Endoscopic submucosal dissection for early esophageal squamous cell carcinoma: long-term results from a Western cohort.

BACKGROUND: Although endoscopic submucosal dissection (ESD) is established as first-choice treatment for early esophageal squamous cell carcinoma (ESCC) worldwide, most data are derived from Asian studies. We aimed to evaluate the long-term outcomes of ESD for patients with early ESCC in a Western cohort. METHODS: In this retrospective cohort study, patients with early ESCC amenable to ESD were included from four tertiary referral hospitals in the Netherlands between 2012 and 2017. All ESD procedures were performed by experienced endoscopists, after which the decision for additional treatment was made on a per-patient basis. Outcomes were curative resection rate, ESCC-specific survival, and overall survival. RESULTS: Of 68 included patients (mean age 69 years; 34 males), ESD was technically successful in 66 (97%; 95%CI 93%-100%), with curative resection achieved in 34/66 (52%; 95%CI 39%-64%). Among patients with noncurative resection, 15/32 (47%) underwent additional treatment, mainly esophagectomy (n = 10) or definitive chemoradiation therapy (n = 4). Endoscopic surveillance was preferred in 17/32 patients (53%), based on severe comorbidities or patient choice. Overall, 31/66 patients (47%) died during a median follow-up of 66 months; 8/31 (26%) were ESCC-related deaths. The 5-year overall and ESCC-specific survival probabilities were 62% (95%CI 52%-75%) and 86% (95%CI 77%-96%), respectively. CONCLUSION: In this Western cohort with long-term follow-up, the effectiveness and safety of ESD for early ESCC was confirmed, although the rate of noncurative resections was substantial. Irrespective of curative status, the long-term prognosis of these patients was limited mainly due to competing mortality.

Diagnostic value of radiological staging and surveillance for T1 colorectal carcinomas: A multicenter cohort study.

BACKGROUND: The role of radiological staging and surveillance imaging is under debate for T1 colorectal cancer (CRC) as the risk of distant metastases is low and imaging may lead to the detection of incidental findings. OBJECTIVE: The aim of this study was to evaluate the yield of radiological staging and surveillance imaging for T1 CRC. METHODS: In this retrospective multicenter cohort study, all patients of 10 Dutch hospitals with histologically proven T1 CRC who underwent radiological staging in the period 2000-2014 were included. Clinical characteristics, pathological, endoscopic, surgical and imaging reports at baseline and during follow-up were recorded and analyzed. Patients were classified as high-risk T1 CRC if at least one of the histological risk factors (lymphovascular invasion, poor tumor differentiation, deep submucosal invasion or positive resection margins) was present and as low-risk when all risk factors were absent. RESULTS: Of the 628 included patients, 3 (0.5%) had synchronous distant metastases, 13 (2.1%) malignant incidental findings and 129 (20.5%) benign incidental findings at baseline staging. Radiological surveillance was performed among 336 (53.5%) patients. The 5-year cumulative incidence of distant recurrence, malignant and benign incidental findings were 2.4% (95% confidence interval (CI): 1.1%-5.4%), 2.5% (95% CI: 0.6%-10.4%) and 18.3% (95% CI: 13.4%-24.7%), respectively. No distant metastatic events occurred among low-risk T1 CRC patients. CONCLUSION: The risk of synchronous distant metastases and distant recurrence in T1 CRC is low, while there is a substantial risk of detecting incidental findings. Radiological staging seems unnecessary prior to local excision of suspected T1 CRC and after local excision of low-risk T1 CRC. Radiological surveillance should not be performed in patients with low-risk T1 CRC.

Feasibility and Safety of Tailored Lymphadenectomy Using Sentinel Node-Navigated Surgery in Patients with High-Risk T1 Esophageal Adenocarcinoma.

BACKGROUND: Selective lymphadenectomy using sentinel node-navigated surgery (SNNS) might offer a less invasive alternative to esophagectomy in patients with high-risk T1 esophageal adenocarcinoma (EAC). The aim of this study was to evaluate the feasibility and safety of a new treatment strategy, consisting of radical endoscopic resection of the tumor followed by SNNS. METHODS: In this multicenter pilot study, ten patients with a radically resected high-risk pT1cN0 EAC underwent SNNS. A hybrid tracer of technetium-99m nanocolloid and indocyanine green was injected endoscopically around the resection scar the day before surgery, followed by preoperative imaging. During surgery, sentinel nodes (SNs) were identified using a thoracolaparoscopic gammaprobe and fluorescence-based detection, and subsequently resected. Endpoints were surgical morbidity and number of detected and resected (tumor-positive) SNs. RESULTS: Localization and dissection of SNs was feasible in all ten patients (median 3 SNs per patient, range 1-6). The concordance between preoperative imaging and intraoperative detection was high. In one patient (10%), dissection was considered incomplete after two SNs were not identified intraoperatively. Additional peritumoral SNs were resected in four patients (40%) after fluorescence-based detection. In two patients (20%), a (micro)metastasis was found in one of the resected SNs. One patient experienced neuropathic thoracic pain related to surgery, while none of the patients developed functional gastroesophageal disorders. CONCLUSIONS: SNNS appears to be a feasible and safe instrument to tailor lymphadenectomy in patients with high-risk T1 EAC. Future research with long-term follow-up is warranted to determine whether this esophageal preserving strategy is justified for high-risk T1 EAC.

The course of pain and dysphagia after radiofrequency ablation for Barrett's esophagus-related neoplasia.

BACKGROUND: Radiofrequency ablation (RFA) is effective for eradication of Barrett's esophagus (BE) neoplasia, but little is known on the course of pain and dysphagia after RFA. We aimed to describe the course of post-RFA symptoms and to identify possible associated risk factors. METHODS: In this multicenter, observational cohort study, all RFA procedures registered in a prospective database were included. Patient and treatment characteristics were collected from medical records and patients self-registered post-procedural symptoms in electronic symptom diaries for 14 days. Mixed model regression was used for the analyses. RESULTS: In total, 255 diaries were completed. Post-RFA pain was reported for 95 % (95 %CI 93-98) of procedures (median duration 14 days; 25th-75th percentiles [p25-p75] 11-14) and major pain for 64 % (95 %CI 58-69; median duration 8 days, p25-p75 3-13). Post-procedural pain significantly increased with BE length, younger age, and no prior ablation. Dysphagia was present after 83 % (95 %CI 79-88) of procedures (median duration 13 days, p25-p75 9-14). The risk of dysphagia decreased with age and increased when patients experienced more pain. CONCLUSIONS: RFA treatment for BE-related neoplasia seems a significant burden for patients, and post-procedural symptoms should be taken into account when counseling patients before starting endoscopic eradication therapy.

Comparison of focal cryoballoon ablation with 10- and 8-second doses for treatment of Barrett's esophagus-related neoplasia: results from a prospective European multicenter study (with video).

BACKGROUND AND AIMS: Focal cryoballoon ablation (FCBA) is currently being investigated for the treatment of Barrett's esophagus (BE)-related neoplasia in a European multicenter study (Euro-Coldplay study). After inclusion of 28 of 107 patients, the initial dose of 10 seconds was lowered to 8 seconds. The current study aimed to compare the efficacy and safety of a single FCBA treatment session with 10 seconds versus 8 seconds. METHODS: Treatments were performed at 7 European BE referral centers. All 28 patients treated with 10 seconds were compared with 28 consecutive patients treated with 8 seconds. The gastroesophageal junction was ablated circumferentially followed by all visible BE. To assess efficacy and safety, 3 expert adjudicators, blinded to physician and dose, compared pre- and post-treatment images. Primary outcomes were median BE surface regression and stricture rate after single-session FCBA. RESULTS: We included 56 patients (10-second cohort, n = 28; 8-second cohort, n = 28) with a median BE length of C0M2 (Prague classification). Baseline characteristics did not significantly differ between the cohorts. The median BE surface regression after a single FCBA session was comparable for 10 seconds and 8 seconds (80% [95% confidence interval {CI}, 75-90] and 80% [95% CI, 66-90], respectively; P = .65). Strictures requiring dilation were seen in 19% (95% CI, 4-33) and 15% (95% CI, 4-30) of the 10-second and 8-second groups, respectively (P = 1.00). Two patients in the 10-second group developed a severe stricture requiring >3 dilations. CONCLUSIONS: In patients with limited BE, single-session FCBA with 8 seconds showed similar BE surface regression as compared with 10 seconds and may theoretically result in fewer and less severe strictures. Therefore, we suggest using 8 seconds as the standard dose for FCBA. (Clinical trial registration number: NL7253.).

Esophageal Second Primary Tumors in Patients With Head and Neck Squamous Cell Carcinoma: Incidence, Risk Factors, and Overall Survival.

INTRODUCTION: The aim of this registry-based cohort study was to evaluate the potential role of endoscopic esophageal surveillance for esophageal second primary tumors (ESPTs) in Western patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Outcomes were cumulative incidence and risk factors for ESPTs and its effect on overall survival. RESULTS: A total of 47 ESPTs were observed in 1,708 patients with HNSCC, with 10-year cumulative incidence (95% confidence interval) of 2.9% (2.1-3.7). Alcohol and HNSCC location were significant predictors for ESPTs. ESPTs significantly increased the risk of dying (adjusted hazard ratio 3.36, 95% confidence interval 2.16-5.22). DISCUSSION: Endoscopic esophageal surveillance of Western patients with HNSCC with high risk of ESPTs seems justified.

Feasibility of sentinel node navigated surgery in high-risk T1b esophageal adenocarcinoma patients using a hybrid tracer of technetium-99 m and indocyanine green.

BACKGROUND: Minimally invasive esophagectomy with two-field lymphadenectomy is standard of care for T1b esophageal adenocarcinoma (EAC) with a high risk of lymph node metastasis. Sentinel node navigation surgery (SNNS) is a well-known concept to tailor the extent of lymphadenectomy. The aim of this study was to evaluate the feasibility and safety of SNNS with a hybrid tracer (technetium-99 m/indocyanine green/nanocolloid) for patients with high-risk T1b EAC. METHODS: In this prospective, multicenter pilot study, 5 patients with high-risk T1b EAC were included. The tracer was injected endoscopically around the endoscopic resection scar the day before surgery, followed by preoperative imaging (lymphoscintigraphy/SPECT-CT). During surgery, first the SNs were localized and resected based on preoperative imaging and intraoperative gammaprobe- and fluorescence-based detection, followed by esophagectomy. Primary endpoints were the percentage of patients with detectable SNs, concordance between preoperative and intraoperative SN detection, and the additive value of indocyanine green. RESULTS: SNs could be identified and resected in all patients (median 3 SNs per patient, range 2-7). There was a high concordance between preoperative and intraoperative SN detection. In 2 patients additional peritumoral SNs were identified with fluorescence-based detection. None of the resected lymph nodes showed signs of (micro)metastases and no nodal metastases were detected in the surgical resection specimen. CONCLUSIONS: SNNS using technetium-99 m/indocyanine green/nanocolloid seems feasible and safe in patients with high-risk T1b EAC. Indocyanine green fluorescence seems to be of additive value for detection of peritumoral SNs. Whether this approach can optimize selection for esophagectomy needs to be studied in future research.

Novel cryoballoon 180° ablation system for treatment of Barrett's esophagus-related neoplasia: a first-in-human study.

BACKGROUND: The novel 180° cryoballoon (CbAS180) enables semicircumferential treatment over a length of 3 cm per application. This first-in-human study evaluates its feasibility, efficacy, and safety for the treatment of Barrett's esophagus (BE) neoplasia. METHODS: This multicenter study consisted of dose-finding and extension phases. Dose-finding started with the lowest dose possible (1.0 mm/s). For each dose, six patients were treated circumferentially over a 3-cm length. The dose was increased until the median BE regression was ≥ 60 % without serious adverse events (SAEs). In the extension phase, the dose was confirmed in 19 new patients. The outcomes were technical success, BE regression after one treatment, and SAEs. RESULTS: 25 patients (median Prague C0M3) were included (6 dose-finding/19 extension). In two patients, the CbAS180 could not be applied because of unstable balloon positioning. The technical success rate was 96 % (22 /23). In the six dose-finding patients, the starting dose resulted in median BE regression of 94 % (95 % confidence interval [CI] 60 %-97 %) without SAEs and was thus considered effective. Overall median BE regression was 80 % (95 %CI 60 %-90 %). CONCLUSION: Single-session CbAS180 seems feasible, safe, and effective, and is a promising technique for the treatment of patients with BE neoplasia.

Extension of early esophageal squamous cell neoplasia into ducts and submucosal glands and the role of endoscopic ablation therapy.

BACKGROUND AND AIMS: Early esophageal squamous cell neoplasia (ESCN) is preferably treated with en-bloc endoscopic resection. Ablation might be an alternative for flat ESCN, but ESCN extension along the epithelial lining of ducts and submucosal glands (SMGs) might jeopardize ablation efficacy. Clinical studies suggest that local recurrence might arise from such buried ESCN niches after ablation. We studied human endoscopic resection specimens of ESCN to quantify ESCN extension into ducts/SMGs and performed a prospective porcine study to evaluate the depth of radiofrequency ablation (RFA) and CryoBalloon ablation (CBA) into ducts/SMGs. METHODS: Endoscopic submucosal dissection specimens of flat-type ESCN from a Japanese (n = 65) and Dutch cohort (n = 14) were evaluated for presence and neoplastic involvement of ducts/SMGs. Twenty-seven pigs were treated with circumferential RFA (c-RFA; n = 4), focal CBA (n = 20), and focal RFA (n = 3) with 4, 60, and 9 treatment areas, respectively. After prespecified survival periods (0 hours, 8 hours, 2 days, 5 days, and 28 days), treatment areas were evaluated for uniformity and depth of ablation and affected SMGs. RESULTS: Neoplastic extension in ducts/SMGs was observed in most lesions: 58% (38/65) in the Japanese and 64% (9/14) in the Dutch cohort. In the animal study, 33% of SMGs (95% confidence interval, 28-50) were not affected after c-RFA, although the overlying epithelium was ablated. Focal RFA and CBA resulted in uniform ablations with effective treatment of all SMGs. CONCLUSIONS: ESCN extends into ducts/SMGs in most patients. In an animal model, focal RFA and CBA effectively ablated SMGs, whereas c-RFA inadequately ablated SMGs. Given this potential reason for recurrence, endoscopic resection should remain the standard of care.

A novel cryoballoon ablation system for eradication of dysplastic Barrett's esophagus: a first-in-human feasibility study.

BACKGROUND: Endoscopic cryoablation for Barrett's esophagus (BE) might offer advantages over heat-based ablation. Focal cryoballoon ablation has been promising for short-segment BE, whereas the novel 90°-swipe cryoballoon ablation system (CbSAS90) ablates larger areas in a single step (90° over 3 cm). The system allows for dose adjustment. CbSAS90 has been feasible and safe in animal and pre-esophagectomy studies. This is the first clinical study to assess feasibility, safety, and efficacy of CbSAS90 for eradication of dysplastic BE. METHODS: In this prospective study in dysplastic BE patients, dose finding started with semi-circumferential treatment at 0.8 mm/s (dose 1). The dose was escalated by reducing speed by 0.1 mm/s in six patients until BE surface regression was ≥ 80 % without complications ("effective dose"). The effective dose was subsequently confirmed with circumferential treatment in 12 new patients. Post-procedural pain (0 - 10) and dysphagia (0 - 4) were evaluated. Outcomes were feasibility, safety, and BE surface regression. RESULTS: 25 patients were included, with technically successful treatment in 92 % (95 %CI 73 % - 99 %). Median (95 %CI) BE surface regression was 78 % (50 % - 85 %) for dose 1 and 85 % (55 % - 95 %) for dose 2 (0.7 mm/s), which was defined as the effective dose. Circumferential treatment resulted in 93 % (88 % - 96 %) regression. Two of 12 patients with circumferential treatment developed strictures that required dilation. Median pain and dysphagia scores were low (0 - 3 and 0, respectively). CONCLUSIONS: CbSAS90 was feasible and effective for ablating larger BE areas. The optimal dose for circumferential treatment that balances safety and efficacy requires further evaluation.

Optimizing histopathologic evaluation of EMR specimens of Barrett's esophagus-related neoplasia: a randomized study of 3 specimen handling methods.

BACKGROUND AND AIMS: Endoscopic resection is the cornerstone of treatment of Barrett's esophagus (BE)-related neoplasia. However, accurate histopathologic evaluation of endoscopic resection specimens can be challenging, and the preferred specimen handling method remains unknown. Therefore, the aim of our study was to compare 3 different specimen handling methods for assessment of all clinically relevant histopathologic parameters and time required for specimen handling. METHODS: In this multicenter, randomized study EMR specimens of BE-related neoplasia with no suspicion of submucosal invasion during endoscopy were randomized to 3 specimen handling methods: pinning on paraffin using needles, direct fixation in formalin without prior tissue handling, and the cassette technique (small box for enclosing specimens). The histopathologic evaluation scores were assessed by 2 dedicated GI pathologists blinded to the handling method. RESULTS: Of the 126 randomized EMR specimens, 45 were assigned to pinning on paraffin, 41 to direct fixation in formalin, and 40 to the cassette technique. The percentages of specimens with overall optimal histopathologic evaluation scores were similar for the pinning method (98%; 95% confidence interval [CI], 88.0-99.9) and for no handling (90%; 95% CI, 76.9-97.3) but were significantly lower (64%; 95% CI, 47.2-78.8) for the cassette technique (P < .001). Time required for specimen handling was shortest when no handling method was used (P < .001 vs pinning and cassette). CONCLUSIONS: Both pinning on paraffin and direct fixation in formalin resulted in optimal histopathologic evaluation scores in a high proportion of specimens, whereas the cassette technique performs significantly worse, and its use in clinical daily practice should be discouraged. Given the significantly shorter handling time, direct fixation in formalin appears to be the preferred method over pinning on paraffin. However, the latter needs to be confirmed in larger studies with inclusion of all EMR specimens. (Clinical trial registration number: ISRCTN50525266.).

Focal cryoballoon versus radiofrequency ablation of dysplastic Barrett's esophagus: impact on treatment response and postprocedural pain.

BACKGROUND AND AIMS: Radiofrequency ablation (RFA) is safe and effective for eradicating Barrett's esophagus (BE) but is associated with significant postprocedural pain. Alternatively, balloon-based focal cryoablation (CRYO) has recently been developed, which preserves the extracellular matrix and might therefore be less painful. Although data for CRYO are still limited, uncontrolled studies suggest comparable safety and efficacy to RFA in eradicating limited BE areas. Therefore, secondary endpoints such as pain might become decisive for treatment selection. We aimed to compare efficacy and tolerability between focal CRYO and RFA. METHODS: We identified BE patients undergoing focal ablation (either RFA or CRYO) of all visible BE from our prospective cohort in 2 Dutch referral centers. After ablation, patients completed a 14-day digital diary to assess chest pain (0-10), dysphagia (0-4), and analgesics use. A follow-up endoscopy was scheduled after 3 months to assess the BE surface regression (blindly scored by 2 independent BE expert endoscopists). Outcomes were BE surface regression; 14-day cumulative scores (area under the curves [AUCs]) for pain, dysphagia, analgesics, and peak pain. RESULTS: We identified 46 patients (20 CRYO, 26 RFA) with similar baseline characteristics. The BE regression was comparable (88% vs 90%, P = .62). AUCs for pain, dysphagia, and analgesics were significantly smaller after CRYO versus RFA (all P < .01). Peak pain was lower after CRYO (visual analog scale 2 vs 4, P < .01), and the duration of pain was also shorter after CRYO (2 vs 4 days, P < .01). CRYO patients used analgesics for 2 days versus 4 days for RFA (P < .01). CONCLUSIONS: In this multicenter, nonrandomized cohort study, we found no differences in efficacy after a single treatment with CRYO and RFA for short-segment BE. Patients reported less pain after CRYO as compared with RFA. Moreover, CRYO patients used fewer analgesics. Our results suggest a different pain course favoring CRYO over RFA, but a randomized trial is needed for definitive conclusions. (Clinical trial registration number: NCT02249975.).

Cryoablation in the management of Barrett's esophagus.

PURPOSE OF REVIEW: Providing an overview on types of cryotherapy for esophageal application and their role in the management of Barrett's esophagus. RECENT FINDINGS: Recent studies have involved multiple types of cryotherapy including cryospray techniques that use either liquid nitrogen or carbon dioxide as the cryogenic fluid, and the CryoBalloon focal ablation device that uses nitrous oxide. Overall, studies report cryotherapy to be safe and effective in eradicating Barrett's epithelium. However, substantial variations among these studies in design and outcomes preclude direct comparisons of the results. Moreover, little is known of the long-term outcomes of cryotherapy, with only one report describing 5-year follow-up of patients treated with liquid nitrogen cryospray. SUMMARY: The concept of cryotherapy is appealing. By preserving the extracellular matrix and inducing anesthetic effects, cryotherapy has the potential to enable deeper ablations with less pain and a lower rate of stricture formation than radiofrequency ablation. To date, however, these potential benefits remain unproved. Prospective studies with clearly defined endpoints and longer follow-up are necessary to determine the role of cryotherapy in the management of patients with Barrett's esophagus.