American College of Gastroenterology

Return to American College of Gastroenterology Print This

Photodynamic Therapy for Barrett’s Dysplasia: Who, When, and How

At a symposium moderated by James Scheiman, MD, and held in conjunction with the American College of Gastroenterology’s 2003 Annual Meeting, five specialists in gastroenterology and endoscopy discussed the controversial issues surrounding a diagnosis of Barrett’s esophagus. Topics included the pathogenesis of Barrett’s esophagus, risk for adenocarcinoma, and emerging new treatment modalities such as photodynamic therapy.

This program was supported by an unrestricted educational grant from Axcan Pharma Inc.

This material represents a compilation from a series of industry-sponsored educational symposia presented October 10–15, 2003 in conjunction with the Annual Meeting of the American College of Gastroenterology. This compilation is provided for information and critical scrutiny by physician readers, and is not intended to replace clinical judgment by the physician as to a specific patient. The proceedings arise from industry-sponsored sessions, not from the official ACG program, and this synopsis/compilation of these sessions does not represent the official viewpoint of the American College of Gastroenterology.

Barrett’s Esophagus: Scope of the Problem

“Barrett’s esophagus is a precursor condition to the cancer most rapidly increasing in incidence in the United States—adenocarcinoma of the esophagus,” said James Scheiman, MD, Program Chair, Professor of Internal Medicine, University of Michigan Medical School and Director of Endoscopic Research, University of Michigan Health System, Ann Arbor. With a diagnosis of Barrett’s esophagus comes an increased risk for esoph-ageal cancer, along with a number of chemopreventive and management dilemmas. Dr. Scheiman provided an overview of the options and controversies in interventions to reduce the risk of progression from Barrett’s esophagus to cancer, particularly in patients with
dysplasia.

Pathogenesis of Disease
Barrett’s esophagus is characterized as a replacement of any length of the normal squamous esophageal lining with columnar mucosa that is recognized at endoscopy and is confirmed by biopsy to have intestinal metaplasia (Sampliner. Am J Gastroenterol 2002;97(8):1888-95). The condition is associated with a 30- to 60-fold increase in esophageal cancer risk over the general population (Falk. Gastrointest Endosc 1999;49(3 Pt 2):S29-34).

The pathogenesis of Barrett’s esophagus begins with acid reflux disease, which leads to a cascade of preneoplastic changes and can potentially progress to neoplastic changes. “The controversy in treating patients with Barrett’s esophagus with dysplasia revolves around how best to reduce the risk of progression to esophageal cancer,” Dr. Scheiman said. Several new therapeutic modalities have been studied for their potential efficacy in patients who have Barrett’s esophagus with dysplasia.

Emerging Endoscopic Therapies
In patients who have Barrett’s esophagus with high-grade dysplasia, interventions to reduce the risk of malignancy remain under study—and under debate. “Current standard practice in most cases of Barrett’s esophagus with high-grade dysplasia involves surgery. However, the literature on new endoscopic approaches continues to grow, warranting further study and consideration for use in this patient population,” Dr. Scheiman noted. Indeed, photodynamic therapy with porfimer sodium is a treatment option that recently received approval by the US Food and Drug Administration for use in patients who have Barrett’s esophagus with high-grade dysplasia.

In closing, Dr. Scheiman pointed out several areas in which further development in patients who have Barrett’s esophagus with high-grade dysplasia is critical: refinement and evaluation of techniques, such as photodynamic therapy; evaluation of new modalities outside specialty/expert treatment centers; and randomized, controlled studies comparing endoscopic versus surgical intervention, endoscopic versus expectant management, and photodynamic therapy versus surveillance (Scheiman & Wang. Gastrointest Endosc 2003;58: 244-46). “It is hoped that this research will lead to effective alternatives to esophagectomy for patients who have Barrett’s esophagus with high-grade dysplasia,” the speaker concluded.

Barrett’s Esophagus with High-Grade Dysplasia: Current Treatments

Barrett’s esophagus occurs in an estimated 10% of persons with chronic gastroesophageal reflux disease (GERD), and confers a 30- to 60-fold increased risk for esophageal cancer over the general population without Barrett’s esophagus. “Barrett’s esophagus with high- grade dysplasia represents an even higher risk for malignancy, and a key decision-making point in the treatment of this condition,” said Richard Sampliner, MD, Professor of Medicine and Gastroenterology, University of Arizona College of Medicine, and Chief of Gastroenterology at Southern Arizona VA Healthcare System, Tucson (Locke III et al. Gastroenterology 1997;112(5): 1448-1456. Falk. Gastrointest Endosc 1999;(3 Pt 2):S29-34). According to Dr. Sampliner, the goal of treatment of Barrett’s esophagus with high-grade dysplasia is three-fold: to eliminate GERD symptoms, to maintain healed mucosa, and to prevent progression to adenocarcinoma.

Progression to Malignancy
Approximately 5% of patients with Barrett’s esophagus progress over their lifetime to develop adenocarcinoma of the esophagus, the most rapidly increasing cancer incidence in the United States. Barrett’s esophagus is defined as a change in the lining of the distal esophagus that appears columnar on endoscopy and reveals intestinal metaplasia on biopsy. This condition is believed to be due to underlying chronic GERD, and can progress from intestinal metaplasia with no dysplasia to indefinite for dysplasia, to low-grade and then high-grade dysplasia. Recent data point to a variable natural history of high-grade dysplasia. In one study, Schnell and colleagues found that 16% of patients with Barrett’s esophagus and high-grade dysplasia developed esophageal adenocarcinoma over a surveillance period of 7 years. In contrast, Reid and associates found that 59% of a similar patient population developed adenocarcinoma over 5 years of surveillance (Reid et al. Am J Gastroenterol 2000;95(7):1669-76; Schnell et al. Gastroenterology 2001; 120(7):1607-19). “This discrepancy can be explained by how each study defined its patient population and by referral bias. However, the data clearly indicate that high-grade dysplasia is currently our best marker for cancer risk,” Dr. Sampliner said.

Management of High-Grade Dysplasia
“According to the American College of Gastroenterology guidelines, management of Barrett’s esophagus with high-grade dysplasia should include con- firmation of the pathology, as well as a repeat endoscopy with an intensive biopsy protocol, to rule out cancer,” Dr. Samplinar explained. An endoscopic mucosal resection is helpful if the mucosa is irregular (Sampliner. Am J Gastroenterol 2002;97(8):1888-95).

The current options for management of Barrett’s esophagus with high-grade dysplasia include: surveillance, endoscopic ablation therapy, and surgery (Birkmeyer et al. N Engl J Med 2002; 346(15):1128-37)

Surveillance
The surveillance approach involves frequent upper endoscopy with an intensive biosy protocol, with intervention should early cancer be detected (Levine. Gastroenterol Clin North Am 1997; 26(3):613-34).

Surgery
The standard therapy for patients with high-grade dysplasia is esophagectomy. One survey showed that 80% of endoscopists recommend esophagectomy for this patient population (Falk. Gastroint Endsosc 2000;52:197).

Endoscopic ablation therapy
Endoscopic ablation strategies include photodynamic therapy, endoscopic mucosal resection, and argon plasma
coagulation.

Emerging Endoscopic Ablation Therapies
According to Dr. Sampliner, emerging new endoscopic ablation therapies hold promise as an alternative for patients who cannot undergo or refuse to undergo esophagectomy.

First, photodynamic therapy using the photosensitizing agent porfimer sodium was recently approved by the US Food and Drug Administration for use in patients who have Barrett’s esophagus with high-grade dysplasia. In a North American multicenter randomized study, patients with high-grade dysplasia received either omeprazole therapy alone or omeprazole with photodynamic therapy using porfimer sodium. After a minimum of 2 years’ follow-up, the results revealed findings of no high-grade dysplasia in 39% of those receiving omeprazole alone and 77% of those receiving the combination of omeprazole and photodynamic therapy. Similarly, cancer was detected in 28% of the omeprazole group and 13% of the combination arm. (Overholt. Gastrointest Endosc 2003; 124:151). The most serious adverse events associated with photodynamic therapy include photosensitivity reactions and esophageal stenosis (Axcan Pharma. Data on file). “In addition, a cost-effectiveness study has shown an improvement of 1.7 quality years of life expectancy and incremental cost-effectiveness ratio of $12,000 over surveillance endoscopy. In comparison to esophagectomy, the increase in quality years life expectancy was 2.2,” Dr. Sampliner explained (Hur. Dis Dis Sci 2003;48:1273).

Another promising treatment modality is endoscopic mucosal resection. In one large study, Ell and colleagues used endoscopic mucosal resection to treat patients with Barrett’s esophagus lesions characterized as 2 cm or less, moderately differentiated, and limited to the mucosa. After 1 year of follow-up, the results showed remission in 97% of patients, with a 17% rate of local recurrence or metachronous cancer (Ell. Gastroenterology 2000;118: 670).

Finally, argon plasma coagulation has been studied in the United Kingdom in patients with high-grade dysplasia who could not or who refused to undergo surgery. After 3 years of follow-up, 86% had no high-grade dysplasia and 76% had no Barrett’s esophagus; however, 14% developed cancer.

“The data on endoscopic therapy for high-grade dysplasia teach us that this approach is a potentially effective treatment of local disease, but also that a recurrence or metachronous cancer can still develop after elimination of all high-grade dysplasia,” Dr. Sampliner reported. He noted that patient criteria (age, comorbidity, risk aversion, esoph-ageal function) constitute a significant factor in treatment selection and that further study is needed on the long-term use of endoscopic therapies for patients with Barrett’s esophagus with high-grade dysplasia.

Video Case Presentation:
Photodynamic Therapy for High-Grade Dysplasia

As part of a presentation on endoscopic ablation therapy, two esteemed leaders in gastroenterology and endoscopy demonstrated via videotape the use of photodynamic therapy to treat Barrett’s disease with high-grade dysplasia.* The main points presented included:

FDA Approval
n Use of photodynamic therapy with photosensitizer porfimer sodium in patients who have Barrett’s esophagus with high-grade dysplasia who do not
undergo esophagectomy

Clinical Use
• Photodynamic therapy consists of two-part treatment:
– intravenous administration of porfimer sodium 48 hours before treatment
– administration of red light to activate porfimer sodium
• Photodynamic therapy works to destroy Barrett’s mucosal cells, with some selectivity for neoplastic cells
• Can treat up to 7 cm of Barrett’s esophagus per session
• Damage is evident 7 to 8 hours after procedure

Equipment
• System can be used with various laser or lamp types
• Entire unit can fit on endo-scopy cart
• Fibers are one-time use, and cost approximately $600
• Balloons are available in diameter of 18 mm, and varying lengths
• Laser calibrator can be used to program size of Barrett’s esophagus to be treated

Potential Adverse Events
• Acute: pain, nausea, cutaneous photosensitivity
• Delayed: stricture

*Presented by:
Kenneth Wang, MD
Director, Barrett’s Esophagus Unit
Mayo Clinic
Rochester, Minnesota

Bennett Roth, MD
Clinical Professor of Medicine
Chief of Clinical Gastroenterology Director, Digestive Disease Center
UCLA School of Medicine
Los Angeles, California

Endoluminal Therapy for Barrett’s Dysplasia: Unsolved Issues

In select patients with Barrett’s esophagus and high-grade dysplasia, endoluminal therapy has the potential to achieve the same effect as surgery, leaving no residual disease. “Indeed, endoluminal therapy may be an effective treatment option for patients with high-grade dysplasia whose age, comorbidities, and other factors preclude them from undergoing esophagectomy,” said Gregory Ginsberg, MD, Associate Professor of Medicine, University of Pennsylvania School of Medicine, Director of Endoscopic Services, Hospital of the University of Pennsylvania, Philadelphia. Dr. Ginsberg presented some of the unsolved issues in the who, when, where, and why of endoluminal therapy for Barrett’s esophagus.

Endoluminal vs Surgical Therapy
It is well known that patients with Barrett’s disease and high-grade dysplasia are at high risk for the development of esophageal adenocarcinoma. However, accurate biomarkers to predict who will and will not develop malignancy do not yet exist. “While esophagectomy is potentially curative for patients with high-grade dysplasia, the procedure is also associated with a 3% to 13% mortality rate, making patient selection highly important,” Dr. Ginsberg noted (Birkmeyer et al. N Engl J Med 2002; 346:1128). “In patients who are marginal risk candidates for surgery, it is reasonable to consider endoluminal therapy,” he said.

Endoluminal Therapy: Diagnosis and Patient Selection
According to Dr. Ginsberg, the main risk in utilizing endoluminal therapy in patients with high-grade dysplasia is concern over the development of invasive carcinoma before, during, or after therapy. “In addition, we do not want to subject patients who are not curable to endoluminal therapy,” he explained. For this reason, it is important to ensure a complete and accurate diagnosis, and an intensive biopsy protocol to assess for macroscopically distinguishable lesions. Reid and colleagues performed the Seattle biopsy protocol and found that 95% of esophageal cancers in 45 patients with high-grade dysplasia were intramucosal (Reid et al. Am J Gastroenterology 2000;95:3089).

In addition, studies have demonstrated a benefit using endoscopic mucosal resection-enhanced diagnosis, achieving an upgraded pathology in up to approximately 44% and allowing improved assessment of degree of differentiation, lymphovascular invasion, depth of invasion, and margins of resection for any cancers detected (Ahmad et al. GI Endosc 2002;55:390-6; Nijhawan & Wang. GI Endopsc 2000; 52:328-32). Adjunctive use of endoscopic ultrasound remains the optimal tool for detecting the presence of invasive carcinoma, Dr. Ginsberg reported (Scotiniotis et al. GI Endosc 2001;54: 689-96).

In one study, Dr. Ginsberg’s group followed 22 patients who had evidence of only high-grade dysplasia or intramucosal carcinoma by endoscopy, biopsy, and CT scan. All patients then underwent endoscopic ultrasound and surgery. Comparison of endoscopic ultrasound and surgical pathology showed that endoscopic ultrasound was effective in identifying submucosal invasion in five of five cases (one T3) and one of one case of lymph node involvement (Scotiniotis et al. GI Endosc 2001; 54:689-96). “Most importantly, these findings showed a very high negative predictive value,” Dr. Ginsberg noted.

Another important consideration in selecting patients for endoluminal therapy is the distribution of high-grade dysplasia. According to Dr. Ginsberg, further study is needed to evaluate disease factors such as short- or long-segment disease, unifocal versus multifocal disease, and the risk for recurrence or metachronous disease.

Endoluminal Therapy: When, Where, Why to Treat
Debate continues on whether treatment of endoluminal therapy is appropriate pre-dysplasia, or after progression to low-grade disease, high-grade disease, or even intramucosal carcinoma. In addition, there is considerable disagree-ment among researchers as to optimal post-treatment surveillance intervals. Questions as to the duration of surveillance, point to retreat, and point to accept failure remain to be answered. The setting for endoluminal therapy is also under discussion, with many asserting the need for performance of this treatment only at academic medical centers with a commitment to research.

“The why to treat with endoluminal therapy revolves around the difference between efficacy and effectiveness,” Dr. Ginsberg explained. Efficacy with photodynamic therapy has been shown in patients with high-grade dysplasia (Overholt. GI Endosc 1999;49:1-7). Data on effectiveness are now needed to determine whether successful photodynamic therapy will reduce disease-related mortality and will compare favorably with other emerging new therapies, he said (Table 1).

In closing, Dr. Ginsberg emphasized that “the main advantage of resection over ablative therapies is the provision of a histologic specimen for inspection and prognosis. It is hoped that the near future will bring the use of a multimodal treatment approach, incorporating both resection and ablative techniques, individualized according to patient and disease factors.” Further study is needed on endoluminal therapy versus observation, endoluminal therapy versus surgery, comparison of different endoluminal techniques, and use of multimodal endoluminal therapies.

Return to American College of Gastroenterology Print This