Surg Endosc (2014) 28:777–782 DOI 10.1007/s00464-013-3240-9
and Other Interventional Techniques
Endoscopic management of high-grade dysplasia and intramucosal carcinoma: experience in a large academic medical center Kyle A. Perry • Jon P. Walker • Mario Salazar • Andrew Suzo • Jeffrey W. Hazey • W. Scott Melvin
Received: 31 May 2013 / Accepted: 21 September 2013 / Published online: 12 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Background Esophagectomy has been the standard treatment for Barrett’s esophagus (BE) with high-grade dysplasia (HGD) and intramucosal cancer (IMC). Recently, endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) have become the preferred treatment for these patients in some centers. We report a single institution series of patients undergoing endoscopic management of HGD and IMC. Methods Nineteen patients underwent endoscopic treatment for HGD or IMC between 2009 and 2012. The primary outcome measure was progression of BE necessitating esophagectomy. Secondary outcomes included complete eradication of intestinal metaplasia (CE-IM), complete eradication of dysplasia (CE-D), recurrence or progression of BE or dysplasia, and complications. Patients were followed for a median follow-up interval of 19 months following completion of RFA treatment. Results Three patients (16 %) had a presenting diagnosis of IMC, and 16 (84 %) were treated for HGD. Twelve (63 %) had long-segment BE; the median length of BE was
Presented in oral form at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), Baltimore, MD, USA, 17–20 April 2013. K. A. Perry (&) M. Salazar A. Suzo J. W. Hazey W. S. Melvin Division of General and Gastrointestinal Surgery, The Ohio State University, N729 Doan Hall, 410 W. 10th Ave., Columbus, OH 43210, USA e-mail:
[email protected] J. P. Walker Division of Gastroenterology, The Ohio State University, Columbus, OH, USA
5 cm. Ten (53 %) patients underwent EMR prior to RFA. CE-D was achieved in 88 % of patients, and CE-IM was achieved in 65 % of patients. A median of 2 (1–7) treatments were required, and there were no immediate postprocedure complications. Two patients developed recurrent dysplasia following complete eradication of BE, and each case was successfully managed with repeat RFA. Three patients (16 %) required esophagectomy within 6 months following RFA. A complete surgical resection was achieved in each case, and none of the patients developed lymph node metastases. Conclusions Complete eradication of HGD and IMC can be achieved via endoscopic therapy, thus avoiding esophagectomy in the majority of patients. However, a subset of patients will fail this treatment approach and will require surgical resection. With aggressive endoscopic treatment and surveillance, these patients can be identified at an early stage while curative resection is still possible. Keywords Barrett’s esophagus Esophageal cancer High-grade dysplasia Endoscopic mucosal resection Radiofrequency ablation Therapeutic endoscopy
Barrett’s esophagus (BE) is a premalignant condition characterized by replacement of the normal esophageal squamous epithelium by intestinal metaplasia. BE represents the strongest known risk factor for the development of esophageal adenocarcinoma (EAC), particularly in the setting of high-grade dysplasia (HGD), and affects 1–2 % of the adult population [1–3]. Traditionally, esophagectomy has been the mainstay of treatment for these conditions owing to a high rate of disease cure and the lack of a reliable, lowmorbidity alternative. The high morbidity and negative impact on patient quality of life associated with esophageal
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resection have led investigators to pursue less invasive, endoscopic treatment options [4, 5]. Multimodality endoscopic therapy consisting of endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) of the esophageal mucosa has emerged as a potential curative, low-morbidity treatment option. RFA has proven very effective for eliminating both non-dysplastic BE and BE with low-grade dysplasia (LGD) and HGD [6–11]. While early results evaluating the efficacy of combined EMR and RFA for definitive treatment of HGD and intramucosal adenocarcinoma (IMC) have been encouraging, limited information is available regarding the efficacy and durability of this combined treatment approach [7, 8]. The purpose of this study was to review our early experience with the endoscopic management of BE with HGD and IMC.
Materials and methods Patients This retrospective cohort study included a review of all patients undergoing endoscopic treatment for BE or early esophageal cancer at The Ohio State University Wexner Medical Center between April 2009 and June 2012. Inclusion criteria included patients with a presenting diagnosis of BE with confirmed HGD or IMC evaluated for endoscopic treatment. Patients with evidence of invasive esophageal cancer identified by EMR or endoscopic ultrasound at the time of baseline endoscopy, and those who elected to proceed with surgery rather than endoscopic treatment, were excluded. Patient data are maintained in a prospectively collected database approved by our Institutional Review Board. Baseline endoscopic evaluation All patients underwent upper endoscopy with visual inspection of the esophageal mucosa and biopsy of all visual abnormalities to confirm the diagnosis of dysplastic BE prior to treatment with RFA. The diagnostic and therapeutic endoscopies in this series were performed by one of four providers, three gastrointestinal surgeons and one gastroenterologist, according to a standard protocol. Patients with flat BE underwent four-quadrant biopsies every centimeter, and EMR was performed for all nodular lesions. EMR was performed using either a standard EMR cap (Olympus America, Center Valley, PA, USA) technique or a multiband ligator technique (Duette Multiband Mucosectomy System, Cook Medical, Bloomington, IN, USA) based on the endoscopist’s preference. Depending on their size, nodules were resected en bloc or in a piecemeal
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fashion. All specimens were reviewed by an experienced gastrointestinal pathologist. Radiofrequency ablation Ablation procedures were performed using either a balloonbased 360° ablation electrode or focal 90° ablation catheter (Halo360 or Halo90, Covidien, Sunnyvale, CA, USA) using an established protocol [9]. Briefly, the endoscope is inserted per oral, endoscopy of the esophagus and stomach is performed, and a guidewire is left in place. The sizing balloon catheter is inserted over the wire and the automated sizing procedure is performed every 1 cm, beginning 5 cm above the proximal extent of intestinal metaplasia, and continuing to the level of the gastroesophageal junction. The appropriately sized ablation catheter is selected and inserted over the guidewire and followed by the endoscope. Ablation of all visible BE is performed under direct endoscopic visualization using standard energy settings (power = 300 W and energy density = 12 J/cm2). Following ablation, the balloon catheter is removed and cleaned while the endoscope is used to remove any debris or coagulum from the ablated area. This process is repeated a second time to ensure a complete ablation. Two months after the initial ablation procedure, subjects underwent repeat endoscopy to evaluate for remaining visible BE. Focal ablation using a scope-mounted 90° ablation catheter (Halo90, BARRX Medical, Sunnyvale, CA, USA) was performed to eliminate all remaining visible BE under direct endoscopic visualization. Repeat endoscopy and ablation was performed every 2 months until complete eradication of all visible BE was achieved, with a maximum of four RFA treatments. Endoscopic surveillance Following complete eradication of BE or after the fourth attempted ablation, patients were placed on a standard surveillance protocol consisting of four-quadrant biopsies along the entire length of their original BE segment every 3 months. If there was no detectable BE upon endoscopic visualization or histologic evaluation on four consecutive endoscopies, the surveillance interval was increased to 1 year. Patients with recurrent dysplastic BE were recommended to undergo repeat RFA treatment using the same protocol described above. Outcome measures The primary outcome measure for this study was failure of endoscopic management necessitating esophagectomy. Secondary outcomes included complete eradication of intestinal metaplasia (CE-IM), complete eradication of
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dysplasia (CE-D), recurrence or progression of BE or dysplasia, number of endoscopic treatments performed, and complications of endoscopic treatment. Statistical analysis Data were analyzed using Stata 12 (Stata Corp, College Station, TX, USA). Data are presented as mean (±SD) or median (range) where appropriate. Univariate analysis was performed using either the Student’s t test or the Mann– Whitney U test as appropriate, and the Chi square test was used to compare dichotomous variables. A p value \0.05 was considered statistically significant.
Results Eighty-seven patients underwent RFA for treatment of BE during the study period, and 19 met the inclusion criteria for this study. Patients had a mean age of 68 ± 8 years, and 14 (74 %) were male. All patients were given proton pump inhibitor therapy for acid reflux control prior to RFA, and 3 (16 %) underwent Nissen fundoplication due to inadequate reflux control and persistent esophagitis prior to mucosal ablation. Three (16 %) had a presenting diagnosis of IMC, and 16 (84 %) were treated for HGD. The median length of BE was 5 cm. Twelve (63 %) had long-segment BE (length [3 cm), with a median length of 6 (4–11) cm, and seven patients had short-segment BE with a median length of 2 (1–3) cm. There were no demographic differences between patients with long- and short-segment BE (Table 1). Ten (53 %) patients were found to have nodular BE and underwent EMR prior to ablative therapy. These included three patients with short-segment BE (43 %) compared with seven patients with long-segment BE (58 %;
p = 0.515). Intramucosal cancer (IMC) was identified in three EMR specimens. A margin-negative resection was achieved in each case, and they all underwent subsequent RFA. Six patients had nodules with evidence of HGD which extended to the radial margin, and one nodule showed non-dysplastic BE. Initial RFA was successfully completed in all patients, with no immediate post-procedure complications. Complete follow-up data were available for 17 (89 %) patients. Two patients did not return following the initial RFA, could not be reached for follow-up, and were excluded from this analysis. One patient died of an unrelated cause 10 months following successful eradication of BE. Overall, CE-D was achieved in 88 % (n = 15) of patients, and CE-IM was achieved in 65 % (n = 11). CE-IM was achieved in all patients with short-segment BE, while CE-D was achieved in 80 % (p = 0.208) and CE-BE in 40 % (p = 0.011) of patients with long-segment BE (Fig. 1). A median of 2 (1–7) treatments were required, and there were no immediate post-procedure complications. The median number of treatments required was 2 (1–3) for patients with short-segment BE and 2 (1–8) for those with long-segment BE (p = 0.283). Three patients (16 %) required esophagectomy within 6 months following their initial RFA treatment. Two patients, one with short-segment BE and one with longsegment BE, developed nodules containing adenocarcinoma, with subsequent EMR specimens that showed a positive deep margin and margin-negative resection with submucosal invasion, respectively. A third had persistent nodular long-segment BE with extensive LGD and HGD following EMR, and elected to proceed with surgery rather than continued endoscopic treatment and surveillance. A
Table 1 Characteristics and indications for patients with ssBE and lsBE’ who underwent endoscopic management of HGD or IMC Characteristic
Overall (n = 12)
ssBE (n = 7)
lsBE (n = 12)
p value
Age, years [mean ± SD]
68 ± 8.2
68.0 ± 8.4
68.6 ± 8.4
0.886a
Gender, male [n (%)] Indication [n (%)]
14 (74)
5 (71)
9 (75)
0.865b
HGD
16 (84)
6 (86)
10 (83)
0.891b
IMC
3 (16)
1 (14)
2 (17)
HGD high-grade dysplasia, IMC intramucosal carcinoma, lsBE longsegment Barrett’s esophagus, ssBE short-segment Barrett’s esophagus’ a b
p value by t test p value by v2 test
Fig. 1 Rates of complete eradication of dysplasia (CE-D) and intestinal metaplasia (CE-IM) in patients with short- (ssBE) and long-segment Barrett’s esophagus (lsBE). *p \ 0.05
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complete surgical resection was achieved in each case, and none of the patients had developed lymph node metastases. At a median follow-up interval of 19 (9–44) months, none of the patients in this series developed strictures requiring endoscopic dilation following RFA, and there were no complications associated with EMR. Two patients (17.6 %) developed recurrent dysplasia following complete eradication of BE. Each case occurred in patients with short-segment BE, and they were successfully managed with repeat RFA. Among patients who achieved complete resolution of BE following RFA, 5 (46 %) developed recurrent BE during the follow-up period. Fifty percent of patients with long-segment BE developed recurrent nondysplastic BE during endoscopic surveillance compared with 43 % of patients with short-segment BE (p = 0.819).
Discussion The central aim of this study was to review the efficacy and durability of endoscopic management of HGD and IMC using EMR and RFA. We found that this treatment approach achieved CE-D in 88 % of patients and CE-IM in 65 % of patients with minimal morbidity. While these outcomes were achieved in all patients with short-segment BE, CE-IM was achieved in only 40 % of those with longsegment BE. Recurrent BE developed in 43 % of patients during endoscopic surveillance, and two patients developed invasive cancer following endoscopic therapy and subsequently underwent margin- and lymph node-negative esophageal resection. The optimal treatment for patients with HGD and IMC remains controversial. Esophagectomy remains the gold standard treatment for this condition with long-term survival rates approaching population norms in this patient population. However, while incremental improvements have been made with the evolution of minimally invasive esophagectomy, this remains a highly morbid procedure that negatively impacts patient quality of life [4, 5, 12, 13]. Multimodality endoscopic management has the potential to successfully treat patients while limiting morbidity and maintaining quality of life. Questions remain, however, regarding the initial efficacy and durability of these approaches, as well as the ability to surgically treat patients at an early stage following failed endoscopic management. In a large, North American randomized, sham-controlled trial, RFA eliminated HGD or LGD in 81 % of patients, while complete eradication of BE was achieved in 77 % of patients [9]. In this study, however, half of the patients had a diagnosis ofLGD, and patients with IMC were not included. Subsequent cohort studies examining populations with HGD and early EAC have demonstrated CE-IM rates ranging from 43 to 65 % [14–17]. In a study
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of 142 patients with HGD or early EAC, Ganz et al. [14] demonstrated CE-D in 80.4 % of patients, and CE-IM in 54.3 % of patients. A recent European multicenter registry study examining combined RFA and EMR for the management of patients with HGD and early esophageal cancer showed CE-D in 81 % of patients and CE-BE in 62 % of patients [18]. They also found that increasing the length of the BE segment was associated with a longer time to CEBE. In our series, we demonstrated similar initial eradication rates with CE-D in 88 % of patients and CE-BE in 65 % of patients. Also, although not statistically significant, the rate of CE-IM following up to four RFA treatments in patients with long-segment BE was 40 % compared with 100 % of those with short-segment BE. Despite the relatively high success rate for eradication of BE in this series, three patients required esophagectomy for adequate treatment of their disease. Of note, none of the patients diagnosed with IMC at baseline developed recurrent malignant nodules. Two patients with HGD at baseline developed focal nodules following RFA that demonstrated a positive deep margin or evidence of submucosal invasion at the time of subsequent EMR. Each of these patients underwent curative resection with early-stage, node-negative disease. Reports of disease progression requiring esophagectomy during attempted endoscopic therapy in large cohort studies have been less than 5 %. In their series, Ganz et al. found no patients with progression to cancer requiring esophagectomy, whereas a large European registry study found progression of disease in 5.1 % of patients and development of invasive cancer in 3 % of patients within 1 year [14, 18]. The third patient in our series who underwent esophagectomy had persistent long-segment nodular BE with multifocal HGD following multiple EMR procedures. Rather than persist with intensive endoscopic management and surveillance, she elected to proceed with surgery, preferring the peace of mind that she had undergone a definitive therapy prior to progression to invasive cancer. While it is intuitively appealing that endoscopic management and esophageal preservation should maintain patient quality of life, little is known about the impact of patient anxiety during the process of slow or incomplete eradication of BE and prolonged intensive endoscopic surveillance, or the worry about potential disease recurrence or progression. Comparative studies of the impact of endoscopic and surgical interventions on global and diseasespecific quality of life in this patient population are needed to assist with patient counseling when considering the available treatment options, particularly for healthy patients with long-segment, multifocal HGD. The durability of remission and need for ongoing endoscopic surveillance remains a major question following successful ablative therapy. In the present study, we found
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recurrent BE in a significant proportion of patients, although dysplasia recurred in only two patients. Fleischer et al. [11] demonstrated persistent CE-IM in 90 % of patients treated for non-dysplastic BE at 5-year follow-up. The 3-year follow-up of the AIM dysplasia Trial for patients with LGD or HGD, found sustained CE-D in 98 % of patients and CE-IM in 91 % of patients at 3-year follow-up [10]. Phoa et al. [19] reported 5-year follow-up of 54 patients who underwent RFA with or without EMR for HGD or early EAC, and found sustained remission of dysplasia in 90 % of patients. Three patients developed early EAC that was successfully managed endoscopically. Haidry et al. [18] reported CE-D in 94 % of patients at 19 months. While the number of patients is small and the follow-up interval relatively short, the outcomes in this series support the concept that aggressive endoscopic management of patients with HGD and IMC can avoid esophagectomy in a significant proportion of patients. It also suggests that with intensive endoscopic surveillance, patients with disease progression can be identified at an early stage and undergo curative esophageal resection. The need for surgery in a subset of patients and the tendency to develop recurrent BE following CE-IM, however, underscores the need for intensive surveillance following successful treatment and the need for long-term studies to identify the rates of disease progression and survival following subsequent esophageal resection. Establishing the recurrence rates of dysplastic BE and progression to cancer during long-term follow-up will also allow accurate cost-effectiveness analyses comparing surgical and endoscopic management. Finally, studies regarding disease-specific quality of life for patients undergoing surgical and endoscopic therapy are needed to clarify the impact of these treatment strategies on global and disease-specific quality of life. Disclosures Drs. Perry, Salazar, Suzo, Walker, Hazey, and Melvin report no biomedical financial interests or potential conflicts of interest relevant to the subject matter of this article.
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