Outcomes of ulcer healing after combination therapy and monotherapy
The primary outcomes of ulcer healing after combination therapy and monotherapy were the ulcer reduction rates at 4 weeks of treatment. As shown in Table 2, the ulcer reduction rate was significantly higher in the experimental group than that in the control group after 4 weeks of treatment (97% vs 94%, P < 0.001). The secondary outcomes were the healing rate, the improvement rate, ulcer area, maximum diameter, and perpendicular diameter after 4 weeks of treatment or 8 weeks of treatment, which were also summarized in Table 2. After 4 weeks of treatment, the experimental group showed a post-ESD ulcer healing rate of 18.2% and an improvement rate of 94.2% whereas the control group showed a post-ESD ulcer healing rate of 20.3% and an improvement rate of 88.7%. The healing rate and improvement rate of post-ESD ulcers did not show statistically significant differences between the 2 drug regimens (P > 0.05). Moreover, at 4 weeks of treatment, the differences between the experimental group and control group in terms of ulcer area (36.35 ± 51.36 mm2 vs 55.04 ± 67.56 mm2), maximum diameter (6.30 ± 5.04 mm vs 7.80 ± 5.96 mm), and perpendicular diameter (3.55 ± 3.18 mm vs 4.74 ± 3.64 mm) were statistically significant (P = 0.011, P = 0.027, P = 0.004, respectively). At 8 weeks, the ulcer healing rate in both groups was 90.6%, and the ulcer improvement rate in both groups was 100% (Table 2).
Subgroup analysis of factors influencing ulcer reduction post-ESD
Subgroup analysis was performed to investigate the factors affecting the efficacy of rebamipide plus lansoprazole for post-ESD ulcer reduction at 4 weeks (Table 3). For factors recorded as numerical data, the group's mean value was used to determine thresholds for age (60 years), BMI (23.22), initial ulcer area (1,084.45 mm2), initial maximum diameter (35.50 mm), and initial perpendicular diameter (27.29 mm) that defined 2 factor-based subgroups. For qualitative factors, patients were divided into subgroups based on existing categories or the presence or absence of the factor. The results indicated that the subgroup factors related to ulcer healing included patient age and BMI; initial ulcer area, maximum diameter, and perpendicular diameter; lesion site and pathological grade; and the presence of underlying disease or Hp infection.
Logistic regression analysis of factors influencing post-ESD ulcer reduction
Univariate and multivariate logistic regression models were used to analyze the factors influencing ulcer reduction at 4 weeks. The results are shown in Table 4. The dependent variable was a post-ESD ulcer reduction. Moreover, the mean ulcer reduction rate defines the cutoff value of the variable (≥95% vs <95%). The independent variables were the relevant variables determined by our subgroup analysis. Univariate analysis revealed that lesion site (gastric antrum vs others), patient sex, and the use of combination therapy (PPI + rebamipide vs PPI monotherapy) were associated with ulcer reduction. Multivariate analysis indicated that combination therapy (PPI + rebamipide vs PPI monotherapy) and lesion site (gastric antrum vs others) were independent factors associated with greater post-ESD ulcer reduction. The adjusted odds ratios (ORs) were 4.31 (2.51–7.39) and 0.47 (0.28–0.80), respectively.
Logistic regression analysis of factors influencing post-ESD ulcer healing
Univariate and multivariate logistic regression models were used to analyze the factors affecting post-ESD ulcer healing at 4 weeks. The results are shown in Table 5. The dependent variable was post-ESD ulcer healing. The independent variables were the relevant variables determined by our subgroup analysis. Our univariate analysis revealed that pathological grade (cancer + HIN vs LIN + others), initial ulcer area (≥1,084.45 mm2 vs <1,084.45 mm2), initial maximum diameter (≥35.5 mm vs <35.5 mm), and perpendicular diameter (≥27.29 mm vs <27.29 mm) were related to ulcer healing. The multivariate analysis indicated that pathological grade (cancer + HIN vs LIN + others) and initial maximum diameter (≥35.5 mm vs <35.5 mm) were independent factors that influenced post-ESD ulcer reduction. The adjusted ORs were 0.33 (0.17–0.62) and 0.36 (0.17–0.75), respectively.
Logistic regression analysis of factors influencing post-ESD ulcer improvement
Univariate and multivariate logistic regression models were used to analyze the factors that affect post-ESD ulcer improvement at 4 weeks. The results are shown in Table 6. The dependent variable was whether the post-ESD ulcer improved. The independent variables were the relevant variables determined by our subgroup analysis. Univariate analysis revealed that the initial ulcer area (≥1,084.45 mm2 vs <1,084.45 mm2), initial maximum diameter (≥35.5 mm vs <35.5 mm), and perpendicular diameter (≥27.29 mm vs <27.29 mm) were related to ulcer improvement. Multivariate analysis indicated the initial maximum diameter (≥35.5 vs <35.5) was an independent factor that influenced post-ESD ulcer reduction. The adjusted OR was 0.34 (0.14–0.81, P = 0.015).
The PPI treatment of 8 weeks is the standard therapy for the common gastric ulcer. However, there is no standardized regimen for the treatment of gastric large iatrogenic ulcers induced by ESD. Previous medical therapy contained the PPI alone, mucosa protectant alone, as well as the combination of these 2 drugs, and the course for the treatment is 4 to 8 weeks. Previous studies showed that with PPI alone or mucosa protectant alone for 4 weeks, the ulcer healing rate was 11.5%–36%; however, the ulcer healing rate in the combination therapy group was 9.5%–68%, indicating that the combination therapy was better. In our study, we performed a large-scale, multicenter, prospective, randomized, double-blind, parallel-group, positive-controlled trial to evaluate optimal treatment for post-ESD ulcer.
At 4 weeks, the ulcer improvement rates in the experimental and control groups were 94.2% and 88.7%, respectively. However, the rates of ulcer area reduction were 0.97 ± 0.034 and 0.94 ± 0.078 in the experimental and control groups, respectively, and this difference between the 2 groups was statistically significant. Therefore, combination therapy promoted ulcer healing more successfully than monotherapy. This conclusion is consistent with the results of previous studies. The ulcer healing at week 4 was less than 21%, indicating that the course for therapy should be longer than 4 weeks. The ulcer healing rates for initial maximum diameter ≥35.5 mm and <35.5 mm at week 8 were 84.6% and 94.7% (P < 0.007), indicating that initial maximum diameter of ulcer is an important factor for healing of post-ESD ulcer and 8 weeks' treatment is recommended. Whether the conventional ulcer classification system proposed by Sakita (13) was suitable to be employed in this study needs discussion. This classification system is a valuable guide for the clinical treatment and prognosis of ulcers, but it is not objective or continuous. Moreover, the distinction between A- and H-stage ulcers is not clear. Therefore, a new method is required to improve the evaluation of post-ESD ulcers, particularly giant iatrogenic ulcers.
Numerous factors may influence post-ESD ulcer healing, including ulcer area, ulcer site, pathological grade, blood coagulation status, Hp infection, and other comorbidities. However, studies investigating post-ESD ulcer healing have not achieved consensus regarding the importance of these factors. Our study showed that the combination therapy and lesions located in the gastric antrum were both positively associated with the ulcer healing. Oh et al. (18) showed that the degree of ulcer healing within 4 weeks was determined by the initial size of the ulcer. Similarly, Nakamura et al. (15) also suggested that the initial size of the ulcer and the location of lesion could affect healing of post-ESD ulcer, which supports our results. Therefore, the longer course of treatment should be taken for the bigger initial size of the post-ESD ulcer.
The most significant complication that occurs during post-ESD ulcer healing is bleeding. In our study, the overall incidence of bleeding was 5.33%, which was far lower than the results reported in the foreign literature (13%–38%) (19). The most likely explanation for this is the significant reduction in the incidence of bleeding that has occurred in recent years as endoscopy instruments have improved allowing the coagulation of blood vessels using hot biopsy forceps. In this study, the overall incidences of bleeding in control and experimental groups were 7.14% and 4.17% with no significant difference.
The reasons for choosing to evaluate rebamipide and the PPI lansoprazole were as follows. First, antacids are still the most effective treatment for post-ESD ulcers (20), and several studies have shown that the clinical efficacy of PPIs is superior to that of H2RAs. Second, PPIs combined with a mucosal protective agent is better able to promote ulcer healing compared to PPI monotherapy. A meta-analysis that included 11 randomized controlled trials indicated that the clinical efficacy of combination therapy is superior to PPI monotherapy (16). Finally, rebamipide has more significant effects on the healing of post-ESD ulcers than other mucosal protective agents (16). It may act by promoting the expression of gastric mucosal protective factors (Prostaglandin E and Cyclooxygenase 2), promoting the synthesis of various growth factors (epidermal growth factor [EGF], EGF receptor, and vascular endothelial growth factor), inhibiting gastric mucosal injury factors, inhibiting Hp adherence to endothelial cells, inhibiting the production of interleukin 8/leukotriene B4, or inhibiting the expression of adhesion molecules CD11b/CD18 and intercellular cell adhesion molecule-1.
In the preliminary stages of this trial, we tested 3 methods for ulcer diameter measurement: direct measurement through the endoscope biopsy channel using an endoscopic measuring instrument (Olympus, Tokyo, Japan); measurement by comparison with a visual reference (a paper disk) using Amedicom System image analysis software for image distance measurements; direct measurement of the post-ESD specimens. Similar studies from abroad commonly apply the first method of measurement (17). However, during the resection operation, the large size of the post-ESD ulcers made it difficult to visualize them within a single field. Moreover, the ulcers were not located in the same plane. Hence, the first 2 methods lacked the accuracy required for the measurement of such ulcers. Therefore, we chose to use the resected specimen measurement as a surrogate for the measurement of the corresponding post-ESD ulcer. However, because of the drastically reduced sizes of the ulcers 4 and 8 weeks postoperatively, we were able to employ the second method and obtain relatively accurate measurements.
In conclusion, both the PPI monotherapy and the PPI plus rebamipide treatments ended up with low post-ESD ulcer healing rates in the first 4 weeks of postoperative treatment. After 8 weeks of treatment, over 90% of ulcers were in the healing or scarring stage. Compared with lansoprazole alone, rebamipide combined with lansoprazole significantly accelerated the rate of ulcer reduction but did not improve the rate of ulcer healing at 4 weeks of therapy.
CONFLICTS OF INTEREST
Guarantor of the article: Yunsheng Yang, MD.
Specific author contributions: Bin Yan and Zhongsheng Lu contributed equally to this work. Yunsheng Yang designed research. Zhongsheng Lu, Zhizheng Ge, Side Liu, Xuegang Guo, Dean Tian, Yuxiu Yang, Xiaobo Li, Wei Gong, Zhiguo Liu, Mei Liu, Bingxi Zhou, Kabing Zhao, and Jing Yang performed research. Bin Yan and Fei Pan analyzed data. Bin Yan wrote the paper.
Financial support: Nursery Science and Technology Innovation Fund of Chinese PLA General Hospital, no: 13KMM02, 18KMM02.
Potential competing interests: The authors declare no conflict of interest.
WHAT IS KNOWN
- ✓ ESD induced deep and large gastrointestinal ulcers, resulted in an increased risk of perforation, bleeding, and abdominal pain.
- ✓ The optimal treatment for ESD-induced ulcers is unknown.
WHAT IS NEW HERE
- ✓ The rebamipide and lansoprazole combination therapy accelerates the reduction rate of post-ESD ulcer compared with the lansoprazole monotherapy at 4 weeks of therapy.
- ✓ Our data provide the evidence that rebamipide can significantly promote the reduction rate of post-ESD ulcer at 4 weeks of therapy.
1. Gotoda T, Kondo H, Ono H, et al. A new endoscopic mucosal resection procedure using an insulation-tipped electrosurgical knife for rectal flat lesions: Report of two cases. Gastrointest Endosc 1999;50:560–3.
2. Ono H, Kondo H, Gotoda T, et al. Endoscopic mucosal resection for treatment of early gastric cancer. Gut 2001;48:225–9.
3. Isomoto H, Shikuwa S, Yamaguchi N, et al. Endoscopic submucosal dissection for early gastric cancer: A large-scale feasibility study. Gut 2009;58:331–6.
4. Kakushima N, Fujishiro M, Kodashima S, et al. Histopathologic characteristics of gastric ulcers created by endoscopic submucosal dissection. Endoscopy 2006;38:412–5.
5. Kakushima N, Fujishiro M, Yahagi N, et al. Helicobacter pylori
status and the extent of gastric atrophy do not affect ulcer healing after endoscopic submucosal dissection. J Gastroenterol Hepatol 2006;21:1586–9.
6. Kakushima N, Tanaka M, Sawai H, et al. Gastric obstruction after endoscopic submucosal dissection. United Eur Gastroenterol J 2013;1:184–90.
7. Nonaka K, Miyazawa M, Ban S, et al. Different healing process of esophageal large mucosal defects by endoscopic mucosal dissection between with and without steroid injection in an animal model. BMC Gastroenterol 2013;13:72.
8. Arakawa T, Higuchi K, Fujiwara Y, et al. 15th anniversary of rebamipide: Looking ahead to the new mechanisms and new applications. Dig Dis Sci 2005;50(Suppl 1):S3–11.
9. Takayama M, Matsui S, Kawasaki M, et al. Efficacy of treatment with rebamipide for endoscopic submucosal dissection-induced ulcers. World J Gastroenterol 2013;19:5706–12.
10. Fujiwara S, Morita Y, Toyonaga T, et al. A randomized controlled trial of rebamipide plus rabeprazole for the healing of artificial ulcers after endoscopic submucosal dissection. J Gastroenterol 2011;46:595–602.
11. Kato T, Araki H, Onogi F, et al. Clinical trial: Rebamipide promotes gastric ulcer healing by proton pump inhibitor after endoscopic submucosal dissection—A randomized controlled study. J Gastroenterol 2010;45:285–90.
12. Kobayashi M, Takeuchi M, Hashimoto S, et al. Contributing factors to gastric ulcer healing after endoscopic submucosal dissection including the promoting effect of rebamipide. Dig Dis Sci 2012;57:119–26.
13. Sakita T. Endoscopic diagnosis of gastric cancer. Gan No Rinsho 1972:Suppl:108–14. [Japanese]
14. Asakuma Y, Kudo M, Matsui S, et al. Comparison of an ecabet sodium and proton pump inhibitor (PPI) combination therapy with PPI alone in the treatment of endoscopic submucosal dissection (ESD)—Induced ulcers in early gastric cancer: Prospective randomized study. Hepatogastroenterology 2009;56:1270–3.
15. Nakamura K, Ihara E, Akiho H, et al. Limited effect of rebamipide in addition to proton pump inhibitor (PPI) in the treatment of post-endoscopic submucosal dissection gastric ulcers: A randomized controlled trial comparing PPI plus rebamipide combination therapy with PPI monotherapy. Gut Liver 2016;10:917–24.
16. Nishizawa T, Suzuki H, Kanai T, et al. Proton pump inhibitor alone vs proton pump inhibitor plus mucosal protective agents for endoscopic submucosal dissection-induced ulcer: A systematic review and meta-analysis. J Clin Biochem Nutr 2015;56:85–90.
17. Shin WG, Kim SJ, Choi MH, et al. Can rebamipide and proton pump inhibitor combination therapy promote the healing of endoscopic submucosal dissection-induced ulcers? A randomized, prospective, multicenter study. Gastrointest Endosc 2012;75:739–47.
18. Oh TH, Jung HY, Choi KD, et al. Degree of healing and healing-associated factors of endoscopic submucosal dissection-induced ulcers after pantoprazole therapy for 4 weeks. Dig Dis Sci 2009;54:1494–9.
19. Yamamoto H, Sekine Y, Higashizawa T, et al. Successful en bloc resection of a large superficial gastric cancer by using sodium hyaluronate and electrocautery incision forceps. Gastrointest Endosc 2001;54:629–32.
20. Fujishiro M, Chiu PW, Wang HP. Role of antisecretory agents for gastric endoscopic submucosal dissection. Dig Endosc 2013;25(Suppl 1):86–93.
21. Uedo N, Takeuchi Y, Yamada T, et al. Effect of a proton pump inhibitor or an H2-receptor antagonist on prevention of bleeding from ulcer after endoscopic submucosal dissection of early gastric cancer: A prospective randomized controlled trial. Am J Gastroenterol 2007;102:1610–6.
22. Yang Z, Wu Q, Liu Z, et al. Proton pump inhibitors versus histamine-2-receptor antagonists for the management of iatrogenic gastric ulcer after endoscopic mucosal resection or endoscopic submucosal dissection: A meta-analysis of randomized trials. Digestion 2011;84:315–20.
23. Arakawa T, Kobayashi K, Yoshikawa T, et al. Rebamipide: Overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing. Dig Dis Sci 1998;43:5S–13S.
24. Tarnawski AS, Chai J, Pai R, et al. Rebamipide activates genes encoding angiogenic growth factors and Cox2 and stimulates angiogenesis: A key to its ulcer healing action? Dig Dis Sci 2004;49:202–9.
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