- Email: [email protected]
Endoscopic Ablation Therapy: Imaging and Advanced Technology in Action
Imaging and Advanced Technology Michael B. Wallace, Section Editor
Endoscopic Ablation Therapy: Imaging and Advanced Technology in Action HERBERT C. WOLFSEN Division of Gastroenterology and Hepatology, Mayo Clinic Florida, Jacksonville, Florida; and Mayo Clinic College of Medicine, Rochester, Minnesota
M
ore than any other area of gastrointestinal endoscopy, ablation therapy has incorporated numerous imaging and technology advances to produce clinically important results for the treatment of Barrett’s esophagus (BE) and superficial esophageal cancer to prevent the development of invasive malignancy (endoprevention).1 Focal ablation methods that use thermal energy have been available for many years. Devices such as thermal lasers, multipolar electrocoagulation, heater probe, and argon plasma coagulation have been used to treat BE since the mid 1980s.2 The important work by Sampliner and others established the proof of principal that Barrett’s glandular mucosa ablation was technically feasible and that gastric acid suppression was important to successful mucosal remodeling to squamous epithelium.3 However, limitations of these “point-and-shoot”–type focal devices with variable tissue effects included areas of overtreatment (with risk of stricture and perforation) and undertreatment (with the risk of persistent subsquamous disease and subsequent development of carcinoma).
Role of Advanced Imaging The safe and effective use of any ablation device requires the best possible endoscopic imaging for the initial detection and characterization of disease and thereafter to target therapy. The use of high-resolution endoscopy (HRE) with narrow-band imaging (NBI) has been particularly important. Controlled studies have found that the use of HRE and NBI detected more BE and higher grades of dysplasia in patients with fewer biopsies compared with standard resolution white-light endoscopy.4 Sharma et al5 recently presented results of a randomized, controlled, international, multicenter study where the use of HRE and HRE plus NBI detected a similar proportion of patients with BE. However, the use of NBI detected significantly more dysplastic lesions, including high-grade dysplasia (HGD) or cancer, with fewer biopsies per procedure compared with HRE alone. Another important development has been the increased use of endoscopic mucosal resection (EMR) to remove any mucosal irregularities suspicious for the presence of neoplasia. Over the past 5 years in North America, the use of EMR
has steadily increased with en bloc or piecemeal resections that use injected-assisted, cap-assisted, or ligation-assisted devices.6 Advantages of EMR include removing high-risk mucosal lesions, recovering tissue specimens for quantitative and qualitative histologic analysis to determine the depth of disease invasion, and detection of locally advanced disease including lymphatic or neural involvement. The use of advanced imaging and technologies such as HRE with NBI and EMR has made an important difference in the use of ablation therapy.7
Ablation Devices: Photodynamic Therapy Photodynamic therapy (PDT) uses a photosensitizer drug such as porfimer sodium (Photofrin, Mont St. Hilaire, Quebec, Canada) that is activated by a high-power light energy device (using 630-nm red light) to produce ablation of the gut epithelium (porfimer sodium photodynamic therapy [Ps-PDT]). Ps-PDT effects include the triggering of apoptosis and vascular inflammation with ischemia. The intensity of the photodynamic effect seems to be related to tissue photosensitizer and oxygen content, rather than selective drug cellular uptake or elimination. Porfimer sodium is the most commonly used photosensitizer for PDT in North America and previously studied applications include Barrett’s dysplasia and carcinoma, esophageal squamous cell carcinoma, and cholangiocarcinoma.8 –10 The most important Ps-PDT study (PHO BAR) was performed in patients with Barrett’s HGD.11 This multicenter prospective randomized trial included a reference laboratory to standardize the histologic diagnosis of HGD. Of the nearly 500 patients previously diagnosed with HGD and evaluated for the study, only 208 met the criteria of Dr Haggitt’s laboratory at the University of Washington. The study also included surveillance endoscopy with a rigorous biopsy protocol that documented progression to invasive carcinoma in 28% of the patients treated with omeprazole alone (no PDT). This demonstrated the serious risks asso© 2009 by the AGA Institute
0016-5085/09/$36.00 doi:10.1053/j.gastro.2009.08.039 GASTROENTEROLOGY 2009;137:1225–1237
Imaging and Advanced Technology continued
ciated with a surveillance endoscopy approach (“watch and wait”) for patients with a confirmed diagnosis of HGD. The treatment arm of the study permitted up to 3 PsPDT treatments, but no other endoscopy therapy was allowed. High-risk nodular lesions were treated with additional laser light application of 50 J/cm2 light dose. Results were reported on a per-patient basis. Therefore, the presence of intestinal metaplasia or dysplasia in a single biopsy would mean the patient did not have a complete response to treatment. At 24 months of follow-up, a mean 52% of Ps-PDT treated patients had complete resolution of Barrett’s disease (complete response for intestinal metaplasia), whereas 77% had complete elimination of HGD. Most important, adenocarcinoma occurrence was significantly lower in the Ps-PDT group (13%) compared with the control group (28%). Although the study demonstrated that endoscopic therapy was a safe and effective treatment as an alternative to esophageal resection surgery, it was not a realistic portrayal of how Ps-PDT is used in clinical practice. The Mayo Clinic recently published a retrospective cohort study that compared the long-term outcomes of patients with BE and HGD treated with either Ps-PDT or esophagectomy between 1994 and 2000 with an average follow-up of 5 years for both groups. The 129 Ps-PDT patients were significantly older with significantly more cardiac disease and higher age-adjusted comorbidity compared with the 70 patients who underwent surgery. Before ablation treatment, highrisk nodular lesions were removed in 80% of patients using EMR via band ligation or cap techniques. HGD was eliminated in 86% of patients treated with Ps-PDT, although 30% of patients underwent subsequent endoscopic treatment for recurrent HGD, including 5.4% of patients who progressed to carcinoma. Overall survival, however, was similar in both groups, with 9% mortality in the PDT group and 8.5% in the surgery group. There were no deaths related to esophageal cancer.12 A similar study in patients with T1a mucosal adenocarcinoma treated with either Ps-PDT (132 patients) or surgery (46 patients) also found equivalent overall survival.13 Recurrent carcinoma was detected in 12% of patients in the Ps-PDT group that was successfully retreated using endoscopic therapy without an impact on overall survival. These studies and many other single-center studies using Ps-PDT have established the role of endoscopic ablation therapy for patients with Barrett’s HGD and early carcinoma.14 The future role of Ps-PDT largely depends on efforts to improve treatment dosimetry parameters to avoid complications, such as stricture and disease recurrence from incomplete ablation.15
Radiofrequency Ablation This form of ablation applies high-power radiofrequency energy using bipolar electrodes that alternate electric and magnetic fields producing vibration of ions 1226
and water molecules in the target tissue with rapid heating (and thermal destruction) to a controlled ablation depth of 0.5 mm. It is important, therefore, that all nodular and thickened dysplastic and neoplastic tissue be removed using EMR to permit controlled superficial ablation of endoscopically flat mucosa. Circumferential ablation uses electrodes wrapped around a catheter-based balloon device of varying diameters from 18 to 34 mm (Halo 360). Focal ablation is performed using an endoscope-mounted device with an electrode surface area of 13 ⫻ 20 mm (Halo 90). Recently, a randomized, sham-controlled study (AIM) was conducted in 19 centers in the United States for the eradication of Barrett’s dysplasia and to reduce the risk of invasive carcinoma.7 Patients with high-risk nodular lesions underwent EMR study randomization to either radiofrequency ablation (RFA) or sham procedures (11 patients). All patients were maintained on twice daily esomeprazole 40 mg. All histopathology slides were reviewed by a centralized expert laboratory at Cleveland Clinic. There were a total of 127 patients with either low-grade dysplasia (64 patients) or HGD (63 patients). Overall, clearance of dysplasia was noted in 86% at 1 year (81% of HGD patients and 90% for low-grade dysplasia patients). All intestinal metaplasia was eradicated in 77% of patients. Progression from HGD to carcinoma was detected in 4 of 21 patients in the sham treatment group versus 1 of 42 patients in the RFA group. Subsquamous intestinal metaplasia was found in 5.1% of RFA patients compared with 40.0% in the control group. There were 298 total RFA procedures (mean of 3.5 per patient) and 3 serious adverse events: 1 patient underwent endoscopic therapy for bleeding after RFA and 2 patients were hospitalized with chest pain. There were no perforations or procedure-related deaths. Strictures developed in 5 patients after RFA (6.0%) that were treated with endoscopic dilations (mean of 2.6 procedures). Although, these results reflect 12 months of follow-up data, the study demonstrates that RFA is more effective than surveillance biopsy protocol in HGD patients, and that surveillance is no longer acceptable strategy. And for patients with endoscopically flat HGD, RFA is the treatment of choice compared with other methods of ablation or surgery (Table 1). This conclusion is also supported by the results of a recent multicenter randomized trial compared the use of RFA with stepwise radical endoscopic resection using the band ligation device. RFA was found to be equivalently effective in the ablation of Barrett’s dysplasia, with significantly fewer events such as bleeding or stricture.16 RFA, therefore, is clearly the preferred method for ablation of endoscopically flat Barrett’s dysplasia. Future technical improvements include providing variable balloon catheter distention pressure for the Halo 360 device (4.5–7.5 psi), a new, smaller diameter, 18-mm catheter, and alignment of the automated catheter sizing algo-
Imaging and Advanced Technology continued
Table 1. Comparison of Randomized Controlled Trials in Barrett’s Esophagus With High-Grade Dysplasia
Medical therapy Nodular disease Ablation treatments
Ps-PDT (n ⫽ 138 in 30 centers)11
RFA (n ⫽ 42 in 19 centers)7
Omeprazole 20 mg bid Additional 50 J/cm PDT light dose Up to 3 sessions, circumferential only (mean 2.3) 52% 77% 13%
Esomeprazole 40 mg bid Endoscopic mucosal resection Up to 4 sessions (circumferential and focal) (mean 3.5) 73.8% 81.0% 2.4%
36% 24 months
6.0% 12 months
CR-IM CR-HGD Progression to cancer Stricture Follow-up
bid, twice daily; CR-IM, complete response with clearance of intestinal metaplasia; CR-HGD, complete response with clearance of high-grade dysplasia; Ps-PDT, porfimer sodium photodynamic therapy; RFA, radiofrequency energy ablation.
multicenter study from 4 centers using liquid nitrogen cryotherapy for BE HGD. At the time of analysis, 27 of 45 patients had completed treatment (mean of 4.3 sessions), with clearance of HGD in 93% and eradication of intestinal metaplasia in 56%. None of the patients progressed to carcinoma and there were no treatment-related adverse events.18 Similar, results were also reported by Greenwald et al19 in an uncontrolled, multicenter study of patients treated with liquid nitrogen cryotherapy for palliative treatment of esophageal carcinoma. Canto et al20 recently reported an uncontrolled, single-center experience with CO2 cryotherapy in 44 patients with Barrett’s HGD or intramucosal carcinoma. For those patients completing treatment, clearance of HGD and intestinal metaplasia was ⬎90% at median follow-up of 11.8 months.20 These 3 early stage studies suggest that cryotherapy is safe and useful; however, controlled, comparative trials are required to address its role in the realm of endoscopic ablation technologies.
Future Challenges rithm for the selection of the smallest diameter device, based on the previous measurements. Also planned are additional focal ablation devices to treat larger areas than the current Halo 90 device. Devices with variable power density are undergoing clinical testing for nondysplastic BE and esophageal squamous cell carcinoma. Other important issues will be the continuation of the AIM trial to provide long-term results at 3 and 5 years, and sponsoring a large, multicenter, controlled trial of ablation in nondysplastic BE with prolonged follow-up (ⱖ10 years), to allow comparative assessment of important treatment endpoints, such as the development of dysplasia and neoplasia.17
Cryotherapy Cryotherapy uses freezing of the gut mucosa to induce cell death by extracellular ice crystal formation, producing fluid shifts and disruption of cellular membranes and organelles (solution effect injury). Rapid freezing forms intracellular ice increasing cell kill by edema, ischemia, and mechanical disruption of cell membranes. Commercially available cryogen systems use liquid nitrogen or carbon dioxide. These cryogens are delivered by endoscopically placed spray catheters alongside venting and decompression tubes to prevent gastric distention and perforation. Dosimetry studies suggest that spray freezing with liquid nitrogen (⫺196°C) or rapid expansion of carbon dioxide with induction of tissue hypothermia by the Joule-Thompson effect (⫺78°C), may produce tissue depth of injury of ⬎4 mm, similar to that produced by Ps-PDT. There are no controlled trials available studying the use of cryotherapy. Recently, however, Shaheen et al18 presented results of an uncontrolled,
Well-performed studies with Ps-PDT and RFA have definitely established the role of endoscopic ablation therapy in the treatment of patients with BE HGD and early cancer in expert centers. To maintain this record of treatment success, it is critically important that ablation centers have an entire program in place for the detection, treatment and follow-up of esophageal dysplasia and neoplasia.21 Such a programmatic evaluation should begin with a very careful endoscopic examination (ideally using HRE with NBI or chromendoscopy) for the detection of all areas of dysplasia and neoplasia, especially nodular high-risk lesions, followed by EMR to remove all such areas. After complete mucosal healing with high doses of acid blocker medication, ablation of all the residual Barrett’s mucosa (typically 3– 4 sessions within 12 months) is recommended to prevent the development of metachronous dysplasia or neoplasia. Thereafter, it remains important to continue life-long, aggressive acid suppression therapy (or antireflux surgery). Long-term surveillance endoscopy is also recommended to monitor the esophageal lining, especially the distal esophagus and esophageal junction areas (referred to as “the hot zone” by Dr Overholt), for the early detection and removal of any mucosal abnormality suggestive of residual or recurrent disease.22 Careful attention to these endoscopic and clinical practices is crucial to maintain the record of success established thus far as we await further advances and improvements in this area of endoscopic imaging and technology. References 1. Wolfsen HC. Endoprevention of esophageal cancer: endoscopic ablation of Barrett’s metaplasia and dysplasia. Exp Rev Med Devices 2005;2:713–723. 1227
Imaging and Advanced Technology continued
2. Sampliner RE. Prevention of adenocarcinoma by reversing Barrett’s esophagus with mucosal ablation. World J Surg 2003;27: 1026 –1029. 3. Wolfsen HC. Endoluminal therapy for Barrett’s esophagus. Gastrointest Endosc Clin North Am 2007;17:59 – 82. 4. Wolfsen HC, Crook JE, Krishna M, et al. Prospective, controlled tandem endoscopy study of narrow band imaging for dysplasia detection in Barrett’s Esophagus. Gastroenterology 2008;135: 24 –31. 5. Sharma P, Bansal A, Hawes R, et al. Detection of metaplasia (IM) and neoplasia in patients with Barrett’s esophagus (BE) using high-definition white light endoscopy (HD-WLE) versus narrow band imaging (NBI): a prospective, multi-center, randomized, crossover trial (Abstract 945). Gastrointest Endosc 2009;69: AB135. 6. Waxman I, Konda VJ. Mucosal ablation of Barrett esophagus. Nat Rev Gastroenterol Hepatol 2009;6:393– 401. 7. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med 2009; 360:2277–2288. 8. Wolfsen HC. Uses of photodynamic therapy in premalignant and malignant lesions of the gastrointestinal tract beyond the esophagus. J Clin Gastroenterol 2005;39:653– 664. 9. Wolfsen HC. Present status of photodynamic therapy for highgrade dysplasia in Barrett’s esophagus. J Clin Gastroenterol 2005;39:189 –202. 10. Prasad GA, Wang KK, Baron TH, et al. Factors associated with increased survival after photodynamic therapy for cholangiocarcinoma. Clin Gastroenterol Hepatol 2007;5:743–748. 11. Overholt BF, Lightdale CJ, Wang KK, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett’s esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005;62:488 – 498. 12. Prasad GA, Wang KK, Buttar NS, et al. Long-term survival following endoscopic and surgical treatment of high-grade dysplasia in Barrett’s esophagus. Gastroenterology 2007;132:1226 –1233. 13. Prasad GA, Wu TT, Wigle DA, et al. Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett’s esophagus. Gastroenterology 2009 Jun 12 [Epub ahead of print].
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14. Panjehpour M, Overholt BF. Porfimer sodium photodynamic therapy for management of Barrett’s esophagus with high-grade dysplasia. Lasers Surg Med 2006;38:390 –395. 15. Gill KR, Wolfsen HC, Preyer NW, et al. Pilot study on light dosimetry variables for photodynamic therapy of Barrett’s esophagus with high-grade dysplasia. Clin Cancer Res 2009;15:1830 –1836. 16. Van Vilsteren F, Pouw R, Seewald S, et al. A multi-center randomized trial comparing stepwise radical endoscopic resection versus radiofrequency ablation for Barrett esophagus containing high-grade dysplasia and/or early cancer. (Abstract 939) Gastrointest Endosc 2009;69:AB133. 17. Fleischer DE, Overholt BF, Sharma VK, et al. Endoscopic ablation of Barrett’s esophagus: a multicenter study with 2.5-year followup. Gastrointest Endosc 2008;68:867– 876. 18. Shaheen N, Greenwald B, Dumot J, et al. Safety and efficacy of endoscopic spray cryotherapy for Barrett’s esophagus with highgrade dysplasia (Abstract W1387) Gastrointest Endosc 2009; 69:AB357. 19. Greenwald B, Dumot J, Abrams J, et al. Endoscopic spray cryotherapy for esophageal cancer: safety and efficacy (Abstract W1352). Gastrointest Endosc 2009;69:AB349. 20. Canto M, Gorospe E, Shin E, et al. Carbon dioxide cryotherapy is a safe and effective treatment of Barrett’s esophagus (BE) with HGD/intramucosal carcinoma (Abstract W1323). Gastrointest Endosc 2009;69:AB341. 21. Bergman JJ. Radiofrequency ablation— great for some or justified for many? N Engl J Med 2009;360:2353–2355. 22. Panjepour M, Overholt B, Phan-Brooks M, et al. Photodynamic therapy (PDT) for Barrett’s esophagus with dysplasia: long-term follow-up of gastroesophageal junction area is recommended (Abstract W1317). Gastrointest Endosc 2009;69:AB339.
Reprint requests Address requests for reprints to: Herbert C. Wolfsen, MD, Division of Gastroenterology & Hepatology, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, Florida 32224. e-mail: [email protected]; Phone: (904) 953-2221; Fax: (904) 953-7260. Conflicts of interest The authors disclose no conflicts.
Endoscopic Ablation Therapy: Imaging and Advanced Technology in Action HERBERT C. WOLFSEN Division of Gastroenterology and Hepatology, Mayo Clinic Florida, Jacksonville, Florida; and Mayo Clinic College of Medicine, Rochester, Minnesota
M
ore than any other area of gastrointestinal endoscopy, ablation therapy has incorporated numerous imaging and technology advances to produce clinically important results for the treatment of Barrett’s esophagus (BE) and superficial esophageal cancer to prevent the development of invasive malignancy (endoprevention).1 Focal ablation methods that use thermal energy have been available for many years. Devices such as thermal lasers, multipolar electrocoagulation, heater probe, and argon plasma coagulation have been used to treat BE since the mid 1980s.2 The important work by Sampliner and others established the proof of principal that Barrett’s glandular mucosa ablation was technically feasible and that gastric acid suppression was important to successful mucosal remodeling to squamous epithelium.3 However, limitations of these “point-and-shoot”–type focal devices with variable tissue effects included areas of overtreatment (with risk of stricture and perforation) and undertreatment (with the risk of persistent subsquamous disease and subsequent development of carcinoma).
Role of Advanced Imaging The safe and effective use of any ablation device requires the best possible endoscopic imaging for the initial detection and characterization of disease and thereafter to target therapy. The use of high-resolution endoscopy (HRE) with narrow-band imaging (NBI) has been particularly important. Controlled studies have found that the use of HRE and NBI detected more BE and higher grades of dysplasia in patients with fewer biopsies compared with standard resolution white-light endoscopy.4 Sharma et al5 recently presented results of a randomized, controlled, international, multicenter study where the use of HRE and HRE plus NBI detected a similar proportion of patients with BE. However, the use of NBI detected significantly more dysplastic lesions, including high-grade dysplasia (HGD) or cancer, with fewer biopsies per procedure compared with HRE alone. Another important development has been the increased use of endoscopic mucosal resection (EMR) to remove any mucosal irregularities suspicious for the presence of neoplasia. Over the past 5 years in North America, the use of EMR
has steadily increased with en bloc or piecemeal resections that use injected-assisted, cap-assisted, or ligation-assisted devices.6 Advantages of EMR include removing high-risk mucosal lesions, recovering tissue specimens for quantitative and qualitative histologic analysis to determine the depth of disease invasion, and detection of locally advanced disease including lymphatic or neural involvement. The use of advanced imaging and technologies such as HRE with NBI and EMR has made an important difference in the use of ablation therapy.7
Ablation Devices: Photodynamic Therapy Photodynamic therapy (PDT) uses a photosensitizer drug such as porfimer sodium (Photofrin, Mont St. Hilaire, Quebec, Canada) that is activated by a high-power light energy device (using 630-nm red light) to produce ablation of the gut epithelium (porfimer sodium photodynamic therapy [Ps-PDT]). Ps-PDT effects include the triggering of apoptosis and vascular inflammation with ischemia. The intensity of the photodynamic effect seems to be related to tissue photosensitizer and oxygen content, rather than selective drug cellular uptake or elimination. Porfimer sodium is the most commonly used photosensitizer for PDT in North America and previously studied applications include Barrett’s dysplasia and carcinoma, esophageal squamous cell carcinoma, and cholangiocarcinoma.8 –10 The most important Ps-PDT study (PHO BAR) was performed in patients with Barrett’s HGD.11 This multicenter prospective randomized trial included a reference laboratory to standardize the histologic diagnosis of HGD. Of the nearly 500 patients previously diagnosed with HGD and evaluated for the study, only 208 met the criteria of Dr Haggitt’s laboratory at the University of Washington. The study also included surveillance endoscopy with a rigorous biopsy protocol that documented progression to invasive carcinoma in 28% of the patients treated with omeprazole alone (no PDT). This demonstrated the serious risks asso© 2009 by the AGA Institute
0016-5085/09/$36.00 doi:10.1053/j.gastro.2009.08.039 GASTROENTEROLOGY 2009;137:1225–1237
Imaging and Advanced Technology continued
ciated with a surveillance endoscopy approach (“watch and wait”) for patients with a confirmed diagnosis of HGD. The treatment arm of the study permitted up to 3 PsPDT treatments, but no other endoscopy therapy was allowed. High-risk nodular lesions were treated with additional laser light application of 50 J/cm2 light dose. Results were reported on a per-patient basis. Therefore, the presence of intestinal metaplasia or dysplasia in a single biopsy would mean the patient did not have a complete response to treatment. At 24 months of follow-up, a mean 52% of Ps-PDT treated patients had complete resolution of Barrett’s disease (complete response for intestinal metaplasia), whereas 77% had complete elimination of HGD. Most important, adenocarcinoma occurrence was significantly lower in the Ps-PDT group (13%) compared with the control group (28%). Although the study demonstrated that endoscopic therapy was a safe and effective treatment as an alternative to esophageal resection surgery, it was not a realistic portrayal of how Ps-PDT is used in clinical practice. The Mayo Clinic recently published a retrospective cohort study that compared the long-term outcomes of patients with BE and HGD treated with either Ps-PDT or esophagectomy between 1994 and 2000 with an average follow-up of 5 years for both groups. The 129 Ps-PDT patients were significantly older with significantly more cardiac disease and higher age-adjusted comorbidity compared with the 70 patients who underwent surgery. Before ablation treatment, highrisk nodular lesions were removed in 80% of patients using EMR via band ligation or cap techniques. HGD was eliminated in 86% of patients treated with Ps-PDT, although 30% of patients underwent subsequent endoscopic treatment for recurrent HGD, including 5.4% of patients who progressed to carcinoma. Overall survival, however, was similar in both groups, with 9% mortality in the PDT group and 8.5% in the surgery group. There were no deaths related to esophageal cancer.12 A similar study in patients with T1a mucosal adenocarcinoma treated with either Ps-PDT (132 patients) or surgery (46 patients) also found equivalent overall survival.13 Recurrent carcinoma was detected in 12% of patients in the Ps-PDT group that was successfully retreated using endoscopic therapy without an impact on overall survival. These studies and many other single-center studies using Ps-PDT have established the role of endoscopic ablation therapy for patients with Barrett’s HGD and early carcinoma.14 The future role of Ps-PDT largely depends on efforts to improve treatment dosimetry parameters to avoid complications, such as stricture and disease recurrence from incomplete ablation.15
Radiofrequency Ablation This form of ablation applies high-power radiofrequency energy using bipolar electrodes that alternate electric and magnetic fields producing vibration of ions 1226
and water molecules in the target tissue with rapid heating (and thermal destruction) to a controlled ablation depth of 0.5 mm. It is important, therefore, that all nodular and thickened dysplastic and neoplastic tissue be removed using EMR to permit controlled superficial ablation of endoscopically flat mucosa. Circumferential ablation uses electrodes wrapped around a catheter-based balloon device of varying diameters from 18 to 34 mm (Halo 360). Focal ablation is performed using an endoscope-mounted device with an electrode surface area of 13 ⫻ 20 mm (Halo 90). Recently, a randomized, sham-controlled study (AIM) was conducted in 19 centers in the United States for the eradication of Barrett’s dysplasia and to reduce the risk of invasive carcinoma.7 Patients with high-risk nodular lesions underwent EMR study randomization to either radiofrequency ablation (RFA) or sham procedures (11 patients). All patients were maintained on twice daily esomeprazole 40 mg. All histopathology slides were reviewed by a centralized expert laboratory at Cleveland Clinic. There were a total of 127 patients with either low-grade dysplasia (64 patients) or HGD (63 patients). Overall, clearance of dysplasia was noted in 86% at 1 year (81% of HGD patients and 90% for low-grade dysplasia patients). All intestinal metaplasia was eradicated in 77% of patients. Progression from HGD to carcinoma was detected in 4 of 21 patients in the sham treatment group versus 1 of 42 patients in the RFA group. Subsquamous intestinal metaplasia was found in 5.1% of RFA patients compared with 40.0% in the control group. There were 298 total RFA procedures (mean of 3.5 per patient) and 3 serious adverse events: 1 patient underwent endoscopic therapy for bleeding after RFA and 2 patients were hospitalized with chest pain. There were no perforations or procedure-related deaths. Strictures developed in 5 patients after RFA (6.0%) that were treated with endoscopic dilations (mean of 2.6 procedures). Although, these results reflect 12 months of follow-up data, the study demonstrates that RFA is more effective than surveillance biopsy protocol in HGD patients, and that surveillance is no longer acceptable strategy. And for patients with endoscopically flat HGD, RFA is the treatment of choice compared with other methods of ablation or surgery (Table 1). This conclusion is also supported by the results of a recent multicenter randomized trial compared the use of RFA with stepwise radical endoscopic resection using the band ligation device. RFA was found to be equivalently effective in the ablation of Barrett’s dysplasia, with significantly fewer events such as bleeding or stricture.16 RFA, therefore, is clearly the preferred method for ablation of endoscopically flat Barrett’s dysplasia. Future technical improvements include providing variable balloon catheter distention pressure for the Halo 360 device (4.5–7.5 psi), a new, smaller diameter, 18-mm catheter, and alignment of the automated catheter sizing algo-
Imaging and Advanced Technology continued
Table 1. Comparison of Randomized Controlled Trials in Barrett’s Esophagus With High-Grade Dysplasia
Medical therapy Nodular disease Ablation treatments
Ps-PDT (n ⫽ 138 in 30 centers)11
RFA (n ⫽ 42 in 19 centers)7
Omeprazole 20 mg bid Additional 50 J/cm PDT light dose Up to 3 sessions, circumferential only (mean 2.3) 52% 77% 13%
Esomeprazole 40 mg bid Endoscopic mucosal resection Up to 4 sessions (circumferential and focal) (mean 3.5) 73.8% 81.0% 2.4%
36% 24 months
6.0% 12 months
CR-IM CR-HGD Progression to cancer Stricture Follow-up
bid, twice daily; CR-IM, complete response with clearance of intestinal metaplasia; CR-HGD, complete response with clearance of high-grade dysplasia; Ps-PDT, porfimer sodium photodynamic therapy; RFA, radiofrequency energy ablation.
multicenter study from 4 centers using liquid nitrogen cryotherapy for BE HGD. At the time of analysis, 27 of 45 patients had completed treatment (mean of 4.3 sessions), with clearance of HGD in 93% and eradication of intestinal metaplasia in 56%. None of the patients progressed to carcinoma and there were no treatment-related adverse events.18 Similar, results were also reported by Greenwald et al19 in an uncontrolled, multicenter study of patients treated with liquid nitrogen cryotherapy for palliative treatment of esophageal carcinoma. Canto et al20 recently reported an uncontrolled, single-center experience with CO2 cryotherapy in 44 patients with Barrett’s HGD or intramucosal carcinoma. For those patients completing treatment, clearance of HGD and intestinal metaplasia was ⬎90% at median follow-up of 11.8 months.20 These 3 early stage studies suggest that cryotherapy is safe and useful; however, controlled, comparative trials are required to address its role in the realm of endoscopic ablation technologies.
Future Challenges rithm for the selection of the smallest diameter device, based on the previous measurements. Also planned are additional focal ablation devices to treat larger areas than the current Halo 90 device. Devices with variable power density are undergoing clinical testing for nondysplastic BE and esophageal squamous cell carcinoma. Other important issues will be the continuation of the AIM trial to provide long-term results at 3 and 5 years, and sponsoring a large, multicenter, controlled trial of ablation in nondysplastic BE with prolonged follow-up (ⱖ10 years), to allow comparative assessment of important treatment endpoints, such as the development of dysplasia and neoplasia.17
Cryotherapy Cryotherapy uses freezing of the gut mucosa to induce cell death by extracellular ice crystal formation, producing fluid shifts and disruption of cellular membranes and organelles (solution effect injury). Rapid freezing forms intracellular ice increasing cell kill by edema, ischemia, and mechanical disruption of cell membranes. Commercially available cryogen systems use liquid nitrogen or carbon dioxide. These cryogens are delivered by endoscopically placed spray catheters alongside venting and decompression tubes to prevent gastric distention and perforation. Dosimetry studies suggest that spray freezing with liquid nitrogen (⫺196°C) or rapid expansion of carbon dioxide with induction of tissue hypothermia by the Joule-Thompson effect (⫺78°C), may produce tissue depth of injury of ⬎4 mm, similar to that produced by Ps-PDT. There are no controlled trials available studying the use of cryotherapy. Recently, however, Shaheen et al18 presented results of an uncontrolled,
Well-performed studies with Ps-PDT and RFA have definitely established the role of endoscopic ablation therapy in the treatment of patients with BE HGD and early cancer in expert centers. To maintain this record of treatment success, it is critically important that ablation centers have an entire program in place for the detection, treatment and follow-up of esophageal dysplasia and neoplasia.21 Such a programmatic evaluation should begin with a very careful endoscopic examination (ideally using HRE with NBI or chromendoscopy) for the detection of all areas of dysplasia and neoplasia, especially nodular high-risk lesions, followed by EMR to remove all such areas. After complete mucosal healing with high doses of acid blocker medication, ablation of all the residual Barrett’s mucosa (typically 3– 4 sessions within 12 months) is recommended to prevent the development of metachronous dysplasia or neoplasia. Thereafter, it remains important to continue life-long, aggressive acid suppression therapy (or antireflux surgery). Long-term surveillance endoscopy is also recommended to monitor the esophageal lining, especially the distal esophagus and esophageal junction areas (referred to as “the hot zone” by Dr Overholt), for the early detection and removal of any mucosal abnormality suggestive of residual or recurrent disease.22 Careful attention to these endoscopic and clinical practices is crucial to maintain the record of success established thus far as we await further advances and improvements in this area of endoscopic imaging and technology. References 1. Wolfsen HC. Endoprevention of esophageal cancer: endoscopic ablation of Barrett’s metaplasia and dysplasia. Exp Rev Med Devices 2005;2:713–723. 1227
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2. Sampliner RE. Prevention of adenocarcinoma by reversing Barrett’s esophagus with mucosal ablation. World J Surg 2003;27: 1026 –1029. 3. Wolfsen HC. Endoluminal therapy for Barrett’s esophagus. Gastrointest Endosc Clin North Am 2007;17:59 – 82. 4. Wolfsen HC, Crook JE, Krishna M, et al. Prospective, controlled tandem endoscopy study of narrow band imaging for dysplasia detection in Barrett’s Esophagus. Gastroenterology 2008;135: 24 –31. 5. Sharma P, Bansal A, Hawes R, et al. Detection of metaplasia (IM) and neoplasia in patients with Barrett’s esophagus (BE) using high-definition white light endoscopy (HD-WLE) versus narrow band imaging (NBI): a prospective, multi-center, randomized, crossover trial (Abstract 945). Gastrointest Endosc 2009;69: AB135. 6. Waxman I, Konda VJ. Mucosal ablation of Barrett esophagus. Nat Rev Gastroenterol Hepatol 2009;6:393– 401. 7. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med 2009; 360:2277–2288. 8. Wolfsen HC. Uses of photodynamic therapy in premalignant and malignant lesions of the gastrointestinal tract beyond the esophagus. J Clin Gastroenterol 2005;39:653– 664. 9. Wolfsen HC. Present status of photodynamic therapy for highgrade dysplasia in Barrett’s esophagus. J Clin Gastroenterol 2005;39:189 –202. 10. Prasad GA, Wang KK, Baron TH, et al. Factors associated with increased survival after photodynamic therapy for cholangiocarcinoma. Clin Gastroenterol Hepatol 2007;5:743–748. 11. Overholt BF, Lightdale CJ, Wang KK, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett’s esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005;62:488 – 498. 12. Prasad GA, Wang KK, Buttar NS, et al. Long-term survival following endoscopic and surgical treatment of high-grade dysplasia in Barrett’s esophagus. Gastroenterology 2007;132:1226 –1233. 13. Prasad GA, Wu TT, Wigle DA, et al. Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett’s esophagus. Gastroenterology 2009 Jun 12 [Epub ahead of print].
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14. Panjehpour M, Overholt BF. Porfimer sodium photodynamic therapy for management of Barrett’s esophagus with high-grade dysplasia. Lasers Surg Med 2006;38:390 –395. 15. Gill KR, Wolfsen HC, Preyer NW, et al. Pilot study on light dosimetry variables for photodynamic therapy of Barrett’s esophagus with high-grade dysplasia. Clin Cancer Res 2009;15:1830 –1836. 16. Van Vilsteren F, Pouw R, Seewald S, et al. A multi-center randomized trial comparing stepwise radical endoscopic resection versus radiofrequency ablation for Barrett esophagus containing high-grade dysplasia and/or early cancer. (Abstract 939) Gastrointest Endosc 2009;69:AB133. 17. Fleischer DE, Overholt BF, Sharma VK, et al. Endoscopic ablation of Barrett’s esophagus: a multicenter study with 2.5-year followup. Gastrointest Endosc 2008;68:867– 876. 18. Shaheen N, Greenwald B, Dumot J, et al. Safety and efficacy of endoscopic spray cryotherapy for Barrett’s esophagus with highgrade dysplasia (Abstract W1387) Gastrointest Endosc 2009; 69:AB357. 19. Greenwald B, Dumot J, Abrams J, et al. Endoscopic spray cryotherapy for esophageal cancer: safety and efficacy (Abstract W1352). Gastrointest Endosc 2009;69:AB349. 20. Canto M, Gorospe E, Shin E, et al. Carbon dioxide cryotherapy is a safe and effective treatment of Barrett’s esophagus (BE) with HGD/intramucosal carcinoma (Abstract W1323). Gastrointest Endosc 2009;69:AB341. 21. Bergman JJ. Radiofrequency ablation— great for some or justified for many? N Engl J Med 2009;360:2353–2355. 22. Panjepour M, Overholt B, Phan-Brooks M, et al. Photodynamic therapy (PDT) for Barrett’s esophagus with dysplasia: long-term follow-up of gastroesophageal junction area is recommended (Abstract W1317). Gastrointest Endosc 2009;69:AB339.
Reprint requests Address requests for reprints to: Herbert C. Wolfsen, MD, Division of Gastroenterology & Hepatology, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, Florida 32224. e-mail: [email protected]; Phone: (904) 953-2221; Fax: (904) 953-7260. Conflicts of interest The authors disclose no conflicts.