[MOL] Barrett's Esophagus [00299]

Burning Issues In Barrett's Esophagus

M. Brian Fennerty, MD

Introduction
Barrett's esophagus is a premalignant histologic condition of the esophagus that arises in the setting of chronic gastroesophageal reflux disease. Recent evidence indicates that the malignant tumor arising from Barrett's esophagus, esophageal adenocarcinoma, is the most rapidly rising incident tumor of all malignancies. Additionally, recent epidemiological evidence directly links esophageal adenocarcinoma to chronic reflux. Given that 20% of adult Americans have reflux and as many as 10% of individuals with reflux will have Barrett's, the pool of patients requiring surveillance endoscopy and biopsy for Barrett's may be 1%-2% of the adult population. Thus, the issue of Barrett's esophagus has important clinical and economic ramifications.
Barrett's esophagus was thought to be an irreversible premalignant lesion, but recent evidence suggests that this might not be the case. This symposium held at the American College of Gastroenterology 64th Annual Meeting in Phoenix, Ariz, Wednesday, October 20, 1999, was structured to cover the current state-of-the-art knowledge regarding endoscopic ablation/reversal techniques.

Is There a Rationale for Reversal Therapy in Patients With Barrett's Esophagus?
Prateek Sharma, MD, from the University of Kansas, covered the salient historical features of therapy for Barrett's esophagus.^[1] Because Barrett's arises in the clinical setting of gastroesophageal reflux disease, it should not seem surprising that the effect of antireflux therapy on Barrett's esophagus has been extensively investigated. Early studies with continuous long-term therapy with H₂-receptor antagonists did not demonstrate regression of Barrett's esophagus. Similar negative results have been demonstrated following antireflux surgery. In the multicenter VA Cooperative study, Kim and colleagues^[2] demonstrated that there was no decrease in length of Barrett's over a 2-year period (5.7 cm at entry and 6.1 cm at conclusion). In this study, the surgery was performed by skilled antireflux surgeons -- therefore, if surgery alone was to affect the length of Barrett's, it should have been observed in this trial.
In 1989, proton pump inhibitors became clinically available, and given their superior antisecretory potency, these agents were also extensively evaluated for efficacy not only in controlling gastroesophageal reflux symptoms, but as a therapeutic strategy for reversing Barrett's as well. Unfortunately, no clinically relevant reversal has been noted with this class of agents. Sampliner and associates^[3] studied the effect of 60 mg of lansoprazole for 3 years in patients with Barrett's esophagus. At the conclusion of the study, the mean length of Barrett's had not significantly changed (5.3 cm versus 5.7 cm at entry). Thus, pharmacological or surgical control of gastroesophageal reflux does not result in the reversal of Barrett's esophagus.
However, in the course of observing patients treated with these agents, especially those treated with proton pump inhibitors, the appearance of squamous islands within the Barrett's segment was noted. As Barrett's was thought to arise as a result of an abnormal tissue response to injury in an abnormal acid-reflux environment, it was hypothesized that perhaps reversal of this lesion would require not only control of reflux but also a reinjury of the mucosa to effect a reversal of the epithelium. Thus, the stage was set to apply endoscopic methods to test this hypothesis.

Superficial Injury of Barrett's Epithelium: Is it Effective in Reversing Barrett's?
Richard Sampliner, MD, from the University of Arizona, reviewed current data regarding superficial methods of injuring the metaplastic Barrett's epithelium in an attempt to restore the native squamous epithelium.^[4] A number of endoscopic thermal methods that only superficially penetrate the epithelium are available and have been evaluated, including multipolar electrocoagulation (MPEC), heater probe (HP), and argon plasma coagulation (APC). The advantage of these modalities is that they are readily available to most gastroenterologists and most gastroenterologists are skilled in the use of one or more of these techniques. Therefore, if successful, this process could be applied without referral to specialty centers, etc. Furthermore, because of their limited depth of injury, morbidity with these techniques should also be minimal.
The first approach studied was MPEC. In a pilot study, Sampliner and associates demonstrated that endoscopic and histologic reversal of Barrett's could be achieved with this device following normalization of intraesophageal acid exposure with omeprazole.^[5] What was interesting in this study was that the mean dose of omeprazole needed to achieve esophageal normalization was 56 mg -- a dose much higher than normally used clinically. This finding not only underscored that these techniques were combination therapies (acid control and device "reinjury"), but that prior studies of acid control alone may have undertreated these patients.
Sampliner also presented the preliminary results of the multicenter prospective trial of MPEC therapy involving the University of Arizona, Oregon Health Sciences University, and UCLA.^[6] In this study of 54 patients with Barrett's, complete endoscopic reversal was seen in 96% and histologic reversal in 94% of those treated with MPEC, following control of acid secretion with omeprazole 40 mg bid. Only two strictures were noted and both of these patients had had strictures prior to the therapy. Thus, this form of therapy appears potentially effective and associated with little morbidity. These patients are now being prospectively followed for durability of reversal and other clinical outcomes.
APC has also been extensively evaluated in this setting. APC uses argon gas to transmit electrical energy from a probe to the epithelial surface, producing heat. Similar to what has been observed with MPEC, most patients will demonstrate both endoscopic and histologic reversal. While touted as a safe thermal method, 2 patients in an early series^[7] were perforated by the procedure and 1 of these patients died. Therefore, the safety of APC in this setting requires further scrutiny.
Heater probe has been less extensively studied as a thermal endoscopic method than has MPEC or APC, but appears to be similarly effective and relatively nonmorbid. Because of the limited depth of injury, these thermal techniques have been mainly applied to patients with nondysplastic Barrett's. Whether they would be similarly effective in dysplastic Barrett's is largely unknown.

What About Deeper Injury Methods to Ablate/Reverse Barrett's?
Ken Wang, MD, of the Mayo Clinic in Rochester, Minn, reviewed data regarding thermal injury with laser and nonthermal injury with photodynamic therapy (PDT).^[8] Patients with dysplasia and/or early cancer may require deeper injury to ablate the neoplastic tissue and elicit an epithelial response, restoring the native squamous epithelium. Both laser and PDT have been studied in this regard. Laser in the form of argon, KTP (potassium-titanyl-phosphate), and Nd:YAG all appear effective in limited series of patients and short-term follow-up. However, there is experience in over 100 patients with neoplastic Barrett's using PDT. Overholt and colleagues^[9] have published their experience in a single center using porfimer sodium as the photosensitizing agent and laser light from a centering balloon to activate the chemical and produce injury to the abnormal epithelium. In this series, the majority of patients had reversal of their dysplasia and/or cancer.
Although follow-up is limited, this approach appears promising at this time.
However, the deeper injury obtained with these devices also is associated with increased morbidity. One third of patients develop esophageal strictures, phototoxicity is common and requires avoidance of direct sunlight for 30 days, and chest pain requiring analgesics is frequent. Moreover, the cost of this procedure is high. The ongoing prospective, randomized trial of PDT in patients with Barrett's and high-grade dysplasia will determine its place in the treatment of these patients, but unfortunately, these results will not be available for another year.

Should We Do This at All?
M. Brian Fennerty, MD, of the Oregon Health Sciences University, discussed the case against ablation therapy of Barrett's at this time.^[10] The two potential beneficial outcomes of reversing Barrett's are: 1) prevention of cancer in the 10% of Barrett's patients who will eventually develop cancer; and 2) elimination of the need for life-long surveillance exams in the 90% who will not ever develop cancer and have benign disease. Additional benefit to these patients is an improved quality of life as they are reassured and no longer "phobic" about their risk of developing cancer. Given the lack of a reliable marker to exclude cancer risk, a reversal technique may have great clinical and/or economic benefit.
Why not apply these techniques then? Or put another way, what don't we know? Concerning ablative technologies, we don't know the following: the most effective technique, the least morbid technique, and the most cost-effective technique. From a clinical outcomes perspective we don't know: the effect of these endoscopic techniques on functional status or quality of life, morbidity or mortality, and the direct and indirect costs of these approaches. Most important, we do not yet know whether we have eliminated all of the Barrett's and thus eliminated the risk of developing cancer. There are now numerous reports of underlying Barrett's epithelium below the neo-squamous new mucosa. What if we don't lower the risk of cancer with these techniques but instead hamper our ability to survey this epithelium for dysplasia in the future? Then not only have we not done any good, but we have done potential harm as well.^[11]
Therefore, while there has been a paradigm shift in our understanding of Barrett's in that it is at least partially reversible, we are still unable to determine whether these techniques are clinically appropriate. Until such data are available, these approaches must remain within the research arena pending proof of their efficacy. The rare exception will be in the patient with high-grade dysplasia who either is not a surgical candidate or who refuses surgery. In these patients we have the potential to improve outcomes with little risk and so ablation therapy may be justified, especially using PDT.

Other Related Abstracts
The long-term outcomes of patients with Barrett's treated with endoscopic ablation techniques were investigated by Landan and colleagues^[12] from the Phoenix VA Medical Center. Nine patients with prior ablation using APC were prospectively followed. In 6 of these 9 patients, intestinal metaplasia was demonstrated on a subsequent biopsy. In 1 patient, it was not noted until an exam performed 415 days following apparent reversal. Data such as these, which have also been demonstrated in patients treated with PDT and MPEC, suggest that Barrett's may either return or is not entirely eliminated. If so, these patients may remain at risk for developing adenocarcinoma. Moreover, our ability to monitor these patients for dysplasia is hindered and we may have worsened the situation. These data serve to emphasize the investigational nature of these techniques.

Concluding Commentary
We may be on the brink of a dramatic therapeutic advancement in patients with Barrett's esophagus. However, the lack of demonstrated benefit of endoscopic reversal/ablative techniques dictates that we temper our enthusiasm until definitive data are available. Improvement in outcomes and assurance of no residual Barrett's will be necessary before we incorporate these techniques into clinical practice.

References

Sharma P. The rationale for ablation therapy. Program and abstracts of the American College of Gastroenterology 64th Annual Scientific Meeting; October 16-20, 1999; Phoenix, Ariz.
Kim Sl, Waring JP, Sampliner RE, et al. Effects of antireflux therapy on the extent of Barrett's epithelium. Gastroenterol 1993;104:A118.
Sampliner RE. Effect of up to 3 years of high-dose lansoprazole on Barrett's esophagus. Am J Gastroenterol 1994;89:1844.
Sampliner RE. Superficial injury (MPEC, APC). Program and abstracts of the American College of Gastroenterology 64th Annual Scientific Meeting; October 16-20, 1999; Phoenix, Ariz.
Sampliner RE, Camargo E, Faigel D, et al. Efficacy and safety of reversal of Barrett's esophagus with high-dose omeprazole and electrocoagulation. Gastroenterology 1999;116:A298.
Sampliner RE, Fennerty MB, Garewal HS. Reversal of Barrett's esophagus with acid suppression and multipolar electrocoagulation: preliminary results. Gastrointest Endosc 1996;44:532.
Byrne JP, Armstrong GR, Attwood SEA. Restoration of the normal squamous lining in Barrett's esophagus by argon beam plasma coagulation. Am J Gastroenterol 1998;93;1810.
Wang K. Deep injury (PDT, Laser). Program and abstracts of the American College of Gastroenterology 64th Annual Scientific Meeting; October 16-20, 1999; Phoenix, Ariz.
Overholt E, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett's esophagus: Follow-up in 100 patients. Gastrointest Endosc 1999;49:1.
Fennerty MB. The case against ablation therapy. Program and abstracts of the American College of Gastroenterology 64th Annual Scientific Meeting; October 16-20, 1999; Phoenix, Ariz.
Fennerty MB. Perspectives on endoscopic eradication of Barrett's esophagus: Who are appropriate candidates and what is the best method? Gastrointest Endosc 1999;49:S24.
Landan D, Ramirez FC. Long-term follow-up of patients with Barrett's Esophagus treated with Argon plasma coagulation (APC). Am J Gastroenterol 1999;94:2590. Program and abstracts of the American College of Gastroenterology 64th Annual Scientific Meeting; October 16-20, 1999; Phoenix, Ariz. Abstract 26.