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adenocarcinoma post endoscopic resection
Digestive and Liver Disease 45 (2013) 1028–1033
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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Digestive Endoscopy
Survival in esophageal high-grade dysplasia/adenocarcinoma post endoscopic resection Bashar J. Qumseya, Abraham M. Panossian, Cynthia Rizk, David J. Cangemi, Christianne Wolfsen, Massimo Raimondo, Timothy A. Woodward, Michael B. Wallace, Herbert C. Wolfsen ∗ Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, United States
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Article history: Received 7 December 2012 Accepted 19 June 2013 Available online 9 August 2013 Keywords: Barrett oesophagus Endoscopic resection Esophageal adenocarcinoma Longterm survival
a b s t r a c t Background: Endoscopic resection followed by ablative therapy is frequently used to treat esophageal high-grade dysplasia or early esophageal adenocarcinoma. Aims: To study outcomes in patients with high-grade dysplasia compared to those with esophageal adenocarcinoma after endoscopic resection. Methods: Retrospective, observational, descriptive, single-centre study from a prospective database. We extracted data from 116 endoscopic resections. Survival was plotted using Kaplan–Meier curves multivariable Cox-proportional hazard assess for possible predictors of survival post-endoscopic resection was performed. Results: 116 patients (64 esophageal adenocarcinoma, 52 high-grade dysplasia) underwent endoscopic resection from May 2003 to June 2010. Mean age was 71 ± 11 years for high-grade dysplasia and 72 ± 10 years for esophageal adenocarcinoma. Median follow-up was 17 months. Eighty-five patients had negative margins on endoscopic resection. Five-year survivals for high-grade dysplasia and esophageal adenocarcinoma were 86% (range 68–100%) and 78% (59–96%), respectively. Survival was not significantly different between groups (p = 0.20). Overall mortality rate was 10.6% (9/85). At multivariable Cox regression increased Barrett’s oesophagus length was associated with worse survival (HR 1.18 [1.06–1.33], p = 0.0039). Survival was not affected by the pathology before resection: HR 2.4 [95%CI, 0.70–8.4], p = 0.16. Conclusions: Survival in patients with high-grade dysplasia of the oesophagus is similar to those with esophageal adenocarcinoma. Longer Barrett’s oesophagus segments are associated with decreased survival. © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction The incidence of esophageal adenocarcinoma (EAC) is on the rise [1,2]. Barrett’s oesophagus is one of the major risk factors for the development of esophageal cancer [3], which is thought to evolve through a sequence of low-grade dysplasia (LGD) that progresses to high-grade dysplasia (HGD) and eventually progresses to adenocarcinoma [4]. Studies have suggested that there is improved survival in BE patients who undergo surveillance [5–8], which is both recommended by the major gastrointestinal associations [9–11] and is a common practice among US endoscopists [12]. HGD is more common than EAC; yet, outcomes in patients with HGD
∗ Corresponding author at: Division of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, United States. Tel.: +1 9049536319. E-mail address: [email protected] (H.C. Wolfsen).
have not been compared head-to-head with patients with EAC. Studies have shown that 3–50% of patients with HGD may have a concurrent undetected neoplasia [13]. Until recently, the main treatment for patients with HGD or early esophageal adenocarcinoma was esophagectomy [14–16]. This treatment is not ideal given its risks and associated complications [17–19]. Endoscopic treatment has gained increased acceptance. Endoscopic resection (ER), also called endoscopic mucosal resection (EMR), involves the resection of dysplastic or neoplastic esophageal lesions using a diathermy snare. ER can be used for both staging and for curative intent [20]. Several studies have reviewed the utility of ER, with or without ablation therapy, for treatment of EAC and HGD in patients with BE [21–24]. Ablative therapies include photodynamic therapy (PDT), radiofrequency ablation (RFA), cryotherapy, and argon plasma coagulation (APC) [25–27]. This study aims to analyze the outcomes and survival in a cohort of patients with esophageal HGD who underwent endoscopic management compared to those with EAC who also had endoscopic
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B.J. Qumseya et al. / Digestive and Liver Disease 45 (2013) 1028–1033
management. We hypothesize that outcomes, including long-term survival in patients with HGD, are similar to those of patients with EAC. 2. Patients and methods 2.1. Data collection We conducted a retrospective, observational, descriptive study using a prospective ER database. This study was approved by the Mayo Clinic Institutional Review Board. The database contains information about 195 esophageal ERs that were performed in 175 patients at a tertiary referral centre from May 2003 to June 2010. These patients were referred to our centre with a diagnosis of HGD or EAC based on outside assessment. We included patients who were confirmed to have HGD or EAC on the ER specimen. Patients who did not have HGD or EAC on the ER specimen were excluded. We used our institution’s electronic medical records to extract the following data on each patient: age at the time of ER, sex, use of aspirin or nonsteroidal anti-inflammatory drugs, previous diagnosis of BE, maximum BE segment length, histology and disease TNM staging based on endoscopic ultrasound and computed tomographic (CT) scan results, use of ablative therapies before and after ER (including photodynamic therapy (PDT), radiofrequency ablation (RFA), argon plasma coagulation (APC), and cryoablation), need for esophagectomy, survival, and follow-up times. The primary outcome of this study was survival at the end of the follow-up period. Details of survival and cause of death were obtained from the database or from medical records. Most of the patients had longterm follow-up at our institution. Otherwise, the patient status was obtained from the referring physician. 2.2. Standard protocol First, patients were evaluated by an experienced gastroenterologist (H.W.) using a standard protocol, and including a review of medical history and CT scan of chest, abdomen, and pelvis. This was followed by esophagogastroduodenoscopy (EGD) to detect suspicious lesions, such as raised nodules and discrete, depressed, or flat lesions that are associated with abnormal mucosal or vascular features of neoplasia. In the absence of visible lesions, advanced imaging techniques (narrow band imaging and/or confocal laser endomicrosopy) were used in some patients as part of other investigative studies to better delineate the abnormal mucosal or vascular features of dysplasia. At a separate encounter, patients underwent endosonography and staging of possible cancers. If indicated lymph nodes that were suspicious for the presence of neoplasia were removed by fine needle aspiration. If there was no evidence of locally advanced disease, ER was used to remove suspicious areas at the same encounter. Patients were considered for surgery if they had a confirmed diagnosis of EAC with positive ER margins or features suggestive of a risk of nodal metastases, including poor differentiation, perineural or lymphovascular invasion, and submucosal invasion. For patients with a piecemeal resection who also had carcinoma at the edge of one of the resected pieces. Surgical triage was individualized on the basis of endoscopic assessment of whether a radical resection (R0) had been achieved since the true lateral margins could not be assessed. Triage was also based on the patient preference. For patients who did not undergo surgery, surveillance was performed at 2–3-month intervals following the Seattle protocol, with ablative therapy and biopsy or ER of any remaining Barrett metaplasia. Following complete eradication of Barrett metaplasia, patients were followed by endoscopy with surveillance biopsy of neosquamous epithelium at yearly intervals. All pathology reviewed was performed by an experienced
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GI pathologist who reviewed and reported results for all patients in our Barrett’s programme.
2.3. Endoscopic resection Methods of ER have been described in detail elsewhere [28]. Briefly, the majority of ER procedures were performed using the multiband mucosectomy method with or without saline injection lift to remove the most suspicious lesions (DT-6-5F; Cook Medical, Bloomington, IN). The Wallace “rosette pattern” of 4–6 additional resections was then performed to completely remove the tissue around the index resection margin including up to 75% of the lumen circumference. Index lesions greater than 3 cm in diameter were removed using the cap technique with Olympus accessories (K008; Olympus America Inc, Centre Valley, PA).
2.4. Endoscopic ablation therapy Prior to ablation therapy, patients were prescribed high daily doses of a proton pump inhibitor medication before the morning and evening meals; this was done to aggressively control acid reflux and optimize the results of ablation therapy. Patients returned for treatment every 3–6 months until all esophageal glandular mucosa had been successfully ablated and replaced with neosquamous epithelium. Surveillance endoscopy was performed every 6–12 months thereafter to detect and treat any recurrent or residual Barrett mucosa using additional ER or ablation. Our methods of ablative modalities have been previously described. These include the use of porfimer sodium PDT [29,30], RFA [31], APC [28], and cryotherapy [28,32–35]. Details of each of these techniques are not described here because of space limitations. The choice of which ablative modality to use was individualized based on best evidence at the time, patient comorbidities, and patient preference. In general, PDT seems to have been performed between 2003 and 2008, with RFA largely replacing it in recent years.
2.5. Statistical analysis We used SAS software, version 9.2 (SAS Institute Inc, Cary, NC) for statistical analysis. For continuous variables, we used the Shapiro–Wilk test to assess normality. For normal variables, we reported means (standard deviations). For skewed data, we reported medians with interquartile ranges or ranges. For discrete data, we reported proportions. We used the Student t-test to assess the differences between means for normal data and we used the Wilcoxon rank sum test for continuous skewed data. We used the Fisher exact or 2 test to assess the differences between proportions in different categories. Survival was plotted using Kaplan–Meier curves and reported as proportion with 95% confidence intervals (CIs). The log-rank 2 test was used to assess the difference in survival between groups. A p value of less than .05 indicated statistical significance. We fit univariable Cox-proportional hazard models for all candidate predictors of survival. We included age and gender in the multivariable model into all other predictors that reached significance in a univariable analysis with p < 0.3. We tested for co-linearity and confounding. Effect modification between variables were also tested. Using the final multivariable model, we reported the effect of predictors on survival as hazard ratios (HR) with 95% confidence intervals and p-values. We tested the proportional hazards assumption by calculating Martingale residuals for the variables included in the final model. This study was reviewed and approved by the Mayo Clinic Institutional Review Board.
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Fig. 1. Flow chart of the study patients. Abbreviations: AC, adenocarcinoma; EAC, early adenocarcinoma; BE, Barrett’s oesophagus; ER, endoscopic resection; HGD, high-grade dysplasia; IFD, indefinite for dysplasia; LGD, low-grade dysplasia; CR-IM, complete remission of intestinal metaplasia; NDBE, non-dysplastic Barrett’s oesophagus; EGD, esophagogastroduodunoscopy.
3. Results Of the 175 patients referred to our institution, only 116 were confirmed to have HGD or EAC on repeat EGD with ER. The remaining 59 patients were found to have LGD, indefinite for dysplasia, or no dysplasia. Those 116 patients formed the study group. Of the 116 patients, 64 had EAC and 52 had HGD (Fig. 1). Patient characteristics are summarized in Table 1. Most patients were elderly men with a previous diagnosis of BE, who were referred for evaluation
and treatment of esophageal dysplasia and neoplasia. Median follow-up times were 20 months for patients with HGD and 17 months for patients with EAC. 3.1. Negative margins of resection on ER Of the 116 patients in the study, 85 (73%) had either HGD or EAC with negative ER margins. Overall survival in this cohort was 97% (95%CI, 93.5–100%) at 1 year and 83.5% (95%CI, 72–95%) at 5 years of follow-up, respectively. Survival analysis is summarized in
Table 1 Baseline characteristics of the study population (N = 116). Characteristic
HGD
EAC
P value
Patients, no. (%) Age, mean (SD) (years) Presence of BE, no. (%) BE length, median (IQR) (cm) Male, no. (%) Follow-up time, median (range) (mo)
52 (45) 71 (11) 52 (100) 3 (2–7) 47 (90) 20 (0.5–71)
64 (55) 72 (10) 61 (95) 2 (1–6) 52 (81) 17 (0.3–63)
.27 .43 .25 .42 .20 .17
Abbreviations: BE, Barrett oesophagus; EAC, esophageal adenocarcinoma; HGD, high-grade dysplasia; IQR, interquartile range.
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Table 2 Pathology on most recent follow-up EGD after ER and endoscopic ablative therapy.a Pathology on original ER
Normal
HGD (n = 45) EAC (n = 33)
29 (64) 21 (64)
BE 11 (24) 5 (15)
IFD
LGD
HGD
AC
2 (4) 2 (6)
1 (2) 1 (3)
1 (2) 0 (0)
1 (2) 4 (12)
Abbreviations: AC, adenocarcinoma; BE, Barrett oesophagus; EAC, esophageal adenocarcinoma; ER, endoscopic resection; HGD, high-grade dysplasia; IFD, indefinite for dysplasia; LGD, low-grade dysplasia. a Values are number (percentage).
Fig. 2 using Kaplan–Meier curves. For the HGD group, the 1-year and 5-year survivals were 98% (95%CI, 94–100%) and 86% (95%CI, 68–100%), respectively. One and 5-year survivals for the EAC group were 96% (95%CI, 89–100%) and 78% (95%CI, 59–96%), respectively. Survival was not significantly different between the two groups (P = 0.2). In multivariable Cox regression analysis, controlling for age, gender, and ablative modality, increased BE length was associated with worse survival (HR 1.18 [1.06–1.33], p = 0.0039). Survival was not affected by the pathology before ER (i.e. HGD vs. EAC): HR 2.4 [95%CI, 0.70–8.4], p = 0.16. Six of the 85 patients (7%) had cancer recurrence or detection of metachronous lesions on follow-up EGD. Median time to cancer detection was 11 months (range, 2–14 months). Three patients with recurrence were referred to surgery and had esophagectomy. Adenocarcinoma (T1N0M0) was confirmed on 2 surgical specimens, while the third specimen showed LGD only. One of these patients died from complications after surgery and the other 2 were alive at last follow-up. Among the 3 patients who had recurrence but did not have surgery, 1 patient was lost to follow-up, and the other 2 were treated with additional ER (1 patient had ER and APC). Of the latter 2 patients, 1 died within 2 months (not related to esophageal cancer or its treatment), and the other was alive at last follow-up. The overall mortality rate for this cohort was 11% (9/85). None of the deaths were related to esophageal cancer, although 1 death was related to complications from esophagectomy. Of the 85 patients, 78 (92%) had at least 1 follow-up EGD. After a mean (SD) follow-up of 29 (21) months, 64% of patients in either group (29/45) had normal esophageal mucosa. Similarly, 40 of 45 patients (89%) with HGD and 26 of 33 patients (79%) with a history of EAC had no evidence of dysplasia on follow-up EGD (Table 2). Among 93 patients who had at least 1 follow-up EGD, ablation therapies after ER were distributed as follows: RFA in 52 patients (56%) (median treatments, 2; range, 1–6); PDT in 24 patients (26%) (median treatments, 1; range, 1–3); APC in 9 patients (10%) (median treatment, 1; range, 1–3); and cryotherapy in 4 patients (3.3%). More patients with HGD had RFA compared to patients with EAC (63.5% vs. 29.7%, p = 0.003). There was no difference in PDT, APC, or cryotherapy between both groups (Table 3).
3.2. Positive margins for cancer on ER Among the 64 EAC patients, 31 had positive margins on ER. Seventeen had positive deep and lateral margins, 7 had positive deep margins only, and 7 had positive lateral margins and negative deep margins. All of these patients were referred to surgery, and 13 then had esophagectomy. Reasons for not having surgery included poor surgical candidacy (4 patients), refusal of surgery (6 patients), lost to follow-up (2 patients), negative repeat ER (2 patients), went back to home institution (2 patients), while 2 patients refused surgery and later died but not from esophageal cancer. For the 13 patients who had esophagectomy for positive ER margins, 8 had positive deep and lateral margins, 4 had positive deep margins only, and 1 had negative deep margins with positive lateral margin. Nine of the 13 patients had submucosal tumour (T1b) on ER and 4 had intramucosal lesions (T1a). All 13 patients had incomplete tumour resection by ER (positive margins). Of the 13 patients, 6 (46%) had no evidence of cancer on esophagectomy; 3 (23%) had mucosal tumour (T1a), including 1 patient with positive lymph node metastasis; 3 (23%) had submucosal tumours (T1b), including 2 patients with nodal metastasis; and 1 (8%) had involvement of muscularis propria (T2). The 5-year survival for patients who had esophagectomy for positive ER margins was 81% (95%CI, 59–100%). 3.3. Complications The most common complication was esophageal strictures, which occurred in 31 patients (27%). All strictures required endoscopic dilation. In addition, five patients had dilation for symptomatic dysphagia, but no strictures were visible on endoscopy. Among patients who had endoscopic dilations, the median number of dilations needed to resolve strictures was 2 (range 1–7). Of the 116 patients, none had esophageal perforation and 14 (12%) had minor bleeding at the time of ER that was treated endoscopically (injection of epinephrine, with or without endoclip placement). None of those patients needed blood transfusion, although 2 were admitted to the hospital for overnight observation. No delayed bleeding was noted in any of the treated patients. 4. Discussion As the incidence of EAC is increasing, more patients are being referred for endoscopic management of esophageal HGD or EAC. This usually means ER to remove suspicious lesions followed by ablative therapy aimed at eradicating dysplasia and BE. Table 3 Number of patients who received various ablative modalities.
Fig. 2. Kaplan–Meir curves of survival after endoscopic resection in patients with intramucosal adenocarcinoma of high grade dysplasia of the oesophagus. EAC, esophageal adenocarcinoma; HGD, high-grade dysplasia.
PDT RFA APC Cryotherapy
HGD (n = 52)
EAC (n = 64)
7 (13.5%) 33 (63.5%) 5 (9.6%) 2 (3.8%)
17 (26.6%) 19 (29.7%) 4 (6.3%) 2 (3.1%)
p-Value 0.07 0.003 0.46 0.83
PDT, photodynamic therapy; RFA, radiofrequency ablation; APC, argon plasma coagulation; HGD, high grade dysplasia; EAC, Esophageal Adenocarcinoma.
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In this study, we reported the overall 5-year survival in patients with HGD or EAC to be 83.5% (95%CI, 72–95%). Long-term survival in patients with HGD or EAC has been reported previously. Prasad et al. [35] reported their experience in a retrospective study of 129 patients who underwent PDT, with or without ER. The mean age for their patients was 64.5 years and the 5-year survival was about 90%. Ell et al. [21] studied 100 patients in Germany who had ER and were followed up for a mean of 36.7 months. Mean age was 62 years, and the calculated 5-year survival was 98%. Another study from two centres in Germany that was reported by Pech et al. [24], recently studied 114 patients with a mean age of 62 years and a median follow-up of 4.1 years and reported a 5-year survival of 93%. While those studies appear to report better survival than our study, the mean age of our cohort was older (70 years for the HGD and 72 years for the EAC group). When adjusting for the older cohort, survival rates in this analysis seem to be in line with what has been previously reported. In contrast to the above studies, we focused on patients with HGD. Survival in patients with HGD was found to be better than that with EAC, yet the difference was not statistically significant. Survival between both groups was also similar when we controlled for age, gender, ablative modality and BE length. These results, confirm that HGD is to be treated aggressively, because long-term survival appears to be similar to that in patients who have adenocarcinoma. In addition, we have reported a positive relationship between BE length and survival in patients with BE. For each 1 cm increase in BE length, there is a 20% increase in the rate of death when controlling for age, gender, baseline pathology and ablative modality. This association is very interesting and deserves further investigation in larger, prospective studies. The rate of cancer recurrence (or the development of metachronous lesions) is one of the important factors to be considered when choosing endoscopic versus surgical management. Previous studies have placed this rate at 6.6–21.5% [20,21,24,25,35]. Our study found the recurrence rate to be about 7% over the followup period. This is among the lowest in the reported literature, with only one study showing a lower recurrence rate of 6.6% [24]. Complications of endoscopic management were uncommon, except for esophageal strictures, which were common (27% of all patients). No perforations, extensive bleeding (with a decline in haemoglobin of more than 2 g/dL, need for transfusion, or need for surgery), or deaths related to the procedures were noted in any of the patients. Therefore, endoscopic therapy appears to be safe in experienced hands and cancer recurrence rates are low. When compared to the high morbidity and mortality of surgery, we believe that endoscopic management is the better option for those patients and should be consider the standard of care. Esophageal strictures are common and yet they are readily managed with endoscopic dilation. In this study, 116 patients had ER for suspected HGD or EAC. Of those, a large minority, 31 patients (27%), were found to have invasive adenocarcinoma. This illustrates the usefulness of ER as a staging tool in such patients. In patients who had incomplete tumour resection by ER (positive deep or lateral margins), but had esophagectomy, the 5-year survival was 81%. Raja et al. [36] analyzed 129 patients who had submocosal esophageal cancer and who underwent an esophagectomy. They reported a 5-year survival of 71%. Similarly, Lee et al. [37] reported a 5-year survival of 67% in patients with submucosal cancer with negative lymph nodes (pN0). The reported 5-year survival in our study seems to be higher than that reported previously. However, our cohort also includes some patients with intramucosal tumours (T1a) who went to surgery because of positive resection margins. This is likely to have influenced the survival in our cohort. Patients who had residual tumours on ER (positive margins) formed an interesting subgroup of patients. Almost half of these patients (46%), who had esophagectomy for residual tumour on ER,
did not have any evidence of tumour after resection. An additional 23% were found to have mucosal tumour (T1a) only. However, one patient with a T1a tumour had positive lymph node metastasis. Thus, 8 of the 13 patients (62%) who underwent surgery may not have benefited from the esophagectomy. Given the high morbidity and mortality of this procedure, the routine referral to surgery of patients with positive ER margins may be questionable. Perhaps a better approach may be to perform further ER on the affected area to confirm the presence of residual tumour and to resect possible intramucosal tumours. Patients who had positive ER margins but did not undergo surgery formed a high risk group. Many of them were poor surgical candidates due to multiple comorbidities and/or advanced age. Many of those patients went back to their home institution and/or were lost to follow-up. By definition, these patients had more advanced disease (worse than T1a) and were not the focus of this study. Therefore, we did not analyze outcomes for those patients. However, we did account for each of them in our discussion. Our study has some limitations. These include both the retrospective design and that this is the experience of a single, tertiary referral centre. These limit the generalizability of data to other clinical settings but do not affect the internal validity of the study. In addition, the small sample size means that the study is likely underpowered. Therefore, a multicenter study with larger numbers is needed to better assess long-term survival for those patients. Five-year survival in patients with EAC of the oesophagus undergoing ER followed by ablative therapy appears to be similar to patients with HGD undergoing similar management. The overall survival in both groups is high. Longer BE segments seem to be independently associated with worse survival regardless if the baseline histology. Aggressive endoscopic management is indicated, safe, and complications are readily manageable. Funding sources None. Conflict of interest Dr. Wolfsen is a consultant for CSA Medical, Ninepoint Medical, and Oncoscope. He receives research funding from BARRx Medical and Olympus America, Inc. Dr. Wallace is a consultant for Ninepoint Medical. He receives research funding from Olympus America, Inc, American BioOPTICS, and Fujinon. References [1] Vizcaino AP, Moreno V, Lambert R, et al. Time trends incidence of both major histologic types of esophageal carcinomas in selected countries, 1973–1995. International Journal of Cancer 2002;99:860–8. [2] Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. Journal of the National Cancer Institute 2005;97:142–6. [3] Sharma P, Falk GW, Weston AP, et al. Dysplasia and cancer in a large multicenter cohort of patients with Barrett’s esophagus. Clinical Gastroenterology and Hepatology 2006;4:566–72. [4] Cameron AJ, Carpenter HA. Barrett’s esophagus, high-grade dysplasia, and early adenocarcinoma: a pathological study. American Journal of Gastroenterology 1997;92:586–91. [5] Incarbone R, Bonavina L, Saino G, et al. Outcome of esophageal adenocarcinoma detected during endoscopic biopsy surveillance for Barrett’s esophagus. Surgical Endoscopy 2002;16:263–6. [6] Ferguson MK, Durkin A. Long-term survival after esophagectomy for Barrett’s adenocarcinoma in endoscopically surveyed and nonsurveyed patients. Journal of Gastrointestinal Surgery 2002;6:29–35, discussion 6. [7] Fountoulakis A, Zafirellis KD, Dolan K, et al. Effect of surveillance of Barrett’s oesophagus on the clinical outcome of oesophageal cancer. British Journal of Surgery 2004;91:997–1003. [8] Cooper SC, El-agib A, Dar S, et al. Endoscopic surveillance for Barrett’s oesophagus: the patients’ perspective. European Journal of Gastroenterology & Hepatology 2009;21:850–4.
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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Digestive Endoscopy
Survival in esophageal high-grade dysplasia/adenocarcinoma post endoscopic resection Bashar J. Qumseya, Abraham M. Panossian, Cynthia Rizk, David J. Cangemi, Christianne Wolfsen, Massimo Raimondo, Timothy A. Woodward, Michael B. Wallace, Herbert C. Wolfsen ∗ Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, United States
a r t i c l e
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Article history: Received 7 December 2012 Accepted 19 June 2013 Available online 9 August 2013 Keywords: Barrett oesophagus Endoscopic resection Esophageal adenocarcinoma Longterm survival
a b s t r a c t Background: Endoscopic resection followed by ablative therapy is frequently used to treat esophageal high-grade dysplasia or early esophageal adenocarcinoma. Aims: To study outcomes in patients with high-grade dysplasia compared to those with esophageal adenocarcinoma after endoscopic resection. Methods: Retrospective, observational, descriptive, single-centre study from a prospective database. We extracted data from 116 endoscopic resections. Survival was plotted using Kaplan–Meier curves multivariable Cox-proportional hazard assess for possible predictors of survival post-endoscopic resection was performed. Results: 116 patients (64 esophageal adenocarcinoma, 52 high-grade dysplasia) underwent endoscopic resection from May 2003 to June 2010. Mean age was 71 ± 11 years for high-grade dysplasia and 72 ± 10 years for esophageal adenocarcinoma. Median follow-up was 17 months. Eighty-five patients had negative margins on endoscopic resection. Five-year survivals for high-grade dysplasia and esophageal adenocarcinoma were 86% (range 68–100%) and 78% (59–96%), respectively. Survival was not significantly different between groups (p = 0.20). Overall mortality rate was 10.6% (9/85). At multivariable Cox regression increased Barrett’s oesophagus length was associated with worse survival (HR 1.18 [1.06–1.33], p = 0.0039). Survival was not affected by the pathology before resection: HR 2.4 [95%CI, 0.70–8.4], p = 0.16. Conclusions: Survival in patients with high-grade dysplasia of the oesophagus is similar to those with esophageal adenocarcinoma. Longer Barrett’s oesophagus segments are associated with decreased survival. © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction The incidence of esophageal adenocarcinoma (EAC) is on the rise [1,2]. Barrett’s oesophagus is one of the major risk factors for the development of esophageal cancer [3], which is thought to evolve through a sequence of low-grade dysplasia (LGD) that progresses to high-grade dysplasia (HGD) and eventually progresses to adenocarcinoma [4]. Studies have suggested that there is improved survival in BE patients who undergo surveillance [5–8], which is both recommended by the major gastrointestinal associations [9–11] and is a common practice among US endoscopists [12]. HGD is more common than EAC; yet, outcomes in patients with HGD
∗ Corresponding author at: Division of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, United States. Tel.: +1 9049536319. E-mail address: [email protected] (H.C. Wolfsen).
have not been compared head-to-head with patients with EAC. Studies have shown that 3–50% of patients with HGD may have a concurrent undetected neoplasia [13]. Until recently, the main treatment for patients with HGD or early esophageal adenocarcinoma was esophagectomy [14–16]. This treatment is not ideal given its risks and associated complications [17–19]. Endoscopic treatment has gained increased acceptance. Endoscopic resection (ER), also called endoscopic mucosal resection (EMR), involves the resection of dysplastic or neoplastic esophageal lesions using a diathermy snare. ER can be used for both staging and for curative intent [20]. Several studies have reviewed the utility of ER, with or without ablation therapy, for treatment of EAC and HGD in patients with BE [21–24]. Ablative therapies include photodynamic therapy (PDT), radiofrequency ablation (RFA), cryotherapy, and argon plasma coagulation (APC) [25–27]. This study aims to analyze the outcomes and survival in a cohort of patients with esophageal HGD who underwent endoscopic management compared to those with EAC who also had endoscopic
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management. We hypothesize that outcomes, including long-term survival in patients with HGD, are similar to those of patients with EAC. 2. Patients and methods 2.1. Data collection We conducted a retrospective, observational, descriptive study using a prospective ER database. This study was approved by the Mayo Clinic Institutional Review Board. The database contains information about 195 esophageal ERs that were performed in 175 patients at a tertiary referral centre from May 2003 to June 2010. These patients were referred to our centre with a diagnosis of HGD or EAC based on outside assessment. We included patients who were confirmed to have HGD or EAC on the ER specimen. Patients who did not have HGD or EAC on the ER specimen were excluded. We used our institution’s electronic medical records to extract the following data on each patient: age at the time of ER, sex, use of aspirin or nonsteroidal anti-inflammatory drugs, previous diagnosis of BE, maximum BE segment length, histology and disease TNM staging based on endoscopic ultrasound and computed tomographic (CT) scan results, use of ablative therapies before and after ER (including photodynamic therapy (PDT), radiofrequency ablation (RFA), argon plasma coagulation (APC), and cryoablation), need for esophagectomy, survival, and follow-up times. The primary outcome of this study was survival at the end of the follow-up period. Details of survival and cause of death were obtained from the database or from medical records. Most of the patients had longterm follow-up at our institution. Otherwise, the patient status was obtained from the referring physician. 2.2. Standard protocol First, patients were evaluated by an experienced gastroenterologist (H.W.) using a standard protocol, and including a review of medical history and CT scan of chest, abdomen, and pelvis. This was followed by esophagogastroduodenoscopy (EGD) to detect suspicious lesions, such as raised nodules and discrete, depressed, or flat lesions that are associated with abnormal mucosal or vascular features of neoplasia. In the absence of visible lesions, advanced imaging techniques (narrow band imaging and/or confocal laser endomicrosopy) were used in some patients as part of other investigative studies to better delineate the abnormal mucosal or vascular features of dysplasia. At a separate encounter, patients underwent endosonography and staging of possible cancers. If indicated lymph nodes that were suspicious for the presence of neoplasia were removed by fine needle aspiration. If there was no evidence of locally advanced disease, ER was used to remove suspicious areas at the same encounter. Patients were considered for surgery if they had a confirmed diagnosis of EAC with positive ER margins or features suggestive of a risk of nodal metastases, including poor differentiation, perineural or lymphovascular invasion, and submucosal invasion. For patients with a piecemeal resection who also had carcinoma at the edge of one of the resected pieces. Surgical triage was individualized on the basis of endoscopic assessment of whether a radical resection (R0) had been achieved since the true lateral margins could not be assessed. Triage was also based on the patient preference. For patients who did not undergo surgery, surveillance was performed at 2–3-month intervals following the Seattle protocol, with ablative therapy and biopsy or ER of any remaining Barrett metaplasia. Following complete eradication of Barrett metaplasia, patients were followed by endoscopy with surveillance biopsy of neosquamous epithelium at yearly intervals. All pathology reviewed was performed by an experienced
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GI pathologist who reviewed and reported results for all patients in our Barrett’s programme.
2.3. Endoscopic resection Methods of ER have been described in detail elsewhere [28]. Briefly, the majority of ER procedures were performed using the multiband mucosectomy method with or without saline injection lift to remove the most suspicious lesions (DT-6-5F; Cook Medical, Bloomington, IN). The Wallace “rosette pattern” of 4–6 additional resections was then performed to completely remove the tissue around the index resection margin including up to 75% of the lumen circumference. Index lesions greater than 3 cm in diameter were removed using the cap technique with Olympus accessories (K008; Olympus America Inc, Centre Valley, PA).
2.4. Endoscopic ablation therapy Prior to ablation therapy, patients were prescribed high daily doses of a proton pump inhibitor medication before the morning and evening meals; this was done to aggressively control acid reflux and optimize the results of ablation therapy. Patients returned for treatment every 3–6 months until all esophageal glandular mucosa had been successfully ablated and replaced with neosquamous epithelium. Surveillance endoscopy was performed every 6–12 months thereafter to detect and treat any recurrent or residual Barrett mucosa using additional ER or ablation. Our methods of ablative modalities have been previously described. These include the use of porfimer sodium PDT [29,30], RFA [31], APC [28], and cryotherapy [28,32–35]. Details of each of these techniques are not described here because of space limitations. The choice of which ablative modality to use was individualized based on best evidence at the time, patient comorbidities, and patient preference. In general, PDT seems to have been performed between 2003 and 2008, with RFA largely replacing it in recent years.
2.5. Statistical analysis We used SAS software, version 9.2 (SAS Institute Inc, Cary, NC) for statistical analysis. For continuous variables, we used the Shapiro–Wilk test to assess normality. For normal variables, we reported means (standard deviations). For skewed data, we reported medians with interquartile ranges or ranges. For discrete data, we reported proportions. We used the Student t-test to assess the differences between means for normal data and we used the Wilcoxon rank sum test for continuous skewed data. We used the Fisher exact or 2 test to assess the differences between proportions in different categories. Survival was plotted using Kaplan–Meier curves and reported as proportion with 95% confidence intervals (CIs). The log-rank 2 test was used to assess the difference in survival between groups. A p value of less than .05 indicated statistical significance. We fit univariable Cox-proportional hazard models for all candidate predictors of survival. We included age and gender in the multivariable model into all other predictors that reached significance in a univariable analysis with p < 0.3. We tested for co-linearity and confounding. Effect modification between variables were also tested. Using the final multivariable model, we reported the effect of predictors on survival as hazard ratios (HR) with 95% confidence intervals and p-values. We tested the proportional hazards assumption by calculating Martingale residuals for the variables included in the final model. This study was reviewed and approved by the Mayo Clinic Institutional Review Board.
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Fig. 1. Flow chart of the study patients. Abbreviations: AC, adenocarcinoma; EAC, early adenocarcinoma; BE, Barrett’s oesophagus; ER, endoscopic resection; HGD, high-grade dysplasia; IFD, indefinite for dysplasia; LGD, low-grade dysplasia; CR-IM, complete remission of intestinal metaplasia; NDBE, non-dysplastic Barrett’s oesophagus; EGD, esophagogastroduodunoscopy.
3. Results Of the 175 patients referred to our institution, only 116 were confirmed to have HGD or EAC on repeat EGD with ER. The remaining 59 patients were found to have LGD, indefinite for dysplasia, or no dysplasia. Those 116 patients formed the study group. Of the 116 patients, 64 had EAC and 52 had HGD (Fig. 1). Patient characteristics are summarized in Table 1. Most patients were elderly men with a previous diagnosis of BE, who were referred for evaluation
and treatment of esophageal dysplasia and neoplasia. Median follow-up times were 20 months for patients with HGD and 17 months for patients with EAC. 3.1. Negative margins of resection on ER Of the 116 patients in the study, 85 (73%) had either HGD or EAC with negative ER margins. Overall survival in this cohort was 97% (95%CI, 93.5–100%) at 1 year and 83.5% (95%CI, 72–95%) at 5 years of follow-up, respectively. Survival analysis is summarized in
Table 1 Baseline characteristics of the study population (N = 116). Characteristic
HGD
EAC
P value
Patients, no. (%) Age, mean (SD) (years) Presence of BE, no. (%) BE length, median (IQR) (cm) Male, no. (%) Follow-up time, median (range) (mo)
52 (45) 71 (11) 52 (100) 3 (2–7) 47 (90) 20 (0.5–71)
64 (55) 72 (10) 61 (95) 2 (1–6) 52 (81) 17 (0.3–63)
.27 .43 .25 .42 .20 .17
Abbreviations: BE, Barrett oesophagus; EAC, esophageal adenocarcinoma; HGD, high-grade dysplasia; IQR, interquartile range.
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Table 2 Pathology on most recent follow-up EGD after ER and endoscopic ablative therapy.a Pathology on original ER
Normal
HGD (n = 45) EAC (n = 33)
29 (64) 21 (64)
BE 11 (24) 5 (15)
IFD
LGD
HGD
AC
2 (4) 2 (6)
1 (2) 1 (3)
1 (2) 0 (0)
1 (2) 4 (12)
Abbreviations: AC, adenocarcinoma; BE, Barrett oesophagus; EAC, esophageal adenocarcinoma; ER, endoscopic resection; HGD, high-grade dysplasia; IFD, indefinite for dysplasia; LGD, low-grade dysplasia. a Values are number (percentage).
Fig. 2 using Kaplan–Meier curves. For the HGD group, the 1-year and 5-year survivals were 98% (95%CI, 94–100%) and 86% (95%CI, 68–100%), respectively. One and 5-year survivals for the EAC group were 96% (95%CI, 89–100%) and 78% (95%CI, 59–96%), respectively. Survival was not significantly different between the two groups (P = 0.2). In multivariable Cox regression analysis, controlling for age, gender, and ablative modality, increased BE length was associated with worse survival (HR 1.18 [1.06–1.33], p = 0.0039). Survival was not affected by the pathology before ER (i.e. HGD vs. EAC): HR 2.4 [95%CI, 0.70–8.4], p = 0.16. Six of the 85 patients (7%) had cancer recurrence or detection of metachronous lesions on follow-up EGD. Median time to cancer detection was 11 months (range, 2–14 months). Three patients with recurrence were referred to surgery and had esophagectomy. Adenocarcinoma (T1N0M0) was confirmed on 2 surgical specimens, while the third specimen showed LGD only. One of these patients died from complications after surgery and the other 2 were alive at last follow-up. Among the 3 patients who had recurrence but did not have surgery, 1 patient was lost to follow-up, and the other 2 were treated with additional ER (1 patient had ER and APC). Of the latter 2 patients, 1 died within 2 months (not related to esophageal cancer or its treatment), and the other was alive at last follow-up. The overall mortality rate for this cohort was 11% (9/85). None of the deaths were related to esophageal cancer, although 1 death was related to complications from esophagectomy. Of the 85 patients, 78 (92%) had at least 1 follow-up EGD. After a mean (SD) follow-up of 29 (21) months, 64% of patients in either group (29/45) had normal esophageal mucosa. Similarly, 40 of 45 patients (89%) with HGD and 26 of 33 patients (79%) with a history of EAC had no evidence of dysplasia on follow-up EGD (Table 2). Among 93 patients who had at least 1 follow-up EGD, ablation therapies after ER were distributed as follows: RFA in 52 patients (56%) (median treatments, 2; range, 1–6); PDT in 24 patients (26%) (median treatments, 1; range, 1–3); APC in 9 patients (10%) (median treatment, 1; range, 1–3); and cryotherapy in 4 patients (3.3%). More patients with HGD had RFA compared to patients with EAC (63.5% vs. 29.7%, p = 0.003). There was no difference in PDT, APC, or cryotherapy between both groups (Table 3).
3.2. Positive margins for cancer on ER Among the 64 EAC patients, 31 had positive margins on ER. Seventeen had positive deep and lateral margins, 7 had positive deep margins only, and 7 had positive lateral margins and negative deep margins. All of these patients were referred to surgery, and 13 then had esophagectomy. Reasons for not having surgery included poor surgical candidacy (4 patients), refusal of surgery (6 patients), lost to follow-up (2 patients), negative repeat ER (2 patients), went back to home institution (2 patients), while 2 patients refused surgery and later died but not from esophageal cancer. For the 13 patients who had esophagectomy for positive ER margins, 8 had positive deep and lateral margins, 4 had positive deep margins only, and 1 had negative deep margins with positive lateral margin. Nine of the 13 patients had submucosal tumour (T1b) on ER and 4 had intramucosal lesions (T1a). All 13 patients had incomplete tumour resection by ER (positive margins). Of the 13 patients, 6 (46%) had no evidence of cancer on esophagectomy; 3 (23%) had mucosal tumour (T1a), including 1 patient with positive lymph node metastasis; 3 (23%) had submucosal tumours (T1b), including 2 patients with nodal metastasis; and 1 (8%) had involvement of muscularis propria (T2). The 5-year survival for patients who had esophagectomy for positive ER margins was 81% (95%CI, 59–100%). 3.3. Complications The most common complication was esophageal strictures, which occurred in 31 patients (27%). All strictures required endoscopic dilation. In addition, five patients had dilation for symptomatic dysphagia, but no strictures were visible on endoscopy. Among patients who had endoscopic dilations, the median number of dilations needed to resolve strictures was 2 (range 1–7). Of the 116 patients, none had esophageal perforation and 14 (12%) had minor bleeding at the time of ER that was treated endoscopically (injection of epinephrine, with or without endoclip placement). None of those patients needed blood transfusion, although 2 were admitted to the hospital for overnight observation. No delayed bleeding was noted in any of the treated patients. 4. Discussion As the incidence of EAC is increasing, more patients are being referred for endoscopic management of esophageal HGD or EAC. This usually means ER to remove suspicious lesions followed by ablative therapy aimed at eradicating dysplasia and BE. Table 3 Number of patients who received various ablative modalities.
Fig. 2. Kaplan–Meir curves of survival after endoscopic resection in patients with intramucosal adenocarcinoma of high grade dysplasia of the oesophagus. EAC, esophageal adenocarcinoma; HGD, high-grade dysplasia.
PDT RFA APC Cryotherapy
HGD (n = 52)
EAC (n = 64)
7 (13.5%) 33 (63.5%) 5 (9.6%) 2 (3.8%)
17 (26.6%) 19 (29.7%) 4 (6.3%) 2 (3.1%)
p-Value 0.07 0.003 0.46 0.83
PDT, photodynamic therapy; RFA, radiofrequency ablation; APC, argon plasma coagulation; HGD, high grade dysplasia; EAC, Esophageal Adenocarcinoma.
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In this study, we reported the overall 5-year survival in patients with HGD or EAC to be 83.5% (95%CI, 72–95%). Long-term survival in patients with HGD or EAC has been reported previously. Prasad et al. [35] reported their experience in a retrospective study of 129 patients who underwent PDT, with or without ER. The mean age for their patients was 64.5 years and the 5-year survival was about 90%. Ell et al. [21] studied 100 patients in Germany who had ER and were followed up for a mean of 36.7 months. Mean age was 62 years, and the calculated 5-year survival was 98%. Another study from two centres in Germany that was reported by Pech et al. [24], recently studied 114 patients with a mean age of 62 years and a median follow-up of 4.1 years and reported a 5-year survival of 93%. While those studies appear to report better survival than our study, the mean age of our cohort was older (70 years for the HGD and 72 years for the EAC group). When adjusting for the older cohort, survival rates in this analysis seem to be in line with what has been previously reported. In contrast to the above studies, we focused on patients with HGD. Survival in patients with HGD was found to be better than that with EAC, yet the difference was not statistically significant. Survival between both groups was also similar when we controlled for age, gender, ablative modality and BE length. These results, confirm that HGD is to be treated aggressively, because long-term survival appears to be similar to that in patients who have adenocarcinoma. In addition, we have reported a positive relationship between BE length and survival in patients with BE. For each 1 cm increase in BE length, there is a 20% increase in the rate of death when controlling for age, gender, baseline pathology and ablative modality. This association is very interesting and deserves further investigation in larger, prospective studies. The rate of cancer recurrence (or the development of metachronous lesions) is one of the important factors to be considered when choosing endoscopic versus surgical management. Previous studies have placed this rate at 6.6–21.5% [20,21,24,25,35]. Our study found the recurrence rate to be about 7% over the followup period. This is among the lowest in the reported literature, with only one study showing a lower recurrence rate of 6.6% [24]. Complications of endoscopic management were uncommon, except for esophageal strictures, which were common (27% of all patients). No perforations, extensive bleeding (with a decline in haemoglobin of more than 2 g/dL, need for transfusion, or need for surgery), or deaths related to the procedures were noted in any of the patients. Therefore, endoscopic therapy appears to be safe in experienced hands and cancer recurrence rates are low. When compared to the high morbidity and mortality of surgery, we believe that endoscopic management is the better option for those patients and should be consider the standard of care. Esophageal strictures are common and yet they are readily managed with endoscopic dilation. In this study, 116 patients had ER for suspected HGD or EAC. Of those, a large minority, 31 patients (27%), were found to have invasive adenocarcinoma. This illustrates the usefulness of ER as a staging tool in such patients. In patients who had incomplete tumour resection by ER (positive deep or lateral margins), but had esophagectomy, the 5-year survival was 81%. Raja et al. [36] analyzed 129 patients who had submocosal esophageal cancer and who underwent an esophagectomy. They reported a 5-year survival of 71%. Similarly, Lee et al. [37] reported a 5-year survival of 67% in patients with submucosal cancer with negative lymph nodes (pN0). The reported 5-year survival in our study seems to be higher than that reported previously. However, our cohort also includes some patients with intramucosal tumours (T1a) who went to surgery because of positive resection margins. This is likely to have influenced the survival in our cohort. Patients who had residual tumours on ER (positive margins) formed an interesting subgroup of patients. Almost half of these patients (46%), who had esophagectomy for residual tumour on ER,
did not have any evidence of tumour after resection. An additional 23% were found to have mucosal tumour (T1a) only. However, one patient with a T1a tumour had positive lymph node metastasis. Thus, 8 of the 13 patients (62%) who underwent surgery may not have benefited from the esophagectomy. Given the high morbidity and mortality of this procedure, the routine referral to surgery of patients with positive ER margins may be questionable. Perhaps a better approach may be to perform further ER on the affected area to confirm the presence of residual tumour and to resect possible intramucosal tumours. Patients who had positive ER margins but did not undergo surgery formed a high risk group. Many of them were poor surgical candidates due to multiple comorbidities and/or advanced age. Many of those patients went back to their home institution and/or were lost to follow-up. By definition, these patients had more advanced disease (worse than T1a) and were not the focus of this study. Therefore, we did not analyze outcomes for those patients. However, we did account for each of them in our discussion. Our study has some limitations. These include both the retrospective design and that this is the experience of a single, tertiary referral centre. These limit the generalizability of data to other clinical settings but do not affect the internal validity of the study. In addition, the small sample size means that the study is likely underpowered. Therefore, a multicenter study with larger numbers is needed to better assess long-term survival for those patients. Five-year survival in patients with EAC of the oesophagus undergoing ER followed by ablative therapy appears to be similar to patients with HGD undergoing similar management. The overall survival in both groups is high. Longer BE segments seem to be independently associated with worse survival regardless if the baseline histology. Aggressive endoscopic management is indicated, safe, and complications are readily manageable. Funding sources None. Conflict of interest Dr. Wolfsen is a consultant for CSA Medical, Ninepoint Medical, and Oncoscope. He receives research funding from BARRx Medical and Olympus America, Inc. Dr. Wallace is a consultant for Ninepoint Medical. He receives research funding from Olympus America, Inc, American BioOPTICS, and Fujinon. References [1] Vizcaino AP, Moreno V, Lambert R, et al. Time trends incidence of both major histologic types of esophageal carcinomas in selected countries, 1973–1995. International Journal of Cancer 2002;99:860–8. [2] Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. Journal of the National Cancer Institute 2005;97:142–6. [3] Sharma P, Falk GW, Weston AP, et al. Dysplasia and cancer in a large multicenter cohort of patients with Barrett’s esophagus. Clinical Gastroenterology and Hepatology 2006;4:566–72. [4] Cameron AJ, Carpenter HA. Barrett’s esophagus, high-grade dysplasia, and early adenocarcinoma: a pathological study. American Journal of Gastroenterology 1997;92:586–91. [5] Incarbone R, Bonavina L, Saino G, et al. Outcome of esophageal adenocarcinoma detected during endoscopic biopsy surveillance for Barrett’s esophagus. Surgical Endoscopy 2002;16:263–6. [6] Ferguson MK, Durkin A. Long-term survival after esophagectomy for Barrett’s adenocarcinoma in endoscopically surveyed and nonsurveyed patients. Journal of Gastrointestinal Surgery 2002;6:29–35, discussion 6. [7] Fountoulakis A, Zafirellis KD, Dolan K, et al. Effect of surveillance of Barrett’s oesophagus on the clinical outcome of oesophageal cancer. British Journal of Surgery 2004;91:997–1003. [8] Cooper SC, El-agib A, Dar S, et al. Endoscopic surveillance for Barrett’s oesophagus: the patients’ perspective. European Journal of Gastroenterology & Hepatology 2009;21:850–4.
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