oesophageal cancer - mucosal immunology · histology: 80% of type i cancers with intestinal type...
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Oesophageal 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 65 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 female ratio 7:1 3:1
Localization Distal oesophagus Middle (proximal) oesophagus
Long-term prognosis better worse
Risk factors
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
Histological classification
Increased risk of second primary cancers such as
Head and neck Lung
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?
Missing serosa layer of the oesophagus
Oesophageal carcinoma 6
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 7
Universitätsklinik für Viszerale Chirurgie und Medizin
Diagnosis
Primary diagnostic tools
Staging
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)
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 8
Universitätsklinik für Viszerale Chirurgie und Medizin
Pathology
histological type grade (required for staging!) tumour invasion/budding presence/abscence of Barrett`s
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
+++ ++ 0 Her2-neu expression (in 20-25%)
Oesophageal carcinoma 9
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 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
Oesophageal carcinoma 10
Universitätsklinik für Viszerale Chirurgie und Medizin
Therapy
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
Crucial factors of therapy planning: Tumour stage Histological type Patient`s performance status (ECOG)
Endoscopic resection
Surgery + perioperative RTx/CTx
Palliative treatment
Major staging groups:
Oesophageal carcinoma 11
Universitätsklinik für Viszerale Chirurgie und Medizin
Early cancer (T1a)- Endoscopic therapy modalities
Limitations of endoscopic therapy:
Ell et al: Gastrointest Endosc 2007; 65, 3-10
- 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.
1. Endoscopic mucosal resection (EMR) - «ligate and cut» - «suck and cut» - «grab and cut»
2. Endoscopic ablation procedures (RFA, cryoablation, photodynamic therapy)
Size: tumour<2cm EUS staging is essential: w/o invasion beyond mucosa and ulceration Histology: G1-2
Endoscopic resection/ablation vs. oesophagectomy: Similar median cancer-free survival Less morbidity
Precondition:
Oesophageal carcinoma 12
Universitätsklinik für Viszerale Chirurgie und Medizin
Limited/locally advanced cancer (T1b-T4) - Surgery
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
Oesophagogastrectomy with systematic lymph-node dissection
Oesophageal carcinoma 13
Universitätsklinik für Viszerale Chirurgie und Medizin
Radiation therapy
Definitive: 50-60(-65) Gy (for cervical oesophagus) Pre/postoperative: 40-50 Gy Palliative: individual
brachytherapy (local control rate 25-35%)
Squamous cell carcinoma - more radiosensitive
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
Chemotherapy
Cunningham et al. N Engl J Med 2006;355:11-20.
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)
Oesophageal carcinoma 14
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 15
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 16
Universitätsklinik für Viszerale Chirurgie und Medizin
Therapeutic algorythm for medically fit patients
Mod. NCCN guidelines Esophageal carcinoma Version 2.2013
Limited disease Local disease Locally advanced
Tis T1a T1b N0 T1b N1
EMR/ ESD
EMR+ RFA
RFA
or or
Disseminated (M1)/ Residual disease
T2
Neoadj. RCTx
Neoadj. RCTx
T3/T4
Potentially resectable?
S u r g e r y
definitive RCTx
Restaging- resectable?
R0 R1/2
Postop. CTx
Postop. RCTx
yes no
yes no
Palliative RCTx
Palliative RCTx BSC
Karnofsky index ≥ 60%/
ECOG ≤2
yes no
Oesophageal carcinoma 17
Universitätsklinik für Viszerale Chirurgie und Medizin
Therapeutic algorythm for medically unfit* patients
Mod. NCCN guidelines Esophageal carcinoma Version 2.2013
Limited disease Local disease Locally advanced
Tis T1a T1b N0 T1b N1
EMR/ ESD
EMR+ RFA
RFA
or
Disseminated (M1)/ Residual disease
T2 T3/T4
Fit for CTx/RTx?
definitive RCTx
Consider RCTx
yes no
Palliative RCTx BSC
Karnofsky index ≥ 60%/
ECOG ≤2
yes no
definitive CTx
BSC
definitive RTx
or
or
*medically unfit for surgery surgery not elected
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
Mod. NCCN guidelines Esophageal carcinoma Version 2.2013
Oesophageal carcinoma 19
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 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 PPI for patients with Barrett`s Aspirin?, statins?
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 oesophagus cancer vs. general population
Annual cancer risk for patients with Barrett`s:
with low-grade dysplasia: 1 %
Pohl et al: Am J Gastroenterol 2013; 108:200–207
long-standing GERD/Barrett`s
length of Barrett`s
male gender ≥ 50yrs Cancer risk association with
with nondysplastic Barrett`s: 0.12-0.4 %
with high-grade dysplasia: 5 %
Oesophageal carcinoma 21
Universitätsklinik für Viszerale Chirurgie und Medizin
Prevention
Prevention of oesophageal 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 Esophagectomy
3 mo first year 6 mo second year
then annual until 5 yrs
Consider RFA for patients with nondysplastic Barrett`s - long-segment - severe GERD symptoms - family history of Barrett`s or oesophageal carcinoma
Rustgi et al: N Engl J Med 2014 Dec;371:2499-2509