Cholangiocellular Carcinoma Diagnostic Tools, Medical Strategy

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Cholangiocellular Carcinoma Diagnostic Tools, Medical Strategy
Cholangiocellular Carcinoma
Diagnostic Tools, Medical Strategy and
New Options
Joachim Mössner, University of Leipzig, Germany
Mainz, September 20, 2008
Diagnosis
Therapy
Curative Resection
Neoadjuvant Therapy
Palliation
Proximal Bile Duct Carcinoma: Prognosis
Bismuth Type
Survival
20-30% resectable (R 0)
15-25% 5 years
Type I, II, (III)
70-80% non-resectable
Type IV , III & T3
4-6 mons
(median)
Problem
intra-/periductal tumor growth
⇒ cholestasis, sepsis, liver failure
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Cancer: Clinical Presentation
Prevalence 2 - 4 / 100 000
Manifestation
Cholestasis
>90%
Pain
10%
Tumorstage
Resectability
10-30%
Lymphnodes N1
30-50%
Distant Metastasis M1
10-20%
Survival
Type I, II, (III)
15-25% 5 yrs
Type IV , III & T3
4 – 6 mons
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Cancer - Early Diagnosis?
¾ Sporadic BDC (>90%)
¾ Symptomatic (icterus / pain) ⇒ 80% incurable
¾ Perihilar bile duct stenosis (without scar due to
cholecystectomy: 90 % probability of tumour
¾ Elevation of gamma-GT ⇒ MRCP (stenosis?)
¾ Risk groups (<10%)
¾
¾
¾
¾
¾
PSC (prevalence 10%; initial incidence 1% / year)
Caroli Syndrome
Choledochocele
Hepatolithiasis
Colitis ulcerosa (0.5%)
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Cancer - Early Diagnosis?
¾ Multi step diagnosis (screening for PSC)
¾
¾
¾
¾
¾
Dominant stenosis (MRC, ERC)
Biopsy, Brush Cytology (Aneuploidy, FISH)
Tumor (Fe3+MRT, ID-US)
Fluorodeoxyglucose-PET
CA 19-9 (>100 U/l [anicteric] ≈ malignant)
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Proximal Bile Duct Carcinoma
Clinical Staging
4.5
4.5 mm
mm
ERC & EUS
15 MHz
6 French
3.5
3.5 mm
mm
MRI (+ EndoremTM)
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Proximal Bile Duct Carcinoma
ERC
MRC
PTC
Extent
Correct
overestimated
underestimated
29%
42%
31%
36%
41%
23%
53%
31%
13%
Otto et al: Z Gastroenterol 2004
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Visual Grading (0 - IV)
of enhancement in PET Scan
G-0= no tumor
G-I= probably no tumor
G-II= enhanced focal uptake
G IV= tumor
(G-III= probably tumor)
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Cancer
F-18-Deoxy-Glucose Positron Emission Tomography
frontal (5mm slices)
Detection of Primary Tumor
Sensitivity 92 %
Specificity 82-93%
(26 BDC vs 20 Controls)
Kluge R et al: Hepatology 2001
T / N 3.2
Mrs F. W., 44 ys
Bismuth Type IV
R 0 Resection
pT3 pN1 Mx; G3
Tumor 2.4 x 1.2 x 2.7 cm
transversal
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Interventional Palliation of Bile Duct Tumors
Biliary Drainages Primary Care and Palliation
Plastic Endoprostheses (Stent / Pigtails)
Metal Stents (distal stenosis)
PTC-drainages in occlusion / cholangitis
Local Tu-Ablation
199-Iridium-Brachytherapy (& ext. radiatio)
Photodynamic therapy (PDT)
Duodenal Metal Stent (duodenal stenosis)
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Stents – Plastic vs Metal
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Stents: Plastic vs Metal
Stent Patency
Knyrim: Endoscopy 1993
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Cancer - Palliation with Endoprostheses
Plastic
Metal
n [ Case Series]
597 [ 7 Series ]
209 [ Series ]
Bismuth III / IV
35% / 2%
42% / 21%
Bilateral Drainage
48%
34%
Patency
2-3 mons
3-8 mons
Cholangitis
18-33%
6 - 36%
30d-Mortality
8-43%
6 - 36%
Median Survival
2 - 6 mons
3 - 6 mons
1988 – 2000
1993 – 1998
Berr F et al: 2001
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Cancer
unilateral vs bilateral drainage
retrospective analysis (n=99, Bismuth II&III)
liver lobe
one
both
both
ERC contr
++
++
++
Drainage
++
no
++
Survival
4.8
1.5
7.4 (mons)
Chung & Haber: GI Endosc 1998
B.J., 75 ys
Bismuth IV
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Drainage: preoperatively?
PBD: preoperative bile duct drainage
No evidence of either a positive or adverse effect of preoperative
endoscopic biliary stent placement on the outcome of surgery in
patients with pancreatic cancer
Saleh MM et al: Gastrointest Endosc 2002; 56: 529-34
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Preoperative Stent in Cholestasis?
• Surgery in patients with obstructive
jaundice caused by a periampullary
(pancreas, papilla, distal bile duct) tumor
associated with higher risk of
postoperative complications than in nonjaundiced patients
• vs
• Negative effects of drainage, such as an
increase of infectious complications
– van der Gaag et al: Preoperative biliary drainage for
periampullary tumors causing obstructive jaundice; DRainage
vs. (direct) OPeration (DROP-trial). BMC Surg 2007; 7:3
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Photodynamic Therapy
→ Oxidative Stress
→ Apoptosis
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Cancer
Tumor Necrotizing Effect of PDT; 4 mm depth
section of tumor 24 days after PDT
bile duct
0
5
depth
(mm)
2
8
peritoneum
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Photodynamic Therapy of Bile Duct Carcinoma
ERC prior to PDT
Photodynamic Therapy
3 Drainages
Mr. Ferdinand S., 63 ys
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Photodynamic Therapy of Non-resectable
Bile Duct Cancer
Ortner MA et al: Gastroenterology 1998; 114: 536-42
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Phase II Study PDT
23 patients with non resectable bile duct carcinoma
Bismuth: IV = 21; III = 2
Stage: II = 10, III = 2, IV =11
day 1:
day 2-4:
Photofrin (2 mg/kg bw i.v.)
PDT 240 J/cm
Bilirubin 12 ± 5 ⇒ 2 ± 3 mg/dL
30-day mortality
4%
Median survival
341 days
Tumor/Tissue fluorescence
Ratio 1.8 at 24h, 2.2 at 48h
Pahernik S et al: 1998
Berr F et al: 2000
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Photodynamic Therapy of Bile Duct Cancers
left lobe
right lobe
phase-II study (n = 23, palliative )
local response
PDTs / patient
progression free
74%
3 (1 – 7)
5.5 mons
(3.5 – 14)
24h: 1st PDT session
72h: 2nd PDT session
E.P.
61 ys
10 days post PDT
cumulatives survival (%)
Wiedmann, Berr, Mössner et al: GI
Endoscopy 2004
Causes of death
12 mons
Progression
13
Infections
7
EV-Bleeding
2
Lung embolus
1
4.3 ys
time post diagnosis days
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Non Resectable Bile Duct Cancer
Randomised Study: PDT & Endoprosthesis vs Endoprosthesis
Percentage Survival
150
( Kaplan-Meier )
Group A
p < 0.0001
(n=20; PDT & EP)
Group B (n=19; EP only)
] Randomized
100
Group C (n=31; PDT & EP) Compassionate
50
Photofrin (6 mons)
300 mg / 2 cycles
= 3 500.- €
0
0
500
1000
1500
2000
Days
Ortner, … Berr, …. Mössner ….: Gastroenterology 2003; 125: 1355-63
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Hilar Bile Duct Cancer – Duodenal Stent
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Hilar Bile Duct Cancer – Duodenal Stent
20 patients included
10 no reintervention
10 reinterventions
2 distal stent migrations
4 stent occlusions
2 patients living
4 tumor ingrowth
2 gastroenterostomy
Schiefke, Mössner, Caca et al: GI Endoscopy 2003
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Cancer: PTCD + Drainage of Abscess
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Cancer: PTCD + Portimplantation
Hypotrophy right LL
Caca, Mössner et al: GI Endoscopy 2004
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Neoadjuvant Photodynamic Therapy
Local Downstaging prior to Surgery
Bismuth Type IIIb
ERC prior to PDT
Mr. M.U., 57 ys
3 weeks post PDT (prior to surgery)
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Photodynamic Therapy
Neoadjuvant
7 patients, 42-73 a
BDCa Bismuth 1 type II, 1 type IIIb
(T1b-3 N0-1 M0) 2 type IIIa, 3 type IV
day 1
day 2-4
Tumor/Tissue fluorescence
Ratio 1.8 at 24h, 2.2 at 48h
PhotofrinR (2 mg/kg bw i.v.)
PDT: Tu & 2cm-margin (630nm,240 J/cm)
week 5-6 resection R0 & hemihepatect 5
& Whipple 1, & LTX 1
bilioent. anastomosis - pp cure
without late strictures
follow-up 1 ½ years (11 mons – 3 ½ ys)
83% relapse free after 1 year
2 relapses (6 mons M1, liver
19 mons LN, pancreas)
Pahernik et al: 1998; Berr, Mössner et al: 2000; Wiedmann, Mössner et
al: Cancer 2003
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Cancer
Phase I/II Studies: RCT & combined CT
Therapy
n
Response
Rate
Median
Survival
(mons)
McMasters,
1997
5-FU & 45 Gy
9
PR
CR
[ 22 ]
Aretxabala,
1999
5-FU & 45 Gy
18
PR+NC 10/18
[ PD 5/18 ]
Ducreux, 1998 5-FU /
Cisplatin
25
PR 6/25 (24%) 10
Sanz5-FU/ FS /
Altamira, 1998 Carboplatin
14
PR 3/14 (22%) 5
Mezger
13
PR 1 (8%), SD
11
19
PR 3/19 (16%) 6.5
1998 Gemcitabine
Raderer 1999
Gemcitabine
6/9
3/9
[ 46% 24
mons ]
16
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Cancer
Chemotherapy: Phase II Studies 2003/4
Autor (year)
n
Drugs
Dose
(mg/m2)
Toxicities
RR
(WHO III/IV°) % (%)
Survival
mons
Kim 2003
42
Xeloda/
Cisplatin
2.000-2,500
60
Neutropenia 20
Vomiting 12
21
9,1
Xeloda / Gemcitabine
1.300
800
Neutropenia 10
32
./.
Knox 2003
Patt 2004
26
Xeloda
2.000
Thrombopenia 8
19
9.0
Knox 2004
27
Gemcitabine / 5-FU
900/200
Port infection 19
Leukopenia 7
33
5.3
Hsu 2004
30
Gemcitabine / 5-FU /
Leucovorine
800/2.000/
300
Infections 31
Leukopenia 14
21
4.7
Kornek 2004
25
26
Gemcitabine / MMC
Xeloda / MMC
2.000/8
2.000/8
Leukopenia 17
Leukopenia
20
31
6.7
9.3
André 2004
33
23
Oxaliplatin /
Gemcitabine
100 /
1.000
Neutropenia 14
Thrombopenia 0
Anemia 9
Nausea, Vomiting 5
36
22
15.4
7.6
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Palliative Chemotherapy in Bile Duct Cancer
• Median survival 6 mons
• Bendamustine safely administered in pats with
hilar bile duct cancer and impaired liver function
• A potential role of bendamustine in combination
therapies for bile duct cancer will be a subject
of further trials
• Schoppmeyer K, Kreth F, Wiedmann M, Mössner J,
Preiss R, Caca K: A pilot study of bendamustine in
advanced bile duct cancer. Anticancer Drugs 2007; 18:
697-702
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Endoscopic-Interventional Therapy of Bile Duct Carcinoma
¾
¾
¾
¾
¾
Bile Duct Drainage (endoscopical / percutaneous)
¾ Standard therapy
¾ Minor prolongation of survival ( about 3 mons)
¾ Risk of bacterial cholangitis / sepsis
¾ Regular control ( CRP, WBC, Sono ) / change of drainage
Brachytherapy with 199-Iridium
¾ Low risk, no documented prolongation of survival
Photodynamic therapy with Photofrin for local tumor ablation
¾ Tumor selectiv
¾ Low risk
¾ Efficient until 4 mm depth
¾ Suitable for palliation of cholestasis
¾ Prolongation of survival probable
Combination therapy (PDT & RCT)
¾ Prospectiv studies needed
Stents for duodenal stenosis due to tumor (up to 20 %)
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Bile Duct Cancer - Summary
Diagnosis
Screen
Stenosis
Carcinoma
GGT-Elevation ⇒ MRC, ERC:
PSC, Caroli
⇒ Fe3+MRT, ductal US:
⇒ Biopsy, Cytology, CA 19-9, [PET]:
⇒ Staging (Bismuth, TNM-Class.):
Stenosis ?
Tumor ?
Dignity ?
Resectability ?
Therapy
Curative Resection (en bloc)
Neoadjuvant Rx & Resection
or LTX
Palliative Therapy
(Drainages, PDT, RCT, D-Stent)
Bismuth Type 1,2,3b; Tx, N 0-1, M 0
Bismuth Type 3a,(4); Tx, N 0-1, M 0
(in studies)
Bismuth Type 4; Tx N3 or M1
Medizinische Klinik & Poliklinik II
Universität Leipzig
JM 2008
Partners in Cooperation
Universitätsklinikum Leipzig
Division of Medicine II
Division of Surgery II
F. Berr, now in Salzburg
J. Hauss
K. Caca, now in Ludwigsburg
S. Jonas
U. Halm
K. Kohlhaw, now in Borna
M. Wiedmann, now in Berlin
P. Lamesch, now in Stuttgart
H. Witzigmann, now in Dresden
Division of Diagnostic Radiology
Division of Nuclear Medicine
W. Schneider
R. Kluge
F. Schmidt
Division of Pathology
Charité, Humboldt Univ. Berlin
A. Tannapfel, now in Bochum
M. E. A. Ortner, now in Lausanne
C. Wittekind

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