Accepted Manuscript Preoperative vs Postoperative Eradication of Helicobacter pylori in 150 Patients with Gastric Cancer: A Randomized Controlled Trial Michitaka Honda, MD PhD, Naoki Hiki, MD, PhD, Souya Nunobe, MD, PhD, Manabu Ohashi, MD, PhD, Koshi Kumagai, MD, PhD, Yoshikazu Hashimoto, MD, Shinji Mine, MD, Satoshi Kamiya, MD, Takeshi Sano, MD, PhD, Toshiharu Yamaguchi, MD, PhD PII:
S1072-7515(15)00274-4
DOI:
10.1016/j.jamcollsurg.2015.03.052
Reference:
ACS 7874
To appear in:
Journal of the American College of Surgeons
Received Date: 31 January 2015 Revised Date:
9 March 2015
Accepted Date: 26 March 2015
Please cite this article as: Honda M, Hiki N, Nunobe S, Ohashi M, Kumagai K, Hashimoto Y, Mine S, Kamiya S, Sano T, Yamaguchi T, Preoperative vs Postoperative Eradication of Helicobacter pylori in 150 Patients with Gastric Cancer: A Randomized Controlled Trial, Journal of the American College of Surgeons (2015), doi: 10.1016/j.jamcollsurg.2015.03.052. 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
Preoperative vs Postoperative Eradication of Helicobacter pylori in 150 Patients with Gastric Cancer: A Randomized Controlled Trial
RI PT
Michitaka Honda, MD PhD1, Naoki Hiki, MD, PhD1, Souya Nunobe, MD, PhD 1, Manabu
Ohashi, MD, PhD1, Koshi Kumagai, MD, PhD1, Yoshikazu Hashimoto, MD2, Shinji Mine, MD1,
SC
Satoshi Kamiya, MD1, Takeshi Sano, MD, PhD1, Toshiharu Yamaguchi, MD, PhD1
1. Department of Gastroenterological Surgery, Gastroenterological Center, Cancer Institute
M AN U
Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
2. Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan
Correspondence address:
TE D
Naoki Hiki, Department of Gastroenterological Surgery, Gastroenterological Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan. Phone: 81-3-3520-0111. FAX: 81-3-3520-0141
EP
email: [email protected]
AC C
Disclosures: Nothing to disclose.
Short title: Eradicating Helicobacter pylori Perioperatively
1
ACCEPTED MANUSCRIPT
BACKGROUND: The Maastricht, Asia-Pacific consensus guidelines strongly recommend eradication of Helicobacter pylori in patients who have a history of gastric cancer. This
RI PT
open-label, single-center, randomized controlled trial was conducted to investigate the appropriate timing of eradication for patients undergoing gastrectomy.
STUDY DESIGN: One hundred fifty patients scheduled to undergo gastrectomy were allocated to either a “preoperative” and a “postoperative” group. The eradication regimen was a common
SC
triple therapy: lansoprazole, amoxicillin and clarithromycin. Patients in the preoperative group were treated with the regimen followed by surgery, whereas patients in the postoperative group
M AN U
were treated after postoperative day 8. The primary endpoint was the proportion of patients achieving successful eradication in the remnant stomach. The definition of successful eradication was negativity in both the C13 urea breath test and for the antigen in feces at 6 months after surgery.
TE D
RESULTS: Eight patients were excluded, and the remaining 142, 70 in the preoperative group and 72 in the postoperative group, were included on an intention to treat basis. The procedures employed were gastrectomy with Billroth I, Roux-en-Y, and pylorus-preserving gastrectomy in
EP
18, 70 and 57 patients, respectively. The proportion of patients showing successful eradication hardly differed between the two groups, 68.6% versus 69.4% (p=1.000) in the pre- and
AC C
postoperative groups, respectively. Subgroup analysis also demonstrated no significant difference among the reconstruction methods used. CONCLUSIONS: Preoperative H. pylori eradication therapy for gastric cancer patients scheduled for gastrectomy is not necessary, regardless of the planned reconstruction procedure.
2
ACCEPTED MANUSCRIPT
Helicobacter pylori infection is strongly associated with the incidence of gastric cancer1, and H. pylori eradication has been recommended for prevention of gastric cancer2-4. Because severe
RI PT
atrophy of the stomach mucosa caused by H. pylori infection is a high-risk factor for gastric cancer, eradication therapy should be ideally performed before such mucosal atrophy occurs. Furthermore, it is clear that patients who have a history of gastric cancer are at particularly high risk, and therefore eradication therapy is recommended if they are positive for H. pylori 5. Two
SC
previous randomized controlled trials (RCT) have proved that endoscopic resection for early gastric cancer is effective for prevention of new gastric carcinogenesis 6, 7, and that 12.5% of new
M AN U
gastric cancers arise in the upper third of the stomach. These results suggest that there is a certain risk of carcinogenesis in the remnant stomach in patients who have undergone subtotal gastrectomy. Accordingly, the Maastricht, Asia-Pacific consensus guidelines for gastric cancer prevention strongly recommend H. pylori eradication to prevent infection in the remnant
TE D
stomach in patients with a history of gastrectomy for gastric cancer8. With regard to the appropriate timing of H. pylori eradication, a previous RCT9 to evaluate whether eradication should be performed in before or after surgery found that there was
EP
no difference between the two groups in the proportion of patients showing successful eradication. This RCT included patients who underwent Billroth I reconstruction, although some
AC C
clinical studies have reported that the eradication rate decreased after gastrectomy for a number of reasons, such as a higher pH caused by reflux of bile to the remnant stomach, a reduced ability for gastric peristalsis, and impaired absorption in the small bowel10-13. It is presumed that these postoperative conditions would depend upon the type of surgical procedure or anastomosis employed, and thus have a strong influence on H. pylori eradication. Therefore, the present RCT was conducted to investigate the appropriate timing of eradication for patients scheduled to undergo Roux en Y (R-Y) reconstruction or pylorus-preserving gastrectomy (PPG). 3
ACCEPTED MANUSCRIPT
Preoperative H. pylori eradication has not been performed routinely at our institution so far. We conducted the present RCT of patients undergoing PPG or R-Y reconstruction for gastric
RI PT
cancer to verify the hypothesis that the proportion of patients achieving successful eradication would be higher for preoperative than for postoperative eradication. Our aim was to provide information for clinicians about treatment options regarding H. pylori eradication for gastric
SC
cancer patients.
Methods
M AN U
Study design
This study was an open-label, single-center, randomized controlled trial. The study protocol received approval from the institutional review board under the principles of the Declaration of Helsinki. All patients provided written informed consent to participate. This trial
TE D
was registered with the University Hospital Medical Information Network Clinical Trials Registry system (http://www.umin.ac.jp/ctr/index.htm): registration number 000002669. Inclusion criteria
EP
Eligible patients were those older than 20 years of age with a diagnosis of gastric adenocarcinoma confirmed by histological examination. Other inclusion criteria were as follows:
AC C
(1) planned R0 resection for gastric cancer, (2) planned distal gastrectomy or pylorus-preserving gastrectomy, (3) positivity for H. pylori infection by both the C13 urea breath test (UBT) and detection of serum antigen, (4) no history of eradication treatment, (5) no medication with proton pomp inhibitor before enrollment in the trial, and (6) ability to receive medications orally. Exclusion criteria The exclusion criteria were as follows: (1) severe liver or kidney dysfunction; an ALT level of
S1072-7515(15)00274-4
DOI:
10.1016/j.jamcollsurg.2015.03.052
Reference:
ACS 7874
To appear in:
Journal of the American College of Surgeons
Received Date: 31 January 2015 Revised Date:
9 March 2015
Accepted Date: 26 March 2015
Please cite this article as: Honda M, Hiki N, Nunobe S, Ohashi M, Kumagai K, Hashimoto Y, Mine S, Kamiya S, Sano T, Yamaguchi T, Preoperative vs Postoperative Eradication of Helicobacter pylori in 150 Patients with Gastric Cancer: A Randomized Controlled Trial, Journal of the American College of Surgeons (2015), doi: 10.1016/j.jamcollsurg.2015.03.052. 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
Preoperative vs Postoperative Eradication of Helicobacter pylori in 150 Patients with Gastric Cancer: A Randomized Controlled Trial
RI PT
Michitaka Honda, MD PhD1, Naoki Hiki, MD, PhD1, Souya Nunobe, MD, PhD 1, Manabu
Ohashi, MD, PhD1, Koshi Kumagai, MD, PhD1, Yoshikazu Hashimoto, MD2, Shinji Mine, MD1,
SC
Satoshi Kamiya, MD1, Takeshi Sano, MD, PhD1, Toshiharu Yamaguchi, MD, PhD1
1. Department of Gastroenterological Surgery, Gastroenterological Center, Cancer Institute
M AN U
Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
2. Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan
Correspondence address:
TE D
Naoki Hiki, Department of Gastroenterological Surgery, Gastroenterological Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan. Phone: 81-3-3520-0111. FAX: 81-3-3520-0141
EP
email: [email protected]
AC C
Disclosures: Nothing to disclose.
Short title: Eradicating Helicobacter pylori Perioperatively
1
ACCEPTED MANUSCRIPT
BACKGROUND: The Maastricht, Asia-Pacific consensus guidelines strongly recommend eradication of Helicobacter pylori in patients who have a history of gastric cancer. This
RI PT
open-label, single-center, randomized controlled trial was conducted to investigate the appropriate timing of eradication for patients undergoing gastrectomy.
STUDY DESIGN: One hundred fifty patients scheduled to undergo gastrectomy were allocated to either a “preoperative” and a “postoperative” group. The eradication regimen was a common
SC
triple therapy: lansoprazole, amoxicillin and clarithromycin. Patients in the preoperative group were treated with the regimen followed by surgery, whereas patients in the postoperative group
M AN U
were treated after postoperative day 8. The primary endpoint was the proportion of patients achieving successful eradication in the remnant stomach. The definition of successful eradication was negativity in both the C13 urea breath test and for the antigen in feces at 6 months after surgery.
TE D
RESULTS: Eight patients were excluded, and the remaining 142, 70 in the preoperative group and 72 in the postoperative group, were included on an intention to treat basis. The procedures employed were gastrectomy with Billroth I, Roux-en-Y, and pylorus-preserving gastrectomy in
EP
18, 70 and 57 patients, respectively. The proportion of patients showing successful eradication hardly differed between the two groups, 68.6% versus 69.4% (p=1.000) in the pre- and
AC C
postoperative groups, respectively. Subgroup analysis also demonstrated no significant difference among the reconstruction methods used. CONCLUSIONS: Preoperative H. pylori eradication therapy for gastric cancer patients scheduled for gastrectomy is not necessary, regardless of the planned reconstruction procedure.
2
ACCEPTED MANUSCRIPT
Helicobacter pylori infection is strongly associated with the incidence of gastric cancer1, and H. pylori eradication has been recommended for prevention of gastric cancer2-4. Because severe
RI PT
atrophy of the stomach mucosa caused by H. pylori infection is a high-risk factor for gastric cancer, eradication therapy should be ideally performed before such mucosal atrophy occurs. Furthermore, it is clear that patients who have a history of gastric cancer are at particularly high risk, and therefore eradication therapy is recommended if they are positive for H. pylori 5. Two
SC
previous randomized controlled trials (RCT) have proved that endoscopic resection for early gastric cancer is effective for prevention of new gastric carcinogenesis 6, 7, and that 12.5% of new
M AN U
gastric cancers arise in the upper third of the stomach. These results suggest that there is a certain risk of carcinogenesis in the remnant stomach in patients who have undergone subtotal gastrectomy. Accordingly, the Maastricht, Asia-Pacific consensus guidelines for gastric cancer prevention strongly recommend H. pylori eradication to prevent infection in the remnant
TE D
stomach in patients with a history of gastrectomy for gastric cancer8. With regard to the appropriate timing of H. pylori eradication, a previous RCT9 to evaluate whether eradication should be performed in before or after surgery found that there was
EP
no difference between the two groups in the proportion of patients showing successful eradication. This RCT included patients who underwent Billroth I reconstruction, although some
AC C
clinical studies have reported that the eradication rate decreased after gastrectomy for a number of reasons, such as a higher pH caused by reflux of bile to the remnant stomach, a reduced ability for gastric peristalsis, and impaired absorption in the small bowel10-13. It is presumed that these postoperative conditions would depend upon the type of surgical procedure or anastomosis employed, and thus have a strong influence on H. pylori eradication. Therefore, the present RCT was conducted to investigate the appropriate timing of eradication for patients scheduled to undergo Roux en Y (R-Y) reconstruction or pylorus-preserving gastrectomy (PPG). 3
ACCEPTED MANUSCRIPT
Preoperative H. pylori eradication has not been performed routinely at our institution so far. We conducted the present RCT of patients undergoing PPG or R-Y reconstruction for gastric
RI PT
cancer to verify the hypothesis that the proportion of patients achieving successful eradication would be higher for preoperative than for postoperative eradication. Our aim was to provide information for clinicians about treatment options regarding H. pylori eradication for gastric
SC
cancer patients.
Methods
M AN U
Study design
This study was an open-label, single-center, randomized controlled trial. The study protocol received approval from the institutional review board under the principles of the Declaration of Helsinki. All patients provided written informed consent to participate. This trial
TE D
was registered with the University Hospital Medical Information Network Clinical Trials Registry system (http://www.umin.ac.jp/ctr/index.htm): registration number 000002669. Inclusion criteria
EP
Eligible patients were those older than 20 years of age with a diagnosis of gastric adenocarcinoma confirmed by histological examination. Other inclusion criteria were as follows:
AC C
(1) planned R0 resection for gastric cancer, (2) planned distal gastrectomy or pylorus-preserving gastrectomy, (3) positivity for H. pylori infection by both the C13 urea breath test (UBT) and detection of serum antigen, (4) no history of eradication treatment, (5) no medication with proton pomp inhibitor before enrollment in the trial, and (6) ability to receive medications orally. Exclusion criteria The exclusion criteria were as follows: (1) severe liver or kidney dysfunction; an ALT level of
