MDT stricturen Mitomycin 2015.pdf

ORIGINAL ARTICLE

Treatment of Refractory Gastrointestinal Strictures With Mitomycin C A Systematic Review Tarun Rustagi, MD,* Harry R. Aslanian, MD, FASGE,* and Loren Laine, MD, AGAF*w

Background and Aims: Refractory benign gastrointestinal (GI) strictures represent a difficult management problem given the limited therapeutic interventions available. We performed a systematic review of all published cases using mitomycin C in the treatment of GI strictures. Methods: Searches of MEDLINE and Embase databases were performed to identify studies reporting application of mitomycin C for GI strictures. Review of titles/abstracts, full review of potentially relevant studies, and data abstraction were performed independently by 2 authors. Results: Of 549 citations, 24 studies with 145 patients (74% pediatric and 26% adult) met inclusion criteria. Esophageal strictures were the most common (79%) site of refractory strictures treated with mitomycin C, with caustic injury the most common underlying etiology. The concentration (range, 0.1 to 2 mg/mL; median, 0.4 mg/mL), number of applications (range, 1 to 12; median, 1), duration of applications (range, 1 to 5; median, 2 min), and technique of application (cotton pledget, spray, injection, special catheters) varied among studies. Ninety-one patients (73%; children: 80%, adults: 59%) had a complete response; 26 (21%) had a partial response. Only 1 (0.7%) adverse event was reported: cutaneous sclerosis attributed to microperforation and mitomycin C extravastion after injection. Mean follow-up was 23 (4 to 60) months. Conclusions: Local mitomycin C application seems to be a safe and effective therapy for benign refractory GI strictures of varying etiology in both pediatric and adult populations. Although the results of this systematic review are highly encouraging, it should be considered investigational. Additional randomized trials and larger prospective studies are needed to confirm these results and better define the optimal application technique, and the optimal dose, concentration, and duration of mitomycin C application. Key Words: mitomycin C, refractory, GI, esophageal, stricture, stenosis, dilation, endoscopic

(J Clin Gastroenterol 2015;00:000–000)

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efractory benign gastrointestinal (GI) strictures are an important health problem in adult and pediatric populations, and pose a challenge to gastroenterologists and

Received for publication June 1, 2014; accepted December 16, 2014. From the *Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven; and wVA Connecticut Healthcare System, West Haven, CT. The authors declare that they have nothing to disclose. Reprints: Tarun Rustagi, MD, Section of Digestive Diseases, 333 Cedar Street, 1080 LMP, New Haven, CT 06520-8019 (e-mail: tarun. [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

J Clin Gastroenterol

Volume 00, Number 00, ’’ 2015

surgeons.1–3 The etiology of these benign recalcitrant strictures varies depending on the location in the GI tract and the age group. Common etiologies include postsurgical anastomotic strictures, injury from ingestion of caustic agents, radiation therapy, severe gastroesophageal reflux, and chronic inflammatory conditions.1,3–5 Standard therapy for endoscopically accessible strictures is intraluminal dilation with through-the-scope balloons or dilators passed over a wire (eg, Savary-Gilliard).1,6,7 Strictures refractory to endoscopic dilation represent a difficult management problem given the limited therapeutic interventions available. Intralesional or systemic steroids in combination with dilation have been used in both adult and pediatric patients; however, long-term efficacy has been limited.8–11 Endoscopic stricture incision may have a role in a small number of cases, although it is technically challenging with the potential for significant complications.12–14 Surgical interventions replacing or bypassing the diseased GI segment are associated with substantial morbidity and mortality, and have the potential risk of anastomotic strictures.15–18 Mitomycin C, which inhibits DNA synthesis and reduces fibroblastic collagen formation, also has been suggested as a potential therapeutic option in the treatment of refractory benign GI stricture.19–21 The aim of this study was to perform a systematic review and structured analysis of all published adult and pediatric cases employing mitomycin C in the treatment of GI strictures and stenoses.

METHODS Study Criteria Inclusion criteria for studies in the systematic review were developed to identify relevant articles. The population was any patient with a GI tract stricture or stenosis, and the intervention was mitomycin C. The definition of refractory stricture was variable across studies, however, all patients had 5 or more endoscopic dilations before local mitomycin C application. The most commonly used definition for refractory esophageal strictures was inability to dilate to 14 mm diameter over 5 sessions at 2-week interval. Information that was required to be reported for inclusion in the systematic review were ages of patient (adult vs. pediatric); number, dosage, and technique of mitomycin C application; and outcomes of symptomatic response and/or complications.

Literature Search We searched MEDLINE and Embase databases for studies published from inception through November 2013. www.jcge.com |

Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.

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Search terms included, “mitomycin C,” or “mitomycin,” in combination with, “stricture,” “strictures,” “stenosis,” or “stenoses.” No language restriction was applied to the search filter. Non-English language papers were translated using online Google translation web site (https://translate.google.com) and appropriate language interpreters as needed. The initial screen did not limit the use of mitomycin C to the GI tract to broaden the search and avoid missing relevant articles. The titles and abstracts of all potentially relevant studies were screened for eligibility. The reference lists of studies of interest were then manually reviewed for additional articles. Two reviewers (T.R. and H.R.A.) independently screened the titles and abstracts of all the articles according to the predefined inclusion and exclusion criteria. Studies considered potentially relevant by either author were retrieved and reviewed in full by both authors independently to determine eligibility. Interreviewer discrepancies were resolved by rereview of the original article by the 2 reviewers together, with consensus achieved in all cases.

Data Abstraction Studies were divided into 2 groups based on the age of the treated population: pediatric (below 18 y) and adult (18 y and above). Data regarding the age of patient population treated; location of stricture; etiology of stricture; description of stricture; technique of mitomycin C application; dosage, number of and interval between applications; duration of follow-up; complications; and response were extracted in each group. Complete response was defined as complete resolution of symptoms without need for further intervention. Partial response was defined as incomplete resolution of symptoms with continued need for intervention but with reduced frequency, such as increased interval between dilatations. No symptomatic improvement with no reduction in need for therapeutic intervention was considered as no response to mitomycin C therapy. Sideeffects and complications related to the drug mitomycin C or to the endoscopic application technique/procedure were analyzed.

RESULTS Five hundred forty-nine potentially relevant citations were identified by our primary search of the electronic databases, and 24 studies with a total of 145 subjects met eligibility criteria for inclusion in the systematic review. The detailed process of this literature search is shown in Figure 1 depicting the PRISMA flow diagram. The characteristics of each included study are shown in Table 1. Of 24 studies included in this systematic review, only 1 was a randomized controlled trial (with 40 patients)21 and 3 were prospective studies (with a total of 44 patients).20,26,36 The remaining 20 publications were case reports or small case series. Seventeen studies described 87 pediatric cases (70% of total patients), whereas application of mitomycin C for 38 adult patients was reported in 9 studies (30% of total patients). Two studies included both pediatric and adult patients.26,27 Data extracted from these studies are presented in Table 2.

Location and Etiology of Stricture The esophagus was the most commonly reported site of GI strictures treated with mitomycin C, accounting for 79% of cases. Treatment of recalcitrant anal strictures was assessed in only 1 study, performed in pediatric patients.34

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FIGURE 1. Flow chart describing the literature search conducted for this systematic review. GI indicates gastrointestinal.

The most common underlying etiology of recurrent strictures was caustic/corrosive injury to the esophagus, accounting for 60% of all treated patients. Postsurgical/anastomotic strictures were the next most common etiology, representing 18% of treated patients. Among adult patients, 5 cases due to benign esophageal stricture developing after endoscopic submucosal dissection for superficial esophageal carcinoma were included in the postsurgical/anastomotic category. Other pediatric etiologies included congenital (n = 4; esophageal atresia in 3 and anal stenosis in 1), postradiation therapy (n = 2), peptic strictures secondary to severe gastroesophageal reflux (n = 2), Crohn’s disease (n = 1), and dystrophic epidermolysis bullosa (n = 1).

Local Application of Mitomycin C Mitomycin C was reported to be freshly prepared by the pharmacist immediately before the application in most of the studies. Varying concentrations of mitomycin C, ranging from 0.1 to 2 mg/mL, were used with median and mean values of 0.4 and 0.5 mg/mL, respectively. The number of mitomycin C applications varied between 1 and 12, with an overall median of 1. The mean number of applications was 2 and 2.6 in pediatric and adult patients, respectively, although the majority [67 children (79%) and 24 adults (63%)] required only 1 to 2 applications (Table 2). If mitomycin C was applied more than once, intervals ranged from 1 week to 13 months, with a median of 4 weeks. A variety of application techniques were reported. Sixteen studies with 71% of the patients reported topical application of mitomycin C onto the lesion with a cottonsoaked pledget using a grasper forceps for 1 to 5 (median 2) minutes under endoscopic vision or fluoroscopic guidance or both. To prevent mitomycin C from touching normal mucosa, studies have either used an overtube or frontloaded the pledget in a standard cap used for band ligation of varices attached to the end of the endoscope.

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2015 Wolters Kluwer Health, Inc. All rights reserved.


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Design


Case report

Case report

Prospective clinical trial

Frohlich et al,24

Olutoye et al,25

Rosseneu et al,26

Case series

Case series

Uhlen et al,23

2

15

1

1

4

1

84, 96

Mean 58.7 (0-132)

24

30

Mean 42 (12-72)

96

18

Age (mo)

Esophageal; 12- Topical with cotton15 cm from soaked pledget for dental arch 2 min using a rigid endoscope

Topical with cottonEsophageal; soaked pledget for Proximal: 2 min using a 1 mm, 3-5 mm flexible endoscope length; distal: 3 mm, 15 mm length Topical with cottonEsophageal; soaked pledget for 99% stenosis, 4 min under 10 mm endoscopic vision. thickness Type of scope not reported

1

0.4

0.1

1 in 3 patients, 2 in 1 patient

1

2

Not reported

Median 4 (1-8)

16

Not reported

2

1

ConcentrInterval ation No. Between (mg/mL) Applications Applications

0.4 3 Topical with cottonEsophageal; soaked pledget Circular, 7 cm using a flexible length endoscope 0.4 2 Caustic Esophageal; Topical with cottonDistal 1/3 of soaked pledget for esophagus 1 min using a flexible endoscope Topical with cotton- 0.1 in 14, Median 2, 9 caustic, 2 anastomotic, 2 Esophageal; Mean 2.7 Length 22 mm soaked pledget for 0.3 in 1 peptic, 1 Crohn’s, 1 (1-12) 2-5 (3.5) min in 14 (8-50), with a dystrophic epidermolysis children; sprayed median bullosa on 1 child. All diameter of using flexible 1.5 mm (1-6), total occlusion endoscope in 1 patient 0.4 5 or more Caustic Esophageal; Not Sprayed on using a reported flexible endoscope, left on for 5 min Caustic

2 caustic, 2 anastomotic

Radiation

Caustic

Indication

Type of Application

None

None

None

None

None

None

None

Complications 24

Followup (mo)

Doubled time Not interval for reported dilations

6 Reduction of stenosis from 99% to 80%, swallowed liquids without problems Mean All 4 24 asympto(19-27) matic without further dilations 18 Asymptomatic without further dilations 20 Asymptomatic without further dilations 10 complete, 2 60 partial, and 3 no success

Asymptomatic without further dilations

Outcome


Broto et al,27

Case report

1

Cases

Site; Description of Stricture

Rahbar et al,22

Pediatric cases Afzal Case report et al,19

References

TABLE 1. The Characteristics of 24 Included Studies

J Clin Gastroenterol Treatment of Refractory GI Strictures With Mitomycin C

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Case series

Case series

6

2

Median 84 (60-114)

24, 72

Mean 33 (12-84)

180

48

Age (mo)

3 caustic, 3 esophageal atresia

Caustic

Caustic

Radiation

Anastomotic

Indication

Type of Application

2 and 4

Mean 5.5 (2-8)

2

2

Not 1 in 3 reported patients, 2 in 3 patients

0.1

0.1

1

1

2-56

6 and 8

Median 2 (1-4)

Not reported

2

ConcentrInterval ation No. Between (mg/mL) Applications Applications

None

None

None

None

None

Complications

33

9

Followup (mo)

20 2 (50%) Asymptomatic without further dilations 2 reduced frequency of dilatation Not 1 reported asymptomatic without further dilations, 1 required partial resection of esophagus for distal stricture Mean All with 51.6 clinical, (39.6endoscopic 56.4) and radiologic



Outcome

Esophageal; Not Local application reported (details not reported)

Topical with cottonEsophageal; 2 soaked pledget strictures in introduced the 2-year-old retrograde child through protective sheet in gastrostomy for 1 min, using a flexible endoscope

Esophageal; Topical with cotton1 mm, 10 mm soaked pledget for length 2 min under endoscopic guidance. Type of scope not reported Topical application Complete using a flexible hypopharyngendoscope. eal and upper Further details esophageal not reported stenosis Esophageal; 5- Topical with cottonsoaked pledget for 10 cm long 2 min using a puntiform flexible endoscope esophageal stenosis

Site; Description of Stricture


Coopman et al,32

Heran et al,31

4

Ortolan et al,30

Case series

1

Zur et al,29 Case report

Cases

1

Design

Case report

Daher et al,28

References

TABLE 1. (continued)

Rustagi et al Volume 00, Number 00, ’’ 2015



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Randomized 40 (20 in clinical treattrial ment arm) Prospective 16 clinical trial

El-Asmar et al,21


Adult cases Gillespie Case series et al,37

12

1

Mean 65 (50-83)

Not reported

33.6 ± 10.8

4

Topical with cottonsoaked pledget for 3 min, using a rigid endoscope during first application and fluoroscopic guidance alone during second application Anal strictures; Topical with cottonNot reported soaked pledget for 5 min. No scope was used Esophageal; Not Via drug-eluding reported microporous catheter balloon for total of 3 min using a flexible endoscope Topical with cottonEsophageal; mean stricture soaked pledget for 5 min using a rigid length endoscope 1.85 ± 0.65 Esophageal; 10 Nelaton catheter (soaked cotton with long application) for strictures 5 min using a rigid >3 cm; 6 endoscope patients