Oesophageal cancer - mucosalimmunology.ch

Transcrição

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
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.
3
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
4
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
5
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)
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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)
7
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
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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
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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
Endoscopic resection
Surgery + perioperative RTx/CTx
Palliative treatment
10
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
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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
12
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.
13
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.
14
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
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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
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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
17
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
18
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
19
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
20
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
21

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