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Early esophageal cancer treatment: Is it now an endoscopic disease?



Historically, the use of endoscopy in Barrett’s disease was focused on the diagnosis of high-grade dysplasia and carcinoma. Surveillance endoscopy utilized fiber-optic endoscopes with limited resolution, reusable biopsy forceps, and SLR type photographic imaging. Patients diagnosed with high-grade dysplasia or cancers were then referred for surgery. Surgery meant undergoing in Ivor-Lewis esophagectomy via right thoracotomy and laparotomy with the anastomosis performed in the chest, or trans-hiatal esophagectomy, with anastomosis performed at the level of the clavicles. These procedures were associated with significant morbidity and a risk of mortality including anastomotic leaks, bleeding, pneumonia, laryngeal nerve injury, aspiration, heart attack and dysrrhythmia, wound infection, urinary tract infection, fistula, and stricture.

Dr. Herbert C Wolfsen

In the mid-1990s, this landscape began to change. Based on the pioneering work of Gene Overholt, Charlie Lightdale, and Ken Wang, endoscopic treatment was approved for obstructing esophageal cancer using porfimer sodium PDT that combined a photosensitizer drug with red laser light for mucosal ablation. The approval for high-grade dysplasia was based on the first ever prospective, multicenter, international, randomized and controlled trial using PDT for patients with Barrett’s esophagus and high-grade dysplasia. Important study design features were a control group followed with intensive surveillance and a centralized pathology laboratory. Even with its associated photosensitivity and strictures, this study demonstrated efficacy for endoscopic ablation of Barrett’s high-grade dysplasia and decreased numbers of patients progressing to adenocarcinoma (Gastrointest. Endosc. 1995;42:507-12; Gastrointest. Endosc. 2005:62;488-98).

Radiofrequency energy devices were the next important development in endoscopic ablation. A multicenter, randomized, sham-controlled trial of RFA utilizing a centralized pathology laboratory at the Cleveland Clinic was published by Nick Shaheen and colleagues in the New England Journal of Medicine in 2009. This study demonstrated higher clearance rates of Barrett’s metaplasia and dysplasia with dramatically lower rates of progression to cancer and treatment-associated stricture when compared with the previous PDT study. These excellent results have been durable over several years of follow-up. Similar positive results were recently reported in patients with Barrett’s low-grade dysplasia treated with RFA (N. Engl. J. 2009;360:2277-88; JAMA 2014;311:1209-17).

Subsequently, endoscopic ultrasound was used to characterize locally advanced esophageal cancer and paraesophageal lymph nodes. The weak link of EUS however was staging superficial carcinomas. A meta-analysis from Mayo Clinic Florida presented at DDW 2014 found that EUS was excellent for detection of nodal disease but had only 56% sensitivity for the detection of submucosal disease. Endoscopic mucosal resection has been utilized to provide this information. EMR is an excisional biopsy to determine the grade of carcinoma differentiation, invasion of blood vessels, nerves or lymphatics, and disease extension to deep or lateral margins.

The clinical utility of these endoscopic advancements was demonstrated in a Mayo cohort study comparing clinical outcomes in patients with Barrett’s high-grade dysplasia and subsequently Barrett’s mucosal pT1a carcinoma treated with endoscopic therapy using EMR and porfimer sodium PDT, compared with patients who underwent esophageal resection surgery. While disease recurrence requiring additional endoscopic treatment was more common in the EMR/PDT group, the overall patient survival was similar between the groups. These findings have been confirmed by this NCI SEER database study of nearly 2,000 esophageal cancer patients over 10 years that found similar cancer-specific survival between patients treated with endoscopic or surgical therapy (Clin. Gastroenterol. Hepatol. 2013;11:1424-9; Gastroenterology 2007;132:1226-33; Gastroenterology 2009;137:815-23; Gastroenterology 2014;146:652-60).

These results support the use of endoscopic treatment as first-line therapy for early esophageal cancer patients at most referral centers. However, our most important clinical challenge remains the fact that most esophageal cancer patients are diagnosed with advanced disease, beyond the reach of our endoscopic therapies. And the vast majority of these patients have never been diagnosed with Barrett’s disease. Our next great challenge is to take what we have learned from the 5%-8% of Barrett’s cancer patients that we follow in endoscopy surveillance and apply these technologies to find the other 95% of esophageal cancer patients.

Dr. Wolfsen is in the division of gastroenterology and hepatology, Mayo Clinic, Jacksonville, Fla. His comments were made at the annual Digestive Disease Week during the ASGE and AGA joint Presidential Plenary.

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