Oesophageal cancer - mucosalimmunology.ch
Transcrição
Oesophageal cancer - mucosalimmunology.ch
Oesophageal cancer Dr. med. Henrik Csaba Horváth Universitätsklinik für Viszerale Chirurgie und Medizin Epidemiology 8th most common cancer worldwide Male/Female ratio: 3,5-4 Mean age at Dx 65 yrs Epidemiology in Switzerland 500-550 new cases/yr 400-450 deaths/yr Change of incidence in the last decades: US National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) Data base. Oesophageal carcinoma Bundesamt für Statistik Neuchatel 2 Universitätsklinik für Viszerale Chirurgie und Medizin Histological classification Squamous cell carcinoma (SCC) Adenocarcinoma 90% Melanoma Leiomyosarcoma Carcinoid Lymphoma adenocarcinoma SCC others Histology and esophageal cancer incidence (National Cancer Institute US) Oesophageal adenocarcinoma melanoma prostate cancer SCC Adenocarcinoma Ennzinger et al: N Engl J Med 2003;349:2241-52. breast cancer lung cancer colorectal cancer Relative change in the incidence of esophageal adenocarcinoma and other malignancies Pohl et al: J Natl Cancer Inst (2005) 97 (2): 142-146. Oesophageal carcinoma 3 Universitätsklinik für Viszerale Chirurgie und Medizin Histological classification Male to female ratio Localization Long-term prognosis Risk factors Adenocarcinoma Squamous cell carcinoma 7:1 3:1 Distal oesophagus Middle (proximal) oesophagus better worse GERD Barrett`s oesophagus Obesity (BMI) Increased age Alendronate? MSR1, ASCC1, CTHRC1 mutations 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 Oesophageal carcinoma 4 Universitätsklinik für Viszerale Chirurgie und Medizin Prognosis and stage at diagnosis 5-year overall survival Stage 0 (T1is) Stage IA (T1a,b N0): IB (T2 N0): Stage IIA (T3, N0): IIB (T1-2, N1): Stage III (T4 N0, T3 N1, T1-2 N2): Stage IV (N3 or M1): 98% 70% 50-55% 15-35% 15-27% 4-15% 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? Missing serosa layer of the oesophagus Oesophageal carcinoma 5 Universitätsklinik für Viszerale Chirurgie und Medizin Diagnosis Clinical presentation Progressive dysphagia (75%) Weight loss (57%) Odynophagia (17%) Heartburn unresponsive to treatment Hoarseness due to recurrent laryngeal nerve palsy Respiratory symptoms due to esophagotracheal fistules Bleeding/anaemia History of smoking/alcohol intake History of GERD (in Barrett`s carcinoma) Oesophageal carcinoma 6 Universitätsklinik für Viszerale Chirurgie und Medizin Diagnosis Primary diagnostic tools Oesophago-gastroduodenoscopy + biopsy - location relative to teeth/EGJ - length of the tumour - extent of circumferential involvement - degree of obstruction - if present characteristics of Barrett`s (Prague crit.) - 6-8 biopsies (no cytologic brushings/washings) Barium oesophagography Bronchoscopy (for mid-oesophageal tumours) Staging Endoscopic ultrasound - hypoechoic expansion of the mucosal wall layer + mediastinal and perigastric LN - accuracy of overall staging 70-80%, nodal staging with FNAB 90% - consider wire-guided EUS in obstructing tumours (risk of perforation) CT scan of the chest and abdomen PET-CT (initial assesment of distal metastases, to determine the response to therapy) – of prognostic value? Minimal invasive staging with laparoscopy/thoracoscopy (distant metastases <1 cm of size) Oesophageal carcinoma 7 Universitätsklinik für Viszerale Chirurgie und Medizin Pathology histological type grade (required for staging!) tumour invasion/budding presence/abscence of Barrett`s Her2-neu expression (in 20-25%) +++ ++ 0 Role of HER2 (human epidermal growth factor receptor) -neu overexpression? Higher rate in adenocarcinomas vs SCC (15-30% vs 15-10%) Positive correlation with tumour invasion/lymph node metastasis Poorer survival (esp. in SCC) Langer et al.: Mod Pathol 2011; 24, 908-916 Oesophageal carcinoma 8 Universitätsklinik für Viszerale Chirurgie und Medizin 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 with intestinal type tumour growing pattern, type II/III more agressive, similar tumourbiological characteristics of gastric cancer (therapeutic consequences) Surgery: type I transthoracal, type II/III transhiatal surgery Siewert et al: Ann Surg 2000; 232:353–361 Oesophageal carcinoma 9 Universitätsklinik für Viszerale Chirurgie und Medizin Therapy Crucial factors of therapy planning: Tumour stage Histological type Patient`s performance status (ECOG) Major staging groups: Early cancer (Tis, T1a N0) Limited disease (T1b-2 N0-1 M0) Locally advanced disease (T3-4 N0-1 M0) Advanced (Tx Nx M1)/recurrent disease Oesophageal carcinoma Endoscopic resection Surgery + perioperative RTx/CTx Palliative treatment 10 Universitätsklinik für Viszerale Chirurgie und Medizin Early cancer (T1a)- Endoscopic therapy modalities 1. Endoscopic mucosal resection (EMR) - «ligate and cut» - «suck and cut» - «grab and cut» 2. Endoscopic ablation procedures (RFA, cryoablation, photodynamic therapy) Endoscopic resection/ablation vs. oesophagectomy: Similar median cancer-free survival Less morbidity Precondition: Size: tumour<2cm EUS staging is essential: w/o invasion beyond mucosa and ulceration Histology: G1-2 Limitations of endoscopic therapy: - angiolymphatic invasion irrespective of tumour depth nodal metastases can be present (T1a 1.3%) positive resection margins in 1/3 of cases recurrent/metachronous lesions (in 11% of patients) Zehetner et al: J Thorac Cardiovasc Surg 2011;141:39-47. Ell et al: Gastrointest Endosc 2007; 65, 3-10 Oesophageal carcinoma 11 Universitätsklinik für Viszerale Chirurgie und Medizin Limited/locally advanced cancer (T1b-T4) - Surgery Oesophagogastrectomy with systematic lymph-node dissection 1. Transthoracic (right thoracotomy+laparotomy±cervical anastomosis) less anastomatic leakage rate 2. Transhiatal (laparotomy+cervical anastomosis) less postoperative morbidity 3. Thoracoabdominal 4. Minimal invasive esophagectomy (laparoscopy/thoracoscopy) shorter hospitalisation, less postop morbidity/mortality, less pulmonary compl., preserves QOL Preconditions for surgical therapy: Tumour is resectable Patient is fit Is surgery alone feasible? No, combined therapy approach is necessary Oesophageal carcinoma 12 Universitätsklinik für Viszerale Chirurgie und Medizin Radiation therapy Definitive: Pre/postoperative: Palliative: 50-60(-65) Gy (for cervical oesophagus) 40-50 Gy individual brachytherapy (local control rate 25-35%) Radiotherapy - as part of the multimodal therapy with CTx - for cancer in the cervical tu. (no surgery possible) - as single therapy for palliation/rescue only Squamous cell carcinoma - more radiosensitive Chemotherapy Surgery + perioperative CTx for adenocarcinomas: MAGIC study (Epirubicin+Cisplatin+5-FU) Better overall survival (HR for death, 0.75; 95% CI, 0.60 to 0.93; P = 0.009 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;355:11-20. Oesophageal carcinoma 13 Universitätsklinik für Viszerale Chirurgie und Medizin Chemotherapy Surgery + neoadjuvant RCTx: CROSS study OS (HR 0.657; 95% CI, 0.495 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;366:2074-84. Oesophageal carcinoma 14 Universitätsklinik für Viszerale Chirurgie und Medizin Targeted therapies VEGF-inhibitors EGFR-inhibitors Her2-neu 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): 3304–3314 Hong et al: Semin Radiat Oncol 2013 23:31-37 Oesophageal carcinoma 15 Universitätsklinik für Viszerale Chirurgie und Medizin Therapeutic algorythm for medically fit patients Local disease Tis T1a EMR/ ESD T1b N0 Limited disease T1b N1 T2 T3/T4 Karnofsky index ≥ 60%/ ECOG ≤2 Potentially resectable? EMR+ RFA yes Neoadj. RCTx or Disseminated (M1)/ Residual disease Locally advanced no Neoadj. RCTx yes definitive RCTx or Palliative RCTx no BSC Restagingresectable? yes S u r g e r y RFA R0 R1/2 Postop. CTx Postop. RCTx no Palliative RCTx Mod. NCCN guidelines Esophageal carcinoma Version 2.2013 Oesophageal carcinoma 16 Universitätsklinik für Viszerale Chirurgie und Medizin Therapeutic algorythm for medically unfit* patients Local disease Tis T1a EMR/ ESD T1b N0 Limited disease T1b N1 Locally advanced T2 Disseminated (M1)/ Residual disease T3/T4 Karnofsky index ≥ 60%/ ECOG ≤2 Fit for CTx/RTx? EMR+ RFA yes no definitive RCTx or or yes no BSC Palliative RCTx BSC definitive CTx RFA or Consider RCTx definitive RTx *medically unfit for surgery surgery not elected Mod. NCCN guidelines Esophageal carcinoma Version 2.2013 Oesophageal carcinoma 17 Universitätsklinik für Viszerale Chirurgie und Medizin 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 Mod. NCCN guidelines Esophageal carcinoma Version 2.2013 Oesophageal carcinoma 18 Universitätsklinik für Viszerale Chirurgie und Medizin Treatment of advanced (metastatic, disseminated) disease Palliative chemotherapy SCC has poor response, adenocarcinoma second/third line CTx cisplatin/oxaliplatin+5-FU/capecitabine + docetaxel + ramucirumab (anti-VEGFR2) + trastuzumab (anti-HER2-neu) Management of pain Improvement of dysphagia Endoscopy: self-expanding metal stents covered stents (oesophago-tracheal fistules) tumor ablation (YAG-laser, photodynamic therapy, cryotherapy) Treatment of bleedings Endoscopy: APC, Adrenalin, Clipping, Hemospray Adequate nutrition enteral(PEG tube)/parenteral nutrition Oesophageal carcinoma 19 Universitätsklinik für Viszerale Chirurgie und Medizin 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 PPI for patients with Barrett`s Aspirin?, statins? Surveillance for patients with Barrett`s is essential. Why? 100x risk of oesophagus cancer vs. general population Annual cancer risk for patients with Barrett`s: with nondysplastic Barrett`s: 0.12-0.4 % with low-grade dysplasia: 1% with high-grade dysplasia: 5% Cancer risk association with male gender ≥ 50yrs long-standing GERD/Barrett`s Wang et al: Am J Gastroenterol. 2008 Mar;103(3):788-97 Wani et al: Clin Gastroenterol Hepatol. 2011;9(3):220-227 length of Barrett`s Pohl et al: Am J Gastroenterol 2013; 108:200–207 Oesophageal carcinoma 20 Universitätsklinik für Viszerale Chirurgie und Medizin Prevention Prevention of oesophageal cancer in patients with Barrett`s Barrett`s esophagus No dysplasia 2x 6 mo, then 3yrs (LSB) 4 yrs (SSB) High-grade dysplasia Low-grade dysplasia 2x 6 mo, then annual mucosal irregularity Unifocal/ visible EMR Consider RFA for patients with nondysplastic Barrett`s - long-segment - severe GERD symptoms - family history of Barrett`s or oesophageal carcinoma Multifocal/ unvisible Esophagectomy RFA 3 mo first year 6 mo second year then annual until 5 yrs Wang et al: Am J Gastroenterol. 2008 Mar;103(3):788-97 Rustgi et al: N Engl J Med 2014 Dec;371:2499-2509 Oesophageal carcinoma 21