Effectiveness of modified oral steroid administration for preventing esophageal stricture after entire circumferential endoscopic submucosal dissection

Effectiveness of modified oral steroid administration for preventing esophageal stricture after... Summary Esophageal stricture occurs at a high rate after endoscopic submucosal dissection, especially after entire circumferential dissection, leading to poor quality of life. This retrospective cohort study evaluated the stricture rate in circumferential mucosal defect cases following modified steroid administration. We enrolled 22 consecutive patients who underwent entire circumferential endoscopic submucosal dissection for superficial esophageal cancer between April 2010 and April 2015 at our hospital. Until January 2013, a systemic steroid—prednisolone—was administered at 30 mg/day and tapered over 8 weeks in the original method group (original group). From February 2013, 30 mg of prednisolone was administered orally for 3 weeks and then the dose was reduced in 5 mg decrements every 3 weeks. This group was classified as the modified method group (modified group). We retrospectively compared the stricture rates between the two groups. The postoperative stricture rate was significantly lower in the modified group (36.4%; 4/11 patients) than in the original group (82%; 9/11 patients; P = 0.04). The mean number of endoscopic balloon dilatation procedures was significantly lower in the modified group (6.2 ± 11.3) than in the original group (19.4 ± 15.3; P = 0.023). Pneumonia and oral herpes infection, which are adverse events potentially associated with steroid administration, were observed in the original group. Candida esophagitis, arthritis, and steroid-related myopathy were observed in the modified group. This modified systemic steroid administration was effective for patients with entire circumferential mucosal defect. The safety of this method was also demonstrated. INTRODUCTION With advances in technology and skill, endoscopic submucosal dissection (ESD) has become widely used for the treatment of superficial esophageal cancer. ESD enables en bloc resection, even when the lesion has spread to occupy the entire circumference. However, multivariate analysis has shown that a mucosal defect of more than three quarters of the circumference of the esophageal lumen is a reliable predictor of esophageal stricture.1,2 Esophageal stricture after ESD dramatically decreases quality of life, and necessitates repeated endoscopic balloon dilation (EBD).3,4 Several recent reports have found that either systemic steroid administration5 or intralesional steroid injection6,7 effectively prevents stricture after ESD. Oral steroid administration was first reported by Yamaguchi et al.5 Subsequently, Sato et al.8 and Kadota et al.9 demonstrated preventive measures for esophageal stricture by applying the Yamaguchi protocol. On the other hand, steroid injections are commonly used and effective for the prevention for esophageal stricture. Wang and Ma performed a meta-analysis and revealed that intralesional steroid injections reduce the incidence of esophageal stricture more effectively than oral steroids.10 However, these reports incorporated few cases of entire circumferential ESD (cESD). Recently, Kadota et al. reported the effectiveness of administering a combination of steroid injections and oral steroids.9 However, a high stricture rate was found in a limited number of lesions with entire cESD, regardless of prophylactic treatment. Based on the current somewhat limited data, it appears difficult to prevent esophageal stricture in cases of entire cESD via the Yamaguchi protocol. Hence, a modified steroid regimen is required. The aim of this study is to clarify the effectiveness and safety of a modified oral steroid therapy. PATIENTS AND METHODS Patients ESD for superficial esophageal cancer was performed to treat 583 lesions in 418 patients from April 2010 to April 2015. Among them, ESD of the entire circumference of the esophagus was performed in 25 patients with superficial esophageal cancer. Three patients were excluded because additional surgery was performed after ESD. Consequently, 22 patients were enrolled in this study after they provided written informed consent. ESD An EG450-RD5 scope (Fujifilm Medical Co., Ltd., Tokyo Japan) and a dual knife (Olympus Optical Co., Ltd., Tokyo, Japan) were used for ESD. Glycerol with small amounts of indigocarmine and epinephrine was used for injection, and a VIO300 high-frequency generator (Erbe, Tübingen, Germany) was used for radiofrequency ablation. The extent of the lesion was identified by spraying with iodine, and dots were marked around the lesion. The lesion was lifted by injecting glycerol into the submucosal layer at its posterior end, and submucosal dissection was performed. The same procedure was subsequently performed on the anterior end of the lesion. Submucosal dissection was performed by making a tunnel in the posterior wall, then in the anterior wall, and continuing at each side until the lesion was resected en bloc (Fig. 1). Exteriorized small vessels were treated by a hemostatic procedure, and a submucosal injection was given during submucosal dissection, if required. Fig. 1 View largeDownload slide Endoscopic views of the esophagus in a typical nonstricture case in the modified group. (A) Chromoendoscopy with iodine staining revealed a discolored area in the mid-thoracic esophagus. The superficial esophageal cancer extended entire circumference. (B) Submucosal dissection was performed by making a tunnel in the posterior wall, then in the anterior wall. (C) Artificial ulcer. (D) Resected specimen. (E) Resected specimen with iodine staining. (F) Follow-up esophagoscopy. 5 months after ESD revealed no postprocedural stricture, and this patient experienced no dysphagia. Fig. 1 View largeDownload slide Endoscopic views of the esophagus in a typical nonstricture case in the modified group. (A) Chromoendoscopy with iodine staining revealed a discolored area in the mid-thoracic esophagus. The superficial esophageal cancer extended entire circumference. (B) Submucosal dissection was performed by making a tunnel in the posterior wall, then in the anterior wall. (C) Artificial ulcer. (D) Resected specimen. (E) Resected specimen with iodine staining. (F) Follow-up esophagoscopy. 5 months after ESD revealed no postprocedural stricture, and this patient experienced no dysphagia. An intralesional steroid injection was administered immediately after ESD, and a steroid was injected a few days later if muscle damage was observed during the ESD procedure. Triamcinolone acetonide (Kenacort; 40 mg/mL; Bristol-Myers Squibb Co., Tokyo, Japan) was diluted with saline and a 25-gauge needle was used to inject the solution evenly into the residual submucosal tissue of the ulcer bed in 0.5 mL increments. The initial injections were given at the margins of the ulcer followed by linear injections from the distal to the proximal sides of the margin. Injections of 80–120 mg of Kenacort were administered. Steroid administration regimen The steroid was administered orally a few days after ESD because it was necessary to confirm that there were no adverse events, including pneumonia and delayed perforation. A proton pump inhibitor, cotrimoxazole, and bisphosphonate were administered simultaneously. Until January 2013, the original 8-week oral steroid regimen commenced at a dose of 30 mg for 2 weeks, followed by 25 mg for 2 weeks, and then 20 mg, 15 mg, 10 mg, and 5 mg doses for 1 week as per Yamaguchi's report (Fig. 2). The group that received this dosage regimen was classified as the original group. From February 2013, a modified method was performed in which 30 mg of steroid was administered for 3 weeks, and then the dose was reduced in 5 mg decrements every 3 weeks (Fig. 3). This group was classified as the modified group. There were 11 patients in each group. Fig. 2 View largeDownload slide Schema of steroid administration regimen in the original group. Fig. 2 View largeDownload slide Schema of steroid administration regimen in the original group. Fig. 3 View largeDownload slide Schema of steroid administration regimen in the modified group. Fig. 3 View largeDownload slide Schema of steroid administration regimen in the modified group. Follow-up Endoscopic examination was performed at 1, 4, 8, 12, 16, and 20 weeks after ESD. The prevalence of esophageal stricture was evaluated at each examination. In addition to scheduled endoscopies, this procedure was also performed if the patient began to experience symptoms of dysphagia when swallowing food. When esophageal stricture was observed, EBD was conducted until the stricture was resolved. A postoperative stricture was defined as the presence of a stenosis of the esophageal lumen progressing to the point where a 9.8-mm diameter upper gastrointestinal endoscope (GIF H260; Olympus Co.) could not be passed through it. The day that the stricture was confirmed by endoscopy was defined as the day of occurrence. Evaluation The primary endpoint of this study was the incidence rate of postoperative stricture after esophageal ESD. The secondary endpoints were the number of EBD procedures required to resolve any strictures and the rate of adverse events during oral steroid administration. Statistics Continuous variables were compared using the Student's t test, and categorical variables were compared using the χ2 test or Fisher's exact test, as appropriate. A P value of <0.05 was considered statistical significance. RESULTS The clinicopathological characteristics of the study participants are shown in Table 1. Both groups were similar in terms of sex, lesion location, number of cases under general anesthesia, tumor invasion, and tumor size. The number of cases receiving intralesional steroid injection was smaller in the original group, but the difference was not significant. Table 1 Patient characteristics Original group Modified group P value Number 11 11 Sex  Men 11 11 n.s.  Women 0 0 Age, years [mean (SD)] 72.4 (8.9) 65.3 (12.2) 0.19 Location 0.33  Upper 3 0  Middle 6 7  Lower 2 4 Macroscopic type 0.035  0–2a 1 0  0–2c 10 6  0–2b 0 5 Tumor size, mm [mean (SD)] 64.1 (12.8) 67.3 (11.0) 0.49 Longitudinal length, mm [mean (SD)] 72.6 (16.8) 76.5 (11.1) 0.47 Depth of tumor invasion 0.59  EP/LPM 9 8  MM/SM1 1 3  SM2 1 0 Cases under general anesthesia 9 10 n.s. Intralesional injection 6 10 0.074 Original group Modified group P value Number 11 11 Sex  Men 11 11 n.s.  Women 0 0 Age, years [mean (SD)] 72.4 (8.9) 65.3 (12.2) 0.19 Location 0.33  Upper 3 0  Middle 6 7  Lower 2 4 Macroscopic type 0.035  0–2a 1 0  0–2c 10 6  0–2b 0 5 Tumor size, mm [mean (SD)] 64.1 (12.8) 67.3 (11.0) 0.49 Longitudinal length, mm [mean (SD)] 72.6 (16.8) 76.5 (11.1) 0.47 Depth of tumor invasion 0.59  EP/LPM 9 8  MM/SM1 1 3  SM2 1 0 Cases under general anesthesia 9 10 n.s. Intralesional injection 6 10 0.074 EP, epithelium; LPM, lamina propria mucosae; MM, muscularis mucosa; n.s., not significant; SD, standard deviation; SM, submucosa. View Large Table 1 Patient characteristics Original group Modified group P value Number 11 11 Sex  Men 11 11 n.s.  Women 0 0 Age, years [mean (SD)] 72.4 (8.9) 65.3 (12.2) 0.19 Location 0.33  Upper 3 0  Middle 6 7  Lower 2 4 Macroscopic type 0.035  0–2a 1 0  0–2c 10 6  0–2b 0 5 Tumor size, mm [mean (SD)] 64.1 (12.8) 67.3 (11.0) 0.49 Longitudinal length, mm [mean (SD)] 72.6 (16.8) 76.5 (11.1) 0.47 Depth of tumor invasion 0.59  EP/LPM 9 8  MM/SM1 1 3  SM2 1 0 Cases under general anesthesia 9 10 n.s. Intralesional injection 6 10 0.074 Original group Modified group P value Number 11 11 Sex  Men 11 11 n.s.  Women 0 0 Age, years [mean (SD)] 72.4 (8.9) 65.3 (12.2) 0.19 Location 0.33  Upper 3 0  Middle 6 7  Lower 2 4 Macroscopic type 0.035  0–2a 1 0  0–2c 10 6  0–2b 0 5 Tumor size, mm [mean (SD)] 64.1 (12.8) 67.3 (11.0) 0.49 Longitudinal length, mm [mean (SD)] 72.6 (16.8) 76.5 (11.1) 0.47 Depth of tumor invasion 0.59  EP/LPM 9 8  MM/SM1 1 3  SM2 1 0 Cases under general anesthesia 9 10 n.s. Intralesional injection 6 10 0.074 EP, epithelium; LPM, lamina propria mucosae; MM, muscularis mucosa; n.s., not significant; SD, standard deviation; SM, submucosa. View Large The results of this study are shown in Table 2. Both en bloc and R0 resections were achieved in both groups. The post-ESD stricture rate in the modified group was 36.4% (4/11 patients), which was significantly lower than that in the original group (9/11 patients; 82%) (Table 3). The median number of EBD procedures was 0 in the modified group and 25 in the original group. The mean number of EBD procedures among those requiring EBD was 6.2 ± 11.3 in the modified group and 19.4 ± 15.3 in the original group, which was a statistically significant difference (P = 0.023). No patients complained of persistent dysphagia. However, some patients complained of dysphagia when they ate very quickly despite the fact that the stricture had been released. The incidence of patients who complained of this intermittent dysphagia was 36% and 27% in the original and modified groups, respectively. Risk factors for esophageal stricture were then analyzed. In the univariate analysis, total steroid use was identified as a possible risk factor (odds ratio [OR], 7.88; 95% confidence interval [CI], 1.10–56.1; P = 0.039). Multivariate analysis adjusted for each factor which was potentially associated with risk factors (P < 0.2) revealed that total steroid use tended to be an independent risk factor for post-ESD stricture (Table 4). Perforation, an adverse event associated with EBD, was observed in 1 patient in the modified group. This patient subsequently recovered with conservative treatment. No adverse event associated with ESD such as post-ESD bleeding, perforation, or delayed perforation was observed in either group. Pneumonia and oral herpes infection, which are adverse events potentially associated with steroid administration, were observed in the original group. Candida esophagitis, arthritis, and steroid-related myopathy were also observed in the modified group (Table 5). Because no symptoms potentially caused by candida esophagitis were observed in any of our patients, we did not routinely administer prophylactic antifungals. However, we sometimes administer prophylactic systemic antifungal treatment before follow-up endoscopy. Table 2 Clinical results of circumferential ESD Original Modified P value En bloc resection rate, % 100 100 n.s. R0 resection rate, % 100 100 n.s. Procedure time, min [mean (SD)] 118.9 (24.7) 102.3 (29.8) 0.11 Length of stay (median, days) 28 30 0.69 Adverse events Perforation 0 0 n.s. Post-ESD bleeding 0 0 n.s. Local recurrence 0 0 n.s. Original Modified P value En bloc resection rate, % 100 100 n.s. R0 resection rate, % 100 100 n.s. Procedure time, min [mean (SD)] 118.9 (24.7) 102.3 (29.8) 0.11 Length of stay (median, days) 28 30 0.69 Adverse events Perforation 0 0 n.s. Post-ESD bleeding 0 0 n.s. Local recurrence 0 0 n.s. ESD, endoscopic submucosal dissection; n.s., not significant; SD, standard deviation. View Large Table 2 Clinical results of circumferential ESD Original Modified P value En bloc resection rate, % 100 100 n.s. R0 resection rate, % 100 100 n.s. Procedure time, min [mean (SD)] 118.9 (24.7) 102.3 (29.8) 0.11 Length of stay (median, days) 28 30 0.69 Adverse events Perforation 0 0 n.s. Post-ESD bleeding 0 0 n.s. Local recurrence 0 0 n.s. Original Modified P value En bloc resection rate, % 100 100 n.s. R0 resection rate, % 100 100 n.s. Procedure time, min [mean (SD)] 118.9 (24.7) 102.3 (29.8) 0.11 Length of stay (median, days) 28 30 0.69 Adverse events Perforation 0 0 n.s. Post-ESD bleeding 0 0 n.s. Local recurrence 0 0 n.s. ESD, endoscopic submucosal dissection; n.s., not significant; SD, standard deviation. View Large Table 3 Comparison of postprocedural strictures after ESD and the number of EBD sessions Original Modified P value Stricture 9 4 0.04 Number of EBD procedures [mean (SD)] [range] 19.4 (15.3) [0–42] 6.2 (11.3) [0–28] 0.023 Original Modified P value Stricture 9 4 0.04 Number of EBD procedures [mean (SD)] [range] 19.4 (15.3) [0–42] 6.2 (11.3) [0–28] 0.023 EBD, endoscopic balloon dilation; ESD, endoscopic submucosal dissection; SD, standard deviation. View Large Table 3 Comparison of postprocedural strictures after ESD and the number of EBD sessions Original Modified P value Stricture 9 4 0.04 Number of EBD procedures [mean (SD)] [range] 19.4 (15.3) [0–42] 6.2 (11.3) [0–28] 0.023 Original Modified P value Stricture 9 4 0.04 Number of EBD procedures [mean (SD)] [range] 19.4 (15.3) [0–42] 6.2 (11.3) [0–28] 0.023 EBD, endoscopic balloon dilation; ESD, endoscopic submucosal dissection; SD, standard deviation. View Large Table 4 Risk factors to develop the esophageal stricture (A-D). Odds 95% CI P A: Steroid use group (univariate OR) Modified group Reference Original 7.88 1.10–56.1 0.039 B: Steroid use group, OR adjusted for intralesional steroids Intralesional injection Positive Reference Negative 2.47 0.18–33.6 0.50 Total steroid use Modified Reference Original 6.07 0.77–47.9 0.087 C: Steroid use group, OR adjusted for age Age 0.97 0.89–1.07 0.54 Total steroid use Modified Reference Original 10.0 1.16–86.4 0.036 D: Steroid use group, OR adjusted for macroscopic tumor type Macroscopic type Flat & elevated type Reference depressed type 0.62 0.062–6.11 0.68 Total steroid use Modified Reference Original 9.53 1.06–85.4 0.044 Odds 95% CI P A: Steroid use group (univariate OR) Modified group Reference Original 7.88 1.10–56.1 0.039 B: Steroid use group, OR adjusted for intralesional steroids Intralesional injection Positive Reference Negative 2.47 0.18–33.6 0.50 Total steroid use Modified Reference Original 6.07 0.77–47.9 0.087 C: Steroid use group, OR adjusted for age Age 0.97 0.89–1.07 0.54 Total steroid use Modified Reference Original 10.0 1.16–86.4 0.036 D: Steroid use group, OR adjusted for macroscopic tumor type Macroscopic type Flat & elevated type Reference depressed type 0.62 0.062–6.11 0.68 Total steroid use Modified Reference Original 9.53 1.06–85.4 0.044 View Large Table 4 Risk factors to develop the esophageal stricture (A-D). Odds 95% CI P A: Steroid use group (univariate OR) Modified group Reference Original 7.88 1.10–56.1 0.039 B: Steroid use group, OR adjusted for intralesional steroids Intralesional injection Positive Reference Negative 2.47 0.18–33.6 0.50 Total steroid use Modified Reference Original 6.07 0.77–47.9 0.087 C: Steroid use group, OR adjusted for age Age 0.97 0.89–1.07 0.54 Total steroid use Modified Reference Original 10.0 1.16–86.4 0.036 D: Steroid use group, OR adjusted for macroscopic tumor type Macroscopic type Flat & elevated type Reference depressed type 0.62 0.062–6.11 0.68 Total steroid use Modified Reference Original 9.53 1.06–85.4 0.044 Odds 95% CI P A: Steroid use group (univariate OR) Modified group Reference Original 7.88 1.10–56.1 0.039 B: Steroid use group, OR adjusted for intralesional steroids Intralesional injection Positive Reference Negative 2.47 0.18–33.6 0.50 Total steroid use Modified Reference Original 6.07 0.77–47.9 0.087 C: Steroid use group, OR adjusted for age Age 0.97 0.89–1.07 0.54 Total steroid use Modified Reference Original 10.0 1.16–86.4 0.036 D: Steroid use group, OR adjusted for macroscopic tumor type Macroscopic type Flat & elevated type Reference depressed type 0.62 0.062–6.11 0.68 Total steroid use Modified Reference Original 9.53 1.06–85.4 0.044 View Large Table 5 Adverse events potentially associated with steroid administration Treatment-related disease Original Modified P value Pneumonia 2 0 0.48 Oral herpes infection 1 0 1.0 Candida esophagitis 0 7 0.004 Arthritis 0 1 1.0 Steroid-related myopathy 0 2 0.48 Total number of AE 3 8 0.043 Treatment-related disease Original Modified P value Pneumonia 2 0 0.48 Oral herpes infection 1 0 1.0 Candida esophagitis 0 7 0.004 Arthritis 0 1 1.0 Steroid-related myopathy 0 2 0.48 Total number of AE 3 8 0.043 AE, Adverse event. View Large Table 5 Adverse events potentially associated with steroid administration Treatment-related disease Original Modified P value Pneumonia 2 0 0.48 Oral herpes infection 1 0 1.0 Candida esophagitis 0 7 0.004 Arthritis 0 1 1.0 Steroid-related myopathy 0 2 0.48 Total number of AE 3 8 0.043 Treatment-related disease Original Modified P value Pneumonia 2 0 0.48 Oral herpes infection 1 0 1.0 Candida esophagitis 0 7 0.004 Arthritis 0 1 1.0 Steroid-related myopathy 0 2 0.48 Total number of AE 3 8 0.043 AE, Adverse event. View Large DISCUSSION This is the first study to report the feasibility and effectiveness of modified oral steroid administration for ESD cases with entire circumferential mucosal defects. The safety of cESD was also demonstrated in this study. This modified method shows high potential as a preventive measure against esophageal stricture compared with previous methods. Few reports have detailed cases of entire cESD. In the report by Yamaguchi et al., esophageal stricture developed in all 3 patients who underwent entire cESD.5 In the report by Kadota et al., esophageal stricture developed in 10 of 14 patients (71%) who underwent a combination of local steroid injections and oral systemic steroid administration.9 Sato et al. reported that esophageal stricture developed in 10 of 10 patients who underwent steroid administration and EBD, although EBD was conducted when resistance to the endoscope was encountered.8 In the case of intralesional steroid injections alone, Takahashi et al. reported that esophageal stricture developed in 10 patients who underwent entire cESD and intralesional steroid injections.11 Although it is impossible to compare the results of those reports with our results, the frequency of esophageal stricture could be decreased from half to one third. Another impressive feature was the decrease in the number of EBD procedures. EBD has a potential risk of perforation or bleeding and repeated dilatations can worsen scarring, which results in recurrence of strictures that are more difficult to treat.12,13 According to previous reports, local or systemic steroid administration leads to a reduction in the number of EBD procedures required to treat strictures, without increasing the number of complications.14 In fact, the results of this study showed that modified steroid administration decreased the mean number of EBD procedures significantly. Adverse events related to steroid administration are of great concern. Oliveira et al. stated that treatment with high-dose corticosteroids may be associated with adverse events including immunosuppression, diabetes, psychiatric disorders, osteoporosis, and peptic disease.14 In this study, the main adverse event in the modified group was candida esophagitis, which was observed at a significantly higher rate than in the original group; however, all cases were manageable by conservative treatment. None of the adverse events were difficult to manage by conservative treatment among the limited number of patients in this study. It was not possible to identify the causative bacteria for the patient who developed pneumonia. However, steroids induce an immunosuppressive state, putting patients at risk of infections such as pneumocystis pneumonia (PCP), which has a high mortality rate.15 Bactrim prophylaxis was thus administered through the entire course of steroid treatment. The literature supports prophylaxis for PCP in patients administered steroids in doses greater than 20 mg for 1 month or longer.16 There were no patients with psychiatric disorders or peptic ulcer disease in either of our study groups. As for diabetes, this study had four diabetic patients in the original group and one in the modified group. Control of blood sugar levels was managed by experts, and none of the patients developed uncontrolled diabetes in this study. Nonetheless, close attention should be paid to adverse events. This treatment has a potential drawback if histological assessment reveals invasion depth below the muscularis mucosa (MM), which indicates a potential risk of lymph node metastasis. Specifically, chemoradiotherapy (CRT) as an additional treatment would be delayed because it is necessary to first confirm the absence of esophageal strictures, though there would be no delay if the patient opts for surgery. Indeed, two patients received CRT because of findings of pathological invasion below the MM and positive lymphovascular involvement. The interval between ESD and CRT was 157 days and 217 days for these two patients. Moreover, a recurrence of lymph node metastasis was observed in one patient, who later died of esophageal cancer, despite receiving additional treatment. There are some limitations to this study. First, it was a retrospective study with a small sample size. Second, the treatment periods differed between the original and modified groups, with the modified treatment starting after obtaining poor results from the original group. A prospective randomized controlled study would be ideal for evaluating the effectiveness of steroid administration; however, cases with cESD are very limited, and new preventive methods are required as soon as possible, making it difficult to perform randomized controlled studies. In conclusion, although this study had a small number of patients, it suggests that modified systemic steroid administration may be as effective as standard, longer courses of steroid treatment for patients with entire circumferential mucosal defects. The safety of this method was also demonstrated. Although there were no differences in the technical aspects of the procedures between the original and modified groups, duration of steroid administration was definitely longer in modified group. Accordingly, psychological stress may have been higher in the modified group. In addition, the rate of strictures was still not small; therefore, it is essential to carefully observe patients and promptly treat esophageal strictures that develop after entire cESD. Notes Special author contributions: Authorship: Toshiro Iizuka; Conception and design: Toshiro Iizuka, Daisuke Kikuchi; Analysis and interpretation of the data: Toshiro Iizuka, Daisuke Kikuchi; Drafting of the article: Toshiro Iizuka, Daisuke Kikuchi, Shu Hoteya, Mitsuru Kaise; Acquisition of data: Toshiro Iizuka, Daisuke Kikuchi, Shu Hoteya, Mitsuru Kaise; General supervision of the research group: Department of gastroenterology, Toranomon Hospital; Critical revision of the article: Mitsuru Kaise Final approval of the article: Toshiro Iizuka, Daisuke Kikuchi, Shu Hoteya, Mitsuru Kaise. References 1 Ono S , Fujishiro M , Niimi K et al. Predictors of postoperative stricture after esophageal endoscopic submucosal dissection for superficial squamous cell neoplasms . Endoscopy 2009 ; 41 : 661 – 5 . Google Scholar CrossRef Search ADS PubMed 2 Katada C , Muto M , Manabe T et al. Esophageal stenosis after endoscopic mucosal resection of superficial esophageal lesion . Gastrointest Endosc 2003 ; 57 : 165 – 9 . Google Scholar CrossRef Search ADS PubMed 3 Yoda Y , Yano T , Kaneko K et al. Endoscopic balloon dilatation for benign fibrotic strictures after curative nonsurgical treatment for esophageal cancer . Surg Endosc 2012 ; 26 : 2877 – 83 . Google Scholar CrossRef Search ADS PubMed 4 Isomoto H , Yamaguchi N , Nakayama T et al. Management of esophageal stricture after complete circular endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma . BMC Gastroenterol 2011 ; 11 : 46 . Google Scholar CrossRef Search ADS PubMed 5 Yamaguchi N , Isomoto H , Nakayama T et al. Usefulness of oral prednisolone in the treatment of esophageal stricture after endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma . Gastrointest Endosc 2011 ; 73 : 1115 – 21 . Google Scholar CrossRef Search ADS PubMed 6 Hashimoto S , Kobayashi M , Takeuchi M et al. The efficacy of endoscopic triamcinolone injection for the prevention of esophageal stricture after endoscopic submucosal dissection . Gastrointest Endosc 2011 ; 74 : 1389 – 93 . Google Scholar CrossRef Search ADS PubMed 7 Hanaoka N , Ishihara R , Takeuchi Y et al. Intralesional steroid injection to prevent stricture after endoscopic submucosal dissection for esophageal cancer: a controlled prospective study . Endoscopy 2012 ; 44 : 1007 – 11 . Google Scholar CrossRef Search ADS PubMed 8 Sato H , Inoue H , Kobayashi Y et al. Control of severe strictures after circumferential endoscopic submucosal dissection for esophageal carcinoma: oral steroid therapy with balloon dilation or balloon dilation alone . Gastrointest Endosc 2013 ; 78 : 250 – 7 . Google Scholar CrossRef Search ADS PubMed 9 Kadota T , Yano T , Kato T et al. Prophylactic steroid administration for strictures after endoscopic resection of large superficial esophageal squamous cell carcinoma . Endosc Int Open 2016 ; 4 : E1267 – 74 . Google Scholar CrossRef Search ADS PubMed 10 Wang W , Ma Z . Steroid administration is effective to prevent strictures after endoscopic esophageal submucosal dissection: a network metaanalysis . Medicine (Baltimore) 2015 ; 94 : e1664 . Google Scholar CrossRef Search ADS PubMed 11 Takahashi H , Arimura Y , Okahara S et al. Randomized controlled trial of endoscopic steroid injection for prophylaxis of esophageal stenoses after extensive endoscopic submucosal dissection . BMC Gastroenterol 2015 ; 15 : 1 . Google Scholar CrossRef Search ADS PubMed 12 Takahashi H , Arimura Y , Okahara S et al. Risk of perforation during dilation for esophageal strictures after endoscopic resection in patients with early squamous cell carcinoma . Endoscopy 2011 ; 43 : 184 – 9 . Google Scholar CrossRef Search ADS PubMed 13 Cheng Y S , Li M H , Yang R J et al. Restenosis following balloon dilation of benign esophageal stenosis . World J Gastroenterol 2003 ; 9 : 2605 – 8 . Google Scholar CrossRef Search ADS PubMed 14 Oliveira J F , Moura E G , Bernardo W M et al. Prevention of esophageal stricture after endoscopic submucosal dissection: a systematic review and meta-analysis . Surg Endosc 2016 ; 30 : 2779 – 91 . Google Scholar CrossRef Search ADS PubMed 15 Tasaka S , Tokuda H . Pneumocystis jirovecii pneumonia in non-HIV-infected patients in the era of novel immunosuppressive therapies . J Infect Chemother 2012 ; 18 : 793 – 806 . Google Scholar CrossRef Search ADS PubMed 16 Limper A H , Knox K S , Sarosi G A et al. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients . Am J Respir Crit Care Med 2011 ; 183 : 96 – 128 . Google Scholar CrossRef Search ADS PubMed © The Authors 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Effectiveness of modified oral steroid administration for preventing esophageal stricture after entire circumferential endoscopic submucosal dissection

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The International Society for Diseases of the Esophagus
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© The Authors 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.
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Abstract

Summary Esophageal stricture occurs at a high rate after endoscopic submucosal dissection, especially after entire circumferential dissection, leading to poor quality of life. This retrospective cohort study evaluated the stricture rate in circumferential mucosal defect cases following modified steroid administration. We enrolled 22 consecutive patients who underwent entire circumferential endoscopic submucosal dissection for superficial esophageal cancer between April 2010 and April 2015 at our hospital. Until January 2013, a systemic steroid—prednisolone—was administered at 30 mg/day and tapered over 8 weeks in the original method group (original group). From February 2013, 30 mg of prednisolone was administered orally for 3 weeks and then the dose was reduced in 5 mg decrements every 3 weeks. This group was classified as the modified method group (modified group). We retrospectively compared the stricture rates between the two groups. The postoperative stricture rate was significantly lower in the modified group (36.4%; 4/11 patients) than in the original group (82%; 9/11 patients; P = 0.04). The mean number of endoscopic balloon dilatation procedures was significantly lower in the modified group (6.2 ± 11.3) than in the original group (19.4 ± 15.3; P = 0.023). Pneumonia and oral herpes infection, which are adverse events potentially associated with steroid administration, were observed in the original group. Candida esophagitis, arthritis, and steroid-related myopathy were observed in the modified group. This modified systemic steroid administration was effective for patients with entire circumferential mucosal defect. The safety of this method was also demonstrated. INTRODUCTION With advances in technology and skill, endoscopic submucosal dissection (ESD) has become widely used for the treatment of superficial esophageal cancer. ESD enables en bloc resection, even when the lesion has spread to occupy the entire circumference. However, multivariate analysis has shown that a mucosal defect of more than three quarters of the circumference of the esophageal lumen is a reliable predictor of esophageal stricture.1,2 Esophageal stricture after ESD dramatically decreases quality of life, and necessitates repeated endoscopic balloon dilation (EBD).3,4 Several recent reports have found that either systemic steroid administration5 or intralesional steroid injection6,7 effectively prevents stricture after ESD. Oral steroid administration was first reported by Yamaguchi et al.5 Subsequently, Sato et al.8 and Kadota et al.9 demonstrated preventive measures for esophageal stricture by applying the Yamaguchi protocol. On the other hand, steroid injections are commonly used and effective for the prevention for esophageal stricture. Wang and Ma performed a meta-analysis and revealed that intralesional steroid injections reduce the incidence of esophageal stricture more effectively than oral steroids.10 However, these reports incorporated few cases of entire circumferential ESD (cESD). Recently, Kadota et al. reported the effectiveness of administering a combination of steroid injections and oral steroids.9 However, a high stricture rate was found in a limited number of lesions with entire cESD, regardless of prophylactic treatment. Based on the current somewhat limited data, it appears difficult to prevent esophageal stricture in cases of entire cESD via the Yamaguchi protocol. Hence, a modified steroid regimen is required. The aim of this study is to clarify the effectiveness and safety of a modified oral steroid therapy. PATIENTS AND METHODS Patients ESD for superficial esophageal cancer was performed to treat 583 lesions in 418 patients from April 2010 to April 2015. Among them, ESD of the entire circumference of the esophagus was performed in 25 patients with superficial esophageal cancer. Three patients were excluded because additional surgery was performed after ESD. Consequently, 22 patients were enrolled in this study after they provided written informed consent. ESD An EG450-RD5 scope (Fujifilm Medical Co., Ltd., Tokyo Japan) and a dual knife (Olympus Optical Co., Ltd., Tokyo, Japan) were used for ESD. Glycerol with small amounts of indigocarmine and epinephrine was used for injection, and a VIO300 high-frequency generator (Erbe, Tübingen, Germany) was used for radiofrequency ablation. The extent of the lesion was identified by spraying with iodine, and dots were marked around the lesion. The lesion was lifted by injecting glycerol into the submucosal layer at its posterior end, and submucosal dissection was performed. The same procedure was subsequently performed on the anterior end of the lesion. Submucosal dissection was performed by making a tunnel in the posterior wall, then in the anterior wall, and continuing at each side until the lesion was resected en bloc (Fig. 1). Exteriorized small vessels were treated by a hemostatic procedure, and a submucosal injection was given during submucosal dissection, if required. Fig. 1 View largeDownload slide Endoscopic views of the esophagus in a typical nonstricture case in the modified group. (A) Chromoendoscopy with iodine staining revealed a discolored area in the mid-thoracic esophagus. The superficial esophageal cancer extended entire circumference. (B) Submucosal dissection was performed by making a tunnel in the posterior wall, then in the anterior wall. (C) Artificial ulcer. (D) Resected specimen. (E) Resected specimen with iodine staining. (F) Follow-up esophagoscopy. 5 months after ESD revealed no postprocedural stricture, and this patient experienced no dysphagia. Fig. 1 View largeDownload slide Endoscopic views of the esophagus in a typical nonstricture case in the modified group. (A) Chromoendoscopy with iodine staining revealed a discolored area in the mid-thoracic esophagus. The superficial esophageal cancer extended entire circumference. (B) Submucosal dissection was performed by making a tunnel in the posterior wall, then in the anterior wall. (C) Artificial ulcer. (D) Resected specimen. (E) Resected specimen with iodine staining. (F) Follow-up esophagoscopy. 5 months after ESD revealed no postprocedural stricture, and this patient experienced no dysphagia. An intralesional steroid injection was administered immediately after ESD, and a steroid was injected a few days later if muscle damage was observed during the ESD procedure. Triamcinolone acetonide (Kenacort; 40 mg/mL; Bristol-Myers Squibb Co., Tokyo, Japan) was diluted with saline and a 25-gauge needle was used to inject the solution evenly into the residual submucosal tissue of the ulcer bed in 0.5 mL increments. The initial injections were given at the margins of the ulcer followed by linear injections from the distal to the proximal sides of the margin. Injections of 80–120 mg of Kenacort were administered. Steroid administration regimen The steroid was administered orally a few days after ESD because it was necessary to confirm that there were no adverse events, including pneumonia and delayed perforation. A proton pump inhibitor, cotrimoxazole, and bisphosphonate were administered simultaneously. Until January 2013, the original 8-week oral steroid regimen commenced at a dose of 30 mg for 2 weeks, followed by 25 mg for 2 weeks, and then 20 mg, 15 mg, 10 mg, and 5 mg doses for 1 week as per Yamaguchi's report (Fig. 2). The group that received this dosage regimen was classified as the original group. From February 2013, a modified method was performed in which 30 mg of steroid was administered for 3 weeks, and then the dose was reduced in 5 mg decrements every 3 weeks (Fig. 3). This group was classified as the modified group. There were 11 patients in each group. Fig. 2 View largeDownload slide Schema of steroid administration regimen in the original group. Fig. 2 View largeDownload slide Schema of steroid administration regimen in the original group. Fig. 3 View largeDownload slide Schema of steroid administration regimen in the modified group. Fig. 3 View largeDownload slide Schema of steroid administration regimen in the modified group. Follow-up Endoscopic examination was performed at 1, 4, 8, 12, 16, and 20 weeks after ESD. The prevalence of esophageal stricture was evaluated at each examination. In addition to scheduled endoscopies, this procedure was also performed if the patient began to experience symptoms of dysphagia when swallowing food. When esophageal stricture was observed, EBD was conducted until the stricture was resolved. A postoperative stricture was defined as the presence of a stenosis of the esophageal lumen progressing to the point where a 9.8-mm diameter upper gastrointestinal endoscope (GIF H260; Olympus Co.) could not be passed through it. The day that the stricture was confirmed by endoscopy was defined as the day of occurrence. Evaluation The primary endpoint of this study was the incidence rate of postoperative stricture after esophageal ESD. The secondary endpoints were the number of EBD procedures required to resolve any strictures and the rate of adverse events during oral steroid administration. Statistics Continuous variables were compared using the Student's t test, and categorical variables were compared using the χ2 test or Fisher's exact test, as appropriate. A P value of <0.05 was considered statistical significance. RESULTS The clinicopathological characteristics of the study participants are shown in Table 1. Both groups were similar in terms of sex, lesion location, number of cases under general anesthesia, tumor invasion, and tumor size. The number of cases receiving intralesional steroid injection was smaller in the original group, but the difference was not significant. Table 1 Patient characteristics Original group Modified group P value Number 11 11 Sex  Men 11 11 n.s.  Women 0 0 Age, years [mean (SD)] 72.4 (8.9) 65.3 (12.2) 0.19 Location 0.33  Upper 3 0  Middle 6 7  Lower 2 4 Macroscopic type 0.035  0–2a 1 0  0–2c 10 6  0–2b 0 5 Tumor size, mm [mean (SD)] 64.1 (12.8) 67.3 (11.0) 0.49 Longitudinal length, mm [mean (SD)] 72.6 (16.8) 76.5 (11.1) 0.47 Depth of tumor invasion 0.59  EP/LPM 9 8  MM/SM1 1 3  SM2 1 0 Cases under general anesthesia 9 10 n.s. Intralesional injection 6 10 0.074 Original group Modified group P value Number 11 11 Sex  Men 11 11 n.s.  Women 0 0 Age, years [mean (SD)] 72.4 (8.9) 65.3 (12.2) 0.19 Location 0.33  Upper 3 0  Middle 6 7  Lower 2 4 Macroscopic type 0.035  0–2a 1 0  0–2c 10 6  0–2b 0 5 Tumor size, mm [mean (SD)] 64.1 (12.8) 67.3 (11.0) 0.49 Longitudinal length, mm [mean (SD)] 72.6 (16.8) 76.5 (11.1) 0.47 Depth of tumor invasion 0.59  EP/LPM 9 8  MM/SM1 1 3  SM2 1 0 Cases under general anesthesia 9 10 n.s. Intralesional injection 6 10 0.074 EP, epithelium; LPM, lamina propria mucosae; MM, muscularis mucosa; n.s., not significant; SD, standard deviation; SM, submucosa. View Large Table 1 Patient characteristics Original group Modified group P value Number 11 11 Sex  Men 11 11 n.s.  Women 0 0 Age, years [mean (SD)] 72.4 (8.9) 65.3 (12.2) 0.19 Location 0.33  Upper 3 0  Middle 6 7  Lower 2 4 Macroscopic type 0.035  0–2a 1 0  0–2c 10 6  0–2b 0 5 Tumor size, mm [mean (SD)] 64.1 (12.8) 67.3 (11.0) 0.49 Longitudinal length, mm [mean (SD)] 72.6 (16.8) 76.5 (11.1) 0.47 Depth of tumor invasion 0.59  EP/LPM 9 8  MM/SM1 1 3  SM2 1 0 Cases under general anesthesia 9 10 n.s. Intralesional injection 6 10 0.074 Original group Modified group P value Number 11 11 Sex  Men 11 11 n.s.  Women 0 0 Age, years [mean (SD)] 72.4 (8.9) 65.3 (12.2) 0.19 Location 0.33  Upper 3 0  Middle 6 7  Lower 2 4 Macroscopic type 0.035  0–2a 1 0  0–2c 10 6  0–2b 0 5 Tumor size, mm [mean (SD)] 64.1 (12.8) 67.3 (11.0) 0.49 Longitudinal length, mm [mean (SD)] 72.6 (16.8) 76.5 (11.1) 0.47 Depth of tumor invasion 0.59  EP/LPM 9 8  MM/SM1 1 3  SM2 1 0 Cases under general anesthesia 9 10 n.s. Intralesional injection 6 10 0.074 EP, epithelium; LPM, lamina propria mucosae; MM, muscularis mucosa; n.s., not significant; SD, standard deviation; SM, submucosa. View Large The results of this study are shown in Table 2. Both en bloc and R0 resections were achieved in both groups. The post-ESD stricture rate in the modified group was 36.4% (4/11 patients), which was significantly lower than that in the original group (9/11 patients; 82%) (Table 3). The median number of EBD procedures was 0 in the modified group and 25 in the original group. The mean number of EBD procedures among those requiring EBD was 6.2 ± 11.3 in the modified group and 19.4 ± 15.3 in the original group, which was a statistically significant difference (P = 0.023). No patients complained of persistent dysphagia. However, some patients complained of dysphagia when they ate very quickly despite the fact that the stricture had been released. The incidence of patients who complained of this intermittent dysphagia was 36% and 27% in the original and modified groups, respectively. Risk factors for esophageal stricture were then analyzed. In the univariate analysis, total steroid use was identified as a possible risk factor (odds ratio [OR], 7.88; 95% confidence interval [CI], 1.10–56.1; P = 0.039). Multivariate analysis adjusted for each factor which was potentially associated with risk factors (P < 0.2) revealed that total steroid use tended to be an independent risk factor for post-ESD stricture (Table 4). Perforation, an adverse event associated with EBD, was observed in 1 patient in the modified group. This patient subsequently recovered with conservative treatment. No adverse event associated with ESD such as post-ESD bleeding, perforation, or delayed perforation was observed in either group. Pneumonia and oral herpes infection, which are adverse events potentially associated with steroid administration, were observed in the original group. Candida esophagitis, arthritis, and steroid-related myopathy were also observed in the modified group (Table 5). Because no symptoms potentially caused by candida esophagitis were observed in any of our patients, we did not routinely administer prophylactic antifungals. However, we sometimes administer prophylactic systemic antifungal treatment before follow-up endoscopy. Table 2 Clinical results of circumferential ESD Original Modified P value En bloc resection rate, % 100 100 n.s. R0 resection rate, % 100 100 n.s. Procedure time, min [mean (SD)] 118.9 (24.7) 102.3 (29.8) 0.11 Length of stay (median, days) 28 30 0.69 Adverse events Perforation 0 0 n.s. Post-ESD bleeding 0 0 n.s. Local recurrence 0 0 n.s. Original Modified P value En bloc resection rate, % 100 100 n.s. R0 resection rate, % 100 100 n.s. Procedure time, min [mean (SD)] 118.9 (24.7) 102.3 (29.8) 0.11 Length of stay (median, days) 28 30 0.69 Adverse events Perforation 0 0 n.s. Post-ESD bleeding 0 0 n.s. Local recurrence 0 0 n.s. ESD, endoscopic submucosal dissection; n.s., not significant; SD, standard deviation. View Large Table 2 Clinical results of circumferential ESD Original Modified P value En bloc resection rate, % 100 100 n.s. R0 resection rate, % 100 100 n.s. Procedure time, min [mean (SD)] 118.9 (24.7) 102.3 (29.8) 0.11 Length of stay (median, days) 28 30 0.69 Adverse events Perforation 0 0 n.s. Post-ESD bleeding 0 0 n.s. Local recurrence 0 0 n.s. Original Modified P value En bloc resection rate, % 100 100 n.s. R0 resection rate, % 100 100 n.s. Procedure time, min [mean (SD)] 118.9 (24.7) 102.3 (29.8) 0.11 Length of stay (median, days) 28 30 0.69 Adverse events Perforation 0 0 n.s. Post-ESD bleeding 0 0 n.s. Local recurrence 0 0 n.s. ESD, endoscopic submucosal dissection; n.s., not significant; SD, standard deviation. View Large Table 3 Comparison of postprocedural strictures after ESD and the number of EBD sessions Original Modified P value Stricture 9 4 0.04 Number of EBD procedures [mean (SD)] [range] 19.4 (15.3) [0–42] 6.2 (11.3) [0–28] 0.023 Original Modified P value Stricture 9 4 0.04 Number of EBD procedures [mean (SD)] [range] 19.4 (15.3) [0–42] 6.2 (11.3) [0–28] 0.023 EBD, endoscopic balloon dilation; ESD, endoscopic submucosal dissection; SD, standard deviation. View Large Table 3 Comparison of postprocedural strictures after ESD and the number of EBD sessions Original Modified P value Stricture 9 4 0.04 Number of EBD procedures [mean (SD)] [range] 19.4 (15.3) [0–42] 6.2 (11.3) [0–28] 0.023 Original Modified P value Stricture 9 4 0.04 Number of EBD procedures [mean (SD)] [range] 19.4 (15.3) [0–42] 6.2 (11.3) [0–28] 0.023 EBD, endoscopic balloon dilation; ESD, endoscopic submucosal dissection; SD, standard deviation. View Large Table 4 Risk factors to develop the esophageal stricture (A-D). Odds 95% CI P A: Steroid use group (univariate OR) Modified group Reference Original 7.88 1.10–56.1 0.039 B: Steroid use group, OR adjusted for intralesional steroids Intralesional injection Positive Reference Negative 2.47 0.18–33.6 0.50 Total steroid use Modified Reference Original 6.07 0.77–47.9 0.087 C: Steroid use group, OR adjusted for age Age 0.97 0.89–1.07 0.54 Total steroid use Modified Reference Original 10.0 1.16–86.4 0.036 D: Steroid use group, OR adjusted for macroscopic tumor type Macroscopic type Flat & elevated type Reference depressed type 0.62 0.062–6.11 0.68 Total steroid use Modified Reference Original 9.53 1.06–85.4 0.044 Odds 95% CI P A: Steroid use group (univariate OR) Modified group Reference Original 7.88 1.10–56.1 0.039 B: Steroid use group, OR adjusted for intralesional steroids Intralesional injection Positive Reference Negative 2.47 0.18–33.6 0.50 Total steroid use Modified Reference Original 6.07 0.77–47.9 0.087 C: Steroid use group, OR adjusted for age Age 0.97 0.89–1.07 0.54 Total steroid use Modified Reference Original 10.0 1.16–86.4 0.036 D: Steroid use group, OR adjusted for macroscopic tumor type Macroscopic type Flat & elevated type Reference depressed type 0.62 0.062–6.11 0.68 Total steroid use Modified Reference Original 9.53 1.06–85.4 0.044 View Large Table 4 Risk factors to develop the esophageal stricture (A-D). Odds 95% CI P A: Steroid use group (univariate OR) Modified group Reference Original 7.88 1.10–56.1 0.039 B: Steroid use group, OR adjusted for intralesional steroids Intralesional injection Positive Reference Negative 2.47 0.18–33.6 0.50 Total steroid use Modified Reference Original 6.07 0.77–47.9 0.087 C: Steroid use group, OR adjusted for age Age 0.97 0.89–1.07 0.54 Total steroid use Modified Reference Original 10.0 1.16–86.4 0.036 D: Steroid use group, OR adjusted for macroscopic tumor type Macroscopic type Flat & elevated type Reference depressed type 0.62 0.062–6.11 0.68 Total steroid use Modified Reference Original 9.53 1.06–85.4 0.044 Odds 95% CI P A: Steroid use group (univariate OR) Modified group Reference Original 7.88 1.10–56.1 0.039 B: Steroid use group, OR adjusted for intralesional steroids Intralesional injection Positive Reference Negative 2.47 0.18–33.6 0.50 Total steroid use Modified Reference Original 6.07 0.77–47.9 0.087 C: Steroid use group, OR adjusted for age Age 0.97 0.89–1.07 0.54 Total steroid use Modified Reference Original 10.0 1.16–86.4 0.036 D: Steroid use group, OR adjusted for macroscopic tumor type Macroscopic type Flat & elevated type Reference depressed type 0.62 0.062–6.11 0.68 Total steroid use Modified Reference Original 9.53 1.06–85.4 0.044 View Large Table 5 Adverse events potentially associated with steroid administration Treatment-related disease Original Modified P value Pneumonia 2 0 0.48 Oral herpes infection 1 0 1.0 Candida esophagitis 0 7 0.004 Arthritis 0 1 1.0 Steroid-related myopathy 0 2 0.48 Total number of AE 3 8 0.043 Treatment-related disease Original Modified P value Pneumonia 2 0 0.48 Oral herpes infection 1 0 1.0 Candida esophagitis 0 7 0.004 Arthritis 0 1 1.0 Steroid-related myopathy 0 2 0.48 Total number of AE 3 8 0.043 AE, Adverse event. View Large Table 5 Adverse events potentially associated with steroid administration Treatment-related disease Original Modified P value Pneumonia 2 0 0.48 Oral herpes infection 1 0 1.0 Candida esophagitis 0 7 0.004 Arthritis 0 1 1.0 Steroid-related myopathy 0 2 0.48 Total number of AE 3 8 0.043 Treatment-related disease Original Modified P value Pneumonia 2 0 0.48 Oral herpes infection 1 0 1.0 Candida esophagitis 0 7 0.004 Arthritis 0 1 1.0 Steroid-related myopathy 0 2 0.48 Total number of AE 3 8 0.043 AE, Adverse event. View Large DISCUSSION This is the first study to report the feasibility and effectiveness of modified oral steroid administration for ESD cases with entire circumferential mucosal defects. The safety of cESD was also demonstrated in this study. This modified method shows high potential as a preventive measure against esophageal stricture compared with previous methods. Few reports have detailed cases of entire cESD. In the report by Yamaguchi et al., esophageal stricture developed in all 3 patients who underwent entire cESD.5 In the report by Kadota et al., esophageal stricture developed in 10 of 14 patients (71%) who underwent a combination of local steroid injections and oral systemic steroid administration.9 Sato et al. reported that esophageal stricture developed in 10 of 10 patients who underwent steroid administration and EBD, although EBD was conducted when resistance to the endoscope was encountered.8 In the case of intralesional steroid injections alone, Takahashi et al. reported that esophageal stricture developed in 10 patients who underwent entire cESD and intralesional steroid injections.11 Although it is impossible to compare the results of those reports with our results, the frequency of esophageal stricture could be decreased from half to one third. Another impressive feature was the decrease in the number of EBD procedures. EBD has a potential risk of perforation or bleeding and repeated dilatations can worsen scarring, which results in recurrence of strictures that are more difficult to treat.12,13 According to previous reports, local or systemic steroid administration leads to a reduction in the number of EBD procedures required to treat strictures, without increasing the number of complications.14 In fact, the results of this study showed that modified steroid administration decreased the mean number of EBD procedures significantly. Adverse events related to steroid administration are of great concern. Oliveira et al. stated that treatment with high-dose corticosteroids may be associated with adverse events including immunosuppression, diabetes, psychiatric disorders, osteoporosis, and peptic disease.14 In this study, the main adverse event in the modified group was candida esophagitis, which was observed at a significantly higher rate than in the original group; however, all cases were manageable by conservative treatment. None of the adverse events were difficult to manage by conservative treatment among the limited number of patients in this study. It was not possible to identify the causative bacteria for the patient who developed pneumonia. However, steroids induce an immunosuppressive state, putting patients at risk of infections such as pneumocystis pneumonia (PCP), which has a high mortality rate.15 Bactrim prophylaxis was thus administered through the entire course of steroid treatment. The literature supports prophylaxis for PCP in patients administered steroids in doses greater than 20 mg for 1 month or longer.16 There were no patients with psychiatric disorders or peptic ulcer disease in either of our study groups. As for diabetes, this study had four diabetic patients in the original group and one in the modified group. Control of blood sugar levels was managed by experts, and none of the patients developed uncontrolled diabetes in this study. Nonetheless, close attention should be paid to adverse events. This treatment has a potential drawback if histological assessment reveals invasion depth below the muscularis mucosa (MM), which indicates a potential risk of lymph node metastasis. Specifically, chemoradiotherapy (CRT) as an additional treatment would be delayed because it is necessary to first confirm the absence of esophageal strictures, though there would be no delay if the patient opts for surgery. Indeed, two patients received CRT because of findings of pathological invasion below the MM and positive lymphovascular involvement. The interval between ESD and CRT was 157 days and 217 days for these two patients. Moreover, a recurrence of lymph node metastasis was observed in one patient, who later died of esophageal cancer, despite receiving additional treatment. There are some limitations to this study. First, it was a retrospective study with a small sample size. Second, the treatment periods differed between the original and modified groups, with the modified treatment starting after obtaining poor results from the original group. A prospective randomized controlled study would be ideal for evaluating the effectiveness of steroid administration; however, cases with cESD are very limited, and new preventive methods are required as soon as possible, making it difficult to perform randomized controlled studies. In conclusion, although this study had a small number of patients, it suggests that modified systemic steroid administration may be as effective as standard, longer courses of steroid treatment for patients with entire circumferential mucosal defects. The safety of this method was also demonstrated. Although there were no differences in the technical aspects of the procedures between the original and modified groups, duration of steroid administration was definitely longer in modified group. Accordingly, psychological stress may have been higher in the modified group. In addition, the rate of strictures was still not small; therefore, it is essential to carefully observe patients and promptly treat esophageal strictures that develop after entire cESD. Notes Special author contributions: Authorship: Toshiro Iizuka; Conception and design: Toshiro Iizuka, Daisuke Kikuchi; Analysis and interpretation of the data: Toshiro Iizuka, Daisuke Kikuchi; Drafting of the article: Toshiro Iizuka, Daisuke Kikuchi, Shu Hoteya, Mitsuru Kaise; Acquisition of data: Toshiro Iizuka, Daisuke Kikuchi, Shu Hoteya, Mitsuru Kaise; General supervision of the research group: Department of gastroenterology, Toranomon Hospital; Critical revision of the article: Mitsuru Kaise Final approval of the article: Toshiro Iizuka, Daisuke Kikuchi, Shu Hoteya, Mitsuru Kaise. References 1 Ono S , Fujishiro M , Niimi K et al. Predictors of postoperative stricture after esophageal endoscopic submucosal dissection for superficial squamous cell neoplasms . Endoscopy 2009 ; 41 : 661 – 5 . Google Scholar CrossRef Search ADS PubMed 2 Katada C , Muto M , Manabe T et al. Esophageal stenosis after endoscopic mucosal resection of superficial esophageal lesion . Gastrointest Endosc 2003 ; 57 : 165 – 9 . Google Scholar CrossRef Search ADS PubMed 3 Yoda Y , Yano T , Kaneko K et al. Endoscopic balloon dilatation for benign fibrotic strictures after curative nonsurgical treatment for esophageal cancer . Surg Endosc 2012 ; 26 : 2877 – 83 . Google Scholar CrossRef Search ADS PubMed 4 Isomoto H , Yamaguchi N , Nakayama T et al. Management of esophageal stricture after complete circular endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma . BMC Gastroenterol 2011 ; 11 : 46 . Google Scholar CrossRef Search ADS PubMed 5 Yamaguchi N , Isomoto H , Nakayama T et al. Usefulness of oral prednisolone in the treatment of esophageal stricture after endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma . Gastrointest Endosc 2011 ; 73 : 1115 – 21 . Google Scholar CrossRef Search ADS PubMed 6 Hashimoto S , Kobayashi M , Takeuchi M et al. The efficacy of endoscopic triamcinolone injection for the prevention of esophageal stricture after endoscopic submucosal dissection . Gastrointest Endosc 2011 ; 74 : 1389 – 93 . Google Scholar CrossRef Search ADS PubMed 7 Hanaoka N , Ishihara R , Takeuchi Y et al. Intralesional steroid injection to prevent stricture after endoscopic submucosal dissection for esophageal cancer: a controlled prospective study . Endoscopy 2012 ; 44 : 1007 – 11 . Google Scholar CrossRef Search ADS PubMed 8 Sato H , Inoue H , Kobayashi Y et al. Control of severe strictures after circumferential endoscopic submucosal dissection for esophageal carcinoma: oral steroid therapy with balloon dilation or balloon dilation alone . Gastrointest Endosc 2013 ; 78 : 250 – 7 . Google Scholar CrossRef Search ADS PubMed 9 Kadota T , Yano T , Kato T et al. Prophylactic steroid administration for strictures after endoscopic resection of large superficial esophageal squamous cell carcinoma . Endosc Int Open 2016 ; 4 : E1267 – 74 . Google Scholar CrossRef Search ADS PubMed 10 Wang W , Ma Z . Steroid administration is effective to prevent strictures after endoscopic esophageal submucosal dissection: a network metaanalysis . Medicine (Baltimore) 2015 ; 94 : e1664 . Google Scholar CrossRef Search ADS PubMed 11 Takahashi H , Arimura Y , Okahara S et al. Randomized controlled trial of endoscopic steroid injection for prophylaxis of esophageal stenoses after extensive endoscopic submucosal dissection . BMC Gastroenterol 2015 ; 15 : 1 . Google Scholar CrossRef Search ADS PubMed 12 Takahashi H , Arimura Y , Okahara S et al. Risk of perforation during dilation for esophageal strictures after endoscopic resection in patients with early squamous cell carcinoma . Endoscopy 2011 ; 43 : 184 – 9 . Google Scholar CrossRef Search ADS PubMed 13 Cheng Y S , Li M H , Yang R J et al. Restenosis following balloon dilation of benign esophageal stenosis . World J Gastroenterol 2003 ; 9 : 2605 – 8 . Google Scholar CrossRef Search ADS PubMed 14 Oliveira J F , Moura E G , Bernardo W M et al. Prevention of esophageal stricture after endoscopic submucosal dissection: a systematic review and meta-analysis . Surg Endosc 2016 ; 30 : 2779 – 91 . Google Scholar CrossRef Search ADS PubMed 15 Tasaka S , Tokuda H . Pneumocystis jirovecii pneumonia in non-HIV-infected patients in the era of novel immunosuppressive therapies . J Infect Chemother 2012 ; 18 : 793 – 806 . Google Scholar CrossRef Search ADS PubMed 16 Limper A H , Knox K S , Sarosi G A et al. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients . Am J Respir Crit Care Med 2011 ; 183 : 96 – 128 . Google Scholar CrossRef Search ADS PubMed © The Authors 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Diseases of the EsophagusOxford University Press

Published: Jul 1, 2018

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