Esophageal cancer - Mucosal Immunology · Esophageal cancer stage distribution at diagnosis for the US male and female between 1999 and 2006 ... Early cancer - Endoscopic therapy

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



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



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



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?



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)



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



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



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:



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:



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



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



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



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)



Therapy of limited/ locally advanced disease

Stahl et al: Annals of Oncology 21 (Supplement 5): v46–v49, 2010



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



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



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



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



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



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

Documents

Esophageal cancer - Mucosal Immunology · Esophageal cancer stage distribution at diagnosis for the US male and female between 1999 and 2006 ... Early cancer - Endoscopic therapy