Once Barrett's esophagus is diagnosed, the goals of therapy include the control of symptoms of GERD and the maintenance of healed esophageal mucosa. Other treatment objectives include the regression or removal of Barrett's-type tissue and the secondary prevention of adenocarcinoma in patients with known Barrett's esophagus.
A critical question is whether regression of Barrett's esophagus occurs in response to medical or surgical therapy. The natural history of Barrett's esophagus can be altered by the use of medical therapies and by endo-
scopic surveillance with periodic biopsies (Sampliner, 2000). Regression is defined as a decrease in the length and surface area of Barrett's esophagus, along with the emergence of islands of squamous epithelium in the Barrett's segment. The extent of regression is difficult to assess because intestinal metaplasia may underlie the islands of squamous re-epithelial-ization, a situation called pseudo-regression (Sampliner, 2000). Biopsy is useful in ruling out progression to dysplasia or adenocarcinoma; however, complete regression of the lesion cannot be definitively proven by this technique. In long-term clinical studies, consistent acid-suppression therapy with proton-pump inhibitors decreases cell proliferation and increases differentiation in Barrett's esophagus, but the clinical importance of such effects is not clear.
Proton-pump inhibitors have become the predominant medical therapy for Barrett's esophagus because of their potent acid-suppressing effects and favorable safety profile (Falk, 2001). Proton-pump-inhibitor therapy in patients with Barrett's esophagus can in some cases cause an increase in squamous islands in the Barrett's esophagus segment, but data are insufficient to support the concept of complete regression of Barrett's esophagus (Sampliner, 2000; Castell, 2001). Patients who are appropriate candidates for surgery may elect antireflux surgery. Fundoplication effectively controls reflux symptoms in most patients, but Barrett's metaplas-tic epithelium generally persists (Haag et al, 1999). Conflicting data exist as to whether effective antireflux surgery can slow the occurrence and progression of Barrett's esophagus (Lagergren et al, 1999; Klaus and Hinder, 2001). Progression of Barrett's esophagus to high-grade dysplasia and carcinoma has been shown to be less common after antireflux surgery than during medical therapy (Klaus and Hinder, 2000). In contrast, a Swedish study found no difference between surgical and medical therapies in this situation. However, and more importantly, few patients with Barrett's esophagus show complete regression after medical or surgical therapy alone. Until more accurate and effective therapeutic modalities become available or molecular markers are developed or validated that can predict in whom cancer will develop, esophagectomy must be considered the standard means of managing Barrett's esophagus with high-grade dysplasia.
Failure of conventional treatments has led to the emergence of newer endoscopic mucosal ablation techniques in combination with acid-suppression therapy (Sharma, 2001a). The aim of these new treatment options is to literally remove the metaplastic columnar epithelium. Highdose acid-suppression therapy is started immediately after ablation, with the premise that the new epithelium will be squamous and devoid of intestinal metaplasia. At present, 3 techniques have been evaluated: endo-scopic thermal ablation, endoscopic mucosal resection, and photodynamic therapy. To date, however, the impact of endoscopic ablative therapy on neoplastic progression in Barrett's esophagus has not been defined.
The goal is to replace the specialized esophageal mucosa with normal squamous mucosa. Ablation of the Barrett's metaplastic epithelium has the potential in theory to remove its malignant potential. The major concern is that columnar epithelium may persist under the newly formed squa-mous epithelium and retain its malignant potential (Grade et al, 1999). This may occur because the depth of ablation was insufficient or because the esophageal stem cells have been irreversibly altered. Following ablative therapy, it is critical that antisecretory therapy with high-dose protonpump inhibitors be employed immediately as this has been shown to reduce the likelihood of recurrence of columnar epithelium (Overholt, 2000a). Such therapy most likely provides an environment that allows the esophageal progenitor cells to develop into squamous mucosa (Overholt, 2000a).
Important issues for further investigation include the optimal depth of ablation; other considerations include the safety, feasibility, and cost of this treatment. Mucosal ablative techniques are best suited for patients who are poor candidates for surgery and patients treated in the setting of a clinical trial. Factors involved in patient selection for these techniques include the degree of dysplasia, the extent of disease, and patient age (Pacifico and Wang, 2002).
Thermal ablative techniques include multipolar coagulation, argonplasma coagulation, Nd:YAG laser therapy, and argon laser therapy. Pho-todynamic therapy and Nd:YAG laser therapy are used for neoplastic lesions, whereas argon-plasma coagulation and multipolar coagulation have been used successfully in nondysplastic Barrett's mucosa. These therapies have been shown to result in reversal of Barrett's epithelium to varying degrees, but a decrease in adenocarcinoma risk has not been established with any of them (Wang and Sampliner, 2001). Thus, long-term control of neoplastic risk has not been demonstrated, and in most studies some intestinal mucosa persists beneath new squamous mucosa. Further investigation is needed to determine which patients are most likely to benefit from such therapy and which therapies are most effective.
Endoscopic mucosal resection has been used in the treatment of superficial squamous cell cancers and gastric malignancies. Attention has now moved to high-grade Barrett's esophagus and early esophageal adenocar-cinoma. Endoscopic ultrasonography is necessary to determine the feasibility of endoscopic mucosal resection. Only lesions classified as T0 or T1N0, involving only the mucosa and muscularis mucosae but not the submucosa, can potentially be treated with this technique. Endoscopic mucosal resection has also been used for removing areas of high-grade dysplasia in an attempt to avoid esophagectomy. Endoscopic mucosal resection remains an investigative strategy, and studies have yet to show whether endoscopic mucosal resection in the esophagus is an effective and safe procedure for Barrett's esophagus (Sampliner, 2003). A recent study found that endoscopic mucosal resection was very effective at removing T1 esophageal cancers en bloc, with 97% of all patients having no residual cancer detectable at pathology review after surgery (May et al, 2003).
Photodynamic therapy is a technique for the nonsurgical treatment of patients with dysplasia within Barrett's esophagus. The primary end point for photodynamic therapy is eradication of dysplasia. The effectiveness of photodynamic therapy varies with the photosensitizer used and the wavelength of light applied to activate the drug. Given the success of esophageal resection, the use of photodynamic therapy should be reserved for patients who are not candidates for surgery (Overholt, 2000b) or investigational protocols. Complications of photodynamic therapy include esophageal stricturing, and side effects of the photosensitizer are not trivial; these factors must be considered in the decision-making process and be weighed against any potential benefit (May et al, 2002).
Photodynamic therapy seems to control high-grade dysplasia within Barrett's esophagus in about 80% of cases. Long-term results are not available, but the preliminary results are promising (Wang, 2000; Wang and Sampliner, 2001). However, high-grade dysplasia has been detected several months after completion of photodynamic therapy. This most likely indicates that genetic abnormalities persisted even though there was initial histologic downgrading. Therefore, documentation of histo-logic removal of dysplasia alone may be an inadequate end point for pho-todynamic therapy in Barrett's esophagus (Krishnadath et al, 2000). This suggests that since the genetic abnormalities remain, the epithelium still harbors the potential to develop high-grade dysplasia or adenocarcinoma despite histologic improvement (Krishnadath et al, 2000).
Combined Endoscopic Mucosal Resection and Photodynamic Therapy
Endoscopic mucosal resection and photodynamic therapy can also be used together in selected circumstances to treat patients with early-stage esophageal cancers (May et al, 2003). In a study of 17 patients, combined endoscopic mucosal resection and photodynamic therapy appeared to remove the superficial cancer and eliminate the remaining mucosa at risk for cancer development (Buttar et al, 2001a). In a more recent study of 103 patients, photodynamic therapy with supplemental Nd:YAG photoablation and continuous therapy with an acid-suppressing agent was found to reduce the length of Barrett's esophagus, eliminate high-grade dyspla-sia, and potentially reduce the risk of progression to adenocarcinoma (Overholt et al, 2003).
In addition to the therapeutic interventions mentioned above, pharmaceutical agents may prevent neoplastic development or progression in Barrett's epithelium. In case-control studies (Farrow et al, 1998; Langman et al, 2000) and in a recent meta-analysis (Corley et al, 2003), NSAIDs were found to reduce the incidence of esophageal adenocarcinoma. These data suggest that NSAIDs may be effective chemopreventive agents in patients with Barrett's esophagus. In this regard, a selective COX-2 inhibitor was shown to inhibit the proliferation of cultured Barrett's eso-phageal epithelial cells, and cell proliferation was restored by exogenous prostaglandins (Buttar et al, 2002a). A COX-2 inhibitor also increased apoptosis in Barrett's-associated adenocarcinoma cells that expressed COX-2 (Souza et al, 2000). In an animal model of Barrett's esophagus, non-selective COX (sulindac) and selective COX-2 (MF-tricyclic) inhibitors significantly reduced the incidence of esophageal cancer relative to controls, and these drugs showed an equivalent chemopreventive effect (Buttar et al, 2002b). These findings provide further evidence that NSAIDs may be effective chemopreventive agents against Barrett's esophagus, resulting in a decreased incidence of esophageal cancer in humans. A clinical trial evaluating a selective COX-2 inhibitor is ongoing in patients with Barrett's esophagus and mucosal dysplasia.
Another agent that has been evaluated in a limited number of patients with Barrett's esophagus is difluoromethylornithine (DFMO). DFMO is an inhibitor of ornithine decarboxylase that regulates the rate-limiting enzyme in the synthesis of mucosal polyamines. Polyamines are known to regulate cellular proliferation and differentiation (Garewal et al, 1992). DFMO is a potent inhibitor of epithelial carcinogenesis in a variety of animal model systems. Furthermore, DFMO has been shown to inhibit the growth of Barrett's epithelium-derived cell lines, suggesting a role for this compound in the treatment of this disease (Garewal et al, 1988). Gerner et al (1994) performed a biomarker modulation trial to evaluate the effect of oral DFMO on polyamine levels in 8 patients with Barrett's esophagus. DFMO was shown to decrease polyamine levels, particularly levels of spermidine, in Barrett's epithelium. Studies have yet to be done to determine whether this decrease in polyamine levels has an effect on neoplas-tic development progression in Barrett's epithelia. Chemoprevention is a field in its infancy, and future studies of existing and new agents are likely to provide important insights into the difficult problem of interrupting the process of carcinogenesis in Barrett's epithelium. What is being learned from prevention studies in other epithelial premalignant conditions is already being applied to the esophagus.
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