Transcript Diapositiva 1 - Epatoncologia.it

Intermediate stage HCC treatment options:
DEB-TACE
TACE: an evolving technique toward improving
the treatment of HCC
From
Non-selective
treatment of the
entire liver
parenchyma
From
“Homemade”
drug-in-oil
emulsions and
embolic agents
(“conventional”
TACE)
To
Selective
treatment
(segmental
approaches with
microcatheters)
To
Drug-eluting bead
(calibrated
embolic
microsphere)
Lencioni R. Personal communication.
Hong K, et al. Clin Cancer Res. 2006;12:2563-7.
www.biocompatibles.com.
Advances in TACE delivery: DC Bead
DC Bead
 Embolic microsphere developed for TACE
 Actively sequesters doxorubicin hydrochloride
from solution and releases it in a controlled
and sustained fashion
www.biocompatibles.com
Mechanism of Loading the Drug Eluting Beads
with Doxorubicin
The doxorubicin is loaded and eluted by “reversible
ionic exchange mechanism”
Hydrated Beads
Loaded Beads
SO3
SO3
Dex
SO3
SO3
SO3
Dex
SO3
SO3
SO3
SO3
SO3
SO3
SO3
SO3
SO3
Dex
Dex
SO3
Dex
Dex
SO3
SO3 SO3
Dex Dex
SO3
Dex
SO3
SO3
Dex
SO3
SO3
SO3
Dex
Hydration shell associated
with PVA and ionic groups
Dex
SO3
Bulk (non-bound)
water
SO3
Dex
Interaction of doxorubicin with
SO3 groups displaces water
from the hydration shells
www.biocompatibles.com
Drug Eluting Bead Drug Distribution
Schematic showing the relative drug distribution for standard arterial
chemotherapy vs conventional TACE vs PRECISION TACE with DEB
Chemotherapy
TACE
Doxorubicin
Arterial
Injection
DEB, drug-eluting beads; TACE, transarterial chemoembolization.
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
Drug-eluting
Bead
1. Doxorubicin
+
Iodised Oil
2. Embolization
Doxorubicin
Drug-eluting
Bead
DEB-TACE vs. conventional TACE:
Pharmacokinetics
 Serum doxorubicin levels at different time points in patients receiving TACE with
DC-bead (n=13) or conventional TACE (n=5)1
800
600
400
200
0
DEB-TACE
1000
Doxorubicin at serum (ng/mL)
Doxorubicin at serum (ng/mL)
1000
Conventional TACE
800
600
400
200
0
DC, doxorubicin-capable (doxorubicin loaded); DEB, drug-eluting beads; TACE, transarterial chemoembolization.
1. Varela M, et al. J Hepatol 2007;46:47481.
Chemoembolization of HCC with Drug-Eluting
Beads DEB-TACE
RECIST
EASL criteria
CR
0 (0%)
7 (25.9%)
PR
12 (44.4%)
11 (40.7%)
SD
7 (25.9%)
1 (3.7%)
P
5 (18.5%)
5 (18.5%)
NA
3 (11.1%)
3 (11.1%)
Total
27
27
CR, complete response; PR, partial response, SD, stable
disease; P, progressive disease; NA, not available; OR objective
response (CR+PR) of 66.6% according to EASL criteria
according to an intention-to-treat perspective.
Varela M et al. J Hepatol. 2007; 46(3): 474-81
Systemic Exposure (Cmax)
PRECISION TACE with DEB vs Conventional TACE
CMAX ng/mL
2000
1500
PRECISION TACE
Conventional TACE
1000
500
0
Varela et al
[150 mg]
Poon et al
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
Varela et al
Raoul et al
Systemic Exposure (AUC)
PRECISION TACE with DEB vs Conventional TACE
AUC (ng/mixmin)
2000
1500
PRECISION TACE
Conventional TACE
1000
500
0
Varela et al
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
Varela et al
Trial Design
Randomized phase II study to assess the safety and efficacy of chemoembolization with DEB and
doxorubicin (PRECISION TACE with DEB) in an international, multi-center trial
Primary endpoints: 6 month tumor RR
Measured by MRI, response criteria EASL (necrosis)
Secondary endpoints: safety, response (RECIST), local tumor response (EASL), AFP, time to discharge,
cardiotoxicity, QoL
Eligible Patients
• HCC not suitable for curative treatments
• Patients with multinodular HCC without
• Vascular invasion
• Extrahepatic spread
• Recurrence following resection or
percutaneous ablation
• Performance status ECOG 0 and 1
• Patients with preserved liver function (Child
Pugh A and B)
• Patients on the transplant list who may not
receive a transplant within 6 months
R
A
N
D
O
M
I
Z
A
T
I
O
N
n=100
n=100
DEB
cTACE
DEB=drug eluting beads (chemoembolization with DEB and doxorubicin); cTACE=conventional
transarterial chemoembolization.
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
Exclusion Criteria (Main)
Exclusion Criteria
Patients with another primary tumor
Patients previously with chemo- or radiotherapy
Advanced liver disease
 Bilirubin levels >3 mg/dL
Advanced tumorial disease
 Vascular invasion or extrahepatic spread
 Diffuse HCC defined as >50% tumor involvement of the whole liver
Any contraindication for doxorubicin administration
Any contraindication for hepatic embolization procedures
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
Protocol Design and Treatment Schedule
Patient Population
Visit 1
Baseline Assessment/Randomization
Visit 2
1st Chemoembolization Treatment
Visit 3
1 Month MRI
Visit 4
2nd
Chemoembolization Treatment
Visit 5
3 Month MRI
Visit 6
3rd
Chemoembolization Treatment
Visit 7
6 Month MRI & Study Completion
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
212 Patients Enrolled
Vienna
Athens
Mainz
Lille
Frankfurt
Lyon
Zurich
Geneva
Paris – Villejuif (HPB)
Paris – HPS
Nice
Hannover
Paris – Villejuif (GR)
Lausanne
Paris – Clichy
Damstadt
0
5
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
10
15
20
25
30
Patient Demographics
Characteristics
DEB (n=102)
cTACE (n=110)
Sex (Male/Female)
67.0 years (±9.2)
67.3 years (±8.8)
Age Mean (±sd)
88/14
97/13
Etiology (HepC/HepB/Alcohol alone/Other and
Mixed
20/14/41/27
12/13/52/33
Okuda (i/II)
88/14
104/6
BCLC (A/B/C)*
26/76/0
29/81/0
No. Lesions Median (interquartile range)
2 (1-4)
2 (1-4)
Sum Longest Diameter Mean (±sd)
9.4cm (±6.15)
9.0cm (±6.00)
Liver Involvement Mean (±sd)
16.9% (±15.0)
16.5% (±14.2)
* BCLC Classification according to tumor stage (Llovet et al Lancet 2003).
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
Baseline Stratification:
Four Prognostic Factors
DEB (n=102)
Characteristics
cTACE (n=110)
n
%
n
%
A
83
81.4
91
82.7
B
19
18.6
19
17.3
0
78
76.5
81
73.6
1
24
23.5
29
26.4
No
54
52.9
63
57.3
Yes
48
47.1
47
42.7
No
91
89.2
97
88.2
Yes
11
10.8
13
11.8
Child Pugh
ECOG
Bilobar
Recurrent Disease
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
Analyzed Population
212 Patients
Randomized
DEB
n=102
cTACE
n=108
9
T1
n=93
2
T1
n=108
Analyzed Population
Reason
DEB
cTACE
Surgical Treatment
1
1
Patient or Physician Decision
3
Progression
1
Post-Consent Ineligibility
4
1
Total
9
2
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
Product, Dose and Technique Guidelines
Precision TACE with DEB
2 x 2 mL vials of DEB (total 4 mL) loaded at 37.5 mg/mL for total doxorubicin dose
of 150 mg
1 vial of 300-500 μm followed by 1 vial of 500-700 μm
cTACE
Doxorubicin dose of 50-75 mg/m2 to maximum of 150 mg
Physician preference for embolic
Technique for both groups
Unifocal tumors treated with selective segmental chemoembolization
Microcatheter could be used
Bilobar disease: both lobes treated within a 3-week period
Embolization to stasis in 2nd or 3rd order branches
DEB group: additional bland embolic could be used
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
Number of Treatments
Percentage of Patients in the Analyzed Population Who
Received 1, 2 or 3 Chemoembolization Treatments
DEB
cTACE
100
100 100
80
82.8 81.5
60
61.3
40
56.5
20
0
1
2
No of Treatments
Note: 8 DEB patients, and 5 cTACE patients received 2 sessions at T1
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
3
Technical
success
DEB 97%
cTACE 99%
Doxorubicin Dose Per Treatment
Mean Dose of Doxorubicin at
Embolization Procedure
DEB (mg)
n=93
cTACE (mg)
n=108
Treatment 1
142.1
102.9
Treatment 2
116.33
91.6
Treatment 3
96.8
68.4
160
140
120
100
80
DEB
60
cTACE
40
20
0
Treatment 1
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
Treatment 2
Treatment 3
DEB-TACE vs. conventional TACE:
Tumour response
PRECISION V trial
70
60
Response (%)
50
40
59
(63%)
48
(52%)
30
20
DEB-TACE
56
(52%)
DCR
47
(44%)
CR
cTACE
DCR
25
(27%)
24
(22%)
10
0
DEB-TACE
cTACE, conventional TACE.
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
OR
cTACE
OR
CR
6-Month Response in Less
Advanced Patients
Response (%)
70
60
61
50
50
40
30
20
10
0
63
56
46
48
67
61
58
54
54
48
51
46
35
27
21
Child Pugh B
25
25
ECOG 1
DEB cTACE
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
28
52
45
27
21
Unilobar
Disease Control
Objective Response
Complete Response
Not Recurrent
6-Month Response in More
Advanced Patients
DEB demonstrated statistically significant
advantage in advanced patients
Response (%)
Objective Response (P=.038) and Disease Control (P=.026)
70
60
P≤.05
63
63
59
50
40
49
44
10
0
21
14
16
Child Pugh B
ECOG 1
DEB cTACE
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
54
49
32
29
32
25
55
40
37
30
20
73
31
27
17
13
Bilobar
Disease Control
Objective Response
Complete Response
15
Recurrent
Disease
DEB-TACE: Overall and progression-free survival
in a Phase II trial
Survival probability (%)
100
Overall survival (median=26 mo.)
Progression-free survival (median=20 mo.)
80
60
40
• N=20 (total)
• Embolization repeated
up to twice if <90%
necrosis on MRI
20
0
0
10
20
Time (months)
DEB, drug-eluting beads; TACE, transarterial chemoembolization.
1. Reyes DK, et al. Cancer J 2009; 15:526532.
30
40
DEB-TACE vs. bland embolization: Recurrence
rates
1.0
Patients embolized at set time intervals (2 months),
with a maximum of 3 embolizations
Recurrence rate
0.8
DEB-TACE (n=41)
0.6
P < 0.0001
Bland embolization (n=43)
0.4
0.2
0
1
3
DEB, drug-eluting beads; TACE, transarterial chemoembolization.
1. Malagari K et al. Cardiovasc Intervent Radiol 2010; 33:541-51.
6
Time (months)
9
12
Incidence of New Lesions at 6 Months
The probability of new lesions forming was the same in both study
arms
DEB (n=93)
cTACE (n=108)
New Lesions at 6m
n
%
N
%
New Lesions
20
21.5
20
18.5
No New Lesions
68
73.1
78
72.2
Missing
5
5.4
10
9.3
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
Time-to-Progression: All Lesions
Probability of No Progression
1.0
×
0.8
×
×
×
×
×
××
DEB: Median 217 days ± 7.84
CEL: Median 196 days ± 14.92
× × ×
× ×
0.6
×
×
0.4
×
×
×
×
×
0.2
0
0
50
100
150
200
Days
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
250
300
350
Safety-Related Events per 100 Treatments
Related* Grade 3 and 4 AEs
Related* AEs
100
20
80
79
60
40
10
58
20
5
0
0
DEB
cTACE
17
15
13
DEB
* Related is investigator-assessed “definitely or probably related to treatment”
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
cTACE
Doxorubicin-Related Side Effects
Events per 100 Patients
40
DEB cTACE
35
Alopecia
Mucosis
Marrow Suppression
Skin Discoloration
30
25
P=.0001
20
15
10
5
0
DEB
cTACE
Adapted from Lencioni R et al. Poster Presented at ASCO Annual Meeting; May 29-June 2, 2009; Orlando, FL.
Safety-Serious Adverse Events (SAEs)
SAEs
Related* SAEs
Events per 100 Treatments
25
8
7
20
22
22
5
15
7
6
6
4
10
3
2
5
1
0
0
DEB
cTACE
DEB
* Related is investigator-assessed “definitely or probably related to treatment”
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
cTACE
Gastrointestinal and Liver Serious Adverse
Events (SAEs)
Liver Toxicity
Pancreatic &
Gallbladder Pathology
GI Bleeding
Abscess and infection
GI Ulcer
Ascites
Hospitalization for TIPS
Intratumoral Bleeding
DEB
cTACE
Other
0
2
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
4
6
8
10
Serious Adverse Events Advanced Disease
DEB
cTACE
SAE Event Rates*
40
30
32
32
26
20
31
24
31
27
19
10
0
Child Pugh B
ECOG 1
• Per 100 patients, events within 30 days of treatment.
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
Bilobar Disease Recurrent Disease
Liver Toxicity: AST & ALT Levels
DEB
cTace
AST
1: T1 Pre emb (LOCF)
4: T2 Pre emb
7: T3 Pre emb
2: T1 Pre discharge
5: T2 Pre discharge
8: T3 Pre discharge
AST Units/L
250
200
150
P=.001
100
50
0
12
3
4 5
6
7 8
9
Timepoint
ALT
ALT Units/L
200
150
P=.001
100
50
0
12
3
4 5
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
6
7 8
9
Timepoint
3: 1 month
6: 3 months
9: 6 months
Deaths
Causes of Death
Deaths Due to Disease Progression
3
2
1
0
DEB
cTACE
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
DEB
cTACE
Progression
1
3
Cardiac
2
1
GI Bleed
1
Infection
1
2
Liver Failure
2
2
Unknown
1
Total
8
8
DEB-TACE vs. conventional TACE: Tolerability
PRECISION V trial
DEB-TACE associated with improved tolerability vs conventional TACE:1
• Significant reduction in serious liver toxicity (p < 0.001)
• Significantly lower rates of doxorubicin-related side effects (p = 0.0001)
Adverse effects of systemic doxorubicin
Event
DEB-TACE
(n = 93)
Events, n
Conventional TACE
(n = 108)
Patients, n (%)
Events, n
Patients, n (%)
22 (20.4)
Alopecia
1
1
(1.1)
23
Marrow
suppression
5
5
(5.4)
8
6
(5.6)
Mucositis
4
4
(4.3)
7
6
(5.6)
Skin
discolouration
2
2
(1.2)
2
2
(1.9)
DEB, drug-eluting beads; TACE, transarterial chemoembolization.
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010;33:4152.
Summary
Overall, compared to cTACE, DEB has
Greater objective response (P=.11)
Lower related SAEs and AEs
Compared to cTACE, DEB has a significant (P<.05) advantage in
Objective response in more advanced patients (P=.038)
Disease control in more advanced patients (P=.026)
Compared to cTACE, DEB has a highly significant
advantage in the (P<.01)
Reduction of doxorubicin associated side effects
in all patients (P=.0001)
Reduction of liver toxicity in all patients
(AST: P=.001; ALT P=.0001)
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
Conclusion
PRECISION TACE with DEB is safe, efficacious and reproducible
There is a significant advantage of PRECISION TACE with DEB
in more advanced patients – those with more compromised
liver function, poorer performance status, bilobar disease and
recurrent disease – greater response, greater disease control
and improved safety
Currently AASLD guidelines do not recommend
chemoemboliztion for Child B and ECOG 1 patients. The
PRECISION V data show that these patients can now be
safely treated with PRECISION TACE with DEB
Combination of PRECISION TACE with DEB and Sorafenib is
currently being investigated with the aim of further improving the
long-term outcomes of intermediate-stage HCC patients
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52.
DEB-TACE: Summary
DEB-TACE is a valuable alternative to conventional TACE,
providing:
 Improved pharmacokinetics with reduced systemic exposure to
doxorubicin1
 Reduced liver toxicity2,3
 Fewer doxorubicin-related side effects2
 Improved response rates in patients with negative prognostic
factors, including:2
– Child-Pugh B status
– ECOG PS 1
– Bilobar disease
– Recurrent disease
DEB, drug-eluting beads; ECOG PS, Eastern Cooperative Oncology Group performance status; TACE, transarterial chemoembolization.
1. Varela M, et al. J Hepatol 2007;46:474-481; 2. Lencioni R, et al. ASCO 2009, abstr 4523; 3. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
DEB-TACE vs. conventional TACE:
Liver toxicity (ALT-AST levels)
PRECISION V trial
AST (units/L)
p=0.001
200
150
100
50
0
200
ALT (units/L)
Mean ratio pre-discharge/pre-TACE
250
p<0.001
DEB-TACE
Conventional
TACE
150
100
50
0
1st
2nd
3rd
Chemoembolization procedure
DEB, drug-eluting beads; TACE, transarterial chemoembolization.
1. Lencioni R, et al. ASCO 2009; abstr. 4523. Poster discussion available at: www.asco.org; 2. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.