Oesophageal cancer - Mucosal Immunology · Histology: 80% of type I cancers with intestinal type tumour growing pattern, type II/III more agressive, similar tumourbiological characteristics

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



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 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



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



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)



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)



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%)



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



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:



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:



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



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)



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



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



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



Therapeutic algorythm for medically unfit* patients


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



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 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



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 %



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

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Oesophageal cancer - Mucosal Immunology · Histology: 80% of type I cancers with intestinal type tumour growing pattern, type II/III more agressive, similar tumourbiological characteristics