Esophageal cancer. Dr. med. Henrik Csaba Horváth

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1 Esophageal cancer Dr. med. Henrik Csaba Horváth

2 Epidemiology 8th most common cancer worldwide Male/Female ratio: 3,5-4 Mean age at Dx 64 yrs Epidemiology in Switzerland new cases/yr deaths/yr Change of incidence in the last decades: US National Cancer Institute s Surveillance Epidemiology and End Results (SEER) Data base. Bundesamt für Statistik Neuchatel Oesophageal carcinoma 2

3 Histological classification Squamous cell carcinoma (SCC) Adenocarcinoma Melanoma Leiomyosarcoma Carcinoid Lymphoma 90% adenocarcinoma SCC others Histology and esophageal cancer incidence (National Cancer Institute US) Oesophageal adenocarcinoma melanoma prostate cancer SCC Adenocarcinoma breast cancer lung cancer colorectal cancer Ennzinger et al: N Engl J Med 2003;349: Relative change in the incidence of esophageal adenocarcinoma and other malignancies Pohl et al: J Natl Cancer Inst (2005) 97 (2): Oesophageal carcinoma 3

4 Histological classification Adenocarcinoma Squamous cell carcinoma Male to femal ratio 7:1 3:1 Localization Distal oesophagus Middle (distal) oesophagus Long-term prognosis better worse Risk factors - male gender - long-standing GERD - length of Barrett`s - HGD (59% vs 4%) GERD Barrett`s oesophagus Smoking Obesity (BMI) Increased age H. pylori (?) Alcohol consumption Smoking Achalasia History of thoracic radiation Low socioeconomic status Poor oral hygiene Increased risk of second primary cancers such as Head and neck Lung Pohl et al: Am J Gastroenterol 2013; 108: Oesophageal carcinoma 4

5 Prognosis and stage at diagnosis 5-year overall survival Stage 0 (T1is) 98% Stage IA (T1a,b N0): 70% IB (T2 N0): 50-55% Stage IIA (T3, N0): 15-35% IIB (T1-2, N1): 15-27% Stage III (T4 N0, T3 N1, T1-2 N2): 4-15% Stage IV (N3 or M1): 0-2% Esophageal cancer stage distribution at diagnosis for the US male and female between 1999 and 2006 (SEER data base) At presentation, 57% patients are Stage III 24% patients are Stage II 5-year survival rates for esophageal cancer by stage at diagnosis for the US male and female between 1999 and 2006 (SEER data base) Why is the diagnosis of a locally advanced carcinoma so common? Oesophageal carcinoma 5

6 Diagnosis Clinical presentation Dysphagia (75%) Weight loss (57%) Odynophagia (17%) Hoarseness due to recurrent laryngeal nerve palsy Respiratory symptoms due to esophagotracheal fistules Bleeding Heartburn/history of GERD (Barrett`s carcinoma) History of smoking/alcohol intake Primary diagnostic tools Oesophago-gastroduodenoscopy + biopsy Barium oesophagography Bronchoscopy (for mid-oesophageal tumours) Staging Endoscopic ultrasound (accuracy of overall staging 72%, nodal staging with FNAB 90%) CT scan of the chest and abdomen PET-CT (initial and to determine the response to therapy) of prognostic value? Minimal invasive staging (laparoscopy/thoracoscopy) Oesophageal carcinoma 6

7 Classification of adenocarcinomas in the EGJ Siewert 1996/2000 Localization of tumour center Type I: within 1 to 5 cm above EGJ Type II: within 1 cm above and 2 cm below EGJ Type III: between 2 to 5 cm below EGJ Clinical relevance? Lymphatic spread: Type I (6%) vs type II (22%) and type III (38%) Grading: better in type I tumours vs type II/III Histology: 80% of type I cancers have intestinal type tumour growing pattern, type II/III more agressive Type II/III tumourbiological characteristics of gastric cancer (therapeutic consequences) Surgery: type I transthoracal, type II/III transhiatal Siewert et al: Ann Surg 2000; 232: Oesophageal carcinoma 7

8 Pathology histological type tumour invasion grade (required for staging!) presence/abscence of Barrett`s Role of HER2-neu overexpression? Her2-neu expression in 20-25% of esophageal tumours Higher rate in adenocarcinomas vs SCC Positive correlation with tumour invasion/lymph node metastasis Poorer survival Langer et al.: Mod Pathol 2011; 24, Oesophageal carcinoma 8

9 Therapy Crucial factors of therapy planning: Tumour stage Histological type Patient`s performance status Major staging groups: Early cancer (Tis, T1a N0) Limited disease (T1-2 N0-1 M0) Locally advanced disease (T3-4 N0-1 M0) Advanced (Tx Nx M1)/recurrent disease Endoscopic resection Surgery + perioperative RTx/CTx Palliative treatment Oesophageal carcinoma 9

10 Early cancer - Endoscopic therapy modalities 1. Endoscopic mucosal resection (EMR) 2. Endoscopic ablation procedures (RFA, cryoablation, photodynamic therapy) Endoscopic resection/ablation vs. esophagectomy: Similar median cancer-free survival Less morbidity Precondition: EUS staging is essential (nodularity, lateral spread) Tumour<2cm, G1-2, w/o invasion beyond mucosa and ulceration Limitations of endoscopic therapy: - angiolymphatic invasion irrespective of tumour depth - nodal metastases (7% of T1 tumours) - positive resection margins in 1/3 of cases - recurrent/metachronous lesions in 11% of patients Zehetner et al: J Thorac Cardiovasc Surg 2011;141: Ell et al: Gastrointest Endosc 2007; 65, 3-10 Oesophageal carcinoma 10

11 Surgery Esophagogastrectomy 1. Transthoracic (right thoracotomy+laparotomy±cervical anastomosis) 2. Transhiatal (laparotomy+cervical anastomosis) 3. Thoracoabdominal 4. Minimal invasive esophagectomy (laparoscopy/thoracoscopy) shorter hospitalisation, less postop morbidity/mortality, less pulmonary complications, preserves QOL with systematic lymph-node dissection less anastomatic leakage rate less postoperative morbidity Preconditions for surgical therapy: Tumour is resectable Patient is fit Is surgery alone feasible? No, combined modality therapy is necessary Oesophageal carcinoma 11

12 Radiation therapy Definitive: 50 (-60) Gy (for tumours of cervical oesophagus Gy) Preoperative: Gy Postoperative Gy Palliative: individual brachytherapy (local control rate 25-35%) Squamous cell carcinoma - more radiosensitive Preoperative radiation versus surgery alone no improved survival in long-term randomized trials Post-op radiation versus surgery alone no improved survival, but higher stricture rate improved local recurrence rates in node negative mid- to upper-third SCCs benefit if positive margins/residual tumours Radiotherapy as part of the multimodal therapy with CTx for cancer in the cervical esophagus (no surgery possible) as single therapy for palliation/rescue only Oesophageal carcinoma 12

13 Chemotherapy Surgery + neoadjuvant RCTx: CROSS study OS (HR 0.657; 95% CI, to 0.871; P = 0.003) Median OS 49,4 vs 24,0 mo R0 92% vs 69% (P<0.001) down staging: complete pathological response (pt0 pn0) and/or size reduction of tumours in 29% of patients van Hagen et al: N Engl J Med 2012;366: Oesophageal carcinoma 13

14 Chemotherapy Surgery + perioperative CTx for adenocarcinomas: MAGIC study (Epirubicin+Cisplatin+5-FU) Better OS (HR for death, 0.75; 95% CI, 0.60 to 0.93; P = Better five-year survival rate: 36 percent vs. 23% Better progression-free survival (HR for progression, 0.66; 95% CI, 0.53 to 0.81; P<0.001) Cunningham et al. N Engl J Med 2006;355: Oesophageal carcinoma 14

15 Therapy of limited/ locally advanced disease Stahl et al: Annals of Oncology 21 (Supplement 5): v46 v49, 2010 Oesophageal carcinoma 15

16 Targeted therapies Which targeted terapy modilities may play a role in the treatment of esophageal cancer? EGFR-inhibitors Her2-neu VEGF-inhibitors MET/HGF-pathway inhibitors (crizotinib, rilotumumab) (inhibition of tumour endothelial cells) Aurora kinases A (and B)- inhibitors (centrosome amplification) Heat-shock protein 90-inhibitor Hedgehog-inhibition Mukherjee et al: Dig Dis Sci. 2010; 55(12): Hong et al: Semin Radiat Oncol :31-37 Oesophageal carcinoma 16

17 Postoperative treatment of limited/locally advanced disease Which factors have impact on the postop treatment? 1. Histology 2. Surgical margins (shows the best correlation with survival) 3. Preoperative (radio)chemotherapy 4. Nodal status Which patient group(s) do not need a postoperative chemotherapy? Patients who have not received preoperative Tx Patients who have received preoperative Tx * If age<50yrs, grade>1, lymphovascular/neural invasion R0 R1 R2 SCC observation CTx Adenocarcinoma ptis, pt1 N0 pt2 N0* pt1-2 N1 pt3-4a Nx obs CTx CTx CTx (palliation) CTx (palliation) SCC Adenocarcinoma R0 R1 R2 obs CTx CTx/ observation CTx/ observation CTx/ palliation CTx/ palliation Oesophageal carcinoma 17

18 Follow-up After endoscopic therapy (EMR) for Tis, T1a cancers: 1st year: 3 mo endoscopy After 1 yr: annual endoscopy After surgery for T1b-4 cancers Physical exam, laboratory, endoscopy First (1-)2 years: 3-6 mo 3-5 years: 6-12 mo After 5 years: annual Oesophageal carcinoma 18

19 Treatment of advanced (metastatic, disseminated) disease Palliative chemotherapy SCC: cisplatin+5-fu Adenocc: cisplatin+irinotecan cisplatin+5fu+docetaxel epirubicin+oxaliplatin+capecitabine (±panitimumab) Management of pain Improvement of dysphagia Endoscopy: esophageal stents (also for trecheo-esophageal fistules) brachytherapy (better long-term effects?) photodynamic therapy (for bleeding, better acute tumour response) YAG-laser therapy (for bleeding, more perforations) Adequate nutrition enteral(peg tube)/parenteral nutrition Oesophageal carcinoma 19

20 Prevention Smoking cessation (risk of SCC decreases after one decade) Moderation of alcohol intake Substitution fresh fruits and vegetables for high-salt/ nitrosamine-preserved food Aspirin, selenium, black raspberries No screening for patients with long-term GERD for Barrett`s - high number of people having reflux symptoms - 40% of patients with Barrett`s without reflux symptoms Surveillance for patients with Barrett`s is essential. Why? 100x risk of esophagus cancer vs. general population LGD: 3-4% HGD: 0.5-1% Cancer: % of patients with Barrett`s esophagus/yr Wang et al: Am J Gastroenterol Mar;103(3): Wani et al: Clin Gastroenterol Hepatol. 2011;9(3): Oesophageal carcinoma 20

21 Prevention Prevention of esophageal cancer in patients with Barrett`s Barrett`s esophagus No dysplasia Low-grade dysplasia High-grade dysplasia 2x 6 mo, then 3yrs (LSB) 4 yrs (SSB) 2x 6 mo, then annual mucosal irregularity Unifocal/ visible Multifocal/ unvisible EMR Esophagectomy RFA/PDT 3 mo first year 6 mo second year then annual until 5 yrs Wang et al: Am J Gastroenterol Mar;103(3): Oesophageal carcinoma 21