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Background
Barrett's esophagus (BE), a complication of chronic esophagitis, is characterized by metaplasia in the epithelial lining the esophagus. The resulting cellular change is a pre-malignant phase that may lead to esophageal cancer. While the exact cause of BE is unclear, it may arise as a result of damage to the esophagus caused by chronic gastric reflux secondary to gastro-esophageal reflux disease (GERD). Thus, it is not surprising that BE is more commonly seen in patients with GERD. In addition to GERD, other risk factors for BE include age (50 years or older), ethnicity (Caucasian), and male sex. Diagnosis of BE is based on endoscopic biopsy of the esophagus. Short-segment (less than 2 to 3 cm) and long-segment (greater than 2 to 3 cm) BE are distinguished solely on the length of metaplastic epithelium above the esophago-gastric junction (Rajan et al, 2001). Emphasis is often placed on long-segment BE because these patients reportedly are at higher risk of developing adenocarcinoma than patients with short-segment BE. However, Schnell and colleagues (1992) reported that patients with short-segment BE exhibited the same incidence of esophageal cancer as their counterparts with long-segment BE. This provided a rationale for surveillance of patients with short-segment BE.
Barrett esophagus is a precancerous condition, and endoscopic biopsies to screen for high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) are recommended based on previously reported incidence rates of HGD and EAC of 0.5% and 0.9%, respectively. However, recent study findings suggest that incidence rates are lower than previously reported. To estimate the incidence of HGD or EAC in patients with BE in a population-based cohort,Hvid-Jensen, et al. (2011) analyzed data from pathology and cancer registries on 11,028 patients in Denmark who had been diagnosed with BE through endoscopic biopsy. During a median 5.2 years of follow-up, the incidence of EAC was 1.2 cases per 1000 person-years). The incidence rate of HGD or EAC combined was 2.6 cases per 1000 person-years, yielding a standardized incidence ratio of 21.1. Diagnosis of low-grade dysplasia at baseline or during follow-up increased the risk for HGD or EAC fivefold. The incidence rate of EAC among patients without low-grade dysplasia was 1.0 case per 1000 person-years (95% CI, 0.7 to 1.3) (0.1% per person-year), and the incidence rate among those with low-grade dysplasia was 5.1 cases per 1000 person-years (95% CI, 3.0 to 8.6) (0.51% per person-year). Although this study reaffirms that BE is a significant risk factor for development of EAC, the absolute risk of 0.12% is considerably lower than earlier estimates of 0.8% and, more recently, 0.5%, which have been used as a basis for current screening and surveillance recommendations. Another recent, large population-based study estimated incidence of EAC at 0.13% (Bhat, et al., 2011). On the basis of these estimates, the relative risk for EAC in patients with BE compared with the general population drops from a previously cited range of 30 to 40 to approximately 11. In an accompanying editorial, Kahrilis (2011) commented that these risk estimates have been progressively decreasing as issues of publication bias, duplicate counting, and inclusion of prevalent cancers have been taken into account.
The key to the management of BE is the level of dysplasia that endoscopic biopsies reveal. Most patients with BE will need to undergo future endoscopies to assure there is no progression of the condition. For BE patients with no signs of dysplasia on 2 consecutive endoscopic biopsies, the American College of Gastroenterology (ACG) recommended a follow-up endoscopy at 3 years. For patients with low-grade dysplasia (LGD) as the highest grade after a follow-up endoscopy with concentrated biopsies in the area of dysplasia, the ACG recommended annual endoscopy until there is no dysplasia. The finding of high-grade dysplasia (HGD), believed to be the stage that occurs before esophageal cancer, requires a repeat endoscopy or intervention, depending on the extent of the dysplasia. Focal HGD (less than 5 crypts) may be followed with 3-month surveillance (Sampliner, 2002).
The ACG guidelines also stated that the therapeutic objectives for BE are the same as those for GERD: (i) control of symptoms of GERD, and (ii) maintenance of healed mucosa. In general, patients with BE have greater esophageal acid exposure than other GERD patients, and control of symptoms may require higher than usual doses of proton pump inhibitors (PPIs). If once-daily dosing of a PPI fails to control symptoms, then twice-daily dosing should be tried. For patients who still have regurgitation despite control of esophageal acid exposure, as well as those with extra esophageal manifestations, anti-reflux surgery may be necessary. Fundoplication can effectively control reflux symptoms in most patients, but does not usually result in elimination of the pre-malignant epithelium (Sampliner, 2002).
The Society for Surgery of the Alimentary Tract (SSAT)’s guideline on the management of patients with BE (SSAT, 2002) stated that treatments include surveillance endoscopy and biopsy; medical therapy such as PPIs, H-2 receptor antagonists, and prokinetic agents; surgical anti-reflux procedure such as fundoplication (e.g., Nissen, Hill, Belsey, Dor, Toupet procedures); as well as photodynamic therapy (PDT); other energy sources; and excisional techniques. While the SSAT guideline (2002) considered PDT, other energy sources, and excisional techniques as investigational procedures, an article on BE that appeared on the ACG’s website considers PDT an accepted option for the treatment of BE (Azodo and Romero, 2006). It stated that if BE patients are diagnosed with HGD, there are 4 options:
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Do nothing/surveillance endoscopy and biopsy. (Note: HGD can regress to LGD or it may progress to esophageal cancer); or
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Increase dosage of acid suppression medications, and have another endoscopic examination in 3 months ;or
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Esophagectomy; or
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PDT.
In June 2003, the United States Food and Drug Administration (FDA) approved PDT with Photofrin for the treatment of HGD in patients with BE who do not undergo esophagectomy. The FDA approval is based on 2-year follow-up data from phase I and II clinical studies (Overholt, 2003). The data indicated that patients who received PDT with Photofrin had an 80 % chance of being cancer-free, while controls had a 50 % chance of being cancer-free. These researchers found that porfimer-PDT with supplemental Nd:YAG photo-ablation and continuous treatment with omeprazole reduced the length of Barrett's mucosa, and eliminated HGD.
Furthermore, PDT plus maintenance medical therapy has been reported to lower the incidence of esophageal cancer in BE patients. In a randomized, controlled, phase III clinical trial, Overholt and colleagues (2005) examined the impact of porfimer sodium (POR) and PDT on patients with BE and with HGD. A total of 485 patients were screened, with 208 in the intent-to-treat group and 202 in the safety population. Patients were randomized on a 2:1 basis to compare PDT with POR plus omeprazole (PORPDT) with omeprazole only (OM). The main outcome measure was complete HGD ablation occurring at any time during the study period. There was a significant difference (p < 0.0001) in favor of PORPDT (77 %; [106/138]) compared with OM (39 %; [27/70]) in complete ablation of HGD at any time during the study period. The occurrence of esophageal adenocarcinoma in the PORPDT group (13 %; n = 18) was markedly lower (p < 0.006) compared with the OM group (28 %; n = 20). The safety profile showed 94 % of patients in the PORPDT group and 13 % of patients in the OM group had treatment-related adverse effects. The authors concluded that PORPDT in conjunction with omeprazole is an effective therapy for ablating HGD in patients with BE and in reducing the incidence of esophageal adenocarcinoma. In addition, Foroulis and Thorpe (2006) reported that PDT is effective in ablating HGD/intra-mucosal adenocarcinoma complicating BE in the majority of cases, while it also seems to be quite effective in treating T1b/limited T2 adenocarcinomas.
An assessment of PDT for Barrett’s esophagus by the National Institute for Clinical Excellence (2004) found “Current evidence on the safety of photodynamic therapy for high-grade dysplasia in Barrett's oesophagus appears adequate to support the use of this procedure. Photodynamic therapy appears efficacious in downgrading dysplasia in Barrett's oesophagus, when used for the treatment of high-grade dysplasia (a premalignant lesion). However, its efficacy in preventing the progression of Barrett's oesophagus to invasive cancer is not clear.”
Available guidelines on the management of BE indicated that surgery may be necessary if pharmacotherapy has failed. Surgery may include fundoplication and esophagectomy. Conio and colleagues (2005) stated that esophagectomy remains the standard treatment for patients with HGD and superficial adenocarcinoma. However, since the morbidity and mortality rate for esophagectomy is high, and some patients are not surgical candidates, alternative treatments have gained popularity. In this regard, ablative techniques such as argon plasma coagulation (APC), cryotherapy, laser therapy, multi-polar electro-coagulation (MPEC), PDT, radiofrequency ablation, and ultrasonic therapy have been employed for this purpose. However, the effectiveness of many of these ablative interventions (except for PDT) has not been established especially the long-term control of cancer risk.
Several studies have demonstrated that endoscopic mucosal resection (EMR) is safe and effective for complete resection of superficial lesions, and offers the advantage of histopathological verification. However, larger lesions are less suitable for EMR since they often require piecemeal resection, making it impossible to be conclusive about the completeness of the resection at the lateral margins. Two devices for EMR had been cleared by the FDA through the 510(k) process for endoscopic mucosal resection in the upper gastrointestinal tract: (i) the Olympus Distal Attachment/EMR Kit, and (ii) the Cook Ireland Duette multi-band mucosectomy device.
Endoscopic treatments offer an effective alternative to esophagectomy for patients with BE and HGD. Menon, et al. (2010) conducted a comprehensive literature search to identify studies of endoscopic treatments for BE or EAC. Ninety-nine papers on 101 studies (n=3,042 participants) were included in the review. There were 12 comparative studies (seven were randomized controlled trials, five were cohort studies with uncontrolled allocation to treatment groups). The authors reported that the quality of the included studies was low, with methods and outcomes inconsistently reported across the trials. Rates of complete eradication of BE at three months post treatment were: argon plasma coagulation 85.5% (n=435, range zero to 100%), cryoablation 81.8% (n=11), thermocoagulation 100% (n=13), endoscopic mucosal resection 100% (n=1), laser ablation 77.3% (n=75, range 22.2% to 100%), multipolar electro-coagulation 88.5% (n=26) and radiofrequency ablation 69% (n=171, range 21.9% to 97.7%). Rates of complete eradication across seven techniques of photodynamic therapy varied from zero to 56.4%. Complete eradication rates of HGD at three months post-treatment were: argon plasma coagulation 85.7% (n=7), cryoablation 100% (n=1), endoscopic mucosal resection 96.3% (n=27, range 92.9% to 100%), radiofrequency ablation 90.3% (n=103, range 90.2% to 90.9%) and combined photodynamic therapy and endoscopic mucosal resection 66.7% (n=3). Rates of complete eradication across seven techniques of photodynamic therapy varied from zero to 100%. The investigators stated that further research was required to identify the endoscopic treatments that provided the best outcomes for patients with BE in relation to long-term safety, esophageal cancer prevention, continuation of drug therapy, optimal frequency of post-treatment endoscopic surveillance and quality of life after different endoscopic treatments.
Stein and Feith (2005) stated that endoscopic ablation are associated with high tumor recurrence rates and persistence of pre-malignant BE. Also, Shaheen (2005) stated that ablative therapies hold promise for individuals with superficial cancer or HGD. Most series using these modalities featured relatively short follow-up, and longer-term outcomes will be necessary to better describe the effects of these therapies.
Spechler (2005) noted that endoscopic ablative therapies may not be effective if neoplastic cells have invaded the submucosa or disseminated through mucosal lymphatic channels, and a number of studies suggested that the endoscopic therapies usually leave metaplastic or neoplastic epithelium with malignant potential behind. Limited data suggested that intensive endoscopic surveillance might be a reasonable approach for elderly or infirm patients, but some patients managed in this fashion have developed incurable esophageal cancers.
An assessment of argon plasma coagulation by the Institute for Clinical Effectiveness and Health Policy (IECS) found that, with the respect to BE, studies have not demonstrated complete disappearance of dysplastic lesions. Cases of microscopic persistence has been found, and the impact that this treatment may have in the development of malignant lesions in the long-term is unknown (Pichon Riviere et al, 2005). In a prospective, randomized, un-blinded, controlled trial (n = 40), Ackroyd et al (2004) evaluated the safety and effectiveness of APC in the ablation of BE in patients who have undergone anti-reflux surgery. Patients in the control group received endoscopic surveillance. Treatment was repeated until either no Barrett's epithelium remained or a maximum of 6 treatment sessions. One month after the final treatment, complete ablation was achieved in 12 patients. In the remaining 8 patients, a reduction of over 95 % was observed. One patient died of an unrelated cause at 9 months. At one year, 1 patient with residual Barrett's epithelium regressed completely, while relapse of BE was observed in another patient because of fundoplication failure. Buried glands were observed in 35 % patients at 1 month, but only 5 % at 1 year. Dysplasia was never observed. In the surveillance group, partial regression was observed in 11 patients, and in 3 patients with short-segment BE, regression was complete. The length of BE increased in 2 patients. While 2 patients had LGD initially, this was not evident at 1 year. Overall, complete ablation was achieved in 63 % (12/19) patients in the ablation group, and 15 % (3/20) in the surveillance group (p < 0.01). These researchers concluded that APC of BE is safe and effective. The effects are durable, and buried glands may resolve with time. Moreover, the authors stated that long-term follow-up studies are needed to evaluate the impact of APC on cancer risk. A randomized trial comparing APC with PDT found that both were equally effective in eradicating Barrett’s mucosa. However, APC was less effective than PDT in eradicating dysplasia within the Barrett’s segment (Ragunath et al, 2005).
In December 2007, the CryoSpray Ablation system (CSA Medical, Inc.) received FDA 510(k) marketing clearance as a cryosurgical tool for destruction of unwanted tissue during general surgery, specifically for endoscopic applications. The cryo-catheter applies liquid nitrogen thereby destroying unwanted tissue by the application of extreme cold to a selected site. However, the clinical effectiveness of cryotherapy in the management of patients with BE has not been established.
In a review on argon plasma coagulation, bipolar cautery, and cryotherapy for the treatment of BE, Dumot and Greenwald (2008) stated that endoscopic cryotherapy ablation is a relatively new technique with studies focusing on HGD and early-stage cancer in high-risk patients. It has an acceptable safety profile, and early results showed response in a significant number of patients in whom other modalities have failed. The authors noted that future developments with cryospray ablation technology may improve outcomes especially with uneven surfaces, with dosing capable of reaching the submucosa. Moreover, in the updated guidelines for the diagnosis, surveillance and therapy of BE by the Practice Parameters Committee of the American College of Gastroenterology, Wang and Sampliner (2008) stated that endoscopic cryotherapy has also been reported to eliminate BE, although there is very limited data about its efficacy; and cryotherapy is beginning clinical trials.
In a prospective, single-center, pilot study (n = 11), Johnston and associates (2005) assessed the safety and the effectiveness of cryotherapy on patients with a long-standing history of BE; with degrees of dysplasia ranging from none to multi-focal HGD. Subjects were also treated with 40 mg rabeprazole thrice-daily during the treatment period. Elimination of acid reflux was confirmed via 24-hour esophageal pH studies. Cryoablation was applied hemi-circumferentially to 4-cm long segments at monthly intervals, until the entire segment of BE was eliminated. There was reversal of BE in all patients. In 78 % (9/11) patients who completed the protocol, there was complete endoscopic and histologic reversal of BE. There was no subsquamous specialized intestinal metaplasia at the 6-month follow-up, and no complications occurred. The authors concluded that based on preliminary results, low-pressure spray cryoablation of BE under direct endoscopic visualization is safe and easy to perform. Its relative lack of patient discomfort and its simplicity and demonstrated effectiveness make it a modality that should be further explored in the ablation of gastrointestinal mucosal lesions such as BE and perhaps early esophageal cancer. It is interesting to note that Johnston (2005) stated that it has yet to be determined if the risks associated with ablative interventions are less than the risk of BE progressing to cancer. The author also stated that it remains to be seen if endoscopic ablative therapy can eliminate or significantly reduce the risk of cancer, eliminate the need for surveillance endoscopy, or is cost-effective.
In an open-label study, Dumot et al (2009) evaluated the safety and effectiveness of a unique non-contact method of liquid nitrogen cryoablation as measured by histological response rate and cancer-free survival. Patients with BE and HGD or intra-mucosal carcinoma (IMCA) who were deemed inoperable or who refused esophagectomy are included in this study. Age, length of BE, and previous ablation were not exclusion criteria. Cryoablation was administered every 6 weeks until endoscopic resolution. Endoscopic mucosal resection was used for pathologic staging of nodular areas before cryoablation and focal residual areas during the follow-up period. Histological response was defined by the worst pathology obtained at any level of the esophagus or gastric cardia in 1 of 3 categories: (i) incremental = absence of HGD and IMCA in all biopsy specimens, (ii) partial = residual IMCA with absence of any dysplasia, and (iii) complete = absence of any intestinal metaplasia or dysplasia. A total of 30 patients underwent ablation; 9 had undergone previous ablation or mucosectomy. Twenty-seven of 30 patients (90 %) had down-grading of pathology stage after treatment. Elimination of cancer or down-grading of HGD at last follow-up was 68 % for HGD and 80.0 % for IMCA, with a median follow-up period of 12 months (25th percentile, 6; 75th percentile, 24). Minor adverse events included mild pain (n = 7), a low incidence of mild strictures (n = 3), and lip ulcer (n = 1). One major adverse event (perforation) in a patient with Marfan syndrome occurred with the prototype system. During follow-up, 3 of 6 patients with complete response had recurrence of dysplasia or cancer in the gastric cardia. The authors concluded that patients with BE and HGD or IMCA have a positive response to endoscopic cryotherapy at 1-year follow-up. The drawbacks of this study were that it was a small, non-randomized, single-center study with a heterogeneous cohort of patients with a relatively short follow-up (1 year). The authors stated that further study with long-term follow-up is needed and is currently under way.
Greenwald et al (2010) examined the safety, tolerability, and effectiveness of liquid nitrogen endoscopic spray cryotherapy ablation in a large cohort across multiple study sites. Parallel prospective treatment studies at 4 tertiary care academic medical centers in the U.S. assessed spray cryotherapy in patients with BE with or without dysplasia, early stage esophageal cancer, and severe squamous dysplasia who underwent cryotherapy ablation of the esophagus. All patients were contacted between 1 and 10 days after treatment to assess for side effects and complications of treatment. The main outcome measurement was the incidence of serious adverse events and side effects from treatment. Complete response for HGD (CR-HGD), all dysplasia (CR-D), intestinal metaplasia (CR-IM) and cancer (CR-C) were assessed in patients completing therapy during the study period. A total of 77 patients were treated for Barrett's HGD (58.4 %), IMCA (16.9 %), invasive carcinoma (13 %), BE without dysplasia (9.1 %), and severe squamous dysplasia (2.6 %). Twenty-two patients (28.6 %) reported no side effects throughout treatment. In 323 procedures, the most common complaint was chest pain (17.6 %) followed by dysphagia (13.3 %), odynophagia (12.1 %), and sore throat (9.6 %). The mean duration of any symptoms was 3.6 days. No side effects were reported in 48 % of the procedures (155/323). Symptoms did not correlate with age, gender, diagnosis, or to treatment early versus late in the patient's or site's experience. Logit analysis showed that symptoms were greater in those with a Barrett's segment of 6 cm or longer. Gastric perforation occurred in 1 patient with Marfan's syndrome. Esophageal stricture developed in 3, all successfully treated with dilation. In 17 HGD patients, cryotherapy produced CR-HGD, CR-D, and CR-IM of 94 %, 88 %, and 53 %, respectively. Complete regression of cancer and HGD was seen in all 7 patients with IMCA or stage I esophageal cancer. The authors concluded that endoscopic spray cryotherapy ablation using liquid nitrogen in the esophagus is safe, well-tolerated, and effective. The drawbacks of this study include (i) lack of a standardized scale to characterize post-treatment symptoms and the use of different time points to contact patients at different study sites, (ii) effectiveness data were available for only a subset of patients who completed treatment and had at least one follow-up endoscopy with biopsy during the study period, and (iii) lack of long-term follow-up data. The authors noted that studies are ongoing to further determine the safety, tolerability and effectiveness of endoscopic spray cryotherapy ablation.
In a review on endoscopic ablation of metaplasia and dysplasia in patients with BE, Wolfsen (2005) stated that the FDA’s approval for the use of porfimer sodium PDT was an important milestone, as this treatment has been proven to safely ablate Barrett's glandular epithelium including HGD, and significantly decrease the risk for the development of invasive cancer. The author noted that newer methods of mucosal ablation, such as the radiofrequency balloon, have been developed for the treatment of patients with BE. These newly developed techniques are able to treat large fields of glandular epithelium in a short treatment procedure. It will be extremely important to document the safety, durability, and effectiveness of these devices in preventing the development of esophageal carcinoma. Ultimately, the impact of successful Barrett's ablation on the incidence of Barrett's carcinoma, and the need for post-ablation surveillance endoscopy must be determined.
The British Society of Gastroenterology’s guidelines for the diagnosis and management of BE (Watson et al, 2005) stated that endoscopic ablation remains experimental, and should be carried out only in the context of prospective, randomized trials.
Dunkin and associates (2006) ascertained the optimal treatment parameters for the ablation of human esophageal epithelium using a balloon-based bipolar radiofrequency (RF) energy electrode. Immediately prior to esophagectomy, participants underwent esophagoscopy and ablation of 2 separate, 3-cm long, circumferential segments of non-tumor-bearing esophageal epithelium using a balloon-based bipolar RF energy electrode. Subjects were randomized to one of three energy density groups: 8, 10, or 12 J/cm2. Radiofrequency energy was applied one time (1x) proximally and two times (2x) distally. Following resection, sections from each ablation zone were evaluated using hematoxylin-eosin and diaphorase. Histological endpoints were complete epithelial ablation (yes/no), maximum ablation depth, and residual ablation thickness after tissue slough. Outcomes were compared according to energy density group and 1x versus 2x treatment. A total of 13 male subjects (aged 49 to 85 years) with esophageal adenocarcinoma underwent the ablation procedure followed by total esophagectomy. Complete epithelial removal occurred in the following zones: 10 J/cm2 (2x) and 12 J/cm2 (1x and 2x). The maximum depth of injury was the muscularis mucosae: 10 and 12 J/cm2 (both 2x). A second treatment (2x) did not significantly increase the depth of injury. Maximum thickness of residual ablation after tissue slough was only 35 micron. The authors concluded that complete removal of the esophageal epithelium without injury to the submucosa or muscularis propria is possible using this balloon-based RF electrode at 10 J/cm2 (2x) or 12 J/cm2 (1x or 2x). A second application (2x) does not significantly increase ablation depth. These data have been used to select the appropriate settings for treating intestinal metaplasia in trials currently under way.
Hubbard and Velanovich (2007) presented their early experience of the effects of endoluminal ablation using radiofrequency on the reflux symptoms and completeness of ablation in post-fundoplication patients. A total of 7 patients who have had either a laparoscopic or open Nissen fundoplication and BE underwent endoscopic endoluminal ablation of the Barrett's metaplasia using the Barrx device (RF ablation). Pre-procedure, none of the patients had significant symptoms related to GERD. One to 2 weeks after the ablation, patients were questioned as to the presence of symptoms. Pre-procedure and post-procedure, they completed the GERD-HRQL symptom severity questionnaire (best possible score = 0; worst possible score = 50). Patients had follow-up endoscopy to assess completeness of ablation 3 months after the original treatment. All patients completed the ablation without complications. No patients reported recurrence of their GERD symptoms. The median pre-procedure total GERD-HRQL score was 2, compared to a median post-procedure score of 1. One patient had residual Barrett's metaplasia at 3 months follow-up, requiring re-ablation. The authors concluded that this preliminary report of a small number of patients demonstrated that endoscopic endoluminal RF ablation of Barrett's metaplasia using the Barrx device is safe and effective in patients who have already undergone anti-reflux surgery. There appears to be no disruption in the fundoplication or recurrence of GERD-related symptoms. Nevertheless, longer-term follow-up with more patients is needed.
In a study published in the New England Journal of Medicine, Shaheen et al (2009) evaluated if endoscopic RF ablation could eradicate dysplastic BE and reduce the rate of neoplastic progression. A total of 127 patients with dysplastic BE were randomly assigned in a 2:1 ratio to receive either RF ablation (ablation group) or a sham procedure (control group). Randomization was stratified according to the grade of dysplasia and the length of BE. Primary outcomes at 12 months included the complete eradication of dysplasia and intestinal metaplasia. In the intention-to-treat analyses, among patients with LGD, complete eradication of dysplasia occurred in 90.5 % of those in the ablation group, as compared with 22.7 % of those in the control group (p < 0.001). Among patients with HGD, complete eradication occurred in 81.0 % of those in the ablation group, as compared with 19.0 % of those in the control group (p < 0.001). Overall, 77.4 % of patients in the ablation group had complete eradication of intestinal metaplasia, as compared with 2.3 % of those in the control group (p < 0.001). Patients in the ablation group had less disease progression (3.6 % versus 16.3 %, p = 0.03) and fewer cancers (1.2 % versus 9.3 %, p = 0.045). Patients reported having more chest pain after the ablation procedure than after the sham procedure. In the ablation group, 1 patient had upper gastrointestinal hemorrhage, and 5 patients (6.0 %) had esophageal stricture. The authors concluded that in patients with dysplastic BE, RF ablation was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression.
Few studies have focused exclusively on the efficacy of radiofrequency ablation for patients with low-grade dysplasia; rather, such patients commonly have been included as a subgroup in eradication trials that have involved primarily patients without dysplasia or patients with high-grade dysplasia, a feature that can confound the interpretation of study results. The recent report of the AIM Dysplasia Trial (Shaheen, et al., 2011) included only 32 subjects with low grade dysplasia achieving mid-term (three year) followup.
In an editorial that accompanied the afore-mentioned study, Bergman (2009) stated that "[p]ersonally, I think it is still too early to promote radiofrequency ablation for patients with nondysplastic Barrett's esophagus. Is complete response after ablation maintained over time, thus reducing the risk of progression to high-grade dysplasia or cancer? Will ablation improve patients' quality of life and decrease costs, as compared with the surveillance strategy? More important, can we define a stratification index predicting disease progression or response to therapy? We run the risk of losing the momentum to enroll patients in a trial that is required at this stage: a randomized comparison of endoscopic surveillance and radiofrequency ablation for nondysplastic Barrett's esophagus. Such a study might truly revolutionize the management of this condition and answer the question as to whether radiofrequency ablation is great just for some or justified for many".
In an editorial commenting on the study by Shaheen et al (2009), Johnson (2009) stated that these data are consistent with recent study findings demonstrating the effectiveness of photodynamic ablative therapy for patients with HGD and mucosal adenocarcinoma. The editorialist noted, however, that less-radical strategies, such as ablation and endoscopic mucosal resection only of visible lesions, seem to offer patients excellent efficacy with negligible morbidity or mortality. The editorialist stated that the finding by Shaheen et al of decreased incidence of cancer in the radiofrequency ablation group should be viewed with caution, noting that malignancies were so rare in this cohort that a single incident cancer would have resulted in a loss of statistical significance.
Johnson (2009) stated that, although a growing amount of data seems to support the use of endoscopic ablative therapy in BE with HGD, advocating the same therapy for LGD is premature. Johnson explained that the implications of these 2 diagnoses are markedly different, and more data on the natural history and appropriate management of LGD are needed. Furthermore, whether the results achieved by expert academic investigators in Shaheen et al can be extrapolated to procedures performed by less-experienced endoscopists in a community-practice setting remains to be seen.
Wani et al (2009) determined the cancer incidence in BE patients after ablative therapy and compared these rates to cohort studies of BE patients not undergoing ablation. A MEDLINE search of the literature on the natural history and ablative modalities in BE patients was performed. Patients with non-dysplastic BE (ND-BE), LGD, or HGD and follow-up of at least 6 months were included. The rate of cancer in patients undergoing ablation and from the natural history data was calculated using weighted-average incidence rates (WIR). A total of 53 articles met the inclusion criteria for the natural history data. Pooled natural history data showed cancer incidence of 5.98/1,000 patient-years (95 % CI: 5.05 to 6.91) in ND-BE; 16.98/1,000 patient-years (95 % CI: 13.1 to 20.85) in LGD; and 65.8/1,000 patient-years (95 % CI: 49.7 to 81.8) in HGD patients. A total of 65 articles met the inclusion criteria for BE patients undergoing ablation (1,457 patients, ND-BE; 239 patients, LGD; and 611 patients, HGD). The WIR for cancer was 1.63/1,000 patient-years (95 % CI: 0.07 to 3.34) for ND-BE; 1.58/1,000 patient-years (95 % CI: 0.66 to 3.84) for LGD; and 16.76/1,000 patient-years (95 % CI: 10.6 to 22.9) for HGD patients. The authors concluded that compared to historical reports of the natural history of BE, ablation may be associated with a reduction in cancer incidence, although such a comparison is limited by likely heterogeneity between treatment and natural history studies. The greatest benefit of ablation was observed in BE patients with HGD. The authors also stated that ablation of ND-BE awaits evidence demonstrating that the costs and risks associated with the procedure are out-weighed by the benefits before widespread use of this is adopted in clinical practice. Similarly, spontaneous regression of LGD has been demonstrated in the majority of BE patients, and the vast majority of subjects with ND and LGD will not benefit from ablation therapy.
An updated draft of the California Technology Assessment Forum's report on RFA as a treatment of dysplastic BE (CTAF, 2011) states that RFA for the treatment of BE does not meet CTAF criteria 4 to 5 for the treatment of individuals with LGD. The CTAF technology assessment also summarizes the American Gastroenterological Association (AGA)'s position on the management of BE. The CTAF assessment noted that the AGA does not make a formal recommendation (which would include the strength of the evidence and the quality of the evidence) regarding the endoscopic treatment of LGD. In their review of the literature on treatment of LGD (primarily focusing on the Shaheen study), they stated that "ablative therapies can eradicate low grade dysplasia in the short-term for the majority of patients, but the reports do not establish the benefit of that eradication .... In the absence of long-term studies showing efficacy, it is not clear that the potential benefit of ablation in reducing cancer risk for patients who have Barrett’s esophagus with low-grade dysplasia warrants the risks and substantial expense of the ablative procedures".
In the position statement, the AGA suggests that endoscopic eradication therapy could be a therapeutic option for patients with confirmed LGD in BE, acknowledging that there are controversies about the management of dysplasia in this population and that the risk of progression to cancer can vary. The AGA supports "shared decision making" with respect to whether or not endoscopic eradication or surveillance is preferred for each individual.
Shaheen and Frantz (2010) evaluated timing and patient selection for endoscopic ablative therapy in BE. Most recent data described radiofrequency ablation (RFA), but other data pertain to PDT and other modalities. Most studies are cohort or case series. Reversion to squamous epithelium is the most common primary outcome. Cancer incidence data are scarce. Radiofrequency ablation appears well-tolerated. The main side-effect is chest pain, which can be managed with oral analgesics. Stricture occurs in 0 to 8 % and is amenable to endoscopic dilatation. Infrequent side-effects include bleeding and perforation. Complete reversion to squamous epithelium occurs in more than 90 % of non-dysplastic and LGD and more than 80 % in HGD patients, and the treatment appears durable for at least 2 to 5 years of available follow-up. Treatment of low-grade or non-dysplastic disease may be cost-effective. Data on PDT suggest that all-cause mortality is similar to surgery for dysplastic BE. The stricture rate appears higher, and rates of complete reversion to neosquamous epithelium are lower than that of RFA, although definitive comparisons are lacking. The authors concluded that the excellent efectiveness, side-effect profile, and cost-effectiveness appear to make RFA the intervention of choice in cases of HGD. Radiofrequency ablation for LGD may be of value in young patients and/or those with long segment or multi-focal disease. Treatment of non-dysplastic BE is of uncertain value. Photodynamic therapy appears to have a higher stricture rate and to be more expensive than RFA.
Shaheen et al (2010) evaluated the influence of dysplastic BE on quality of life (QoL) and examined if endoscopic treatment of dysplastic BE with RFA improves QoL. These researchers analyzed changes in QoL in the AIM Dysplasia Trial, a multi-center study of patients with dysplastic BE who were randomly allocated to RFA therapy or a sham intervention. They developed a 10-item questionnaire to assess the influence of dysplastic BE on QoL. The questionnaire was completed by patients at baseline and 12 months. A total of 127 patients were randomized to RFA (n = 84) or sham (n = 43). At baseline, most patients reported worry about esophageal cancer (71 % RFA, 85 % sham) and esophagectomy (61 % RFA, 68 % sham). Patients also reported depression, impaired QoL, worry, stress, and dissatisfaction with the condition of their esophagus. Of those randomized, 117 patients completed the study to the 12-month end point. Compared with the sham group, patients treated with RFA had significantly less worry about esophageal cancer (p = 0.003) and esophagectomy (p = 0.009). They also had significantly reduced depression (p = 0.02), general worry about the condition of their esophagus (p ≤0.001), impact on daily QoL (p = 0.009), stress (p = 0.03), dissatisfaction with the condition of their esophagus (p ≤0.001), and impact on work and family life (p = 0.02). The authors concluded that inclusion in the treatment group of this randomized, sham-controlled trial of RFA was associated with improvement in disease-specific health-related quality of life. This improvement appears secondary to a perceived decrease in the risk of cancer. The major drawback pf this study was that while the methodology employed to develop this tool provides high content validity, the test-retest reliability of the tool and its convergent validity have not been established. Furthermore, a reference time-frame was not created in the questionnaire and it may need adjustment based on the intervention considered. Further work is needed to define the operating characteristics of this tool.
dos Santos et al (2010) reported their initial experience with RFA in association with anti-reflux procedure for Barrett's metaplasia and LGD. A total of 14 patients (10 male and 4 female patients) presented with Barrett's metaplasia (n = 11) or LGD (n = 3) were included in the study. Median age was 60 years (38 to 80 years). The severity of BE was classified by length (in cms), appearance (circumferential/non-circumferential), and histology (1, normal; 2, Barrett's metaplasia; and 3, LGD). Radiofrequency ablation was performed with the HALO 360 degrees or 90 degrees systems. Median follow-up was 17 months. The mean number of ablative procedures undertaken was 2.6 (range of 1 to 6). There was no mortality, but there were 2 peri-operative complications after the anti-reflux procedure (pneumonia, n = 1; atrial fibrillation, n = 1). One patient had mild dysphagia requiring a single dilation 2 months after ablation. The mean length of BE decreased from 6.2 to 1.2 cm after treatment (p = 0.001). Barrett's grade decreased significantly (p = 0.003). Before therapy, circumferential BE was present in 13 patients. At last endoscopy, only 1 patient had circumferential BE present. The number of RFA treatments was significantly (p < 0.05) associated with success. All patients receiving 3 or more treatments had complete resolution of Barrett's metaplasia. The authors concluded that RFA performed either before or after an anti-reflux procedure is safe. This approach is effective for reducing or eliminating metaplasia and dysplasia. They stated that long-term studies will be necessary to determine whether this approach can provide durable control of both reflux and BE.
Fleischer et al (2010) noted that the AIM-II Trial included patients with non-dysplastic BE (NDBE) treated with RFA. Complete eradication of NDBE (complete response-intestinal metaplasia [CR-IM]) was achieved in 98.4 % of patients at 2.5 years. These researchers reported the proportion of patients demonstrating CR-IM at 5-year follow-up. After endoscopic RFA of NDBE up to 6 cm, patients with CR-IM at 2.5 years were eligible for longer-term follow-up. At 5 years, these investigators obtained 4-quadrant biopsies from every 1 cm of the original extent of BE. All specimens were reviewed by 1 expert gastrointestinal pathologist, followed by focal RFA and repeat biopsy if NDBE was identified. Primary outcomes were (i) proportion of patients demonstrating CR-IM at 5-year biopsy, and (ii) proportion of patients demonstrating CR-IM at 5-year biopsy or after the single-session focal RFA. Of 60 eligible patients, 50 consented to participate. Of 1,473 esophageal specimens obtained at 5 years, 85 % contained lamina propria or deeper tissue (per patient, mean of 30 , standard deviation [SD] of 13). CR-IM was demonstrated in 92 % (46/50) of patients, while 8 % (4/50) had focal NDBE; focal RFA converted all these to CR-IM. There were no buried glands, dysplasia, strictures, or serious adverse events. Kaplan-Meier CR-IM survival analysis showed probability of maintaining CR-IM for at least 4 years after first durable CR-IM was 0.91 (95 % confidence interval [CI]: 0.77 to 0.97) and mean duration of CR-IM was 4.22 years (standard error [SE]: 0.12). The authors concluded that in patients with NDBE treated with RFA, CR-IM was demonstrated in the majority of patients (92 %) at 5-year follow-up, biopsy depth was adequate to detect recurrence, and all failures (4/4, 100 %) were converted to CR-IM with single-session focal RFA.
There are several drawbacks with the findings of the afore-mentioned study, which included (i) a lack of concurrent control arm, (ii) a lack of histological confirmation of intestinal metaplasia prior to any focal ablation after the 1-year follow-up, (iii) a lack of standardized post 2.5-year anti-secretory medication regimen. Up to 2.5 years, all patients were provided with oral esomeprazole 40 mg per day (with escalation to twice per day for 1 month post-RFA). The inability to assess adequacy of acid suppression and compliance with medication during the post 2.5-year period, however, limits the ability to draw conclusions about the role of these factors in disease recurrence or persistent cure, (iv) there is an inherent lack of precision in identifying the precise location of the distal terminus of the esophagus and in accurately distinguishing this from the proximal extent of the stomach. This may be important regarding accurate assessment of the presence or absence of intestinal metaplasia in the esophagus after ablative therapy, and (v) the interval of 2 months from salvage RFA to subsequent biopsy to assess CR-IM after salvage was short. It is possible that after salvage RFA occult intestinal metaplasia was present that would have been detected after additional time or with further biopsy sessions.
In an editorial on RFA of BE, Falk (2010) stated that "[t]he technique of RFA represents a major advance in the treatment of Barrett’s esophagus with high-grade dysplasia. With further clinical outcomes, data RFA will likely have an important role in selected individuals with well-documented low-grade dysplasia in the following settings: (i) meticulous biopsies performed on high-dose therapy with a proton pump inhibitor; (ii) confirmation by one or more expert gastrointestinal pathologists; and (iii) multifocal lowgrade dysplasia .... I urge the gastroenterology community to avoid the temptation of performing RFA of nondysplastic Barrett’s epithelium -- a management strategy not supported by rigorous clinical studies".
Shaheen, et al. (2011) assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE. The investigators performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included, 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events. The investigators reported that, after 2 years, 101 of 106 patients had complete eradication of all dysplasia (95%) and 99 of 106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51 of 52 (98%) and intestinal metaplasia was eradicated in 51 of 52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50 of 54 (93%) and intestinal metaplasia was eradicated in 48 of 54 (89%). After 3 years, dysplasia was eradicated in 55 of 56 of subjects (98%) and intestinal metaplasia was eradicated in 51 of 56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in greater than 85% of patients and intestinal metaplasia in greater than 75%, without maintenance RFA. Serious adverse events occurred in 4 of 119 subjects (3.4%); the rate of stricture was 7.6%. Five of 119 subjects (4.2%) who received any RFA as part of this trial have experienced disease progression. In an overall observation period of 363 years, this corresponds to an annual rate of overall disease progression of 1/73 patient-years, or 1.37% per patient per year, and an annual rate of progression to EAC of 1/181 patient-years, or 0.55% per patient per year. Stratified by baseline histology at study entry, for subjects enrolled with LGD, the annual rate of overall disease progression was 1/49 patient-years, or 2.04% per patient per year, and the annual rate of progression to EAC was 1/197 patient-years, or 0.51% per patient per year. Among subjects enrolled with HGD, the annual rate of overall disease progression was 1/166 patient-years, or 0.60% per patient per year, and the annual rate of progression to EAC was 1/166 patient-years, or 0.60% per patient per year.
The Blue Cross and Blue Shield Association Technology Evaluation Center (2010) concluded that RFA of non-dysplastic and low-grade dysplastic BE does not meet the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria. The assessment found that the available evidence is insufficient to show that radiofrequency ablation plus surveillance achieves a better net health outcome than surveillance alone among patients with non-dysplastic or low-grade dysplastic Barrett’s esophagus.
Guidelines on ablative therapies for BE from the National Institute for Health and Clinical Excellence (2010) recommend the use of RFA only for persons with flat HGD, taking into account the evidence of their long-term efficacy, cost and complication rates. NICE interventional procedure guidance (2010) concluded that, although there was adequate evidence for radiofrequency ablation for high-grade dysplasia, the evidence for low-grade and non-dysplastic Barrett's was inadequate in quantity and quality, and the balance of risks and benefits are not clear. The guidance stated: "NICE encourages further research into epithelial RFA for Barrett’s oesophagus. This should address the balance of risks and benefits of the procedure in patients with Barrett’s oesophagus and either LGD or no dysplasia, and long-term outcomes in patients with Barrett’s oesophagus of any histological type."
The Austrialian Medical Services Advisory Committee (MSAC, 2011) did not support coverage of radiofrequency ablation (RFA) for the treatment of Barrett's esophagus with low grade dysplasia, on the basis of its high cost and uncertainty of clinical benefit due to uncertainty of progression rate from Barrett’s esophagus with low grade dysplasia (LGD) to esophageal cancer. MSAC did support coverage of RFA for Barrett's esophagus with high-grade dysplasia (HGD), based on a better safety profile and lower cost than esophagectomy, but noting a lack of evidence of comparative clinical effectiveness. MSAC advised that the diagnosis of HGD should be confirmed by two expert pathologists with experience in upper gastrointestinal pathology, that treatment options for patients with HGD should be reviewed by an appropriate multidisciplinary team, and that RFA should be performed (where indicated) by an appropriately qualified specialist gastroenterologist or surgeon who has received specific training in the procedure.
Bennett, et al. (2012) performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. The authors used a Delphi process to develop consensus statements. The authors stated that, despite generally low quality of evidence, they were able to achieve consensus around several clinical statements, including: patients that receive ablative or surgical therapy require endoscopic follow-up; endoscopic therapy for HGD is preferred to surveillance; endoscopic therapy for HGD is preferred to surgery; the combination of endoscopic resection and radiofrequency ablation is the most effective therapy; and after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. The authors stated that they focused on statements concerning HGD and EA as evidence relating to LGD is particularly weak. The authors explained that they "focused on patient populations with high-risk disease rather than including those statements about LGD, a condition for which there are even less objective data in the literature."
Das and colleagues (2009) carried out an economic analysis evaluating the cost-effectiveness of endoscopic ablation of non-dysplastic BE. A Markov model evaluated 3 competing strategies in a hypothetical 50-year-old cohort with non-dysplastic BE from a societal perspective. Strategy I -- natural history of Barrett's disease (without surveillance); strategy II -- surveillance performed according to the ACG practice guidelines; strategy III -- endoscopic ablative therapy. The model was biased against ablative therapy with a conservative estimate of complete response and continued standard surveillance even after complete ablation. All potential complications were accounted for, and an incomplete histological response after ablation was presumed to have the same risk of progression as untreated Barrett's. Transitional probabilities, discounted cost, and utility values to estimate quality-adjusted life-years (QALY) were obtained from published information. Direct costs were used in the analysis. In baseline analysis, the ablative strategy yielded the highest QALY and was more cost-effective than endoscopic surveillance. In a Monte Carlo analysis, the relative risk of developing cancer in the strategy based on endoscopic ablation was decreased compared with the other strategies. In threshold analysis, the critical determinants of cost-effectiveness of the ablative strategy were rate of complete response to ablation, total cost of ablation, and risk of progression to dysplasia. The authors concluded that within the limits of the model, ablation for non-dysplastic BE is more cost-effective than endoscopic surveillance. They stated that clinical trials of ablative therapy in non-dysplastic BE are needed to establish its effectiveness in reducing cancer risk.
The Society of Thoracic Surgeons' practice guideline on the management of BE with HGD (Fernando et al, 2009) stated that RF ablation may be effective for ablation of HGD; however, further trials are needed before this can be recommended in preference to currently available ablative therapies.
Sharma and colleagues (2007) evaluated the dose-response, safety, and effectiveness of circumferential endoscopic ablation of BE by using an endoscopic balloon-based ablation device (HALO360 System). This study was conducted in 2 serial phases: (i) dosimetry phase and (ii) effectiveness phase. The dosimetry phase evaluated the dose-response and the safety of delivering 6 to 12 J/cm2; while the effectiveness phase used 10 J/cm2 (delivered twice [x2]) for all patients, followed by EGD with biopsies at 1, 3, 6, and 12 months. A second ablation procedure was performed if BE was present at 1 or 3 months. Patients received esomeprazole 40 mg twice-daily for 1 month after ablation, and 40 mg every day thereafter. Post-ablation symptoms were quantified by using a 14-day symptom diary (scale, 0 to 100). A complete response (CR) was defined as all biopsy specimens negative for BE at 12 months. Patients were 18 to 75 years of age, with a diagnosis of BE (without dysplasia), with histopathology re-confirmation of the diagnosis within 6 months of enrollment. In the dosimetry phase, 32 patients (29 men; mean age of 56.8 years) were enrolled. Median symptom scores returned to a score of 0 of 100 by day 3. There were no dose-related serious adverse events, and the outcomes at 1 and 3 months permitted the selection of 10 J/cm2 (x2) for the subsequent effectiveness phase of the study. In the effectiveness phase, 70 patients (52 men, 18 women; mean age of 55.7 years) were enrolled. Median symptom scores returned to a score of 0 of 100 by day 4. At 12 months (n = 69; mean of 1.5 sessions), a CR for BE was achieved in 70 % of patients. There were no strictures and no buried glandular mucosa in either study phase (4,306 biopsy fragments evaluated). The authors concluded that circumferential ablation of non-dysplastic BE by using this balloon-based ablation device can be performed with no subsequent strictures or buried glands and with complete elimination of BE in 70 % of patients at 1-year follow-up. They also noted that it is important to continue evaluating ablative modalities for the entire spectrum of BE disease, not just HGD. The present study represents an excellent first step, and several well-designed studies are currently underway that will address each of these potential benefits for non-dysplastic BE, LGD, and HGD.
In a review on BE and new therapeutic modalities, Sharma and Fleischer (2007) stated that as longer-term trial outcomes become available for circumferential and focal ablation, if the current safety and effectiveness result remain favorable and durable, and if cost-effectiveness studies are favorable, they may offer this therapy to selected patients with non-dysplastic intestinal metaplasia to reduce their risk for progression to dysplasia and cancer.
Roorda et al (2007) presented their early experience with RF energy ablation therapy for BE with and without dysplasia. They performed HALO(360) ablation followed by twice-daily PPI and 3-monthly surveillance for up to 12 months. If metaplasia or dysplasia were present at follow-up, the patients received a second ablation. A total of 13 patients (12 males) were treated, 3 with HGD, 4 with LGD, and 6 with non-dysplastic intestinal metaplasia. The mean baseline BE length was 6 cm (range of 2 to 12); 9 patients had an hiatal hernia and 2 had a prior fundoplication. Esophageal pH less than 4.0 for less than 4 % of time was achieved only in 5/13 patients. A mean of 1.4 ablation sessions were performed, without serious adverse events or strictures. Complete eradication of BE was achieved in 6/13 (46 %) patients. The mean endoscopic surface regression was 84 % (from a mean length of 6 +/- 1 cm to 1.2 +/- 0.5 cm, p < 0.001). Complete elimination of dysplasia was achieved in 5/7 (71 %) patients. Ablation efficacy was better in those patients who had maximal pH control (p < 0.05). HALO(360) ablation of BE with or without dysplasia is safe, well-tolerated and effective in the community setting. Follow-up ablation further reverses residual BE or dysplasia. The authors stated that early results of this technology are promising. Moreover, further study will be needed to address the durability of effect and its cost-effectiveness.
Furthermore, Ganz et al (2008) reported that endoscopic circumferential RF ablation is a promising modality for the treatment of BE that contains HGD. In this study, researchers used registry data to identify 142 patients with BE (mean length, 6 cm) and HGD who underwent circumferential ablation at any of 16 academic and community medical centers in the United States. HGD was confirmed by at least 2 pathologists. After the initial ablative therapy, patients had follow-up endoscopy at 3-month intervals with repeat circumferential ablation. Prior endoscopic mucosal resection for focal lesions had been performed in 17 % of participants. At 1-year follow-up, biopsy data were available for 92 of the 142 patients; the data showed complete HGD responses in 90.2 % and complete remission of specialized columnar metaplasia in 62.5 %. No patients were referred for esophagectomy, and no serious adverse events were reported. Commenting on this study, Johnson (2008) noted that several aspects of the study are troubling. Johnson stated that the 1-year follow-up period might not be adequate to assess the results fully, and the histologic analysis (which can vary considerably) was not standardized. The commentator noted that the lack of data on 50 of the 142 patients is concerning, and an intention-to-treat analysis would dramatically lower the "success" rates. Nonetheless, the commentator stated, the combination of endoscopic mucosal resection of focal lesions followed by ablation of residual BE seems particularly attractive compared with esophagectomy. The commentator concluded that longer follow-up and more-complete data collection are necessary to assess more accurately the true efficacy of circumferential ablation.
Of all the academic medical centers in the United States, Mayo Clinic has performed the most RF ablation procedures to treat BE. Its website on BE (2008) states that RF ablation is a fairly new procedure that is still being studied. However, research shows that more than 70 % of those treated are free of dysplasia up to 12 months after treatment. Complications can include esophageal perforation (rupture) and strictures (narrowing). The long-term effectiveness of ablation procedures in preventing cancer is still being studied.
The American College of Gastroenterology's updated guidelines for the diagnosis, surveillance and therapy of BE (Wang and Sampliner, 2008) stated that "further evaluation of the most recent technology; radiofrequency ablation is awaited. Cryotherapy is beginning clinical trials and older technologies are becoming more refined (e.g., photodynamic therapy with the development of new agents). Documentation of the frequency and duration of the surveillance protocol after endoscopic ablation therapy requires careful study".
In a review, McAllaster et al (2009) noted that traditionally, esophagectomy has been the standard treatment for BE with HGD. This practice is supported by studies revealing unexpected adenocarcinoma in 29 to 50 % of esophageal resection specimens for HGD. In addition, esophagectomy employed prior to tumor invasion of the muscularis mucosa results in 5-year survival rates in excess of 80 %. Although esophagectomy can result in improved survival rates for early-stage cancer, it is accompanied by significant morbidity and mortality. Recently, more accurate methods of surveillance and advances in endoscopic therapies have allowed scientists and clinicians to develop treatment strategies with lower morbidity for HGD. Early data suggested that carefully selected patients with HGD can be managed safely with endoscopic therapy, with outcomes comparable to surgery, but with less morbidity. This is an especially attractive approach for patients that either can not tolerate or decline surgical esophagectomy. For patients that are surgical candidates, high-volume centers have demonstrated improved morbidity and mortality rates for esophagectomy. The addition of laparoscopic esophagectomy adds a less invasive surgical resection to the treatment armanentarium. The authors concluded that esophagectomy will remain the gold-standard treatment of BE with HGD until clinical research validates the role of endoscopic therapies.
A recent paper argued that ablative therapy should not be used for patients with non-dysplastic BE (Sharma et al, 2009). First, ablative therapy has not been proven to reduce the risk of developing adenocarcinoma of the esophagus. Because the lifetime cancer risk for patients with non-dysplastic BE is low 5 % to 8 %) (Anderson et al, 2003), a clinical trial would require a large number of patients and a very long follow-up to prove that ablation significantly lowers risk. The authors argued that such an undertaking might be acceptable for a treatment that is inexpensive, safe, and convenient, but current ablation techniques do not meet these criteria. They argued that ablation does not reduce or eliminate the need for ablation, because BE can recur with any form of ablation. The authors cited a report that indicated that intestinal mucosa recurred within a mean follow-up of 51 months in 66 % of patients who underwent complete ablation with argon plasma coagulation (Mork et al, 2007). The authors noted that RFA has been used successfully in non-dysplastic BE; in 1 study, the procedure’s complete ablation rate was 70 % with minimal complications (Sharma et al, 2007). However, the authors noted that all types of ablation therapy have 3 drawbacks: (i) 3 to 5 sessions are required to eliminate Barrett mucosa completely; (ii) markers of hyper-proliferation (Ki-67 staining, p53 staining, and cyclooxygenase-2 expression) have been observed in some patients who received ablation therapy for non-dysplastic BE; because these markers are rarely found prior to ablation therapy, their presence in the neosquamous epithelium suggests that ablation poses an intrinsic risk for cancer, although long-term follow-up data are lacking; and (iii) the ablation procedures in most clinical trials to date have been performed by experts in specialized referral centers, and it is unlikely that the success rates quoted in these trials can be achieved in a community setting.
In a review of the literature, Gilbert, et al. (2011) stated that the general prevalence of BE is estimated at 1.6-3% and follows a demographic distribution similar to EAC. Both short-segment (<3 cm) and long-segment (≥3 cm) BE confer a significant risk for EAC that is increased by the development of dysplasia. The author stated that the treatment for flat high-grade dysplasia is endoscopic radiofrequency ablation therapy. The author noted that the benefits of ablation for non-dysplastic BE and BE with low-grade dysplasia have yet to be validated.
In summary, there is adequate evidence to support the use of endoscopic mucosal resection, esophagectomy, fundoplication, PDT, and RFA in the treatment of patients with BE who have HGD when medical therapy has failed. On the other hand, although the data to support the use of other ablative interventions in the treatment of BE are promising, more well-designed (larger, randomized, double-blinded) studies are needed to draw any definitive conclusions.
Jankowski and Odze (2009) stated that gastro-intestinal cancers account for about 25 % of all cancer deaths in the Western world. There is a need for a preventive strategy that can utilize biomarkers in order to stratify patients into appropriate screening or surveillance programs. In cancer biology, the best biomarkers are germline adenomatous polyposis coli mutations, which are highly predictive of colon cancer. In other areas, such as BE, despite early excellent success in identifying the importance of p16, p53, and aneuploidy in esophageal adenocarcinoma pathogenesis, useful biomarkers are still not widely used in clinical practice. New molecular biomarkers may be identified in the next decade, such as epigenetic methylation patterns and genetic polymorphisms. In the meantime, clinicians must rely on robust, inexpensive methods such as standard histopathology. Dysplasia is still the mainstay of cancer prediction in most inflammatory disorders of the gastrointestinal tract and is an independent marker of cancer risk.
Jin et al (2009) performed a multi-center, double-blinded validation study of 8 BE progression prediction methylation biomarkers. Progression or non-progression were determined at 2 years (tier 1) and 4 years (tier 2). Methylation was assayed in 145 non-progressors and 50 progressors using real-time quantitative methylation-specific PCR. Progressors were significantly older than non-progressors (70.6 versus 62.5 years; p < 0.001). These researchers evaluated a linear combination of the 8 markers, using coefficients from a multi-variate logistic regression analysis. Areas under the ROC curve (AUC) were high in the 2-year, 4-year, and combined data models (0.843, 0.829, and 0.840; p < 0.001, < 0.001, and < 0.001, respectively). In addition, even after rigorous over-fitting correction, the incremental AUCs contributed by panels based on the 8 markers plus age versus age alone were substantial (Delta-AUC = 0.152, 0.114, and 0.118, respectively) in all 3 models. The authors concluded that a methylation biomarker-based panel to predict neoplastic progression in BE has potential clinical value in improving both the efficiency of surveillance endoscopy and the early detection of neoplasia.
In a retrospective cohort study, Barthel et al (2010) examined the response of tumor-associated BE to chemoradiation therapy. The study cohort consisted of 43 patients with stage I to IVA esophageal adenocarcinoma associated with BE who received either neoadjuvant or definitive chemoradiation therapy and underwent either esophagectomy or surveillance. Main outcome measurement was the presence and extent of BE after chemoradiation therapy of esophageal adenocarcinoma associated with endoscopically documented pre-treatment BE. Barrett's esophagus persisted after chemoradiation therapy in 93 % (40/43) of cases (95 % CI: 83 % to 99 %). Twenty-seven patients received neoadjuvant chemoradiation therapy before esophagectomy. Persistent BE was detected in all 27 surgical specimens (100 %). In 59 % (16/27) of the cases, there was complete pathologic tumor response. Sixteen patients received definitive chemoradiation therapy. Persistent pre-treatment BE was identified in 88 % (14/16) by surveillance endoscopy (95 % CI: 60 % to 98 %). The mean length of BE before and after chemoradiation was 6.6 cm and 5.8 cm, respectively (p = 0.38). The authors concluded that chemoradiation therapy of esophageal adenocarcinoma (EAC) does not eliminate tumor-associated BE, nor does it affect the length of the BE segment. Moreover, it should be noted that Hvid-Jensen and colleagues (2011) found that the rate of progression from BE to LGD then to HGD is much smaller than previously thought. These investigators stated that BE is a strong risk factor for EAC, but the absolute annual risk, 0.12 %, is much lower than the assumed risk of 0.5 %, which is the basis for current surveillance guidelines.
Wani (2012) discussed the various controversies that surround the management of LGD in BE. Data on the clinical course of LGD patients with regards to rates of progression to HGD and EAC are highly variable. Recent data suggested that the rate of progression to EAC may be similar to that of patients with non-dysplastic BE (0.4 to 0.5 % per year). There is significant inter-observer variability in the diagnosis of LGD even among expert gastro-intestinal pathologists. Data on various endoscopic eradication therapies (EET) specifically in this patient population are limited. Eradication of LGD and intestinal metaplasia can be achieved by RFA. Although treatment appears to be durable for up to 3 years, progression to HGD and EAC can occur, high-lighting the need for close endoscopic surveillance even after EET. The authors concluded that there is a need to risk-stratify BE patients with LGD to identify patients most likely to progress using a reliable and objective system that incorporates clinical features, advanced imaging techniques and biomarkers. If such a high-risk group could be identified, they may benefit from EET, whereas, the majority may be managed conservatively.
Bremholm and associates (2012) noted that BE is a pre-malignant condition in the esophagus. Esophageal adenocarcinomas have the fastest increase of incidence of all solid tumors in the western world. Barrett's esophagus is defined as areas with macroscopic visible columnar epithelium and intestinal metaplasia oral of the anatomical gastroesophageal junction. The extent of the endoscopic findings is described by the Prague classification. The metaplasia is histologically confirmed by the presence of intestinal metaplasia. The diagnosis of BE can only be made by a combined macroscopic and microscopic examination. The histological description should include evaluation of dysplasia, and if present it should be classified as LGD or HGD. All patients are offered relevant anti-reflux treatment with PPI or surgery. Ablation or mucosal resection of metaplastic epithelia with or without LGD is experimental and it is not recommended outside controlled studies. Treatment of HGD and carcinoma in-situ is handled in departments treating esophageal cancer. Follow-up with endoscopy and biopsy can be offered. Follow-up endoscopy with biopsy can only be recommended after thorough information to the patients, as evidence for the value is scarce.
Fuji Intelligent Chromo Endoscopy (FICE):
According to the manufacturer, "[a]s a basic principle, F.I.C.E. imaging is implemented based on Spectral Estimation Technology. Spectral Estimation Technology takes an ordinary endoscopic image from the video processor and arithmetically processes, estimates and produces an image of a given, dedicated wavelength of light. Now, for the first time ever, this technology is put to practical use in the field of endoscopy by Fujinon. The expected advantage of this new digital processing system is a dramatic enhancement in the detection and identification of pathologic changes. The F.I.C.E. system is expected to enable doctors to supplement differences in experiences and to diagnose clinical findings more accurately than ever before. In contrast to a system in which an optical filter is used, this digital processing system is able to switchover between an ordinary image and a F.I.C.E. image in a split second."
In a review on advanced imaging of the gastro-intestinal tract Goetz and Kiesslich (2009) stated that digital chromoendoscopy techniques such as narrow band imaging, i-scan, or FICE offer new possibilities of easily and reversibly obtaining enhanced tissue contrast. Advanced imaging techniques have provided the endoscopist with an armamentarium of novel modalities for detection, characterization and microscopy of lesions during endoscopy. In addition, functional and molecular imaging give insight into dynamic processes of tissues in their natural surroundings.
According to ClinicalTrials.gov, a service of the National Institutes of Health, a clinical trial on the role of the FICE for the detection of dysplasia in BE and in post-ablation BE was suspended recently (2011).
Germline Mutations in Barrett Esophagus/Esophageal Adenocarcinoma:
Barrett esophagus occurs in 1% to 10 % of the general population and is believed to be the precursor of EAC. The incidence of EAC has increased 350 % in the past 30 years without clear etiology. Finding pre-disposition genes may improve pre-morbid risk assessment, genetic counseling, and management. Genome-wide multi-platform approaches may lead to the identification of genes important in BE/EAC development. Orloff et al (2011) identified risk alleles or mutated genes associated with BE/EAC. Model-free linkage analyses of 21 concordant-affected sibling pairs with BE/EAC and 11 discordant sibling pairs (2005 to 2006) were carried out. Significant germline genomic regions in independent prospectively accrued series of 176 white patients with BE/EAC and 200 ancestry-matched controls (2007 to 2010) were validated and fine mapped. Integrating data from these significant genomic regions with somatic gene expression data from 19 BE/EAC tissues yielded 12 "priority" candidate genes for mutation analysis (2010). Genes that showed mutations in cases but not in controls were further screened in an independent prospectively accrued validation series of 58 cases (2010). Main outcome measures were identification of germline mutations in genes associated with BE/EAC cases, and functional interrogation of the most commonly mutated gene. Three major genes, MSR1, ASCC1, and CTHRC1 were associated with BE/EAC (all p < 0.001). In addition, 13 patients (11.2 %) with BE/EAC carried germline mutations in MSR1, ASCC1, or CTHRC1. MSR1 was the most frequently mutated, with 8 of 116 (proportion, 0.069; 95 % CI: 0.030 to 0.130; p < 0.001) cases with c.877C>T (p.R293X). An independent validation series confirmed germline MSR1 mutations in 2 of 58 cases (proportion, 0.035; 95 % CI: 0.004 to 0.120; p = 0.09). MSR1 mutation resulted in CCND1 up-regulation in peripheral-protein lysate. Immunohistochemistry of BE tissues in MSR1-mutation carriers showed increased nuclear expression of CCND1. The authors concluded that MSR1 was significantly associated with the presence of BE/EAC in derivation and validation samples, although it was only present in a small percentage of the cases. They stated that future independent studies are needed to replicate their data in other patient populations to confirm the conclusions. Furthermore, larger cohort studies may be necessary to determine the usefulness of these genes and their variant in risk assessment and pre-morbid diagnosis.
MicroRNAs as Biomarkers for Barrett's Esophagus Progression:
Bansal et al (2011) evaluated feasibility and clinical accuracy of novel microRNA (miRNA) biomarkers for prediction of BE dysplasia. Paired fresh-frozen and hematoxylin/eosin specimens from a prospective tissue repository where only biopsies with the lesion of interest (i.e., intestinal metaplasia (IM) or HGD/EAC) occupying greater than 50 % of biopsy area were included. Tissue miRNA expression was determined by microarrays and validated by quantitative reverse transcription-PCR (qRT-PCR). Three groups were compared: group A, IM tissues from BE patients without dysplasia; group B, IM tissues from group C patients; and group C, dysplastic tissues from BE patients with HGD/EAC. Overall, 22 BE patients, 11 with and without dysplasia (mean age 64 +/- 8.2 and 63 +/- 11.6 years, respectively, all Caucasian males) were evaluated. Nine miRNAs were identified by high-throughout analysis (miR-15b, -21, -192, -205, 486-5p, -584, -1246, let-7a, and -7d) and qRT-PCR confirmed expression of miR-15b, -21, 486-5p, and let-7a. Two of 4 miRNAs (miR-145 and -203, but not -196a and -375) previously described in BE patients also exhibited differential expression. Sensitivity and specificity of miRNAs for HGD/EAC were miR-15b: 87 and 80 %, miR-21: 93 and 70 %, miR-203: 87 and 90 %, miR-486-5p: 82 and 55 %, and miR-let-7a: 88 and 70 %, respectively. MiRNA-15b, -21, and -203 exhibited field effects (i.e., groups A and B tissues while histologically similar yet exhibited different miRNA expression). The authors concluded that this pilot study demonstrated feasibility of miRNAs to discriminate BE patients with and without dysplasia with reasonable clinical accuracy. However, the specific miRNAs need to be evaluated further in future prospective trials.
Confocal Laser Endomicroscopy:
Probe-based confocal laser endomicroscopy (pCLE) is an imaging technique that allows real-time in-vivo histological assessment of BE.
In a prospective, multi-center, randomized, clinical trial, Wallace and colleagues (2012) evaluated if use of pCLE in addition to high-definition white light (HDWL) could aid in determination of residual BE. After an initial attempt at ablation, patients were followed-up either with HDWL endoscopy or HDWL plus pCLE, with treatment of residual metaplasia or neoplasia based on endoscopic findings and pCLE used to avoid over-treatment. Main outcome measurements included the proportion of optimally treated patients, defined as those with residual BE who were treated and had complete ablation plus those without BE who were not treated and had no evidence of disease at follow-up. The study was halted at the planned interim analysis based on a priori criteria. After enrollment was halted, all patients who had been randomized were followed to study completion. Among the 119 patients with follow-up, there was no difference in the proportion of patients achieving optimal outcomes in the 2 groups (15/57, 26 % for HDWL; 17/62, 27 % with HDWL + pCLE). Other outcomes were similar in the 2 groups. The authors concluded that this study yielded no evidence that the addition of pCLE to HDWL imaging for detection of residual BE or neoplasia can provide improved treatment.
Bertani et al (2012) stated that many endoscopic imaging modalities have been developed and introduced into clinical practice to enhance the diagnostic capabilities of upper endoscopy. In the past, detection of dysplasia and carcinoma of esophagus had been dependent on biopsies taken during standard white-light endoscopy (WLE). Recently high-resolution (HR) endoscopy enables us to visualize esophageal mucosa but resolution for glandular structures and cells is still low. Probe-based confocal laser endomicroscopy is a new promising diagnostic technique by which details of glandular and vascular structures of mucosal layer can be observed. However, the clinical utility of this new diagnostic tool has not yet been fully explored in a clinical setting.
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