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Multifocal Cryoballoon Ablation for Eradication of Barrett's Esophagus-Related Neoplasia: A Prospective Multicenter Clinical Trial

Canto, Marcia Irene MD, MHS1; Trindade, Arvind J. MD2; Abrams, Julian MD3; Rosenblum, Michael PhD4; Dumot, John MD5; Chak, Amitabh MD5; Iyer, Prasad MD6; Diehl, David MD7; Khara, Harshit S. MD7; Corbett, F. Scott MD8; McKinley, Matthew MD2; Shin, Eun Ji MD, PhD1; Waxman, Irving MD9; Infantolino, Anthony MD10; Tofani, Christina MD9; Samarasena, Jason MD11; Chang, Kenneth MD11; Wang, Bingkai BS4; Goldblum, John MD12; Voltaggio, Lysandra MD13; Montgomery, Elizabeth MD13; Lightdale, Charles J. MD2; Shaheen, Nicholas J. MD, MPH14

Author Information
The American Journal of Gastroenterology: November 2020 - Volume 115 - Issue 11 - p 1879-1890
doi: 10.14309/ajg.0000000000000822
  • Open



Barrett's esophagus (BE) is a known precursor to esophageal adenocarcinoma. Endoscopic eradication therapy (EET) of neoplastic BE is currently the most widely accepted approach worldwide. For patients with non-nodular dysplastic BE, professional society guidelines recommend radiofrequency ablation (RFA) as the primary ablative modality because of high safety, efficacy, durability (1–5), and level 1 evidence, demonstrating prevention of esophageal cancer (6,7). However, other ablative modalities, including carbon dioxide cryotherapy (8), liquid nitrogen spray cryotherapy (9–12), and argon plasma coagulation (APC) (13–15), have been developed and used as alternative primary or rescue EET.

Cryotherapy involves the application of cryogen to freeze tissue and induce cell death through acute intracellular ice formation and cell burst, microvascular thrombosis and ischemia, apoptosis, and tissue coagulation necrosis (16). There are 2 types of endoscopic cryotherapy; the first type involves direct application of liquid nitrogen to the esophageal mucosa from a catheter (spray cryotherapy), whereas the second type involves freezing the epithelial cells by surface contact through a balloon infused with nitrous oxide (cryoballoon ablation or CBA). Spray cryotherapy involves multiple direct applications of cryogen to freeze, then thaw, for a precise number of seconds, requiring a decompression tube to vent the excess gas delivered into the upper gastrointestinal (GI) tract. Alternatively, in CBA, the cryogen is contained within the balloon, thus obviating the need for ventilation and eliminating the risk of barotrauma. First described in a porcine model in 2011 (17) and then subsequently reported in human pilot studies (18–20), CBA is performed with a portable, commercially available system (C2 focal Cryoballoon; For Pentax Medical Corporation – Montvale, New Jersey, USA, Redwood City, CA) that consists of a small handheld controller housing a capsule containing the liquid nitrous oxide, which is connected to a disposable, low-pressure, compliant, transparent balloon catheter. This catheter is advanced through the channel of a therapeutic upper endoscope or via a separate side channel attached to a diagnostic upper endoscopy, created specifically to house this catheter. The nitrous oxide is heated within the hand controller, released from the controller down the catheter shaft to a small opening in the diffuser centered within the balloon, resulting in balloon inflation and a discrete, well-defined ice patch approximately 2–3 cm in diameter after 10 seconds of cryogen application (8,18,20) (Figure 1). To allow more tailored therapy, the balloon is configured in both cylindrical and pear shapes, with the latter designed to allow easier treatment of the GEJ.

Figure 1.
Figure 1.:
Image of the cryoballoon focal ablation system (generation 1), consisting of focal (left) and pear-shaped (right) cryoballoon catheters (a) and a nitrous oxide–containing capsule (b) that is loaded into the handle of the controller (c). Endoscopic image of dysplastic Barrett's esophagus showing nitrous oxide spray emitted from the diffuser at the center of the cryoballoon directed to the mucosa in contact, resulting in discrete ice patch. The opposite wall shows white confluent ice patches between 4 and 9 o'clock positions (d).

Single-center clinical trials suggest a potential role for CBA in treating dysplastic BE. One study from the Netherlands reported 100% eradication and squamous regeneration for focal CBA of islands (18) in 30 patients. In a prospective single center clinical trial involving 41 patients with neoplastic BE, the complete eradication of all dysplasia (CE-D) and CE-IM rates were 95% and 88%, respectively (21). We evaluated the safety and efficacy of multifocal CBA in treatment-naive patients with neoplastic BE from multiple academic and community medical centers.


Study design and selection criteria

We conducted a multicenter, prospective clinical trial of CBA treatment in dysplastic BE and intramucosal adenocarcinoma (ImCA). At 11 American sites (2 community and 9 academic), we recruited outpatients age 18 years or older, with histologically confirmed previously untreated (“treatment naive”) BE with low-grade dysplasia (LGD), high-grade dysplasia (HGD), or ImCA. The maximal length of BE was 6 cm or less (excluding visible columnar islands) and Prague classification C ≥ 0, M > 1. Patients with nodularity in their BE segment were required be treated with endoscopic mucosal resection (EMR) at least 6 weeks before study entry. Furthermore, any ImCA had to be at low risk for recurrence, as defined by the pathology results negative for positive margin for ImCA, absence of poorly differentiated carcinoma in the resected specimen, and absence of lymphovascular invasion. We excluded patients with BE with no or indefinite findings of dysplasia after central pathology review. Other exclusion criteria included enrollment in previous CBA clinical trials (20,21), pregnancy or plans for pregnancy during the period of study participation, esophageal varices, uncontrolled coagulopathy, hiatal hernias >4 cm, previous distal esophagectomy, esophageal cancer more advanced than T1a, active esophagitis of Los Angeles classification grade B or greater, symptomatic untreated strictures, esophageal stenosis/stricture preventing advancement of the therapeutic endoscope, severe medical comorbidities precluding endoscopy, life expectancy ≤3 years as judged by the site investigator, and inability to provide informed consent. Patients with strictures that were previously dilated could receive CBA at a subsequent procedure >2 weeks later.

To participate in the trial, each physician was required to observe live cases performed by an experienced physician and undergo supervised training on live or explant porcine model or a proctored patient case. In addition, all physicians independently performed a minimum of 7 CBA procedures before enrolling patients in the study.

The study protocol was approved by the institutional review board at each participating site. The study was registered on (NCT02514525). An independent data and safety monitoring board monitored the trial. The site investigators and their research teams collected the data and reviewed and entered the data into the electronic database and the sponsor, Pentax Medical Corporation, maintained the study database. At the end of the trial, the study database was transferred to the project P.I., who reviewed and analyzed the data with assistance from an independent study biostatistician. All authors had access to the study data and reviewed and approved the final manuscript.

Endoscopic intervention

We performed upper endoscopy procedures on an outpatient basis according to the site's standard of care for procedural sedation or anesthesia. The baseline examination required high definition white light endoscopy and digital mucosal enhancement (narrow band imaging; Olympus America [Center Valley, PA], or I-Scan; Pentax Medical Corporation) to assess baseline characteristics of BE. If at the initial examination there were no concerning lesions or nodularity, CBA was performed using the focal cryoballoon system (C2 Cryoballoon/Pentax Medical Corporation) (Figure 1a–c) with a 10-second cryogen dose for each ablation site, based on previous clinical studies (18,20,21). We used either a therapeutic channel endoscope to allow through-the-scope placement of the cryoballoon catheter or a standard channel high definition upper endoscope with the accessory side channel that held the balloon catheter alongside the endoscope (21). During CBA, the tip of the endoscope was placed at the proximal margin of the cryoballoon to enable complete visualization of the treatment area through the transparent balloon and to promote precise targeting and minimal ice patch overlap. The full dose of nitrous oxide was released from the central diffuser after confirming the direction of the spray with a 1 second “prepuff,” creating a discrete white ice patch (Figure 1d). The entire gastroesophageal region, from the most proximal extent of the BE to 1 cm into the gastric cardia, was treated circumferentially, moving from distal to proximal. Because the catheter rotates within the balloon, circumferential treatment could be achieved without repositioning the balloon. The number of ablations needed to treat the entire Barrett's segment was at the discretion of the endoscopist. Based on the patient's anatomy, the investigator could also use the pear-shaped focal balloon (Figure 1a) as a secondary device, if there was difficulty with stabilizing balloon position at the GEJ or esophagus because of pre-existing or new stenosis (Figure 2).

Figure 2.
Figure 2.:
Endoscopic image of dysplastic BE before treatment (a). Post-treatment endoscopic image of the esophagus corresponding to (a) showing complete eradication of BE (b). BE, Barrett's esophagus.

After completion of CBA for all visible BE, we assessed for typical red mucosal color change (21) shortly after the ice melted. If there were any “skip” areas ≤5 mm without post-CBA mucosal change, we applied an additional 5 seconds of cryogen. Any skip areas >5 mm were treated with full 10-second dose of cryogen. Each CBA procedure was recorded with digital image capture and/or digital video recording.

Patients could receive up to 5 ablation treatment sessions within 12 months, with each treatment session separated by 10–12 weeks.

All patients were prescribed a proton pump inhibitor equivalent to esomeprazole 40 mg, dosed once or twice daily for treatment of gastroesophageal reflux disease during the duration of the trial. Additional medications to optimize acid inhibition, such as histamine receptor antagonists (H2 blocker, such as famotidine) and/or sucralfate, were allowed at the discretion of the enrolling site.

Immediately after CBA and for each of 7 days after each treatment procedure, patients completed a 10-point visual analogue scale to assess post-CBA pain severity. They were also contacted by study site personnel at 1, 7, and 30 days post-CBA to assess for pain and dysphagia.


All patients returned every 10–12 weeks for endoscopic reassessment and retreatment, until the earlier of either no visible residual columnar epithelium in the tubular esophagus with all biopsies negative for intestinal metaplasia or the 12-month follow-up visit. At each follow-up endoscopy, we carefully examined the distal esophagus for any concerning mucosal lesions, which could be treated with EMR (6), or flat residual columnar mucosa, which could be treated with CBA. If there was no endoscopic evidence of BE and treatment was unnecessary, then we obtained endoscopic biopsies. Patients with LGD at study entry underwent surveillance endoscopy every 6 months in year 1, and those with HGD or ImCA at baseline underwent surveillance endoscopy every 3 months (5). At follow-up procedures, we documented the appearance of the GEJ and distal esophagus with digital image capture and/or digital video recording.

At any treatment endoscopy, small flat residual BE islands could be treated with APC if these were fewer than 3 in number and all were <5 mm in maximum diameter (“touch-up ablation”).

Twelve months after the first CBA, we assessed patients with high definition white light endoscopy, digital mucosal enhancement, and obtained protocol biopsies with large capacity forceps, beginning at the gastric cardia (1 cm distal to the GEJ or top of the gastric folds) and then from the distal esophagus in 4 quadrants every 1 cm through the original length of the BE. We sampled any visible mucosal abnormalities first and placed these in separate pathology specimen containers from random biopsies. If at the 12-month follow-up visit there was visible BE, we treated any residual columnar mucosa. If there was no visible BE but random biopsies showed intestinal metaplasia in the tubular esophagus, we treated the patient at 15 months.

Histologic analysis

Biopsy and EMR specimens were processed at each site, where local pathologist(s) reviewed them as part of standard care. Eligible patients with a local diagnosis of LGD, HGD, or ImCA were consented and enrolled. Baseline samples (hematoxylin and eosin stained, formalin-preserved) from potentially eligible patients were also sent to the central pathology core consisting of 2 expert GI pathologists (L.S.V. and E.M.) with expertise in BE pathology. If the readings of the 2 central pathologists were discordant, then a third expert GI pathologist (J.G.) interpreted the slides and a final concordant diagnosis, consisting of agreement of 2 out of 3 pathologists, was assigned. Patients were eligible for continued study participation only if the central pathology reading was consistent with LGD or HGD. Tissue samples from follow-up examinations were also sent to the central pathology laboratory for interpretation.

Central core pathologists assessed each biopsy specimen for tissue type, presence or absence of subsquamous intestinal metaplasia (“buried BE”), and worst histologic grade (nondysplastic, indefinite, LGD, HGD, and ImCA) using the standardized Vienna classification for GI neoplasia (22). In addition, all EMR specimens were assessed for worst histologic grade and lateral and deep margin involvement by cancer, if applicable. “Buried BE” was defined as the esophageal columnar mucosa with intestinal metaplasia completely covered by squamous epithelium and obtained from a nontargeted (random) biopsy, interpreted as endoscopically normal by the gastroenterologist.

Safety monitoring

All serious adverse events were reported within 24 hours. A 3-person data and safety monitoring board met quarterly, reviewed all adverse events, and adjudicated potential likelihood of the causal relationship to the CBA treatment and device.

Statistical analysis

This prospective clinical trial aimed to assess the safety and efficacy of CBA for neoplastic BE. A sample size of 87 was necessary for a 2-sided 95% confidence interval (CI) with a width of 0.15 when the CE-D was 91%. When factoring in a 20% dropout rate, the targeted enrollment was 115. The reference CE-D rate was based on the meta-analysis of RFA studies (CE-D, 91%; 95% CI, 70%–86%) (23) (PASS; NCSS Statistical Software, Kaysville, Utah).

The primary outcome variable was the assessment of CBA efficacy, defined as the percentage of patients who achieved CE-D assessed at 12 months for all patients (intention-to-treat or ITT analysis) and all patients completing all endoscopy (per protocol or PP analysis).

Secondary outcome variables included assessment of CBA efficacy for eradication all BE, defined as the percentage of patients who achieve complete eradication of all intestinal metaplasia (CE-IM) in all biopsies, assessed at 12 months, for all patients, and by group according to baseline worst pathology grade. Other secondary outcome variables included progression of HGD to esophageal cancer at 12 months, progression of LGD to HGD or cancer at 12 months, incidence of subsquamous esophageal intestinal metaplasia (“buried BE”), the number of CBA treatments required to achieve CE-D and CE-IM at 12 months, the postprocedure chest discomfort at baseline and follow-up (visual analog scores), use of narcotic analgesics post-CBA, and proportion of patients who developed adverse events, including bleeding and esophageal stricture (defined as a symptomatic intrinsic esophageal stenosis requiring endoscopic dilation). In addition, we assessed technical aspects of CBA, such as mean procedure time (from the start to the end of the CBA procedure), technical success rate, median number of CBA treatment visits, and predictors of response to therapy (univariate and bivariate analyses).

To account for missing outcome data in the primary analysis, we used the doubly robust weighted least squared (DR-WLS) estimator (24,25). It adjusts for differences in baseline variables between those with measured outcomes and those with missing outcomes to reduce potential bias caused by systematic differences between these groups (e.g., if those with missing outcomes have higher disease severity at baseline). This estimator involves 2 working models: an outcome regression model for CE-D and CE-IM and a propensity score model for missing outcomes. In both models, baseline variables known to affect outcome (age, sex, baseline worst dysplasia grade, and length of BE at baseline) were adjusted. This estimator is consistent as long as at least one of the models is correct, under the missing at random assumption (26) and the assumption that everyone has a positive probability of completing the trial (i.e., having their primary outcome measured), regardless of their baseline variables. The adjusted CE-D and CE-IM with SD and 95% CI were calculated using the estimator. CIs were computed using the BCa bootstrap method. Furthermore, sensitivity analysis was performed to include best and worst CE-D and CE-IM, assuming all unevaluable patients with missing 12-month outcome data were treatment successes or failures.



Of the 1793 patients screened from March 2016 to April 2018, 143 were enrolled, received baseline CBA, and fulfilled the study criteria before central histopathology review. Of these patients, 23 did not meet the study's entry criteria after enrollment (16 had no dysplasia after central pathology review, 1 had no baseline biopsy samples, 1 had BE length >6 cm, 4 did not complete baseline assessment, and 1 had untreated nodularity), leaving 120 eligible patients who completed a baseline visit (“full analysis or ITT set”). During the course of the study, 17 exited the study (2 because of consent withdrawal, 7 missed visits, 4 because of medical comorbidity or death unassociated with their esophageal condition, 1 loss of health insurance, and 3 converted to another treatment modality) and 9 were unevaluable at 12 months because of protocol deviations (1 missed visit, 6 received treatment, and/or 2 had no protocol biopsies), leaving 94 patients who successfully completed CBA and study visits (evaluable patients or PP set) (Figure 3, patient flow chart). The characteristics of the study patients are detailed in Table 1. The mean BE length was 3.2 cm (range 1–6 cm), with a 46% EMR rate before CBA. Nine patients (8%) had pre-existing strictures, of which 3 required dilation before subsequent CBA.

Figure 3.
Figure 3.:
Patient flow chart. APC, argon plasma coagulation; BE, Barrett's esophagus; CBA, cryoballoon ablation.
Table 1.
Table 1.:
Patient characteristics

Main study outcomes

In the ITT analysis, CE-D was achieved in 91/120 patients (76%) (95% CI 67%–83%) (Figure 4, orange bar). Considering all evaluable patients (n = 94, PP analysis) with the 12-month outcome data, CE-D was achieved in 91/94 patients (97%) (95% CI 88%–99%) (Figure 4, blue bar). Considering the ITT group of 120 patients, the DR-WLS estimated probability of CE-D after adjusting for possible differences in key baseline variables (age, sex, BE length, and worst BE dysplasia grade) was 96% (SD = 2%, 95% CI 90%–100%).

Figure 4.
Figure 4.:
Main study outcomes. Main study outcomes with sensitivity analysis showing the rates for complete eradication of all dysplasia (CE-D) and complete eradication of all intestinal metaplasia (CE-IM) with 95% confidence intervals. The blue bars show the PP outcomes in 94 evaluable patients with available data 12 months. The orange bars show the ITT outcomes of CE-D and CE-IM assuming all 17 dropped patients and 9 unevaluable patients failed at 12 months (n = 120). ITT, intention to treat; PP, per protocol.

Overall, in the ITT group, CE-IM was achieved in 86/120 patients (72%, 95% CI 63%–79%) (Figure 4, orange bar), whereas in the PP group of 94 evaluable patients, CE-IM was achieved in 86/94 patients (91%) (95% CI 90%–99%) (Figure 4, blue bar). Considering the ITT group of 120 patients, the DR-WLS estimated probability of the CE-IM rate was 91% (SD = 3%, 95% CI 83%–96%).

There were no significant differences in the CE-D and CE-IM rates when stratified by highest baseline dysplasia grade (P = 0.42 and P = 0.61, respectively).

Patients who achieved CE-IM at 12 months required a median of 2 CBA procedures (interquartile range [IQR] 2–3) to attain CE-IM.

Treatment failure and disease progression

There were 3 patients who were treated with RFA at the first or subsequent visit because of difficulty in positioning the cryoballoon at the distal esophagus and GEJ (n = 2) or technical difficulty due to repeated cryoballoon deflation (n = 1). These technical difficulties due to balloon migration were not encountered after the pear-shaped cryoballoon became available as an alternative device for patients with narrowing at the distal esophagus or GEJ. These patients were considered failures in the ITT analysis. There were 2 patients with HGD who did not respond to treatment at 1 year. The first patient had persistent HGD at 1 year despite 3 CBA treatments and 2 EMRs. The second patient achieved CE-IM at 9 months. However, at 12 months, although no visible esophageal columnar mucosa was evident, a random biopsy showed buried HGD. Therefore, this patient was a failure for both CE-D and for CE-IM at 12 months.

One patient (1/120 or 0.8%), with Prague C5M6 BE developed neoplastic progression from baseline HGD to ImCA during the course of treatment. This patient received 3 CBA treatments, then, subsequently developed 2 other nodules with ImCA, which were completely resected at separate endoscopy sessions. At the 12-month examination, this patient had no visible esophageal columnar mucosa, and Seattle protocol biopsies obtained from 4 quadrants every 1 cm from the gastric cardia and neosquamous esophagus were negative. However, at 15 months, another 3 nodules were resected; 2 of which contained gastric mucosa without IM and one proved to be a third ImCA at a different location from the previous EMRs. At 24 months, the patient had multiple EMRs performed for mucosal irregularity, and these specimens, as well as those obtained using the Seattle biopsy protocol, showed no residual or buried BE.

Technical success and treatment procedure detail

All but 13 of the 303 CBA treatment procedures (4.2%) were completed successfully. Of the 13 procedures terminated because of technical failure, 9 were terminated because of device-related failure, 1 because of mucosal injury secondary to balloon distension, and 3 because of difficulty in balloon positioning with either balloon migration or incomplete contact with a patulous GEJ. The median ablation time (time from first passage of the CBA catheter to the withdrawal of the catheter) was 11 minutes (IQR 7–16 minutes).

The median number of 10-second cryogen applications performed at the initial treatment was 7 (IQR 5–10). “Touch-up” CBA (5 seconds) for skip areas <5 mm was applied in 37% of initial treatments and 18% (range 12%–28%) of subsequent treatment visits. “Touch up” APC for residual islands <5 mm was performed in 3% (range 3.2%–5.6%) of all procedure visits at 3, 6, and 9 months.

Safety and adverse effects

No serious adverse events were noted to be directly due to CBA or to occur during CBA treatment. All SAE's were delayed. Self-limited post-CBA bleeding not requiring blood transfusion associated with ongoing clopidogrel use occurred in 1 patient (0.8% of patients) 1 week after treatment. Endoscopy revealed a postablation esophageal ulcer with pigmented material, which was treated with thermal cautery. Two patients had SAE's related to treatment of posttherapy strictures. One of these patients (0.8% of patients) developed a perforation related to the dilation of a stricture that developed within 30 days from the initial CBA treatment. This perforation was successfully treated with an esophageal stent, followed by thoracoscopy, partial decortication, drainage of effusion, and jejunostomy tube placement. The patient fully recovered. The second stricture patient was admitted for observation after dilation of the stricture resulting in a deep laceration, necessitating clip placement at the 6-month visit. The overall hospitalization rate was 3/120 or 2.5%. The incidence of serious adverse events was 1% (i.e., 1 perforation, 1 upper GI bleed, 1 deep laceration leading to hospitalization for observation and no additional treatment was performed) for the 303 treatment procedures.

There were no perforations attributable to inflation of the cryoballoon. One patient developed a device-related adverse event, consisting of a balloon trauma during a CBA procedure leading to a mucosal laceration, which was treated prophylactically with an endoscopic clip but did not lead to postprocedure symptoms, bleeding, or hospitalization.

Symptomatic esophageal strictures requiring dilation developed in 15 patients (12.5%), treated with a median of 1 dilation procedure (IQR 1–2). Dysphagia developed within 30 days of CBA treatment in 60% of these patients with strictures, and after 30 days in the remainder (median number of days to stricture onset 39 days, IQR 31–45). All but 1 stricture developed after the initial CBA treatment session. Most (87%) of these strictures were associated mild solid food dysphagia and a stenosis that was traversable with the adult upper endoscope. Forty-seven percent of the patients who developed a post-CBA stricture had previous EMR, 3 patients had a pre-existing stricture or Schatzki ring, and 4 reported nonsteroidal anti-inflammatory drug or aspirin use. There was no difference in the post-CBA stricture rate in patients with and without previous EMR (12.3% vs 11.3%, respectively, P = 1.0). Multivariate logistic regression analyses showed that baseline BE (Prague M) length was the only significant independent predictor of post-CBA stricture formation after controlling for previous EMR, baseline highest dysplasia grade, and pre-existing esophageal stricture (odd ratio 1.45, 95% CI 1.01–2.07, P = 0.044).

When assessed after regaining consciousness in the recovery room after initial treatment, post-CBA pain was mild, with a median visual analog pain score of 2, with IQR 0-5 (using a scale of 0-10, with 0=no pain and 10=most severe pain) (Figure 5). Postprocedure chest pain quickly resolved, with a median score of 1 (IQR 0–2) at day 1 postprocedure and 0 (IQR 0-0) at day 7 postprocedure for the index CBA treatment (Figure 5). Furthermore, for all treatment procedures, a total of 8%, 1.7%, and 0.3% of patients required narcotic analgesics immediately postprocedure, at day 1, and at day 7, respectively. The highest use of narcotics for pain was after the baseline treatment, when 13% of patients needed these medications immediately postprocedure.

Figure 5.
Figure 5.:
Postcryoablation pain scores. Median postprocedure pain scores (by visual analogue scale 1–10, where 0 = no pain and 10 = worse pain ever) with interquartile range (bars) after cryoballoon ablation immediately postprocedure and days 1–7 for the index (orange), 3 month (green), 6 month (blue), and 9 month (lavender) treatment, where applicable.

Subsquamous intestinal metaplasia

At baseline, no patient had evidence of subsquamous intestinal metaplasia (buried BE) (Table 1). One patient (0.8%) had buried BE in samples from neosquamous mucosa. This patient had baseline HGD (Prague C5M6) and received a total of 3 CBA treatments. At 9 months, biopsies showed CE-D and intestinal metaplasia. However, at 12 months, 4-quadrant random biopsies showed buried intestinal metaplasia. At 15 months, the physician performed high definition white light endoscopy, narrow band imaging, confocal laser and volumetric laser endomicroscopy with a flat tiny columnar island detected by narrow band imaging, and mild squamous scarring from previous CBA (Figure 6). Volumetric laser endomicroscopy visualized one dilated gland, and the targeted-EMR specimen reviewed locally and by central pathology showed no buried BE. Multilevel protocol surveillance biopsies have been negative to date.

Figure 6.
Figure 6.:
“Buried” Barrett's esophagus. High resolution white light image of the distal esophagus postcryoballoon ablation showing no visible residual columnar esophageal mucosa (a) at the 12-month follow-up. A single random biopsy showed subsquamous intestinal-type gland with high-grade dysplasia. Subsequent careful inspection focused on the level of this biopsy 3 cm proximal to the gastroesophageal junction showed a minute flat columnar island (b), more apparent with narrow band imaging (c).

Predictors of response to therapy

Univariate analysis of the PP group showed that patients with <3 cm Prague M (63% of patients) were more likely to achieve CE-IM than those with >3 cm (98% vs 80%, respectively, P = 0.004). The median Prague M length of 86 patients in the PP group who achieved CE-IM was 2.5 cm (IQR 2.0–4.0 cm), whereas the median maximum BE length in the 8 patients who did not achieve CE-IM was 5 cm (IQR 4.0–5.5 cm). The highest BE dysplasia grade, sex, race, smoking, body mass index, aspirin or nonsteroidal anti-inflammatory drug use, presence of a hiatal hernia, previous EMR, and old age younger than 65 years were not associated with CE-IM in the univariate and bivariate analyses.


Endoscopic therapy has become the favored approach for treatment of neoplastic BE in the past decade. RFA of dysplastic BE leads to CE-D in 91% (95% CI 87%–95%) and CE-IM in 78% (95% CI 70%–86%) (23) and significantly decreased risk of esophageal cancer in patients with LGD (27,28) or HGD (6,7). When combined with endoscopic resection, curative treatment of ImCA is also highly successful (29,30). However, RFA may not be successful in some patients, particularly those with longer lengths of BE and/or a hiatal hernia (31). BE may recur in 15% (32) or more of patients after CE-IM is achieved with RFA, and this risk does not abate in subsequent years such that lifelong surveillance of patients undergoing successful RFA is mandatory. RFA may also not be commercially available or reimbursable (33) in some areas. RFA is also costly, considering the capital expense for the generator, disposable catheters, and repeat procedures (34,35). Finally, post-RFA pain can be severe.

Consequently, other endoscopic ablative modalities, such as cryotherapy, have been developed, albeit not as extensively and rigorously studied, as alternative therapies. Liquid nitrogen spray cryotherapy (Cryospray Ablation System; CSA Medical, Baltimore, MD) has been used as a “salvage” treatment for failed RFA (31,36,37) or as a primary treatment modality for neoplastic BE with high success (Table 2) (11,38). Similarly, cryotherapy can effectively eradicate dysplasia (8,39), but it has a relatively lower CE-IM rate (8) when compared with RFA. CBA represents an extension of these past cryotherapies and has encouraging albeit limited data. In a single center trial, multifocal CBA of the entire extent of BE (maximum length 3.9 cm, range 1–14 cm) in 41 patients led to high CE-D and CE-IM of neoplastic BE, including patients previously untreated and those who failed other therapies (21).

Table 2.
Table 2.:
Summary of clinical outcomes of endoscopic ablative therapies for Barrett's neoplasia

In the current study, we report the largest prospective trial to date in patients with “treatment-naive” BE with confirmed ImCA, HGD, and LGD, with or without previous EMR for mucosal lesions, undergoing CBA. Our multicenter study shows that most patients achieve complete CE-D (97%) and CE-IM (92%) assuming the best-case scenario using the PP population or the worst-case scenario using the ITT population (CE-D 76% and CE-IM 72%). CE-IM was achieved in an average of 2 procedures within 1 year, with the PP efficacy outcomes comparable with the single center results in consecutive CBA-treated patients with BE of any length (CE-D 95%, CE-IM 88%) (21). The CE-D and CE-IM rates of CBA in the PP analysis of the current trial are comparable with those reported for RFA or liquid nitrogen and CO2 cryotherapy (Table 2). Importantly, subjects developed minimal postprocedural pain and required little narcotic analgesia. The latter results are consistent with a study from the Netherlands comparing postprocedure pain and narcotic use in RFA- and CBA-treated patients (19) and a second study comparing postprocedure pain in RFA- and liquid nitrogen cryotherapy-treated patients (40). In the Dutch study comparing RFA and CBA, CBA patients reported less pain and less use of narcotic analgesics when compared with RFA, with comparable treatment efficacy (19).

Regarding safety, our study results suggest that CBA has low rates of postprocedural bleeding and hospitalization, similar to those reported with RFA (41). The stricture rate in our trial (12.5%) is somewhat higher than that reported for RFA (5.6% (23)) in a meta-analysis of earlier studies from 2008 to 2013. However, stricture rates after RFA in studies with a proportion of ImCA patients more similar to ours (42,43) or with more routine use of EMR (44) showed rates (14%–19% (6,42)) more comparable with that seen in our study. In this trial, EMR did not influence stricture formation but baseline BE length did. A much larger study might provide insight on the factors promoting stricture formation, but it is possible that technical issues might have led to strictures after CBA, such as overlapping ice patches without sufficient thaw, resulting in higher energy and deeper injury.

In our study, one patient had an isolated biopsy showing subsquamous BE with HGD. This was not confirmed at follow-up endoscopy with advanced endoscopic imaging techniques and EMR. This finding may represent “pseudoburied” BE, where a tiny island of residual columnar tissue is not well visualized (45) rather than completely buried (“invisible”) BE detected by random biopsy (46) because the physician noted a subtle endoscopic abnormality (in retrospect, a tiny columnar island (Figure 6). Buried BE is a finding common to all endoscopic eradication therapies, including RFA (47–50), photodynamic therapy (51), cryotherapy (11,39), APC (52,53), and EMR (54) after successful eradication. The reported incidence rate for subsquamous IM after RFA varies from 2% (47) to 5.6% (55). Although reports of buried BE after ablation are common, the reports of buried cancer are rare (47–50,56–58), calling into question the relevance of the finding of isolated islands of buried BE. Because minute islands of columnar epithelium may be missed during cursory inspection, these findings highlight the need for meticulous endoscopic inspection before and after ablative therapy. Subtle findings in a postablation patient such as small raised nodules (56) or flat tiny columnar islands (that might indicate partially buried BE or neoplasia) or reddish discoloration of squamous mucosa (dilated irregular blood vessels) (47) should lead to EMR, which is potentially curative. Life-long surveillance is also necessary after endoscopic eradication of neoplastic BE.

CBA has some unique features that make it easy to use. First, the nitrogen liquid/gas is contained in the balloon, obviating the need for gas venting with an orogastric tube or abdominal compression, which are measures routinely used during liquid nitrogen cryotherapy. Second, because the cryogen is contained within the balloon instead of being released into the lumen of the esophagus, freezing is time and energy efficient, with no need for repeated freeze-thaw cycles. The potential time effectiveness of this procedure is highlighted by our average CBA time at the first treatment session of only 11 minutes. Third, the focal ice patches are discrete, sharply defined, and highly visible through the transparent cryoballoon so that targeted ablation is remarkably accurate and minimizes normal mucosal injury. There is also a well-defined erythematous mucosal change in the area of the ice patch after it melts, which marks the treated area. These, in turn, can be used to minimize over-treatment of the mucosa and cryogen delivery time. Fourth, the CBA equipment is portable and the controller occupies a small footprint; small capsules replace heavy and large liquid nitrogen tanks that need to be exchanged or refilled. Fifth, the cryoballoon is compliant and balloon pressure is maintained at 3.5 psi (a pressure much lower than that of dilating balloons) by the controller, allowing stability of treatment within pre-existing strictures with little risk for mucosal laceration. The availability of a pear-shaped balloon further aids in positioning of the balloon, especially around the GE junction. By contrast, treatment of residual BE within strictures using other modalities can be challenging. Finally, CBA is relatively low cost, with no or minimal capital expense and affordable disposable cryoballoon catheters.

The strengths of our study include the large sample size, standardized endoscopist training and experience, standardized CBA technique and dosing, prospective multicenter data collection from both expert academic and community sites, and central expert pathology review of all biopsies and EMR specimens.

Our study also has several limitations. First, there was no control or comparison arm; we designed the study this way to enable efficient accrual and determination of CE-D and CE-IM parameters, which are essential for planning a large randomized comparative controlled trial assessing the utility of CBA against RFA. Furthermore, because devices, treatment procedures, and pathology assessments were billed to insurance as part of standard-of-care at each site, there was some variability in follow-up and treatment at the 12-month endpoint assessment. There were 17 patients who dropped out, and 9 patients in our study who were unevaluable because of protocol deviations (total 26 patients or 22% with missing outcomes). However, we performed an ITT analysis, such that these outcomes represent the most conservative interpretation of the efficacy of this therapy. These results suggest that even under the most unfavorable assumptions, with all subjects lacking 12 month data treated as failures, CBA results are within the range of those reported with RFA. Furthermore, the sensitivity analysis showed no significant differences in the characteristics of patients with missing data and the ITT group regarding factors known to influence treatment outcomes, suggesting that differential drop out was unlikely. In addition, the maximum BE length allowed for inclusion in this trial was 6 cm because of the focal nature of the treatments provided by this version of the device. Therefore, we are unable to extrapolate our results to patients with longer segments of BE. A “next generation” cryoballoon system is currently under development, which allows for larger area ablation of BE (59,60) by “sweeping” cryogen over a wide area (90° or 180° of the esophageal circumference (59,60)). Clinical trials using this next generation system are ongoing. Finally, we did not measure health related quality of life, which would be relevant for future patient-centered and cost-effectiveness research.

In conclusion, in this large multicenter single-arm prospective clinical trial of CBA in patients with previously unablated neoplastic BE, with or without previous EMR, CBA-induced eradication of dysplasia in over three-fourths of patients, with good safety and excellent patient tolerability. More research using the newer wide area CBA system in a larger population will better define its efficacy and clinical utility. Based on these results, head-to-head comparisons of CBA to other modalities of EET are warranted.


Guarantor of the article: Marcia Irene Canto, MD, MHS.

Specific author contributions: M.I.C.: conception and design of the work, acquisition of data, analysis and interpretation of data, draft of the manuscript, critical revision of the manuscript, and final approval of the manuscript. A.J.T., J.D., A.C., F.S.C., E.M.: acquisition of data, revision of the manuscript, and final approval of the manuscript. J.A.: design of the work, acquisition of data, critical revision of the manuscript, and final approval of the manuscript. M.R.: design of the work, biostatistical analysis and interpretation of data, critical revision of the manuscript, and final approval of the manuscript. N.J.S.: conception and design of the work, acquisition of data, analysis and interpretation of data, draft of the manuscript, critical revision of the manuscript, and final approval of the manuscript. C.J.L.: design of the work, acquisition of the data, revision of the manuscript, final approval of the manuscript. B.W.: biostatistical analysis and interpretation of data, final approval of the manuscript. P.I., D.D., H.K., M.M., E.J.S., A.I., I.W., C.T., J.S., K.C., L.V.: acquisition of data and final approval of the manuscript.

Financial support: Research grant from C2 Cryoballoon/Pentax Medical Corporation; statistical analysis supported by Johns Hopkins Institute for Clinical and Translational Research (ICTR). The sponsor maintained the study database but played no role in the study design, analysis, or interpretation of the data.

Potential competing interests: M.I.C.: royalty from UpToDate, research grant recipient from Endogastric Solutions and C2 Therapeutics/Pentax Medical Corporation; consultant for Exigo Management Consultants and Exact Sciences. A.J.T.: consultant for Pentax Medical and Olympus America; research grant from Nine Point Medical. J.A.: consultant for C2 Therapeutics. M.R.: President of Evolution Trial Design, Inc. J.D.S: research grant CSA Medical. A.C.: equity holder for Lucid Diagnostics; consultant for Interspace Diagnostics; research grant C2 Therapeutics/Pentax Medical Corporation. P.I.: research funding from Exact Sciences, C2 Therapeutics, Medtronic, Nine Point Medical; consultant C2 Therapeutics, Medtronic, CSA Medical. E.J.S.: consultant Boston Scientific and Medtronic. K.C.: consultant for Apollo Endosurgery, C2 Therapeutics/Pentax Medical Corporation, Cook Medical, Endogastric Solutions, Medtronic, Olympus, Ovesco. L.V.: CT Therapeutics/Pentax Medical Corporation salary support for research. E.M.: CT therapeutics/Pentax Medical Corporation salary support for research. CJ Lightdale: consultant for C2 Therapeutics, Boston Scientific, and CDX Diagnostics. N.J.S. consultant for Boston Scientific, Cook Medical, Cernostics, and Shire; research grant recipient from CDx Medical, C2 Therapeutics/Pentax Medical Corporation, Medtronic, Interpace Diagnostics, Lucid Diagnostics, and CSA Medical. All remaining co-authors have no disclosures.

Study Highlights


  • ✓ Limited single-center data suggest a potential role for multifocal CBA as a primary treatment modality for Barrett's neoplasia.


  • ✓ This multicenter trial confirms that multifocal CBA for previously unablated neoplastic BE is safe, well tolerated, and effective in inducing CE-D and intestinal metaplasia.


We appreciate the contributions of Michael Smith and Vivek Kaul to the planning of this trial.


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