Photodynamic therapy for large superficial squamous cell carcinoma of the esophagus

ORIGINAL ARTICLE: Clinical Endoscopy

Photodynamic therapy for large superficial squamous cell carcinoma of the esophagus Toshiaki Tanaka, MD, Satoru Matono, MD, Takeshi Nagano, MD, Kazutaka Murata, MD, Susumu Sueyoshi, MD, Hideaki Yamana, MD, Kazuo Shirouzu, MD, Hiromasa Fujita, MD Kurume, Japan

Background: Photodynamic therapy (PDT) has been found to be safe and effective in patients with small early esophageal squamous cell carcinoma (SCC). However, its efficacy for widespread superficial SCC has not yet been confirmed. Objective: To assess the long-term survival, complications, and recurrence of PDT for large superficial esophageal SCC. Design: Retrospective study. Setting: Tertiary referral center. Patients: A total of 38 patients with superficial SCC of the esophagus. All patients had a large unifocal lesion or multifocal lesions that were too large to be resected endoscopically. In addition, all patients were physiologically unfit for esophagectomy or had refused surgery. Interventions: PDT with porfimer sodium. Main Outcome Measurements: Clinical follow-up, long-term survival, complications, and recurrence were evaluated. Results: Thirty-one patients (82%) had mucosal cancer (T1m), and 7 (18%) had submucosal cancer (T1sm). No patient had lymph node involvement. Nineteen patients had other primary malignancies. Complete remission was achieved in 33 (87%). At the time of writing, 28 patients (74%) were alive without recurrence. After a median follow-up period of 64 months (range, 7-125 months) after PDT, the overall 5-year survival rate was 76%. There was no treatment-related mortality. Limitations: Retrospective study with a small number of patients. Conclusions: This long-term follow-up study revealed that PDT was a potentially curative treatment for large superficial esophageal SCC. PDT might be a reasonable alternative to esophagectomy or to endoscopic resection for patients with superficial SCC of the esophagus without lymph node metastasis. (Gastrointest Endosc 2011;73: 1-6.)

Endoscopic therapy is increasingly used as an alternative to surgery in patients with early squamous cell carcinoma (SCC) of the esophagus. Endoscopic resection, such as EMR and endoscopic submucosal dissection (ESD), is now a standard treatment for superficial SCC of the esoph-

agus, especially for cancer confined within the mucosa.1-3 However, endoscopic resection is usually not recommended for circumferential lesions of two-thirds or more because of the high risk of the development of persistent esophageal stricture after the treatment.1,4 Therefore,

Abbreviations: CR, complete remission; ESD, endoscopic submucosal dissection; PDT, photodynamic therapy; SCC, squamous cell carcinoma.

Current affiliations: Department of Surgery, Kurume University School of Medicine, Kurume, Japan.

DISCLOSURE: All authors disclosed no financial relationships relevant to this publication.

Reprint requests: Toshiaki Tanaka, MD, PhD, Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume-shi, Fukuoka, 830-0011, Japan.

Copyright © 2011 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2010.08.049 Received June 7, 2010. Accepted August 28, 2010.

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esophagectomy has remained the mainstay of curative treatment for large superficial esophageal SCC that cannot be totally removed by endoscopic resection.5,6 However, patients with esophageal SCC often have serious comorbidities or other primary malignancy and are unfit for esophagectomy. Their poor general condition requires minimally invasive treatment. Photodynamic therapy (PDT) is another endoscopic treatment modality used for both superficial esophageal cancer and obstructing advanced esophageal cancer.7 In addition to endoscopic resection, PDT has been found to be safe and effective for superficial esophageal SCC.8-11 Although PDT theoretically can be used for a superficial lesion of any size or circumference, it has usually been used for only small superficial SCC of the esophagus. Little is known about the results after PDT for patients with large or multifocal superficial esophageal SCC, which is not recommended for endoscopic resection. The present retrospective study investigated the outcomes of PDT in early esophageal SCC patients who had a lesion too large to be removed by endoscopic resection.

Take-home Message ●

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In a retrospective study of 38 patients with superficial esophageal squamous cell carcinoma too large to be removed by endoscopic resection, the complete response rate of photodynamic therapy was 87% with a 5-year survival rate of 76%. Photodynamic therapy showed acceptable safety and efficacy in patients with severe comorbidities.

PATIENTS AND METHODS From September 1999 to October 2007, a total of 52 consecutive patients with superficial SCC of the esophagus underwent PDT at Kurume University Hospital. Excluding 14 patients who had undergone earlier therapy, 38 patients without earlier therapy were included in this retrospective study. PDT was used with curative intent as the primary method to eradicate the mucosal disease. Some patients (n ⫽ 7) had refused surgery, whereas others (n ⫽ 31) were evaluated to be at too high a risk for esophageal resection because of significant comorbidities. In addition, all of the patients had large or multiple superficial carcinomas that could not be totally removed by endoscopic resection or had serious comorbidities that precluded endoscopic resection procedures. Endoscopic resection had been used for lesions not exceeding one-half of the circumference before the use of the ESD technique. ESD has been used since 2005, and endoscopic resection has been used in superficial esophageal cancer of up to two-thirds circumference in our institution. Written informed consent was obtained from each of the patients before PDT. The pretreatment workup included physical examination, standard laboratory tests, chest radiograph, upper GI endoscopy with Lugol staining, upper GI barium swallow, EUS, US of the cervical and abdominal regions, and CT of the neck, chest, and abdomen. The depth of the tumor invasion was evaluated with EUS, using a 20-MHz miniprobe (UM-3R; Olympus, Tokyo, Japan). At 20 MHz frequency, EUS shows 5 distinct layers of the esophageal wall. Lesions not affecting the integrity of the third layer (submucosa) were diagnosed as T1m (mucosal cancer). Invasion of the submucosa (T1sm) was diagnosed when there was evidence of thickening in the third layer but not 2

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Figure 1. An EUS image of superficial esophageal cancer. EUS shows a hypoechoic thickening in both the mucosal and the submucosal layers (solid arrow) and a hypoechoic thickening in the mucosal layer (dashed arrows); accordingly, this lesion was assessed as T1sm cancer with continuous T1m cancer.

affecting the integrity of the fourth layer (muscularis propria) (Fig. 1). Since 2004, positron-emission tomography has been routinely included in the clinical staging workup. To identify the precise extent of lesions, chromoendoscopy using the Lugol iodine staining method was performed during the treatment of PDT. PDT was performed only for lesions confirmed histologically to be cancer. PDT procedures were performed with porfimer sodium (Photofrin; Wyeth Japan, Tokyo, Japan) and an excimerdye laser (EDL-1; Hamamatsu Photonics, Hamamatsu, Japan).12-14 All patients received 2 mg/kg Photofrin 48 hours before light irradiation. A quartz fiber was used, either a microlens fiber or a cylindric diffusing fiber with a treatment length of 10 mm, to carry the laser light (630-nm wavelength) through the accessory channel of the endoscope to the lesions. No centering device was used. The total light dose was 75 J/cm2, at 4 mJ/pulse and 40-Hz pulse frequency. The light fiber was placed at the distal aspect of the tumor and then withdrawn proximally to treat the entire length of tumor. PDT was usually perwww.giejournal.org

Tanaka et al

formed with the patient under conscious sedation by periodic intravenous administration of midazolam. Endoscopic examination was performed 7 days after treatment to confirm the development of tissue necrosis. After the administration of Photofrin, patients were shielded from sunlight until discharge from the hospital. Because Photofrin is also taken up by normal cells, patients were advised to avoid intense sunlight for ⱖ1 month. Posttreatment surveillance consisted of upper GI endoscopy, CT, and positron-emission tomography if necessary. Upper GI endoscopy examinations with Lugol staining and biopsy were conducted at intervals of 1, 3, 6, 9, and 12 months and every 6 months thereafter until 3 years after the treatment and then annually. CT was conducted every 6 months until 3 years after the treatment and then annually for monitoring the lymph nodes or discovering any distant metastasis. The outcome after PDT was evaluated in January 2010. The survival period was calculated to be from the date of PDT to the date of death or the most recent follow-up. All survival data were analyzed by using StatView software, version 5 (SAS Institute, Cary, NC, USA). Survival curves were produced by using the Kaplan-Meier method.

PDT for esophageal cancer

Table 1. Patient and lesion characteristics Median age, y (range) Male/female, n

64 (44-80) 31/7

Tumor location, n Upper third

3

Middle third

30

Lower third

5

Tumor type,* n 0-I ⫹ IIc

3

0-IIa ⫹ IIc

3

0-IIb

3

0-IIc

29

Tumor length, cm ⬍2

5

⬍5

18

ⱖ5

15

Circumference of lumen, n

RESULTS Patient characteristics are shown in Table 1. Twentyseven patients (71%) had a lesion of one-half or more circumference. Thirty-three patients (87%) had a lesion ⱖ2 cm in length, and of them 15 patients (40%) had a lesion ⱖ5 cm in length. Thirteen patients (34%) had multifocal superficial cancer of the esophagus at the time of the PDT treatment. The distribution of clinical tumor stage for these patients was T1m (mucosal cancer) in 31 patients (82%) and T1sm (submucosal cancer) in 7 patients (18%). No patient had lymph node involvement detected by pretreatment workup. Nineteen patients (50%) had ⱖ1 previous other primary malignancies. The sites of previous other malignancies were the head and neck in 11 patients, the stomach in 5 patients, the liver in 3 patients, and elsewhere in 3 patients. Three of these 19 patients had 2 previous other malignancies. An average of 1.8 PDT treatment courses were administered per patient (range, 1-4 courses). The median delivered light dose of the first PDT course was 800 J (range, 300-950 J). The average treatment time of PDT was 80 minutes (range, 30-100 minutes). Twenty-two patients (58%) had only 1 PDT course, and the rest needed multiple PDT courses. Repeat courses were performed for those with a recurrence or a failure to respond to initial treatment as assessed by follow-up endoscopic surveillance. Five patients had 3 or 4 PDT courses to treat the development of new lesions in the esophagus. The clinical outcomes after PDT are summarized in Table 2. There was no treatment-related mortality. Complete remission (CR) was achieved in 33 (87%) of the 38 www.giejournal.org

Less than one-half

11

Less than total

17

Total

10

Depth of invasion T1m

31

T1sm

7

Multifocal lesions Yes

13

No

25

*Tumors were classified according to the Paris endoscopic classification15: 0-I, protruded; 0-IIa, elevated; 0-IIb, flat; 0-IIc, depressed.

patients; 25 patients (66%) achieved CR after the first PDT course, and 8 patients (21%) received ⱖ2 PDT courses to achieve CR because of an initially incomplete response. Overall, 27 (87%) of the 31 patients with mucosal cancer achieved CR, and 6 (86%) of the 7 patients with submucosal cancer achieved CR. In 6 (18%) of the 33 patients with CR, a recurrence developed. Endoscopic images from a representative study patient who achieved CR after PDT are shown in Figure 2. Recurrent disease at the site of the PDT treatment developed in 4 patients; recurrence developed at 12 months after the PDT in 2 patients and in another 2 patients at 18 months after the PDT. They underwent a successful additional PDT course. In the remaining 2 patients, recurrent disease in the lung or lymph nodes developed at 12 and 18 months after the PDT, respectively. Volume 73, No. 1 : 2011 GASTROINTESTINAL ENDOSCOPY

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Table 2. Treatment and follow-up results PDT courses per patient Complete response, n (%)

1.8 33 (87)

T1m

27

T1sm

6

Recurrence, n (%)

6 (18)

Esophagus

4

Lung

1

Lymph node

1

Death, n (%)

10 (26)

Recurrence

3

Other primary malignancy

6

Other disease

1

Alive, n (%)

28 (74)

PDT, photodynamic therapy.

They underwent chemotherapy or chemoradiotherapy. Of the 5 patients with an incomplete response to PDT, 3 patients received argon plasma coagulation, and the other 2 patients underwent surgery. At the time of writing, 28 patients (23 mucosal and 5 submucosal cancer patients) were alive without evidence of recurrent disease at a median follow-up period of 64 months (range, 7-142 months). In total, 10 patients died: 3 of recurrent disease, 6 of other primary malignancy, and 1 of pulmonary emphysema. The overall 5-year survival rate was 76% for all patients (Fig. 3). Chest pain after the treatment was the most common complication, occurring in 12 patients (32%), and fever (⬎38°C) occurred in 8 patients (21%). All of these complications were well managed with nonsteroidal antiinflammatory drugs. Cutaneous photosensitivity occurred in 6 patients (16%) and was not severe. Slight stricture formation at the site of PDT occurred in 4 patients (11%) who received multiple PDT courses, 3 of whom had a total circumference lesion. Three patients underwent 4 PDT courses, and 1 patient underwent 2 courses. They were well managed with 1 to 3 attempts of balloon dilation. There were no allergic reactions to the Photofrin administration. There was no treatment-related mortality.

DISCUSSION Endoscopic therapy for esophageal SCC limited to the mucosal layer has been proposed as an alternative to surgical resection given the low risk of lymph node metastasis in these patients.1,5,6,16,17 In this study, we evaluated the outcomes after PDT in superficial esophageal SCC. Patients treated with PDT in our series had large 4

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superficial lesions that could not be totally removed by endoscopic resection. In addition, most of these patients had serious comorbidities precluding esophagectomy. The overall survival in our series of patients with mucosal esophageal SCC treated with PDT was similar to that in patients treated surgically in earlier studies.5,6,16,17 Our CR rate was 87%. There were no treatment-related deaths. Given these results, PDT appears to be an alternative to esophagectomy or to endoscopic resection for patients with large and/or multiple superficial esophageal SCC without lymph node involvement. Radical surgery has been the mainstay of curative treatment for esophageal SCC. Although minimally invasive surgery has increased in the past decade, esophagectomy still carries relatively high morbidity and mortality rates, even in a high-volume center.18,19 Furthermore, evidence accumulating from the results of radical esophagectomy with lymphadenectomy has revealed that mucosal SCC in the esophagus has a very low rate of lymph node metastasis.5,6,16,17 These results have led to the increasing use of endoscopic treatment modalities, such as endoscopic resection and ablative therapy, for superficial esophageal SCC. Moreover, patients with esophageal SCC have a strong tendency toward the development other primary carcinomas, such as head and neck cancer and gastric cancer. In patients with esophageal SCC, their general condition is frequently poor as a result of alcohol and tobacco abuse. These conditions require the wider use of minimally invasive treatment. EMR and ESD have been accepted as definitive treatment for superficial esophageal SCC, especially for cancer confined to within the mucosal layer, in the past decade.1,4,20 Makuuchi1 reported a 5-year disease-specific survival rate of 98% after EMR for superficial esophageal SCC. Ishihara et al2 reported an overall 5-year survival rate of 80% after endoscopic resection of mucosal cancer. These results in patients with mucosal SCC when treated with EMR are similar to those of patients treated surgically.5,6,16,17 Moreover, the technical developments in ESD have extended the role of endoscopic resection to the management of superficial esophageal cancer. However, there is a limitation in the use of endoscopic resection regarding the circumference of the esophagus affected by the lesion. Circumferential resections are typically avoided because of the high risk of persistent stricture formation. Ono et al3 reported postoperative stricture in 18% of cases treated with ESD. According to the guidelines of the Japan Esophageal Society for the diagnosis and treatment of esophageal SCC, endoscopic resection is indicated for lesions not exceeding two thirds of the circumference.4 PDT also has been used for the treatment of superficial esophageal cancer. Sibille et al8 reported a CR rate of 87% with a 5-year survival rate of 74% for T1 or T2 SCC or adenocarcinoma. Savary et al9 reported CR for esophageal SCC of 84%. PDT also has been shown to be effective for early adenocarcinoma or high-grade intraepithelial neowww.giejournal.org

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PDT for esophageal cancer

Figure 2. Endoscopic images of a study patient. A, Circumferential lesion (arrows) at the middle thoracic esophagus. B, Chromoendoscopy with Lugol staining to demarcate the lesion. C, Necrotic and ulcerative changes in the ablated area 7 days after PDT. D, Primary site with normal squamous mucosa appearance on endoscopy at 6 months after PDT with all biopsy specimens negative for cancer.

Figure 3. Overall survival of all patients with initiation of PDT.

plasia in Barrett’s esophagus. Pech et al10 treated 31 patients with early esophageal adenocarcinoma using PDT. They showed 100% CR with a 5-year survival rate of 80%. An excimer-dye laser was used in the present study. Findings have shown that the excimer-dye laser has a stronger photodynamic effect than the argon dye laser at the same light energy doses in experimental animal models as well www.giejournal.org

as in clinical practice.21,22 The light dose used in PDT with an excimer-dye laser is generally lower than that needed in PDT with an argon dye laser. The lower light dose is associated with less degenerative change to the esophageal wall by thermal energy. This might explain, in part, the low rate of complications, including chest pain or stricture formation, after PDT in this study. However, PDT has usually only been applied in small superficial esophageal cancer so far. There is as yet no report regarding PDT for large superficial esophageal SCC. Compared with endoscopic resection, the advantages of PDT are the simplicity of the procedure, the low complication rate, and theoretically no limitation regarding the size or circumference of the lesion. EUS has been shown to provide the most accurate assessment of tumor invasion. A recent meta-analysis reported that the sensitivity and specificity of EUS to diagnose T1 were 81.6% and 99.4%, respectively.23 However, differentiating T1m from T1sm cancer remains difficult even with a high-frequency miniprobe EUS. Rampado et al24 reported that the sensitivity and specificity to differentiate T1m from T1sm cancer were 62% and 76.5%, respectively. The major disadvantage of PDT is that PDT does not allow histologic examination of the lesion, including assessment of tumor invasion. Volume 73, No. 1 : 2011 GASTROINTESTINAL ENDOSCOPY

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Brachytherapy was also used for superficial esophageal cancer with or without external radiation therapy.25 Nemoto et al26 reported that the 5-year survival rates for T1a and T1b cancer patients treated with brachytherapy and/or external radiation therapy were 62% and 42%, respectively. Compared with brachytherapy, the advantage of PDT is the feasibility of repeat treatment for a recurrent lesion without the risk of the formation of any severe esophageal ulcer. Radiofrequency ablation and cryotherapy are emerging as alternative ablation therapies with high CR rates similar to those of PDT, mostly for Barrett esophagus with early neoplasm, in recent years.27-30 These methods are available for a wide-spreading lesion without severe posttreatment complications as well as PDT. However, these promising ablation therapies still lack long-term results. They might become alternatives to conventional treatment procedures for a superficial esophageal cancer after the assessment of long-term results in many cases. In summary, most patients in our series had severe comorbidities for esophagectomy and had large or multifocal superficial SCC that could not be totally removed by endoscopic resection. CR was achieved in 87% of patients after PDT and the 5-year survival rate was 76% in all patients. These results are similar to those of earlier reports of esophagectomy or endoscopic resection. Therefore, our results suggest that PDT may be a promising alternative to surgical resection for large superficial SCC in the esophagus or as an alternative to endoscopic resection for superficial SCC. REFERENCES 1. Makuuchi H. Endoscopic mucosal resection for mucosal cancer in the esophagus. Gastrointest Endosc Clin North Am 2001;11:445-58. 2. Ishihara R, Tanaka H, Iishi H, et al. Long-term outcome of esophageal mucosal squamous cell carcinoma without lymphovascular involvement after endoscopic resection. Cancer 2008;112:2166-72. 3. Ono S, Fujishiro M, Niimi K, et al. Long-term outcomes of endoscopic submucosal dissection for superficial esophageal squamous cell neoplasms. Gastrointest Endosc 2009;70:860-6. 4. Kuwano H, Nishimura Y, Ohtsu A, et al. Guidelines for diagnosis and treatment of carcinoma of the esophagus. April 2007 edition: part I. Edited by the Japan Esophageal Society. Esophagus 2008;5:61-73. 5. Pennathur A, Farkas A, Krasinskas AM, et al. Esophagectomy for T1 esophageal cancer: outcomes in 100 patients and implications for endoscopic therapy. Ann Thorac Surg 2009;87:1048-55. 6. Fujita H, Sueyoshi S, Yamana H, et al. Optimum treatment strategy for superficial esophageal cancer: endoscopic mucosal resection versus radical esophagectomy. World J Surg 2001;25:424-31. 7. Hopper C. Photodynamic therapy: a clinical reality in the treatment of cancer. Lancet Oncol 2000;1:212-9. 8. Sibille A, Lambert R, Souquet JC, et al. Long-term survival after photodynamic therapy for esophageal cancer. Gastroenterology 1995;108: 337-44. 9. Savary JF, Grosjean P, Monnier P, et al. Photodynamic therapy of early squamous cell carcinoma of the esophagus: a review of 31 cases. Endoscopy 1998;30:258-65.

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10. Pech O, Gossner L, May A, et al. Long-term results of photodynamic therapy with 5-aminolevulinic acid for superficial Barrett’s cancer and high-grade intraepithelial neoplasia. Gastrointest Endosc 2005;62: 24-30. 11. Keeley SB, Pennathur A, Gooding W, et al. Photodynamic therapy with curative intent for Barrett’s esophagus with high grade dysplasia and superficial esophageal cancer. Ann Surg Oncol 2007;14:2406-10. 12. Yano T, Muto M, Minashi K, et al. Photodynamic therapy as salvage treatment for local failures after definitive chemoradiotherapy for esophageal cancer. Gastrointest Endosc 2005;62:31-6. 13. Nakamura T, Fukui H, Shirakawa K, et al. Photodynamic therapy of superficial esophageal cancer with a transparent hood. Gastrointest Endosc 2004;60:120-4. 14. Yoshida K, Suzuki S, Mimura S, et al. Photodynamic therapy for superficial esophageal cancer: a phase III study using PHE and excimer dye laser [Japanese]. Jpn J Cancer Chemother 1993;20:2063-6. 15. Participants in the Paris Workshop. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon. Gastrointest Endosc 2003;58(Suppl):S3-43. 16. Tachibana M, Hirahara N, Kinugasa S, et al. Clinicopathologic features of superficial esophageal cancer: results of consecutive 100 patients. Ann Surg Oncol 2008;15:104-16. 17. Bollschweiler E, Baldus SE, Schröder W, et al. High rate of lymph-node metastasis in submucosal esophageal squamous-cell carcinomas and adenocarcinoma. Endoscopy 2006;38:149-56. 18. Fujita H, Kakegawa T, Yamana H, et al. Mortality and morbidity rates, postoperative course, quality of life, and prognosis after extended radical lymphadenectomy for esophageal cancer. Ann Surg 1995;22:654-62. 19. Lerut T, Nafteux P, Moons J, et al. Three-field lymphadenectomy for carcinoma of the esophagus and gastroesophgeal junction in 174 R0 resection: impact on staging, disease-free survival, and outcome. Ann Surg 2004;240:962-74. 20. Pech O, May A, Rabenstein T, et al. Endoscopic resection of early oesophageal cancer. Gut 2007;56:1625-34. 21. Okunaka T, Kato H, Konaka C, et al. A comparison between argon-dye and excimer-dye laser for photodynamic effect in transplanted mouse tumor. Jpn J Cancer Res 1992;83:226-31. 22. Mimura S, Narahara H, Uehara H, et al. Photodynamic therapy for gastric cancer [Japanese]. Jpn J Cancer Chemother 1996;23:41-6. 23. Puli SR, Reddy JB, Bechtold ML, et al. Staging accuracy of esophageal cancer by endoscopic ultrasound: a meta-analysis and systematic review. World J Gastroenterol 2008;14:1479-90. 24. Rampado S, Bocus P, Battaglia G, et al. Endoscopic ultrasound: accuracy in staging superficial carcinomas of the esophagus. Ann Thorac Surg 2008;85:251-6. 25. Gaspar LE, Nag S, Herskovic A, et al. American Brachytherapy Society (ABS) consensus guidelines for brachytherapy of esophageal cancer. Int J Radiat Oncol Biol Phys 1997;38:127-32. 26. Nemoto K, Yamada S, Hareyama M, et al. Radiation therapy for superficial esophageal cancer: a comparison of radiotherapy methods. Int J Radiat Oncol Biol Phys 2001;50:639-44. 27. Ganz RA, Overholt BF, Sharma VK, et al. Circumferential ablation of Barrett’s esophagus that contains high-grade dysplasia: a U.S. multicenter registry. Gastrointest Endosc 2008;68:35-40. 28. van Vilsteren FG, Bergman JJ. Endoscopic therapy using radiofrequency ablation for esophageal dysplasia and carcinoma in Barrett’s esophagus. Gastrointest Endosc Clin North Am 2010;20:55-74. 29. Shaheen NJ, Greenwald BD, Peery AF, et al. Safety and efficacy of endoscopic spray cryotherapy for Barrett’s esophagus with high-grade dysplasia. Gastrointest Endosc 2010;71:680-5. 30. Greenwald BD, Dumot JA, Abrams JA, et al. Endoscopic spray cryotherapy for esophageal cancer: safety and efficacy. Gastrointest Endosc 2010;71:686-93.

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