ESOPHAGEAL CANCER Disclosures Sushil Ahlawat, MD, FACP, FASGE, AGAF Associate Professor of Medicine Director of Endoscopy RUTGERS NJMS Nothing to disclose. Esophageal Carcinoma: subtypes Subtype Squamous cell carcinoma (SCC) Adenocarcinoma (EAC) Geographic distribution Asia, Africa, South America, African American in North America North America, Europe Risk factors Alcohol, tobacco GERD, Obesity Precursor lesion Esophageal squamous dysplasia Barrett s esophagus Esophageal Adenocarcinoma (EAC) Epidemiology Risk factors Staging and therapy Early stage disease & endoscopic therapy Prognoses Future developments Epidemiology In 2014,18,000 new cases of esophageal ca, 60% of which were EAC The incidence of EAC in the US was 2.5 per 100,000 people in 2011 The incidence of EAC has continued to increase in the US but may be reaching a plateau Trend of incidence of EAC in US SEER Cancer Registry SEER cancer registry, US 1
Risk factors of EAC Male sex Advancing age White race GERD Obesity Tobacco use Barrett s esophagus Risk Factors of EAC Risk of EAC is 8-fold greater in patients with recurrent GERD symptoms Patients with long standing symptoms, nocturnal symptoms, or more frequent symptoms are at increased risk Severity of symptoms is not associated with increased risk of EAC GERD erosive esophagitis aberrant healing process BE (0.12% to 0.60% per year) EAC Approximately 50-60% patients with EAC do not have GERD Rubenstein JH, Shaheen N. Gastroenterology 2015:149:302. Shaheen N, Ransohoff DF. JAMA 2002; 287: 1972-81 Tramacere I, et al.epidemiology 2011; 22: 344-9. Risk Factors of EAC Obesity increases risk by x2.4 to 2.8 Abdominal obesity increases risk of BE & EAC Mechanical effect of obesity hiatal hernia increased risk of GERD Hormonal effects of obesity (IGF) alterations of adipokines BE EAC Risk factors of EAC Infection with H pylori appears to protect against EAC EAC risk is reduced in population with H pylori prevalence; meta-analysis of 15 studies showed EAC risk decreased by 41% among those with H pylori However, HPE neither cause or worsens GERD Singh S, et al. Clin Gastroenterol Hepatol 2013; 11: 1399-412. Fischbach LA, et al. Am J Gastroenterol2014; 109: 357-68. Malfertheiner P,et al. Gut 2012; 61: 646-64. Risk factors of EAC Alcohol is not risk factor for EAC but risk of SCC is x3 to x5 among those taking 3 or > drinks/day Tobacco use increased the risk of EAC by 2.18 fold High intake of red meats, fats, processed foods increase risk High intake of fiber, fresh fruits, and vegetables lowers the risk Statins, aspirin, NSAIDs lower risk Endoscopic screening & surveillance (EAC) BE is precursor of EAC 6-12% of patient with long standing GERD have BE on endoscopic screening 40% patients with BE do not have GERD Annual cancer risk of EAC is 0.12 to 0.40% in non-dysplastic BE Dysplasia in BE signals increased risk: 1% for LGD and >5% for HGD Tramacere I, et al. Ann Oncol 2012; 23: 287-97. Kubo A, et al. Nutr Res Rev 2010; 23: 230-46. Hvid-Jensen F, et al. N Engl J Med 2011; 365: 1375-83. de Jonge PJ, et al Gut 2010;59: 1030-6. Dulai GS, et al. Gastroenterology 2002; 122: 26-33. 2
Endoscopic screening and surveillance Endoscopic surveillance every 3 years is recommended for non-dysplastic BE 80-90 percent EAC diagnosed in patient with no BE EAC detected during endoscopic surveillance for BE is more likely to be early stage, amenable to curative therapy & survival is longer compared to those with symptoms in whom EAC is diagnosed Clinical presentation Progressive dysphagia, weight loss, refractory GERD, GIB Less common symptoms: Fe def anemia, oropharyngeal dysphagia Asymptomatic: discovered during screening or surveillance endoscopy (<15% cases of EAC) Only 25% of patients with EAC present with localized disease Spechler SJ, et al.gastroenterology 2011; 140(3): e18-e52. Cooper GS, et al. Am J Gastroenterol 2009;104: 1356-62. Diagnosis CT doesn t accurately identify localized EAC Barium esophagogram Endoscopy: diagnosis and plan of therapy Stricture, mass, ulcer, nodule, subtle irregularity in the mucosa Size, location and morphology EAC occur in distal esophagus or GE junction in 75% of patients Rubenstein JH, Shaheen N. Gastroenterology 2015:149:302. 3
Staging and LN metastasis Management: Staging Endoscopy with or without mucosal resection (EMR) CT chest/abdomen Endoscopic ultrasound (EUS) PET scan Holscher AH, et al. Ann Surg 2011;254:802. N Engl J Med 2014;371:2499-509. Role of EUS in staging Highly accurate for T, N staging Not reliable for T1a vs T1b endoscopic appearance size, diameter, failure to rise with submucosal injection, multifocality, mucosectomy/large biopsy Lymph node >10 mm, round, smooth, hypoechoic Accuracy 80; FNA increases accuracy to 92-98% Restaging after chemo-radiation EUS accuracy for T (30-60%), N (40-70%) PET /CT better accuracy than EUS Qumaeya B, et al. GIE 2015;81:865 Management: Mucosal Tumors (Stage 0 or 1a) Stage 0 or 1a: HGD or EAC limited to the mucosa Risk of LN metastasis is 0 Esophagectomy Endoscopic therapy Visible lesions, <2 cm in size Small resectable areas of dysplastic BE Moderate or well differentiated grade EAC Lack of lymphovascular invasion Gastroenterology 2011;141:42 Rubenstein JH, Shaheen N. Gastroenterology 2015:149:302. Pech O, et al. Gastroenterology 2014;146:652. 4
Endoscopic therapy Endoscopic resection EMR, ESD Provides histologic data: depth of invasion, grade, LVI Staging and treatment Endoscopic ablation RFA, Cryoablation, Argon, PDT Doesn t provide histologic data Buried glands Hybrid (resection+ ablation) Endoscopic therapy Endoscopic eradication of residual BE 30% recurrence of EAC without adjuvant BE eradication Stepwise radical endoscopic resection of residual BE High rate of stricture formation compared to ablation therapy Most reported modality is RFA 80% success in complete remission of dysplasia in patients with T1a EAC Recurrence of BE in 33% within 2 years after complete eradication of BE (cohort without cancer at baseline) Aggressive surveillance is recommended: q 3 months for 1 year, q 6 months during 2 nd year, and annually thereafter Haidry RJ, et al. Gastroenterology 2013;145:87 Gupta M, et al. Gastroenterology 2013;145:79. Pech O, et al. Gastroenterology 2014;146:652 Van Vilsteren FG, et al. Gut 2011;60:765.. Rustgi AK, El-Serag HB. N Engl J Med 2014;371:2499-2509. Management: Mucosal Tumors Stage 1b Stage 1b : tumors that have penetrated muscular mucosae and have invaded submucosa sm1, sm2, sm3 Risk of LN metastasis is up to 13-56% ESD for selected sm1/sm2 (<2 cm, no lymphovascular invasion, <500mmicton invasion) Radical esophagectomy Holscher AH, et al. Ann Surg 2011;254:802. Rubenstein JH, Shaheen N. Gastroenterology 2015:149:302. 5
Management: locally advanced tumors Stage IIA:T 2 N 0 M 0 Stage IIB:T 3 N 0 M 0 ; T 1-2 N 1 M 0 Neo-adjuvant CRT Esophagectomy Surgical outcome better in highvolume centers Minimally invasive esophagectomy may have similar outcomes but is technically challenging Overall 3-year survival is 30-60 % Poor outcome in residual, node +, completely resected disease adjuvant CRT benefits SCC,?EAC Wouters MW, et al. Cancer 2012;118:1754 Stage III:T 4 N 0 M 0, T 3 N 1 M 0, T 1-2 N 2 M 0 Stage IV:T any N any M 1 Management: Advanced Tumors 5 yr survival is <15% Endoscopic placement of SEMS High dose intraluminal brachytherapy Endosocpic dilation or ablation, placement of plastic stents, bypass surgery or chemoradiotherapy are NOT recommended Low efficacy & high complications Palliative chemotherapy Unresectable, metastatic, recurrent disease Sreedharan A, et al. Cochrane Database Syst Rev 2009; 4: CD005048. Zhu HD, et al. Lancet Oncol 2014; 15: 612-9. Types Self-expanding metal (nitinol) stents (SEMS) Fully covered (FC) Do not have any exposed bare metal More prone to stent migration Partially covered (PC) Small portion of exposed bare metal at the proximal & distal ends to allow embedding into esophageal wall Less prone to stent migration Uncovered (UC) Original SEMS Tumor or granulation tissue ingrowth Palliative Treatment of Malignant Esophageal Stricture FC or PC SEMS equally effective & safe Stents with anti-reflux features may have decreased GER & complications Special features (niti-s) to reduce migration rate can cause traumatic injury & major adverse events Insufficient evidence to recommend one type of SEMS over other type SEPS conforms less easily to stricture, high complication rate including migrations, & increased failure rate of stent placement because of wider diameter of delivery system Didden P. Curr Gastroenterol Rep 2013;15:319 6
Palliative Treatment of Malignant Esophageal Fistula Fistula result from invasion of respiratory tract or pleural cavity, mediastinal or lung ca invasion of esophagus Closure rate 73-100% with covered SEMS FC or PC SEMS can be used as long as covering completely seals the fistula Treatment of choice for malignant fistula Shin JH. Radiology 2004;232:252 Stent Placement as a Bridge to Surgery Neo-adjuvant CRT used in regionally localized esophageal cancer Stent could serve as bridge to surgery during neoadjuvant CRT by maintaining nutrition Stent-related complications can be avoided by performing esophagectomy shortly after neo-adj CRT is completed Several studies reported benefit in improving dysphagia & maintaining nutrition; however, complications such as perforation, migration leading SB perforation & obstruction have been reported Stent Placement as a Bridge to Surgery Low curative resection rate reported in recent studies due to progression or discovery of metastatic disease Oncologic outcome including 3-year survival negatively impacted with stent placement Mechanism of negative oncologic outcomes SEMS expansive radial force causes peri-stent fibrosis compromising the normal plane of dissection SEMS fixating spur might cause micro-perforation disseminating tumor cells SEMS insertion increases level of circulating neoplastic cells CRT can accentuate stent-related complication such as fistula Inability to accurately restage tumor after stent insertion J Am Coll Surg 2015;220:287 Irradiation Stents SEMS loaded with I 125 combines the advantages of stents & brachytherapy into a single treatment modality Prolongs survival, sustained relief of dysphagia in advanced or non-resectable esophageal cancer No difference in complications compared to SEMS Non FDA device in Asian populations, no data from US Not recommended in US Stent- related Complications: Early Immediately or within 2-4 weeks Chest pain up to 60%, moderate to severe lasting 10 days, requiring analgesics in 90%, rarely need to remove stent Fever GERD mixed data on effectiveness of stent w/anti-relfux valve Globus sensation Perforation Stent migration 7-75% Bleeding: 1% Lancet 2014:15:546 7
Stent-related Complications: Delayed Recurrent dysphagia rate 53-65% requiring re-intervention in 50% Tumor over- or ingrowth: 2 nd stents restores luminal patency Migration in 7-75%:Endoscopic repositioning or exchange for new stent Food impaction: endoscopy Recurrence of stricture: 50% Spontaneous stent fracture & collapse endoscopic stent in stent technique Fistula formation Due to radial force causing pressure necrosis, next to proximal or distal margin, managed by covered stent Death: 0.5-2% Wang MQ et al. J Vasc Interv Radiol 2001;12:465 Homann N, et al. Dig Dis Sci 2008;53:334 Ramirez FC, et al. Gastrointest Endosc 1997;45:360 Prognosis The overall 5-year survival rate of EAC in US is17% Patients are diagnosed when regional (30%) or distant (40%) metastasis has already occurred 5-year survival for localized disease is 39% and 4% when distant metastasis is present 60-70% have not been receiving guidelines concordant therapy Management appear to improve by discussion with multidisciplinary tumor board Summary The main risk factors for EAC are GERD, obesity, cigarette smoking; cigarette smoking & alcohol consumption are main risk factors for SCC Endoscopic screening detects BE & periodic surveillance of BE detects dysplasia and early EAC Endoscopic hybrid therapy (EMR+RFA) is effective & safe for mucosal tumors Esophagectomy preceded by neoadjuvant CRT is the treatment of choice for localized tumors Endoscopic placement of SEMS is first line palliative options for dysphagia due to advanced or recurrent tumors 8