Durability of radiofrequency ablation for treatment of esophageal squamous cell neoplasia: 5-year follow-up of a treated cohort in China

doi:10.1016/j.gie.2018.10.030

Gastrointestinal Endoscopy

Volume 89, Issue 4, April 2019, Pages 736-748.e2

https://doi.org/10.1016/j.gie.2018.10.030 Get rights and content

Background and Aims

Radiofrequency ablation (RFA) is an accepted treatment for flat Barrett’s neoplasia. Less is known about RFA for esophageal squamous cell neoplasia (ESCN). Our group has reported several prospective studies of RFA for ESCN in China with promising results through 12 months of follow-up. In this cohort study we aimed to evaluate longer term outcomes after RFA for ESCN.

Methods

Patients with flat unstained lesions (USLs) on Lugol’s endoscopy containing moderate-/high-grade intraepithelial neoplasia (MGIN/HGIN) or mucosal cancer were treated with RFA every 3 months until complete remission (CR; no MGIN or a worse histologic grade). Patients with CR at 12 months (CR12) were included for follow-up and underwent annual Lugol’s endoscopy with biopsy sampling and re-RFA for flat USLs. The clinical course of patients with persistent ESCN at 12 months (treatment failures) is also reported.

Results

Among the 78 patients in CR12, 67 (86%) had sustained CR during a median of 48 months (interquartile range, 48-48) of follow-up and 5 endoscopies (interquartile range, 4-6). Recurrence occurred in 7 of 78 patients (9%; MGIN, n = 6; HGIN, n = 1); all lesions were managed with RFA. Four other patients (5%) had progression (to HGIN, n = 1; submucosal esophageal squamous cell carcinoma, n = 3). During follow-up protocol violations occurred in 46 of 78 patients (59%). Of the 12 treatment failures, progression occurred in 6. Overall, 2 patients developed subepithelial disease that was not visible after Lugol’s endoscopy. Based on post-hoc analysis, the pink-color sign at baseline (a pink color change after Lugol’s endoscopy) significantly predicted failure after RFA.

Conclusions

RFA is relatively easy to apply and can efficiently treat large areas with ESCN. Despite protocol violations that may have interfered with the efficacy of RFA in 59% of patients, most patients with CR12 had sustained CR during follow-up. However, some patients progressed to advanced disease and 2 developed subepithelial disease, not visible after Lugol’s endoscopy. Based on currently available data, we advise the restriction of the use of RFA for flat MGIN and HGIN without the pink-color sign on Lugol’s chromoendoscopy. (Clinical trial registration number: NCT02047305.)

Section snippets

Methods

The original 12-month study (clinicaltrials.gov identifier NCT02047305) was conducted between October 2008 and October 2011 at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences in Beijing, China.10, 11 The present study was an extension of this study and was conducted between October 2009 and October 2016. The protocol was approved by the Cancer Institute and Hospital, Chinese Academy of Medical Sciences Institutional Review Board, and a written informed consent was signed

Patients

Ninety-six patients were included in the original study, of which 78 were eligible for inclusion in the current follow-up study. Six patients from the original study were excluded: 3 patients with focal RFA at baseline and 3 with discontinued follow-up before 12 months (lost to follow-up [n = 2] or unrelated death [n = 1]). The 12 treatment failures at 12 months were not formally included in this follow-up study, yet the clinical course was assessed retrospectively (Fig. 2). The baseline

Discussion

This is the first study to assess the long-term durability of RFA treatment of MGIN, HGIN, and ESCC-m. In the 78 patients whose RFA resulted in complete eradication of ESCN during the treatment phase (CR12), most (86%) sustained this eradication through 5 years after initial treatment. A few patients (9%) developed recurrent disease, and all could be treated with re-RFA. Progressive disease was observed in 5%, and half of these could be curatively treated with ESD. In contrast, the 12 patients

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Citation Excerpt :
For c-RFA, a single application of 1 × 10 J was used, which is the currently advised ablation regimen for treatment of early ESCN.5,16 Although double c-RFA regimens may lower the risk of skipped zones, (subepithelial) recurrences in clinical long-term follow-up studies were observed after single as well as double c-RFA regimens.7,16 Finally, circumferential CBA was not included in this study, because currently no large-area CBA device is available.
Early esophageal squamous cell neoplasia (ESCN) is preferably treated with en-bloc endoscopic resection. Ablation might be an alternative for flat ESCN, but ESCN extension along the epithelial lining of ducts and submucosal glands (SMGs) might jeopardize ablation efficacy. Clinical studies suggest that local recurrence might arise from such buried ESCN niches after ablation. We studied human endoscopic resection specimens of ESCN to quantify ESCN extension into ducts/SMGs and performed a prospective porcine study to evaluate the depth of radiofrequency ablation (RFA) and CryoBalloon ablation (CBA) into ducts/SMGs.
Endoscopic submucosal dissection specimens of flat-type ESCN from a Japanese (n = 65) and Dutch cohort (n = 14) were evaluated for presence and neoplastic involvement of ducts/SMGs. Twenty-seven pigs were treated with circumferential RFA (c-RFA; n = 4), focal CBA (n = 20), and focal RFA (n = 3) with 4, 60, and 9 treatment areas, respectively. After prespecified survival periods (0 hours, 8 hours, 2 days, 5 days, and 28 days), treatment areas were evaluated for uniformity and depth of ablation and affected SMGs.
Neoplastic extension in ducts/SMGs was observed in most lesions: 58% (38/65) in the Japanese and 64% (9/14) in the Dutch cohort. In the animal study, 33% of SMGs (95% confidence interval, 28-50) were not affected after c-RFA, although the overlying epithelium was ablated. Focal RFA and CBA resulted in uniform ablations with effective treatment of all SMGs.
ESCN extends into ducts/SMGs in most patients. In an animal model, focal RFA and CBA effectively ablated SMGs, whereas c-RFA inadequately ablated SMGs. Given this potential reason for recurrence, endoscopic resection should remain the standard of care.
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Prospective study of endoscopic focal cryoballoon ablation for esophageal squamous cell neoplasia in China
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Citation Excerpt :
Patients with a pink-color sign after Lugol staining were excluded from this study. The pink-color sign is a pink discoloration that typically occurs 2 to 3 minutes after Lugol staining and is associated with more advanced stages of ESCN and with poor outcomes after radiofrequency ablation (RFA).12 Other exclusion criteria were nonflat visible abnormalities, synchronous USLs containing MGIN or worse, esophageal stenosis preventing passage of the endoscope, previous endoscopic resection or ablation, or a history of esophageal cancer.
Esophageal squamous cell neoplasia (ESCN) has a significant risk for progression to cancer. Current treatment options, endoscopic mucosal resection (EMR) or submucosal dissection (ESD), have their limitations. The cryoballoon focal ablation system (CbFAS) is a novel endoscopic ablation therapy device. We aimed to assess the safety, tolerability, and efficacy of CbFAS for eradication of ESCN.
In this single-center prospective trial in China, patients with 1 flat unstained lesion (USL) on Lugol chromoendoscopy that contained moderate- or high-grade intraepithelial neoplasia (MGIN or HGIN, respectively) were enrolled. CbFAS was performed using side-by-side applications of 10 seconds, treatment was repeated at 3-month intervals until a complete response (CR) was established. The response at 12 months was the primary trial endpoint. Safety phone calls were performed at 2, 7, and 30 days after the initial CbFAS.
We enrolled 80 patients (59 MGIN, 21 HGIN) with a median USL length of 3 cm (interquartile range [IQR], 3-4). Seventy-nine received treatment, with a median of 5 side-by-side applications (IQR, 4-7) per patient over a median of 8 minutes (IQR, 5-10). After a single treatment, 70 of 78 patients (90%) exhibited CR, and 1 was lost to follow-up. The other 8 with persisting USLs were retreated, and all achieved CR after this second treatment. At 12 months after the initial CbFAS, 76 of 78 patients (97%) exhibited CR and 2 (3%) had recurrent MGIN. No strictures or serious adverse events occurred. Four patients developed self-limiting mucosal lacerations on balloon inflation. The postprocedure median pain score was 1 of 10 (IQR, 0-2) at day 2 and 0 (0-0) at days 7 and 30.
The results suggest that the CbFAS is safe, well tolerated, and effective in inducing endoscopic and histologic remission in patients with ESCN of limited size. (Clinical trial registration number: NCT02605759.)

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: DISCLOSURE: The following authors disclosed financial relationships relevant to this publication: J.J.G.H.M. Bergman: Consultant for Medtronic Inc. All other authors disclosed no financial relationships relevant to this publication. Research support for this study was provided by Medtronic, Inc.

: If you would like to chat with an author of this article, you may contact Dr Bergman at [email protected] or Dr Wang at [email protected].

^∗: Drs Yu and van Munster contributed equally to this article.

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Original articleClinical endoscopyDurability of radiofrequency ablation for treatment of esophageal squamous cell neoplasia: 5-year follow-up of a treated cohort in China

Background and Aims

Methods

Results

Conclusions

Section snippets

Methods

Patients

Discussion

Gastroenterology

Gastrointest Endosc

Gastrointest Endosc

Gastrointest Endosc

Gastrointest Endosc

Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012

Int J Cancer

Epidemiology of esophageal cancer in Japan and China

J Epidemiol

Rural cancer early diagnosis and treatment committee of experts. Work report on the early diagnosis and treatment for cancer in rural areas of China 2015/2016

Squamous esophageal histology and subsequent risk of squamous cell carcinoma of the esophagus. A prospective follow-up study from Linxian, China

Cancer

Histological precursors of oesophageal squamous cell carcinoma: results from a 13 year prospective follow up study in a high risk population

Gut

Endoscopic and surgical resection of T1a/T1b esophageal neoplasms: a systematic review

World J Gastroenterol

Risk of multiple squamous cell carcinomas both in the esophagus and the head and neck region

Carcinogenesis

Stepwise radical endoscopic resection versus radiofrequency ablation for Barrett's oesophagus with high-grade dysplasia or early cancer: a multicentre randomised trial

Gut

Endoscopic radiofrequency ablation for early esophageal squamous cell neoplasia: report of safety and effectiveness from a large prospective trial

Endoscopy

Original article
Clinical endoscopy
Durability of radiofrequency ablation for treatment of esophageal squamous cell neoplasia: 5-year follow-up of a treated cohort in China