Original article
Safety and efficacy of carbon dioxide cryotherapy for treatment of neoplastic Barrett’s esophagus
Authors
Marcia Irene Canto1, 2, Eun Ji Shin1, Mouen A. Khashab1, Daniela Molena3, Patrick Okolo1, Elizabeth Montgomery4, Pankaj Pasricha1
Institutions
Institutions listed at end of article.
submitted 6. July 2014 accepted after revision 19. January 2015
Background and study aims: Endoscopic cryotherapy has been used successfully for the ablation of Barrett’s esophagus but outcome data are limited. The aim of this study was to assess the long-term safety and efficacy of carbon dioxide (CO2) cryotherapy as primary or rescue treatment for Barrett’s esophagus with high grade dysplasia (HGD) or neoplasia. Patients and methods: This was a retrospective, single-center, nonrandomized study carried out in an academic, tertiary care center and affiliated community hospital. A total of 78 patients with neoplastic Barrett’s esophagus who had not undergone previous ablation (treatment-naïve group) or who had persistent or recurrent neoplasia despite previous treatment (rescue treatment group) were enrolled. Visible Barrett’s lesions, when present, were removed by endoscopic mucosal resection, which was followed by CO2 cryotherapy until neoplasia had been eradicated, or intervening therapy was necessary, or treatment was considered to have failed. Surveillance biopsies were obtained at standard intervals. Rates of complete response for cancer, HGD, and intestinal metaplasia were calculated. Treatment failure, recurrence, adverse events, progression, and mortality were also recorded.
Results: Between 2006 and 2013, 64 evaluable patients (20 treatment naïve, 44 rescue treatment) were treated and followed up (median time 4.2 years). At 1 year, the overall complete response rates were 77 % for cancer (10/13), 89 % for dysplasia 57/64), 94 % for HGD (60/64; 100 % for treatment naïve, 91 % for rescue treatment), and 55 % for intestinal metaplasia (35/64). Long-term complete response for neoplasia with rescue therapy was 87 % (56/64). Disease-specific mortality was 1/68 (2 %). Treatment failed to eradicate neoplasia in four patients (6 %) (all in the rescue group). Recurrent or new intestinal metaplasia was detected in 20/64 (31 %) after two negative follow-up procedures. Serious adverse events were noted in two patients (3 %). Post-cryotherapy pain occurred in four patients (6 %; only two needed analgesics). No bleeding or new strictures were noted. Buried Barrett’s was detected in 5/68 patients (7 %). Conclusions: CO2 cryotherapy was a safe and effective primary curative or rescue therapy for Barrett’s neoplasia.
Introduction
to stricture formation requiring multiple dilations [8, 9]. Multiple ablative modalities have been used with varying success, including photodynamic therapy (PDT), argon plasma coagulation (APC), radiofrequency ablation (RFA), and cryotherapy. Endoscopic cryotherapy is a type of mucosal ablation that involves noncontact delivery of cryogen to cause tissue destruction by extreme cold temperature. There are currently two cryotherapy devices that have been used for Barrett’s esophagus and are available in the United States. These devices differ in the type and method of cryogen delivery. The CryoSpray Ablation device (CSA Medical Inc., Baltimore, Maryland, USA) delivers liquid
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1391734 Published online: 31.3.2015 Endoscopy 2015; 47: 582–591 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Marcia Irene Canto, MD, MHS Division of Gastroenterology The Johns Hopkins University 1800 Orleans Street Blalock 407 Baltimore, MD 21287 United States Fax: +1-410-614-2490
[email protected] !
Endoscopic therapy of Barrett’s esophagus with high grade dysplasia (HGD) and early intramucosal esophageal adenocarcinoma (ECA) (neoplasia) is an accepted and proven viable alternative to esophagectomy [1, 2]. Endoscopic ablation achieves in situ destruction of Barrett’s esophagus and leads to replacement of intestinal metaplasia with normal squamous epithelium when a nonacid environment is maintained. For greatest success, ablation is generally combined with endoscopic mucosal resection (EMR) of neoplastic lesions [3 – 7], as stepwise complete EMR may lead
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Carbon dioxide cryotherapy of Barrett’s esophagus. a Prior to therapy. b During therapy. c Immediately after therapy.
nitrogen at– 196oC, whereas the Polar Wand device (GI Supply, Camp Hill, Pennsylvania, USA) delivers compressed carbon dioxide (CO2), which freezes to – 78oC. The latter technique is based on the principle of the Joule – Thomson effect, which results in a drop in temperature due to rapid expansion of a compressed gas. Although there is some published evidence on the potential safety and efficacy of liquid nitrogen cryotherapy [8 – 11], there is very limited information on CO2 cryotherapy for treatment of Barrett’s esophagus [10]. The aim of the current study was to investigate the safety and efficacy of endoscopic CO2 cryotherapy for primary or rescue treatment of Barrett’s esophagus and associated HGD and early ECA with or without previous EMR of lesions.
Patients and methods !
Study design and patients This study was a retrospective analysis of a prospective institutional review board-approved Barrett’s esophagus database at an academic tertiary referral center (The Johns Hopkins Hospital in Baltimore, Maryland) and an affiliated community hospital. Patients who were treated from 2006 to 2013 were included in the study. Inclusion criteria were consecutive adult outpatients with pathologically confirmed visible Barrett’s esophagus of any length, and/or HGD or ECA, and who were referred for endoscopic therapy and were treated with CO2 cryotherapy. Cryotherapy was offered as an alternative primary or rescue therapy after discussion of the risks and benefits of all available ablative treatments; treatment decisions were made on an individual patient basis. Cryotherapy was performed in patients with refractory (persistent or recurrent) Barrett’s esophagus with neoplasia after prior endoscopic therapy (i. e. EMR(s), one course of PDT, three sessions of RFA), and/or esophageal varices, esophageal strictures, and history of postablation esophageal bleeding on antiplatelet or anticoagulation therapy. Patients with Barrett’s ECA had to be surgically unfit or to have declined surgery, and had to have no evidence of disease beyond the mucosa or regional and distant metastases. Patients with HGD or ECA and prior EMR were included if there was residual neoplasia (defined as a deep margin suspicious or positive for submucosal disease) or biopsy- or EMRpositive mucosal ECA, with or without an esophageal stricture. Patients previously treated with another type of endoscopic abla-
tion were eligible if treatment was completed > 2 months prior to initiation of cryotherapy. Patients were excluded from the study if they had: no residual neoplasia after EMR and repeat endoscopic biopsies; non-traversable, persistent, esophageal strictures despite endoscopic dilation; inoperable, advanced and/or metastatic ECA; esophageal cancer other than adenocarcinoma; active gastrointestinal (GI) bleeding; medical instability; severe co-morbid illness; or a life expectancy of < 5 years. Patients were stratified into two groups: primary treatment group (no prior ablative therapy, treatment native), or rescue treatment group (prior ablation for neoplasia with RFA, PDT, APC). Previous treatment in the latter group was considered to have failed if there was recurrent or persistent Barrett’s esophagus with dysplasia or ECA after completed therapy, prior ablation could not be completed, or the patient declined further ablation treatments as a result of adverse events (i. e. esophageal stricture, bleeding). Data from the prospective database were analyzed during the middle of the study (2009) [11]and at study termination (2013). The study was reviewed and approved by the Johns Hopkins Medical Institutions Institutional Review Board. Informed consent was obtained from all patients.
Intervention At baseline, all patients underwent sedated, outpatient, high resolution, white light endoscopy with contrast enhancement. Mucosal biopsies were obtained according to a standardized protocol [12]. All patients were on chronic antacid therapy with a proton pump inhibitor (PPI), with or without a histamine receptor antagonist, for the duration of the study. One experienced endoscopist (M.I.C.) performed all endoscopic procedures. EMR was performed at least 2 weeks prior to ablation therapy in order to remove visible lesions in the Barrett’s segment (Duette procedure; Cook Medical, Bloomington, Indiana, USA). Following EMR, the specimen was placed in saline prior to orientation, pinning, and fixing in 10 % formalin. Post-EMR dysplasia grade was assessed for treatment eligibility. The primary goal of cryotherapy treatment was the eradication of all neoplasia. The secondary goal was eradication of all intestinal metaplasia. The Food and Drug Administration-approved Polar Wand system using compressed CO2 (cryogen) in a pressurized tank was used. Cryogen was delivered at 6 – 8 L/min through a low-pressure flexible polyethylene catheter with a 0.005-inch
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Fig. 1
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opening at the tip. A slim plastic suction catheter attached to the outside tip of the endoscope and connected to a suction canister removed excess gas. The tip of the cryotherapy catheter was placed about 5 – 10 mm outside the tip of the endoscope and " Fig. 1, positioned about 10 mm from the mucosal surface (● ●" Video 1). The timing for cryogen dosing started when ice formation was observed. The goal for each treatment session was to freeze all visible columnar mucosa and perform focal or circumferential ablation in patients with Barrett’s esophagus less than 8 cm in length. In patients with extra-long Barrett’s segments (> 8 cm), at least one half of the Barrett’s segment was treated in one session, with priority given to the areas or levels with dysplasia according to baseline biopsy. The typical cryotherapy treatment area was approximately 3 – 5 cm. In patients with long Barrett’s segments, two or three areas were treated during the ablation session. The next cryogen dose was applied only after complete ice thaw was noted (usually within 30 seconds). Cryogen dosing was adjusted during the course of the study according to the results from published porcine dosimetry [13, 14] and human studies [10]. In the initial phase of the study (2005 – 2007), 10 seconds of ice effect was applied to the mucosal surface for 4 – 8 cycles, with intervening complete thaw of the ice based on endoscopic visualization of ice thaw. In the second phase of the study (2007 – 2013), the cryogen dose was escalated to 15 seconds of ice for 6 – 8 cycles, based upon our clinical results and dosing study [14]. Intraprocedure and immediate postprocedure adverse events were recorded. After cryotherapy, patients were discharged home with instructions to resume a normal diet. No additional medications, including analgesics, were prescribed unless the patient was symptomatic at discharge. Patients were called within 1 week after their endoscopic treatments, and postprocedure symptoms, if present, were recorded. Patients returned for additional cryotherapy sessions every 4 – 6 weeks, until there was endoscopic and pathological evidence of complete eradication of Barrett’s neoplasia or treatment failure.
Surveillance Targeted endoscopic biopsies were obtained from any visible lesions and Barrett’s esophagus 2 – 3 months after the last treatment session. EMR was performed for any lesion that caused concern to the endoscopist. Random four-quadrant biopsies were also obtained with large-capacity forceps every 1 – 2 cm from any visible columnar mucosa, neosquamous-lined esophagus, and the gastroesophageal junction. Patients returned for endoscopic surveillance every 3 months for the first year, every 6 months for the second and third years, and then annually thereafter. All evaluable patients had to have at least two 2 – 3-month post-cryotherapy follow-up biopsies.
Video 1
Endoscopic carbon dioxide cryotherapy of Barrett’s esophagus with high grade dysplasia in a patient with esophageal varices.
Online content including video sequences viewable at: www.thieme-connect.de
Pathology Formalin-fixed mucosal biopsy specimens were evaluated for the presence or absence of intestinal metaplasia with goblet cells in biopsies from the esophagus or gastroesophageal junction. The highest grade of neoplasia in each set of biopsies was graded according to the Vienna Classification by experienced GI pathologists who were not blinded to the endoscopic treatments, as part of standard care [15]. EMR specimens were routinely assessed for the presence of dysplasia or cancer at the lateral and deep margins. Any post-cryotherapy pseudoregression (subsquamous intestinal metaplasia) in EMR and biopsy specimens was noted.
Recurrences and treatment failures Recurrence of Barrett’s esophagus was defined as any esophageal biopsy with intestinal metaplasia after two sets of negative postcryotherapy biopsies (at 3 and 6 months). These patients with persistent or recurrent Barrett’s esophagus were treated with any ablative technique (cryotherapy, RFA or APC) as “top-up therapy” to achieve complete eradication of intestinal metaplasia if the Barrett’s segment was < 5 mm in size or located at the gastroesophageal junction. Cryotherapy treatment was classified as failed if there was a lack of response (persistent HGD) or progression of disease (HGD to ECA). EMR was performed for treatment for lesions or localized neoplasia. If EMR was not possible because of multifocal neoplasia or scarring from previous treatments, or if there was residual neoplasia after this rescue EMR, the options of continued cryotherapy, versus alternative ablative therapies (RFA, PDT), versus esophagectomy in surgically fit patients were discussed. PDT was performed if RFA or EMR rescue were not feasible or successful in surgically unfit patients. Subsequent treatment decisions were made on an individual patient basis.
Study outcomes For the efficacy analysis, the primary end point of the study was the complete endoscopic and pathological response for neoplasia (HGD or ECA) after at least two negative biopsy procedures following the last cryotherapy session. Secondary end points included complete response for cancer, HGD, and neoplasia at 1 year and 3 years or at the last available biopsy or end of study. The response rate for complete elimination of any esophageal intestinal metaplasia was also determined. Treatment failure was defined as persistent HGD or progression of HGD to ECA after at least four cryotherapy sessions. The presence of intestinal metaplasia with or without neoplasia in any follow-up biopsy was calculated at study end, with new or incident intestinal metaplasia defined as intestinal metaplasia detected after more than 1 year of negative follow-up biopsies and recurrent intestinal metaplasia defined as intestinal metaplasia detected within 1 year. Vital status (dead or alive) and cause of death were ascertained by review of updated medical records or from internet search (obituaries, social security death index) for patients without documented follow-up within 1 year from study end on 31 December 2013. Overall and disease-related mortality were calculated. For the safety analysis, the incidence of any adverse event (any new esophageal stricture, esophageal stricture requiring dilation, perforation, chest pain, bleeding, and subsquamous intestinal metaplasia) was calculated for the entire data set, including patients who did not complete cryotherapy treatment. Adverse events were graded as severe if they resulted in hospitalization.
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Patient characteristics (entire cohort).
Primary treatment
Prior treatment
All
n = 21
n = 47
n = 68
P
Age, mean ± SD, years
70.9 ± 10.9
67 ± 11.0
69 ± 11.0
0.17
Age > 65 years, n (%)
14 (67)
33 (70)
47 (60)
0.78
Male sex, n (%)
19 (90)
35 (74)
54 (79)
0.52
Barrett’s length, mean ± SD, cm
5.9 ± 3.8
5.1 ± 3.6
5.3 ± 3.7
0.40
Short ( < 3 cm)
6 (27)
17 (37)
23 (34)
Long (3 – 8 cm)
11 (50)
21 (46)
32 (47)
5 (24)
8 (17)
13 (19)
Multifocal HGD or cancer, n (%)
15 (71)
28 (60)
43 (63)
Smoking, n (%)
13 (62)
19 (40)
32 (47)
0.21
Ineligible for surgery, n (%) 1
18 (86)
34 (72)
52 (76)
0.19
Hiatal hernia > 3 cm, n (%)
7 (33)
12 (26)
19 (28)
0.56
Sigmoid esophagus, n (%)
7 (33)
23 (49)
30 (44)
0.29
13 (62)
36 (77)
19 (28)
0.39
28 (60)
28 (41)
< 0.0001
28 (60)
28 (41)
22 (47)
22 (32)
Barrett’s length group, n (%)
0.74
Ultra long (8 – 15 cm)
Barrett’s lesion treated with prior EMR, n (%) Prior ablation, n (%)
0
RFA PDT Prior Nissen fundoplication, n (%)
0
2 (4)
Prior esophageal resection for ECA, n (%)
0
1 (2)
Baseline esophageal stricture(s), n (%)
3 (14)
Baseline esophagitis, n (%) Baseline esophageal ulcer, n (%) Bleeding risk, n (%) 2 Surgical hiatal hernia/PEH repair before or during treatment, n (%)
2 (3)
0.42
1.0
1 (1)
1.0
25 (53)
28 (41)
0.003
1 (5)
9 (19)
10 (15)
0.16
0
8 (17)
8 (12)
0.05
13 (62)
20 (42)
33 (48)
0.19
3 (14)
9 (19)
12 (19)
0.73
18 (86)
36 (76)
54 (79)
Highest neoplasia grade at baseline, n (%)
1.0
HGD Intramucosal ECA T1a 3
3 (14)
7 (15)
10 (15)
Submucosal ECA T1b 3
0
4 (9)
4 (6)
39 (83)
59 (87) 3 (4)
Highest neoplasia grade after cryotherapy, n (%)
1.0
No intestinal metaplasia, intestinal metaplasia no dysplasia, or indefinite for dysplasia
20 (95)
LGD
0
3 (6)
HGD
1 (5)
6 (13)
7 (10)
Intramucosal ECA T1a
0
1 (2)
1 (1)
Submucosal ECA T1b or greater
0
1 (2)
1 (1)
HGD, high grade dysplasia; EMR, endoscopic mucosal resection; RFA, radiofrequency ablation; PDT, photodynamic therapy; ECA, esophageal adenocarcinoma; PEH, paraesophageal hernia; LGD, low grade dysplasia. 1 Based on age or multiple medical co-morbidities. 2 Risk from chronic anticoagulation, esophageal varices, anti-platelet therapy. 3 All patients had residual ECA after treatment with EMR and were ineligible for surgery.
Statistical analysis
Results
Descriptive statistics (frequency counts, proportions, median, interquartile range [IQR]) were calculated. The Fisher’s exact test was used for comparison of categorical variables. Treatment response rates were calculated at specified time points (1 year, 3 years, and at study end). Mortality rates were calculated at study end. Univariate and bivariate analyses were performed to determine the association of various factors with cryotherapy treatment failure. All statistical analyses were performed using the Stata software, version 9.2 (StataCorp, College Station, Texas, USA). P values of < 0.05 were considered to be statistically significant.
! " Fig. 2. Of 78 The study flow (CONSORT) diagram is shown in ● patients who met the inclusion criteria, 68 were evaluable. Baseline characteristics of all treated patients are detailed in ●" Table 1. The majority of patients had long (32 /68 [47 %]) or extra-long (13/68 [19 %]) Barrett’s segments. Two-thirds of patients had multifocal HGD. Most patients (76 %) were considered ineligible for surgery based on age and multiple medical co-morbidities. The 21 patients who had cryotherapy for primary treatment (treatment-naïve patients) were similar to the 47 patients who had undergone previous ablation with respect to age, sex, Barrett’s segment length, presence of hiatal hernia, prior EMR, esophagitis, and highest pre-treatment neoplasia grade. Patients who had been previously treated were more likely to have baseline esophageal strictures from prior EMR, RFA, and/or PDT (53 % vs. 14 %; P = 0.003). A total of 28 patients (60 %) in the prior treatment group had undergone previous ablation; 12/47 (26 %) had
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Table 1
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All patients with history of Barrett’s HGD or esophageal cancer treated with cryotherapy at JHH between 2006 and 2013 assessed for eligibility (n = 78)
Enrollment
Fig. 2 CONSORT flow diagram. HGD, high grade dysplasia; JHH, Johns Hopkins Hospital; CR, complete response; IM, intestinal metaplasia.
Excluded (n = 10) • No dysplasia at baseline (n = 8) • Advanced esophageal cancer (n=2)
Cryotherapy as rescue therapy after prior ablation (n = 47)
Cryotherapy as primary treatment (n = 21)
Treatment and follow-up Incomplete treatment (n = 4) Analysis Analyzed (n = 44)
Analyzed (n = 20)
CR-neoplasia n = 20
Failure n = 0
CR-IM n = 14
Recurrent IM n=6
CR-neoplasia n = 40
CR-IM n = 24
Recurrent IM n = 14
recurrent Barrett’s esophagus after at least two negative esophagogastroduodenoscopy (EGD) with biopsy procedures, and 16 / 47 (34 %) had persistent Barrett’s esophagus or dysplasia despite therapy. Almost half (33 /68 [48 %]) of all patients had either a history of prior upper GI bleeding (n = 9) or were at risk for postablation bleeding from chronic anticoagulation therapy (n = 7), antiplatelet therapy (n = 24), and/or esophageal varices (n = 1). A total of 40 patients (59 %) had absolute or relative contraindications to conventional therapy with RFA or EMR: baseline active esophagitis despite antacid therapy (n = 10), esophageal ulcer(s) (n = 8), esophageal stricture (n = 28), esophageal varices (n = 1), RFA balloon-induced laceration (n = 1), severe upper GI bleeding after EMR or RFA (n = 2), and/or residual or recurrent cancer (n = 14).
Cryotherapy dosimetry The median number of ablation sessions (treatment days) was dependent upon length of the original Barrett’s segment: patients with Barrett’s segment < 3 cm had a median of 2 sessions, those with 3 – 8 cm had a median of 4 sessions, and those with > 8 cm had a median of 7 sessions. Patients who showed a complete response for HGD at 1 year had undergone a median of 4 cryotherapy sessions (IQR 2 – 6.5).
Treatment response All patients had at least two follow-up biopsy procedures after treatment, and 85 % (54 /64) had more than 1 year of follow-up data. The median follow-up time for the entire group was 4.2 years (IQR 2.2 – 5.7 years), with no difference between the treatment groups. For the efficacy analysis, a total of 64 patients were evaluable following the exclusion of four treatment-naïve patients who had persistent HGD after only 1 – 3 cryotherapy sessions and subsequently opted for surgery (n = 2) or alternative ab" Fig. 2). The two patients who underwent lative therapy (n = 2) (●
Failure n = 4
CR-neoplasia n=2
esophagectomy had ultralong multifocal nodular Barrett’s esophagus. One of these patients showed a complete response for neoplasia after EMR and cryotherapy in the esophagus but residual intramucosal cancer at the gastroesophageal junction after EMR; the resected specimen showed only polypoid HGD. The other surgical patient had multifocal nodular HGD and needed chronic anticoagulation for prosthetic heart valve. The resected esophagus showed multifocal HGD and LGD, but no cancer. The two surgically unfit patients with non-nodular Barrett’s esophagus with HGD underwent RFA as rescue therapy. Both patients developed post-RFA strictures, which required dilation. In the 64 patients who completed cryotherapy, the complete response for dysplasia at 1 year was 57 /64 (89 %); 19 /20 (95 %) in treatment-naïve patients and 38/44 (86 %) in previously treated patients (P = 0.42). Complete response for HGD at 1 year was found in 60 /64 (94 %; 100 % for treatment-naïve and 91 % for pre" Table 2). The complete reviously ablated patients; P = 0.30) (● sponse for HGD at 3 years or study end appeared higher for treatment-naïve patients (100 % vs. 84 %) but this difference did not reach statistical significance, most likely because of a lack of statistical power (P = 0.08). The four treatment-naïve patients with intramucosal cancer at baseline and residual HGD and/or positive EMR lateral margin, were free of all neoplasia at 1 year, 3 years, and study end. Furthermore, 67 % of previously treated patients were disease-free at 1 year, 3 years, and study end, including a surgically unfit patient who progressed to ECA after " Fig. 3). Hence, 56 /64 (87 %) of all patients had long-term PDT (● elimination of all neoplasia, with greater chance of success in treatment-naïve patients (100 %) compared with previously ablated patients (82 %) (Fisher’s exact test, P = 0.049). At study end, the complete response for neoplasia for cryotherapy patients who did not need rescue therapy was 29/32 (91 %), which was comparable to that for those who received rescue therapy (27/32 [84 %]; P = 0.71). The overall complete response rate for intestinal
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Table 2
587
Short and long term eradication rates of Barrett’s neoplasia (evaluable patients n = 64).
P
Primary treatment
Prior ablation
All
n = 20
n = 44
n = 64
4.5 ± 2.1 (0.83 – 6.7)
4.2 ± 1.9 (0.66 – 6.7)
4.2 ± 1.9 (0.66 – 6.7)
0.82
Dysplasia at 1 year
19 /20 (95)
38 /44 (86)
57 /64 (89) 95 %CI 79 % – 94 %
0.42
HGD at 1 year
20 /20 (100)
40 /44 (91)
60 /64 (94) 95 %CI 85 % – 98 %
0.30
HGD at 3 years or to study end 2
20 /20 (100)
37 /44 (84)
57 /64 (89) 95 %CI 79 % – 94 %
0.08
ECA at 1 year
4 /4 (100)
6 /9 (67)
10 /13 (77) 95 %CI 50 % – 92 %
0.26
ECA at 3 years or at last visit > 3 years 2
4 /4 (100)
6 /9 (67)
10 /13 (77) 95 %CI 50 % – 92 %
1.00
Dysplasia/ECA at 3 years or at last visit 2
20 /20 (100)
36 /44 (82)
56 /64 (87) 95 %CI 83 % – 97 %
0.05
Intestinal metaplasia at 1 year
14 /20 (70)
21 /44 (48)
35 /64 (55) 95 %CI 42 % – 66 %
0.11
Intestinal metaplasia at 3 years2
17 /20 (85)
26 /44 (59)
43 /64 (67) 95 %CI 55 % – 77 %
0.73
Follow-up time, median ± SD (IQR), years
Residual low grade dysplasia at study end, n (%)
0
3 (7)
3 (5)
0.55
Treatment failure, n/N (%) 3
0
4 /44 (9)
4 /64 (6)
0.30
Detection of intestinal metaplasia after 2 negative EGDs, n/N (%)
6 /20 (30)
14 /44 (32)
20 /64 (31)
1.00
HGD in new or recurrent intestinal metaplasia
2 /6 (33)
6 /14 (43)
8 /20 (40)
0.69
Intestinal metaplasia detected at > 1 year (new)
2 /6 (33) 2 /20 (10)
7 /14 (50) 7 /44 (16)
9 /20 (45) 9 /64 (14)
0.64
HGD in new intestinal metaplasia
1 /2 (50) 1 /20 (5)
4 /7 (57) 4 /44 (9)
5 /9 (56) 5 /64 (8)
Intestinal metaplasia detected at < 1 year (recurrent), n/N (%)
4 /6 (67) 4 /20 (20)
7 /14 (50) 7 /44 (16)
11 /20 (55) 11 /64 (17)
HGD in recurrent intestinal metaplasia
1 /4 (25)
4 /7 (57)
5 /11 (45)
Location of new or recurrent intestinal metaplasia at GEJ or distal esophagus within 2 cm, n/N (%)
5 /6 (83)
12 /14 (86)
17 /20 (85)
1.00
Successful treatment of HGD in patients with new/recurrent intestinal metaplasia, n/N (%)
2 /2 (100)
9 /10 (90)
11 /12 (92)
1.00
IQR, interquartile range; HGD, high grade dysplasia; ECA, esophageal adenocarcinoma; LGD, low grade dysplasia; EGD, esophagogastroduodenoscopy; GEJ, gastroesophageal junction. 1 Complete response defined as complete eradication after treatment. 2 Patients may have had a combination of rescue therapies for recurrent neoplasia after complete response for HGD after cryotherapy. 3 Treatment failure defined as persistence of HGD or progression to ECA.
metaplasia at 1 year and 3 years or study end was 35/64 (55 %) " Taand 43 /64 (67 %), respectively, with no difference by group (● ble 2). Cryotherapy treatment failed in 4 of the 64 patients (6 %) as a result of persistent or recurrent HGD (n = 3) or recurrence of intramucosal cancer (n = 1). All four patients were in the previously ablated group and were surgically unfit. Two of these patients were successfully treated with EMR, RFA, and/or PDT. The one elderly, high risk patient with recurrent intramucosal cancer despite prior multiple endoscopic therapies, progressed to advanced cancer after noncompliance with follow-up and treatments. The overall disease progression rate to cancer was 2 /68 patients (2.9 %; or 2 in 286 patient-years, annual progression rate 0.7 % per year) for all treated patients, including those who did not complete therapy. Overall and disease-related mortality from esophageal cancer for the entire cohort over the 8-year study period were 10 /68 (14.7 %) and 1 /68 (1.5 %), respectively.
Treatment failure and recurrence After successful treatment with cryotherapy, 6 treatment-naive and 14 previously treated patients developed intestinal metaplasia during follow-up. The overall detection rate of intestinal me-
Fig. 3 Endoscopic image of circumferential superficial necrosis in the esophagus 2 days after cryotherapy. Prior to cryotherapy treatment, this surgically unfit patient had multifocal high grade dysplasia in a long Barrett’s segment. The endoscopic mucosal resection (EMR) specimen had a deep margin positive for a T1 submucosal esophageal adenocarcinoma. He had suffered severe adverse events from photodynamic therapy (dehydration, acute renal failure) and EMR (gastrointestinal bleeding with hemodynamic instability). The patient was disease-free for more than 5 years after cryotherapy treatment.
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Complete response rates, n/N (%) 1
Original article
taplasia following a complete response for neoplasia with two negative EGD with biopsy procedures following completion of " Tacryotherapy was 20 /64 (31 %), with no difference by group (● ble 2). Nine of these patients (45 %; or 14 % [9 /64] of the entire cohort) were detected after more than 1 year of complete response for intestinal metaplasia, suggesting metachronous rather than " Table 2). The remaining 11 /20 patients (or recurrent disease (● 17 % of the entire cohort) had recurrent intestinal metaplasia detected less than 1 year from completion of treatment. The major" Table 2) of new or recurrent intestinal metaity (17 /20 [85 %]) (● plasia was located at or within 2 cm of the gastroesophageal junction. Multifocal neoplasia, long Barrett’s segments ( > 8 cm), and hiatal hernia size (> 3 cm) were significantly associated with a higher risk of treatment failure and/or recurrence after adjusting " Table 3). All six patients with a for prior endoscopic treatment (● large hiatal or paraesophageal hernia in whom treatment failed or who had recurrent disease had successful endoscopic therapy and sustained neoplasia remission after laparoscopic hernia repair. Treatment of new or recurrent HGD was successful in all but one of the 12 patients (all surgically unfit) using single or combina" Table tion rescue endoscopic therapy (EMR, RFA, and/or PDT) (● 2). The one elderly patient developed a new cancer at the gastroesophageal junction. EMR of this lesion showed a T1b submucosal cancer with a positive deep margin. Cryotherapy downgraded the biopsies to HGD and provided local disease control prior to the patient’s death from medical co-morbidities.
Safety The adverse events associated with CO2 cryotherapy are summar" Table 4. The overall adverse event rate was 9 % (6/68) ized in ● and the serious adverse event rate was 3 % (2/68). Post-treatment chest and/or upper abdominal pain were uncommon. No strictures developed in the treatment-naïve group. No patient developed GI bleeding, including patients with esophageal varices and chronic anticoagulation therapy. Two patients were hospitalized after cryotherapy: one for transient abdominal pain and minute sub-diaphragmatic gas but no free leak or perforation, and the other for postprocedural bradycardia. Buried Barrett’s was noted in 7.3 %; all were associated with an endoscopically visible lesion or minute columnar island and were successfully treated with EMR (final pathology diagnosis two HGD, one LGD, two no dysplasia).
Discussion !
Table 3 Factors associated with treatment failure or recurrent disease (multivariate logistic regression, evaluable patients n = 68).
Dependent variable
Prior endoscopic treatment
P
Adjusted
95 % confidence
odds ratio
interval
2.1
0.59 – 7.2
0.26
Multifocal neoplasia
3.8
1.1 – 13.5
0.04
Large hiatal hernia > 3 cm
3.2
1.0 – 10.1
0.04
Long Barrett’s segment > 8 cm
4.2
1.3 – 13.4
0.02
Since the original development and first clinical use of CO2 cryotherapy in 1999 [16], only one small prospective pilot study in 20 patients, which used the technique for treatment of nondysplastic Barrett’s esophagus, has been reported [10]. No study has evaluated CO2 cryotherapy for Barrett’s neoplasia. The current study reports, for the first time, the safety and efficacy of CO2 cryotherapy for the treatment of HGD or ECA. The 8-year study tracked the short and long term outcomes of outpatient endoscopic CO2 cryotherapy in consecutive patients with Barrett’s esophagus with HGD or cancer who were treated at a single academic center, regardless of previous therapy or risk factors. The complete response rate was 94 % for HGD (100 % in treatment-naïve patients) and 77 % for ECA. There was very low progression to cancer (2.9 %) and ECA-related mortality (1.5 %). Results from this predominantly high risk cohort demonstrated that CO2 cryotherapy is safe and effective for complete eradication of neoplastic Barrett’s esophagus. The current practice standard for ablation of non-nodular or flat neoplastic Barrett’s esophagus with HGD is RFA [12], with short term complete response rates for HGD of 81 % [17]. The 3-year complete response rate for dysplasia in RFA-treated patients within a clinical trial with salvage RFA for recurrences and double-dose PPI therapy was 98 % [18]. The current data suggest that the short and long term complete response rates for neoplasia with CO2 cryotherapy are potentially comparable to RFA; however, no direct comparison has yet been performed. In general, EMR is the preferred approach for the primary treatment of neoplastic Barrett’s lesions, including mucosal Barrett’s cancer [12, 19 – 21] and residual neoplasia [20]. Ablation should be generally reserved for flat Barrett’s lesions without cancer [12, 17,18,21 – 24]. However, PDT [3, 25] and liquid nitrogen cryotherapy [26] have been used successfully to treat ECA. In the current study, 10 /68 patients (15 %) had intramucosal cancer and 4 /68 (6 %) had submucosal cancer at baseline, and the overall P*
Primary treatment
Prior ablation
All
n = 24
n = 44
n = 68
All treatment-related adverse events, n (%)
4 (17)
2 (5)
6 (9)
0.17
Postprocedure pain, n (%)
4 (17) 1
0
4 (6)
0.01
Pain requiring narcotics
2 (8.3)
0
2 (3)
0.21
Esophageal stricture (dilated), n (%)
0
1 (2)
1 (2)
1.0
Fever
0
0
0
Bleeding
0
0
0
Hospitalization, n (%)
1 (4)
1 (2)
2 (3)
1.0
Any buried intestinal metaplasia, n (%)
3 (13)
2 (5)
5 (7)
0.34
* Differences between groups were not statistically significant.
Canto Marcia Irene et al. Carbon dioxide cryotherapy for Barrett’s esophagus … Endoscopy 2015; 47: 582–591
Table 4 Cryotherapy treatmentrelated adverse events (entire cohort).
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complete response rate for ECA was 77 %. The complete response for cancer in the current study was lower than that reported for other retrospective cohorts, but these cohorts may not be comparable. In the current study, previous treatment had failed in 69 % of patients and four patients had submucosal cancers that were inoperable. The CO2 cryotherapy treatment outcomes in the current study were also almost identical to those of liquid nitrogen cryotherapy (complete response of 97 % – 100 % for HGD and 75 % for ECA [27 – 29]). However, CO2 cryotherapy is less costly and more userfriendly than liquid nitrogen cryotherapy, which requires abdominal compressions and a gastric decompression tube. The overall complete response rates for intestinal metaplasia in the current study (1 year 55 %, 3 years 67 %) were lower than those reported for RFA (77.4 % – 98 % [17, 30]), APC (77 %) [31], and liquid nitrogen cryotherapy (84 % at 2 years) [27]. However, when only treatment-naïve patients are considered (comparable to published data), the rates were 70 % and 85 % at 1 and 3 years, respectively. Recurrent intestinal metaplasia frequently develops after ablation therapy regardless of treatment type. In the current study, recurrent intestinal metaplasia was present in 31 % after successful CO2 cryotherapy. Similarly, recurrent intestinal metaplasia is detected in 15 % – 30 % [27, 32] of liquid nitrogen cryotherapy patients and 13.9 % – 25.9 % [18, 33] of RFA patients. In the current study, the new or recurrent intestinal metaplasia usually developed at the gastroesophageal junction or close to it (the “hot zone”) [33, 34]. One possible explanation for recurrence of intestinal metaplasia after cryotherapy is that acid reflux may not be optimally controlled [35], as it was in RFA trials [17] and a recent APC trial, where PPI dosage was adjusted according to 24hour pH monitoring results [36]. Another possible factor is that cryotherapy-related gas distension affects cryogen delivery to the distal esophagus and gastroesophageal junction. The median number of CO2 cryotherapy sessions required per patient in order to achieve a complete response for HGD was 4, which is comparable to that reported for liquid nitrogen cryotherapy (mean 3.9 ± 2.9 sessions) [28] and APC (mean 4 ± 1.6 sessions) [36] but greater than that for RFA (3.5) [17]. One possible explanation is that 19 % of the current study cohort had ultralong Barrett’s segments (> 8 cm) and 28 % had hiatal hernias of > 3 cm. Long Barrett’s segments and large hernia sacs significantly increase the number of RFA sessions required [37]. Laparoscopic repair of these large hernias might improve results [38]. Another possible reason for multiple sessions is that conservative cryogen dosimetry was used for the first 2 years of the study. A human pilot study of CO2 cryotherapy in nondysplastic Barrett’s esophagus used a different cryogen dose (5 – 7 applications of 20 – 30 seconds) and reported a median of 2 sessions per patient. Two studies using liquid nitrogen cryotherapy reported varying cryogen dosimetry (2 cycles × 20 seconds, 4 cycles × 10 seconds, then 2 cycles × 20 seconds) [27, 28]. Cryogen dosimetry is a critical factor influencing treatment response. More research is needed on optimization of cryogen dose to achieve the highest safety, efficacy, and efficiency of treatment for Barrett’s esophagus. Perhaps the most appealing aspect of CO2 cryotherapy is the excellent safety profile. The overall serious adverse event rate in the current study was low (2.9 %) and comparable to that for RFA (3.4 %) [18]. The incidence of post-RFA pain is 12.9 % [39] to 57.5 % [40]. It is usually mild to moderate in severity [17, 39], but may require narcotic analgesics or hospitalization [17]. In contrast, only 5.9 % of patients in the current study had any pain after cryotherapy (2.9 % needed narcotics), and nearly all ate a normal diet.
Liquid nitrogen cryotherapy can also cause chest pain (17.6 % – 23 % [29, 41]), dysphagia (13.3 % [29]), odynophagia (12.1 % [29]), and sore throat (9.6 % [29]). High power (90 W) APC can cause serious adverse events in 9.8 % of patients (bleeding, perforation) [31]. No GI bleeding was observed in the current study despite a relatively high proportion of patients with risk factors for postablation bleeding [17, 42]. In fact, two patients had previously experienced esophageal bleeding that required transfusion after undergoing RFA and resuming aspirin after 1 – 2 weeks. Few esophageal strictures were observed after CO2 cryotherapy (1.5 %), even in patients with pre-existing strictures. In contrast, the stricture rate of RFA is 6 % – 7.6 % [17, 18] (8 % in ultra-long Barrett’s segments [42]). Finally, no free perforation was observed, although one patient who was treated early on in the study might have had a microscopic perforation, which was successfully managed with conservative treatment. No similar problem developed when using the newer device with greater suction. Liquid nitrogen cryotherapy has resulted in one gastric perforation requiring surgery [41]. Overall, CO2 cryotherapy had high patient tolerability and a low adverse event profile, even in patients with risk factors for adverse events. The strengths of this study are the long follow-up period, and consistent treatment and surveillance methods at one site. Furthermore, a single experienced operator performed all treatments and this may reduce the variability of results. All clinically relevant outcomes were tracked, including failures, recurrences, and overall and disease-related mortality. Finally, an unselected population was treated over a finite period without restrictions on Barrett’s segment length or previous endoscopic ablation, and the selection and outcomes of treatment(s) were considered in the context of other available treatments. This might make the current study results closer to “real life” clinical practice. The study has several limitations. These include the limited sample size, retrospective analysis, nonrandomized design, and lack of a comparison or control treatment arm. However, the study provides important information on cryogen dosing, safety, and efficacy that is needed for large randomized controlled trials. Second, the trial may have limited generalizability as a result of the referred patient population and academic center location. Larger comparative trials and community-based studies are needed. Third, the central pathology interpretation of biopsies was not blinded. However, at The Johns Hopkins Medical Institutions, the majority of Barrett’s esophagus samples are interpreted by one expert (E.M.), resulting in consistency of interpretation. Fourth, the treatment of new or recurrent intestinal metaplasia was not limited to cryotherapy but also included alternative endoscopic therapies. However, the effect of intervening therapies was controlled for and it was found that high long term complete response rates for neoplasia were comparable for cryotherapy as single therapy or as part of multimodal therapy. With the high cost of RFA and liquid nitrogen cryotherapy ablative therapies, a comparably effective but lower cost technique, such as CO2 cryotherapy, should be studied as an alternative or adjunctive option. Randomized trials of the cost-effectiveness using various ablative techniques and single or multimodality approaches for treatment of Barrett’s neoplasia are needed. In conclusion, CO2 cryotherapy was shown to be a safe and effective primary curative or rescue therapy for Barrett’s neoplasia.
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Original article
Original article
Competing interests: Dr. Canto has received research grant from C2Therapeutics, Inc. (Redwood City, California, USA) for clinical trial participation. She has been a consultant for BarrX Medical (Covidien, Sunnyvale, California, USA). Dr. Shin has received material support from GI Supply (Camp Hill, Pennsylvania, USA) for a research study. Dr. Pasricha is an inventor of carbon dioxide cryotherapy and a consultant for GI Supply (which licensed the technology from Johns Hopkins University). Institutions 1 Division of Gastroenterology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland, United States 2 Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, United States 3 Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland, United States 4 Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, United States
Acknowledgments !
This study was supported by The Johns Hopkins Barrett’s Esophagus and Esophageal Cancer Research Fund, The Jerry D’Amato Charity Foundation.
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Correction Canto MI, Shin EJ, Khashab MA et al. Safety and efficacy of carbon dioxide cryotherapy for treatment of neoplastic Barrett's esophagus. Endoscopy 2015, 47; DOI: 10.1055/s-0034-1391734 The author’s name Mouen Khashab was corrected to Mouen A. Khashab.
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