Barrett's esophagus: Photodynamic therapy for ablation of dysplasia, reduction of
specialized mucosa and treatment of superficial esophageal cancer

Bergein F. Overholt and Masoud Panjehpour

Laser Center
Thompson Cancer Survival Center
Knoxville, TN 37916

ABSTRACT

Fifteen patients with Barrett's esophagus and dysplasia were treated with photodynamic therapy. Four 
patients also had early, superficial esophageal cancers and 5 had esophageal polyps. Light was delivered 
via a standard diffuser or a centering esophageal balloon. Eight patients maintained on omeprazole and 
followed for 6-54 months are reported.

Photodynamic therapy ablated dysplastic or malignant mucosa in patients with superficial cancer. Healing 
and partial replacement of Barrettes mucosa with normal squamous epithelium occurred in all patients and 
complete replacement with squamous epithelium was found in two. Side effects included photosensitivity 
and mild-moderate chest pain and dysphagia for 5-7 days. In three patients with extensive circumferential 
mucosal ablation in the proximal esophagus, healing was associated with esophageal strictures which were 
treated successfully by esophageal dilation. Strictures were not found in the distal esophagus.

Photodynamic therapy combined with long-term acid inhibition provides effective endoscopic therapy of 
Barrettes mucosal dysplasia and superficial (Tis-T1) esophageal cancer. The windowed centering balloon 
improves delivery of photodynamic therapy to diffusely abnormal esophageal mucosa.

2. INTRODUCTION

Barrett's esophagus has an increased occurrence of mucosal dysplasia and adenocarcinoma in the 
specialized glandular mucosa 1-11 Esophagectomy is recommended for Barrettes adenocarcinoma and for 
selected cases with severe dysplasia. However, surgical resection is associated with a significant morbidity 
and mortality'2~'5. An alternative non-operative therapy with lower risks and reduce costs is desirable.

3. MATERIALS AND METHODS

All patients referred for PDT had repeated endoscopic examinations and biopsies demonstrating Barrettes 
esophagus and dysplasia. Five patients had esophageal polyps and 3 of these had early cancers less than 1.5 
cm in size (Table 1). In patients with
biopsy proven adenocarcinomas, only those with lesions that were interpreted Tis-1, N-0, M 0'6 by 
endoscopic ultrasound (EUS) and computed tomography were included in the study. However, one patient 
with a T-2 lesion was included in the study and treated since he was not a surgical candidate due to 
pulmonary obstructive disease. Eight patients followed from 6-54 months are reproted. The study was 
approved by the Institutionai Review Board of the Thompson Cancer Survival Center.

Porfimer sodium 2 mg/Kg (PhotofrinR Quadra Logics Technologies, Inc., Vancouver, BC, Canada) was 
injected intravenously. Forty-eight hours later 630 nm light was endoscopically delivered using a 
cylindrical diffuser. An argon-pumped dye-laser (Lambda Plus, Coherent, Palo Alto, CA) tuned to a 
wavelength of 630 nm was used to provide endoscopic delivery of the red light to the esophagus via a 
fiberoptic probe. A 400 micron 2.0 or 2.5 cm cylindrical diffuser, was attached to the extension fiber and 
inserted through the endoscope into the esophageal lumen or later in the study, into the center of a 
centering esophageal balloon to deliver light intraluminally to the targeted area. Power density was 400 
mW/cm of diffuser with a treatment time of 12.5 minutes per segment of treated esophagus, providing 
energy density of 300 Joules/cm from the diffuser.

In 4 patients (cases #2,3,6,7), a 2 or a 3 cm windowed, 25 mm diameter esophageal centering balloon was 
used to deliver the light. The deflated balloon was passed into the esophagus, endoscopically positioned 
and inflated. A small endoscope (Fujinon EVG-FP; Wayne, NJ) was passed alongside the shaft of the 
centering balloon to verify and monitor the position of the balloon during PDT. All patients were sedated 
with meperidine and midazolam during the procedure. l Oxygen was administered by nasal catheter at 2-3 
I/min. Atropine sulfate 0.4 mg and glucagon 1 mg were given intravenously if secretions or esophageal 
motility were excessive. ~After initial balloon studies on patients #2,3 and 7, the diffuser energy density 
was reduced to 250 Joules/cm.

The centering balloon'7~'9 consisted of two major parts: 1) A semi-flexible tube containing two small 
concentric vinyl tubes and 2) an inflatable cylindrical balloon attached to the distal end. The inner tube 
used to introduce the cylindrical diffuser into the balloon was optically clear and had an inside diameter of 
approximately 2.0 mm, allowing use of commercially available cylindrical diffusers for photodynamic 
therapy. A removable stylet was placed inside the inner tube to increase the stiffness during passage into 
the esophagus. The second tube was used for inflation and deflation of the balloon.

The overall length of the cylindrical balloon was 63 mm with an outside diameter of 25 mm when fully 
inflated. The balloon was tapered at both ends providing an effective cylindrical length of 36 mm. A 360 
degree 2 or 3 cm balloon window was prepared as described previouslyt9. The balloon was constructed 
from an optically clear polyurethane membrane with thickness of approximately 0.11 mm (Datascope 
Corporation, Paramus, New Jersey).
EUS was performed with the Olympus MB-3 instrument (Olympus Corporation of
America, New Hyde Park, NY). Endoscopies were performed with the Fujinon EVG-CT and EVG-FP 
(Wayne, New Jersey) and Olympus GIF-100 and GIF-1T100 endoscopes ( New Hyde Park, New York). A 
follow-up endoscopy was performed at 48 hours to determine if additional light treatment was required. 
Subsequent endoscopies were performed at 1 week, 3, 6, 9 and 12 months. Biopsies of healed mucosal 
areas that demonstrated squamous epithelium were evaluated for underlying glandular mucosa. All 
patients were treated with omeprazole, 20 mg twice a day for the first 3 months and then once a day. All 
patients were treated as outpatients and received intermittent intravenous fluids at home for 5-7 days 
following PDT.

4. RESULTS

With the diffuser aione, extensive injury to exposed mucosa was observed along with destruction of 
dysplastic epithelium and small cancers. However, there were occasional small areas of mucosa that were 
not damaged, presumably due to the effects of esophageal motility, cardiac and respiratory movement on 
the position of the probe and from shadowing due to prominent esophageal folds around the diffuser probe 
in the non-distended esophagus20.

The centering balloon system was developed to provide uniform, circumferential and predictable light 
delivery to esophageal mucosa and to eliminate irregular light delivery and the "hill and valley" effect due 
to shadowing caused by esophageal folds in the noirdistended esophagus. In the first 2 patients treated with 
300 J/cm using the balloon system (case #2,3), marked circumferential edema, superficial ulceration and 
mucosal hemorrhage was found. Therefore the energy density was reduced to 250 J/cm in patient #6 and 
200 J/cm in patient #7 in order to determine the proper dosimetry. At 200 J/cm, only mild edema and 
mucosal injury were observed, necessitating a second treatment. The effect at 250 J/cm produced 
circumferential mucosal injury sufficient to destroy the dysplastic mucosa but in this patient a second 
interstitial light treatment was administered to complete the ablation of a 1.3 cm T-2, N-0 adenocarcinoma.

In all patients, full repair of the damaged mucosa required up to 6 months. Healing was associated with the 
appearance of granulation tissue in areas where the mucosa had been destroyed. Sites of previous Barrett's 
mucosa were replaced completely or partially with squamous epithelium beginning at 3 months. Multiple 
biopsies, including "jumbo" biopsies in some, of these areas did not reveal underlying glandular mucosa 
except a few gastric glands in one case. Reduction of the amount of the surface area of Barrett's mucosa, 
was noted in all cases. In patients receiving PDT targeted to early cancers only (#1,6,8), the treated areas 
were replaced entirely with squamous epithelium. In all patients receiving PDT to the entire segment of 
Barrett«s mucosa, a marked reduction in the surface area of Barrett's mucosa was found. In these patients, 
the healing process was associated with the squamocolumnar junction being relocated distally an average 
of 4.8 cm.

Three patients (cases #3,6-7) underwent a second light treatment to residual tumor
tissue or to small areas of esophageal mucosa that were not significantly damaged from the initial PDT 
treatment. In one patient (case #8), a second course of PDT was given due to recurrence of superficial 
cancer at 3 months.

In the first patient treated with the balloon (case #2), the position of the balloon apparently did not change 
when repositioning was attempted, resulting in a probable "double-dose" of light to a segment of the 
esophagus. As a result, the study was modified to use a small endoscope to monitor the exact position of 
the balloon during the treatment procedure in subsequent patients.

Full dose (300 J/cm) PDT treatment produced mild-moderate chest pain and dysphagia lasting for 
approximately 1 week but this gradually improved in ail patients. An esophageal stricture developed in one 
patient who had PDT for an early adenocarcinoma in an island of Barrettes mucosa at 25 cm and in 2 
additional patients undergoing treatment to the proximal esophagus. The strictures responded to dilation. 
Areas distal to 30 cm treated with PDT did not develop esophageal strictures even though esophageal 
injury was sometimes extensive.

5. DISCUSSION

Barrett's esophagus' is characterized by replacement of normal esophageal squamous epithelium by 
specialized columnar epithelium in some patients with a hiatal hernia and esophagitis. The incidence of 
carcinoma in Barrett's esophagus is estimated to be 30-40 times that of the normal population3~6 
occurring in approximately 10% of cases7~9. Annual or biennial screening endoscopy with multiple 
biopsies is recommended for detection of dysplasia or early adenocarcinoma. Esophagectomy is 
recommended for Barrett's adenocarcinoma and for selected cases with high grade dysplasia'015.

A minimally invasive treatment resulting in the reduction of Barrett's mucosa is desirable. Certainly, an 
alternative to esophagectomy as a treatment modality is needed due to the morbidity and mortality of 
esophagectomy'1~1215. Various investigators have reported attempts to reduce the extent of Barrett's 
mucosa using medicaf1~24 or surgical therapy25~27 but the results have been controversial and have not 
consistently reduced either dysplasia or the extent of Barrett's mucosa. Other investigators have used argon 
or Nd:YAG laser thermal ablation of Barrett's mucosa followed by omeprazole therapy for acid 
suppression with generally favorable, albeit limited, results29~32.

Photodynamic therapy(PDT)33 has been used for treatment of superficial esophageal cancer2034~42 and 
represents a possible non-operative alternative to esophagectomy for Barrett's esophagus. PDT for the 
treatment of Barrett's esophagus with dysplasia has only recently been described. Overholt et af  reported 
reduction of the extent of Barrett's mucosa and dysplasia and elimination of superficial carcinoma in a 
patient with early esophageal adenocarcinoma treated with PDT and maintained on omeprazole.

Laukka et aP3 used "low dose" PDT for the treatment of Barrett's esophagus in 10
patients. They described an average 3 cm reduction in the length of the Barrett's segment but no change in 
the dysplasia grade in patients treated with "low-dose PDT' and maintained for 6 months on omeprazole 20 
mg daily. The photosensitizer used in their work was 1.5 mg/Kg of hematoporphyrin derivative followed 
48 hours later with photoradiation with 630 nm light using a 1.0-1.5 cm cylindrical diffuser to produce a 
light dose of 150-200 J/cm. No description of the degree of mucosal destruction was provided in their 
abstract. The role of "low dose" PDT in the treatment of Barrett's esophagus will need further study.

This report presents eight patients treated with PDT for dysplasia and in 4 of the cases, early esophageal 
adenocarcinoma in Barrett's esophagus. All patients were maintained on long-term omeprazole to achieve 
acid suppression following PDT. Extensive mucosal ablation was observed after PDT. Follow-up 
endoscopic findings and biopsies demonstrated a reduction of the extent of Barrett's mucosa in all patients 
with replacement of much of the treated glandular mucosa by squamous epithelium. The replacement with 
squamous epithelium was associated with a relocation of the squamocolumanr junction distally an average 
of 4.8 cm in the patients treated for dysplasia. In 2 patients a virtual complete replacement of Barrett's 
mucosa was found following PDT. In the patients with superficial cancers, the treated areas also healed 
with squamous epithelium.

With one exception, high grade dysplasia was abolished in all patients. In case #3, an area of dysplastic 
mucosa located near the squamocolumnar junction was not adequately destroyed. At the 6 month 
follow-up, dysplasia was found to persist. A second treatment is planned.
l
We have found the balloon technique to be more effective than the diffuser in the treatment of diffuse 
superficial lesions such as dysplasia but that targeted PDT with the diffuser is necessary for treatment of 
well defined lesions such as the small cancers treated in 4 of our patients. However, in our patients with 
treatment of 6-10 cm of the esophagus with the full light dose of 300 J/cm, dysphagia and moderate chest 
pain developed following PDT. As a result, we have modified our study design to provide 250 J/cm light 
using a 2 cm diffuser and a 2 or a 3 cm windowed centering balloon. We now restrict treatment to 3-5 cm 
during a single PDT session.

We agree with Berensorf6 that ablation of Barrett~s mucosa is essential if squamous epithelization is to 
occur with healing of the damaged mucosa. Indeed, our experience indicates that extensive mucosal 
ablation is required. For example, in patient #8, the first PDT treatment produced only partial tumor and 
mucosal destruction. At the three month follow-up, the tumor was present on biopsy as was Barrett's 
mucosa in the treated area. A second treatment resulted in much greater mucosal damage and tumor 
destruction. After healing, the tumor was no longer present and the mucosa demonstrated squamous 
epithelium throughout the treated area.

In summary, we have reported the ablation of superficial cancer in 4 patients, the ablation of dysplasia in 7 
and the reduction of the extent of Barrett's mucosa in 8 patients
who were treated with PDT and were maintained on omeprazole. It is our opinion that both mucosal 
ablation and long-term acid inhibition are essential for reduction of the extent of Barrett's mucosa. We also 
believe patient outcomes are improved by the use of PDT as the treatment modality for Barrett's dysplasia 
and/or superficial carcinoma.

6. ACKNOWLEDGEMENTS

The authors acknowledge the significant contributions to this work provided by Elmeria Teffetellar, RN, 
Rick Sneed, Mark Rose and Paul Buckley.

7. LEGEND

Table 1. * = Patients were treated with omeprazole following PDT (see Text). ** = 2nd treatment planned 
(see Text); M = male; F = female; Tx = treatment; N = none; LG = low grade; HG = high grade; cm = 
centimeters; BE = Barrett's esophagus; Ca = cancer; Tis = limited to mucosa; T1 = limited to 
mucosa/submucosa; T2 = Invasion to muscularis propria; NA = not applicable

8. REFERENCES

1.
2.
3.
4.

5. 6.

7.
8.
9.

Barrett N. Chronic peptic ulcer of the oesophagus and esophagitis. Brit J Surg 1950;38:175-182.
Allison PR, Johnstone AS. The oesophagus lined with gastric mucous membrane. Thorax 1953;8:87-101.
Cameron AJ, Ott BJ, Payne WS. The incidence of adenocarcinoma in columnarlined (Barrett's ) 
esophagus. NEJM 1985:313:857-9.
Spechler SJ, Robbins AH, Rubins HB, et al. Adenocarcinoma and Barrett's esophagus. An overrated risk: 
Gastroenterology 1984;87:927-33.
Spechler SJ, Goyal RK. Barrett's esophagus. New Engl J Med 1987;315:362-371. Sprung DJ, Ellis FH, 
Gibb SP. Incidence of Adenocarcinoma in Barrett's esophagus Am J Gastroenterol 1984;79(A):817.
Sjogren R W Jr, Johnson LF. Barrett's Esophagus: A review. Amer J. Med 1983;74:313-321.
Haggitt RC, Dean PJ. Adenocarcinoma in Barrett's epithelium. In: Spechler SJ, Goyal RK, eds. Barrett's 
esophagus: pathophyslology, diagnosis, and management. New York: Elsevier Science, 1985.
Naef AP, Savar M, Ozello L: Columnar-lined lower esophagus: An acquired lesion with malignant 
predisposition. J Thorac Cardiovasc Surg. 1975;70:826-835.
10. Hamilton SR, Smith RRL. The relationship between columnar epithelial dysplasia and invasive 
adenocarcinoma arising in Barrett's esophagus. Am J Clin Pathol 1987;87:301.
Reid BJ. Barrett's Esophagus and Esophageal Adenocarcinoma. Gastroenterol Clinics N Amer 
1991;20:817-834.
Levine DS, Haggitt RC, Blount PL et al. An endoscopic biopsy protocol can differentiate high-grade 
dysplasia from early adenocarcinoma in Barrett's
13.

14. 15. 16. 17.

18.
19.
20.
21.
22.

25. 26.

27.
28.

esophagus. Gastroenterology 1993;105:40-50
Reid BJ, Weinstein WM, Lewin KH, et al. Endoscopic biopsy can detect highgrade dysplasia or early 
adenocarcinoma in Barrett's esophagus without grossly recognizalel neoplastic lesions. Gastroenterology 
1988;94:81-90.
Pera M, Trastek VF, Carpenter HA, et al. Barrett's esophagus with high grade dysplasia: An indication for 
esophagectomy? Ann Thorac Surg 1992;54:199-204. Rice TW, Falk GW, Achkar E and Petras RE. 
Surgical management of high-grade dysplasia in Barrett's esophagus. Am J Gastroent 1993;88: 1832-1836.
Beahrs OH, Henson DE, Hutter RVP, Myers MH, eds. Manual for staging of cancer (esophagus). 3rd ed. 
Philadelphia: J.B. Lippincott Co., 1988:63-5.
Panjehpour M, Overholt BF, DeNovo R. Sneed R. Peterson M. Centering balloon to improve esophageal 
photodynamictherpay. Lasers in Surg & Med 1992;12:631638.
Overholt BF, Panjehpour M, DeNovo R and Peterson M. A centering balloon for photodynamic therapy for 
esophageal cancer tested in a canine model. Gastrointest Endosc 1993;39:782-7.
Overholt BF, Panjehpour M, DeMovo RC and Petersen MG. Photodynamic therapy for esophageal cancer 
using a 180  windowed esophageal balloon. Lasers Surg and Med 1994; 14:27-33.
Overholt BF, Panjehpour M, Teffetellar E and Rose M. Photodynamic therapy for treatment of early 
adenocarcinoma in Barrett's esophagus. Gastroint Endoscopy 1993;39:73-76.
Seitz JF, Biovannini M, Padaut-Cesana J. et. al. Inoperable nonmetastatic squamous cell carcinoma of the 
esophagus managed by concomitant chemotherapy (5-fluorouracil and cisplatin) and radiation therapy. 
Cancer 1990;66:214-219.
Coia LR, Paul AR and Endstrom PF. Combined radiation and chemotherapy as primary management of 
adenocarcinoma of the esophagus and gastroesophageal junction. Cancer 1988;61:643-649.
23. Hou B. Qun-Bin X and Li D. Thermo-Chemo-Radiotherapy of esophageal cancer: a preliminary report 
of 34 cases. Cancer 1989;64:1777-1782.
24.

Hidenobu K, Hidemasa M, Yasuyuki O. et. al. Heat, drugs, and radiation given in combination is palliative 
for unresectable esophageal cancer. Int. J. Radiation Oncology Biol. Phys. 1988;14:1147-1152.
Deviere J. Buset M, Dumonceau J-M, Rickaert F. Cremer M. Regression of Barrett's esophagus with 
omeprazole. N Engi J Med 1989;320:1497-1498.
Patel GK, Clift SA, Schaefer RA, Read RC, Texter EC Jr. Resolution of severe dysplastic (Ca in situ) 
changes with regression of columnar epithelium in Barrett's esophagus on medical treatment. 
Gastroenterology 1982;82:1147(A).
Gore S. Healy CJ, Sutton R. Shepherd NA and Wilkinson SP. Regression of columnar lined (Barrett's) 
oesophagus with continuous omeprazole therapy. Gastroent. 1992; 102:75(A) .
Sampliner RE, Mackel C, Jennings D and Greski-Rose P. Effects of 12 months of a proton pump inhibitor 
(lansoprazole) on Barrett's esophagus--a randomized trial. Gastroent. 1992:102:157tA).
29. 30. 31. 32. 33.

34. 35.

36.

37. 38.

39.

40. 41. 42. 43.

44.









45.
46.
Igbal TH, Neumann CS and Cooper BT. Omeprazole treatment of patients with Barrett's oesophagus. Gut 
(supplement) 1993;34:S19.
Brand DL, Yivisaker JT, Gelfand M, Pope CR. Regression of columnar esophageal (Barrett's) epithelium 
after anti-reflux surgery. N Engl J Med 1980;302:844-848.
Williamson WA, Ellis FH, Gibb SP. Effect of anti-reflux operation on Barrett's mucosa. Ann Thor Surg 
1990;49:537-542.
Sampliner RE. Antireflux surgery and Barrett's esophagus regression: Wheel of Fortune or To Tell the 
Truth? Am J Gastroenterol 1991 ;86:645-646.
Johnson TD, Berenson MM and Brandon KN. Restoration of normal esophageal mucosa after argon laser 
photoablation and omeprazole treatment of esophageal columnar epithelium (Abstract). Clin Res. 
1991;39:39.
Brandt LJ and Kauvar DR. Laser-induced transient regression of Barrett's epithelium. Gastointest Endosc. 
1992;38:619-622.
Sampliner RE, Hixson W. Fennerty B and Garewal HS. Regression of Barrett's Esophagus by Laser 
Ablation in an Anacid Environment. Dig Dis Sci. 1993;38:365368.
Berenson MM, Johnson TD, Markowitz NR, Buchi KN and Samowitz WS. Restoration of squamous 
mucosa after ablation of Barrett's esophageal epithelium. Gastroenterology 1993; 104:1686-1691.
Manyak MJ, Russo A, Smith PD, Glatsein E. Photodynamic Therapy, Review Article. J. Clin. Oncol. 
1988;6:380-391.
Hayata Y. Kato H. Okitsu H. Kawaguchi M, Konaka C. Photodynamic Therapy with Hematoporphyrin 
Derivative in Cancer of the Upper Gastrointestinal Tract. Seminars in Surgical Oncology 1985;1:1-11.
Tian ME, Qui SL, Ji Q. Preliminary Results of Hematoporphyrin Derivative-Laser Treatment for 13 Cases 
of Early Esophageal Carcinoma. Adv. Exp. Med. Biol. 1985; 193:21 -25.
Fujimaki M, Nakayama K. Endoscopic Laser Treatment of Superficial Esophageal Cancer. Seminars in 
Surgical Oncology 1986; 2:248-256.
McCaughan JS Jr., Nims TA, Guy JT, Hicks WJ, Williams TE, Laufman LR. Photodynamic Therapy for 
Esophageal Tumors. Arch. Surg. 1989;124:74-80.
Tajiri H. Daikuzono N. Joffe SN, Oguro Y. Photoradiation Therapy in Early Gastrointestinal Cancer. 
Gastrointest. Endosc. 1987;33:88-90.
Patrice T. Foultier MT, Yactayo S. Adam F. Galmiche JP, Douet MC, Le Bodic L. Endoscopic 
Photodynamic Therapy With Hematoporphyrin Derivative for Primary Treatment of Gastrointestinal 
Neoplasms in Inoperable Patients. Dig. Dis. and Sci. 1990;35:545-552.
Wagnieres G. Monnier Ph. Savary M, Cornaz P. Chatelain A, van den Bergh H. Photodynamic Therapy of 
Early Cancer in the Upper Aerodigestive Tract and Bronchi: Instrumentation and Clinical Results. SPIE 
Institute Series 1990;1S 6:249271.
Monnier P. Savary M, Fontolliet C, et al. Photodetection and Photodynamic Therapy of "Early" Squamous 
Cell Carcinomas of the Pharynx, Oesophagus and Trachea-bronchial Tree. Lasers in Med. Sci. 
1990;5:149-168.
Calzavara F. Tomio L, Corti L, Zorat PL, Barone I. Oesophageal Cancer Treated
by Photodynamic Therapy Alone or Followed by Radiation Therapy. J. Photochem. and Photobiol. 
1990;6:167-194. Laukka MA, Wang KK, Cameron AJ, Gutta KV and Balm RK. Low dose photodynamic 
therapy in the treatment of Barrett's esophagus. AM J Gastroent. 1993;88:1491 (A).