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Journal of Digestive Diseases 2015; 16; 370–376
doi: 10.1111/1751-2980.12255
Original article
Intramuscular injection of mitomycin C combined with endoscopic dilation for benign esophageal strictures Yin ZHANG,*,† Xiang WANG,‡ Li LIU,‡ Jian Ping CHEN* & Zhi Ning FAN‡ *Department of Digestive Disease, The First People’s Hospital of Changzhou, Changzhou, †Department of Digestive Endoscopy and Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University and ‡Department of Digestive Endoscopy, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu Province, China
OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of intramuscular injection of either mitomycin C or dexamethasone with endoscopic dilation for benign esophageal strictures after esophageal surgery or endoscopic submucosal dissection. METHODS: Patients with benign esophageal strictures were retrospectively enrolled in this study and divided into three groups: mitomycin C group (mitomycin C injection with endoscopic dilation, dexamethasone group (dexamethasone injection and dilation) and dilation group (physiological saline injection and dilation). The patients’ characteristics, locations of lesions, number of previous dilations, esophageal diameters after dilation, grades of dysphagia before and after the procedure and dysphagiafree period during the follow-up period were recorded. RESULTS: Altogether 74 patients including 25 in the mitomycin C group, 25 in the dexamethasone group KEY WORDS:
CONCLUSION: Intramuscular injection of mitomycin C or dexamethasone may prolong the dysphagia-free period and decrease the frequency of repeat dilations compared with conventional endoscopic dilations in patients with benign esophageal strictures.
benign esophageal stricture, dexamethasone, endoscopic dilation, mitomycin C.
Correspondence to: Zhi Ning FAN, Department of Digestive Endoscopy, The First Affiliated Hospital with Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, Jiangsu Province 210029, China. Email: [email protected] Conflict of interest: None. © 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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and 24 in the dilation group were enrolled. The diameter of the esophagus before the procedure was 3.32 ± 0.90 mm, 3.92 ± 1.55 mm and 3.70 ± 1.30 mm, respectively, while that was increased to 12.77 ± 1.62 mm, 12.14 ± 1.28 mm and 12.73 ± 1.42 mm after endoscopic dilation in the mitomycin C, dexamethasone and conventional dilation groups. The dysphagia-free period was 4.88 ± 1.66 months in the mitomycin C group, 4.02 ± 1.77 months in the dexamethasone group and 2.41 ± 1.26 months in the dilation group (P < 0.05).
INTRODUCTION Benign esophageal strictures have known to be caused by several diseases, including peptic disease, corrosive and radiation injury, as well as surgical anastomosis and infection, etc.1 In recent years, esophageal strictures after endoscopic submucosal dissection (ESD) are more frequently seen in clinical setting. Common treatments for benign esophageal strictures include
Journal of Digestive Diseases 2015; 16; 370–376 esophageal dilation with Savary-Gilliard bougie or expansion balloon, endoprosthetic deployment and steroid injection.2,3 In most patients benign esophageal stricture can be treated effectively with several sessions of dilation; however, a small proportion of patients do not respond to this therapy.4 Up to 40% of benign esophageal strictures are anastomotic strictures that occur after esophagectomy.5 With the development of treatment modalities, ESD has been increasingly used for early superficial and submucosal esophageal tumors, with a reliable en bloc resection rate.6 However, ESD is challenging for esophageal lesions in large sizes with deep invasion due to a high risk of stricture, which affects the patient’s daily life.7 Ono et al.8 reported that the rate of postoperative esophageal strictures was as high as 93% in patients with lesions that were more than half the luminal circumference. For the other types of strictures the treatments are also challenging. As an auxiliary treatment to endoscopic dilation, intralesional steroid injection has been applied since 1970 when this technique was first introduced by Mendelsohn and Maloney.9 However, after being studied for decades, including in some randomized controlled trials (RCTs) with small sample sizes, it remains unknown whether local steroid injection decreases the frequency of repeated dilations or prolongs the dysphagia-free period in patients with benign esophageal strictures.2 Mitomycin C is a chemotherapeutic agent that reduces the formation of scar when applied to surgical lesions. It has been widely used in children experience postoperative esophageal strictures who have undergone surgical repairs for esophageal atresia or those who have caustic esophageal strictures.10,11 In recent studies, mitomycin C has also been used for the treatment of esophageal strictures after ESD in adults.12 Furthermore, previous studies13,14 have supported the application of mitomycin C in combination with endoscopic dilation as an alternative option that is both effective and safe for treating benign esophageal strictures. In this study, we aimed to investigate whether mitomycin C injection combined with dilation might prolong the dysphagia-free period compared with either dexamethasone injection combined with dilation or conventional endoscopic dilation alone.
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PATIENTS AND METHODS Patients From January 2013 to January 2014, patients diagnosed as benign esophageal stricture with grade 3 or 4 dysphagia at the Department of Digestive Disease, The First People’s Hospital of Changzhou (Changzhou, Jiangsu Province, China), the Department of Digestive Endoscopy, The Second Affiliated Hospital of Nanjing Medical University and the Department of Digestive Endoscopy, The First Affiliated Hospital with Nanjing Medical University (Nanjing, Jiangsu Province, China) were enrolled in the study. The study was approved by the Institutional Ethics Committees of the three hospitals. Inclusion criteria were: (i) patients with pathologically confirmed benign esophageal strictures, including those having anastomotic stricture or stricture after ESD; and (ii) the length of the strictures was less than 3 cm, in the absence of esophageal distortion or angulation. Patients with a previous history of stent placement or drug injection, those suspected of malignant tumor recurrence, having other esophageal and gastric diseases or severe systemic diseases were excluded from the study. The enrolled patients were then divided into three groups according to the treatments: (i) the mitomycin C group, patients receiving mitomycin C injection together with endoscopic dilation; (ii) the dexamethasome group, age-matched and gendermatched patients who received dexamethasone injection and endoscopic dilation; and (iii) the dilation group, patients receiving 10 mL 0.9% physiological saline injection and endoscopic dilation. Endoscopic dilation A commercially available standard therapeutic endoscope (GIF-Q260, Olympus, Tokyo, Japan) was used for endoscopic dilation in all patients. A set of SavaryGilliard bougies (SGD-100-1, Wilson-Cook Medical Inc., Winston-Salem, NC, USA) or expansion balloon (CRE Wireguided Balloon Dilator, Boston Scientific, Minneapolis, MI, USA) were prepared for the dilation. An injection needle (INJ1-A1, Medwork GmbH, Höchstadt, Germany) was used for the injections. Mitomycin C (10 mg of 1 mg/mL, Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou, Zhejiang Province, China) and dexamethasone (5 mg of 0.5 mg/mL, Anyang Jiuzhou Pharmaceutical Co., Ltd., Anyang, Henan Province, China) were prepared before the
© 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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procedure. Endoscopic dilation was performed by experienced endoscopists (Xiang WANG, Jian Ping CHEN and Zhi Ning FAN) who have performed esophageal dilation and stent insertion for more than 300 patients every year. The presence and severity of the strictures were determined by esophagogastroduodenoscopy (EGD) in patients under conscious sedation with midazolam or propofol at the left lateral position. The diameter of the esophagus before dilation was recorded. The diameter of the stricture was evaluated using the biopsy forceps, which was approximately 5 mm when the forceps was opened. If the endoscope was able to pass through the stricture, gastric and duodenal cavities were observed and endoscopic dilation was then performed. The dilation was performed first when the endoscope was unable to pass through the stricture. Endoscopic dilation was performed using either the Savary-Gilliard bougie or expansion balloon depending on the preference of the operator. The target diameter of the esophagus was no less than 12 mm, which was considered sufficient to drain the esophagus. When dilating using a set of bougies, each bougie was gently inserted through the guidewire under fluoroscopic guidance and was held for 1–2 min. While dilating with a balloon, the balloon was inserted through the channel of the endoscope and the pressure was increased to 101 kPa and held for 1–2 min. If there was not any bleeding or perforation after repeated endoscopic examinations, a total of 10 mL of mitomycin C or dexamethasone was injected into the muscle layer of the dilated lesion in four quadrants (at the 3-, 6-, 9- and 12-o’clock positions). After the injection, the patients were re-examined to confirm that no bleeding or perforation had occurred (Figure 1). Postoperative care After endoscopic dilation, all the patients were treated with omeprazole 40 mg twice daily (AstraZeneca, London, UK). The patients were fasted for 24 h after the procedure, and they were then permitted to intake semi-solid food when there were no complaints such as fever, chest or abdominal pain, chest distress, subcutaneous emphysema or elevated white blood cell (WBC) count. Peripheral complete blood count was evaluated daily until the results returned to normal level. Antibiotics were not routinely applied unless the WBC counts reached an abnormal level or the patients had a fever. The patients were then discharged and kept on anti-reflux therapy with a proton pump
Figure 1. Intramuscular injection of mitomycin C combined with endoscopic dilation. (a) Esophageal stricture after esophagectomy. (b) Endoscopic view after dilation with Savary-Gilliard bougies. (c) Injecting mitomycin C into the muscular layer of the lesion. (d) Follow-up endoscopy one month after the procedure.
inhibitor (PPI) for 4 weeks. All the patients were followed up at the Outpatient Department of Gastroenterology or via telephone every 2 to 4 weeks for at least 6 months. Those who had dysphagia recurred during the follow-up period were treated endoscopically again. Definitions Dysphagia was graded according to the consistency of food the patients were able to eat: 0, be able to eat a normal diet; 1, unable to swallow certain solid food; 2, unable to swallow any solid food; 3, unable to swallow semi-solid food; and 4, unable to swallow liquids.15 The location of esophageal lesions was classified as follows: upper esophagus, shorter than 15 cm from the incisor; middle esophagus, 15–40 cm from the incisor; lower esophagus, below 40 cm from the incisor. The technical success of the procedure was defined as an uneventful dilation with either the bougies or balloon and the intramuscle injection of the drug into the lesion (flattening was negative for resistance when injecting the drugs). Clinical success was defined as the absence of dysphagia for at least one week after the procedure.
© 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2015; 16; 370–376
Mitomycin C for strictures
Recurrent dysphagia due to the stricture was defined as the grade of dysphagia either reaching or rising above grade 3 after ruling out the possibility of malignancy. A dysphagia-free period of at least 6 months was defined as the cure of the disease. Major complications related to the endoscopic dilation or the injection of drugs include massive hemorrhage, perforation or severe pain. Minor complications included mild to moderate pain or reflux, fever or elevated WBC count. Perforation was defined as the presence of chest distress or subcutaneous emphysema that was confirmed by chest radiography. Statistical analysis Statistical analyses were performed using SPSS 13.0 (IBM, Armonk, NY, USA). The patients’ characteristics including age, gender, the location and type of stricture, number of anterior dilations, technical success, clinical success, the grade of dysphagia and the diameter of the esophagus before and after endoscopic dilation, and the dysphagia-free period were recorded. Quantitative variables were expressed as Table 1.
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mean ± standard deviation and were analyzed using the one-way ANOVA. The ranked parameters were expressed as medians and ranges and were analyzed using the Kruskal–Wallis test. Qualitative variables were analyzed using χ2 test or Fisher’s exact test. Differences in the continuous variables were tested with the least significant difference test or the Mann– Whitney U test, when appropriate. P ≤ 0.05 was considered statistically significant. RESULTS Altogether 74 patients were enrolled in the study, including 25 receiving mitomycin C injection, 25 receiving dexamethasone injection and 24 receiving physiological saline injection. There were no significant differences among the three groups at the baseline in age, gender, the location or type of esophageal stricture and the number of anterior dilation (Table 1). Anastomotic strictures and strictures after ESD were found in 16 (64.0%) and 9 (36.0%) patients in the mitomycin C group, while those in the dexamethasone group were 18 (72.0%) and 7 (28.0%), respectively. In the dilation group, there were 16 (66.7%) cases with anastomotic strictures and 8
The characteristics and results of mitomycin C injection to treat benign esophageal stricture
Age, years (mean ± SD) Male/female, n Type of stricture, n (%) Anastomotic stricture Stricture after ESD Location, n (%) Upper esophagus Middle esophagus Lower esophagus Dilation before injection, median (range) Technical success, n (%) Clinical success, n (%) Grade of dysphagia, median (range) Before After Diameter of esophagus, mm (mean ± SD) Before dilation After dilation Major complication, n (%) Minor complication, n (%) Dysphagia-free period, months (mean ± SD)
Mitomycin C group (n = 25)
Dexamethasone group (n = 25)
Dilation group (n = 24)
61.08 ± 13.68 16/9
64.00 ± 8.34 15/10
61.17 ± 9.27 16/8
16 (64.0) 9 (36.0)
18 (72.0) 7 (28.0)
16 (66.7) 8 (33.3)
0 (0) 25 (100) 0 (0) 3 (1–5) 25 (100) 25 (100)
0 (0) 25 (100) 0 (0) 3 (1–4) 25 (100) 25 (100)
0 (0) 24 (100) 0 (0) 3 (1–5) 24 (100) 24 (100)
3 (3–4) 1 (1–2)
4 (3–4) 1 (1–2)
4 (3–4) 1 (1–2)
3.32 ± 0.90 12.77 ± 1.62 0 (0) 6 (24.0) 4.88 ± 1.66
3.92 ± 1.55 12.14 ± 1.28 0 (0) 5 (20.0) 4.02 ± 1.77
3.70 ± 1.30 12.73 ± 1.42 0 (0) 3 (12.5) 2.41 ± 1.26
Upper esophagus, shorter than 15 cm from the incisor; middle esophagus, 15–40 cm from the incisor; lower esophagus, lower than 40 cm from the incisor. ESD, endoscopic submucosal dissection; SD, standard deviation.
© 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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(33.3%) with strictures after ESD. All lesions in the three groups were located at the middle esophagus. The median number of anterior dilations was 3 (range 1–5), 3 (range 1–4) and 3 (range 1–5), respectively. All patients in the three groups were graded as 3–4 for dysphagia before endoscopic dilation; however, after dilation the grade of dysphagia was 1–2. All patients achieved technical and clinical success after endoscopic dilation. The diameter of the esophagus before the procedure was 3.32 ± 0.90 mm, 3.92 ± 1.55 mm and 3.70 ± 1.30 mm, respectively, while that was increased to 12.77 ± 1.62 mm, 12.14 ± 1.28 mm and 12.73 ± 1.42 mm, respectively, after endoscopic dilation. There was no difference in the esophageal diameter among the three groups. No major complications such as massive bleeding, leakage or perforation were observed in either of the three groups. Minor complications, including mild to moderate pain and reflux, occurred in six patients in the mitomycin C group, five in the dexamethasone group and three in the dilation group. Elevated WBC count was seen in one patient in the mitomycin C group, one in the dexamethasone group and two in the dilation group, respectively. All patients were treated conventionally and were discharged with no complaints. After discharge, all patients received both telephone and clinical follow-up for more than 6 months. The dysphagia-free period was 4.88 ± 1.66 months, 4.02 ± 1.77 months and 2.41 ± 1.26 months, respectively, in the mitomycin C, dexamethasome and dilation groups, respectively. When dysphagia relapsed, the endoscopic procedure was repeated. DISCUSSION With the rapidly rising incidence of esophageal cancer during the past decades,16 surgery is considered the curative therapy for such patients regardless of subsequent neoadjuvant therapy. And endoscopic therapies are being widely used as potential curative approaches for early esophageal carcinomas.17 However, benign esophageal strictures are not rare in patients with esophageal anastomoses and those receiving circumferential ESD.18,19 Dysphagia, the most common symptom of esophageal strictures, has a deleterious impact on patients’ quality of life and may lead to severe complications such as aspiration, weight loss and malnutrition.20 The most common treatment option for benign esophageal strictures is endoscopic dilation, including
Journal of Digestive Diseases 2015; 16; 370–376 dilation with bougie, expansion balloon or stent. Ono et al.8 reported that post-ESD esophageal strictures could be successfully managed by temporary dilation with a median of two sessions. In addition, dilation with bougie and balloon is reported to be safe and effective for managing benign esophageal strictures.21 Temporary stent insertions have also been increasingly used for the disease.22 However, it is not the first choice of treatment considering the inflammatory hyperplasia that occurs with partially covered metal stents and a high migration rate with the fully covered metal stents.23 Injections with corticosteroids have been shown to relieve these strictures since it was first mentioned in the 1970s.9 Studies have also reported the effect of local corticosteroid injection combined with dilation on the treatment for benign esophageal strictures. Moreover, some RCTs have revealed that corticosteroid injection combined with dilation may prolong the dysphagia-free period or decrease the frequency of dilation.1,24 However, Hirdes et al.25 reported that corticosteroid injections in combination with dilation did not decrease the frequency of repeated dilation or prolong patency after gastroesophageal anastomotic stricture. Furthermore, corticosteroid injections may be associated with an increased risk of Candida esophagitis. Thus, whether corticosteroid injections are beneficial for benign esophageal strictures continues to be controversial. Mitomycin C is a chemotherapeutic agent that is widely used against cancers of the digestive system because of its ability of generating oxygen radicals and alkylates and cross-linking DNA, thereby inhibiting DNA synthesis.26 Additionally, it also inhibits the proliferation of fibroblasts and collagen synthesis that are the crucial causes of benign esophageal strictures after mechanical injury.12 Of note, the use of mitomycin C was not rare during the past decades. On the contrary, a series of studies have shown the beneficial effects of mitomycin C on caustic esophageal strictures and anastomotic strictures after surgical repair of the esophageal atresia in children, in which a cotton pledget containing the drug is inserted into the esophagus or mitomycin C is injected via catheter balloon. However, most of these studies were small in sample size or lacked a control group.10,27,28 In this study, we compared the effects of mitomycin C injections combined with dilation, dexamethasone injections combined with dilation and conventional endoscopic dilation. The dysphagia-free period during the follow-up period was longest in the mitomycin C group, followed by the dexamethasone group and the conventional dilation group, showing that
© 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2015; 16; 370–376 mitomycin C might have had a more dominant effect than dexamethasone in the treatment of benign esophageal strictures. Moreover, mitomycin C injections did not cause systemic side effects, such as bone marrow suppression or elevated WBC counts. In our study the drugs were injected intramuscularly. Specifically, in the report by Machida et al.,12 the drug was injected into the submucosal layer (avoiding the muscle layer). However, fibroplasia and scarring are predominant in benign esophageal strictures following surgical anastomosis or ESD, even when no mucosal or submucosal layer exists. Therefore, the drug was injected into the muscle layer and the occurrence of any leaks, ulcers or perforations was observed. There were no significant differences in the postoperative complications among the three groups, indicating that both mitomycin C and dexamethasone were safe. There were no major complications, and all minor complications were managed with conventional therapy. In comparison with other studies, the complication rate in our study was low. We believe that this might be attributed to the following reasons: (i) the strictures in our study were less than 3 cm in length, which means that the dilation was relatively simple to perform; (ii) all the endoscopists are very experienced, and the dilation with the Savary-Gilliard bougie or expansion balloon was performed gently and incrementally, which reduced the risk of perforation; (iii) most importantly, we recorded the incidence of chest pain, chest distress and subcutaneous emphysema, but chest radiography was not performed routinely. Some tiny perforations do not cause these symptoms, and the air can be absorbed spontaneously within several days. Some limitations of this study should be noted. First, the concentrations and total doses of these drugs in this study were the same as those previously reported in order to achieve a similar efficiency and safety, as we are still investigating the best dosage for treating the disease. Second, the follow-up period was not long enough to assess the long-term effects of the drugs together with dilation. Third, chest X-ray examination was not performed routinely to confirm perforation even when they are small. Finally, our study was with a retrospective design and a small sample size. Largescale, prospective multicenter trials with long-term follow-up are required to confirm these findings. In conclusion, intramuscular injections of mitomycin C and dexamethasone combined with endoscopic dilation, as well as conventional dilation were all safe. The
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dysphagia-free period was prolonged and the frequency of repeated dilation was decreased using dilation combined with mitomycin C and dexamethasone compared with conventional dilation. Furthermore, mitomycin C may have predominant advantages compared with the other two methods and be an alternative for treating benign esophageal strictures. ACKNOWLEDGMENTS The study was partially supported by grants from the National Natural Science Foundation of China (No. 81172266), the Natural Science Foundation of Jiangsu Province (BK2011859) and Jiangsu Innovation of Medical Team and Leading Talents Cultivation (LJ201127). REFERENCES 1 Altintas E, Kacar S, Tunc B et al. Intralesional steroid injection in benign esophageal strictures resistant to bougie dilation. J Gastroenterol Hepatol 2004; 19: 1388–91. 2 de Wijkerslooth LR, Vleggaar FP, Siersema PD. Endoscopic management of difficult or recurrent esophageal strictures. Am J Gastroenterol 2011; 106: 2080–91. 3 Pereira-Lima JC, Ramires RP, Zamin I Jr, Cassal AP, Marroni CA, Mattos AA. Endoscopic dilation of benign esophageal strictures: report on 1043 procedures. Am J Gastroenterol 1999; 94: 1497–501. 4 Kochman ML, McClave SA, Boyce HW. The refractory and the recurrent esophageal stricture: a definition. Gastrointest Endosc 2005; 62: 474–5. 5 Lew RJ, Kochman ML. A review of endoscopic methods of esophageal dilation. J Clin Gastroenterol 2002; 35: 117–26. 6 Higuchi K, Tanabe S, Azuma M et al. A phase II study of endoscopic submucosal dissection for superficial esophageal neoplasms (KDOG 0901). Gastrointest Endosc 2013; 78: 704–10. 7 Shi Q, Ju H, Yao LQ et al. Risk factors for postoperative stricture after endoscopic submucosal dissection for superficial esophageal carcinoma. Endoscopy 2014; 46: 640–4. 8 Ono S, Fujishiro M, Niimi K et al. Long-term outcomes of endoscopic submucosal dissection for superficial esophageal squamous cell neoplasms. Gastrointest Endosc 2009; 70: 860–6. 9 Mendelsohn HJ, Maloney WH. The treatment of benign strictures of the esophagus with cortisone injection. Ann Otol Rhinol Laryngol 1970; 79: 900–4. 10 Chapuy L, Pomerleau M, Faure C. Topical mitomycin-C application in recurrent esophageal strictures after surgical repair of esophageal atresia. J Pediatr Gastroenterol Nutr 2014; 59: 608–11. 11 El-Asmar KM, Hassan MA, Abdelkader HM, Hamza AF. Topical mitomycin C can effectively alleviate dysphagia in children with long-segment caustic esophageal strictures. Dis Esophagus 2014 Apr 7. doi: 10.1111/dote.12218. [Epub ahead of print] 12 Machida H, Tominaga K, Minamino H et al. Locoregional mitomycin C injection for esophageal stricture after endoscopic submucosal dissection. Endoscopy 2012; 44: 622–5.
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13 Afzal NA, Albert D, Thomas AL, Thomson M. A child with oesophageal strictures. Lancet 2002; 359: 1032. 14 Wu Y, Schomisch SJ, Cipriano C et al. Preliminary results of antiscarring therapy in the prevention of postendoscopic esophageal mucosectomy strictures. Surg Endosc 2014; 28: 447–55. 15 Ogilvie AL, Dronfield MW, Ferguson R, Atkinson M. Palliative intubation of oesophagogastric neoplasms at fibreoptic endoscopy. Gut 1982; 23: 1060–7. 16 Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet 2013; 381: 400–12. 17 Cao Y, Liao C, Tan A, Gao Y, Mo Z, Gao F. Meta-analysis of endoscopic submucosal dissection versus endoscopic mucosal resection for tumors of the gastrointestinal tract. Endoscopy 2009; 41: 751–7. 18 van Heijl M, Gooszen JA, Fockens P et al. Risk factors for development of benign cervical strictures after esophagectomy. Ann Surg 2010; 251: 1064–9. 19 Hordijk ML, van Hooft JE, Hansen BE, Fockens P, Kuipers EJ. A randomized comparison of electrocautery incision with Savary bougienage for relief of anastomotic gastroesophageal strictures. Gastrointest Endosc 2009; 70: 849–55. 20 Shah JN. Benign refractory esophageal strictures: widening the endoscopist’s role. Gastrointest Endosc 2006; 63: 164–7. 21 Lian JJ, Ma LL, Hu JW et al. Endoscopic balloon dilation for benign esophageal stricture after endoscopic submucosal dissection for early esophageal neoplasms. J Dig Dis 2014; 15: 224–9.
Journal of Digestive Diseases 2015; 16; 370–376 22 Saito Y, Tanaka T, Andoh A et al. Novel biodegradable stents for benign esophageal strictures following endoscopic submucosal dissection. Dig Dis Sci 2008; 53: 330–3. 23 Liu J, Hu Y, Cui C, Li Y, Lin X, Fu J. Removable, fully covered, self-expandable metal stents for the treatment of refractory benign esophagogastric anastomotic strictures. Dysphagia 2012; 27: 260–4. 24 Ramage JI Jr, Rumalla A, Baron TH et al. A prospective, randomized, double-blind, placebo-controlled trial of endoscopic steroid injection therapy for recalcitrant esophageal peptic strictures. Am J Gastroenterol 2005; 100: 2419–25. 25 Hirdes MM, van Hooft JE, Koornstra JJ et al. Endoscopic corticosteroid injections do not reduce dysphagia after endoscopic dilation therapy in patients with benign esophagogastric anastomotic strictures. Clin Gastroenterol Hepatol 2013; 11: 795–801.e1. 26 Spier BJ, Sawma VA, Gopal DV, Reichelderfer M. Intralesional mitomycin C: successful treatment for benign recalcitrant esophageal stricture. Gastrointest Endosc 2009; 69: 152–3; discussion 153. 27 Daher P, Riachy E, Georges B, Georges D, Adib M. Topical application of mitomycin C in the treatment of esophageal and tracheobronchial stricture: a report of 2 cases. J Pediatr Surg 2007; 42: E9–11. 28 El-Asmar KM. Topical mitomycin C application for esophageal stricture: safe, precise, and novel endoscopic technique. J Pediatr Surg 2013; 48: 1454–7.
© 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2015; 16; 370–376
doi: 10.1111/1751-2980.12255
Original article
Intramuscular injection of mitomycin C combined with endoscopic dilation for benign esophageal strictures Yin ZHANG,*,† Xiang WANG,‡ Li LIU,‡ Jian Ping CHEN* & Zhi Ning FAN‡ *Department of Digestive Disease, The First People’s Hospital of Changzhou, Changzhou, †Department of Digestive Endoscopy and Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University and ‡Department of Digestive Endoscopy, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu Province, China
OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of intramuscular injection of either mitomycin C or dexamethasone with endoscopic dilation for benign esophageal strictures after esophageal surgery or endoscopic submucosal dissection. METHODS: Patients with benign esophageal strictures were retrospectively enrolled in this study and divided into three groups: mitomycin C group (mitomycin C injection with endoscopic dilation, dexamethasone group (dexamethasone injection and dilation) and dilation group (physiological saline injection and dilation). The patients’ characteristics, locations of lesions, number of previous dilations, esophageal diameters after dilation, grades of dysphagia before and after the procedure and dysphagiafree period during the follow-up period were recorded. RESULTS: Altogether 74 patients including 25 in the mitomycin C group, 25 in the dexamethasone group KEY WORDS:
CONCLUSION: Intramuscular injection of mitomycin C or dexamethasone may prolong the dysphagia-free period and decrease the frequency of repeat dilations compared with conventional endoscopic dilations in patients with benign esophageal strictures.
benign esophageal stricture, dexamethasone, endoscopic dilation, mitomycin C.
Correspondence to: Zhi Ning FAN, Department of Digestive Endoscopy, The First Affiliated Hospital with Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, Jiangsu Province 210029, China. Email: [email protected] Conflict of interest: None. © 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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and 24 in the dilation group were enrolled. The diameter of the esophagus before the procedure was 3.32 ± 0.90 mm, 3.92 ± 1.55 mm and 3.70 ± 1.30 mm, respectively, while that was increased to 12.77 ± 1.62 mm, 12.14 ± 1.28 mm and 12.73 ± 1.42 mm after endoscopic dilation in the mitomycin C, dexamethasone and conventional dilation groups. The dysphagia-free period was 4.88 ± 1.66 months in the mitomycin C group, 4.02 ± 1.77 months in the dexamethasone group and 2.41 ± 1.26 months in the dilation group (P < 0.05).
INTRODUCTION Benign esophageal strictures have known to be caused by several diseases, including peptic disease, corrosive and radiation injury, as well as surgical anastomosis and infection, etc.1 In recent years, esophageal strictures after endoscopic submucosal dissection (ESD) are more frequently seen in clinical setting. Common treatments for benign esophageal strictures include
Journal of Digestive Diseases 2015; 16; 370–376 esophageal dilation with Savary-Gilliard bougie or expansion balloon, endoprosthetic deployment and steroid injection.2,3 In most patients benign esophageal stricture can be treated effectively with several sessions of dilation; however, a small proportion of patients do not respond to this therapy.4 Up to 40% of benign esophageal strictures are anastomotic strictures that occur after esophagectomy.5 With the development of treatment modalities, ESD has been increasingly used for early superficial and submucosal esophageal tumors, with a reliable en bloc resection rate.6 However, ESD is challenging for esophageal lesions in large sizes with deep invasion due to a high risk of stricture, which affects the patient’s daily life.7 Ono et al.8 reported that the rate of postoperative esophageal strictures was as high as 93% in patients with lesions that were more than half the luminal circumference. For the other types of strictures the treatments are also challenging. As an auxiliary treatment to endoscopic dilation, intralesional steroid injection has been applied since 1970 when this technique was first introduced by Mendelsohn and Maloney.9 However, after being studied for decades, including in some randomized controlled trials (RCTs) with small sample sizes, it remains unknown whether local steroid injection decreases the frequency of repeated dilations or prolongs the dysphagia-free period in patients with benign esophageal strictures.2 Mitomycin C is a chemotherapeutic agent that reduces the formation of scar when applied to surgical lesions. It has been widely used in children experience postoperative esophageal strictures who have undergone surgical repairs for esophageal atresia or those who have caustic esophageal strictures.10,11 In recent studies, mitomycin C has also been used for the treatment of esophageal strictures after ESD in adults.12 Furthermore, previous studies13,14 have supported the application of mitomycin C in combination with endoscopic dilation as an alternative option that is both effective and safe for treating benign esophageal strictures. In this study, we aimed to investigate whether mitomycin C injection combined with dilation might prolong the dysphagia-free period compared with either dexamethasone injection combined with dilation or conventional endoscopic dilation alone.
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PATIENTS AND METHODS Patients From January 2013 to January 2014, patients diagnosed as benign esophageal stricture with grade 3 or 4 dysphagia at the Department of Digestive Disease, The First People’s Hospital of Changzhou (Changzhou, Jiangsu Province, China), the Department of Digestive Endoscopy, The Second Affiliated Hospital of Nanjing Medical University and the Department of Digestive Endoscopy, The First Affiliated Hospital with Nanjing Medical University (Nanjing, Jiangsu Province, China) were enrolled in the study. The study was approved by the Institutional Ethics Committees of the three hospitals. Inclusion criteria were: (i) patients with pathologically confirmed benign esophageal strictures, including those having anastomotic stricture or stricture after ESD; and (ii) the length of the strictures was less than 3 cm, in the absence of esophageal distortion or angulation. Patients with a previous history of stent placement or drug injection, those suspected of malignant tumor recurrence, having other esophageal and gastric diseases or severe systemic diseases were excluded from the study. The enrolled patients were then divided into three groups according to the treatments: (i) the mitomycin C group, patients receiving mitomycin C injection together with endoscopic dilation; (ii) the dexamethasome group, age-matched and gendermatched patients who received dexamethasone injection and endoscopic dilation; and (iii) the dilation group, patients receiving 10 mL 0.9% physiological saline injection and endoscopic dilation. Endoscopic dilation A commercially available standard therapeutic endoscope (GIF-Q260, Olympus, Tokyo, Japan) was used for endoscopic dilation in all patients. A set of SavaryGilliard bougies (SGD-100-1, Wilson-Cook Medical Inc., Winston-Salem, NC, USA) or expansion balloon (CRE Wireguided Balloon Dilator, Boston Scientific, Minneapolis, MI, USA) were prepared for the dilation. An injection needle (INJ1-A1, Medwork GmbH, Höchstadt, Germany) was used for the injections. Mitomycin C (10 mg of 1 mg/mL, Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou, Zhejiang Province, China) and dexamethasone (5 mg of 0.5 mg/mL, Anyang Jiuzhou Pharmaceutical Co., Ltd., Anyang, Henan Province, China) were prepared before the
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procedure. Endoscopic dilation was performed by experienced endoscopists (Xiang WANG, Jian Ping CHEN and Zhi Ning FAN) who have performed esophageal dilation and stent insertion for more than 300 patients every year. The presence and severity of the strictures were determined by esophagogastroduodenoscopy (EGD) in patients under conscious sedation with midazolam or propofol at the left lateral position. The diameter of the esophagus before dilation was recorded. The diameter of the stricture was evaluated using the biopsy forceps, which was approximately 5 mm when the forceps was opened. If the endoscope was able to pass through the stricture, gastric and duodenal cavities were observed and endoscopic dilation was then performed. The dilation was performed first when the endoscope was unable to pass through the stricture. Endoscopic dilation was performed using either the Savary-Gilliard bougie or expansion balloon depending on the preference of the operator. The target diameter of the esophagus was no less than 12 mm, which was considered sufficient to drain the esophagus. When dilating using a set of bougies, each bougie was gently inserted through the guidewire under fluoroscopic guidance and was held for 1–2 min. While dilating with a balloon, the balloon was inserted through the channel of the endoscope and the pressure was increased to 101 kPa and held for 1–2 min. If there was not any bleeding or perforation after repeated endoscopic examinations, a total of 10 mL of mitomycin C or dexamethasone was injected into the muscle layer of the dilated lesion in four quadrants (at the 3-, 6-, 9- and 12-o’clock positions). After the injection, the patients were re-examined to confirm that no bleeding or perforation had occurred (Figure 1). Postoperative care After endoscopic dilation, all the patients were treated with omeprazole 40 mg twice daily (AstraZeneca, London, UK). The patients were fasted for 24 h after the procedure, and they were then permitted to intake semi-solid food when there were no complaints such as fever, chest or abdominal pain, chest distress, subcutaneous emphysema or elevated white blood cell (WBC) count. Peripheral complete blood count was evaluated daily until the results returned to normal level. Antibiotics were not routinely applied unless the WBC counts reached an abnormal level or the patients had a fever. The patients were then discharged and kept on anti-reflux therapy with a proton pump
Figure 1. Intramuscular injection of mitomycin C combined with endoscopic dilation. (a) Esophageal stricture after esophagectomy. (b) Endoscopic view after dilation with Savary-Gilliard bougies. (c) Injecting mitomycin C into the muscular layer of the lesion. (d) Follow-up endoscopy one month after the procedure.
inhibitor (PPI) for 4 weeks. All the patients were followed up at the Outpatient Department of Gastroenterology or via telephone every 2 to 4 weeks for at least 6 months. Those who had dysphagia recurred during the follow-up period were treated endoscopically again. Definitions Dysphagia was graded according to the consistency of food the patients were able to eat: 0, be able to eat a normal diet; 1, unable to swallow certain solid food; 2, unable to swallow any solid food; 3, unable to swallow semi-solid food; and 4, unable to swallow liquids.15 The location of esophageal lesions was classified as follows: upper esophagus, shorter than 15 cm from the incisor; middle esophagus, 15–40 cm from the incisor; lower esophagus, below 40 cm from the incisor. The technical success of the procedure was defined as an uneventful dilation with either the bougies or balloon and the intramuscle injection of the drug into the lesion (flattening was negative for resistance when injecting the drugs). Clinical success was defined as the absence of dysphagia for at least one week after the procedure.
© 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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Mitomycin C for strictures
Recurrent dysphagia due to the stricture was defined as the grade of dysphagia either reaching or rising above grade 3 after ruling out the possibility of malignancy. A dysphagia-free period of at least 6 months was defined as the cure of the disease. Major complications related to the endoscopic dilation or the injection of drugs include massive hemorrhage, perforation or severe pain. Minor complications included mild to moderate pain or reflux, fever or elevated WBC count. Perforation was defined as the presence of chest distress or subcutaneous emphysema that was confirmed by chest radiography. Statistical analysis Statistical analyses were performed using SPSS 13.0 (IBM, Armonk, NY, USA). The patients’ characteristics including age, gender, the location and type of stricture, number of anterior dilations, technical success, clinical success, the grade of dysphagia and the diameter of the esophagus before and after endoscopic dilation, and the dysphagia-free period were recorded. Quantitative variables were expressed as Table 1.
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mean ± standard deviation and were analyzed using the one-way ANOVA. The ranked parameters were expressed as medians and ranges and were analyzed using the Kruskal–Wallis test. Qualitative variables were analyzed using χ2 test or Fisher’s exact test. Differences in the continuous variables were tested with the least significant difference test or the Mann– Whitney U test, when appropriate. P ≤ 0.05 was considered statistically significant. RESULTS Altogether 74 patients were enrolled in the study, including 25 receiving mitomycin C injection, 25 receiving dexamethasone injection and 24 receiving physiological saline injection. There were no significant differences among the three groups at the baseline in age, gender, the location or type of esophageal stricture and the number of anterior dilation (Table 1). Anastomotic strictures and strictures after ESD were found in 16 (64.0%) and 9 (36.0%) patients in the mitomycin C group, while those in the dexamethasone group were 18 (72.0%) and 7 (28.0%), respectively. In the dilation group, there were 16 (66.7%) cases with anastomotic strictures and 8
The characteristics and results of mitomycin C injection to treat benign esophageal stricture
Age, years (mean ± SD) Male/female, n Type of stricture, n (%) Anastomotic stricture Stricture after ESD Location, n (%) Upper esophagus Middle esophagus Lower esophagus Dilation before injection, median (range) Technical success, n (%) Clinical success, n (%) Grade of dysphagia, median (range) Before After Diameter of esophagus, mm (mean ± SD) Before dilation After dilation Major complication, n (%) Minor complication, n (%) Dysphagia-free period, months (mean ± SD)
Mitomycin C group (n = 25)
Dexamethasone group (n = 25)
Dilation group (n = 24)
61.08 ± 13.68 16/9
64.00 ± 8.34 15/10
61.17 ± 9.27 16/8
16 (64.0) 9 (36.0)
18 (72.0) 7 (28.0)
16 (66.7) 8 (33.3)
0 (0) 25 (100) 0 (0) 3 (1–5) 25 (100) 25 (100)
0 (0) 25 (100) 0 (0) 3 (1–4) 25 (100) 25 (100)
0 (0) 24 (100) 0 (0) 3 (1–5) 24 (100) 24 (100)
3 (3–4) 1 (1–2)
4 (3–4) 1 (1–2)
4 (3–4) 1 (1–2)
3.32 ± 0.90 12.77 ± 1.62 0 (0) 6 (24.0) 4.88 ± 1.66
3.92 ± 1.55 12.14 ± 1.28 0 (0) 5 (20.0) 4.02 ± 1.77
3.70 ± 1.30 12.73 ± 1.42 0 (0) 3 (12.5) 2.41 ± 1.26
Upper esophagus, shorter than 15 cm from the incisor; middle esophagus, 15–40 cm from the incisor; lower esophagus, lower than 40 cm from the incisor. ESD, endoscopic submucosal dissection; SD, standard deviation.
© 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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(33.3%) with strictures after ESD. All lesions in the three groups were located at the middle esophagus. The median number of anterior dilations was 3 (range 1–5), 3 (range 1–4) and 3 (range 1–5), respectively. All patients in the three groups were graded as 3–4 for dysphagia before endoscopic dilation; however, after dilation the grade of dysphagia was 1–2. All patients achieved technical and clinical success after endoscopic dilation. The diameter of the esophagus before the procedure was 3.32 ± 0.90 mm, 3.92 ± 1.55 mm and 3.70 ± 1.30 mm, respectively, while that was increased to 12.77 ± 1.62 mm, 12.14 ± 1.28 mm and 12.73 ± 1.42 mm, respectively, after endoscopic dilation. There was no difference in the esophageal diameter among the three groups. No major complications such as massive bleeding, leakage or perforation were observed in either of the three groups. Minor complications, including mild to moderate pain and reflux, occurred in six patients in the mitomycin C group, five in the dexamethasone group and three in the dilation group. Elevated WBC count was seen in one patient in the mitomycin C group, one in the dexamethasone group and two in the dilation group, respectively. All patients were treated conventionally and were discharged with no complaints. After discharge, all patients received both telephone and clinical follow-up for more than 6 months. The dysphagia-free period was 4.88 ± 1.66 months, 4.02 ± 1.77 months and 2.41 ± 1.26 months, respectively, in the mitomycin C, dexamethasome and dilation groups, respectively. When dysphagia relapsed, the endoscopic procedure was repeated. DISCUSSION With the rapidly rising incidence of esophageal cancer during the past decades,16 surgery is considered the curative therapy for such patients regardless of subsequent neoadjuvant therapy. And endoscopic therapies are being widely used as potential curative approaches for early esophageal carcinomas.17 However, benign esophageal strictures are not rare in patients with esophageal anastomoses and those receiving circumferential ESD.18,19 Dysphagia, the most common symptom of esophageal strictures, has a deleterious impact on patients’ quality of life and may lead to severe complications such as aspiration, weight loss and malnutrition.20 The most common treatment option for benign esophageal strictures is endoscopic dilation, including
Journal of Digestive Diseases 2015; 16; 370–376 dilation with bougie, expansion balloon or stent. Ono et al.8 reported that post-ESD esophageal strictures could be successfully managed by temporary dilation with a median of two sessions. In addition, dilation with bougie and balloon is reported to be safe and effective for managing benign esophageal strictures.21 Temporary stent insertions have also been increasingly used for the disease.22 However, it is not the first choice of treatment considering the inflammatory hyperplasia that occurs with partially covered metal stents and a high migration rate with the fully covered metal stents.23 Injections with corticosteroids have been shown to relieve these strictures since it was first mentioned in the 1970s.9 Studies have also reported the effect of local corticosteroid injection combined with dilation on the treatment for benign esophageal strictures. Moreover, some RCTs have revealed that corticosteroid injection combined with dilation may prolong the dysphagia-free period or decrease the frequency of dilation.1,24 However, Hirdes et al.25 reported that corticosteroid injections in combination with dilation did not decrease the frequency of repeated dilation or prolong patency after gastroesophageal anastomotic stricture. Furthermore, corticosteroid injections may be associated with an increased risk of Candida esophagitis. Thus, whether corticosteroid injections are beneficial for benign esophageal strictures continues to be controversial. Mitomycin C is a chemotherapeutic agent that is widely used against cancers of the digestive system because of its ability of generating oxygen radicals and alkylates and cross-linking DNA, thereby inhibiting DNA synthesis.26 Additionally, it also inhibits the proliferation of fibroblasts and collagen synthesis that are the crucial causes of benign esophageal strictures after mechanical injury.12 Of note, the use of mitomycin C was not rare during the past decades. On the contrary, a series of studies have shown the beneficial effects of mitomycin C on caustic esophageal strictures and anastomotic strictures after surgical repair of the esophageal atresia in children, in which a cotton pledget containing the drug is inserted into the esophagus or mitomycin C is injected via catheter balloon. However, most of these studies were small in sample size or lacked a control group.10,27,28 In this study, we compared the effects of mitomycin C injections combined with dilation, dexamethasone injections combined with dilation and conventional endoscopic dilation. The dysphagia-free period during the follow-up period was longest in the mitomycin C group, followed by the dexamethasone group and the conventional dilation group, showing that
© 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2015; 16; 370–376 mitomycin C might have had a more dominant effect than dexamethasone in the treatment of benign esophageal strictures. Moreover, mitomycin C injections did not cause systemic side effects, such as bone marrow suppression or elevated WBC counts. In our study the drugs were injected intramuscularly. Specifically, in the report by Machida et al.,12 the drug was injected into the submucosal layer (avoiding the muscle layer). However, fibroplasia and scarring are predominant in benign esophageal strictures following surgical anastomosis or ESD, even when no mucosal or submucosal layer exists. Therefore, the drug was injected into the muscle layer and the occurrence of any leaks, ulcers or perforations was observed. There were no significant differences in the postoperative complications among the three groups, indicating that both mitomycin C and dexamethasone were safe. There were no major complications, and all minor complications were managed with conventional therapy. In comparison with other studies, the complication rate in our study was low. We believe that this might be attributed to the following reasons: (i) the strictures in our study were less than 3 cm in length, which means that the dilation was relatively simple to perform; (ii) all the endoscopists are very experienced, and the dilation with the Savary-Gilliard bougie or expansion balloon was performed gently and incrementally, which reduced the risk of perforation; (iii) most importantly, we recorded the incidence of chest pain, chest distress and subcutaneous emphysema, but chest radiography was not performed routinely. Some tiny perforations do not cause these symptoms, and the air can be absorbed spontaneously within several days. Some limitations of this study should be noted. First, the concentrations and total doses of these drugs in this study were the same as those previously reported in order to achieve a similar efficiency and safety, as we are still investigating the best dosage for treating the disease. Second, the follow-up period was not long enough to assess the long-term effects of the drugs together with dilation. Third, chest X-ray examination was not performed routinely to confirm perforation even when they are small. Finally, our study was with a retrospective design and a small sample size. Largescale, prospective multicenter trials with long-term follow-up are required to confirm these findings. In conclusion, intramuscular injections of mitomycin C and dexamethasone combined with endoscopic dilation, as well as conventional dilation were all safe. The
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dysphagia-free period was prolonged and the frequency of repeated dilation was decreased using dilation combined with mitomycin C and dexamethasone compared with conventional dilation. Furthermore, mitomycin C may have predominant advantages compared with the other two methods and be an alternative for treating benign esophageal strictures. ACKNOWLEDGMENTS The study was partially supported by grants from the National Natural Science Foundation of China (No. 81172266), the Natural Science Foundation of Jiangsu Province (BK2011859) and Jiangsu Innovation of Medical Team and Leading Talents Cultivation (LJ201127). REFERENCES 1 Altintas E, Kacar S, Tunc B et al. Intralesional steroid injection in benign esophageal strictures resistant to bougie dilation. J Gastroenterol Hepatol 2004; 19: 1388–91. 2 de Wijkerslooth LR, Vleggaar FP, Siersema PD. Endoscopic management of difficult or recurrent esophageal strictures. Am J Gastroenterol 2011; 106: 2080–91. 3 Pereira-Lima JC, Ramires RP, Zamin I Jr, Cassal AP, Marroni CA, Mattos AA. Endoscopic dilation of benign esophageal strictures: report on 1043 procedures. Am J Gastroenterol 1999; 94: 1497–501. 4 Kochman ML, McClave SA, Boyce HW. The refractory and the recurrent esophageal stricture: a definition. Gastrointest Endosc 2005; 62: 474–5. 5 Lew RJ, Kochman ML. A review of endoscopic methods of esophageal dilation. J Clin Gastroenterol 2002; 35: 117–26. 6 Higuchi K, Tanabe S, Azuma M et al. A phase II study of endoscopic submucosal dissection for superficial esophageal neoplasms (KDOG 0901). Gastrointest Endosc 2013; 78: 704–10. 7 Shi Q, Ju H, Yao LQ et al. Risk factors for postoperative stricture after endoscopic submucosal dissection for superficial esophageal carcinoma. Endoscopy 2014; 46: 640–4. 8 Ono S, Fujishiro M, Niimi K et al. Long-term outcomes of endoscopic submucosal dissection for superficial esophageal squamous cell neoplasms. Gastrointest Endosc 2009; 70: 860–6. 9 Mendelsohn HJ, Maloney WH. The treatment of benign strictures of the esophagus with cortisone injection. Ann Otol Rhinol Laryngol 1970; 79: 900–4. 10 Chapuy L, Pomerleau M, Faure C. Topical mitomycin-C application in recurrent esophageal strictures after surgical repair of esophageal atresia. J Pediatr Gastroenterol Nutr 2014; 59: 608–11. 11 El-Asmar KM, Hassan MA, Abdelkader HM, Hamza AF. Topical mitomycin C can effectively alleviate dysphagia in children with long-segment caustic esophageal strictures. Dis Esophagus 2014 Apr 7. doi: 10.1111/dote.12218. [Epub ahead of print] 12 Machida H, Tominaga K, Minamino H et al. Locoregional mitomycin C injection for esophageal stricture after endoscopic submucosal dissection. Endoscopy 2012; 44: 622–5.
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13 Afzal NA, Albert D, Thomas AL, Thomson M. A child with oesophageal strictures. Lancet 2002; 359: 1032. 14 Wu Y, Schomisch SJ, Cipriano C et al. Preliminary results of antiscarring therapy in the prevention of postendoscopic esophageal mucosectomy strictures. Surg Endosc 2014; 28: 447–55. 15 Ogilvie AL, Dronfield MW, Ferguson R, Atkinson M. Palliative intubation of oesophagogastric neoplasms at fibreoptic endoscopy. Gut 1982; 23: 1060–7. 16 Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet 2013; 381: 400–12. 17 Cao Y, Liao C, Tan A, Gao Y, Mo Z, Gao F. Meta-analysis of endoscopic submucosal dissection versus endoscopic mucosal resection for tumors of the gastrointestinal tract. Endoscopy 2009; 41: 751–7. 18 van Heijl M, Gooszen JA, Fockens P et al. Risk factors for development of benign cervical strictures after esophagectomy. Ann Surg 2010; 251: 1064–9. 19 Hordijk ML, van Hooft JE, Hansen BE, Fockens P, Kuipers EJ. A randomized comparison of electrocautery incision with Savary bougienage for relief of anastomotic gastroesophageal strictures. Gastrointest Endosc 2009; 70: 849–55. 20 Shah JN. Benign refractory esophageal strictures: widening the endoscopist’s role. Gastrointest Endosc 2006; 63: 164–7. 21 Lian JJ, Ma LL, Hu JW et al. Endoscopic balloon dilation for benign esophageal stricture after endoscopic submucosal dissection for early esophageal neoplasms. J Dig Dis 2014; 15: 224–9.
Journal of Digestive Diseases 2015; 16; 370–376 22 Saito Y, Tanaka T, Andoh A et al. Novel biodegradable stents for benign esophageal strictures following endoscopic submucosal dissection. Dig Dis Sci 2008; 53: 330–3. 23 Liu J, Hu Y, Cui C, Li Y, Lin X, Fu J. Removable, fully covered, self-expandable metal stents for the treatment of refractory benign esophagogastric anastomotic strictures. Dysphagia 2012; 27: 260–4. 24 Ramage JI Jr, Rumalla A, Baron TH et al. A prospective, randomized, double-blind, placebo-controlled trial of endoscopic steroid injection therapy for recalcitrant esophageal peptic strictures. Am J Gastroenterol 2005; 100: 2419–25. 25 Hirdes MM, van Hooft JE, Koornstra JJ et al. Endoscopic corticosteroid injections do not reduce dysphagia after endoscopic dilation therapy in patients with benign esophagogastric anastomotic strictures. Clin Gastroenterol Hepatol 2013; 11: 795–801.e1. 26 Spier BJ, Sawma VA, Gopal DV, Reichelderfer M. Intralesional mitomycin C: successful treatment for benign recalcitrant esophageal stricture. Gastrointest Endosc 2009; 69: 152–3; discussion 153. 27 Daher P, Riachy E, Georges B, Georges D, Adib M. Topical application of mitomycin C in the treatment of esophageal and tracheobronchial stricture: a report of 2 cases. J Pediatr Surg 2007; 42: E9–11. 28 El-Asmar KM. Topical mitomycin C application for esophageal stricture: safe, precise, and novel endoscopic technique. J Pediatr Surg 2013; 48: 1454–7.
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