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Esophageal cancer
Dr. med. Henrik Csaba Horváth
Oesophageal carcinoma 2
Universitätsklinik für Viszerale Chirurgie und Medizin
Epidemiology
US National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) Data base.
8th most common cancer worldwide
Change of incidence in the last decades:
Epidemiology in Switzerland 500-550 new cases/yr 400-450 deaths/yr
Male/Female ratio: 3,5-4 Mean age at Dx 64 yrs
Bundesamt für Statistik Neuchatel
Oesophageal carcinoma 3
Universitätsklinik für Viszerale Chirurgie und Medizin
Histological classification
Relative change in the incidence of esophageal adenocarcinoma and other malignancies
Oesophageal adenocarcinoma
melanoma prostate cancer
breast cancer lung cancer colorectal cancer
Histology and esophageal cancer incidence (National Cancer Institute US)
adenocarcinoma
SCC
others
Pohl et al: J Natl Cancer Inst (2005) 97 (2): 142-146.
Ennzinger et al: N Engl J Med 2003;349:2241-52.
Squamous cell carcinoma (SCC) Adenocarcinoma Melanoma Leiomyosarcoma Carcinoid Lymphoma
90%
SCC Adenocarcinoma
Oesophageal carcinoma 4
Universitätsklinik für Viszerale Chirurgie und Medizin
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
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
Histological classification
Increased risk of second primary cancers such as
Head and neck Lung
- male gender - long-standing GERD - length of Barrett`s - HGD (59% vs 4%)
Pohl et al: Am J Gastroenterol 2013; 108:200–207
Oesophageal carcinoma 5
Universitätsklinik für Viszerale Chirurgie und Medizin
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%
5-year overall survival
Esophageal cancer stage distribution at diagnosis for the US male and female between 1999 and 2006 (SEER data base)
5-year survival rates for esophageal cancer by stage 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
Prognosis and stage at diagnosis
Why is the diagnosis of a locally advanced carcinoma so common?
Oesophageal carcinoma 6
Universitätsklinik für Viszerale Chirurgie und Medizin
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
Staging
Oesophago-gastroduodenoscopy + biopsy Barium oesophagography Bronchoscopy (for mid-oesophageal tumours)
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 7
Universitätsklinik für Viszerale Chirurgie und Medizin
Classification of adenocarcinomas in the EGJ
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
Siewert et al: Ann Surg 2000; 232:353–361
Siewert 1996/2000 Localization of tumour center
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
Oesophageal carcinoma 8
Universitätsklinik für Viszerale Chirurgie und Medizin
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, 908-916
+++ ++ 0
Oesophageal carcinoma 9
Universitätsklinik für Viszerale Chirurgie und Medizin
Therapy
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
Crucial factors of therapy planning: Tumour stage Histological type Patient`s performance status
Endoscopic resection
Surgery + perioperative RTx/CTx
Palliative treatment
Major staging groups:
Oesophageal carcinoma 10
Universitätsklinik für Viszerale Chirurgie und Medizin
Early cancer - Endoscopic therapy modalities
Limitations of endoscopic therapy:
Ell et al: Gastrointest Endosc 2007; 65, 3-10
- 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;141:39-47.
1. Endoscopic mucosal resection (EMR) 2. Endoscopic ablation procedures (RFA, cryoablation, photodynamic therapy)
EUS staging is essential (nodularity, lateral spread) Tumour<2cm, G1-2, w/o invasion beyond mucosa and ulceration
Endoscopic resection/ablation vs. esophagectomy: Similar median cancer-free survival Less morbidity
Precondition:
Oesophageal carcinoma 11
Universitätsklinik für Viszerale Chirurgie und Medizin
Surgery
1. Transthoracic (right thoracotomy+laparotomy±cervical anastomosis) 2. Transhiatal (laparotomy+cervical anastomosis) 3. Thoracoabdominal 4. Minimal invasive esophagectomy (laparoscopy/thoracoscopy) with systematic lymph-node dissection
Preconditions for surgical therapy: Tumour is resectable Patient is fit
Is surgery alone feasible?
No, combined modality therapy is necessary
Esophagogastrectomy less anastomatic leakage rate less postoperative morbidity
shorter hospitalisation, less postop morbidity/mortality, less pulmonary complications, preserves QOL
Oesophageal carcinoma 12
Universitätsklinik für Viszerale Chirurgie und Medizin
Radiation therapy
Definitive: 50 (-60) Gy (for tumours of cervical oesophagus 60-65 Gy) Preoperative: 40-50 Gy Postoperative 45-50 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 13
Universitätsklinik für Viszerale Chirurgie und Medizin
Chemotherapy
Surgery + neoadjuvant RCTx: CROSS study
van Hagen et al: N Engl J Med 2012;366:2074-84.
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
Oesophageal carcinoma 14
Universitätsklinik für Viszerale Chirurgie und Medizin
Chemotherapy
Cunningham et al. N Engl J Med 2006;355:11-20.
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 = 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)
Oesophageal carcinoma 15
Universitätsklinik für Viszerale Chirurgie und Medizin
Therapy of limited/ locally advanced disease
Stahl et al: Annals of Oncology 21 (Supplement 5): v46–v49, 2010
Oesophageal carcinoma 16
Universitätsklinik für Viszerale Chirurgie und Medizin
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): 3304–3314 Hong et al: Semin Radiat Oncol 2013 23:31-37
Oesophageal carcinoma 17
Universitätsklinik für Viszerale Chirurgie und Medizin
Postoperative treatment of limited/locally advanced disease
1. Histology 2. Surgical margins (shows the best correlation with survival) 3. Preoperative (radio)chemotherapy 4. Nodal status
* If age<50yrs, grade>1, lymphovascular/neural invasion
Which factors have impact on the postop treatment?
Which patient group(s) do not need a postoperative chemotherapy?
R0 R1 R2
SCC observation CTx CTx (palliation)
Adenocarcinoma
pTis, pT1 N0
obs
CTx CTx (palliation) pT2 N0*
pT1-2 N1 pT3-4a Nx
CTx
R0 R1 R2
SCC obs CTx/ observation
CTx/ palliation
Adenocarcinoma
CTx
CTx/ observation
CTx/ palliation
Patients who have not received preoperative Tx Patients who have received preoperative Tx
Oesophageal carcinoma 18
Universitätsklinik für Viszerale Chirurgie und Medizin
Follow-up
After surgery for T1b-4 cancers Physical exam, laboratory, endoscopy
After endoscopic therapy (EMR) for Tis, T1a cancers:
1st year: 3 mo endoscopy After 1 yr: annual endoscopy
First (1-)2 years: 3-6 mo 3-5 years: 6-12 mo After 5 years: annual
Oesophageal carcinoma 19
Universitätsklinik für Viszerale Chirurgie und Medizin
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 20
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 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?
Wang et al: Am J Gastroenterol. 2008 Mar;103(3):788-97 Wani et al: Clin Gastroenterol Hepatol. 2011;9(3):220-227
100x risk of esophagus cancer vs. general population LGD: 3-4% HGD: 0.5-1% Cancer: 0.3-0.5%
of patients with Barrett`s esophagus/yr
Oesophageal carcinoma 21
Universitätsklinik für Viszerale Chirurgie und Medizin
Prevention
Prevention of esophageal cancer in patients with Barrett`s
Wang et al: Am J Gastroenterol. 2008 Mar;103(3):788-97
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
EMR
Unifocal/ visible
Multifocal/ unvisible
RFA/PDT Esophagectomy
3 mo first year 6 mo second year
then annual until 5 yrs