Long-term outcomes after endoscopic treatment for Barrett's neoplasia with radiofrequency ablation +/- endoscopic resection:results from the national Dutch database in a 10-year period

OBJECTIVE: Radiofrequency ablation (RFA)±endoscopic resection (ER) is the preferred treatment for early neoplasia in Barrett’s oesophagus (BE). We aimed to report short-term and long-term outcomes for all 1384 patients treated in the Netherlands (NL) from 2008 to 2018, with uniform treatment and follow-up (FU) in a centralised setting. DESIGN: Endoscopic therapy for early BE neoplasia in NL is centralised in nine expert centres with specifically trained endoscopists and pathologists that adhere to a joint protocol. Prospectively collected data are registered in a uniform database. Patients with low/high-grade dysplasia or low-risk cancer, were treated by ER of visible lesions followed by trimonthly RFA sessions of any residual BE until complete eradication of BE (CE-BE). Patients with ER alone were not included. RESULTS: After ER (62% of cases; 43% low-risk cancers) and median 1 circumferential and 2 focal RFA (p25-p75 0–1; 1–2) per patient, CE-BE was achieved in 94% (1270/1348). Adverse events occurred in 21% (268/1386), most commonly oesophageal stenosis (15%), all were managed endoscopically. A total of 1154 patients with CE-BE were analysed for long-term outcomes. During median 43 months (22–69) and 4 endoscopies (1–5), 38 patients developed dysplastic recurrence (3%, annual recurrence risk 1%), all were detected as endoscopically visible abnormalities. Random biopsies from a normal appearing cardia showed intestinal metaplasia (IM) in 14% and neoplasia in 0%. A finding of IM in the cardia was reproduced during further FU in only 33%, none progressed to neoplasia. Frequent FU visits in the first year of FU were not associated with recurrence risk. CONCLUSION: In a setting of centralised care, RFA±ER is effective for eradication of Barrett’s related neoplasia and has remarkably low rates of dysplastic recurrence. Our data support more lenient FU intervals, with emphasis on careful endoscopic inspection. Random biopsies from neosquamous epithelium and cardia are of questionable value. NETHERLANDS TRIAL REGISTER NUMBER: NL7039

Incidence and outcomes of poor healing and poor squamous regeneration after radiofrequency ablation therapy for early Barrett's neoplasia

BACKGROUND: Although endoscopic eradication therapy with radiofrequency ablation (RFA) is effective in most Barrett's Esophagus (BE) patients, some might experience poor healing (PH) and/or poor squamous regeneration (PSR). We aimed to evaluate PH/PSR incidence and treatment outcomes. METHODS: We included all patients treated with RFA for early BE neoplasia, from a nationwide Dutch registry based on a joint treatment protocol. PH was defined as active inflammatory changes or visible ulcerations ≥3 months post-RFA, PSR as <50% squamous regeneration, and treatment success as complete eradication of BE (CE-BE). Results 1,386 patients (median BE C2M5) underwent RFA with baseline low-grade dysplasia (27%), high-grade dysplasia (30%), or early cancer (43%). In all 134 patients with PH (10%), additional time and acid suppression resulted in complete esophageal healing. 67/134 (50%) had normal regeneration with 97% CE-BE. In total, 74 patients had PSR (5%). As compared to patients with normal squamous regeneration, PSR patients had a higher risk for treatment failure (64% versus 2%, RR 27 [95% CI 18-40]) and progression to advanced disease (15% versus <1%, RR 30 [95% CI 12-81]). Higher BMI, longer BE, reflux esophagitis, and <50% squamous regeneration after baseline endoscopic resection were independently associated with PSR in multivariable logistic regression. Conclusions In half of the patients with PH, additional time and acid suppression may lead to normal squamous regeneration and excellent treatment outcomes. However, if patients experience PSR, the risk for treatment failure and progression to advanced disease is significantly increased with a relative risk of 27 and 30, respectively

Extending treatment criteria for Barrett's neoplasia:results of a nationwide cohort of 138 ESDs

BACKGROUND:  The use of endoscopic submucosal dissection (ESD) is gradually expanding for treatment of neoplasia in Barrett's esophagus (BE). We aimed to report outcomes of all ESDs for BE neoplasia performed in the Netherlands. METHODS:  Retrospective assessment of outcomes, using treatment and follow-up data from a joint database. RESULTS:  130/138 patients had complete ESDs, with 126/130 (97 %) en bloc resections. Median (interquartile range (IQR)) procedure time was 121 minutes (90-180). Pathology findings were high grade dysplasia (HGD) (5 %) or esophageal adenocarcinoma (EAC) T1a (43 %) or T1b (52 %; 19 % sm1, 33 % ≥ sm2). Among resections of HGD or T1a EAC lesions, 87 % (95 %CI 75 %-92 %) were both en bloc and R0; the corresponding value for T1b EAC lesions was 49 % (36 %-60 %). Among R1 resections, 10/34 (29 %) showed residual cancer, all detected at first endoscopic follow-up. The remaining 24 patients (71 %) showed no residual neoplasia. Six of these patients underwent surgery with no residual tumor; the remaining 18 underwent endoscopic follow-up during median 31 months with 1 local recurrence (annual recurrence rate 2 %). Among R0 resections, annual local recurrence rate during median 27 months was 0.5 %. CONCLUSION:  In expert hands, ESD allows safe removal of bulky intraluminal neoplasia and submucosal cancer. ESD of the latter showed R1 resection margins in 50 %, yet only one third had persisting neoplasia at follow-up. To better stratify R1 patients with an indication for additional surgery, repeat endoscopy after healing of the ESD might be a helpful possible prognostic factor for residual cancer

Analysis of metastases rates during follow-up after endoscopic resection of early "high-risk" esophageal adenocarcinoma

BACKGROUND AND AIMS: After endoscopic resection (ER) of early esophageal adenocarcinoma (EAC), the optimal management of patients with high-risk histological features for lymph node metastases (LNM) (i.e., submucosal invasion, poor differentiation grade, or lymphovascular invasion (LVI)), remains unclear. We aimed to evaluate outcomes of endoscopic follow-up after ER for high-risk EAC. METHODS: For this retrospective cohort study, data was collected from all Dutch patients managed with endoscopic follow-up (endoscopy, endoscopic ultrasound) after ER for high-risk EAC between 2008 and 2019. We distinguished 3 groups: intramucosal cancers with high-risk features, submucosal cancers with low-risk features, and submucosal cancers with high-risk features. Primary outcome was the annual risk for metastases during follow-up, stratified for baseline histology. RESULTS: A total of 120 patients met the selection criteria. Median FU was 29 months (IQR 15-48). Metastases were observed in 5/25 (annual risk 6.9%; 95% CI 3.0-15), 1/55 (annual risk 0.7%; 95% CI 0-4.0) and 3/40 (annual risk 3.0%; 95% CI 0-7.0) in high-risk intramucosal, low-risk submucosal, and high-risk submucosal cancers, respectively. CONCLUSIONS: Whereas the annual metastasis rate for high-risk submucosal EAC (3.0%) was somewhat lower than expected in comparison with previous reported percentages, the annual metastasis rate of 6.9% for high-risk intramucosal EAC is new and worrisome. This calls for further prospective studies and suggests that strict follow-up of this small subgroup is warranted until prospective data are available

Lymphovascular invasion quantification could improve risk prediction of lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma

AIM: To quantify lymphovascular invasion (LVI) and to assess the prognostic value in patients with pT1b esophageal adenocarcinoma. METHODS: In this nationwide, retrospective cohort study, patients were included if they were treated with surgery or endoscopic resection for pT1b esophageal adenocarcinoma. Primary endpoint was the presence of metastases, lymph node metastases, or distant metastases, in surgical resection specimens or during follow‐up. A prediction model to identify risk factors for metastases was developed and internally validated. RESULTS: 248 patients were included. LVI was distributed as follows: no LVI (n = 196; 79.0%), 1 LVI focus (n = 16; 6.5%), 2–3 LVI foci (n = 21; 8.5%) and ≥4 LVI foci (n = 15; 6.0%). Seventy‐eight patients had metastases. The risk of metastases was increased for tumors with 2–3 LVI foci [subdistribution hazard ratio (SHR) 3.39, 95% confidence interval (CI) 2.10–5.47] and ≥4 LVI foci (SHR 3.81, 95% CI 2.37–6.10). The prediction model demonstrated a good discriminative ability (c‐statistic 0.81). CONCLUSION: The risk of metastases is higher when more LVI foci are present. Quantification of LVI could be useful for a more precise risk estimation of metastases. This model needs to be externally validated before implementation into clinical practice

Individual risk calculator to predict lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma:a multicenter cohort study

Background Lymph node metastasis (LNM) is possible after endoscopic resection of early esophageal adenocarcinoma (EAC). This study aimed to develop and internally validate a prediction model that estimates the individual risk of metastases in patients with pT1b EAC. Methods A nationwide, retrospective, multicenter cohort study was conducted in patients with pT1b EAC treated with endoscopic resection and/or surgery between 1989 and 2016. The primary end point was presence of LNM in surgical resection specimens or detection of metastases during follow-up. All resection specimens were histologically reassessed by specialist gastrointestinal pathologists. Subdistribution hazard regression analysis was used to develop the prediction model. The discriminative ability of this model was assessed using the c-statistic. Results 248 patients with pT1b EAC were included. Metastases were seen in 78 patients, and the 5-year cumulative incidence was 30.9 % (95 % confidence interval [CI] 25.1 %-36.8 %). The risk of metastases increased with submucosal invasion depth (subdistribution hazard ratio [SHR] 1.08, 95 %CI 1.02-1.14, for every increase of 500 μm), lymphovascular invasion (SHR 2.95, 95 %CI 1.95-4.45), and for larger tumors (SHR 1.23, 95 %CI 1.10-1.37, for every increase of 10 mm). The model demonstrated good discriminative ability (c-statistic 0.81, 95 %CI 0.75-0.86). Conclusions A third of patients with pT1b EAC experienced metastases within 5 years. The probability of developing post-resection metastases was estimated with a personalized predicted risk score incorporating tumor invasion depth, tumor size, and lymphovascular invasion. This model requires external validation before implementation into clinical practice

Increased risk of second primary tumours in patients with oesophageal squamous cell carcinoma: a nationwide study in a Western population

Background: Patients with primary oesophageal squamous cell carcinoma are at risk of developing multiple primary tumours in the upper aero digestive tract. To date, most studies are performed in the Asian population. We aimed to evaluate the risk of multiple primary tumours in the upper aero digestive tract and stomach in patients with oesophageal squamous cell carcinoma in a Western population. Methods: We performed a nationwide, retrospective cohort study in collaboration with the Netherlands Cancer Registry. Patients with primary oesophageal squamous cell carcinoma, diagnosed between 2000 and 2016, were included. Primary endpoints were synchronous and metachronous multiple primary tumour risk. Results: The cohort consisted of 9058 patients, diagnosed with oesophageal squamous cell carcinoma (male: 57.3%, median age 67 years). In 476 patients (5.3%), 545 multiple primary tumours have been diagnosed. Most of them were located in the head and neck region (49.5%). Among all multiple primary tumours, 329 (60.4%) were diagnosed synchronously (<6 months after oesophageal squamous cell carcinoma diagnosis) and 216 (39.6%) metachronously (6 months). Patients with oesophageal squamous cell carcinoma had a significantly increased risk of both synchronous (standardised incidence ratio 10.95, 99% confidence interval 9.40–12.53) and metachronous multiple primary tumours (standardised incidence ratio 4.36, 99% confidence interval 3.56–5.10), compared to the general population. The median interval to metachronous second primary tumour diagnosis was 3.0 years (interquartile range 1.8–5.9). Conclusion: Approximately one in 20 patients with primary oesophageal squamous cell carcinoma have a second primary tumour in the upper aero digestive tract or stomach, either at the time of oesophageal squamous cell carcinoma diagnosis or at a later stage. As second primary tumours occur at an increased risk compared to the general population, prospective studies are necessary to investigate the yield and survival benefit of screening for second primary tumours in patients with oesophageal squamous cell carcinoma

Screening for head and neck tumors in patients with esophageal squamous cell carcinoma and vice versa: a nationwide survey among medical specialists

Background and study aims Retrospectively, minimally 5% of patients with esophageal squamous cell carcinoma (ESCC) and 11 % with head and neck squamous cell carcinoma (HNSCC) in Western countries developed a second primary tumor (SPT). SPT screening in ESCC and HNSCC patients is not implemented routinely in daily practice in many Western countries. This study aimed to assess medical specialist knowledge and opinions regarding screening for head and neck SPTs (HNSPTs) in ESCC patients and vice versa in the Netherlands. Methods A nationwide survey among gastroenterologists and head and neck (HN) surgeons was conducted between December 2020 and March 2021. The survey consisted of 27 questions and focused on knowledge of medical specialists of the prevalence and opinions toward implementing screening for HNSPTs in ESCC patients and vice versa. Results One hundred twenty-eight gastroenterologists (20.5%) and 31 HN surgeons (50.0%) completed the survey. The expected median prevalence of HNSPTs in ESCC was 7.0% (interquartile range [IQR]: 5.0-15.0) among gastroenterologists and 5.0% (IQR:3.0-8.0) among HN surgeons. For ESPTs in HNSCC, the expected median prevalence was 9.5% (IQR: 5.0-12.0) among gastroenterologists and 4.0% (IQR: 2.0-5.0) among HN surgeons. Screening for HNSPTs and ESPTs was considered promising by 35.2% and 39.6%, respectively, which increased to 54.7% of the specialists after providing incidence data on SPTs. Of the HN surgeons, 41.3% felt they were as capable as gastroenterologists of performing esophageal screening. Conclusions This Dutch nationwide survey revealed a lack of knowledge and different perspectives among specialists about screening to detect SPTs in ESCC and HNSCC patients. Adequate education seems essential to increase awareness among specialists and improve SPT detection, independent of the need for implementation of screening for SPTs in ESCC and HNSCC patients

Laryngeal Carcinoma in Patients With Inflammatory Bowel Disease:Clinical Outcomes and Risk Factors

BACKGROUND: Inflammatory bowel disease (IBD) patients are at increased risk for developing extra-intestinal malignancies, mainly due to immunosuppressive medication. The risk of developing head and neck cancer in immunosuppressed transplant patients is increased. The relation between IBD patients and laryngeal cancer (LC) remains unclear. We aimed (1) to identify risk factors in IBD patients for LC development and (2) to compare clinical characteristics, outcome, and survival of LC in IBD patients with the general population. METHODS: All IBD patients with LC (1993-2011) were retrospectively identified using the Dutch Pathology Database. We performed 2 case-control studies: (1) to identify risk factors, we compared patients with IBD and LC (cases) with the general IBD population; (2) to analyze LC survival, we compared cases with controls from the general LC population. RESULTS: We included 55 cases, 1800 IBD controls, and 2018 LC controls. Cases were more frequently male compared with IBD controls (P < 0.001). For ulcerative colitis (UC), cases were older at IBD diagnosis (P < 0.001). Crohn's disease (CD) cases were more frequently tobacco users (P < 0.001) and more often had stricturing (P = 0.006) and penetrating (P = 0.008) disease. We found no survival difference. Immunosuppressive medication had no impact on survival. CONCLUSIONS: Male sex was a risk factor for LC in IBD patients. Older age at IBD diagnosis was a risk factor for UC to develop LC. Tobacco use and stricturing and penetrating disease were risk factors for LC development in CD patients. Inflammatory bowel disease was not associated with impaired survival of LC. Immunosuppressive medication had no influence on survival

Laryngeal Carcinoma in Patients With Inflammatory Bowel Disease: Clinical Outcomes and Risk Factors

BACKGROUND: Inflammatory bowel disease (IBD) patients are at increased risk for developing extra-intestinal malignancies, mainly due to immunosuppressive medication. The risk of developing head and neck cancer in immunosuppressed transplant patients is increased. The relation between IBD patients and laryngeal cancer (LC) remains unclear. We aimed (1) to identify risk factors in IBD patients for LC development and (2) to compare clinical characteristics, outcome, and survival of LC in IBD patients with the general population. METHODS: All IBD patients with LC (1993-2011) were retrospectively identified using the Dutch Pathology Database. We performed 2 case-control studies: (1) to identify risk factors, we compared patients with IBD and LC (cases) with the general IBD population; (2) to analyze LC survival, we compared cases with controls from the general LC population. RESULTS: We included 55 cases, 1800 IBD controls, and 2018 LC controls. Cases were more frequently male compared with IBD controls (P < 0.001). For ulcerative colitis (UC), cases were older at IBD diagnosis (P < 0.001). Crohn's disease (CD) cases were more frequently tobacco users (P < 0.001) and more often had stricturing (P = 0.006) and penetrating (P = 0.008) disease. We found no survival difference. Immunosuppressive medication had no impact on survival. CONCLUSIONS: Male sex was a risk factor for LC in IBD patients. Older age at IBD diagnosis was a risk factor for UC to develop LC. Tobacco use and stricturing and penetrating disease were risk factors for LC development in CD patients. Inflammatory bowel disease was not associated with impaired survival of LC. Immunosuppressive medication had no influence on survival