →average treatment cycle was 3 (at least 2, total cycles of all patients was 303)
Chien, 201645) chinese herbal medicine(Kuan-Sin-Yin) Kuan-Sin-Yin(KSY) is a traditional chinese medicine(TCM) decoction is composed of seven herbs (Codonopsis pilosula: 6 g; Atractylodes macrocephala: 6 g; Gly-cyrrhiza uralensis: 6 g; Poria cocogs: 3 g; Astragalus membranaceus:6 g; Ligustrum lucidum:3 g; and Agastache rugose: 6 g; total 36 mg in100 ml). once per day (100 cc, oral use) after breakfast for two weeks in the interval between doses of chemotherapy administered as standard chemotherapy for advanced colon cancer, scheduled biweekly 2 weeks

Table 7

The Characteristics of Comparator and Outcomes in the Included Studies

Study Comparator Outcome
Kummar, 201134) cohort 1
(sequence 1) : placebo with 2nd cycle chemotherapy
(sequence 2) : placebo with 1st cycle chemotherapy
cohort 2
(sequence 1) : placebo with 2nd cycle chemotherapy
(sequence 2) : placebo with 1st cycle chemotherapy		 1. adverse events and toxicity evaluation using National Cancer Institute-Common Toxicity Criteria(NCI-CTC) version 2.0
2. use of anti-diarrheal and anti-emetic Medications
3. pharmacokinetics
4. clinical response evaluation using world health organization(WHO) criteria
Cao, 201135) B: FOLFOX-4 (oxaliplatin/5-flurouracil/leucovorin) + placebo(Ringer’s solution) 1. response rate(RR) evaluation using Response Evaluation Criteria in Solid Tumors(RECIST)
2. progression-free survival (PFS) was defined as the time from random assignment to the first documentation of PD(prgression disease), or death from any cause
3. overall survival(OS)
4. adverse events (AEs) were graded according to the National Cancer Institute-Common Toxicity Criteria(NCI-CTC)
Nishioka, 201136) B: modofied FOLFOX6 (oxaliplatin/5-flurouracil/leucovorin) 1. grade peripheral neuropathy using Neurotoxicity Criteria of Debiopharm (DEB-NTC) and evaluate the effect by KaplanMeier analysis
2. adverse effects of grade 3 except for neuropathy were assessed using the National Cancer Institute-Common Toxicity Criteria(NCI-CTC)
3. anti-tumor effect assessed by the Response to Treatment in Solid Tumors (RECIST)
Yoshikawa, 201237) B: control group, did not take any drugs or placebo 1. the time until the first flatus after the operation
2. the duration of the postoperative hospital stay
3. postoperative complications
4. laboratory data analysis
 (1) body temperature
 (2) heart rate
 (3) WBC count
 (4) lymphocyte count
 (5) C-reactive protein(CRP) level
 (6) β-D-glucan level
 (7) Candida index
Chen, 201438) B: FOLFOX-4 (oxaliplatin/5-flurouracil/leucovorin) + placebo (The placebo group received the same number of capsules containing only inactive ingredients and administered in the same manner as the treatment group.) 1. best overall response (complete response[CR] + partial response [PR] by Response Evaluation Criteria in Solid Tumors(RECIST) 1.1 (National Cancer Institute of Canada, ON, Canada criteria)
2. Progression-free survival (PFS) duration from the date of randomization to the date when disease progression was observed
3. Overall survival (OS) date of initiation of study medication (MB-6 or placebo) until the date of patient death, due to any cause
4. Adverse effects (AE) classified according to System Organ Class and Preferred Term via the MedDRA(McLean, VA, USA) coding dictionary and the severity of AE was graded according to Common Terminology Criteria for Adverse Events(NCI CTCAE) 3.0
Matsuda, 201539) B: second cycle of chemotherapy + placebo(The placebo formulation matched the texture, flavor, and other characteristics of the active drug. dissolve 2.5 g of placbeo in 50 ml of drinking water, divided it into twice or three times in an oral cavity, rinsed their oral cavity with it three times daily) 1. chemotherapy-induced oral mucositis (COM) incidence and its severity using WHO oral mucositis scale
2. duration of grade≥2 oral mucositis
3. hematological and biochemical toxicities observed during treatment
4. nonhematological toxicities observed during the projected treatment
Oki, 201540) B: modified FOLFOX6 (oxaliplatin/5-flurouracil/leucovorin) +placebo (identical to Goshajinkigan, 12-course mFOLFOX6 regimen with placebo at 7.5 g/day, from the first day of mFOLFOX6 therapy continued to be administered orally before meals or between meals on a daily basis until the end of the 12 courses, The placebo was prepared and stored by Yamato Logistics (Tokyo, Japan)) 1. primary neuropathy assessment using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE;version 3.0) and the Neurotoxicity Criteria of Debiopharm (DEB-NTC)
2. time to neuropathy(TTN) comparison using Kaplan-Meier survival curves, log-rank testing and Cox proportional hazards model analysis
3. hematologic and nonhematologic adverse events
4. dose intensity of oxaliplatin until the onset of grade 2 or greater peripheral neuropathy
Katsuno, 201541) B: placebo (Daikenchuto(DKT)and placebo were manufactured by Tsumura & Co. (Tokyo, Japan) and patients were received either oral doses of 15 g/day (5g t.i.d) of DKT or placebo.) 1. time to first bowel movement (BM) after endotracheal tube removal compared using the Cox proportional hazards model
2. changes in Bristol stool scale (BSS) scores
3. changes in the frequency of bowel movement (BM)
4. time to normalization of stool evacuation post-operatively (BSS score 3–5)
5. frequency of hard stools (BSS score 1–2) per day post-operatively
6. quality of life(QOL) by Gastrointestinal Symptom Rating Scale(GSRS, Japanese version) and Functional Assessment of Cancer Therapy-Colorectal (FACT-C) scale
7. serum C-reactive protein (CRP) levels
8. incidence of intestinal obstruction
9. Adverse events(AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 3.0)
Fei, 201842) A: placebo-treated group(patients who did not receive chemotherapy of any kind during the next two years of survival)
C: two-hour intravenous infusion of 5mg/kg bevacizumab(Avastin®), twice in a week for 12 weeks		 1. pathological parameters
 (1) carbohydrate antigen 19-9 (CA19-9)
  (2) carcinoembryonic antigen (CEA)
  (3) matrix metalloproteinases-2(MMP-2)
  (4) matrix metalloproteinase-9(MMP-9)
2. cancer-free survival (CFS)
3. overall survival (OS)
4. non-fatal and fatal adverse events
5. recurrence of colon cancer followed Response Evaluation Criteria In Solid Tumors(RECIST) guidelines
6. treatment costs
Zhou, 200943) B: OLF protocol (Oxaliplatin (L-OHP) +leukovorin(LV)+5-fluorouracil(5-FU)) 1. main clinical symptoms graded by Guiding Principle of Clinical Research on New Drugs of TCM
2. tumor mass
3. quality of life (QOL) assessed by Karnofsky scores
4. carcino-embryonec antigen (CEA)
5. body weight (BW)
6. integral efficacy of treatment
7. survival rate
Xu, 201144) B: FOLFOX4(leucovorin calcium/5-fluorouracil/oxaliplatin) 1. efficacy evaluated by Response Evaluation Criteria in Solid Tumors(RECIST, Therasse et al., 2000)
2. quality of life(QOL) evaluated by Karnofsky Scale
3. toxicity graded according to WHO criteria (Miller et al., 1991)
Chien, 201645) B: no special drug during the interval of 2 times chemotherapy 1. meridian energy level
2. heart rate variability (HRV)
3. cancer-related symptoms evaluated by Common Terminology Criteria for Adverse Events (CTCAE) scale
4. quaity of life assessment by quality-of-life questionnaire with 12-Item Short Form Health Survey (SF12)