CURRENT READINGS
Current Readings: Endoesophageal Management of Early Esophageal Cancer and Dysplastic Barrett Esophagus: A Review of Recent and Influential Studies Christopher W. Towe, MD, and Costas S. Bizekis, MD1 DURABILITY OF RADIOFREQUENCY ABLATION IN BARRETT’S ESOPHAGUS WITH DYSPLASIA. Shaheen NJ, Bergein FO, Richard ES, et al. Gastroenterology 141(2):460-469, 2011. After multiple studies revealed that radiofrequency ablation (RFA) of Barrett esophagus (BE) with dysplasia was safe in selected cases, this randomized trial provided evidence that RFA is efficacious and durable in eradicating dysplastic BE. This trial is an extension of a previous study that documented excellent short-term results and sought to examine the long-term rates of pathologic eradication associated with RFA (compared with sham treatment) in patients with dysplastic BE. The extended follow-up is crucial to further validate that RFA can be used successfully to treat dysplastic BE without significant recurrences. In this randomized multisite trial, participants were recruited based on inclusion criteria that included age 18-80, endoscopically evident (nonnodular) BE, and length of BE o8 cm. Patients with esophageal cancer (EC) or poor life expectancy were excluded. Subjects were randomized to RFA or sham treatment at 2:1 ratio and received endoscopy with biopsy and treatment (or sham treatment) at 6 and 12 months (low-grade dysplasia arm), or 3, 6, 9, and 12 months (highgrade dysplasia [HGD] arm). After completion of the 12-month assessment, patients in the sham group were offered crossover to “open-label” RFA therapy. A total of 127 patients met the inclusion criteria and were randomized according to the study protocol (84 RFA, 43 sham). Of them, 117 (78 RFA, 39 Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York. Address reprint requests to Christopher W. Towe, MD, Department of Cardiothoracic Surgery, New York University School of Medicine, 530 1st Ave, Suite 9V, New York, NY 10016. E-mail: [email protected] 1
Dr Bizekis reports receiving consulting fees from Olympus, Covidien and Endochoice.
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sham) patients completed the 1-year follow-up, but 4 patients in the sham arm developed EC during the study period and were treated surgically. Mean follow-up from RFA treatment was 3.05 years. At the 2-year follow-up, in the overall cohort, 101 of 106 (95%) of subjects had complete eradication of dysplasia (CE-D) and 99 of 106 (93%) had complete eradication of metaplasia (CE-M). At the 3-year follow-up, 98% of available subjects had CE-D and 91% had CE-M (Fig. 1). Five of the 119 subjects (4.2%) who received RFA therapy (including the sham crossover patients) demonstrated progression of their BE, representing an annual rate of progression of 1 case per 73 patient years (1.37%). Although the annual rate of progression for patients receiving RFA was lower than the 1-year progression rate in the sham group (1 case per 6 patient years, 16.3%), this study reiterated the need for meticulous endoscopic monitoring in this high-risk population. This study adds to the growing evidence that supports the long-term outcomes and durability of the reversion to squamous epithelium induced after RFA therapy and confirms the risks of disease progression among untreated patients.
Key Points
Patients in this study had excellent 2- and 3-year CED after RFA treatment (95% and 98%, respectively).
Patients in this study had excellent 2- and 3-year
complete eradication of intestinal metaplasia after RFA treatment (93% and 91%, respectively). Sham-treated patients had a high rate of disease progression (16.3% per year, 1 case per 6 patient years). Of the RFA-treated patients, 4.2% showed progression of their BE (1.37% per year, 1 case per 73 patient years). Meticulous endoscopic monitoring is necessary in patients with BE, even after RFA treatment. 1043-0679/$-see front matter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semtcvs.2013.05.004
ENDOESOPHAGEAL MANAGEMENT OF EARLY EC AND DYSPLASTIC BE
Figure 1. Two- and 3-year outcomes of the AIM-Dysplasia Trial. Complete eradication of intestinal metaplasia (CE-IM) and complete eradication of dysplasia (CE-D), allowing for interim focal “touch-up” RFA.
STEPWISE RADICAL ENDOSCOPIC RESECTION VERSUS RADIOFREQUENCY ABLATION FOR BARRETT’S OESOPHAGUS WITH HIGH-GRADE DYSPLASIA OR EARLY CANCER: A MULTICENTRE RANDOMISED TRIAL. van Vilsteren FG, RE Pouw, Seewald S, et al. Gut 60(6):765-773, 2011. This study compared the efficacy and complication rate from the 2 most common endoluminal treatment options for BE and early EC. The study specifically compares RFA and stepwise radical endoscopic resection (SRER), which has not been done in as much detail elsewhere. The study draws important attention to the complication rates of these less invasive procedures, which has been frequently overlooked in other trials. The study was a prospective randomized multicenter trial to compare the safety of RFA and radical ER among patients with o5 cm of BE HGD or early EC. In both groups, follow-up was performed at 6and 12- months and then annually. The primary outcomes were complete pathologic response for neoplasia (CR-neoplasia) and CE-M. In the radical ER group, CR-neoplasia was achieved in 100% of patients (25/25) and CR-IM was achieved in 92% (23/ 25). In the RFA group, CR-neoplasia was achieved in 96% (21/22) and CR-IM was achieved in 96% (21/22). Stenosis was significantly more common in the SRER group (88%) relative to the RFA group (14%; P o 0.001). The stenosis rate in the SRER group led to a higher total number of therapeutic sessions per patient, largely because of the need for dilations (6 vs 3; P o 0.001). There were very few recurrences of EC in the study (1 patient in the SRER group had a recurrence after 2 years of follow-up) (Fig. 2). Although this study may be discredited by its small sample size and high rate of complications, it is important to address the negative consequences of endoluminal therapy. In this series, SRER was associated with higher rates of symptomatic stenosis, and it suggests that in this regard, RFA may be a preferable therapy. Clearly, technique and patient selection can vastly influence
these results, and more study in this area is mandatory.
Key Points
In patients with BE o5 cm with HGD or early
EC, both SRER and ER followed by RFA are efficacious at eradicating neoplasia and intestinal metaplasia. SRER led to a higher rate of esophageal stenosis (88%) as compared with focal ER followed by RFA (14%). SRER required a higher total number of therapeutic sessions because of dilation sessions for esophageal stenoses (6 vs 3).
ARE ENDOSCOPIC THERAPIES APPROPRIATE FOR SUPERFICIAL SUBMUCOSAL ESOPHAGEAL ADENOECARCINOMA? AN ANALYSIS OF ESOPHAGECTOMY SPECIMENS. Sepesi B, Watson TJ, Zhou D, et al. J Am Coll Surg 210(4):418, 2010. This study attempts to further define the role of endoluminal therapies for early-stage EC by analyzing the patterns of lymph node metastasis in esophagectomy specimens. Given the recent success of endoluminal therapies, significant controversy exists about the extent of disease that should preclude endoluminal therapy given the possibility of lymph node metastasis and therefore the need for surgical lymphadenectomy. The authors analyzed esophagectomy specimens to determine the rate of lymph node metastasis among the various subcategories of early EC, focusing on the most controversial subgroups of T1 lesions that have invaded the submucosa. The study reviewed 258 esophagectomy specimens from 2000-2008, of which 54 were pathologically T1 esophageal adenocarcinomas and in which patients had undergone primary resection without neoadjuvant therapy. The majority of specimens (72%) was from transhiatal esophagectomies with
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Figure 2. Outcome parameters and characteristics of endoscopic treatment.
D2 abdominal and limited posterior mediastinal lymphadenectomy (the remainder was from en bloc esophagectomies with extensive subcarinal lymphadenectomy). The subclassification of the lesions was: 46% were intramucosal (IM), 26% superficial submucosal (SM1), 13 (20%) middle SM (SM2), and 8% deep SM (SM3) carcinoma. Nodal metastases were present in 0% (0/25) of IM, 21% (3/14) of SM1, 36% (4/11) of SM2, and 50% (2/4) of SM3 tumors (Fig. 3). Of the 9 patients with nodal disease, 5 had tumor in 1 lymph node, 1 had 2 positive nodes (stage IIB, n ¼ 6, 11% of all patients), and 3 patients had 3 positive nodes (stage IIIA, 6% of all patients). The rate of lymph node involvement was significantly different between IM and SM tumors (P o 0.0001), although not between the various subclassifications of SM tumors (P ¼ 0.503). There was a trend in improved overall survival among patients with IM tumors (relative to SM), which did not reach statistical significance. This study’s contribution to endoluminal treatment of EC is that it supports limiting endoluminal therapies to intramucosal tumors. This data refutes earlier studies, which showed relatively low rates of lymph node involvement among patients with SM1 tumors. Tumors that invaded the submucosa had unacceptably high rates of lymph node metastases and those patients therefore probably benefit from surgical lymphadenectomy. This study is somewhat
Figure 3. Prevalence of metastatic lymph nodes in T1 esophageal adenocarcinoma.
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limited in its relevance by not including preoperative endoscopic ultrasound examination in its analysis.
Key Points
Pathologically, intramucosal tumors are unlikely to have lymph node metastases.
SM tumors have high rates of lymph node
positivity (21% SM1, 36% SM2, 50% SM3, and 31% overall). Involved lymph nodes were significantly more likely among patients with SM tumors relative to IM. The high prevalence of lymph node metastases among patients with SM tumors (in the opinion of the authors) does not justify an endoluminal approach to cancer therapy.
ENDOSCOPIC RESECTION AND ABLATION VERSUS ESOPHAGECTOMY FOR HIGHGRADE DYSPLASIA AND INTRAMUCOSAL ADENOCARCINOMA. Zehetner J, DeMeester SR, Hagen JA, et al. J Thorac Cardiovasc Surg 141(1):39-47, 2011. This paper is an important study in that it attempts to compare surgical and endoluminal treatment of early EC and dysplastic BE. In a retrospective review of all patients treated for HGD or intramucosal adenocarcinoma from 2001 to April 2010 at a single academic institution, this study compared the morbidity, mortality, survival, and cancer recurrence rates in concurrent patients with HGD or IM cancer treated either with endoscopic therapy or esophagectomy. With the recent success of endoluminal therapies in treatment of early-stage EC, this study demonstrates a “real-world” example of results achieved by a surgical group that has embraced endoscopic therapies. The study consisted of 101 patients who were treated from 2001-2010, of whom 40 received endoluminal therapies and 61 patients received esophagectomy. Age, gender, prevalence of comorbid conditions, and length of BE were similar
Seminars in Thoracic and Cardiovascular Surgery Volume 25, Number 2
ENDOESOPHAGEAL MANAGEMENT OF EARLY EC AND DYSPLASTIC BE between groups, although the pathology of the lesion were different between groups with more patients in the endoluminal group having HGD (P o 0.001) and more patients in the esophagectomy group with IM tumors (P o 0.001). Among the 40 patients receiving endoluminal therapies, a total of 102 ERs and 79 mucosal ablations were performed (median of 3 interventions per patient). Complications of endoluminal therapy were rare with no bleeding that required transfusion or stricture that required dilation. None of the patients who received ER progressed to SM cancer, but metachronous lesions developed in 3 patients (18%). Among patients initially treated for IM cancer, at the time of the last follow-up examination, 53% of the patients no longer had intestinal metaplasia and 82% were free of dysplasia or cancer. Among the patients who received endoluminal therapy for HGD, 26% of the patients progressed to IM cancer during treatment and were successfully treated endoscopically. At the time of last follow-up, 89% of the patients treated endoscopically for HGD had either no intestinal metaplasia or intestinal metaplasia without dysplasia. Esophagectomy was done for HGD in 13 patients and IM adenocarcinoma in 48 patients. The esophagectomy performed via a transthoracic en bloc procedure in 11 patients, a transhiatal procedure in 20 patients, and a vagus-sparing procedure in 30 patients. After esophagectomy, 1 patient’s IM cancer recurred and he died of disease 50 months postoperatively. Although there were no procedurerelated mortalities in either group, the complication rate after esophagectomy was significantly higher than with endoluminal therapy with a 39% total complication rate (24% minor complications and 13% major complications, P o 0.0001). In this cohort, there was no difference in overall survival between endotherapy and esophagectomy (94% at 3 years in both groups). Cancer-related survival was
100% in both groups at 3 years and 100% in the endotherapy group compared with 88% in the esophagectomy group at 5 years.
Key Points
Endoluminal therapy of early-stage (IM) EC and HGD has a low complication rate.
Patients treated with endoluminal therapy for
early-stage (IM) EC and HGD are at risk for a new or metachronous cancer (20%). Esophagectomy is associated with excellent oncologic outcome, but is associated with a high complication rate (39%) including a 13% major complication rate (3.3% leak). Cancer-related survival in both groups is excellent at 3- and 5-years. Advantages of esophagectomy include definitive treatment (ie, “1-shot treatment”). Advantage of endoluminal therapy include low complication rate and reduced risk for chronic reflux, regurgitation, and aspiration.
COMPARISON BETWEEN ENDOSCOPIC AND SURGICAL RESECTION OF MUCOSAL ESOPHAGEAL ADENOCARCINOMA IN BARRETT’S ESOPHAGUS AT TWO HIGHVOLUME CENTERS. Pech O, Bollschweiler E, Manner H, et al. Ann Surg 254(1):67-72, 2011. This study evaluates esophagectomy and ER among patients with intramucosal esophageal adenocarcinoma to determine whether ER is a safe alternative to surgical “gold standard” therapy. Although, like other retrospective studies, it suffers from selection bias inherent in its design, these data reiterate that endoluminal therapy is safe, efficacious, and associated with fewer adverse events than
Figure 4. Comparison of treatment results.
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ENDOESOPHAGEAL MANAGEMENT OF EARLY EC AND DYSPLASTIC BE surgical therapy, but it does demonstrate a recurrence rate after endoluminal therapy. The paper examines 114 patients who received either surgical esophagectomy with 2-field lymphadenectomy or ER in a retrospective case-control study. Patients who were treated surgically were randomly matched in a 2:1 fashion to a cohort of 967 patients who had received endoscopic treatment for HGD or EC based on age, gender, depth of tumor invasion, tumor differentiation grade, and follow-up period. These 76 patients who were treated endoscopically were therefore similar to the surgical group with regard to tumor and demographic variables. Remission was achieved in all surgical patients and in 98.7% of endoscopically treated patients. Major complications occurred in 32% of patients after surgery, including 1 death (2.6%), relative to no complications (0%) after ER. Overall mortality did not differ between the 2 cohorts by univariate analysis. The 1-, 3-, and 5-year overall survival rates in the ER and surgery cohorts was 99% vs 97%, 96% vs 93%, and 89% vs 93%, respectively (Fig. 4). Recurrence was more common among patients treated with ER (5 vs 0 in surgical patients). This study again demonstrates that for selected patients ER is associated excellent results and importantly is not associated with a difference in overall survival relative to patients receiving surgical esophagectomy. ER was associated, however, with a 9% recurrence rate, which reenforces the known need for meticulous follow-up after endoluminal therapy.
Key Points
Overall survival was similar between surgery and endoscopic therapy groups at 1-, 3- and 5-years.
Surgery was associated with significantly more complications than ER (32% vs 0%).
Patients who received ER were more likely have recurrence (9% recurrence rate). SUMMARY The use of RFA to treat dysplastic BE is associated with CE-M in approximately 90% of patients and CE-D in more than 95% at 3 years. RFA has also been used to treat early EC with greater than 90% responses at 2-year follow-up. Radical ER also shows excellent results in treating early EC and dysplastic BE with essentially equivalent rates of pathologic eradication of metaplasia, dysplasia, and neoplasia. Furthermore, in patients treated with RFA and radical ER for early EC, overall survival in retrospective studies is equivalent to unmatched, but
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demographically similar patients treated surgically at 5 years. Unfortunately, by avoiding surgical removal, endoscopic therapies have created a significant risk of recurrence after endoscopic treatment. Until the advent of these less invasive techniques, the goal of EC treatment has always been to aggressively treat primary lesions to reduce morbidity and mortality associated with recurrence. Trials discussed here have shown that recurrence or metachronous lesions after endoscopic therapy occur in approximately 20% of patients. Although many of these patients can be re-treated endoscopically, the success of endoesophageal therapy for recurrent disease is largely unstudied. We have also learned that not all endoscopic therapies are equivalent: although both RFA and radical ER demonstrate successful eradication of metaplasia, dysplasia, and neoplasia, some reports suggest that the risk of stricture after radical ER is particularly high. Technical proficiency in these procedures would likely reduce the rate of complications over time, but it is important to recognize the need to follow-up patients closely and treat any stricture-related dysphagia accordingly. One of the most significant risks associated with the use of endoesophageal therapies is the risk associated with untreated lymph node metastases. Although intramucosal tumors are very rarely associated with metastases, the study discussed here highlights the significant rate of tumor-containing lymph nodes found in patients with tumors that have invaded the submucosa. Despite conflicting evidence, multiple studies have now documented that T1b tumors are associated with 18%-30% risk of lymph node metastases. Even the most superficial subclassification of T1b tumors (SM1) showed a rate 21% rate of lymph node metastases. Although the success of less invasive methods is tempting to surgeons and patients alike, this pathologic marker must remain a “line in the sand” beyond which esophagectomy and lymphadenectomy remain the standard of care. Overall, although the success of endoluminal therapy have been significant, we must appreciate the risks associated with leaving dysplastic and neoplastic tissue in situ and adequately inform patients of the risks associated with these procedures as they become more “main stream.” One question is likely to haunt this field for some time: is surgery or endoscopic therapy a better treatment for early-stage EC? Unfortunately, it is unlikely that a sufficiently sized randomized trial of endoscopic and surgical treatment of HGD or intramucosal EC would be performed owing to the growing body of evidence of therapeutic equivalence and the significant difference in the complication rate associated
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ENDOESOPHAGEAL MANAGEMENT OF EARLY EC AND DYSPLASTIC BE with these procedures. This does not mean that important research in this area is impossible. Research opportunities abound in the management of patients treated with endoscopic techniques: should “highrisk” patients undergo more frequent examinations or other alternative treatment? What molecular markers predict failure of endoesophageal management of EC? What are the strategies to reduce recurrence in patients who have undergone remission of their dysplasia? We have a particular interest in whether laparoscopic fundoplication reduces recurrent HGD after RFA-induced remission, and hypothesize that routine use of fundoplication may significantly reduce the incidence of dysplastic or neoplastic progression. It is imperative that surgeons remain intimately connected to this growing field and forge new roles in the management of these patients. This is an exciting time to treat patients with esophageal pathology. Endoesophageal techniques
for treatment of intramucosal EC and dysplastic BE now offer a less invasive and less morbid alternative to surgery. Both RFA and radical ER demonstrate high rates of pathologic eradication of dysplasia and intestinal metaplasia. Although efficacious, the use of these techniques should be tempered by the significant risk of progression, recurrence, or metachronous lesions. Endoscopic therapy is not appropriate for patients who have significant risk for lymph node metastases, which is likely defined by tumor invasion of the submucosa. Despite these advances, it is important to realize that surgery remains the “gold standard” therapy for patients with EC of any kind and continues to offer patients peace of mind associated with esophageal extirpation. Future research in endoesophageal treatment of early EC and dysplastic BE should further define the risks associated with recurrent and metachronous lesions and identify strategies to reduce recurrence in risk-appropriate patients.
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Current Readings: Endoesophageal Management of Early Esophageal Cancer and Dysplastic Barrett Esophagus: A Review of Recent and Influential Studies Christopher W. Towe, MD, and Costas S. Bizekis, MD1 DURABILITY OF RADIOFREQUENCY ABLATION IN BARRETT’S ESOPHAGUS WITH DYSPLASIA. Shaheen NJ, Bergein FO, Richard ES, et al. Gastroenterology 141(2):460-469, 2011. After multiple studies revealed that radiofrequency ablation (RFA) of Barrett esophagus (BE) with dysplasia was safe in selected cases, this randomized trial provided evidence that RFA is efficacious and durable in eradicating dysplastic BE. This trial is an extension of a previous study that documented excellent short-term results and sought to examine the long-term rates of pathologic eradication associated with RFA (compared with sham treatment) in patients with dysplastic BE. The extended follow-up is crucial to further validate that RFA can be used successfully to treat dysplastic BE without significant recurrences. In this randomized multisite trial, participants were recruited based on inclusion criteria that included age 18-80, endoscopically evident (nonnodular) BE, and length of BE o8 cm. Patients with esophageal cancer (EC) or poor life expectancy were excluded. Subjects were randomized to RFA or sham treatment at 2:1 ratio and received endoscopy with biopsy and treatment (or sham treatment) at 6 and 12 months (low-grade dysplasia arm), or 3, 6, 9, and 12 months (highgrade dysplasia [HGD] arm). After completion of the 12-month assessment, patients in the sham group were offered crossover to “open-label” RFA therapy. A total of 127 patients met the inclusion criteria and were randomized according to the study protocol (84 RFA, 43 sham). Of them, 117 (78 RFA, 39 Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York. Address reprint requests to Christopher W. Towe, MD, Department of Cardiothoracic Surgery, New York University School of Medicine, 530 1st Ave, Suite 9V, New York, NY 10016. E-mail: [email protected] 1
Dr Bizekis reports receiving consulting fees from Olympus, Covidien and Endochoice.
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sham) patients completed the 1-year follow-up, but 4 patients in the sham arm developed EC during the study period and were treated surgically. Mean follow-up from RFA treatment was 3.05 years. At the 2-year follow-up, in the overall cohort, 101 of 106 (95%) of subjects had complete eradication of dysplasia (CE-D) and 99 of 106 (93%) had complete eradication of metaplasia (CE-M). At the 3-year follow-up, 98% of available subjects had CE-D and 91% had CE-M (Fig. 1). Five of the 119 subjects (4.2%) who received RFA therapy (including the sham crossover patients) demonstrated progression of their BE, representing an annual rate of progression of 1 case per 73 patient years (1.37%). Although the annual rate of progression for patients receiving RFA was lower than the 1-year progression rate in the sham group (1 case per 6 patient years, 16.3%), this study reiterated the need for meticulous endoscopic monitoring in this high-risk population. This study adds to the growing evidence that supports the long-term outcomes and durability of the reversion to squamous epithelium induced after RFA therapy and confirms the risks of disease progression among untreated patients.
Key Points
Patients in this study had excellent 2- and 3-year CED after RFA treatment (95% and 98%, respectively).
Patients in this study had excellent 2- and 3-year
complete eradication of intestinal metaplasia after RFA treatment (93% and 91%, respectively). Sham-treated patients had a high rate of disease progression (16.3% per year, 1 case per 6 patient years). Of the RFA-treated patients, 4.2% showed progression of their BE (1.37% per year, 1 case per 73 patient years). Meticulous endoscopic monitoring is necessary in patients with BE, even after RFA treatment. 1043-0679/$-see front matter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semtcvs.2013.05.004
ENDOESOPHAGEAL MANAGEMENT OF EARLY EC AND DYSPLASTIC BE
Figure 1. Two- and 3-year outcomes of the AIM-Dysplasia Trial. Complete eradication of intestinal metaplasia (CE-IM) and complete eradication of dysplasia (CE-D), allowing for interim focal “touch-up” RFA.
STEPWISE RADICAL ENDOSCOPIC RESECTION VERSUS RADIOFREQUENCY ABLATION FOR BARRETT’S OESOPHAGUS WITH HIGH-GRADE DYSPLASIA OR EARLY CANCER: A MULTICENTRE RANDOMISED TRIAL. van Vilsteren FG, RE Pouw, Seewald S, et al. Gut 60(6):765-773, 2011. This study compared the efficacy and complication rate from the 2 most common endoluminal treatment options for BE and early EC. The study specifically compares RFA and stepwise radical endoscopic resection (SRER), which has not been done in as much detail elsewhere. The study draws important attention to the complication rates of these less invasive procedures, which has been frequently overlooked in other trials. The study was a prospective randomized multicenter trial to compare the safety of RFA and radical ER among patients with o5 cm of BE HGD or early EC. In both groups, follow-up was performed at 6and 12- months and then annually. The primary outcomes were complete pathologic response for neoplasia (CR-neoplasia) and CE-M. In the radical ER group, CR-neoplasia was achieved in 100% of patients (25/25) and CR-IM was achieved in 92% (23/ 25). In the RFA group, CR-neoplasia was achieved in 96% (21/22) and CR-IM was achieved in 96% (21/22). Stenosis was significantly more common in the SRER group (88%) relative to the RFA group (14%; P o 0.001). The stenosis rate in the SRER group led to a higher total number of therapeutic sessions per patient, largely because of the need for dilations (6 vs 3; P o 0.001). There were very few recurrences of EC in the study (1 patient in the SRER group had a recurrence after 2 years of follow-up) (Fig. 2). Although this study may be discredited by its small sample size and high rate of complications, it is important to address the negative consequences of endoluminal therapy. In this series, SRER was associated with higher rates of symptomatic stenosis, and it suggests that in this regard, RFA may be a preferable therapy. Clearly, technique and patient selection can vastly influence
these results, and more study in this area is mandatory.
Key Points
In patients with BE o5 cm with HGD or early
EC, both SRER and ER followed by RFA are efficacious at eradicating neoplasia and intestinal metaplasia. SRER led to a higher rate of esophageal stenosis (88%) as compared with focal ER followed by RFA (14%). SRER required a higher total number of therapeutic sessions because of dilation sessions for esophageal stenoses (6 vs 3).
ARE ENDOSCOPIC THERAPIES APPROPRIATE FOR SUPERFICIAL SUBMUCOSAL ESOPHAGEAL ADENOECARCINOMA? AN ANALYSIS OF ESOPHAGECTOMY SPECIMENS. Sepesi B, Watson TJ, Zhou D, et al. J Am Coll Surg 210(4):418, 2010. This study attempts to further define the role of endoluminal therapies for early-stage EC by analyzing the patterns of lymph node metastasis in esophagectomy specimens. Given the recent success of endoluminal therapies, significant controversy exists about the extent of disease that should preclude endoluminal therapy given the possibility of lymph node metastasis and therefore the need for surgical lymphadenectomy. The authors analyzed esophagectomy specimens to determine the rate of lymph node metastasis among the various subcategories of early EC, focusing on the most controversial subgroups of T1 lesions that have invaded the submucosa. The study reviewed 258 esophagectomy specimens from 2000-2008, of which 54 were pathologically T1 esophageal adenocarcinomas and in which patients had undergone primary resection without neoadjuvant therapy. The majority of specimens (72%) was from transhiatal esophagectomies with
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Figure 2. Outcome parameters and characteristics of endoscopic treatment.
D2 abdominal and limited posterior mediastinal lymphadenectomy (the remainder was from en bloc esophagectomies with extensive subcarinal lymphadenectomy). The subclassification of the lesions was: 46% were intramucosal (IM), 26% superficial submucosal (SM1), 13 (20%) middle SM (SM2), and 8% deep SM (SM3) carcinoma. Nodal metastases were present in 0% (0/25) of IM, 21% (3/14) of SM1, 36% (4/11) of SM2, and 50% (2/4) of SM3 tumors (Fig. 3). Of the 9 patients with nodal disease, 5 had tumor in 1 lymph node, 1 had 2 positive nodes (stage IIB, n ¼ 6, 11% of all patients), and 3 patients had 3 positive nodes (stage IIIA, 6% of all patients). The rate of lymph node involvement was significantly different between IM and SM tumors (P o 0.0001), although not between the various subclassifications of SM tumors (P ¼ 0.503). There was a trend in improved overall survival among patients with IM tumors (relative to SM), which did not reach statistical significance. This study’s contribution to endoluminal treatment of EC is that it supports limiting endoluminal therapies to intramucosal tumors. This data refutes earlier studies, which showed relatively low rates of lymph node involvement among patients with SM1 tumors. Tumors that invaded the submucosa had unacceptably high rates of lymph node metastases and those patients therefore probably benefit from surgical lymphadenectomy. This study is somewhat
Figure 3. Prevalence of metastatic lymph nodes in T1 esophageal adenocarcinoma.
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limited in its relevance by not including preoperative endoscopic ultrasound examination in its analysis.
Key Points
Pathologically, intramucosal tumors are unlikely to have lymph node metastases.
SM tumors have high rates of lymph node
positivity (21% SM1, 36% SM2, 50% SM3, and 31% overall). Involved lymph nodes were significantly more likely among patients with SM tumors relative to IM. The high prevalence of lymph node metastases among patients with SM tumors (in the opinion of the authors) does not justify an endoluminal approach to cancer therapy.
ENDOSCOPIC RESECTION AND ABLATION VERSUS ESOPHAGECTOMY FOR HIGHGRADE DYSPLASIA AND INTRAMUCOSAL ADENOCARCINOMA. Zehetner J, DeMeester SR, Hagen JA, et al. J Thorac Cardiovasc Surg 141(1):39-47, 2011. This paper is an important study in that it attempts to compare surgical and endoluminal treatment of early EC and dysplastic BE. In a retrospective review of all patients treated for HGD or intramucosal adenocarcinoma from 2001 to April 2010 at a single academic institution, this study compared the morbidity, mortality, survival, and cancer recurrence rates in concurrent patients with HGD or IM cancer treated either with endoscopic therapy or esophagectomy. With the recent success of endoluminal therapies in treatment of early-stage EC, this study demonstrates a “real-world” example of results achieved by a surgical group that has embraced endoscopic therapies. The study consisted of 101 patients who were treated from 2001-2010, of whom 40 received endoluminal therapies and 61 patients received esophagectomy. Age, gender, prevalence of comorbid conditions, and length of BE were similar
Seminars in Thoracic and Cardiovascular Surgery Volume 25, Number 2
ENDOESOPHAGEAL MANAGEMENT OF EARLY EC AND DYSPLASTIC BE between groups, although the pathology of the lesion were different between groups with more patients in the endoluminal group having HGD (P o 0.001) and more patients in the esophagectomy group with IM tumors (P o 0.001). Among the 40 patients receiving endoluminal therapies, a total of 102 ERs and 79 mucosal ablations were performed (median of 3 interventions per patient). Complications of endoluminal therapy were rare with no bleeding that required transfusion or stricture that required dilation. None of the patients who received ER progressed to SM cancer, but metachronous lesions developed in 3 patients (18%). Among patients initially treated for IM cancer, at the time of the last follow-up examination, 53% of the patients no longer had intestinal metaplasia and 82% were free of dysplasia or cancer. Among the patients who received endoluminal therapy for HGD, 26% of the patients progressed to IM cancer during treatment and were successfully treated endoscopically. At the time of last follow-up, 89% of the patients treated endoscopically for HGD had either no intestinal metaplasia or intestinal metaplasia without dysplasia. Esophagectomy was done for HGD in 13 patients and IM adenocarcinoma in 48 patients. The esophagectomy performed via a transthoracic en bloc procedure in 11 patients, a transhiatal procedure in 20 patients, and a vagus-sparing procedure in 30 patients. After esophagectomy, 1 patient’s IM cancer recurred and he died of disease 50 months postoperatively. Although there were no procedurerelated mortalities in either group, the complication rate after esophagectomy was significantly higher than with endoluminal therapy with a 39% total complication rate (24% minor complications and 13% major complications, P o 0.0001). In this cohort, there was no difference in overall survival between endotherapy and esophagectomy (94% at 3 years in both groups). Cancer-related survival was
100% in both groups at 3 years and 100% in the endotherapy group compared with 88% in the esophagectomy group at 5 years.
Key Points
Endoluminal therapy of early-stage (IM) EC and HGD has a low complication rate.
Patients treated with endoluminal therapy for
early-stage (IM) EC and HGD are at risk for a new or metachronous cancer (20%). Esophagectomy is associated with excellent oncologic outcome, but is associated with a high complication rate (39%) including a 13% major complication rate (3.3% leak). Cancer-related survival in both groups is excellent at 3- and 5-years. Advantages of esophagectomy include definitive treatment (ie, “1-shot treatment”). Advantage of endoluminal therapy include low complication rate and reduced risk for chronic reflux, regurgitation, and aspiration.
COMPARISON BETWEEN ENDOSCOPIC AND SURGICAL RESECTION OF MUCOSAL ESOPHAGEAL ADENOCARCINOMA IN BARRETT’S ESOPHAGUS AT TWO HIGHVOLUME CENTERS. Pech O, Bollschweiler E, Manner H, et al. Ann Surg 254(1):67-72, 2011. This study evaluates esophagectomy and ER among patients with intramucosal esophageal adenocarcinoma to determine whether ER is a safe alternative to surgical “gold standard” therapy. Although, like other retrospective studies, it suffers from selection bias inherent in its design, these data reiterate that endoluminal therapy is safe, efficacious, and associated with fewer adverse events than
Figure 4. Comparison of treatment results.
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ENDOESOPHAGEAL MANAGEMENT OF EARLY EC AND DYSPLASTIC BE surgical therapy, but it does demonstrate a recurrence rate after endoluminal therapy. The paper examines 114 patients who received either surgical esophagectomy with 2-field lymphadenectomy or ER in a retrospective case-control study. Patients who were treated surgically were randomly matched in a 2:1 fashion to a cohort of 967 patients who had received endoscopic treatment for HGD or EC based on age, gender, depth of tumor invasion, tumor differentiation grade, and follow-up period. These 76 patients who were treated endoscopically were therefore similar to the surgical group with regard to tumor and demographic variables. Remission was achieved in all surgical patients and in 98.7% of endoscopically treated patients. Major complications occurred in 32% of patients after surgery, including 1 death (2.6%), relative to no complications (0%) after ER. Overall mortality did not differ between the 2 cohorts by univariate analysis. The 1-, 3-, and 5-year overall survival rates in the ER and surgery cohorts was 99% vs 97%, 96% vs 93%, and 89% vs 93%, respectively (Fig. 4). Recurrence was more common among patients treated with ER (5 vs 0 in surgical patients). This study again demonstrates that for selected patients ER is associated excellent results and importantly is not associated with a difference in overall survival relative to patients receiving surgical esophagectomy. ER was associated, however, with a 9% recurrence rate, which reenforces the known need for meticulous follow-up after endoluminal therapy.
Key Points
Overall survival was similar between surgery and endoscopic therapy groups at 1-, 3- and 5-years.
Surgery was associated with significantly more complications than ER (32% vs 0%).
Patients who received ER were more likely have recurrence (9% recurrence rate). SUMMARY The use of RFA to treat dysplastic BE is associated with CE-M in approximately 90% of patients and CE-D in more than 95% at 3 years. RFA has also been used to treat early EC with greater than 90% responses at 2-year follow-up. Radical ER also shows excellent results in treating early EC and dysplastic BE with essentially equivalent rates of pathologic eradication of metaplasia, dysplasia, and neoplasia. Furthermore, in patients treated with RFA and radical ER for early EC, overall survival in retrospective studies is equivalent to unmatched, but
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demographically similar patients treated surgically at 5 years. Unfortunately, by avoiding surgical removal, endoscopic therapies have created a significant risk of recurrence after endoscopic treatment. Until the advent of these less invasive techniques, the goal of EC treatment has always been to aggressively treat primary lesions to reduce morbidity and mortality associated with recurrence. Trials discussed here have shown that recurrence or metachronous lesions after endoscopic therapy occur in approximately 20% of patients. Although many of these patients can be re-treated endoscopically, the success of endoesophageal therapy for recurrent disease is largely unstudied. We have also learned that not all endoscopic therapies are equivalent: although both RFA and radical ER demonstrate successful eradication of metaplasia, dysplasia, and neoplasia, some reports suggest that the risk of stricture after radical ER is particularly high. Technical proficiency in these procedures would likely reduce the rate of complications over time, but it is important to recognize the need to follow-up patients closely and treat any stricture-related dysphagia accordingly. One of the most significant risks associated with the use of endoesophageal therapies is the risk associated with untreated lymph node metastases. Although intramucosal tumors are very rarely associated with metastases, the study discussed here highlights the significant rate of tumor-containing lymph nodes found in patients with tumors that have invaded the submucosa. Despite conflicting evidence, multiple studies have now documented that T1b tumors are associated with 18%-30% risk of lymph node metastases. Even the most superficial subclassification of T1b tumors (SM1) showed a rate 21% rate of lymph node metastases. Although the success of less invasive methods is tempting to surgeons and patients alike, this pathologic marker must remain a “line in the sand” beyond which esophagectomy and lymphadenectomy remain the standard of care. Overall, although the success of endoluminal therapy have been significant, we must appreciate the risks associated with leaving dysplastic and neoplastic tissue in situ and adequately inform patients of the risks associated with these procedures as they become more “main stream.” One question is likely to haunt this field for some time: is surgery or endoscopic therapy a better treatment for early-stage EC? Unfortunately, it is unlikely that a sufficiently sized randomized trial of endoscopic and surgical treatment of HGD or intramucosal EC would be performed owing to the growing body of evidence of therapeutic equivalence and the significant difference in the complication rate associated
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ENDOESOPHAGEAL MANAGEMENT OF EARLY EC AND DYSPLASTIC BE with these procedures. This does not mean that important research in this area is impossible. Research opportunities abound in the management of patients treated with endoscopic techniques: should “highrisk” patients undergo more frequent examinations or other alternative treatment? What molecular markers predict failure of endoesophageal management of EC? What are the strategies to reduce recurrence in patients who have undergone remission of their dysplasia? We have a particular interest in whether laparoscopic fundoplication reduces recurrent HGD after RFA-induced remission, and hypothesize that routine use of fundoplication may significantly reduce the incidence of dysplastic or neoplastic progression. It is imperative that surgeons remain intimately connected to this growing field and forge new roles in the management of these patients. This is an exciting time to treat patients with esophageal pathology. Endoesophageal techniques
for treatment of intramucosal EC and dysplastic BE now offer a less invasive and less morbid alternative to surgery. Both RFA and radical ER demonstrate high rates of pathologic eradication of dysplasia and intestinal metaplasia. Although efficacious, the use of these techniques should be tempered by the significant risk of progression, recurrence, or metachronous lesions. Endoscopic therapy is not appropriate for patients who have significant risk for lymph node metastases, which is likely defined by tumor invasion of the submucosa. Despite these advances, it is important to realize that surgery remains the “gold standard” therapy for patients with EC of any kind and continues to offer patients peace of mind associated with esophageal extirpation. Future research in endoesophageal treatment of early EC and dysplastic BE should further define the risks associated with recurrent and metachronous lesions and identify strategies to reduce recurrence in risk-appropriate patients.
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