Photodynamic therapy and endoscopic mucosal resection for Barrett's dysplasia and early esophageal adenocarcinoma.

Background: Endoscopic mucosal resection (EMR) and endoscopic ablation with porfimer sodium photodynamic therapy (PDT) have recently been combined to improve the accuracy of histologic staging and remove superficial carcinomas.

Materials and Methods: All patients with Barrett's esophagus and high-grade dysplasia were evaluated with computed tomography and endosonography. Patients with nodular or irregular folds underwent EMR followed by PDT.

Results: In three patients, endoscopic mucosal resection upstaged the diagnosis to mucosal adenocarcinoma (T1N0M0). PDT successfully ablated the remaining glandular mucosa. Complications were limited to transient chest discomfort and odynophagia.

Conclusions: The use of EMR resection in Barrett's high-grade dysplasia patients with mucosal irregularities resulted in histologic upstaging to mucosal adenocarcinoma, requiring higher laser light doses for PDT. PDT after EMR appears to be safe and effective for the complete elimination of Barrett's mucosal adenocarcinoma. EMR should be strongly considered for Barrett's dysplasia patients being evaluated for endoscopic ablation therapy.

Key Words: Barrett's esophagus, endoscopic mucosal resection, endoscopic ultrasound, esophageal cancer, photodynamic therapy

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Barrett's esophagus, associated with chronic gastroesophageal reflux disease, is the most important risk factor for the development of adenocarcinoma, now the most common form of esophageal cancer. (1) Neoplastic degeneration into adenocarcinoma occurs via the development of dysplasia within the specialized intestinal metaplasia characteristic of Barrett's esophagus. Since early carcinoma of the esophagus is limited to the mucosa without involvement of adjacent lymph nodes, esophagectomy with complete resection of Barrett's dysplasia and carcinoma is considered curative. (2) Although partial or total esophagogastrectomy are accepted as the current standard of care for Barrett's high-grade dysplasia or carcinoma, the associated morbidity and mortality are not trivial. Recent studies have found a surgical mortality rate of nearly 20% with esophagectomy in low-volume surgical centers (where the majority of these operations are performed) and rates of serious morbidity approaching 50%. (3-5) These results have spurred the search for minimally invasive methods for the ablation of Barrett's high-grade dysplasia and early cancer. (6)

Endoscopic mucosal resection (EMR) involves injection of saline into the submucosal space to elevate and separate the target mucosa from the deeper layers of the esophageal wall. The target mucosa is then to be removed by one of several techniques, including the "band and snare method." (7) EMR has proven most useful in obtaining large specimens for histologic evaluation of abnormal Barrett's mucosa noted at endoscopy or endosonography. This technique, however, is not considered suitable for the treatment of diffuse, long-segment Barrett's esophagus, where the location of high-grade dysplasia or adenocarcinoma in situ is unknown. (8) Photodynamic therapy (PDT) uses endoscopically applied laser red light energy to activate an intravenously infused photosensitizer, porfimer sodium. The activated photosensitizer reacts with mucosal oxygen to generate superoxide radicals that produce diffuse mucosal necrosis capable of destroying large areas of Barrett's glandular mucosa. Although associated with significant risks of stricture and phototoxicity, porfimer sodium PDT is considered the most attractive minimally invasive therapeutic modality for the treatment of Barrett's dysplasia or mucosal adenocarcinoma. (8-10) This study describes the combined use of EMR and PDT in patients with Barrett's esophagus with high-grade dysplasia referred for endoscopic ablation.

Materials and Methods

Since 1997, we have used porfimer sodium PDT to treat 83 patients with Barrett's high-grade dysplasia or early esophageal adenocarcinoma. An expert pathologist confirmed the referral histologic diagnosis. A cardiothoracic surgeon evaluated all patients and they either refused or were considered not fit for surgery. These patients underwent an extensive evaluation including contrast-enhanced computed tomography and endosonography for staging of their disease. (11) Of these, EMR was used in 3 patients who were found to have irregular or nodular mucosal folds within long-segment Barrett's high-grade dysplasia. EMR used submucosal injection of 20 to 30 mL normal saline, with or without 1:10,000 epinephrine, followed by use of the band ligation device (Boston Scientific, Natick, MA). The target mucosal "pseudopolyp" was removed by a standard polypectomy snare, with recovery of the specimen for histologic analysis. After, EMR patients were treated with double-dose proton pump inhibitor and sucralfate elixir for 4 to 6 weeks. Thereafter, patients underwent intravenous infusion with porfimer sodium (2 mg/kg) and laser light application 48 hours later to deliver 175 to 250 J/cm fiber length using 630 nm red light energy with a 2.5 to 5 cm-length quartz diffusing fiber powered by a diode laser (Diomed, Andover, MA). After treatment, patients were followed every 3 to 6 months with endoscopy with surveillance biopsies using large capacity forceps to sample mucosa every 1 cm in four quadrants through the area previously treated with PDT. Endosonography and contrast-enhanced computed tomography scans were also performed at the time of these interval surveillance examinations, as previously described. (11)

Results

The Table outlines the characteristics and demographics of these patients as well as their referral diagnosis and their diagnosis after EMR. All the patients were men either 68- or 69-years-old with long-standing hypertensive heart disease, coronary artery disease, and diabetes mellitus. Endoscopy documented Barrett's glandular mucosa of 3 cm or greater and mucosal irregularities (nodular, polypoid mucosal protuberances). Endosonography, however, found no other mucosal abnormalities aside from mucosal expansion. There was no suspicious paraesophageal lymphadenopathy found on either contrast-enhanced computed tomography or endosonography. Subsequently, the submucosal injection was performed using a 1:10,000 epinephrine solution of saline producing the "lift sign," indicating no submucosal invasion. (12, 13) EMR was then performed using the band and snare method in each patient, yielding histologic specimens of at least 15 mm diameter. (14) In each case, the initial diagnosis of Barrett's esophagus with high-grade dysplasia was up-staged to adenocarcinoma limited to the mucosa (T1N0M0). After EMR and PDT, these patients have done well, with symptoms limited to self-limited swallowing difficulties and chest discomfort. The combination of EMR followed by porfimer sodium PDT was not associated with stricture formation. At a median follow-up of 13 months (range 6-46 mo), there was no sign of recurrent or persistent Barrett's glandular mucosa, dysplasia or neoplasia. Surveillance biopsy protocols of the distal esophagus documented stable squamous mucosa.

Conclusion

Barrett's esophagus, the result of chronic gastroesophageal reflux disease, is the major risk factor for the development of adenocarcinoma, now the most common form of esophageal cancer. This malignant degeneration occurs via the metaplasia-dysplasia-neoplasia sequence, with Barrett's high-grade dysplasia representing a high-risk lesion for the development of invasive adenocarcinoma. (15, 16) Currently the standard treatment for Barrett's esophagus with high-grade dysplasia, esophageal resection completely removes all Barrett's glandular mucosa with its present and future carcinogenic potential. (17, 18) Unfortunately, however, the majority of patients diagnosed with Barrett's dysplasia or cancer are not ideal surgical candidates. The typical patient is a white male between 65 to 75 years of age with multiple significant medical conditions, such as coronary artery disease and diabetes mellitus. (19, 20) Although most esophagectomy series in the literature are reported from expert academic centers, recent studies indicate that the vast majority of these procedures (80%) are actually performed in smaller community hospitals, and are complicated by operative mortality of nearly 20%, and, in almost half of these patients, major morbidity including anastomotic stricture (13%), anastomotic leak (7%), dumping syndrome (4%), recurrent aspiration (3%), and wound infection, colon necrosis, pyloric channel ulcer, pulmonary embolus and chylothorax (1% each). (3-5, 21) A lower risk, minimally invasive alternative to esophagectomy, such as endoscopic mucosal resection or ablation, is required for those patients who are not candidates for, or are not willing to accept the risks of, surgical resection. (10)

Endoscopic techniques currently available fall into three categories--thermal ablation, photochemical ablation, or mucosal resection. Thermal methods, such as heater probe or argon beam coagulation, have been most effectively applied against small, endoscopically distinct target lesions. These methods also require significant endoscopic expertise to control uniform mucosal treatment, and adequate depth of mucosal destruction. Their use in the treatment of Barrett's mucosa, however, has been associated with a significant incidence of residual glandular mucosa underlying squamous epithelium, and serious complications including esophageal perforation. (22, 23) Similarly, endoscopic mucosal resection is a technique that permits the removal of a target mucosal lesion after submucosal injection of saline and epinephrine, and removal with a polypectomy snare. (24-26) Retrieval of the specimen permits histologic analysis and determination of the lesion depth and stage. One study has suggested that EMR is useful for detecting the presence of invasive carcinoma in the setting of mucosal irregularities with Barrett's high-grade dysplasia. (27) EMR has been most successfully used to remove target mucosal lesions, but since large areas of Barrett's glandular mucosa are left untreated, there is a significant risk of dysplasia progression or the development of metachronous lesions. (28) Similar to the thermal ablation methods, the use of EMR is said to be poorly suited for use in patients with Barrett's high-grade dysplasia. (8, 29)

Alternatively, photodynamic therapy (PDT) ablates large areas of glandular mucosa by a photochemical reaction produced by light energy activation of a photosensitizer. Varying the amount of light energy and the characteristics of the photosensitizer can control the depth of mucosal ablation produced with PDT. For instance, PDT using amino-levulinic acid (ALA) has been successful in ablating Barrett's metaplasia and low-grade dysplasia, with only transient phototoxicity and minimal risk of stricture. (30) This limited mucosal penetration, however, makes ALA-PDT unreliable for the treatment of Barrett's high-grade dysplasia or mucosal carcinoma, PDT using the more powerful photosensitizer porfimer sodium, however, has been proven to destroy Barrett's high-grade dysplastic mucosa and superficial neoplasms. (6, 31) This deeper mucosal penetration carries with it a 25 to 33% risk of esophageal stricture and prolonged photosensitivity lasting 4 to 6 weeks. For most patients, these complications are minor considerations compared with the risks of esophagectomy. (32) Optimal treatment results, however, are vitally dependent on accurate staging of disease, requiring the use of endosonography with availability of high-resolution probes and fine needle aspiration to sample submucosal lesions and suspicious paraesophageal lymph nodes. (33) These techniques, applied by an experienced endosonographer, are necessary to ensure that any carcinoma present is limited to the mucosa (Tis or T1a), since submucosal involvement (T1b or greater) suggests nodal metastasis that obviates the use of endoscopic ablation therapy. (6, 34-38)

The current study describes the use of EMR followed by treatment with porfimer sodium PDT in patients with Barrett's esophagus with high-grade dysplasia referred for endoscopic ablation. This treatment regimen permits the resection and histologic evaluation of mucosal irregularities, even with normal or near-normal endosonographic characteristics, which are likely to harbor invasive carcinoma. (39) In our experience, the data obtained from endosonography and EMR are used to adjust the light energy dosimetry for porfimer sodium PDT for optimal ablation of the remaining Barrett's glandular mucosa. In the current study, this treatment regimen was associated with no additional adverse effects aside from the anticipated transient chest discomfort and swallowing difficulties. These results confirm those of others who have combined use of EMR and PDT for successful endoscopic ablation of superficial esophageal cancer and dysplastic Barrett's glandular mucosa. (40, 41) As part of our clinical standard of care, we now perform EMR routinely before porfimer sodium PDT in our Barrett's dysplasia and early carcinoma patients who have endoscopic or endosonographic irregularities.

Table. Endoscopic mucosal resection and photodynamic therapy in patients
with Barrett's esophagus and high-grade dysplasia (a)

Referral diagnosis  Age (yr)  Post-EMR diagnosis  BE length  Follow-up
                                                               (mo)

    BE + HGD          69        Adenocarcinoma      3 cm        46
    BE + HGD          69        Adenocarcinoma      4 cm        13
    BE + HGD          68        Adenocarcinoma      4 cm         6

(a) EMR, endoscopic mucosal resection; BE. Barrett's esophagus: BE +
HGD, Barrett's esophagus with high-grade dysplasia.

Accepted April 5, 2004.

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RELATED ARTICLE: Key Points

* The past two decades have witnessed an alarming increase in patients diagnosed with Barrett's esophagus and esophageal adenocarcinoma.

* Photodynamic therapy using porfimer sodium has recently been approved for use in patients with Barrett's high-grade dysplasia, as an alternative to surgical resection.

* Mucosal irregularities occurring within the Barrett's glandular mucosa are suspicious for the presence of invasive neoplasm.

* Endoscopic mucosal resection of these mucosal Barrett's irregularities detected mucosal adenocarcinoma.

* Photodynamic therapy after endoscopic mucosal resection appears to be safe and effective for the complete elimination of Barrett's mucosal adenocarcinoma.

H. C. Wolfsen, MD, FACG, FACP, Lois L. Hemminger, ARNP, Massimo Raimondo, MD, and Timothy A. Woodward, MD

From the Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL.

The authors received no outside financial support for the current study and have no proprietary interest in any products or devices described in this manuscript.

This study was approved by the Institutional Review Board of the Mayo Foundation.

Reprint requests to H. C. Wolfsen, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224. Email: [e-mail]