Intermediate stage HCC treatment options : DEB-TACE
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Transcript of Intermediate stage HCC treatment options : DEB-TACE
Intermediate stage HCC treatment options: DEB-TACE
Lencioni R. Personal communication. Hong K, et al. Clin Cancer Res. 2006;12:2563-7.
www.biocompatibles.com.
FromNon-selective
treatment of the entire liver
parenchyma
ToSelective treatment
(segmentalapproaches with microcatheters)
From“Homemade”
drug-in-oil emulsions and embolic agents (“conventional”
TACE)
ToDrug-eluting bead
(calibrated embolic
microsphere)
TACE: an evolving technique toward improving the treatment of HCC
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
Dex
Dex Dex
Dex
Dex
Dex
Dex
Dex Dex
Dex
Dex
Dex
Dex
SO3
SO3
SO3
SO3
SO3SO3SO3
SO3
SO3
SO3
SO3
SO3
SO3
SO3
SO3
SO3
SO3
SO3SO3
SO3
SO3
SO3
SO3
SO3
SO3
SO3
The doxorubicin is loaded and eluted by “reversible ionic exchange mechanism”
Hydrated Beads Loaded Beads
Hydration shell associated with PVA and ionic groups
Bulk (non-bound) water
Interaction of doxorubicin with SO3 groups displaces water
from the hydration shells
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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 Drug-elutingBead
DoxorubicinArterial
Injection
1. Doxorubicin+
Iodised Oil2. Embolization
DoxorubicinDrug-eluting
Bead
DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
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
DEB-TACE Conventional TACE
Baseline
Dox
orub
icin
at
seru
m (
ng/m
L)
1000
5 min
7 d20 m
in
40 min
60 min
2 h6 h
24 h48 h
800
600
400
200
0Baseline
Dox
orub
icin
at
seru
m (
ng/m
L)
1000
5 min
7 d20 m
in
40 min
60 min
2 h6 h
24 h48 h
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;46:47481.
Chemoembolization of HCC with Drug-Eluting Beads DEB-TACE
Varela M et al. J Hepatol. 2007; 46(3): 474-81
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.
Systemic Exposure (Cmax)
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
Varela et al [150 mg]Poon et al
Varela et al Raoul et al0
500
1000
1500
2000PRECISION TACE
Conventional TACE
CM
AX
ng
/mL
PRECISION TACE with DEB vs Conventional TACE
Systemic Exposure (AUC)
Varela et al Varela et al0
500
1000
1500
2000PRECISION TACE
Conventional TACE
AU
C (
ng
/mix
min
)
PRECISION TACE with DEB vs Conventional TACE
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
Trial Design
DEB=drug eluting beads (chemoembolization with DEB and doxorubicin); cTACE=conventional transarterial chemoembolization.
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 trialPrimary 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
DEB
cTACE
n=100
n=100
RANDOMIZATION
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
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; 33:4152.
Protocol Design and Treatment Schedule
Patient Population
Visit 1Baseline Assessment/Randomization
Visit 21st Chemoembolization Treatment
Visit 31 Month MRI
Visit 42nd Chemoembolization Treatment
Visit 53 Month MRI
Visit 63rd Chemoembolization Treatment
Visit 76 Month MRI & Study Completion
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
212 Patients Enrolled
ViennaAthensMainz
LilleFrankfurt
LyonZurich
GenevaParis – Villejuif (HPB)
Paris – HPSNice
Hannover
LausanneParis – Villejuif (GR)
Paris – ClichyDamstadt
0 5 10 15 20 25 301. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
Patient Demographics
* BCLC Classification according to tumor stage (Llovet et al Lancet 2003).
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)
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
Baseline Stratification: Four Prognostic Factors
DEB (n=102) cTACE (n=110)
Characteristics n % n %
Child PughA 83 81.4 91 82.7
B 19 18.6 19 17.3
ECOG0 78 76.5 81 73.6
1 24 23.5 29 26.4
BilobarNo 54 52.9 63 57.3
Yes 48 47.1 47 42.7
Recurrent DiseaseNo 91 89.2 97 88.2
Yes 11 10.8 13 11.8
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
Analyzed Population
Reason DEB cTACE
Surgical Treatment 1 1
Patient or Physician Decision 3
Progression 1
Post-Consent Ineligibility 4 1
Total 9 2
T1n=93
T1n=108Analyzed Population
DEBn=102
cTACEn=108
212 PatientsRandomized
9 2
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
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; 33:4152.
Number of Treatments
Note: 8 DEB patients, and 5 cTACE patients received 2 sessions at T1
Percentage of Patients in the Analyzed Population Who Received 1, 2 or 3 Chemoembolization Treatments
Technical success
DEB 97% cTACE 99%
No of Treatments
100
82.8
61.3
100
81.5
56.5
0
20
40
60
80
100
1 2 3
DEB
cTACE
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
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
60
40
20
0Treatment 1 Treatment 2 Treatment 3
DEB
cTACE
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
DEB-TACE vs. conventional TACE: Tumour response
cTACE, conventional TACE.1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
OR
DEB-TACE
cTACE
CR
DCR
OR
CR
DCR
Res
pons
e (%
)
70
60
50
40
30
20
10
0DEB-TACE cTACE
59(63%)
48(52%)
25(27%)
56(52%)
47(44%)
24(22%)
PRECISION V trial
6-Month Response in Less Advanced Patients
0
20
70
50
40
60
10
30
Child Pugh B ECOG 1
Response (%)
Unilobar Not Recurrent
61
50
27
56
21
46 48
63
48
58
25
35
54
67
54
46
28 27
51
61
5245
2125
DEB cTACE
Complete ResponseObjective ResponseDisease Control
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
6-Month Response in More Advanced Patients
0
20
70
50
40
60
10
30
Child Pugh B ECOG 1
Res
po
nse
(%
)
P≤.05
Bilobar RecurrentDisease
DEB demonstrated statistically significantadvantage in advanced patients
Objective Response (P=.038) and Disease Control (P=.026)
63
44
25
16
21
3237
63
3229
14 17
49
59
49
40
13
27
55
73
54
31
15
DEB cTACE
Complete ResponseObjective ResponseDisease Control
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
DEB-TACE: Overall and progression-free survival in a Phase II trial
DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Reyes DK, et al. Cancer J 2009; 15:526532.
Time (months)
Sur
viva
l pro
babi
lity
(%)
100
40
80
60
40
20
00 10 20 30
Overall survival (median=26 mo.)
Progression-free survival (median=20 mo.)
• N=20 (total)
• Embolization repeated up to twice if <90% necrosis on MRI
DEB-TACE vs. bland embolization: Recurrence rates
Time (months)
Patients embolized at set time intervals (2 months), with a maximum of 3 embolizations
Rec
urre
nce
rate
1.0
1
0.8
0.6
0.4
0.2
0123 6 9
DEB-TACE (n=41)
Bland embolization (n=43) P < 0.0001
DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Malagari K et al. Cardiovasc Intervent Radiol 2010; 33:541-51.
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; 33:4152.
Time-to-Progression: All LesionsP
rob
abil
ity
of
No
Pro
gre
ssio
n
0
0.2
0.4
0.6
0.8
1.0
0 50 100 150 200 250 300 350
Days
CEL: Median 196 days ± 14.92
DEB: Median 217 days ± 7.84×
×
××
×
××
× ×
× ×
×××
×
×××
××
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
Safety-Related Events per 100 Treatments
* Related is investigator-assessed “definitely or probably related to treatment”
DEB cTACE
0
10
20
5
15
13
17
Related* Grade 3 and 4 AEsRelated* AEs
DEB cTACE0
40
80
20
60
58
79
100
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
Doxorubicin-Related Side Effects
Adapted from Lencioni R et al. Poster Presented at ASCO Annual Meeting; May 29-June 2, 2009; Orlando, FL.
0
10
35
40
25
20
30
5
15
DEB cTACE
Ev
ents
pe
r 1
00 P
atie
nts
P=.0001
DEB cTACEAlopecia
Skin DiscolorationMarrow SuppressionMucosis
Safety-Serious Adverse Events (SAEs)
* Related is investigator-assessed “definitely or probably related to treatment”
DEB cTACE
SAEs
0
5
20
25
15
10
Eve
nts
per
100
Tre
atm
ents
22 22
DEB cTACE
Related* SAEs
0
2
7
8
5
4
6
1
3
6
7
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
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
Other
0 2 4 6 8 10
DEBcTACE
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
Serious Adverse Events Advanced Disease
• Per 100 patients, events within 30 days of treatment.
ECOG 1
DEB
0
20
30
40
cTACE
10
Bilobar Disease Recurrent Disease
SA
E E
ven
t R
ates
*
Child Pugh B
19
32
26
32
24
31
27
31
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
Liver Toxicity: AST & ALT Levels
1: T1 Pre emb (LOCF) 2: T1 Pre discharge 3: 1 month4: T2 Pre emb 5: T2 Pre discharge 6: 3 months7: T3 Pre emb 8: T3 Pre discharge 9: 6 months
P=.001
Timepoint
cTace
DEB
AST
250
200
150
100
50
0
AS
T U
nit
s/L
1 2 3 4 5 6 7 8 9ALT
P=.001
Timepoint
200
150
100
50
0
AL
T U
nit
s/L
1 2 3 4 5 6 7 8 9
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
Deaths
Causes of Death DEB cTACE
Progression 1 3
Cardiac 2 1
GI Bleed 1
Infection 1 2
Liver Failure 2 2
Unknown 1
Total 8 8
DEB cTACE
Deaths Due to Disease Progression
0
1
2
3
1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.
DEB-TACE vs. conventional TACE: Tolerability
Adverse effects of systemic doxorubicin
Event DEB-TACE(n = 93)
Conventional TACE(n = 108)
Events, n Patients, n (%) Events, n Patients, n (%)
Alopecia 1 1 (1.1) 23 22 (20.4)
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)
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)
DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Lammer J, et al. Cardiovasc Intervent Radiol 2010;33:4152.
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 significantadvantage 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; 33:4152.
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; 33:4152.
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; 33:4152.
DEB-TACE vs. conventional TACE: Liver toxicity (ALT-AST levels)
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; 33:4152.
Chemoembolization procedure1st 2nd 3rd
AS
T (
units
/L)
ALT
(un
its/L
)
DEB-TACEConventionalTACE
250
0
200
150
100
50
p=0.001
200
0
150
100
50
p<0.001
Mea
n ra
tio p
re-d
isch
arge
/pre
-TA
CE
PRECISION V trial