Roos E. Pouw

Efficacy of Radiofrequency Ablation Combined With Endoscopic Resection for Barrett's Esophagus With Early Neoplasia

BACKGROUND & AIMS Radiofrequency ablation (RFA) is safe and effective for eradicating intestinal metaplasia and neoplasia in patients with Barretts esophagus. We sought to assess the safety and efficacy of RFA in conjunction with baseline endoscopic resection for high-grade intraepithelial neoplasia (HGIN) and early cancer. METHODS This multicenter, prospective cohort study included 24 patients (mean age, 65 years; median Barretts esophagus, 8 cm), with Barretts esophagus of < or =12 cm containing HGIN or early cancer, from 3 European tertiary-care medical centers. Visible lesions were endoscopically resected, followed by serial RFA. Focal escape endoscopic resection was used if Barrett tissue persisted despite RFA. Complete response, defined as all biopsies negative for intestinal metaplasia and neoplasia, was assessed during endoscopy with 4-quadrant biopsies taken every 1 cm of the original Barretts segment 2 months after the patient was last treated. RESULTS Twenty-three patients underwent pre-RFA endoscopic resection for visible lesions; 16 patients had early cancer and 7 patients had HGIN. The worst residual histology results, pre-RFA (after any endoscopic resection) were: HGIN (10 patients), low-grade intraepithelial neoplasia (11 patients), and intestinal metaplasia (3 patients). Neoplasia and intestinal metaplasia were eradicated in 95% and 88% of patients, respectively; after escape endoscopic resection in 2 patients, rates improved to 100% and 96%, respectively. Complications after RFA included melena (n = 1) and dysphagia (n = 1). After additional follow-up (median, 22 months; interquartile range, 17.2-23.8 months) no neoplasia recurred. CONCLUSIONS This European multicenter study to show that early neoplasia in Barretts esophagus can be effectively and safely treated with RFA, in combination with prior endoscopic resection of visible lesions.

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

Objective After focal endoscopic resection (ER) of high-grade dysplasia (HGD) or early cancer (EC) in Barretts oesophagus (BO), eradication of all remaining BO reduces the recurrence risk. The aim of this study was to compare the safety of stepwise radical ER (SRER) versus focal ER followed by radiofrequency ablation (RFA) for complete eradication of BO containing HGD/EC. Methods A multicentre randomised clinical trial was carried out in three tertiary centres. Patients with BO ≤5 cm containing HGD/EC were randomised to SRER or ER/RFA. Patients in the SRER group underwent piecemeal ER of 50% of BO followed by serial ER. Patients in the ER/RFA group underwent focal ER for visible lesions followed by serial RFA. Follow-up endoscopy with biopsies (four-quadrant/2 cm BO) was performed at 6 and 12 months and then annually. The main outcome measures were: stenosis rate; complications; complete histological response for neoplasia (CR-neoplasia); and complete histological response for intestinal metaplasia (CR-IM). Results CR-neoplasia was achieved in 25/25 (100%) SRER and in 21/22 (96%) ER/RFA patients. CR-IM was achieved in 23 (92%) SRER and 21 (96%) ER/RFA patients. The stenosis rate was significantly higher in SRER (88%) versus ER/RFA (14%; p<0.001), resulting in more therapeutic sessions in SRER (6 vs 3; p<0.001) due to dilations. After median 24 months follow-up, one SRER patient had recurrence of EC, requiring ER. Conclusions In patients with BO ≤5 cm containing HGD/EC, SRER and ER/RFA achieved comparably high rates of CR-IM and CR-neoplasia. However, SRER was associated with a higher number of complications and therapeutic sessions. For these patients, a combined endoscopic approach of focal ER followed by RFA may thus be preferred over SRER. Clinical trial number NTR1337.

Stepwise radical endoscopic resection for eradication of Barrett's oesophagus with early neoplasia in a cohort of 169 patients

Background and Aims Endoscopic resection is safe and effective to remove early neoplasia (ie,high-grade intra-epithelial neoplasia/early cancer) in Barretts oesophagus. To prevent metachronous lesions during follow-up, the remaining Barretts oesophagus can be removed by stepwise radical endoscopic resection (SRER). The aim was to evaluate the combined experience in four tertiary referral centres with SRER to eradicate Barretts oesophagus with early neoplasia. Methods Design: Retrospective cohort study. Setting: Four tertiary referral centres. Participants: 169 patients (151 males, age 64 years (IQR 57–71), Barretts oesophagus 3 cm (IQR 2–5)) with early neoplasia in Barretts oesophagus ≤5 cm, without deep submucosal infiltration or lymph node metastases, treated by SRER between January 2000 and September 2006. Intervention: Endoscopic resection every 4–8 weeks, until complete endoscopic and histological eradication of Barretts oesophagus and neoplasia. Results According to intention-to-treat analysis complete eradication of all neoplasia and all intestinal metaplasia by the end of the treatment phase was reached in 97.6% (165/169) and 85.2% (144/169) of patients, respectively. One patient had progression of neoplasia during treatment and died of metastasised adenocarcinoma (0.6%). After median follow-up of 32 months (IQR 19–49), complete eradication of neoplasia and intestinal metaplasia was sustained in 95.3% (161/169) and 80.5% (136/169) of patients, respectively. Acute, severe complications occurred in 1.2% of patients, and 49.7% of patients developed symptomatic stenosis. Conclusions SRER of Barretts oesophagus ≤5 cm containing early neoplasia appears to be an effective treatment modality with a low rate of recurrent lesions during follow-up. The procedure, however, is technically demanding and is associated with oesophageal stenosis in half of the patients.

Properties of the Neosquamous Epithelium After Radiofrequency Ablation of Barrett's Esophagus Containing Neoplasia

OBJECTIVES:Endoscopic radiofrequency ablation (RFA) eradicates intestinal metaplasia and intraepithelial neoplasia associated with Barretts esophagus (BE), restoring an endoscopically normal neosquamous epithelium (NSE). We evaluated the post-RFA NSE for genetic abnormalities and buried glandular mucosa.METHODS:Eligible patients underwent RFA for BE containing early cancer and/or high-grade intraepithelial neoplasia with subsequent complete histological reversion to normal NSE. At baseline, the BE was sampled by brush cytology and biopsies. At least 2 months after RFA, the NSE was sampled by brush cytology, keyhole biopsies, and endoscopic resection. The untreated squamous epithelium was biopsied as a control. The baseline BE and post-RFA NSE were evaluated for immunohistochemical expression of Ki-67 and p53, and genetic abnormalities (DNA–fluorescent in situ hybridization: chromosome 1 and 9, p16 and p53). In addition, biopsy depth was compared for biopsies from the NSE and untreated squamous epithelium. The presence of buried glandular mucosa in NSE was assessed with primary and keyhole biopsy, and endoscopic resection.RESULTS:All pretreatment specimens from all 22 patients showed abnormalities on immunohistochemical staining and fluorescent in situ hybridization, whereas all post-RFA NSE specimens were normal. All the post-RFA biopsies from the NSE contained full epithelia, whereas 37% contained lamina propria, a finding no different from biopsies from untreated squamous epithelium (36% lamina propria). Deeper keyhole biopsies contained lamina propria in 51%. All endoscopic resection specimens contained submucosa, whereas no biopsy or endoscopic resection specimen contained buried glandular mucosa.CONCLUSIONS:Rigorous evaluation of the post-RFA NSE in patients who, at baseline, had BE containing early cancer high-grade intraepithelial neoplasia, showed neither persistent genetic abnormalities nor buried glandular mucosa.

Multimodality endoscopic eradication for neoplastic Barrett oesophagus: results of an European multicentre study (EURO-II)

Objective Focal endoscopic resection (ER) followed by radiofrequency ablation (RFA) safely and effectively eradicates Barretts oesophagus (BO) containing high-grade dysplasia (HGD) and/or early cancer (EC) in smaller studies with limited follow-up. Herein, we report long-term outcomes of combined ER and RFA for BO (HGD and/or EC) from a single-arm multicentre interventional study. Design In 13 European centres, patients with BO≤12 cm with HGD and/or EC on 2 separate endoscopies were eligible for inclusion. Visible lesions (<2 cm length; <50% circumference) were removed with ER, followed by serial RFA every 3 months (max 5 sessions). Follow-up endoscopy was scheduled at 6 months after the first negative post-treatment endoscopic control and annually thereafter. Outcomes: complete eradication of neoplasia (CE-neo) and intestinal metaplasia (CE-IM); durability of CE-neo and CE-IM (once achieved) during follow-up. Biopsy and resection specimens underwent centralised pathology review. Results 132 patients with median BO length C3M6 were included. After entry-ER in 119 patients (90%) and a median of 3 RFA (IQR 3–4) treatments, CE-neo was achieved in 121/132 (92%) and CE-IM in 115/132 patients (87%), per intention-to-treat analysis. Per-protocol analysis, CE-neo and CE-IM were achieved in 98% and 93%, respectively. After a median of 27 months following the first negative post-treatment endoscopic control, neoplasia and IM recurred in 4% and 8%, respectively. Mild-to-moderate adverse events occurred in 25 patients (19%); all managed conservatively or endoscopically. Conclusions In patients with early Barretts neoplasia, intensive multimodality endotherapy consisting of ER combined with RFA is safe and highly effective, and the treatment effect appears to be durable during mid-term follow-up. Trial registration number NTR 1211, http://www.trialregister.nl.

Randomized trial on endoscopic resection-cap versus multiband mucosectomy for piecemeal endoscopic resection of early Barrett's neoplasia

BACKGROUND Endoscopic resection (ER) is an important treatment for high-grade intraepithelial neoplasia and early cancer in Barretts esophagus. ER-cap requires submucosal lifting and positioning of a snare in the cap, making it technically demanding and laborious. Multiband mucosectomy (MBM) uses a modified variceal band ligator and requires no submucosal lifting or positioning of a snare. OBJECTIVE To compare ER-cap and MBM for piecemeal ER of early Barretts neoplasia. DESIGN Randomized, controlled trial. SETTING Tertiary-care and community-care centers. PATIENTS This study involved 84 patients (64 men; median age 70 years) undergoing piecemeal ER of Barretts neoplasia. INTERVENTION Piecemeal ER was performed by using ER-cap (n = 42) or MBM (n = 42). MAIN OUTCOME MEASUREMENTS Safety, efficacy, procedure time, costs. RESULTS Procedure time (34 vs 50 minutes; P = .02) and costs (€240 vs €322; P < .01) were significantly less with MBM compared with ER-cap. MBM resulted in smaller resection specimens than ER-cap (18 ×13 mm vs 20 × 15 mm; P < .01). Maximum thicknesses of specimens and resected submucosa were not significantly different. There were no clinically relevant bleeding episodes. Four perforations occurred, 3 with ER-cap, 1 with MBM (P = not significant). LIMITATIONS Potential bias because of different levels of experience among participating endoscopists. CONCLUSION Piecemeal ER with MBM is faster and cheaper than with ER-cap. Despite the lack of submucosal lifting, MBM appears not to be associated with more perforations. Although MBM results in slightly smaller specimens, the clinical relevance of this may be limited because depth of resections does not differ between both techniques. MBM may thus be preferred for piecemeal ER of early Barretts neoplasia. ( CLINICAL TRIAL REGISTRATION NUMBER NTR1435.).

Risk of Lymph Node Metastasis Associated with Deeper Invasion by Early Adenocarcinoma of the Esophagus and Cardia: Study Based on Endoscopic Resection Specimens

BACKGROUND Most risk estimations for lymph node metastasis in adenocarcinoma of the esophagus and cardia (AEC) with invasion into the muscularis mucosae (m3) or submucosa are based on surgical series. This study aimed to correlate the lymph node metastasis rate with m3 and submucosal infiltration depth of AEC in endoscopic resection specimens. METHODS Patients undergoing endoscopic resection for AEC between January 2000 and March 2008 at two centers were included if the endoscopic resection specimen showed m3 or submucosal cancer. Infiltration into the muscularis mucosae was defined as m3. Submucosal invasion was classified as sm1 (≤ 500 µm) or sm2/3 (> 500 µm). Exclusion criteria were chemotherapy or radiotherapy and nonradical endoscopic resection. RESULTS 82 patients included 57 with m3, 12 with sm1, and 13 with sm2/3 cancers. Of the tumors, 13 were poorly differentiated and five showed lymphovascular invasion. After initial endoscopic resection, seven patients underwent surgery and 75 endoscopic therapy. No lymph node metastases were found in 158 lymph nodes of the esophagectomy specimens and none of the endoscopically treated patients were diagnosed with lymph node metastasis during a median follow-up of 26 months (interquartile range [IQR] 14 - 41). CONCLUSION This study suggests that lymph node metastasis risk for m3 and submucosal AEC may be lower than has been assumed on the basis of surgical series, and that current guidelines are valid regarding suitability of m3 AECs for endoscopic therapy. It may also suggest that selected patients with submucosal cancers are also eligible for endoscopic management. Confirmation of these results is needed in larger series with longer follow-up.

Do we still need EUS in the workup of patients with early esophageal neoplasia? A retrospective analysis of 131 cases

BACKGROUND EUS is often used for locoregional staging of early esophageal neoplasia. However, its value compared with that of endoscopic examination and diagnostic endoscopic resection (ER) may be questioned because diagnostic ER allows histological assessment of submucosal invasion and other risk factors for lymph node metastasis, eg, poor differentiation/lymphovascular invasion. OBJECTIVE To evaluate how often patients were excluded from endoscopic treatment of esophageal neoplasia based on EUS findings. DESIGN Retrospective cohort study. SETTING Tertiary care institution. PATIENTS Patients with early esophageal neoplasia. INTERVENTIONS EUS, diagnostic ER. MAIN OUTCOME MEASUREMENTS Number of patients excluded from endoscopic treatment based on EUS results. RESULTS A total of 131 patients were included (98 men, 33 women; age 66 ± 13 years). In 105 of 131 patients (80%), EUS findings were unremarkable. In 25 of 105 patients (24%), diagnostic ER showed submucosal invasion (n = 17), deep resection margins positive for cancer (n = 2, confirmed at surgery), or poor differentiation/lymphovascular invasion (n = 6). In 26 of 131 patients (20%), EUS findings raised the suspicion of submucosal invasion and/or lymph node metastasis. In the 14 of 26 patients (54%) with abnormal EUS findings, endoscopy results were unremarkable. Diagnostic ER showed submucosal invasion in 7 of 14 (50%) patients, whereas no lymph node metastasis risk factors were found in 7 of 14 patients (50%), who subsequently underwent curative endoscopic treatment. In 12 of 26 patients (46%) with abnormal EUS, endoscopy also raised doubts on whether curative endoscopic treatment could be achieved. After diagnostic ER, no risk factors for lymph node metastasis were found in 3 of 12 patients (25%). LIMITATION Retrospective study. CONCLUSIONS This study shows that EUS has virtually no clinical impact on the workup of early esophageal neoplasia and strengthens the role of diagnostic ER as a final diagnostic step.

Learning to perform endoscopic resection of esophageal neoplasia is associated with significant complications even within a structured training program

BACKGROUND AND STUDY AIMS Endoscopic resection is the cornerstone of endoscopic treatment of esophageal high grade dysplasia or early cancer. Endoscopic resection is, however, a technically demanding procedure, which requires training and expertise. The aim of the current study was to prospectively evaluate efficacy and safety of the first 120 endoscopic resection procedures of early esophageal neoplasia performed by six endoscopists (20 endoscopic resections each) who were participating in an endoscopic resection training program. PATIENTS AND METHODS The program consisted of four tri-monthly 1-day courses with lectures, live-demonstrations, hands-on training on anesthetized pigs, and one-on-one hands-on training days. Gastroenterologists from centers with multidisciplinary expertise in upper gastrointestinal oncology participated, together with an endoscopy nurse and a pathologist. Outcome measures were complete endoscopic removal of the target area and acute complications. RESULTS A total of 120 consecutive esophageal endoscopic resection procedures (85 ER-cap, 35 multiband mucosectomy [MBM]) were performed by six endoscopists: 109 in Barretts esophagus, 11 for squamous neoplasia; 85 piecemeal endoscopic resections (median 3 specimens, interquartile range 2 - 4 specimens). Complete endoscopic removal was achieved in 111 /120 cases (92.5 %). Six perforations occurred (5.0 %): five were effectively treated endoscopically (clips, covered stent), and one patient underwent esophagectomy. There were 11 acute mild bleedings (9.2 %), which were managed endoscopically. Perforations occurred in ER-cap procedures performed by four participants (7.1 % ER-cap vs. 0 % MBM; P = 0.18), and in 1.7 % of the first 10 endoscopic resections and 8.3 % of the second 10 endoscopic resections per endoscopist (P = 0.26). CONCLUSION In this intense, structured training program, the first 120 esophageal endoscopic resections performed by six participants were associated with a 5.0 % perforation rate. Although perforations were adequately managed, performing 20 endoscopic resections may not be sufficient to reach the peak of the learning curve in endoscopic resection.

Stepwise radical endoscopic resection for Barrett’s esophagus with early neoplasia: report on a Brussels’ cohort

BACKGROUND AND STUDY AIMS The aim of this retrospective study was to assess safety and efficacy of stepwise radical endoscopic resection (SRER) in patients with Barretts esophagus with high-grade intraepithelial neoplasia (HGIN) or early cancer. PATIENTS AND METHODS Patients undergoing SRER between 2000 and 2006 were retrospectively evaluated. Patients with Barretts esophagus who also had HGIN or early cancer were included if they had no signs of submucosal infiltration or metastases. SRER was performed using the cap-technique, at 8-week intervals until all Barretts esophagus was removed. Follow-up endoscopy was scheduled every 6 months. RESULTS A total of 34 patients were included (31 male, mean 67 years, median Barretts dimensions C1M4). HGIN / early cancer was eradicated in all patients in a median of two endoscopic resection sessions (IQR 1-2 sessions). Twelve patients underwent additional argon plasma coagulation for small islets or an irregular Z-line. Barretts esophagus was eradicated in 28 patients (82 %). Complications occurred in 3/34 patients (9 %): two perforations, one delayed bleeding. In all, 19 patients (56 %) developed dysphagia, which was resolved with dilatation or stent placement. During a median follow-up period of 23 months (IQR 15 - 41 months), HGIN / early cancer recurred in three patients (9 %): two were retreated with endoscopic resection and one patient was referred for curative surgery. Five patients (15 %) had recurrence of nondysplastic Barretts esophagus. At the end of the follow-up period all patients were free of HGIN / early cancer (one patient after surgery), and 23 patients (68 %) had complete endoscopic and histological eradication of Barretts esophagus. CONCLUSIONS SRER resulted in complete eradication of HGIN/early cancer in all patients, and eradication of Barretts esophagus in a majority of cases. A significant number of patients develop dysphagia, which can be successfully treated endoscopically.