Endoscopic therapy of dysplastic Barrett’s esophagus with RFA has demonstrated a high rate of CE-D and CE-IM, with an acceptable side effect profile.4, 7
The most important remaining issues in this field are the durability of the treatment effect and the longer term outcomes of therapy. Since durability of treatment effect is a determinant of the cost-effectiveness of the procedure,10
and because subjects with recurrent BE after RFA are presumably at continued risk for developing EAC, it is vital to know whether the neosquamous epithelium present after RFA is durable.
Our study demonstrates that the majority of subjects treated with RFA demonstrate CE-D and CE-IM at 2 and 3 year follow-up. In subjects who achieved CE-IM in this study and then subsequently demonstrated recurrent disease, the amount of recurrent disease always involved a minute proportion of the original BE surface area and the grade of recurrent disease was at or below study entry grade in most patients. Half of recurrences (7/14) occurred in subjects felt endoscopically to have either a normal or irregular Z line (without tongues >5 mm in length). Whether some or all of these recurrences might have been averted by mandating routine circumferential treatment of the Z line in the absence of endoscopic evidence of BE is unknown.
Five of the 119 subjects (4.2%) who received RFA therapy as part of this trial did demonstrate disease progression, representing an annual rate of progression of 1 case per 73 patient years (1.37%). While this annual rate is sizably lower than the 1-year progression rate in the SHAM group (1 case per 6 patient years, 16.3%), it points out the need for meticulous endoscopic monitoring of this high-risk population. Given the low number of progressors in this trial, the progression rates we report must be viewed as imprecise. Therefore, we are unable to comment on whether successful ablation (CE-IM after RFA) might allow a lengthening of the currently recommended surveillance intervals for dysplastic BE. However, if larger studies confirm the low rate of progression of treated subjects demonstrated here, our current endoscopic surveillance protocols may be unnecessarily aggressive for a successfully treated patient.
The present study reports the longest duration of follow-up of subjects undergoing RFA for dysplastic BE. Because subjects with dysplastic BE are at highest risk for progression to cancer, such data are essential to understand the value of ablative therapy in the setting of BE. Other strengths of our study include compulsive and complete accounting for all subjects, expert histological analysis of biopsy samples by a central laboratory, a priori protocols for endoscopic treatment, and standardized biopsy procedures with a large number of samples taken. Limitations include the potential for underestimation of residual or recurrent disease due to SSIM. Random biopsies may miss small areas of SSIM, or biopsies may not sample deeply enough to detect residual columnar tissue. Another potential effect of sampling error in this study is that some subjects designated as recurrent BE may have instead had incomplete initial eradication, with false negative histology documenting disease eradication. In such subjects, the apparent recurrent IM would rather truly be failure of the initial therapy. Also, we reported 2 year outcomes based on the 106 of 119 patients that were available for endoscopic biopsy, which could artificially elevate the rate of CE-D and CE-IM if subjects withdrawing consent were more likely to have failed therapy. Therefore, we have additionally reported the most conservative possible response rates considering these 13 patients lost to follow-up patients as failures in the 2 year outcomes, and response rates remained acceptable [101/119 (85%) CE-D and 99/119 (83%) CE-IM]. Also, we allowed subjects into the extension phase of the study only if CE-IM was attained at 2-year follow-up or if a single session of salvage therapy with RFA after a 2-year failure achieved CE-IM. While we felt it was not ethical to continue study participation in subjects who had not responded to therapy by that time, this decision has the effect of artificially elevating our 3 year response rates as calculated by simple proportions, since 2-year failures are no longer in the cohort. The Kaplan-Meier curve is, however, unaffected by this potential bias, since any subject that did not qualify for the study extension would have reached the censoring event for that analysis (and been considered a failure in the survival analysis). Another limitation is that the study sites for this trial are experienced in the care of subjects with dysplastic BE, following rigorous, a priori study protocols. Whether these results can be generalized to community practice settings is unknown. Lastly, because we allowed crossover from the sham arm to RFA, we no longer have a comparison group. While such a group would be beneficial, the ethical issues involved in retaining a sham arm long-term given the risk for disease progression were untenable.
These data add to a small, but growing, body of literature reporting the longterm outcomes and durability of the reversion to squamous epithelium induced after RFA therapy. Fleischer et al recently reported the five year results of their trial for subjects with non-dysplastic BE.11
After primary circumferential RFA followed by touch-up focal RFA, this study demonstrated CE-IM in 98% of evaluable patients at 2.5 year follow-up. In an extension of their trial that did not allow for interval touch-up therapy after 2.5 years, 92% of evaluable patients remained CE-IM at 5-year follow-up, suggesting that the reversion to neosquamous epithelium after RFA is durable in non-dysplastic BE. In the 4 subjects who demonstrated recurrent BE at 5 years, the magnitude of recurrence was minimal and a single additional RFA resulted in subsequent CE-IM.
Pouw et al. reported 44 patients with BE containing HGD and or early cancer using EMR as a diagnostic staging tool at baseline in most, followed by step-wise RFA. After a median of 21 months follow-up (IQR 10–27), CE-D and CE-IM were achieved in 43 of 44 patients (98%) with no cases of recurrence after CE.12
In a retrospective study, Ganz and colleagues reported on 92 subjects with BE and HGD undergoing RFA. At an average 12 months follow-up, CE-D and CE-IM were achieved in 80% and 54%, respectively. Most patients in this trial had a single circumferential ablation and no patient had focal ablation due to its lack of availability.13
Lyday et al reported their experience with 429 subjects undergoing RFA for BE in community practices. Of the 27 subjects in this group with dysplasia who were treated and followed for at least one year, all 27 were CE-D at a mean follow-up of 20 months, and 77% were CE-IM.4
In a multi-center prospective trial, Pouw et al. applied RFA for patients with BE containing HGD and/or early cancer. At 22 months median follow-up in 23 patients, CE-D and CE-IM were achieved at 95% and 88% of patients, respectively. A single salvage EMR in 2 patients elevated the responses rates to 100% CE-D and 96% CE-IM. Once CE-IM was achieved, no patients demonstrated recurrence.14
Sharma, et al. treated patients with LGD (n=10) with RFA.15
At 2-year follow-up, CR-D and CE-IM were 100% and 90%, respectively. In a larger trial, Sharma et al. evaluated RFA in 63 patients with dysplastic BE (39 LGD, 24 HGD). At a median follow-up of 2 years, CE-D and CE-IM were achieved in 95% and 87% of LGD patients and 79% and 67% of HGD patients, respectively. No patient demonstrated neoplastic progression, stricture, or buried glands.16
In a randomized controlled trial, Van Vilsteren, et al. compared RFA to EMR in patients with up to 5 cm of BE containing HGD and or early cancer. At 24 months follow-up, similar outcomes for CE were seen in each group: 100% CE-D and 92% CE-IM in the EMR group, and 96% CE-D and 96% CE-IM in the RFA group. The stenosis rate in the EMR group was significantly higher than that of the RFA group (88% vs. 14%, p<0.001), and there was one perforation in the EMR group.17
In general, the above studies are in concordance with the present data, reporting high rates of CE-D and CE-IM at 1 and 2 years. The remaining variability in outcomes data in these studies may in part reflect the diverse patient populations in the studies, and the way that treatment failure was defined, as well as the relatively recent availability of a focal ablation device for treating the small area of residual BE after primary therapy or in cases of recurrence. Predictors of response to therapy would allow better patient selection. While our study did not demonstrate significant predictors at the 2 year time-point, it was not powered to do so, and larger studies will be necessary to define these variables.
All of the subjects in the present study have been maintained on high-dose proton pump inhibitor therapy with esomeprazole at 40 mg twice daily for the duration of the trial. While this therapy is generally well-tolerated, the optimal medical regimen longterm for the subject after successful ablative therapy is not known. While multiple observational studies suggest that longterm maintenance therapy with high-dose proton pump inhibitor may expose the subject to some increased risk of hip fracture,18, 19
or enteric infection,22, 23
a substantial proportion of subjects with BE will not normalize esophageal acid exposures on once daily proton pump inhibitor therapy,24, 25
and the threat of recurrent neoplasia in this high-risk group may warrant the higher doses of acid suppression. Further investigation will be necessary to better understand optimal maintenance therapy of this population.
In conclusion, follow-up of the subjects from the AIM Dysplasia trial to an average of 3.05 years demonstrates that a high percentage of subjects with both low-grade and high-grade dysplasia retain complete eradication of dysplasia and intestinal metaplasia after treatment. Most subjects with recurrence of disease could again attain complete eradication of intestinal metaplasia with further treatment. Progression of disease was rare in subjects who underwent RFA treatment, and the rate of progression to EAC in this dysplastic cohort was 0.55%. There was no procedure- or cancer-related mortality. The main adverse side effect was stricture occurrence, which occurred in 7.6% of subjects and was correctable with dilation. Further systematic, prospective follow-up of this cohort will allow additional assessment of long term outcomes of ablative therapy in dysplastic BE.