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Photodynamic Therapy for Dysplastic Barrett Esophagus and Early Esophageal Adenocarcinoma
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Photodynamic Therapy for Patients With Barrett Esophagus
Mayo Clin Proc, November 2002, Vol 77
Original Article
Photodynamic Therapy for Dysplastic Barrett Esophagus and Early Esophageal Adenocarcinoma HERBERT C. WOLFSEN, MD; TIMOTHY A. WOODWARD, MD; AND MASSIMO RAIMONDO, MD
• Objective: To evaluate our results using photodynamic therapy (PDT) for the treatment of dysplasia or superficial cancer (T1 N0 M0) in patients with Barrett esophagus. • Patients and Methods: We retrospectively reviewed our clinical experience with 48 patients (34 patients with high-grade dysplasia and 14 patients with superficial cancer in Barrett esophagus) who had been referred for PDT. Initial evaluation included computed tomography and standard and high-frequency catheter endosonography. Follow-up endoscopy was performed 4 to 6 weeks after PDT with ablation of any residual glandular mucosa, using the argon plasma coagulator. Patients were then followed up indefinitely every 3 to 6 months with computed tomography, endosonography, and endoscopic surveillance. • Results: The median series follow-up was 18.5 months (range, 1-56 months). Apparent complete photoablation
of Barrett mucosa and/or superficial neoplasm was documented in 47 of 48 cases. Complications included symptomatic strictures (11 patients), photosensitivity (7 patients), atrial fibrillation (1 patient) or recurrent congestive heart failure (1 patient), and self-limited esophageal perforation (1 patient). Failure to ablate T1 N0 M0 adenocarcinoma occurred in 1 patient. • Conclusions: Porfimer sodium PDT appears to eradicate dysplastic Barrett mucosa and neoplasia. These results are promising; however, long-term studies are needed to document the efficacy of PDT in reducing the morbidity and mortality in such patients. Mayo Clin Proc. 2002;77:1176-1181 5-ALA = 5-aminolevulinic acid; CT = computed tomography; EUS = endosonography; PDT = photodynamic therapy
B
catheter endosonography (EUS). Every patient was seen in consultation by a cardiothoracic surgeon and, by their inclusion in this series, either refused esophageal resection surgery or was deemed an unacceptable medical risk for the operation. All patients underwent extensive patient education and counseling, and detailed informed consent was obtained for all endoscopic procedures, particularly PDT. After PDT, patients were evaluated every 3 to 6 months with CT, EUS, and endoscopic surveillance. These patients were treated per our clinical practice and not as part of an institutional review board–approved study protocol. Patient characteristics are summarized in Table 1. All patients had documented Barrett glandular mucosa with specialized intestinal metaplasia and high-grade dysplasia confirmed by at least 2 experienced histopathologists. Of patients with esophageal adenocarcinoma, only those staged as having T1 N0 MX disease by standard (Olympus EU-M3, Olympus America Inc, Melville, NY) and high-frequency catheter EUS (20-MHz catheter) and contrast-enhanced CT scans of the chest and abdomen were included in this study. Endosonographic-guided biopsy was used to sample any suspicious-appearing paraesophageal lymph nodes.4-7 Our technique of PDT has been described previously.8 After the initial evaluation and patient education, patients underwent intravenous infusion of 2 mg/kg of porfimer sodium (Photofrin, Axcan Scandipharm Inc, Birmingham,
arrett esophagus is a result of long-term acid reflux disease and is thought to be a major risk factor for the development of esophageal adenocarcinoma.1 Photodynamic therapy (PDT) using porfimer sodium has been approved for use in North America, Europe, the United Kingdom, and Japan since the mid-1990s for the palliative treatment of obstructing esophageal cancer.2 Photodynamic therapy has also been used as an alternative to surgery in patients with Barrett esophagus and high-grade dysplasia and superficial esophageal cancer.3 This report describes our experience using porfimer sodium PDT in the treatment of 48 consecutive patients with dysplastic Barrett esophagus and superficial esophageal cancer. PATIENTS AND METHODS Since 1997, 48 consecutive patients with Barrett esophagus and high-grade dysplasia (34 patients) or superficial esophageal cancer (14 patients) have been referred for and treated with PDT at our institution. The initial evaluation included contrast-enhanced computed tomography (CT) of the chest and abdomen and standard and high-frequency From the Division of Gastroenterology and Hepatology and Internal Medicine, Mayo Clinic, Jacksonville, Fla. Address reprint requests and correspondence to Herbert C. Wolfsen, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224 (e-mail: [email protected]). Mayo Clin Proc. 2002;77:1176-1181
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© 2002 Mayo Foundation for Medical Education and Research
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Mayo Clin Proc, November 2002, Vol 77
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Table 1. Patient Characteristics* Characteristic Median age at baseline (range) (y) Median BE segment length (range) (cm) Median follow-up time (range) (mo) Sex, No. (%) Male Female Complete Barrett epithelium ablation with PDT, No. (%) No Yes
Overall (N=48)
Mucosal ACA (n=14)
BE and HGD (n=34)
72 (47-85)
74.5 (64-84.5)
72 (47-85)
.10
5 (2-15)
4 (2-7.5)
6 (2-15)
.046
18.5 (1-56)
18 (2.5-41)
P value
18.5 (1-56)
.50
33 (69) 15 (31)
11 (79) 3 (21)
22 (65) 12 (35)
.50
21 (44) 27 (56)
6 (43) 8 (57)
15 (44) 19 (56)
.94
*Tests of medians were based on Wilcoxon rank sum test; test of association between sex and diagnosis was based on Fisher exact test; and test of association between ablation status and diagnosis was based on χ2 test. ACA = adenocarcinoma; BE = Barrett esophagus; HGD = high-grade dysplasia; PDT = photodynamic therapy.
Ala) followed 48 hours later by photoactivation with use of a 400-µm quartz fiber with a 2.5- or 5.0-cm cylindrical light diffuser (Optiguide fiber and Diomed 630 PDT diode laser, Diomed Inc, Andover, Mass; or PDT dye module 600 series, Nd:YAG/KTP laser 800 series, Laserscope, San Jose, Calif). These systems deliver 632 nm of red light via the cylindrical light diffuser, which is passed through the working channel of a videoendoscope (Olympus GIF-Q140) to deliver light energy to the target lesion (power density, 400 mW/cm; light dose ranging from 150 to 250 J/cm in fiber length). No balloon-centering device was used. All PDT was performed by the same physician (H.C.W.) on an outpatient basis. The expected chest pain and swallowing difficulties after PDT were managed with the use of a liquid diet for up to 3 to 5 days, in addition to the use of oral narcotic and antiemetic medications. All patients were treated with omeprazole or esomeprazole for aggressive gastric acid suppression, typically 40 to 80 mg by mouth twice daily. Esophagogastroduodenoscopy was performed in the usual manner, with conscious sedation with use of meperidine and midazolam after informed consent. Oxygen was administered continuously at 2 to 4 L/min via nasal catheter. Follow-up endoscopy procedures were performed 1 to 3 days after the initial PDT to ensure adequate target site treatment effect. After resolution of cutaneous photosensitivity, usually 4 to 6 weeks later, patients returned for a second endoscopy at which time the argon plasma coagulator was used to thermoablate any residual glandular mucosa (argon gas flow, 1.0 L/min; 45 W power). Patients were then followed up with surveillance endoscopy every 3 to 6 months, with use of standard sized biopsy forceps and standard video endoscopes. At least 2 biopsy specimens were obtained in 4 quadrants (every 1 cm through the
neosquamous segment) to ensure that no visually undetected or “buried” subsquamous Barrett glandular mucosa was present. Statistical analysis included comparisons of Fisher exact test of independence, χ2 test of association, Wilcoxon rank sum test of medians, and Kaplan-Meier survival curve analysis. RESULTS Photodynamic therapy using porfimer sodium was used in 48 patients, with a median follow-up of 18.5 months (range, 1-56 months). Among patients with mucosal adenocarcinoma, 7 of 14 had Barrett segments of 3 cm or less (median segment length in 14 patients, 4 cm; range, 2-7.5 cm). The median length of segment in the 34 patients treated for high-grade dysplasia was 6 cm (range, 2-15 cm). This difference in Barrett segment length was statistically significant (Wilcoxon rank sum test, P=.046). Comparison of the 2 diagnosis groups otherwise found no significant difference in average age (P=.10) or follow-up time after PDT (P=.50). The Fisher exact test found no relationship between sex and diagnosis (P=.50). All patients underwent only 1 course of PDT and porfimer sodium infusion. Treatment results are summarized in Table 2. The Kaplan-Meier survival curve analysis is presented in Figure 1 with an event defined as either death or esophageal resection, which both occurred in cancer patients. Although 27 patients (56%) experienced complete ablation of Barrett epithelium after PDT, another 21 patients (44%) were found to have small amounts of residual Barrett glandular mucosa at follow-up endoscopy that was successfully thermoablated with the argon plasma coagulator. Comparative analysis of these patients found a significant correlation with the length of Barrett segment and incomplete
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Table 2. Photodynamic Therapy Results: Comparison of Patients With Complete vs Incomplete Barrett Epithelium Ablation (N=48)* Barrett epithelium ablation after PDT Characteristic
Complete (n=27)
Incomplete (n=21)
P value
19 8 74.0 20.7
14 7 71.5 10.0
.78 .78 .12 .17
5.0
7.0
.009
Sex Male Female Median age (y) Median follow-up time (mo) Median Barrett esophagus segment length (cm)
*Tests of medians were based on Wilcoxon rank sum test; test of association between sex and diagnosis was based on Fisher exact test; and test of association between ablation status and diagnosis was based on χ2 test. PDT = photodynamic therapy.
ablation after PDT (Table 2). After completion of the argon plasma coagulator treatment for any residual disease, 47 of 48 patients were documented as having successful, complete ablation of Barrett esophagus and high-grade dysplasia and/ or T1 N0 M0 esophageal adenocarcinoma. Treatment complications, including stricture in 11 patients, required an average of 3.7 dilations (range, 1-14). Comparative analysis of these patients found a significant correlation with the length of Barrett segment and development of stricture after PDT (P=.01). Other complications included serious photosensitivity reactions that required medical therapy in 7 patients, new onset of atrial fibrillation in 1 patient, and recurrent congestive heart failure in 1 patient. Patients have been followed up with surveillance endoscopy every 3 to 6 months after PDT. The number of subsequent endoscopy examinations ranged from 1 to 15 (mean, 5.2).
100
Surviving patients (%)
90 80 70 60
Death due to metastatic lung cancer after successful PDT for T1 esophageal ACA Surgery for subsquamous ACA
50 40 30
Follow-up, N=48 Median, 18.5 mo Range, 1-56 mo
20 10 0
100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400
Time (d)
Figure 1. Kaplan-Meier analysis of 48 patients with Barrett esophagus and high-grade dysplasia and/or early esophageal adenocarcinoma (ACA) treated with porfimer sodium photodynamic therapy (PDT).
Mayo Clin Proc, November 2002, Vol 77
Photodynamic therapy failed to ablate a superficial adenocarcinoma completely in 1 patient with a 2.5-cm Barrett segment. At the initial post-PDT endoscopy, the lesion appeared to be completely destroyed with subsequent squamous reepithelialization. Surveillance biopsies, however, detected persistent high-grade adenocarcinoma underneath the neosquamous lining. This patient subsequently underwent curative esophagectomy. The operative specimen featured a tumor mass (16 × 11 × 3 mm) invading the submucosa (Figure 2) but not involving the muscularis. Importantly, the EUS studies performed before and after PDT did not visualize this tumor mass. Other than this case, we have not yet detected “buried Barrett” or recurrent adenocarcinoma in our series. Another patient was diagnosed as having nonadenomatous lung cancer at the time of his first PDT follow-up (6 weeks after treatment). Despite complete ablation of the early esophageal adenocarcinoma, he died of metastatic lung cancer 2 months later. Strictures responded to endoscopic dilation with Savary dilators in a manner similar to strictures related to external beam radiation treatment. Serious photosensitivity reactions required medical attention, including oral corticosteroid treatment. One patient with a 7.5-cm Barrett segment developed atrial fibrillation within 24 hours of PDT. He underwent outpatient cardiac evaluation, which resulted in initiation of heart rate control medication and systemic anticoagulation. Another patient with a 15-cm dysplastic Barrett segment and a history of congestive heart failure developed recurrent congestive heart failure within 72 hours of PDT. She required hospitalization and cardiac evaluation, but no evidence of acute coronary ischemia or new ischemic heart damage was found. Finally, a 69-year-old man with a 10cm dysplastic Barrett mucosal segment developed especially severe chest pain within 48 hours after PDT. Computed tomography found free air in the mediastinum and abdomen, implicating a perforation at the level of the gastroesophageal junction, associated with repeated retching and emesis after PDT.9 This patient was hospitalized, and barium esophageal x-ray films revealed no extravasation of contrast material. Ultimately, the patient recovered fully with only supportive medical care (no surgery was required). During the same period, another 48 patients at our institution have undergone esophageal resection for dysplastic Barrett segment or early esophageal cancer. Interestingly, since the establishment of our PDT program, the number of such surgical cases has nearly tripled. DISCUSSION The rate of Barrett esophagus–associated adenocarcinoma of the esophagus is increasing more rapidly than any other cancer in Europe, the United Kingdom, and the United
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Mayo Clin Proc, November 2002, Vol 77
States.1 Surgical resection of the esophagus in patients with Barrett esophagus and high-grade dysplasia and superficial esophageal cancer has been shown to improve patient survival.10,11 Unfortunately, esophageal resection surgery is associated with significant mortality (4%-6% in expert centers), major morbidity (up to 40%), and decreased postoperative patient quality of life compared with matched controls.12,13 Other than esophagectomy, no other medical or surgical therapy has been shown to cause consistent regression of Barrett glandular mucosa or prevent development of invasive neoplasms.14-17 Endoscopic therapy would seem to be ideally suited for the ablation of dysplastic Barrett epithelium and early esophageal cancer because these diseases are localized to the esophageal mucosa.18 Therefore, endoscopic therapy is highly dependent on accurate staging. Using standard EUS for Barrett esophagus with high-grade dysplasia and early carcinoma has been controversial.19 More recently, the use of high-frequency catheter ultrasonography has allowed detailed characterization of early esophageal cancer by defining lesions not visible at standard EUS (uT0) and visible lesions confined to the mucosa (uT1).20,21 Therefore, highfrequency catheter ultrasonography is useful for evaluating patients for endoscopic therapy because it allows precise differentiation between tumors limited to the mucosa and those infiltrating the submucosa.20-23 Although PDT is not the only form of endoscopic ablative therapy being investigated for the treatment of these diseases,24 the relative selectivity of photosensitizers and the safety of the nonthermal photoablation process make PDT especially useful.25 The most commonly used photosensitizers in PDT are 5-aminolevulinic acid (5-ALA) and porfimer sodium (Photofrin).26 Since 5-ALA PDT has yet to be approved for use in North America, studies describing its use have come from Europe and the United Kingdom (Tables 3 and 4). These studies document 5-ALA PDT to be safe and effective, with only transient photosensitization. However, this form of PDT produces a limited depth of mucosal necrosis and associated residual subsquamous glandular epithelium. Studies using porfimer sodium PDT or more primitive porphyrin sensitizers such as hematoporphyrin derivative have generally been conducted in North America, and the results are also summarized in Tables 3 and 4. These studies document the safety and efficacy of porfimer sodium PDT for Barrett high-grade dysplasia and early esophageal cancer with a much smaller percentage of patients having persistent subsquamous Barrett glandular epithelium. This treatment, however, is associated with prolonged photosensitization.18 The largest published experience with porfimer sodium PDT for Barrett esophagus with high-grade dysplasia or early esophageal cancer was updated recently by Overholt
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Figure 2. Histopathologic specimen showing persistent highgrade adenocarcinoma with overlying neosquamous mucosa after porfimer sodium photodynamic therapy for T1 N0 M0 adenocarcinoma of the distal esophagus (hematoxylin-eosin, original magnification ×100).
et al.37 The methods used in this study included the use of longer light diffusers, mirrored (windowed) balloon-centering devices, and varied light doses. Other differences in technique, compared with our study, included the use of the Nd:YAG laser instead of the argon plasma coagulator for ablation of persistent, endoscopically apparent Barrett glandular mucosa after PDT. Although the doses of red light and porfimer sodium were similar to those used in our series, 27 of 100 total patients required more than 1 infusion of porfimer sodium and additional PDT. The complete ablation of Barrett glandular mucosa was noted in 32 (44%) of 73 patients with Barrett high-grade dysplasia, whereas high-grade dysplasia was eliminated in 64 (88%) of these patients. Superficial esophageal carcinomas were successfully destroyed in 10 (77%) of 13 patients after PDT. The present study documented complete ablation of Barrett epithelium in 27 (56%) of 48 patients after 1 course of porfimer sodium PDT. Analysis of patient characteris-
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Mayo Clin Proc, November 2002, Vol 77
Table 3. Photodynamic Therapy for Early Esophageal Adenocarcinoma* No. of patients
Reference
No. (%) of patients responding
Photosensitizer
Current study Etienne et al,27 2001 Beejay et al,28 2001 Overholt,29 1999 Overholt and Panjehpour,30 1997 Gossner et al,31,32 1999
14 11 5 13
PS PS PS PS
13/14 11/11 4/5 10/13
(93) (100) (80) (77)
7 58
7/7 (100) 36/58 (62)
Tan et al,33 1999
12
PS ALA with mTHPC ALA
Ackroyd et al,34 1999 Gossner et al,35 1998
3 22
ALA ALA
0/3 (0) 17/22 (77)
2/12 (17)
Follow-up (mo) 18.5 9-16 30 19
(median) (range) (mean) (mean)
22 (mean) 2-48 (range) 28 and 36 for the 2 patients 28 (mean) 9.9 (mean)
*ALA = 5-aminolevulinic acid; mTHPC = mesotetrahydroxyphenylchlorin; PS = porfimer sodium.
tics found a significant correlation between Barrett segment length and incomplete Barrett ablation after PDT (Table 2). A similar analysis of patients who developed strictures requiring endoscopic dilation also found a significant correlation with Barrett segment length. After subsequent treatment with argon plasma thermoablation, however, 47 (93%) of 48 patients were documented as having complete ablation of Barrett epithelium. At a median series follow-up time of 18.5 months, subsquamous glandular mucosa has not been detected in any of our patients despite careful endoscopic surveillance with an aggressive biopsy protocol. This protocol successfully detected persistent submucosal, high-grade adenocarcinoma in 1 (7%) of 14 patients who had undergone PDT for T1 N0 M0 esophageal adenocarcinoma. Other complications of PDT, such as esophageal stricture formation, were similar in these studies (23% in the current series compared with 34% in the study by Overholt et al37). Overholt et al37 have adopted the use of longer light-diffusing fibers and mirrored balloon-centering devices in an attempt to reduce complica-
tions such as stricture formation, based on comparisons with historical data. Stricture rates in porfimer sodium PDT series not using these devices, however, are similar to those series that used these devices (Table 4). Our study found a significant correlation with the length of Barrett segment treated with PDT and the subsequent development of esophageal stricture. Therefore, we await further studies comparing these different PDT techniques. The present study is important for several reasons. First, our study population is more diverse than those studied previously. Although all our patients were white, 35% were women, with similar numbers in both diagnostic groups. Second, the only difference noted in the patients with Barrett highgrade dysplasia and those with mucosal adenocarcinoma was the length of the Barrett segment. The significantly shorter Barrett segment length found in patients with early cancer confirms the findings of Rudolph et al39 and emphasizes the risk of carcinogenesis in patients with short segment Barrett esophagus. In addition, all patients were evaluated and treated in a similar manner, including the use
Table 4. Photodynamic Therapy for Barrett Esophagus with High-Grade Dysplasia*
Reference 36
No. of patients
PHO-BAR † Overholt et al,37 1999 Current study Beejay et al,28 2001 Wang,3 1999 Gossner et al,31,32 1999
132 73 34 13 26 14
Gossner et al,35 1998 Barr et al,38 1996 Ackroyd et al,34 1999
10 5 4
Photosensitizer PS PS PS PS HpD ALA with mTHPC ALA ALA ALA
BE elimination (%)
HGD elimination (%)
Stricture rate (%)
Use of fibercentering device
Series average follow-up (mo)
NA 6 0 NA 4 NA
41 44 56 61 35 NA
72 88 100 100 88 100
36 34 23 55 27 NA
Yes Yes No Yes No Yes
12 19 18.5 30 NA NA
20 40 NA
0 0 25
100 100 100
0 0 0
Yes Yes Yes
9.9 26-44 28
Subsquamous BE (%)
*ALA = 5-aminolevulinic acid; BE = Barrett esophagus; HGD = high-grade dysplasia; HpD = hematoporphyrin derivative; mTHPC = mesotetrahydroxyphenylchlorin; NA = not applicable; PS = porfimer sodium. †Thirty-site, international, multicenter randomized controlled trial with 69 observation patients treated with omeprazole only.
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Mayo Clin Proc, November 2002, Vol 77
Photodynamic Therapy for Patients With Barrett Esophagus
of high-frequency catheter EUS and equivalent PDT drug and light doses. To ensure reliable results, uniform methods were used throughout the study. These technical differences aside, our results support the use of porfimer sodium PDT in the treatment of patients with high-grade dysplastic Barrett esophagus and early esophageal carcinoma.
20.
21.
22. 23.
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Nijhawan PK, Wang KK. Endoscopic mucosal resection for lesions with endoscopic features suggestive of malignancy and high-grade dysplasia within Barrett’s esophagus. Gastrointest Endosc. 2000; 52:328-332. Akahoshi K, Chijiiwa Y, Hamada S, et al. Endoscopic ultrasonography: a promising method for assessing the prospects of endoscopic mucosal resection in early gastric cancer. Endoscopy. 1997; 29:614-619. Meyenberger C, Fantin AC. Esophageal carcinoma: current staging strategies. Recent Results Cancer Res. 2000;155:63-72. Murata Y, Suzuki S, Ohta M, et al. Small ultrasonic probes for determination of the depth of superficial esophageal cancer. Gastrointest Endosc. 1996;44:23-28. Maier A, Tomaselli F, Matzi V, Rehak P, Pinter H, Smolle-Jüttner FM. Photosensitization with hematoporphyrin derivative compared to 5-aminolaevulinic acid for photodynamic therapy of esophageal carcinoma. Ann Thorac Surg. 2001;72:1136-1140. Ackroyd R, Brown NJ, Davis MF, et al. Photodynamic therapy for dysplastic Barrett’s oesophagus: a prospective, double blind, randomised, placebo controlled trial. Gut. 2000;47:612-617. Barr H. Barrett’s esophagus: treatment with 5-aminolevulinic acid photodynamic therapy. Gastrointest Endosc Clin N Am. 2000;10: 421-437. Etienne J, Bourg-Heckley G, Dorme N, Raimbert P, Flejou J-F, Guillemin F. Green light Foscan photodynamic therapy (PDT) on 25 oesophageal intramucosal cancers (IMC). Presented at: Photodynamic Association 8th World Congress of Photodynamic Medicine; Vancouver, British Columbia; June 7, 2001. Beejay U, Ribeiro A, Hourigan L, et al. Photodynamic therapy of high grade dysplasia/intramucosal carcinoma in Barrett’s esophagus—30 months follow up [abstract]. Gastrointest Endosc. 2001; 53:AB144. Abstract 4116. Overholt BF. Results of photodynamic therapy in Barrett’s esophagus: a review. Can J Gastroenterol. 1999;13:393-396. Overholt BF, Panjehpour M. Photodynamic therapy for Barrett’s esophagus. Gastrointest Endosc Clin N Am. 1997;7:207-220. Gossner L, May A, Sroka R, Stolte M, Hahn EG, Ell C. Photodynamic destruction of high grade dysplasia and early carcinoma of the esophagus after the oral administration of 5-aminolevulinic acid. Cancer. 1999;86:1921-1928. Gossner L, May A, Pech O, et al. Photodynamic therapy of Barrett’s esophagus with dysplasia or early cancer [abstract]. Gastroenterology. 1999;116(pt 2):A413. Abstract G1811. Tan WC, Fulljames C, Stone N, et al. Photodynamic therapy using 5-aminolaevulinic acid for oesophageal adenocarcinoma associated with Barrett’s metaplasia. J Photochem Photobiol B. 1999;53: 75-80. Ackroyd R, Brown NJ, Davis MF, Stephenson TJ, Stoddard CJ, Reed MWR. Aminolaevulinic acid-induced photodynamic therapy in the treatment of dysplastic Barrett’s oesophagus and adenocarcinoma. Lasers Med Sci. 1999;14:278-285. Gossner L, Stolte M, Sroka R, et al. Photodynamic ablation of highgrade dysplasia and early cancer in Barrett’s esophagus by means of 5-aminolevulinic acid. Gastroenterology. 1998;114:448-455. Wolfsen HC. Photodynamic therapy for mucosal esophageal adenocarcinoma and dysplastic Barrett’s esophagus. Dig Dis. 2002; 20:5-17. Overholt BF, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett’s esophagus: follow-up in 100 patients. Gastrointest Endosc. 1999;49:1-7. Barr H, Shepherd NA, Dix A, Roberts DJ, Tan WC, Krasner N. Eradication of high-grade dysplasia in columnar-lined (Barrett’s) oesophagus by photodynamic therapy with endogenously generated protoporphyrin IX. Lancet. 1996;348:584-585. Rudolph RE, Vaughan TL, Storer BE, et al. Effect of segment length on risk for neoplastic progression in patients with Barrett esophagus. Ann Intern Med. 2000;132:612-620.
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Photodynamic Therapy for Patients With Barrett Esophagus
Mayo Clin Proc, November 2002, Vol 77
Original Article
Photodynamic Therapy for Dysplastic Barrett Esophagus and Early Esophageal Adenocarcinoma HERBERT C. WOLFSEN, MD; TIMOTHY A. WOODWARD, MD; AND MASSIMO RAIMONDO, MD
• Objective: To evaluate our results using photodynamic therapy (PDT) for the treatment of dysplasia or superficial cancer (T1 N0 M0) in patients with Barrett esophagus. • Patients and Methods: We retrospectively reviewed our clinical experience with 48 patients (34 patients with high-grade dysplasia and 14 patients with superficial cancer in Barrett esophagus) who had been referred for PDT. Initial evaluation included computed tomography and standard and high-frequency catheter endosonography. Follow-up endoscopy was performed 4 to 6 weeks after PDT with ablation of any residual glandular mucosa, using the argon plasma coagulator. Patients were then followed up indefinitely every 3 to 6 months with computed tomography, endosonography, and endoscopic surveillance. • Results: The median series follow-up was 18.5 months (range, 1-56 months). Apparent complete photoablation
of Barrett mucosa and/or superficial neoplasm was documented in 47 of 48 cases. Complications included symptomatic strictures (11 patients), photosensitivity (7 patients), atrial fibrillation (1 patient) or recurrent congestive heart failure (1 patient), and self-limited esophageal perforation (1 patient). Failure to ablate T1 N0 M0 adenocarcinoma occurred in 1 patient. • Conclusions: Porfimer sodium PDT appears to eradicate dysplastic Barrett mucosa and neoplasia. These results are promising; however, long-term studies are needed to document the efficacy of PDT in reducing the morbidity and mortality in such patients. Mayo Clin Proc. 2002;77:1176-1181 5-ALA = 5-aminolevulinic acid; CT = computed tomography; EUS = endosonography; PDT = photodynamic therapy
B
catheter endosonography (EUS). Every patient was seen in consultation by a cardiothoracic surgeon and, by their inclusion in this series, either refused esophageal resection surgery or was deemed an unacceptable medical risk for the operation. All patients underwent extensive patient education and counseling, and detailed informed consent was obtained for all endoscopic procedures, particularly PDT. After PDT, patients were evaluated every 3 to 6 months with CT, EUS, and endoscopic surveillance. These patients were treated per our clinical practice and not as part of an institutional review board–approved study protocol. Patient characteristics are summarized in Table 1. All patients had documented Barrett glandular mucosa with specialized intestinal metaplasia and high-grade dysplasia confirmed by at least 2 experienced histopathologists. Of patients with esophageal adenocarcinoma, only those staged as having T1 N0 MX disease by standard (Olympus EU-M3, Olympus America Inc, Melville, NY) and high-frequency catheter EUS (20-MHz catheter) and contrast-enhanced CT scans of the chest and abdomen were included in this study. Endosonographic-guided biopsy was used to sample any suspicious-appearing paraesophageal lymph nodes.4-7 Our technique of PDT has been described previously.8 After the initial evaluation and patient education, patients underwent intravenous infusion of 2 mg/kg of porfimer sodium (Photofrin, Axcan Scandipharm Inc, Birmingham,
arrett esophagus is a result of long-term acid reflux disease and is thought to be a major risk factor for the development of esophageal adenocarcinoma.1 Photodynamic therapy (PDT) using porfimer sodium has been approved for use in North America, Europe, the United Kingdom, and Japan since the mid-1990s for the palliative treatment of obstructing esophageal cancer.2 Photodynamic therapy has also been used as an alternative to surgery in patients with Barrett esophagus and high-grade dysplasia and superficial esophageal cancer.3 This report describes our experience using porfimer sodium PDT in the treatment of 48 consecutive patients with dysplastic Barrett esophagus and superficial esophageal cancer. PATIENTS AND METHODS Since 1997, 48 consecutive patients with Barrett esophagus and high-grade dysplasia (34 patients) or superficial esophageal cancer (14 patients) have been referred for and treated with PDT at our institution. The initial evaluation included contrast-enhanced computed tomography (CT) of the chest and abdomen and standard and high-frequency From the Division of Gastroenterology and Hepatology and Internal Medicine, Mayo Clinic, Jacksonville, Fla. Address reprint requests and correspondence to Herbert C. Wolfsen, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224 (e-mail: [email protected]). Mayo Clin Proc. 2002;77:1176-1181
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© 2002 Mayo Foundation for Medical Education and Research
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Table 1. Patient Characteristics* Characteristic Median age at baseline (range) (y) Median BE segment length (range) (cm) Median follow-up time (range) (mo) Sex, No. (%) Male Female Complete Barrett epithelium ablation with PDT, No. (%) No Yes
Overall (N=48)
Mucosal ACA (n=14)
BE and HGD (n=34)
72 (47-85)
74.5 (64-84.5)
72 (47-85)
.10
5 (2-15)
4 (2-7.5)
6 (2-15)
.046
18.5 (1-56)
18 (2.5-41)
P value
18.5 (1-56)
.50
33 (69) 15 (31)
11 (79) 3 (21)
22 (65) 12 (35)
.50
21 (44) 27 (56)
6 (43) 8 (57)
15 (44) 19 (56)
.94
*Tests of medians were based on Wilcoxon rank sum test; test of association between sex and diagnosis was based on Fisher exact test; and test of association between ablation status and diagnosis was based on χ2 test. ACA = adenocarcinoma; BE = Barrett esophagus; HGD = high-grade dysplasia; PDT = photodynamic therapy.
Ala) followed 48 hours later by photoactivation with use of a 400-µm quartz fiber with a 2.5- or 5.0-cm cylindrical light diffuser (Optiguide fiber and Diomed 630 PDT diode laser, Diomed Inc, Andover, Mass; or PDT dye module 600 series, Nd:YAG/KTP laser 800 series, Laserscope, San Jose, Calif). These systems deliver 632 nm of red light via the cylindrical light diffuser, which is passed through the working channel of a videoendoscope (Olympus GIF-Q140) to deliver light energy to the target lesion (power density, 400 mW/cm; light dose ranging from 150 to 250 J/cm in fiber length). No balloon-centering device was used. All PDT was performed by the same physician (H.C.W.) on an outpatient basis. The expected chest pain and swallowing difficulties after PDT were managed with the use of a liquid diet for up to 3 to 5 days, in addition to the use of oral narcotic and antiemetic medications. All patients were treated with omeprazole or esomeprazole for aggressive gastric acid suppression, typically 40 to 80 mg by mouth twice daily. Esophagogastroduodenoscopy was performed in the usual manner, with conscious sedation with use of meperidine and midazolam after informed consent. Oxygen was administered continuously at 2 to 4 L/min via nasal catheter. Follow-up endoscopy procedures were performed 1 to 3 days after the initial PDT to ensure adequate target site treatment effect. After resolution of cutaneous photosensitivity, usually 4 to 6 weeks later, patients returned for a second endoscopy at which time the argon plasma coagulator was used to thermoablate any residual glandular mucosa (argon gas flow, 1.0 L/min; 45 W power). Patients were then followed up with surveillance endoscopy every 3 to 6 months, with use of standard sized biopsy forceps and standard video endoscopes. At least 2 biopsy specimens were obtained in 4 quadrants (every 1 cm through the
neosquamous segment) to ensure that no visually undetected or “buried” subsquamous Barrett glandular mucosa was present. Statistical analysis included comparisons of Fisher exact test of independence, χ2 test of association, Wilcoxon rank sum test of medians, and Kaplan-Meier survival curve analysis. RESULTS Photodynamic therapy using porfimer sodium was used in 48 patients, with a median follow-up of 18.5 months (range, 1-56 months). Among patients with mucosal adenocarcinoma, 7 of 14 had Barrett segments of 3 cm or less (median segment length in 14 patients, 4 cm; range, 2-7.5 cm). The median length of segment in the 34 patients treated for high-grade dysplasia was 6 cm (range, 2-15 cm). This difference in Barrett segment length was statistically significant (Wilcoxon rank sum test, P=.046). Comparison of the 2 diagnosis groups otherwise found no significant difference in average age (P=.10) or follow-up time after PDT (P=.50). The Fisher exact test found no relationship between sex and diagnosis (P=.50). All patients underwent only 1 course of PDT and porfimer sodium infusion. Treatment results are summarized in Table 2. The Kaplan-Meier survival curve analysis is presented in Figure 1 with an event defined as either death or esophageal resection, which both occurred in cancer patients. Although 27 patients (56%) experienced complete ablation of Barrett epithelium after PDT, another 21 patients (44%) were found to have small amounts of residual Barrett glandular mucosa at follow-up endoscopy that was successfully thermoablated with the argon plasma coagulator. Comparative analysis of these patients found a significant correlation with the length of Barrett segment and incomplete
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Table 2. Photodynamic Therapy Results: Comparison of Patients With Complete vs Incomplete Barrett Epithelium Ablation (N=48)* Barrett epithelium ablation after PDT Characteristic
Complete (n=27)
Incomplete (n=21)
P value
19 8 74.0 20.7
14 7 71.5 10.0
.78 .78 .12 .17
5.0
7.0
.009
Sex Male Female Median age (y) Median follow-up time (mo) Median Barrett esophagus segment length (cm)
*Tests of medians were based on Wilcoxon rank sum test; test of association between sex and diagnosis was based on Fisher exact test; and test of association between ablation status and diagnosis was based on χ2 test. PDT = photodynamic therapy.
ablation after PDT (Table 2). After completion of the argon plasma coagulator treatment for any residual disease, 47 of 48 patients were documented as having successful, complete ablation of Barrett esophagus and high-grade dysplasia and/ or T1 N0 M0 esophageal adenocarcinoma. Treatment complications, including stricture in 11 patients, required an average of 3.7 dilations (range, 1-14). Comparative analysis of these patients found a significant correlation with the length of Barrett segment and development of stricture after PDT (P=.01). Other complications included serious photosensitivity reactions that required medical therapy in 7 patients, new onset of atrial fibrillation in 1 patient, and recurrent congestive heart failure in 1 patient. Patients have been followed up with surveillance endoscopy every 3 to 6 months after PDT. The number of subsequent endoscopy examinations ranged from 1 to 15 (mean, 5.2).
100
Surviving patients (%)
90 80 70 60
Death due to metastatic lung cancer after successful PDT for T1 esophageal ACA Surgery for subsquamous ACA
50 40 30
Follow-up, N=48 Median, 18.5 mo Range, 1-56 mo
20 10 0
100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400
Time (d)
Figure 1. Kaplan-Meier analysis of 48 patients with Barrett esophagus and high-grade dysplasia and/or early esophageal adenocarcinoma (ACA) treated with porfimer sodium photodynamic therapy (PDT).
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Photodynamic therapy failed to ablate a superficial adenocarcinoma completely in 1 patient with a 2.5-cm Barrett segment. At the initial post-PDT endoscopy, the lesion appeared to be completely destroyed with subsequent squamous reepithelialization. Surveillance biopsies, however, detected persistent high-grade adenocarcinoma underneath the neosquamous lining. This patient subsequently underwent curative esophagectomy. The operative specimen featured a tumor mass (16 × 11 × 3 mm) invading the submucosa (Figure 2) but not involving the muscularis. Importantly, the EUS studies performed before and after PDT did not visualize this tumor mass. Other than this case, we have not yet detected “buried Barrett” or recurrent adenocarcinoma in our series. Another patient was diagnosed as having nonadenomatous lung cancer at the time of his first PDT follow-up (6 weeks after treatment). Despite complete ablation of the early esophageal adenocarcinoma, he died of metastatic lung cancer 2 months later. Strictures responded to endoscopic dilation with Savary dilators in a manner similar to strictures related to external beam radiation treatment. Serious photosensitivity reactions required medical attention, including oral corticosteroid treatment. One patient with a 7.5-cm Barrett segment developed atrial fibrillation within 24 hours of PDT. He underwent outpatient cardiac evaluation, which resulted in initiation of heart rate control medication and systemic anticoagulation. Another patient with a 15-cm dysplastic Barrett segment and a history of congestive heart failure developed recurrent congestive heart failure within 72 hours of PDT. She required hospitalization and cardiac evaluation, but no evidence of acute coronary ischemia or new ischemic heart damage was found. Finally, a 69-year-old man with a 10cm dysplastic Barrett mucosal segment developed especially severe chest pain within 48 hours after PDT. Computed tomography found free air in the mediastinum and abdomen, implicating a perforation at the level of the gastroesophageal junction, associated with repeated retching and emesis after PDT.9 This patient was hospitalized, and barium esophageal x-ray films revealed no extravasation of contrast material. Ultimately, the patient recovered fully with only supportive medical care (no surgery was required). During the same period, another 48 patients at our institution have undergone esophageal resection for dysplastic Barrett segment or early esophageal cancer. Interestingly, since the establishment of our PDT program, the number of such surgical cases has nearly tripled. DISCUSSION The rate of Barrett esophagus–associated adenocarcinoma of the esophagus is increasing more rapidly than any other cancer in Europe, the United Kingdom, and the United
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Mayo Clin Proc, November 2002, Vol 77
States.1 Surgical resection of the esophagus in patients with Barrett esophagus and high-grade dysplasia and superficial esophageal cancer has been shown to improve patient survival.10,11 Unfortunately, esophageal resection surgery is associated with significant mortality (4%-6% in expert centers), major morbidity (up to 40%), and decreased postoperative patient quality of life compared with matched controls.12,13 Other than esophagectomy, no other medical or surgical therapy has been shown to cause consistent regression of Barrett glandular mucosa or prevent development of invasive neoplasms.14-17 Endoscopic therapy would seem to be ideally suited for the ablation of dysplastic Barrett epithelium and early esophageal cancer because these diseases are localized to the esophageal mucosa.18 Therefore, endoscopic therapy is highly dependent on accurate staging. Using standard EUS for Barrett esophagus with high-grade dysplasia and early carcinoma has been controversial.19 More recently, the use of high-frequency catheter ultrasonography has allowed detailed characterization of early esophageal cancer by defining lesions not visible at standard EUS (uT0) and visible lesions confined to the mucosa (uT1).20,21 Therefore, highfrequency catheter ultrasonography is useful for evaluating patients for endoscopic therapy because it allows precise differentiation between tumors limited to the mucosa and those infiltrating the submucosa.20-23 Although PDT is not the only form of endoscopic ablative therapy being investigated for the treatment of these diseases,24 the relative selectivity of photosensitizers and the safety of the nonthermal photoablation process make PDT especially useful.25 The most commonly used photosensitizers in PDT are 5-aminolevulinic acid (5-ALA) and porfimer sodium (Photofrin).26 Since 5-ALA PDT has yet to be approved for use in North America, studies describing its use have come from Europe and the United Kingdom (Tables 3 and 4). These studies document 5-ALA PDT to be safe and effective, with only transient photosensitization. However, this form of PDT produces a limited depth of mucosal necrosis and associated residual subsquamous glandular epithelium. Studies using porfimer sodium PDT or more primitive porphyrin sensitizers such as hematoporphyrin derivative have generally been conducted in North America, and the results are also summarized in Tables 3 and 4. These studies document the safety and efficacy of porfimer sodium PDT for Barrett high-grade dysplasia and early esophageal cancer with a much smaller percentage of patients having persistent subsquamous Barrett glandular epithelium. This treatment, however, is associated with prolonged photosensitization.18 The largest published experience with porfimer sodium PDT for Barrett esophagus with high-grade dysplasia or early esophageal cancer was updated recently by Overholt
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Figure 2. Histopathologic specimen showing persistent highgrade adenocarcinoma with overlying neosquamous mucosa after porfimer sodium photodynamic therapy for T1 N0 M0 adenocarcinoma of the distal esophagus (hematoxylin-eosin, original magnification ×100).
et al.37 The methods used in this study included the use of longer light diffusers, mirrored (windowed) balloon-centering devices, and varied light doses. Other differences in technique, compared with our study, included the use of the Nd:YAG laser instead of the argon plasma coagulator for ablation of persistent, endoscopically apparent Barrett glandular mucosa after PDT. Although the doses of red light and porfimer sodium were similar to those used in our series, 27 of 100 total patients required more than 1 infusion of porfimer sodium and additional PDT. The complete ablation of Barrett glandular mucosa was noted in 32 (44%) of 73 patients with Barrett high-grade dysplasia, whereas high-grade dysplasia was eliminated in 64 (88%) of these patients. Superficial esophageal carcinomas were successfully destroyed in 10 (77%) of 13 patients after PDT. The present study documented complete ablation of Barrett epithelium in 27 (56%) of 48 patients after 1 course of porfimer sodium PDT. Analysis of patient characteris-
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Table 3. Photodynamic Therapy for Early Esophageal Adenocarcinoma* No. of patients
Reference
No. (%) of patients responding
Photosensitizer
Current study Etienne et al,27 2001 Beejay et al,28 2001 Overholt,29 1999 Overholt and Panjehpour,30 1997 Gossner et al,31,32 1999
14 11 5 13
PS PS PS PS
13/14 11/11 4/5 10/13
(93) (100) (80) (77)
7 58
7/7 (100) 36/58 (62)
Tan et al,33 1999
12
PS ALA with mTHPC ALA
Ackroyd et al,34 1999 Gossner et al,35 1998
3 22
ALA ALA
0/3 (0) 17/22 (77)
2/12 (17)
Follow-up (mo) 18.5 9-16 30 19
(median) (range) (mean) (mean)
22 (mean) 2-48 (range) 28 and 36 for the 2 patients 28 (mean) 9.9 (mean)
*ALA = 5-aminolevulinic acid; mTHPC = mesotetrahydroxyphenylchlorin; PS = porfimer sodium.
tics found a significant correlation between Barrett segment length and incomplete Barrett ablation after PDT (Table 2). A similar analysis of patients who developed strictures requiring endoscopic dilation also found a significant correlation with Barrett segment length. After subsequent treatment with argon plasma thermoablation, however, 47 (93%) of 48 patients were documented as having complete ablation of Barrett epithelium. At a median series follow-up time of 18.5 months, subsquamous glandular mucosa has not been detected in any of our patients despite careful endoscopic surveillance with an aggressive biopsy protocol. This protocol successfully detected persistent submucosal, high-grade adenocarcinoma in 1 (7%) of 14 patients who had undergone PDT for T1 N0 M0 esophageal adenocarcinoma. Other complications of PDT, such as esophageal stricture formation, were similar in these studies (23% in the current series compared with 34% in the study by Overholt et al37). Overholt et al37 have adopted the use of longer light-diffusing fibers and mirrored balloon-centering devices in an attempt to reduce complica-
tions such as stricture formation, based on comparisons with historical data. Stricture rates in porfimer sodium PDT series not using these devices, however, are similar to those series that used these devices (Table 4). Our study found a significant correlation with the length of Barrett segment treated with PDT and the subsequent development of esophageal stricture. Therefore, we await further studies comparing these different PDT techniques. The present study is important for several reasons. First, our study population is more diverse than those studied previously. Although all our patients were white, 35% were women, with similar numbers in both diagnostic groups. Second, the only difference noted in the patients with Barrett highgrade dysplasia and those with mucosal adenocarcinoma was the length of the Barrett segment. The significantly shorter Barrett segment length found in patients with early cancer confirms the findings of Rudolph et al39 and emphasizes the risk of carcinogenesis in patients with short segment Barrett esophagus. In addition, all patients were evaluated and treated in a similar manner, including the use
Table 4. Photodynamic Therapy for Barrett Esophagus with High-Grade Dysplasia*
Reference 36
No. of patients
PHO-BAR † Overholt et al,37 1999 Current study Beejay et al,28 2001 Wang,3 1999 Gossner et al,31,32 1999
132 73 34 13 26 14
Gossner et al,35 1998 Barr et al,38 1996 Ackroyd et al,34 1999
10 5 4
Photosensitizer PS PS PS PS HpD ALA with mTHPC ALA ALA ALA
BE elimination (%)
HGD elimination (%)
Stricture rate (%)
Use of fibercentering device
Series average follow-up (mo)
NA 6 0 NA 4 NA
41 44 56 61 35 NA
72 88 100 100 88 100
36 34 23 55 27 NA
Yes Yes No Yes No Yes
12 19 18.5 30 NA NA
20 40 NA
0 0 25
100 100 100
0 0 0
Yes Yes Yes
9.9 26-44 28
Subsquamous BE (%)
*ALA = 5-aminolevulinic acid; BE = Barrett esophagus; HGD = high-grade dysplasia; HpD = hematoporphyrin derivative; mTHPC = mesotetrahydroxyphenylchlorin; NA = not applicable; PS = porfimer sodium. †Thirty-site, international, multicenter randomized controlled trial with 69 observation patients treated with omeprazole only.
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Mayo Clin Proc, November 2002, Vol 77
Photodynamic Therapy for Patients With Barrett Esophagus
of high-frequency catheter EUS and equivalent PDT drug and light doses. To ensure reliable results, uniform methods were used throughout the study. These technical differences aside, our results support the use of porfimer sodium PDT in the treatment of patients with high-grade dysplastic Barrett esophagus and early esophageal carcinoma.
20.
21.
22. 23.
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