Prevention Randomised controlled trial
Radiofrequency ablation of Barrett’s oesophagus with confirmed low-grade dysplasia reduces risk of development of high-grade dysplasia and adenocarcinoma 10.1136/ebmed-2014-110019 Christine P J Caygill,1 Piers A C Gatenby1,2 1 UK National Barrett’s Oesophagus Registry, Royal Free Campus, University College London, London, UK; 2Regional Oesophagogastric Unit, Royal Surrey County Hospital, Guildford, UK
Correspondence to: Dr Christine PJ Caygill, UK National Barrett’s Oesophagus Registry, Royal Free Campus, University College London, London NW32PF, UK; [email protected]
Commentary on: Phoa KN, van Vilsteren FG, Weusten BL, et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomised clinical trial. JAMA 2014;311:1209–17.
Context The clinical management of patients with suspected low-grade dysplasia in Barrett’s oesophagus traditionally involves confirming the diagnosis by repeated systematic biopsy on strong acid suppression therapy and expert histopathological review of the sampled mucosa. Thereafter, patients are offered intensive surveillance with a shorter interval than in non-dysplastic Barrett’s oesophagus (due to the increase in risk of development of high-grade dysplasia and adenocarcinoma); however, some patients may also revert to non-dysplastic mucosa. Endoscopic ablative techniques eradicate the premalignant tissue, thereby obviating the need for potential resection or oncological therapy (and the morbidity, mortality and resource associated with these) with promising short-term outcomes. Long-term outcomes are as yet unknown.
Methods This is a randomised controlled trial of 136 patients with low-grade dysplasia within Barrett’s oesophagus, comparing endoscopic radiofrequency ablation to surveillance alone (randomised 1:1) at nine European centres. The intended follow-up was 3 years, with planned interim analyses at 50% and 75% follow-up time. The primary outcome measures were development of high-grade dysplasia or adenocarcinoma during the course of follow-up. Secondary outcome measures were: complete histological eradication of dysplasia, complete histological eradication of intestinal metaplasia and adverse events. The power calculation required a sample size of 120 patients (based on 14% control subjects and 1% of intervention subjects developing the primary end points). A 5% dropout rate was anticipated. Inclusion criteria included age 18–85 years, life expectancy of at least 2 years, diagnosis of low-grade dysplasia within 18 months, and an index qualifying endoscopy within 6 months of randomisation to exclude high-grade dysplasia, adenocarcinoma and any visible abnormalities within the segment. There was rigorous central pathological control. Ablation was undertaken every 3 months using the circumferential HALO360+ device (up to two sessions) and focal HALO90 device (up to three
sessions) with the option of subsequent endoscopic mucosal dissection or argon plasma coagulation to complete endoscopic and histological ablation of the Barrett’s segment. Surveillance endoscopies with four-quadrant biopsy every 2 cm were undertaken every three months from completion of treatment in the intervention arm and randomisation in the control arm.
Findings Five hundred and eleven patients were initially screened, and over half were excluded following pathological review. Seventy patients were randomised and 68 received the intended management in each group. The trial was terminated early due to the significant difference in outcome found at the second interim analysis (at which point all patients had completed at least 2 years of follow-up). Ablation was superior, with one patient (1.5%) developing adenocarcinoma compared to six surveillance patients. Twelve surveillance patients progressed to high-grade dysplasia compared to no progression in any ablation patient. The number needed to treat (NNT) to prevent one case of adenocarcinoma was 13.6 (95% CI 6.8 to 8), while the NNT to prevent one case of high-grade dysplasia or adenocarcinoma was 4 (95% CI 2.8 to 7.1). Complete eradication of dysplasia occurred in 63 of 68 patients (92.6%) in the ablation group, compared to 19 of 68 in the surveillance group (27.9%). Complete eradication of intestinal metaplasia occurred in 60 of 68 patients (88.2%) in the ablation group and none of the surveillance patients. Seventeen patients in the ablation group had endoscopic mucosal resection or argon plasma coagulation for residual columnar mucosa. No patient developed metastatic cancer or died from cancer. One was treated by oesophagectomy and all others had endoscopic therapy or continued surveillance for high-grade dysplasia. There were 15 adverse events (all in the treatment group) in 13 patients, including 3 severe (abdominal pain, bleeding and subsequent stricture development) and 8 which required dilation.
Commentary This paper shows a clear benefit from eradication of the Barrett’s oesophagus epithelium in patients who have demonstrated features of low-grade dysplasia. The treatment was intensive and required multiple outpatient sessions, but was generally well tolerated. Fewer patients suffered complications as a result of treatment than developed high-grade dysplasia or adenocarcinoma in the surveillance arm. The reduction in high-grade dysplasia and adenocarcinoma risk was seen throughout the follow-up period. The rigorous protocol for confirmation of low-grade dysplasia and expert pathology review panel has been fundamental in ascertaining which patients have true low-grade dysplasia, a condition which is challenging to identify consistently. Over one-quarter of the surveillance cohort reverted to non-dysplastic epithelium, showing the variable natural history, and the use of further markers of disease risk (as these become validated) should help guide management further. The second crucial undertaking was the quality of the endoscopic therapy and the option of rescue therapy for the one-quarter of patients who had incomplete ablation. No patient in either the control or treatment group developed distant disease during the course of follow-up and high-quality, three-monthly surveillance endoscopy detected all cancers prior to development of metastatic disease. In conclusion, the transferability of these results into general clinical practice is highly dependent on the quality of endoscopic diagnosis and follow-up, histopathological grading and ablative therapy. Further follow-up to determine the durability of the technique is needed. Competing interests None. Provenance and peer review Commissioned; internally peer reviewed.
Evid Based Med October 2014 | volume 19 | number 5 |
185
Radiofrequency ablation of Barrett’s oesophagus with confirmed low-grade dysplasia reduces risk of development of high-grade dysplasia and adenocarcinoma 10.1136/ebmed-2014-110019 Christine P J Caygill,1 Piers A C Gatenby1,2 1 UK National Barrett’s Oesophagus Registry, Royal Free Campus, University College London, London, UK; 2Regional Oesophagogastric Unit, Royal Surrey County Hospital, Guildford, UK
Correspondence to: Dr Christine PJ Caygill, UK National Barrett’s Oesophagus Registry, Royal Free Campus, University College London, London NW32PF, UK; [email protected]
Commentary on: Phoa KN, van Vilsteren FG, Weusten BL, et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomised clinical trial. JAMA 2014;311:1209–17.
Context The clinical management of patients with suspected low-grade dysplasia in Barrett’s oesophagus traditionally involves confirming the diagnosis by repeated systematic biopsy on strong acid suppression therapy and expert histopathological review of the sampled mucosa. Thereafter, patients are offered intensive surveillance with a shorter interval than in non-dysplastic Barrett’s oesophagus (due to the increase in risk of development of high-grade dysplasia and adenocarcinoma); however, some patients may also revert to non-dysplastic mucosa. Endoscopic ablative techniques eradicate the premalignant tissue, thereby obviating the need for potential resection or oncological therapy (and the morbidity, mortality and resource associated with these) with promising short-term outcomes. Long-term outcomes are as yet unknown.
Methods This is a randomised controlled trial of 136 patients with low-grade dysplasia within Barrett’s oesophagus, comparing endoscopic radiofrequency ablation to surveillance alone (randomised 1:1) at nine European centres. The intended follow-up was 3 years, with planned interim analyses at 50% and 75% follow-up time. The primary outcome measures were development of high-grade dysplasia or adenocarcinoma during the course of follow-up. Secondary outcome measures were: complete histological eradication of dysplasia, complete histological eradication of intestinal metaplasia and adverse events. The power calculation required a sample size of 120 patients (based on 14% control subjects and 1% of intervention subjects developing the primary end points). A 5% dropout rate was anticipated. Inclusion criteria included age 18–85 years, life expectancy of at least 2 years, diagnosis of low-grade dysplasia within 18 months, and an index qualifying endoscopy within 6 months of randomisation to exclude high-grade dysplasia, adenocarcinoma and any visible abnormalities within the segment. There was rigorous central pathological control. Ablation was undertaken every 3 months using the circumferential HALO360+ device (up to two sessions) and focal HALO90 device (up to three
sessions) with the option of subsequent endoscopic mucosal dissection or argon plasma coagulation to complete endoscopic and histological ablation of the Barrett’s segment. Surveillance endoscopies with four-quadrant biopsy every 2 cm were undertaken every three months from completion of treatment in the intervention arm and randomisation in the control arm.
Findings Five hundred and eleven patients were initially screened, and over half were excluded following pathological review. Seventy patients were randomised and 68 received the intended management in each group. The trial was terminated early due to the significant difference in outcome found at the second interim analysis (at which point all patients had completed at least 2 years of follow-up). Ablation was superior, with one patient (1.5%) developing adenocarcinoma compared to six surveillance patients. Twelve surveillance patients progressed to high-grade dysplasia compared to no progression in any ablation patient. The number needed to treat (NNT) to prevent one case of adenocarcinoma was 13.6 (95% CI 6.8 to 8), while the NNT to prevent one case of high-grade dysplasia or adenocarcinoma was 4 (95% CI 2.8 to 7.1). Complete eradication of dysplasia occurred in 63 of 68 patients (92.6%) in the ablation group, compared to 19 of 68 in the surveillance group (27.9%). Complete eradication of intestinal metaplasia occurred in 60 of 68 patients (88.2%) in the ablation group and none of the surveillance patients. Seventeen patients in the ablation group had endoscopic mucosal resection or argon plasma coagulation for residual columnar mucosa. No patient developed metastatic cancer or died from cancer. One was treated by oesophagectomy and all others had endoscopic therapy or continued surveillance for high-grade dysplasia. There were 15 adverse events (all in the treatment group) in 13 patients, including 3 severe (abdominal pain, bleeding and subsequent stricture development) and 8 which required dilation.
Commentary This paper shows a clear benefit from eradication of the Barrett’s oesophagus epithelium in patients who have demonstrated features of low-grade dysplasia. The treatment was intensive and required multiple outpatient sessions, but was generally well tolerated. Fewer patients suffered complications as a result of treatment than developed high-grade dysplasia or adenocarcinoma in the surveillance arm. The reduction in high-grade dysplasia and adenocarcinoma risk was seen throughout the follow-up period. The rigorous protocol for confirmation of low-grade dysplasia and expert pathology review panel has been fundamental in ascertaining which patients have true low-grade dysplasia, a condition which is challenging to identify consistently. Over one-quarter of the surveillance cohort reverted to non-dysplastic epithelium, showing the variable natural history, and the use of further markers of disease risk (as these become validated) should help guide management further. The second crucial undertaking was the quality of the endoscopic therapy and the option of rescue therapy for the one-quarter of patients who had incomplete ablation. No patient in either the control or treatment group developed distant disease during the course of follow-up and high-quality, three-monthly surveillance endoscopy detected all cancers prior to development of metastatic disease. In conclusion, the transferability of these results into general clinical practice is highly dependent on the quality of endoscopic diagnosis and follow-up, histopathological grading and ablative therapy. Further follow-up to determine the durability of the technique is needed. Competing interests None. Provenance and peer review Commissioned; internally peer reviewed.
Evid Based Med October 2014 | volume 19 | number 5 |
185
