Accepted Manuscript Effect of DKT, a Traditional Japanese Herbal Medicine, after Total Gastrectomy for Gastric Cancer: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase II Trial Kozo Yoshikawa, MD, FACS, Mitsuo Shimada, MD, FACS, Go Wakabayashi, MD, FACS, Koichiro Ishida, MD, Takashi Kaiho, MD, Yuko Kitagawa, MD, FACS, Junichi Sakamoto, MD, FACS, Norio Shiraishi, MD, Keisuke Koeda, MD, Erito Mochiki, MD, FACS, Yoshiro Saikawa, MD, Kazuya Yamaguchi, MD, Masayuki Watanabe, MD, FACS, Satoshi Morita, MD, Seigo Kitano, MD, FACS, Shigetoyo Saji, MD, Takashi Kanematsu, MD, FACS, Masaki Kitajima, MD, FACS(Hon) PII:

S1072-7515(15)00196-9

DOI:

10.1016/j.jamcollsurg.2015.03.004

Reference:

ACS 7825

To appear in:

Journal of the American College of Surgeons

Received Date: 2 January 2015 Revised Date:

28 February 2015

Accepted Date: 9 March 2015

Please cite this article as: Yoshikawa K, Shimada M, Wakabayashi G, Ishida K, Kaiho T, Kitagawa Y, Sakamoto J, Shiraishi N, Koeda K, Mochiki E, Saikawa Y, Yamaguchi K, Watanabe M, Morita S, Kitano S, Saji S, Kanematsu T, Kitajima M, Effect of DKT, a Traditional Japanese Herbal Medicine, after Total Gastrectomy for Gastric Cancer: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase II Trial, Journal of the American College of Surgeons (2015), doi: 10.1016/j.jamcollsurg.2015.03.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Yoshikawa K, et al. Effect of DKT, a Traditional Japanese Herbal Medicine, after Total Gastrectomy for Gastric Cancer: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase II

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Trial

Kozo Yoshikawa, MD, FACS1, Mitsuo Shimada, MD, FACS1, Go Wakabayashi, MD, FACS2, Koichiro Ishida, MD3, Takashi Kaiho, MD4, Yuko Kitagawa, MD, FACS5, Junichi Sakamoto, MD, FACS6, Norio Shiraishi, MD7, Keisuke Koeda, MD8, Erito Mochiki, MD, FACS9, Yoshiro

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Saikawa, MD10, Kazuya Yamaguchi, MD11, Masayuki Watanabe, MD, FACS12, Satoshi Morita, MD13, Seigo Kitano, MD, FACS14, Shigetoyo Saji, MD15, Takashi Kanematsu, MD, FACS16,

1

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Masaki Kitajima, MD, FACS(Hon)17

Department of Surgery, Tokushima University, Tokushima, Japan.

2

Department of Surgery, Iwate Medical University, School of Medicine, Morioka, Japan

3

Department of Surgery, National Hospital Organization Osaka Minami Medical Center, Osaka,

Japan Kimitsu Hospital Chiba Japan

5

Department of Surgery Keio University, School of Medicine, Tokyo, Japan

6

Tokai Central Hospital, Kakamigahara, Japan

7

Department of Surgery, Center for Community Medicine, Faculty of Medicine, Oita University,

Oita, Japan

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Department of Surgery, Iwate Medical University, School of Medicine, Morioka, Japan

9

Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical

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University, Saitama, Japan 10 11

Department of Surgery, School of Medicine, Keio University, Tokyo, Japan

Department of Surgical Oncology, Gifu University School of Medicine, Gifu, Japan

12

Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for

Cancer Research, Tokyo, Japan 13

Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of -1-

ACCEPTED MANUSCRIPT Yoshikawa K, et al. Medicine, Kyoto, Japan Oita University, Oita, Japan

15

Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, Japan

16

Nagasaki City Hospital Organization, Nagasaki, Japan

17

International University of Health and Welfare, Tokyo, Japan

Disclosure Information:

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Disclosures outside the scope of this work: Drs Yoshikawa and Shimada received a grant from Tsumura; Dr Kitagawa received a grant and payment for lectures from Tsumura.

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Support: This work was supported by the Japanese Foundation for Multidisciplinary Treatment of Cancer.

The investigators in JFMC42-1002 group are listed in Appendix 1.

Kozo Yoshikawa, M.D.

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Correspondence address:

Department of Surgery, Tokushima University,

3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.

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Phone: +81-88-633-9276 Fax: +81-88-631-9698

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E-mail: [email protected]

Running title: Effect of DKT after Gastrectomy Key words: DKT, Bowel movement, Total gastrectomy

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ACCEPTED MANUSCRIPT Yoshikawa K, et al. ABSTRACT: Background DKT has widely been used to improve abdominal symptoms by being expected to accelerate

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bowel motility. The purpose of this study is to examine the efficacy and safety of Daikenchuto (DKT) for prevention of ileus and associated gastrointestinal symptoms after total gastrectomy. Study Design

245 gastric cancer patients who underwent total gastrectomy were enrolled. Patients received

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either DKT (15.0 g/day) or matching placebo from postoperative day (POD) 1 to POD12.

Primary endpoints were time to first flatus, time to first bowel movement (BM), and frequency

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of BM. Secondary endpoints included quality of life, C reactive protein level, symptoms indicative of a severe gastrointestinal disorderand the incidence of postoperative ileus. Results

A total of 195 patients (DKT, n=96; placebo, n=99) were included in the per-protocol set analysis. There were no significant differences between the groups in terms of patient background

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characteristics. The median time to first BM was shorter in the DKT group than in the placebo group [94.7 h vs. 113.9 h p=0.051]. In patients with high medication adherence, the median time to first BM was significantly shorter in the DKT group than in the placebo group [93.8 h vs. 115.1 h; p=0.014]. Significantly fewer patients in the DKT group had two or more symptoms of

Conclusion

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gastrointestinal dysfunction than those in the placebo group on POD12 (p =0.026).

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DKT administration during the immediate postoperative period after total gastrectomy appears to promote early recovery of postoperative bowel function.

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ACCEPTED MANUSCRIPT Yoshikawa K, et al. ABBREVIATIONS: DKT: Daikenchuto JFMC: Japanese Foundation for Multidisciplinary Treatment of Cancer CRP: C-reactive protein CGRP: calcitonin gene-related peptide VIP: vasoactive intestinal polypeptide AUC: area under curve SD: standard deviation CRLR: calcitonin receptor like receptor Ramp1: receptor activity modifying protein 1

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ADM : adrenomedullin

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COX-2: cyclooxygenase-2

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ACCEPTED MANUSCRIPT Yoshikawa K, et al. INTRODUCTION: Disturbance of bowel movement and paralytic ileus are common complications of abdominal surgery. These sequelae aggravate nutritional deficiencies and increase postoperative

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morbidity, sometimes leading to general dysfunction and often prolonging hospital stay. Daikenchuto (DKT) is a traditional Japanese herbal medicine composed of four crude drugs: dried Japanese pepper, processed ginger, ginseng radix, and maltose powder. DKT is traditionally used in the treatment of chronic gastrointestinal disorders, and it is often prescribed

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to relieve abdominal pain, abdominal distention, Crohn’s disease, irritable bowel syndrome, adhesive ileus, and paralytic ileus 1-7). Although the effects of DKT on gastrointestinal motility

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have not yet been fully explored, recent studies have reported that it also has various different effects. These include: anti-inflammatory properties through the selective inhibition of cyclooxygenase-2 (COX-2) 8) and/or down-regulation of several inflammatory mediators such as tumor necrosis factor-α, interleukin-1b and endothelin-1; prevention of bacterial translocation 9,10)

; and increased gastrointestinal blood flow through the induction of calcitonin gene-related

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peptide (CGRP), substance P, and vasoactive intestinal polypeptide (VIP) 11,12). Several investigators have reported that DKT improves gastrointestinal motility after abdominal digestive surgery. After colorectal surgery, DKT improved postoperative bowel mobility, stimulated bowel movement, and shortened hospital stays 13). In addition, DKT

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increased intestinal motility and decreased postoperative symptoms after total gastrectomy with jejunal pouch interposition 14). However, no multi-center randomized controlled trials have yet

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evaluated the role of DKT after total gastrectomy. Kampo preparations differ from all other herbal medicines because they are

pharmaceutical-grade extract granules, which are manufactured under stringent quality control criteria in Japan, and are comparable to Western pharmaceuticals in terms of their quality and therapeutic strength 15,16). Of the 130+ preparations available, DKT, which is manufactured by Tsumura & Co. (Tokyo, Japan), has been approved by the U.S. Food and Drug Administration as an investigational drug, and several placebo-controlled double-blind trials have been launched in the U.S. to investigate its use for constipation (NCT01139216, NCT01348152) and Crohn’s -5-

ACCEPTED MANUSCRIPT Yoshikawa K, et al. disease (NCT01388933). For instance, a recent randomized controlled trial (NCT00871325) conducted at the Mayo Clinic showed that DKT significantly increased intestinal motility in healthy subjects 17).

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Therefore, we conducted this multi-center randomized controlled trial in order to determine the efficacy of DKT in treating gastrointestinal disorders in patients undergoing total gastrectomy for gastric cancer.

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METHODS:

The protocol was approved by the institutional review board of each participating

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hospital and this trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000004693. Written informed consent was obtained from all patients.

All members of the steering committee and the sponsor jointly designed the trial and collected the data, which were held by the independent Japanese Foundation for

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Multidisciplinary Treatment of Cancer (JFMC) 42-1002 data center. The data were analyzed by the independent data and safety monitoring committee.

Randomized study

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The patients were randomized before operation and Japanese foundation for

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multidisciplinary treatment of cancer performed the randomization.

Patient selection

Eligible patients had gastric cancer and: 1) were planning open total gastrectomy with

Roux-en-Y reconstruction; 2) had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1; 3) were capable of orally taking test reagents; 4) were aged from 20 to 85; 5) had sufficient function of vital organs (including bone marrow, heart, liver, kidneys, and lungs); 6) were in an adequate general condition to undergo total gastrectomy; 7) were inpatients during the study period; and 9) provided written informed consent. -6-

ACCEPTED MANUSCRIPT Yoshikawa K, et al. Patients whose medical histories included any of the following were excluded: previous laparotomy (except appendectomy); previous intestinal resection; ulcerative colitis or Crohn’s disease; emergency operation; a diagnosis of cancer prior to the current gastric

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carcinoma; chemotherapy in the 4 weeks before surgery or during the trial period; and intake of other kampo medicines in the 4 weeks before surgery. Patients who were pregnant or possibly pregnant and those who had synchronous cancers were also excluded.

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Study design and treatment

This multi-center, placebo-controlled, double-blind, randomized, phase II trial of DKT

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versus placebo in patients undergoing total gastrectomy for gastric cancer was conducted at 40 institutions in Japan. DKT and a matching placebo were manufactured by Tsumura & Co. (Tokyo, Japan). The placebo was consisted of dextrin, lactose and various food additives. The placebo formulation matched the texture and other characteristics of the active drug. Patients who met all of the eligibility criteria and none of the exclusion criteria were allocated at random to receive

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oral doses of 15 g/day (5 g three times a day) of either of DKT or placebo from postoperative day (POD) 1 or 2 to 12. DKT was administered by oral or nasogastric tube. The primary end points included time from the end of operation (tracheal tube extubation) until first flatus and defecation, and frequency of defecation per day after surgery.

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The secondary end points were: evaluation of quality of life (QOL) according to the Gastrointestinal Symptom Rating Scale (GSRS, Japanese Version) and Functional Assessment of

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Cancer Therapy – Gastric FACT-Ga; serum C-reactive protein (CRP) levels; presence or absence of severe postoperative bowel movement disorder; presence or absence of postoperative ileus. Adverse events were defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0).

Statistical analysis We determined the difference between the DKT and placebo groups in terms of time from tracheal tube removal until first flatus and defecation. We assumed the mean (SD) of the -7-

ACCEPTED MANUSCRIPT Yoshikawa K, et al. time from extubation until first flatus and defecation in the placebo group to be 2.5 (2.5) days and that DKT would shorten this time by 25%. On the basis of these assumptions, we needed 115 patients per group (230 patients in total) to provide 93.8% power to detect a difference at the 5%

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level of significance in a two-sided test. Accounting for possible dropouts and the considerable uncertainty in the assumption for sample size calculation), the sample size was set at 120 per treatment arm (240 patients in total).

Baseline characteristics were compared between the two groups with the chi-square

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test or Fisher’s exact test. The time from extubation until first flatus and defecation was analyzed using the Wilcoxon test. Calculated parameters are presented as means ± SD. P values of less

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than 0.05 were considered to indicate statistical significance. All statistical analysis was performed using SAS Release 9.2 (SAS Institute, Cary, NC). Monitoring the data

All data was collected the Japanese foundation for multidisciplinary treatment of

RESULTS:

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cancer and query was performed all data.

Characteristics of the patients

We enrolled 245 patients who were scheduled to undergo total gastrectomy for gastric

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cancer at 40 Japanese centers from January 2011 to December 2012. They were assigned at random to a DKT group (n=121) and a placebo group (n=124). After randomization, 38 patients

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(19 in the DKT group and 19 in the placebo group) were found to be ineligible. The reasons for their exclusion were as follows: 22 did not undergo open total gastrectomy (distal gastrectomy etc.), one did not have surgery, three had undergone a previous laparotomy, seven had another intestinal resection at the time of gastrectomy, one received chemotherapy in the preceding 4 weeks, and four withdrew consent. A further 12 patients were not treated for the following reasons: declined treatment (n=1), anastomotic leakage (n=1), difficulty of oral intake (n=1), liver functional disorder (n=1), doctor’s judgment (n=7) and one patient start DKT at 3 POD. Therefore, 195 patients (DKT group: n=96, placebo group: n=99) were included and evaluated in -8-

ACCEPTED MANUSCRIPT Yoshikawa K, et al. the statistical analysis (Fig.1). No significant differences were observed between the two groups in terms of baseline characteristics (general factors, surgical factors, and tumor factors), as shown in Table 1.

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Adverse events and treatment compliance Data from 96 patients in the DKT group and 99 in the placebo group were analyzed for adverse events. In the DKT group, six adverse events of ≥grade 3 occurred: two cases of diarrhea, one of anorexia, one of hypoalbuminemia, one of nausea, and one of elevated amylase level. In

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the placebo group, three adverse events of ≥grade 3 occurred: one of diarrhea, one of dysphagia, and one of nausea. There was no significant difference in the frequency of adverse events of

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≥grade 3 between the two groups, and the safety monitoring committee has judged there to be no causal relationship between these adverse events and test reagents. Therefore, we can state that no DKT-related serious adverse events occurred during the study.

Regarding treatment compliance, 23 of 96 patients (23.9%) in the DKT group and 14 of 99 patients (14.1%) in the placebo group could not complete the study period. The reasons are

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worsen of general condition (n=2), adverse event (n=3), complication (n=4), doctor’s judgment (n=3), rejection of treatment (n=9) and early discharge (n=2) in DKT group and worsen of general condition (n=1), adverse event (n=1), complication (n=4), rejection of treatment (n=5), early discharge (n=2) and unknown (n=2) in placebo group. Mean total doses of reagent did not

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differ significantly between the two groups: 144.51±47.99 g in the DKT group and 150.07±45.41 g in the placebo group.

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The administered route

DKT was administered by nasogastric tube in 14 patients (DKT group) and 16 patients

(placebo group).

Surgical complication

Surgical complications were occurred in 21 patients (21.9%) in DKT group, 30 patients (30.3%) in placebo group. There was no significant difference in frequency of surgical complication between two groups. In detail, anastomotic leakage was occurred in 8 patients (DKT groups) and 3 patients (placebo groups). And abdominal abscess was occurred in one -9-

ACCEPTED MANUSCRIPT Yoshikawa K, et al. patient individually. Post-operative pneumonia was occurred in 2 patients (DKT groups) and 7 patients (placebo groups). Primary and secondary endpoints

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The median time from extubation until first flatus was 68.9h (9.1–234.5) in the DKT group and 68.3 h (1.1–259.8) in the placebo group (p=0.95), and the median time from

extubation until first defecation was 94.7 h (22.8–257.5) in the DKT group and 113.9 h

(27.7–284.3) in the placebo group (p=0.05) (Figure 2A). This demonstrates that DKT accelerated

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bowel movement.

Regarding the secondary endpoints, neither QOL scores (GSRS and FACT-Ga) nor

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serum CRP levels, differed between the two groups. On the other hand, the incidence of bowel movement disorder was significantly lower in the DKT group at 12 POD (p=0.05) (Figure 2B). There was no significant difference between the two groups in the presence or absence of postoperative ileus (three patients in the DKT group, two patients in the control group) or in

Subgroup analysis

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postoperative hospital stay.

Times from extubation until first flatus and defecation were analyzed according to various factors. Time to defecation was significantly shorter in the DKT group than in the control

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group for patients with less than D2 lymph node dissection (DKT: n=35, 90.0 h vs. Placebo: n=31, 108.8 h, P=0.02) (Figure 3A), cumulative DKT intake of greater than 125 g (DKT: n=72,

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94.2 h vs. Placebo: n=83, 115.1 h, P=0.01) (Figure 3B),

DISCUSSION:

This multi-center, randomized, double-blind, placebo-controlled, phase II trial provides

the first evidence that DKT accelerates the time to first bowel movement after total gastrectomy in patients with gastric cancer.

To date, no large-scale trials (>100 patients) have compared use

of DKT with placebo control for patients undergoing abdominal surgery. Among human studies of DKT 12-15,17-22), only three randomized controlled trials have been performed, mainly to - 10 -

ACCEPTED MANUSCRIPT Yoshikawa K, et al. evaluate the effect on intestinal motility. First, Ito et al. showed that, for 24 patients with postoperative ileus after abdominal surgery, oral administration of DKT was not associated with adverse effects, as a non-invasive agent for the treatment of this complication 21). Manabe et al.

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undertook validated scintigraphic assessments of gastric, small bowel, and colonic transit in healthy subjects, and revealed that DKT had a clinically significant pro-motility effect on small bowel and ascending colon transit 17). Most recently, Yoshikawa et al. demonstrated that

postoperative DKT administration significantly shortened the time until first flatus following

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laparoscopic colorectal resection, and that it suppressed postoperative inflammatory response (measured by the CRP level) 22).

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A higher cumulative dose (total 125g or more) of DKT resulted in a positive effect on bowel motility. This suggests that consistent and adequate length of DKT treatment is needed to accelerate bowel motility. In the early post-operative period, there was no significant difference between the two groups. However, after 12 POD, DKT improved gastrointestinal function. Endo et al. also showed that high dosage of DKT (15g/d) for 2weeks improved gastric stasis patients DKT in the gastric lumen

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with total gastrectomy and jejunal pouch interposition 23).

stimulates enteric neurons to release the neurotransmitter acetylcholine (ACh) through a neural reflex involving presynaptic cholinergic receptors and 5-hydroxytryptamine (serotonin) 5-HT3 receptors 24). Moreover, DKT increases the plasma levels of vasoactive intestinal polypeptide

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(VIP) 25), motilin 12, 26), and calcitonin gene-related peptide (CGRP) and substance P 11, 12). As enrolled patients were underwent the total gastrectomy and absorption via stomach was lacked in

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this study, the elevation of the DKT concentration may delayed. Pharmacokinetics of DKT should be analyzed.

In advanced gastric cancer, gastrectomy with D2 lymph node dissection is standard

treatment in Japan. On the other hand, more restricted lymph node dissection (D1, D1+) is adopted for early gastric cancer. Wider lymph node dissection requires the extended dissection of tissue around the stomach including the nerve. In this study, DKT reduced time to first flatus in patients with less than D2 lymph node dissection, suggesting that DKT has a more positive effect in patients with less invasive surgery. These results suggested that the effect of the DKT was - 11 -

ACCEPTED MANUSCRIPT Yoshikawa K, et al. diminished by adhesion and nerve injury. Total 50 patients were dropped out in this study and 22 patients was not underwent total gastrectomy. At first, in advanced gastric cancer, abdominal dissemination was often

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observed, in such case, limited gastrectomy was performed. At second, as extent of gastric cancer was occasionally not cleared. if the tumor was limited in two-third of the stomach, total

gastrectomy was not performed. As the result, these patients were dropped out in this study. This study showed that DKT accelerated the bowel movement after total gastrectomy,

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but these effects were diminished in patient with epidural anesthesia, nerve injury and wider lymph node dissection. These results suggested that the patients with no epidural anesthesia

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because of using anticoagulant agent should take DKT and adhesion barrier to improve the bowel movement and ileus.

In conclusion, DKT appears to rapidly and significantly improve gastrointestinal dysmotility. Our findings suggest that DKT is an effective treatment option after total

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gastrectomy.

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ACCEPTED MANUSCRIPT Yoshikawa K, et al.

Appendix: Members of a multicenter, randomized, double-blind, placebo-controlled phase II trial (JFMC42-1002) group were as follows:

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Steering Committee: Seigo Kitano, Yuko Kitagawa, Junichi Sakamoto, Norio Shiraishi,

Keisuke Koeda, Erito Mochiki, Yoshiro Saikawa, Kazuya Yamaguchi, Masayuki Watanabe Medical Advisor: Masaki Kitajima, Takashi Kanematsu, Shigetoyo Saji

Independent Data and Safety Monitoring Committee: Hitoshi Katai, Naoki Hiki

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Statistical Analyst: Satoshi Morita

Principal Investigators (all in Japan): K. Ogasawara, G. Wakabayashi, C. Shibata, S.

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Takenoshita, M, Okumura, Y. Suzuki, K. Ogata, H. Ishida, T. Kaiho, K. Yanaga, H. Shimada, Y. Kitagawa, M. Matsuda, M. Yoshida, N. Katada, R. Shimoyama, K. Tsukada, S. Ushijima, K. Yoshida, M. Yamada, E. Otusji, Y. Fujiwara, K. Fujitani, K. Uchiyama, K. Ishida, N. Hirabayashi, M. Shimada, M. Kobayashi, K. Kanetaka, Y. Kawashita, A. Togashi, H. Baba, H.

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Takamori, K. Fukuzawa, H. Anai, K. Fujii, H. Orita, S. Kitano, N. Kubo, S. Natsugoe

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ACCEPTED MANUSCRIPT Yoshikawa K, et al. REFERENCES: 1.

Satoh K, Hayakawa T, Kase Y, et al. Mechanisms for Contractile Effect of Dai-kenchu-to in Isolated Guinea Pig Ileum. Dig Dis Sci2001; 46: 250-6. Sakakibara R, Odaka T, Lui Z, et al. Dietary herb extract dai-kenchu-to ameliorates

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2.

constipation in parkinsonian patients (Parkinson's disease and multiple system atrophy). Mov Disord 2005; 20: 261-2.

Ohya T, Usui Y, Arii S, et al. Effect of dai-kenchu-to on obstructive bowel disease in children. Am J Chin Med 2003; 31: 129-35.

4.

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3.

Iwai N, Kume Y, Kimura O, et al. Effects of herbal medicine Dai-Kenchu-to on anorectal

5.

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function in children with severe constipation. Eur J Pediatr Surg. 2007; 17: 115-8. Nakamura T, Sakai A, Isogami I, et al. Abatement of Morphine-Induced Slowing in Gastrointestinal Transit by Dai-kenchu-to, a Traditional Japanese Herbal Medicine. Jpn J Pharmacol 2002; 88: 217-21. 6.

Furukawa Y, Hanyu N, Nakada K, et al. Effects of the Chinese herb medicine

1999; 116: 811. 7.

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“Dai-kenchu-to” on GI motility and for treatment of bowel obstruction. Gastroenterology

Satoh K, Kase Y, Yuzurihara M, et al. Effect of Dai-kenchu-to (Da-Jian-Zhong-Tang) on the

86: 37-44. 8.

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delayed intestinal propulsion induced by chlorpromazine in mice. J Ethnopharmacol 2003;

Hayakawa T, Kase Y, Saito K, et al. Effects of Dai-kenchu-to on intestinal obstruction

9.

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following laparotomy. J Smooth Muscle Res 1999; 35: 47-54. Yoshikawa K, Kurita N, Higashijima J, et al. Kampo medicine "Dai-kenchu-to" prevents bacterial translocation in rats. Dig Dis Sci 2008; 53: 1824-31. 10. Chikakiyo M, Shimada M, Nakao T, et al. Kampo medicine "Dai-kenchu-to" prevents CPT-11-induced small-intestinal injury in rats. Surg Today 2012; 42: 60-7. 11. Sato Y, Katagiri F, Inoue S, et al. Dai-kenchu-to raises levels of calcitonin gene-related peptide and substance P in human plasma. Biol Pharm Bull 2004; 27: 1875-7. 12. Sato Y, Inoue S, Katagiri F, et al. Effects of pirenzepine on Dai-kenchu-to-induced elevation - 14 -

ACCEPTED MANUSCRIPT Yoshikawa K, et al. of the plasma neuropeptide levels in humans. Biol Pharm Bull 2006; 29: 166-71. 13. Suehiro T, Matsumata T, Shikada Y, et al. The effect of the herbal medicines dai-kenchu-to and keishi-bukuryo-gan on bowel movement after colorectal surgery.

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Hepatogastroenterology 2005; 52: 97-100. 14. Endo S, Nishida T, Nishikawa K, et al. Dai-kenchu-to, a Chinese herbal medicine, improves stasis of patients with total gastrectomy and jejunal pouch interposition. Am J Surg 2006; 192: 9-13.

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15. Kaiho T, Tanaka T, Tsuchiya S, et al. Effect of the herbal medicine Dai-kenchu-to on serum ammonia in hepatectomized patients. Hepatogastroenterology 2005; 52: 161-5.

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16. Kono T, Kanematsu T, Kitajima M. Exodus of Kampo, traditional Japanese medicine, from the complementary and alternative medicines: is it time yet? Surgery 2009; 146: 837-40 17. Manabe N, Camilleri M, Rao A, et al. Effect of daikenchuto (TU-100) on gastrointestinal and colonic transit in humans. Am J Physiol Gastrointest Liver Physiol. 2010; 298: G970-5. 18. Sato Y, Katagiri F, Inoue S, et al. Daikenchu-to raises levels of calcitonin gene-related

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peptide and substance P in human plasma. Biol Pharm Bull 2004; 27: 1875-7. 19. Ohya T, Usui Y, Arii S, et al. Effect of dai-kenchu-to on obstructive bowel disease in children. Am J Chin Med 2003; 31: 129-35. 20. Iwai N, Kume Y, Kimura O, et al. Effects of herbal medicine Dai-Kenchu- to on anorectal

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function in children with severe constipation. Eur J Pediatr Surg 2007; 17: 115-8. 21. Itoh T, Yamakawa J, Mai M, et al. The effect of the herbal medicine daikenchu- to on

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post-operative ileus. J Int Med Res 2002; 30: 428-32. 22. Yoshikawa K, Shimada M, Nishioka M, et al. The effects of the Kampo medicine (Japanese herbal medicine) "Daikenchuto" on the surgical inflammatory response following laparoscopic colorectal resection. Surg Today 2012; 42: 646-51. 23. Endo S, Nishida T, Nishikawa K, et al. Dai-kenchu-to, a Chinese herbal medicine, improves stasis of patients with total gastrectomy and jejunal pouch interposition. Am J Surg. 2006; 192:9-13. 24. Shibata C, Sasaki I, Naito H, et al. The herbal medicine Dai-Kenchu-Tou stimulates upper - 15 -

ACCEPTED MANUSCRIPT Yoshikawa K, et al. gut motility through cholinergic and 5-hydroxytryptamine 3 receptors in conscious dogs. Surgery 1999;126:918–24. 25. Nagano T, Itoh H, Takeyama M. Effects of Dai-kenchu-to on levels of 5-hydroxytryptamine

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(serotonin) and vasoactive intestinal peptides in human plasma. Biol Pharm Bull 2000; 23: 352-3.

26. Nagano T, Itoh H, Takeyama M. Effect of Dai-kenchu-to on levels of 3 brain-gut peptides

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(motilin, gastrin and somatostatin) in human plasma. Biol Pharm Bull 1999; 22: 1131-3.

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ACCEPTED MANUSCRIPT Yoshikawa K, et al. Table 1. Baseline Characteristics of the Patients Placebo group (n=99)

73 (76.0) 23 (24.0)

76 (76.8) 23 (23.2)

9 (9.4) 13 (13.5) 39 (40.6) 27 (28.1) 8 (8.3) 68 (33-83)

6 (6.1) 21 (21.2) 29 (29.3) 35 (35.4) 8 (8.1) 67 (28-84)

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p Value

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0.905

90 (93.8) 6 (6.3)

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0.697

0.535 1.000

93 (93.9) 6 (6.1)

63 (65.6) 33 (34.4)

63 (63.6) 36 (36.4)

80 (83.3) 16 (16.7)

88 (88.9) 11 (11.1)

9(9.4) 27 (28.1) 29 (30.2) 31 (32.3) 323 (154-507)

16 (16.2) 23 (23.2) 30 (30.3) 30 (30.3) 318 (174-644)

85 (88.5) 11 (11.5)

90 (90.9) 9 (9.1)

36 (37.5) 22 (22.9) 13 (13.5) 25 (26.0) 258.5 (112-466)

40 (40.4) 16 (16.2) 16 (16.2) 27 (27.3) 255 (130-589)

27 (28.1) 20 (20.8) 22 (22.9) 27 (28.1) 364.5 (10-1558)

45 (45.5) 15 (15.2) 14 (14.1) 25 (25.3) 270 (10-1200)

55 (57.3) 41 (42.7)

47 (47.5) 52 (52.5)

36 (37.5) 60 (62.5)

32 (32.3) 67 (67.7)

TE D

General factors Sex, n (%) Male Female Age, y, n (%)