Optimal Endoluminal Treatment of Barrett's Esophagus: Integrating Novel Strategies into Clinical Practice

Raf Bisschops

Disclosures

Expert Rev Gastroenterol Hepatol. 2010;4(3):319-333. 

In This Article

Additional Ablation Techniques

One of the downsides of ER is the fact that a high risk of metachronous disease exists. Therefore, there is a trend to add an additional ablation of residual Barrett's epithelium, in particular in patients with a long life expectancy. Possible techniques to ablate residual Barrett's are stepwise radical ER (SRER), APC, PDT and, most recently introduced, RFA.

Stepwise Radical Endoscopic Resection

Stepwise radical endoscopic resection is an endoluminal technique that can be used to eradicate all intestinal metaplasia after staging ER of visible lesions ( Table 1 ).[10,21–24] The major advantage of this technique is that the entire Barrett's esophagus can be examined for final histology and that it can reveal possible missed cancers. Resection of a Barrett's segment up to 14 cm has been reported;[72] however SRER is technically more challenging and mostly limited to a 5-cm Barrett's segment.[10] SRER seems to be associated with more complications ( Table 1 ). In one study SRER was performed in 34 patients during a median of two therapeutic sessions.[22] Two perforations and one delayed bleeding occurred (9%), and in 56% of patients dysphagia occurred, necessitating additional dilations or stent placement. Another prospective trial reported a stenosis rate of 26% after SRER and two major complications in 88 procedures.[10] Short-term follow-up shows that SRER is highly effective in eradicating all Barrett's esophagus and also eliminated the genetic alterations that are associated with early neoplasia,[10,73] but in a retrospective series recurrence of HGIN or early cancer occurred in 9% of patients and 15% had recurrent intestinal metaplasia after a median follow-up of 23 months.[22]

Argon Plasma Coagulation

Argon plasma coagulation is a cheap and relatively easy method for ablation of Barrett's epithelium. However, owing to variable settings of the system and nonstandardized delivery of the energy (dependent on probe distance and coagulation duration, which is basically variable to all APC sites) results are inconsistent throughout studies ( Table 2 & Table 3 . In one study by Kahaleh et al., for instance, 39 patients with specialized intestinal metaplasia or low-grade dysplasia were treated with APC ablation. After 36 months there was an endoscopically and histologically identified recurrence of Barrett's epithelium in 62% of the patents, despite maintenance therapy with proton pump inhibitors (PPIs).[74] The results of APC have recently been reviewed, showing effectiveness in eradicating intestinal metaplasia in 58–100% depending on the studies.[75] Recurrence was reported in most studies ranging between 3 and 66% of patients. Owing to these unacceptable rates of persisting or recurring intestinal metaplasia, APC is currently not regarded by most experts as a treatment option for extensive ablation of large areas of Barrett's epithelium. Moreover, adverse events, such as perforation, were reported in up to 3.6% of cases.[76–78] Other adverse events include major bleeding (0–3.9%) and stricture (0–15.4%). Finally, buried Barrett's glands have been reported, which constitute a risk of development of adenocarcinoma under neosquamous epithelium.[75] This feature of buried gland is, however, a feature that is already present in nontreated Barrett's esophagus,[79,80] indicating that even after a complete ablation a meticulous follow-up will be necessary, and that the extent of treatment should be 1 cm proximal to the Z-line.

Photodynamic Therapy

Photodynamic therapy was first perceived as very promising for treating early Barrett's cancer or as an add-on to ER. The principle of PDT is simple. A photosensitizer, absorbed by the Barrett's epithelium, will be excited by a specific light source to cause thermal injury to the mucosa and subsequent ablation. The most commonly used drugs are 5-aminolevulinic acid (5-ALA), which is administered orally 4 h before radiation. Sodium porfimer has to be administered intravenously 48 h prior to the procedure. These photosenziters are then activated by photoradiation by means of a red wave length laser (630–635 nm). Results of the major PDT studies are summarized in Table 4 & Table 5 . In a randomized controlled trial in patients with HGIN, the efficacy of PDT (n = 138; sodium porfimer) versus PPI (n = 70) treatment was assessed.[81] At 24 months, 77% of actively treated patients had remission of Barrett's dysplasia versus 39% in the PPI group. Any patient having decreased dysplasia was considered as a success, which can explain the high remission rate in the PPI group. The 5-year follow-up data showed that there was no residual dysplasia in 59% of PDT-treated patients versus 14% of control patients.[82] Complete neosquamous mucosa was found in 52% of the patients in the PDT group but only 7% in the control group. The rate of progression to cancer was statistically significantly reduced in PDT-treated patients (15 vs 29% in the omeprazole group). The efficacy of 5-ALA is not consistent through different studies ( Table 4 ). The initial response can be as high as 97 and 100%, but a relatively high recurrence rate in patients with early cancer (30%) exists.[83] Other studies have found less promising results, with response rates as low as 67% in patients with Barrett's dysplasia.[84] Another study in which 5-ALA PDT was used after ER, showed that it did not prevent recurrent disease, particularly when there were positive margins in the ER specimen.[85] Several safety issues limit the use of PDT as a primary choice for add-on treatment of Barrett's neoplasia ( Table 5 ).[84,85] Even one treatment-related death has been reported.[84] Another important side effect is cutaneous photosensitivity, causing a degree of sunburn in two-thirds of the patients[81] and acute chest pain and nausea with a risk of dehydration within 2 weeks after PDT. Finally, there is an important price issue related to PDT.

Cryotherapy

Cryotherapy is a noncontact ablation method in which cold temperature is applied to cause tissue damage. A first system, the CryoSpray Ablation system, uses liquid nitrogen that can be sprayed onto the Barrett's mucosa. The results with this system are still preliminary and further studies will need to address the exact role of this technique in the treatment of Barrett's neoplasia. A recent prospective trial evaluated safety and tolerability in 77 patients with nondysplastic Barrett's esophagus, low-grade intraepithelial neoplasia (LGIN), HGIN, intramucosal carcinoma, invasive carcinoma and severe squamous dysplasia.[86] In total, 323 procedures were performed. The most common side effects were chest pain (17.6%), dysphagia (13.3%), odynophagia (12.1%) and sore throat (9.6%). Gastric perforation occurred in one patient. Three patients developed esophageal strictures. Efficacy data on the CryoSpray Ablation device are still sparse. One pilot study in 11 patients with LGIN and HGIN Barrett's esophagus showed complete histological ablation of Barrett's epithelium in nine out of 11 patients. At the 6 months follow-up no residual dysplasia was found.[87] In a larger prospective trial that was not set out to test efficacy of cryotherapy, 17 patients with HGIN were treated with cryotherapy. Complete response for HGIN was 94% and complete response for intestinal metaplasia was 53%.[86] The Polar Wand device is a second system for cryotherapy that uses carbon dioxide for ablation. Preliminary data are promising but are still limited and need further investigation. Canto et al. reported that primary and additional treatment in refractory HGIN or early cancer with this system resulted in a safe and effective ablation in more than 90% of the patients with a mean of six sessions.[88]

Radiofrequency Ablation

Recently, RFA has been introduced as a new ablative therapy for Barrett's esophagus. Its effect has been well studied ( Table 6 ) in several trials, including a sham-controlled trial.[80] Radiofrequency energy is delivered through a balloon-based system for circumferential ablation or with a cap-electrode attached to the tip of an endoscope for focal ablation of small Barrett's islets or the Z-line. Energy settings for ablation in patients were first assessed in the AIM-I trial determining the effect on ablation of intestinal metaplasia without dysplasia.[89] The ideal setting for circumferential RFA was found to be 10 J/cm2. This was further used in the AIM-II trial, showing an efficacy of 70% complete remission of intestinal metaplasia after a maximum of two circumferential RFA treatment sessions in 70 patients with a median Barrett's length of 6 cm. After the introduction of the cap-electrode for focal ablation, the patients in this trial were allowed up to three additional focal treatments. After a mean of 1.9 additional treatments, eradication of intestinal metaplasia was achieved in 98.4% of the patients.[90]

In a recent large, multicenter sham-controlled trial, RFA was compared with a sham procedure (2:1 ratio) in a cohort of 64 patients with LGIN and 63 patients with HGIN.[80] In the intention-to-treat analysis, complete eradication of dysplasia was significantly higher in the actively treated group: 80 versus 11% for the HGIN cohort and 90 versus 37% in the LGIN cohort. After a maximum of four ablation sessions, complete response for intestinal metaplasia was achieved in 77% in the RFA group versus 0% in the sham group. More importantly, progression to a higher grade of dysplasia was found in 16% in the sham group compared with 4% in the RFA group. Particularly in the HGIN cohort, 19% of patients in the sham control group progressed to cancer within 1 year. Several smaller trials have shown the possibility of combining ER of visible lesions with subsequent RFA.[91–94] The largest single-center experience in combining ER and RFA comes from the Amsterdam group.[91–93] In 44 patients, complete histological eradication of dysplasia and complete endoscopic and histological clearance of intestinal metaplasia was achieved in 43 patients (98%), using a maximum of two circumferential and three focal ablation sessions. Three patients required an escape ER because of residual intestinal metaplasia after circumferential and focal RFA. During a mean follow-up of 21 months, one patient experienced recurrence of intestinal metaplasia but there was no recurrence of dysplasia. A recent multicenter European trial confirmed the utility of this therapeutic approach in patients with early Barrett's neoplasia. After ER in 23 out of 24 patients, and a median of one circumferential ablation and one additional focal ablation, eradication of neoplasia was achieved in 95% of patients, and total eradication of intestinal metaplasia was obtained in 88% of patients. After additional escape ER these numbers were 100 and 96%, respectively. After a median follow-up of 22 months and a median of three endoscopies with biopsies of the Z-line and neosquamous epithelium, no neoplasia recurred and total eradication of intestinal metaplasia was maintained in 83% of patients.[94]

Analysis of genetic alterations in patients with HGIN have shown that not only does RFA ablate Barrett's mucosa, but also that genetic alterations associated with neoplasia are no longer present in the neosquamous epithelium.[95]

The safety of the RFA procedures is summarized in Table 7 . Most procedure-related side effects are mild, such as fever, chest or throat pain, superficial mucosal injury, nausea or sedation-related complications.[89] Stricture rate is estimated to be approximately 6%,[80] but in combination with ER complications occur more frequently.[93,94] Circumferential RFA following ER was complicated in the Amsterdam experience with a nontransmural laceration in 7% of patients, which occurred only at the level of the ER scar. A total of 9% of patients developed dysphagia that required dilation. By contrast, no lacerations or stenosis occurred in patients treated with RFA alone. In order to perform RFA safely, the extent of the ER should be limited to 2 cm in length and 50% of the circumference, and the size of the ablation catheter should be selected conservatively.[93] The issue of buried Barrett's glands has been extensively addressed in all RFA studies showing this in one out of 5000 biopsies. Even re-ER specimens after ablation did not show any buried glands.[93] Finally, esophageal function appears to be well preserved according to a study assessing esophageal compliance with functional luminal impedance planimetry.[96]

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