EMR for early stage esophageal cancer: setting the stage for improved patient outcomes

EMR for early stage esophageal cancer: setting the stage for improved patient outcomes EMR is a promising treatment that finally gives gastroenterologists the ability to treat neoplastic lesions in a manner similar to our surgical colleagues. The technique does not destroy tissue. It allows the pathologist to examine the margins of the removed tissue to determine whether the neoplasm has been fully eliminated. Since the comprehensive and thoughtful editorial on this topic by Fleischer I in Gastrointestinal Endoscopy 3 years ago, numerous reports have substantiated that the results achieved with EMR in Japan for early stage squamous cancers of the esophagus and gastric cancers also can be applied to early adenocarcinoma in Barrett's esophagus.2-4 One o~ the advances in endoscopy t h a t has allowed the application of EMR is improved EUS technology that permits accurate staging of early cancers. Imaging with traditional echoendoscopes at 7.5 and 12 MHz has become routine, and the ability to sample regional lymph nodes with FNA has been a tremendous asset in the staging of early cancers. Advancements in digital US imaging, including new multiple-frequency echoendoscopes, should further enhance lymph node detection and tumor staging. Other advanced technology includes high-frequency US probes that can image at both 20 and 30 MHz, which have improved the ability to recognize superficial tumors. Before EMR can be incorporated into standard practice, several fundamental questions m u s t be addressed. These research questions, relevant to many aspects of endoscopic practice, stand at the leading edge of the assessment of new technology. The initial step in such evaluation begins with the easiest question, "Can we do it?" In the case of EMR, this concern clearly has been answered. In expert hands, the technique is achievable and, in highly selected patient populations, has acceptable clinical outcomes. The next relevant research question for EMR is, "Can we do it safely?" Uncertainty persists for this consideration. Reports have indicated variable rates of bleeding (up to 22% at the time of resection, usually immediately controlled with endoscopic hemoCopyright 9 2003 by the American Society for Gastrointestinal Endoscopy 0016-5107/2003/$30.00 + 0 doi:10.1067 /mge.2003.331 244 GASTROINTESTINAL ENDOSCOPY

static techniques, with delayed bleeding less common) and low rates of perforation (<1%). In this issue of Gastrointestinal Endoscopy, the report by May et al.5 compares two EMR methods and describes rare bleeding after either technique. However, given the relatively small n u m b e r s of patients treated, the ability of this study to detect a difference between these two techniques was limited. To achieve sufficient power (0.8) to be truly reasonably certain of equivalency, the investigators would have needed over 160 patients. The study by May et al. 5 in this issue of the journal is the first randomized controlled trial (RCT) to evaluate EMR techniques by experts in the application of EMR to patients with early stage esophageal cancer in Germany. Their impressive skill and previously reported success2,6,7 make t h e m ideal investigators to take research in EMR to "the next level." Their prospective trial compares two commonly applied EMR techniques, a suck-and-ligate technique without injection, with a cap technique with submucosal injection of dilute epinephrine. This comparison has significant clinical implications because the suck-and-ligate technique can be used by most clinicians who perform endoscopic variceal ligation. The need to purchase the specialized endoscopic mucosal caps may, therefore, not be needed for the average practitioner who would not perform this procedure routinely. The patient population included 72 patients undergoing 100 resections. Eighty-two percent of the patients had early stage cancers in Barrett's esophagus. The primary endpoint of the study was the maximum diameter of the resection specimen and the resection area, as well as complication rate. May et al. 5 should be congratulated for performing an important RCT in this exciting new area of endoscopic practice. The size of the study and extremely low complication rate are impressive (one minor episode of bleeding in each group). They conclude both techniques "provide similar efficacy and safety for performing EMR in early esophageal cancer." The current study, like all well done research, raises more questions than it answers. The design was exploratory and cannot establish small differences in the clinical outcome between the techniques. The primary endpoint chosen, the size of the resection specimen, was appropriate for the analysis of a technique but of uncertain clinical relevance. Furthermore, to define clinical equivalence in a clinical trial is a challenge. A statistical definition is based upon complex power calculations that specify that the confidence intervals of the point estimates of the treatment effect are within certain predeterVOLUME 58, NO. 2, 2003

Editorials

mined bounds. The definition of clinical equivalence is really in the eye of the beholder! With that in mind, is the critical question for the results of EMR, the size of the resection specimen? It is clear from the pathology data reported in this study that EMR alone was insufficient for complete resection, with residual cancer found in 62% of patients in the adenocarcinoma group and a substantial proportion of the squamous carcinoma group. Further endoscopic therapy was required in these patient populations. The investigators also have shown that even if the primary cancer can be removed fully in Barrett's esophagus, unless the remainder of the preneoplastic epithelium is treated, additional cancers can arise in 30% of treated individuals on long-term follow-up.6 This calls into question the value of EMR alone in the treatment of early stage cancer, given other available modalities may need to be used. This could be an issue of patient selection. Perhaps certain patients who have superficial cancer that can be shown to be relatively less aggressive by as yet undefined biomarkers might well be treated by EMR, whereas others with widespread mucosal abnormalities should be treated with additional therapies.S, 9 Another relevant question raised by the study of May et al. 5 is generalizability of the technology used. Are the results applicable to endoscopic practice in the United States? May et al.5 used European instn~mentation that is not available in the United States. However, the dimensions of the variceal ligation cap appear to be similar to that available in the United States. The investigators also used the diagonal rim EMR cap, which often is not used in this country because of its propensity to lacerate the tissue. The diameter of the straight EMR cap is only 11 ram, which may not allow as large a specimen to be resected. However, most investigators believe that the straight and diagonal devices probably resect similar amounts of tissue. As with many highly specialized innovative endoscopic procedures such as interventional ERCP and EUS, experts who use this procedure likely have improved outcomes. Although these experts have and should take the lead in demonstrating the longterm safety and efficacy of new endoscopic technology, caution should guide clinical decision-making when less experienced endoscopists consider adding such techniques to their practice. A study recently reported in Gastrointestinal Endoscopy demonstrated that circumferential endoscopic resection can completely remove Barrett's esophagus. By using a simple snare technique in 12 patients with early malignant changes, expert endoscopists confirmed the feasibility and relative safety of such an aggresVOLUME 58, NO. 2, 2003

J Scheiman, K Wang

sive endoscopic approach, lo Only two patients developed strictures, which were successfully treated endoscopically, and only minor bleeding occurred; prudence in the widespread application of EMR is justified given the risks inherent in removal of large areas of mucosa. Further, many questions regarding the technique have yet to be answered. The key outcome measure that must now challenge endoscopic investigators is to provide evidence for the effectiveness of the technique--that it, in fact, does work in the "real world." This will require more RCTs, as cohort studies made up of heterogeneous populations cannot answer the question. So then what are the key questions for future studies of EMR? Before the technique is ready for prime time, direct comparisons with ablative therapies (such as photodynamic therapy, laser, or argon plasma coagulation) alone are likely necessary. The current study supports the concept that in expert hands, either EMR approach--the suck-and-ligate or the cap approach--can provide similar technical results. However, major questions left unanswered concern whether one technique was associated with more residual tumor and the need for additional endoscopic ablative therapy, and]or whether the longterm outcome was effected. In addition, the relative ease of performance of each technique and any differences in patient tolerance were not assessed. Finally and perhaps most importantly, the question of the value or efficiency of the EMR therapy must be answered. This question is the most crucial, yet the most difficult one to answer. Focusing future research on patient-centered outcomes will be the most difficult but a key issue for endoscopic techniques such as EMR to challenge currently accepted strategies such as surgical resection. If localized therapy can provide equivalent cure rates as surgery, then patient-centered outcomes will easily define the value of endoscopic management. This will mandate that centers of excellence develop trials with appropriate study design and power to definitively answer these key questions. If mortality is equivalent, then such outcomes as health-related quality of life will likely favor the endoscopic approach. In addition, economic analyses, which should be essential components of future studies to evaluate endoscopic practice, would also favor a less invasive approach if long-term outcomes are equivalent. Such analyses are relevant to comparative technique trials, such as that by May et al. 5 and, given the current emphasis on practice economics, provide an extraordinary opportunity for endoscopic investigators. This study has clearly set the stage for definitive trials to define the place of EMR in the GASTROINTESTINAL ENDOSCOPY 245

M Fennerty

Editorials

overall management of patients with early stage esophageal cancer. James M. Scheiman, MD Division of Gastroenterology University of Michigan Ann Arbor, Michigan Kenneth K. Wang, MD Mayo Clinic Rochester Minnesota REFERENCES 1. Fleischer D. Endoscopic muc0sal resection: (not) made in the USA (so commonly). A dissection of the definition, technique, use and controversies. Gastrointest Endosc 2000;52:440-4. 2. Ell C, May A, Gossner L, Pech O, Gunter E, Mayer G, et al. Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett's esophagus. Gastroenterology 2000;118: 670-7. 3. 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;52:328-32. 4. Abroad NA, Kochman ML, Long WB, Furth EE, Ginsberg GG. Efficacy, safety, and clinical outcomes of endoscopic mucosal resection: a study of 101 cases. Gastrointest Endosc 2002;55: 390-6. -o

Endoscopic ablation of Barrett's related neoplasia: What is the evidence supporting its use? ~The p o w e r o f accurate observation is commonly called cynicism by those who have not got it." George Bernard S h a w

Barrett's esophagus is characterized by the replacement of the normal squamous esophageal mucosa with a metaplastic columnar epithelium defined by the presence of intestinal metaplasia. 1 Barrett's esophagus is clinically important because of its associated risk for esophageal adenocarcinoma, a tumor distinguished as having one of the most rapidly increasing incidence rates of any malignancy over the last 30 years. 2 Although most patients with Barrett's esophagus will never develop esophageal cancer, it is estimated that approximately 5% will, an increase in incidence 40- to 100-fold that of the general population. Pathophysiologically, Barrett's esophagus is thought to arise as a consequence of a perturbation in the repair of damage to the esophageal epithelium that results from gastroesophageal reflux. Once Barrett's esophagus forms in a patient with GERD, continued Copyright 9 2003 by the American Society for Gastrointestinal Endoscopy 0016-5107/2003/$30.00 + 0 doi:10.1067 /mge.2003.359 246

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5. May A, Gossner L, Behrens A, Kohnen R, Vieth M, Stolte M, et al. A prospective randomized trial of two different endoscopic resection techniques for early cancers of the esophagus. Gastrointest Endosc 2003;58:167-75. 6. May A, Gossner L, Pech O, Fritz A, Mayer G, ller H, et al. Local endoscopic therapy for intraepithelial high-grade neoplasia and early adenocarcinoma in Barrett's oesophagus: acute-phase and intermediate results of a new treatment approach. Eur J Gastroenterol Hepatol 2002;14:1085-91. 7. May A, Gossner L, Pech O, Muller H, Vieth M, Stolte M, et al. Intraepithelial high-grade neoplasia and early adenocarcinoma in short-segment Barrett's esophagus (SSBE): curative treatment using local endoscopic treatment techniques. Endoscopy 2002;34:604-10. 8. Buttar NS, Wang KK, Lutzke LS, Krishnadath KK, Anderson MA. Combined endoscopic mucosal resection and photodynamic therapy for esophageal neoplasia within Barrett's esophagus. Gastrointest Endosc 2001;54:682-8. 9. Pacifico, RJ, Wang KI~ Role of mucosal ablative therapy in the treatment of the columnar-lined esophagus. Chest Surg Clin N Am 2002;12:185-203. 10. Seewald S, Akaraviputh T, Sieta U, Brand F, Groth S, Mendoze G, et al. Circumferential endoscopic mucosal resection and complete removal of Barrett's epithelium: a new approach in the management of Barrett's esophagus containing high-grade intraepithelial neoplasia and intramucosal carcinoma. Gastrointest Endosc 2003;57:854-9.

chronic intermittent exposure of this metaplastic epithelium to gastroduodenal contents (e.g., acid, bile) results in further mucosal injury and inflammation. This inflammation in turn results in the induction of enzymes such as cyclooxygenase-2 that contribute to the production of local tissue prostaglandins as well as other factors that affect tissue proliferation and cell death. 3-5 Mutation-induced alterations in gene function (e.g., 17p loss of heterozygosity) further inhibit the ability of the metaplastic tissue to repair or contain genomic errors, allowing for the clonal expansion of genomically altered cell populations that are at much higher risk of malignant transformation. 6-8 Primary prevention of Barrett's-related esophageal cancer by precluding the initial development of Barrett's esophagus through control of acid reflux, either pharmacologically or surgically, is not an available clinical option because Barrett's esophagus forms early on in a "reflux career" and is likely present before the patient seeks t r e a t m e n t for GERD symptoms. 9 Secondary prevention of Barrett's-related cancer could possibly occur, either through elimination of reflux or by eliminating the metaplastic premalignant tissue. Extensive investigation of "reversal" of Barrett's esophagus by eliminating reflux with either antireflux surgery or potent antisecretory pharmacologic agents has neither demonstrated clinically meaningful reversal nor prevention of Barrett's-related canVOLUME 58, NO. 2, 2003