PDT Under Study for High-Grade Dysplasia in Barrett’s Esophagus

SAN ANTONIO—For patients with high-grade dysplasia in Barrett’s esophagus, photodynamic therapy (PDT) may be a useful minimally invasive option.

“While esophagectomy remains the gold standard and should be considered for every patient with high-grade dysplasia, PDT should be considered for the substantial numbers of patients for whom esophagectomy is contraindicated,” said Scott W. Taber, MD, assistant professor of surgery, University of Louisville School of Medicine.

Problems in Treating Barrett's Esophagus

There remain inherent uncertainties in the approach to Barrett’s esophagus because of difficulties in determining the exact anatomic location of the gastric esophageal junction in the gastric fold (where the specialized columnar epithelium in the tubular esophagus is susceptible to histologic changes).

In addition, agreement is lacking over the proper biopsy criteria, although most physicians biopsy every 2 cm throughout the Barrett’s area, in each of four quadrants with a jumbo biopsy forceps, plus in any location that looks “suspicious,” Dr. Scott Taber said at a symposium held in conjunction with the Society for Thoracic Surgeons annual meeting.

What is agreed upon, Dr. Taber emphasized, is that adenocarcinoma prevalence has been on the rise. “While the ratio of squamous cell cancer of the esophagus to adeno-carcinoma of the esophagus used to be 90/10, the ratio has reversed to 80/20—adenocarcinoma to squamous cell cancer,” he said.

He noted that some attribute the change to masking of GERD (gastroesophageal reflux disease) through patients’ self-medicating with over-the-counter H₂-blockers. “That promotes development of Barrett’s esophagus,” Dr. Taber said. The prevalence of Barrett’s esophagus in the general population may be as high as 7 per thousand, and among those with GERD, it is 8 per thousand.

“While we know that there is progression from Barrett’s esophagus to invasive cancer, we really don’t know how often high-grade dysplasia progresses to invasive disease,” he said. Progression takes place within a time frame of 48 to 60 months.

For lower-stage Barrett’s esophagus, treatment has classically been through acid suppression via H2-blockers or proton pump inhibitors; physical management of GERD through weight loss, abstinence from caffeine, tobacco, and alcohol, other dietary restrictions, and elevating the head of the bed 2 to 3 inches; and antireflux surgery.

Speaking at a satellite symposium of the Society for Thoracic Surgeons annual meeting, Dr. Taber cited several other alternatives, including saline injection followed by mucosectomy, use of an argon coagulator, and photoablation with the Nd:YAG laser.

“The drawback of the latter,” Dr. Taber noted, “is that because treatment is limited to an area of only about 2 cm, multiple endoscopies and treatments are needed.” Furthermore, the laser entails risk of perforations, explosions, and fire.

PDT is approved for the palliation of dysphagia, a common complication of esophageal cancer, and is currently under study for treatment of high-grade dysplasia in Barrett’s esophagus in phase III multicenter clinical trials in the United States and Europe.

The treatment involves administration of a chemical photosensitizer (porfimer sodium, Photofrin), followed by red light exposure of the tumor area. The light exposure initiates a chemical reaction of the photosensitizer within the tumor cells, leading to production of oxygen radicals and cell death.

An earlier study of 55 Barrett’s esophagus patients with high-grade dysplasia with 5-year follow-up showed that 30% converted back to normal squamous mucosa after PDT. Furthermore, a substantial additional proportion of the population improved from high-grade dysplasia to mild or moderate dysplasia (Overholt B et al: Gastrointest Endosc Clin North Am 7:207-217, 1997).

Stricture rates, however, were high, but Dr. Taber attributed this to a high light dose of 300 joules. Areas where treatment overlapped may be getting much higher doses, he noted, suggesting that for the thin lesions of Barrett’s esophagus, 200 joules should be sufficient. Centering balloons currently in development may also prevent areas with doubled dosimetry or skipped areas.

In the current phase III trial with 100 patients using the centering balloon and 170 joules of light energy, preliminary assessment has shown lower stricture rates with fewer skipped areas.

The average Barrett’s esophagus patient, Dr. Taber said, is treated with 200 joules of light for about 500 seconds (8 minutes, 20 seconds) per treatment segment. Treatment sessions for this population average about 30 to 40 minutes.

While phototoxicity occurs in upwards of 20% of patients, careful attention to patient education can lower the risk. Photo bleaching, which inactivates porfimer sodium, can be promoted by asking patients to go into direct sunlight daily for 1 minute by the clock starting between the 1st and 2nd week after injection. Dr. Taber recommended extending the exposure time in the 3rd and 4th weeks. At 30 days, patients should go outside and test an area of skin.

“The question of real interest,” Dr. Taber said, “is whether or not we can start using PDT to treat people in the mild-to-moderate dysplasia phase of Barrett’s esophagus. Will PDT convert or alter their dysplasia pattern? Could we then just treat GERD [gastroesophageal reflux disease], the original cause of their Barrett’s esophagus?”

Dr. Taber noted further that because important questions about the PDT success rate remain unresolved, it is essential that patients should be under the rigorous screening protocol of the phase III trial. Physicians wishing information about enrolling patients in the phase III trial can call QLT PhotoTherapeutics, Inc. (contact Herma Neyndorff at 604-872-7881).

Dr. Taber concluded, “PDT is a useful minimally invasive means for local tumor control in the esophageal lumen. It provides substantial ablation of dysplastic mucosa.”