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KTP laser destruction of dysplasia and early cancer in columnar-lined Barrett's esophagus
KTP laser destruction of dysplasia and early cancer in columnar-lined Barrett’s esophagus Liebwin Gossner, MD, Andrea May, MD, Manfred Stolte, MD, Gerhard Seitz, MD, Eckehard G. Hahn, MD, FACP, Christian Ell, MD Wiesbaden, Bayreuth, Bamberg, and Erlangen-Nuremberg, Germany
Background: The rising incidence of esophageal adenocarcinoma in western countries requires a new strategy in the management of dysplasia in Barrett’s esophagus. Esophagectomy, which has high morbidity and mortality rates, has been recommended to treat patients with severe dysplasia. Strictly superficial laser coagulation with tissue ablation therefore is a desirable option for the management of dysplasia in Barrett’s esophagus because the tissue to be ablated is only about 2 mm thick. Potassium-titanyl-phosphate (KTP) laser light with a wavelength of 532 nm is preferentially absorbed by hemoglobin and therefore combines excellent coagulation with limited tissue penetration. We report first clinical results with KTP laser superficial vaporization of dysplasia and early cancer in Barrett’s esophagus. Methods: Eight men and 2 women 43 to 84 years of age with short segments of Barrett’s esophagus or traditional Barrett’s esophagus and histologically proved low-grade (n = 4) and high-grade (n = 4) dysplasia or early adenocarcinoma (n = 2) were selected for this pilot study. For all patients thermal endoscopic destruction was conducted with a frequency-doubled neodymium:yttrium-aluminum-garnet (Nd:YAG) KTP laser system. Laser therapy was performed by means of the freebeam method with coaxial insufflation of gas. An average of 2.4 sessions per patient were required for ablation of the Barrett’s mucosa. Results: Two to three days after laser treatment the response of the ablated mucosa was assessed with endoscopy and biopsy. Samples taken showed fibrinoid necrosis of the mucosal layer. A complete response was obtained for all 10 patients. Replacement by normal squamous cell epithelium was induced in combination with acid suppression therapy of up to 80 mg omeprazole daily. No complications occurred. In two patients biopsy showed specialized mucosa beneath the restored squamous cell epithelial layer. Follow-up times were as long as 15 months (mean value 10.6 months). Conclusions: KTP laser destruction of Barrett’s esophagus induced mucosal regeneration with normal squamous cell epithelium in combination with acid suppression. Limitation of the depth of thermal destruction in Barrett’s esophagus minimizes risk for perforation or stricture formation. KTP laser ablation of Barrett’s esophagus seems to be feasible and safe in short segments of Barrett’s esophagus with dysplasia or early cancer. (Gastrointest Endosc 1999;49:8-12.)
Received July 28, 1997. For revision January 13, 1998. Accepted April 30, 1998. From the Department of Medicine II, Wiesbaden, Institutes of Pathology, Bayreuth and Bamberg, and Department of Medicine I, University of Erlangen-Nuremberg, Germany. Presented in preliminary form at the annual meeting of the American Gastroenterological Association, San Francisco, May 19-22, 1996. Reprint requests: Liebwin Gossner, MD, Innere Medizin II, Klinikum der Landeshauptstadt Wiesbaden, Ludwig-Erhard-Str. 100, 65199 Wiesbaden, Germany. Copyright © 1999 by the American Society for Gastrointestinal Endoscopy 0016-5107/99/$8.00 + 0 37/1/91385 8
GASTROINTESTINAL ENDOSCOPY
Barrett’s esophagus represents a precancerous condition with a distinctly increased risk for development of adenocarcinoma.1 The reported data on the incidence of malignant transformation range from 1 of 46 to 1 of 441 patient years.2-4 The marked increase in incidence of adenocarcinoma of the esophagus in western countries, at present more than 40% of the total number of esophageal carcinomas, underscores this trend.5-7 Esophageal resection constitutes the only therapeutic option established to date for management of Barrett’s esophagus with high-grade dysplasia or early cancer. In view of the appreciable VOLUME 49, NO. 1, 1999
KTP laser destruction of dysplasia and early cancer in Barrett’s esophagus
L Gossner, A May, M Stolte, et al.
Table 1. Patient characteristics and results of laser ablation therapy Patient no. 1 2 3 4 5 6 7 8 9 10
Age (y)
Sex
Histologic finding/ Tumor grade
M M M M M M F F M M
LD LD LD LD HD HD HD HD T1/G1, Barrett T1/G1, Barrett
38 77 43 59 60 83 74 78 50 84
Area of tumor or dysplasia (cm) 35–39 35–39 34–37 35–37 38–40 39–40 38–40 39–40 40 37–39
EUS finding
Posttreatment status
Follow-up period (mo)
N N N N N N N N uT1* uT1
CR CR CR CR CR CR CR CR CR CR
12 11 8 6 15 12 9 10 10 13
Comment LF LF SE
SE
EUS, Endoscopic ultrasonography; LD, low-grade dysplasia; N, normal; CR, complete remission; LF, laparoscopic fundoplication; SE, residual specialized columnar-lined epithelium; HD, high-grade dysplasia; uT1, tumor depth 2 mm or less at EUS; uT1*, tumor depth 2 mm or more at EUS.
mortality figures, ranging from 4% to 10%, and in the case of carcinoma even as high as 16%,3,8,9 and considering the high mean patient age of 60 to 70 years, the development of alternative, minimally invasive therapeutic modalities appears desirable. The techniques of laser or electrocoagulation, endoscopic mucosectomy, and photodynamic therapy rank as potential candidates for this kind of treatment. The clinical significance of endoscopic therapy lies in the possibility of preventing the development of Barrett’s carcinoma by means of ablation of nondysplastic or dysplastic Barrett’s mucosa. Thus the widely used practice of endoscopic surveillance with endoscopic-histologic mapping might be abandoned. Initial case-based therapeutic experience with ablation of Barrett’s mucosa by means of thermal techniques appears promising. After destruction of specialized columnar epithelium, normal squamous epithelium regenerated when a proton pump inhibitor was used simultaneously.10-13 Reports on the thermal destruction of severe dysplasia or early carcinoma are not available. We report on thermal potassium-titanyl-phosphate (KTP) laser ablation for treatment with the objective of cure of low- and high-grade dysplasia and early carcinoma in 10 patients with Barrett’s esophagus.
an operation or were at high surgical risk either because of their age (patients 2, 6, 7, 8, 10) or accompanying disease (patients 4 and 5). In all borderline cases the decision to proceed with endoscopic therapy was made after comprehensive surgical consultation. One patient with early carcinoma (patient 9) refused surgical intervention despite detailed instructions. Patients with low-grade dysplasia underwent treatment as an alternative to continuing close surveillance because of increased risk for adenocarcinoma. Patients were hospitalized for laser treatment. Clinical staging was conducted with endoscopy, EUS, abdominal sonography, and 24-hour pH-probe testing for patients with low-grade dysplasia. For patients with high-grade dysplasia or early cancer, posteroanterior and lateral radiography of the chest and CT of the chest and the abdomen were performed. Follow-up endoscopy was performed 48 hours after treatment to determine the initial therapeutic effect. Subsequent endoscopic examinations were performed 4 weeks and 2, 3, 6, 9 and 12 months after treatment, and after completion of 1 year of follow-up examinations, every 6 months. In addition EUS and CT were performed 3, 6, and 12 months after treatment for patients with high-grade dysplasia or early cancer. Four-quadrant biopsy specimens at 2-cm intervals were obtained over the entire length of the Barrett’s esophagus.
PATIENTS AND METHODS
Endoscopy was performed with topical anesthesia and intravenous sedation with 1 to 10 mg midazolam. A KTP laser (KTP/YAG XP 800; Laserscope, San Jose, Calif.) delivered light with a wavelength of 532 nm through coaxial fibers inserted through the accessory channel of a flexible video endoscope. Laser therapy was performed by means of a noncontact technique with gas-cooled coaxial fibers and an applied power density of 12 to 18 W. A total energy dose of 300 to 1000 J was applied in the framework of a single treatment scheme. The treatment was per-
Patients Eight men and two women (43 to 84 years of age) with “short segment” Barrett’s esophagus or traditional Barrett’s esophagus and histologically proved low-grade (n = 4) and high-grade dysplasia (n = 4) or early adenocarcinoma of the esophagus (n = 2) (normal EUS findings, uT1N0M0) gave written informed consent to participate in this clinical pilot study (Table 1). All patients with high-grade dysplasia or early cancer could not undergo VOLUME 49, NO. 1, 1999
KTP laser therapy
GASTROINTESTINAL ENDOSCOPY
9
L Gossner, A May, M Stolte, et al.
KTP laser destruction of dysplasia and early cancer in Barrett’s esophagus
formed in two sessions with a semicircular technique. All patients received 20 to 40 mg of omeprazole or even higher doses of 80 mg according to the results of the 24-hour pH-probe studies to allow squamous cell regeneration in an acid-free environment after ablation of the Barrett’s mucosa. Statistical evaluation and ethical aspects Statistical analysis was performed, and patient data and clinical parameters are given as means and ranges. The study was approved by the research ethics committee of the University of Erlangen-Nuremberg according to good clinical practice regulations.
RESULTS
Figure 1. Short segment of columnar-lined Barrett’s esophagus with high-grade dysplasia.
Figure 2. Circular fibrinoid necrosis 2 days after KTP laser therapy.
The length of the Barrett’s segment varied between 0.5 and 4.0 cm (mean length 2.1 cm). All patients with high-grade dysplasia had normal findings at EUS. One of the patients with Barrett’s esophagus and early mucosal cancer had a normal esophageal wall and the other had tumor confined to the mucosa (uT1N0) (Table 1). Fibrinoid necrosis of the mucosa was detected at biopsy and endoscopy 2 to 3 days after laser therapy. All patients with dysplasia or superficial carcinoma group responded to thermal treatment. Complete remission, as determined with biopsy, was achieved by all 10 patients. Re-epithelialization of the existing Barrett’s esophagus by normal squamous epithelium was observed macroscopically and confirmed histologically for all patients (Table 1; Figs. 1 through 3). Normal squamous epithelium replaced the ablated Barrett’s esophagus when ablation was combined with proton pump inhibitor therapy (n = 8) or after laparoscopic fundoplication (n = 2). In two cases specialized columnar epithelium was identified beneath the newly developed squamous epithelium, albeit without evidence of dysplasia. Absence of dysplasia was maintained for as long as 15 months (mean value 10.6 months). An average of 2.4 treatments were required for destruction of dysplastic Barrett’s epithelium (Table 1). Procedurerelated morbidity and mortality attributable to severe complications were not observed. Six patients exhibited transient retrosternal pain and pressure sensations lasting as long as 3 days after laser treatment. These problems were managed easily with symptomatic therapy. Severe side effects were not observed for any patient. DISCUSSION
Figure 3. Squamous mucosal regeneration after KTP laser therapy. 10
GASTROINTESTINAL ENDOSCOPY
Barrett’s esophagus is indisputably a precancerous condition. Surveillance and therapy for Barrett’s esophagus remain controversial, however.14,15 Levine et al.16 advocate close endoscopic surveillance based VOLUME 49, NO. 1, 1999
KTP laser destruction of dysplasia and early cancer in Barrett’s esophagus
on biopsy findings in the sense of watchful waiting. Lack of an established monitoring scheme, the strain on patients of frequent endoscopic examinations, and associated high costs mandate a new concept in clinical management of Barrett’s esophagus. Drug-based or surgical strategies alone do not induce regression of nondysplastic Barrett epithelium. It is only in a very few individual cases that intensive long-term therapy with proton-pump inhibitors or antireflux operations can achieve regression of the border region between squamous epithelium and columnar epithelium and the regrowth of small islands of squamous epithelium within the borders of the columnar epithelium. Carcinoma has developed in Barrett’s mucosa in symptom-free patients with endoscopically inconspicuous findings even after successful antireflux operations.17,18 In cases of high-grade dysplasia and especially in the event of superficial Barrett’s carcinoma (uT1) esophageal resection currently is the therapy of choice.19,20 Despite excellent curative results in early carcinoma, resection continues to be accompanied by substantial morbidity and mortality.21 In contrast, thermal ablation of Barrett’s mucosa constitutes a minimally invasive, organ-preserving therapeutic option. However, only limited clinical experience in managing nondysplastic columnar epithelium has been gained with this method.10-13 Our pilot study confirmed that KTP laser therapy in combination with long-term acid suppression (omeprazole) successfully eliminates moderate and high-grade dysplasia of Barrett’s mucosa, and in individual cases early Barrett’s carcinoma, and achieves mucosal regeneration by means of ingrowth of normal squamous epithelium. The KTP laser appears to be particularly well suited for mucosal destruction because it produces strictly superficial laser coagulation and tissue ablation. The light (532 nm) emitted by the KTP laser is preferentially absorbed by hemoglobin and thus combines excellent coagulation capabilities with limited penetration of tissue. The risk for perforation or formation of strictures is minimized by the purely superficial destruction of tissue. Experimental investigations have shown that the power densities of 12 to 18 W used by our group are adequate for achieving exclusive destruction of the mucosa.22-24 With adjustment of the pulse duration of the laser beam, the depth-penetration effect can be precisely controlled to avoid damage to deeperlying layers of muscle tissue in the wall of the esophagus. Because of its dosimetric accuracy, KTP laser therapy offers reduced risk for perforation in comparison with treatment with a neody-mium:yttriumaluminum-garnet (Nd:YAG) laser, enhanced focusVOLUME 49, NO. 1, 1999
L Gossner, A May, M Stolte, et al.
ing accuracy, and better depth-adapted efficacy compared with electrocoagulation methods and argon plasma coagulation. But even under these improved technical conditions, patches of remaining columnar epithelium were detected in two patients. Thus there is risk for incomplete ablation of the Barrett’s mucosa. Another clear advantage of laser therapy is the ability to destroy tissue in a “paint-brush” manner in contrast to the topical destruction characteristics of thermal contact techniques. Nevertheless, even with noncontact methods, several sessions are necessary to manage extensive Barrett’s segments. Berenson et al.10 found that from 3 to as many as 12 endoscopic sessions involving one to six ablation treatments with an argon laser were needed to induce regrowth of squamous epithelium. Therefore, as demonstrated in our study, the technique of thermal destruction of Barrett’s esophagus should be used mainly to manage focal or short dysplastic Barrett segments. In tubular, circumferential (>2 cm) or longer Barrett’s segments (>3 cm), especially in those with multifocal high-grade dysplasia, photodynamic therapy appears to offer greater advantages. In the latter case Barrett’s segments as long as 10 cm have been ablated during a single therapy session in a very short time.25-27 At this early, investigative stage of development all these local treatments—thermal, nonthermal, and photodynamic— should be restricted to patients with high-grade dysplasia or early cancer who cannot undergo an operation or are at high surgical risk. One report emphasized the importance of adjuvant long-term acid suppression: insufficient acid suppression can lead to the recurrence of columnar epithelium.28 Therefore, because of insufficient drug-induced acid suppression, as documented with 24-hour pHprobe testing, laparoscopic fundoplication was performed on two patients in our study. The combination of initial ablation of columnar metaplasia and the subsequent prevention of acid reflux through laparoscopic fundoplication could in the future provide a therapeutic concept that allows the patient to forgo lifelong use of acid-suppression medications. In summary, KTP laser therapy can be used successfully in the management of low- and high-grade dysplasia and focal early Barrett’s carcinoma. Because of the favorable characteristics of the KTP laser, the method represents an improvement over thermal ablation techniques. In comparison with surgical resection, the method is less expensive and is associated with a distinctly reduced morbidity and no method-related mortality in the treatment of patients with high-grade dysplasia and Barrett’s esophagus. GASTROINTESTINAL ENDOSCOPY
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KTP laser destruction of dysplasia and early cancer in Barrett’s esophagus
ACKNOWLEDGMENT
The authors thank Dr. T. Rabenstein for his helpful assistance. We are grateful to all our colleagues, especially the pathologists, for referring patients to our department.
15.
16.
REFERENCES 1. Tytgat GNJ. Esophageal neoplasms. Curr Opin Gastroenterol 1992;8:591-605. 2. Hameeteman W, Tytgat GNJ, Houthoff HJ, van den Tweel JG. Barrett’s esophagus: development of dysplasia and adenocarcinoma. Gastroenterology 1989;96:1249-56. 3. Pera M, Cameron AJ, Trastek VF, Carpenter HA, Zinsmeister AR. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology 1993;104: 510-3. 4. Spechler SJ, Robbins AH, Rubins HB, Vincent ME, Hecren T, Doos WG, et al. Adenocarcinoma and Barrett’s esophagus: an overrated risk? Gastroenterology 1984;87:927-33. 5. Lund O, Hasenkam JM, Aagaard MT, Kimose HH. Related changes in characteristics of prognostic significance of carcinomas of the esophagus and cardia. Br J Surg 1989;76:1301-7. 6. Blot WJ, Devesa SS, Kneller RW, Fraumeni JF. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 1991;265:1287-9. 7. DeMeester TR, Attwod SEA, Smyrk TC, Hinder RA. Surgical therapy in Barrett’s esophagus. Ann Surg 1990;212: 528-42. 8. Hölscher AH, Bollschweiler E, Schneider PM, Siewert JR. Prognosis of early esophageal cancer: comparison between adeno- and squamous cell carcinoma. Cancer 1995;76: 178-86. 9. Moghissi K. Surgical resection for stage I cancer of the oesophagus and cardia. Br J Surg 1992;79:935-7. 10. Berenson MM, Johnson TD, Markowitz NR, Buchi KN, Samowitz WS. Restoration of squamous mucosa after ablation of Barrett’s esophageal epithelium. Gastroenterology 1993;104:1686-91. 11. Sampliner RE, Hixon LJ, Fennerty MB, Garewal HS. Regression of Barrett’s esophagus by laser ablation in an anacid environment. Dig Dis Sci 1993;38:365-8. 12. Sampliner RE, Fennerty MB, Garewal HS. Reversal of Barrett’s esophagus with acid suppression and multipolar electrocoagulation: preliminary results. Gastrointest Endosc 1996;44:523-5. 13. McBride MA, Vanagunas AA, Breshnahan JP, Barch DB. Combined endoscopic thermal electrocoagulation with high dose omeprazole therapy in complicated heterotopic gastric mucosa of the esophagus. Am J Gastroenterol 1995;90:2029-31. 14. Wright TA, Gray MR, Morris AI, Gilmore IT, Ellis A, Smart
12
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HL, et al. Cost effectiveness of detecting Barrett’s cancer. Gut 1996;39:574-9. Provenzale D, Kemp JA, Arora S, Wong JB. A guide for surveillance of patients with Barrett’s esophagus. Am J Gastroenterol 1994;89:670-80. Levine DS, Haggitt RC, Blount PL, Rabinovitch PS, Rusch VW, Reid BJ. An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett’s esophagus. Gastroenterology 1993;104:40-50. Gore S, Healey LJ, Sutton R, Eyre-Brook IA, Gear MWL, Shepared WA, et al. Regression of columnar-lined (Barrett’s) oesophagus with continuous omeprazole therapy. Aliment Pharmacol Ther 1993;7:623-8. Williamson WA, Ellis FH, Gibb SP. Effect of anti-reflux operation on Barrett’s mucosa. Ann Thorac Surg 1990;49:537-42. Altorki NK, Sunagawa M, Little AG, Skinner D. High-grade dysplasia in columnar-lined esophagus. Am J Surg 1991;161:97-100. Heitmiller RF, Redmond M, Hamilton SR. Barrett’s esophagus with high-grade dysplasia: an indication for prophylactic esophagectomy. Ann Surg 1996;224:66-71. Edwards MJ, Gable DR, Lentsch AB, Richardson JD. The rationale for esophagectomy as the optimal therapy for Barrett’s esophagus with high-grade dysplasia. Ann Surg 1996;223:585-91. Dix T, Barr H. Thermal imaging to compare three lasers for the photodestruction of superficial dysplastic tissue in columnar lined oesophagus [abstract]. Lasers Med Sci 1995;8:221. Gossner L, May A, Hahn EG, Ell C. Vaporization and coagulation properties of the argon-beamer, KTP- and Nd:YAGlaser an experimental comparison [abstract]. Gastrointest Endosc 1996;43:18. Barham CP, Jones RL, Biddlestone LR, Hardwick RH, Sheperd NA, Barr H. Photothermal laser ablation of Barrett’s esophagus: endoscopic and histological evidence of squamous re-epithelialization. Gut 1997;41:281-4. Overholt BF, Panjehpour M. Photodynamic therapy for Barrett’s esophagus: clinical update. Am J Gastroenterol 1996;91:1719-23. Gossner L, Stolte M, Sroka R, Rick K, Hahn EG, Ell C. Photodynamic ablation of high-grade dysplasia and early cancer in columnar-lined Barrett’s esophagus by means of 5aminolevulinic acid induced protoporphyrin IX and laser irradiation. Gastroenterology 1998;114:1448-55. Gossner L, Sroka R, Ell C. A new long range “through the scope” balloon applicator for photodynamic therapy in the esophagus and cardia. Endoscopy. In press. Brandt LJ, Blansky M, Kauvar DR. Repeat laser therapy of recurrent Barrett’s epithelium: success with anacidity [letter]. Gastrointest Endosc 1995;41:267.
VOLUME 49, NO. 1, 1999
Background: The rising incidence of esophageal adenocarcinoma in western countries requires a new strategy in the management of dysplasia in Barrett’s esophagus. Esophagectomy, which has high morbidity and mortality rates, has been recommended to treat patients with severe dysplasia. Strictly superficial laser coagulation with tissue ablation therefore is a desirable option for the management of dysplasia in Barrett’s esophagus because the tissue to be ablated is only about 2 mm thick. Potassium-titanyl-phosphate (KTP) laser light with a wavelength of 532 nm is preferentially absorbed by hemoglobin and therefore combines excellent coagulation with limited tissue penetration. We report first clinical results with KTP laser superficial vaporization of dysplasia and early cancer in Barrett’s esophagus. Methods: Eight men and 2 women 43 to 84 years of age with short segments of Barrett’s esophagus or traditional Barrett’s esophagus and histologically proved low-grade (n = 4) and high-grade (n = 4) dysplasia or early adenocarcinoma (n = 2) were selected for this pilot study. For all patients thermal endoscopic destruction was conducted with a frequency-doubled neodymium:yttrium-aluminum-garnet (Nd:YAG) KTP laser system. Laser therapy was performed by means of the freebeam method with coaxial insufflation of gas. An average of 2.4 sessions per patient were required for ablation of the Barrett’s mucosa. Results: Two to three days after laser treatment the response of the ablated mucosa was assessed with endoscopy and biopsy. Samples taken showed fibrinoid necrosis of the mucosal layer. A complete response was obtained for all 10 patients. Replacement by normal squamous cell epithelium was induced in combination with acid suppression therapy of up to 80 mg omeprazole daily. No complications occurred. In two patients biopsy showed specialized mucosa beneath the restored squamous cell epithelial layer. Follow-up times were as long as 15 months (mean value 10.6 months). Conclusions: KTP laser destruction of Barrett’s esophagus induced mucosal regeneration with normal squamous cell epithelium in combination with acid suppression. Limitation of the depth of thermal destruction in Barrett’s esophagus minimizes risk for perforation or stricture formation. KTP laser ablation of Barrett’s esophagus seems to be feasible and safe in short segments of Barrett’s esophagus with dysplasia or early cancer. (Gastrointest Endosc 1999;49:8-12.)
Received July 28, 1997. For revision January 13, 1998. Accepted April 30, 1998. From the Department of Medicine II, Wiesbaden, Institutes of Pathology, Bayreuth and Bamberg, and Department of Medicine I, University of Erlangen-Nuremberg, Germany. Presented in preliminary form at the annual meeting of the American Gastroenterological Association, San Francisco, May 19-22, 1996. Reprint requests: Liebwin Gossner, MD, Innere Medizin II, Klinikum der Landeshauptstadt Wiesbaden, Ludwig-Erhard-Str. 100, 65199 Wiesbaden, Germany. Copyright © 1999 by the American Society for Gastrointestinal Endoscopy 0016-5107/99/$8.00 + 0 37/1/91385 8
GASTROINTESTINAL ENDOSCOPY
Barrett’s esophagus represents a precancerous condition with a distinctly increased risk for development of adenocarcinoma.1 The reported data on the incidence of malignant transformation range from 1 of 46 to 1 of 441 patient years.2-4 The marked increase in incidence of adenocarcinoma of the esophagus in western countries, at present more than 40% of the total number of esophageal carcinomas, underscores this trend.5-7 Esophageal resection constitutes the only therapeutic option established to date for management of Barrett’s esophagus with high-grade dysplasia or early cancer. In view of the appreciable VOLUME 49, NO. 1, 1999
KTP laser destruction of dysplasia and early cancer in Barrett’s esophagus
L Gossner, A May, M Stolte, et al.
Table 1. Patient characteristics and results of laser ablation therapy Patient no. 1 2 3 4 5 6 7 8 9 10
Age (y)
Sex
Histologic finding/ Tumor grade
M M M M M M F F M M
LD LD LD LD HD HD HD HD T1/G1, Barrett T1/G1, Barrett
38 77 43 59 60 83 74 78 50 84
Area of tumor or dysplasia (cm) 35–39 35–39 34–37 35–37 38–40 39–40 38–40 39–40 40 37–39
EUS finding
Posttreatment status
Follow-up period (mo)
N N N N N N N N uT1* uT1
CR CR CR CR CR CR CR CR CR CR
12 11 8 6 15 12 9 10 10 13
Comment LF LF SE
SE
EUS, Endoscopic ultrasonography; LD, low-grade dysplasia; N, normal; CR, complete remission; LF, laparoscopic fundoplication; SE, residual specialized columnar-lined epithelium; HD, high-grade dysplasia; uT1, tumor depth 2 mm or less at EUS; uT1*, tumor depth 2 mm or more at EUS.
mortality figures, ranging from 4% to 10%, and in the case of carcinoma even as high as 16%,3,8,9 and considering the high mean patient age of 60 to 70 years, the development of alternative, minimally invasive therapeutic modalities appears desirable. The techniques of laser or electrocoagulation, endoscopic mucosectomy, and photodynamic therapy rank as potential candidates for this kind of treatment. The clinical significance of endoscopic therapy lies in the possibility of preventing the development of Barrett’s carcinoma by means of ablation of nondysplastic or dysplastic Barrett’s mucosa. Thus the widely used practice of endoscopic surveillance with endoscopic-histologic mapping might be abandoned. Initial case-based therapeutic experience with ablation of Barrett’s mucosa by means of thermal techniques appears promising. After destruction of specialized columnar epithelium, normal squamous epithelium regenerated when a proton pump inhibitor was used simultaneously.10-13 Reports on the thermal destruction of severe dysplasia or early carcinoma are not available. We report on thermal potassium-titanyl-phosphate (KTP) laser ablation for treatment with the objective of cure of low- and high-grade dysplasia and early carcinoma in 10 patients with Barrett’s esophagus.
an operation or were at high surgical risk either because of their age (patients 2, 6, 7, 8, 10) or accompanying disease (patients 4 and 5). In all borderline cases the decision to proceed with endoscopic therapy was made after comprehensive surgical consultation. One patient with early carcinoma (patient 9) refused surgical intervention despite detailed instructions. Patients with low-grade dysplasia underwent treatment as an alternative to continuing close surveillance because of increased risk for adenocarcinoma. Patients were hospitalized for laser treatment. Clinical staging was conducted with endoscopy, EUS, abdominal sonography, and 24-hour pH-probe testing for patients with low-grade dysplasia. For patients with high-grade dysplasia or early cancer, posteroanterior and lateral radiography of the chest and CT of the chest and the abdomen were performed. Follow-up endoscopy was performed 48 hours after treatment to determine the initial therapeutic effect. Subsequent endoscopic examinations were performed 4 weeks and 2, 3, 6, 9 and 12 months after treatment, and after completion of 1 year of follow-up examinations, every 6 months. In addition EUS and CT were performed 3, 6, and 12 months after treatment for patients with high-grade dysplasia or early cancer. Four-quadrant biopsy specimens at 2-cm intervals were obtained over the entire length of the Barrett’s esophagus.
PATIENTS AND METHODS
Endoscopy was performed with topical anesthesia and intravenous sedation with 1 to 10 mg midazolam. A KTP laser (KTP/YAG XP 800; Laserscope, San Jose, Calif.) delivered light with a wavelength of 532 nm through coaxial fibers inserted through the accessory channel of a flexible video endoscope. Laser therapy was performed by means of a noncontact technique with gas-cooled coaxial fibers and an applied power density of 12 to 18 W. A total energy dose of 300 to 1000 J was applied in the framework of a single treatment scheme. The treatment was per-
Patients Eight men and two women (43 to 84 years of age) with “short segment” Barrett’s esophagus or traditional Barrett’s esophagus and histologically proved low-grade (n = 4) and high-grade dysplasia (n = 4) or early adenocarcinoma of the esophagus (n = 2) (normal EUS findings, uT1N0M0) gave written informed consent to participate in this clinical pilot study (Table 1). All patients with high-grade dysplasia or early cancer could not undergo VOLUME 49, NO. 1, 1999
KTP laser therapy
GASTROINTESTINAL ENDOSCOPY
9
L Gossner, A May, M Stolte, et al.
KTP laser destruction of dysplasia and early cancer in Barrett’s esophagus
formed in two sessions with a semicircular technique. All patients received 20 to 40 mg of omeprazole or even higher doses of 80 mg according to the results of the 24-hour pH-probe studies to allow squamous cell regeneration in an acid-free environment after ablation of the Barrett’s mucosa. Statistical evaluation and ethical aspects Statistical analysis was performed, and patient data and clinical parameters are given as means and ranges. The study was approved by the research ethics committee of the University of Erlangen-Nuremberg according to good clinical practice regulations.
RESULTS
Figure 1. Short segment of columnar-lined Barrett’s esophagus with high-grade dysplasia.
Figure 2. Circular fibrinoid necrosis 2 days after KTP laser therapy.
The length of the Barrett’s segment varied between 0.5 and 4.0 cm (mean length 2.1 cm). All patients with high-grade dysplasia had normal findings at EUS. One of the patients with Barrett’s esophagus and early mucosal cancer had a normal esophageal wall and the other had tumor confined to the mucosa (uT1N0) (Table 1). Fibrinoid necrosis of the mucosa was detected at biopsy and endoscopy 2 to 3 days after laser therapy. All patients with dysplasia or superficial carcinoma group responded to thermal treatment. Complete remission, as determined with biopsy, was achieved by all 10 patients. Re-epithelialization of the existing Barrett’s esophagus by normal squamous epithelium was observed macroscopically and confirmed histologically for all patients (Table 1; Figs. 1 through 3). Normal squamous epithelium replaced the ablated Barrett’s esophagus when ablation was combined with proton pump inhibitor therapy (n = 8) or after laparoscopic fundoplication (n = 2). In two cases specialized columnar epithelium was identified beneath the newly developed squamous epithelium, albeit without evidence of dysplasia. Absence of dysplasia was maintained for as long as 15 months (mean value 10.6 months). An average of 2.4 treatments were required for destruction of dysplastic Barrett’s epithelium (Table 1). Procedurerelated morbidity and mortality attributable to severe complications were not observed. Six patients exhibited transient retrosternal pain and pressure sensations lasting as long as 3 days after laser treatment. These problems were managed easily with symptomatic therapy. Severe side effects were not observed for any patient. DISCUSSION
Figure 3. Squamous mucosal regeneration after KTP laser therapy. 10
GASTROINTESTINAL ENDOSCOPY
Barrett’s esophagus is indisputably a precancerous condition. Surveillance and therapy for Barrett’s esophagus remain controversial, however.14,15 Levine et al.16 advocate close endoscopic surveillance based VOLUME 49, NO. 1, 1999
KTP laser destruction of dysplasia and early cancer in Barrett’s esophagus
on biopsy findings in the sense of watchful waiting. Lack of an established monitoring scheme, the strain on patients of frequent endoscopic examinations, and associated high costs mandate a new concept in clinical management of Barrett’s esophagus. Drug-based or surgical strategies alone do not induce regression of nondysplastic Barrett epithelium. It is only in a very few individual cases that intensive long-term therapy with proton-pump inhibitors or antireflux operations can achieve regression of the border region between squamous epithelium and columnar epithelium and the regrowth of small islands of squamous epithelium within the borders of the columnar epithelium. Carcinoma has developed in Barrett’s mucosa in symptom-free patients with endoscopically inconspicuous findings even after successful antireflux operations.17,18 In cases of high-grade dysplasia and especially in the event of superficial Barrett’s carcinoma (uT1) esophageal resection currently is the therapy of choice.19,20 Despite excellent curative results in early carcinoma, resection continues to be accompanied by substantial morbidity and mortality.21 In contrast, thermal ablation of Barrett’s mucosa constitutes a minimally invasive, organ-preserving therapeutic option. However, only limited clinical experience in managing nondysplastic columnar epithelium has been gained with this method.10-13 Our pilot study confirmed that KTP laser therapy in combination with long-term acid suppression (omeprazole) successfully eliminates moderate and high-grade dysplasia of Barrett’s mucosa, and in individual cases early Barrett’s carcinoma, and achieves mucosal regeneration by means of ingrowth of normal squamous epithelium. The KTP laser appears to be particularly well suited for mucosal destruction because it produces strictly superficial laser coagulation and tissue ablation. The light (532 nm) emitted by the KTP laser is preferentially absorbed by hemoglobin and thus combines excellent coagulation capabilities with limited penetration of tissue. The risk for perforation or formation of strictures is minimized by the purely superficial destruction of tissue. Experimental investigations have shown that the power densities of 12 to 18 W used by our group are adequate for achieving exclusive destruction of the mucosa.22-24 With adjustment of the pulse duration of the laser beam, the depth-penetration effect can be precisely controlled to avoid damage to deeperlying layers of muscle tissue in the wall of the esophagus. Because of its dosimetric accuracy, KTP laser therapy offers reduced risk for perforation in comparison with treatment with a neody-mium:yttriumaluminum-garnet (Nd:YAG) laser, enhanced focusVOLUME 49, NO. 1, 1999
L Gossner, A May, M Stolte, et al.
ing accuracy, and better depth-adapted efficacy compared with electrocoagulation methods and argon plasma coagulation. But even under these improved technical conditions, patches of remaining columnar epithelium were detected in two patients. Thus there is risk for incomplete ablation of the Barrett’s mucosa. Another clear advantage of laser therapy is the ability to destroy tissue in a “paint-brush” manner in contrast to the topical destruction characteristics of thermal contact techniques. Nevertheless, even with noncontact methods, several sessions are necessary to manage extensive Barrett’s segments. Berenson et al.10 found that from 3 to as many as 12 endoscopic sessions involving one to six ablation treatments with an argon laser were needed to induce regrowth of squamous epithelium. Therefore, as demonstrated in our study, the technique of thermal destruction of Barrett’s esophagus should be used mainly to manage focal or short dysplastic Barrett segments. In tubular, circumferential (>2 cm) or longer Barrett’s segments (>3 cm), especially in those with multifocal high-grade dysplasia, photodynamic therapy appears to offer greater advantages. In the latter case Barrett’s segments as long as 10 cm have been ablated during a single therapy session in a very short time.25-27 At this early, investigative stage of development all these local treatments—thermal, nonthermal, and photodynamic— should be restricted to patients with high-grade dysplasia or early cancer who cannot undergo an operation or are at high surgical risk. One report emphasized the importance of adjuvant long-term acid suppression: insufficient acid suppression can lead to the recurrence of columnar epithelium.28 Therefore, because of insufficient drug-induced acid suppression, as documented with 24-hour pHprobe testing, laparoscopic fundoplication was performed on two patients in our study. The combination of initial ablation of columnar metaplasia and the subsequent prevention of acid reflux through laparoscopic fundoplication could in the future provide a therapeutic concept that allows the patient to forgo lifelong use of acid-suppression medications. In summary, KTP laser therapy can be used successfully in the management of low- and high-grade dysplasia and focal early Barrett’s carcinoma. Because of the favorable characteristics of the KTP laser, the method represents an improvement over thermal ablation techniques. In comparison with surgical resection, the method is less expensive and is associated with a distinctly reduced morbidity and no method-related mortality in the treatment of patients with high-grade dysplasia and Barrett’s esophagus. GASTROINTESTINAL ENDOSCOPY
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KTP laser destruction of dysplasia and early cancer in Barrett’s esophagus
ACKNOWLEDGMENT
The authors thank Dr. T. Rabenstein for his helpful assistance. We are grateful to all our colleagues, especially the pathologists, for referring patients to our department.
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16.
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