Upload
alexina-adams
View
218
Download
1
Embed Size (px)
Citation preview
1
JF Geschwind, MDProfessor Radiology, Surgery, and Oncology
Director, Vascular and Interventional Radiology
Johns Hopkins University School of Medicine
Baltimore, Maryland
Drug-Eluting Beads Chemoembolization (DEBDOX) for Hepatocellular Carcinoma in
2011:The Case for a Treatment Standard
2
1. Why Drug-elutingTechnology?
Clear Rationale:
1. Maximize drug delivery
2. Consistent (scientifically reproducible)
3. Long lasting effect/slow release (sustained)
4. Tumor effect vs. systemic side effects
WE HAVE COME A LONG WAY!
3
PEI/RFA Sorafenib
Stage 0PS 0, Child–Pugh A
Very early stage (0)
1 HCC <2cmCarcinoma in situ
Early stage (A)1 HCC or 3 nodules
<3cm, PST 0
Advanced stage (C)
Portal invasion, N1, M1, PST 1–2
End stage (D)
Liver transplantation TACEResection Symptomatictreatment Curative treatments Randomised controlled trials
Associated diseases
YesNo
3 nodules ≤3cm
Increased
Normal
1 HCC
Portal pressure/bilirubin
Llovet JM, et al. J Natl Cancer Inst 2008;100:698–711
Stage DPS >2, Child–Pugh C
HCC
Intermediate stage (B)Multinodular,
PST 0
Stage A–CPS 0–2, Child–Pugh A–B
BCLC staging system and treatment strategy
HCC = hepatocellular carcinoma; BCLC = Barcelona Clinic Liver CancerPEI = percutaneous ethanol injection; RFA = radiofrequency ablationTACE = transarterial chemoembolisation; PST = performance status
4
Chemoembolization of Hepatocellular Carcinoma With Drug-Eluting Beads: Efficacy and Doxorubicin Pharmacokinetics
27 patients with Child-Pugh A
Response rate assessed by CT at 6 months
Response rate: 75%
1- and 2-year survival: 92% and 89% (median follow-up of 28 months)
Do
xoru
bic
in a
t se
rum
, n
g/m
L
Time Post-Procedure
Do
xoru
bic
in a
t se
rum
, n
g/m
LTime Post-Procedure
baseline
5 min20 min
40 min
60 min
2 h 6 h 24 h48 h
7 d
1000
800
600
400
200
0
baseline
5 min20 min
40 min
60 min
2 h 6 h 24 h48 h
7 d
1000
800
600
400
200
0
DEB-TACE
Conventional TACE
DEBDOX: DC Bead®, Drug-Eluting Bead doxorubicinVarela M et al. J Hepatology. 2006; 46(3):474-481.
5
Single Center Phase II Trial of DEBDOX in Patients with Unresectable HCC
Variable Value
Number patients enrolled 20
Mean age, years (range) 64 (41-85)
Sex (M/F) 12/8
Child-Pugh (A/B/C) 15/5/0
BCLC (B/C) 8/12
ECOG (0/1/2) 9/10/1
Hepatitis B/C/other 5/8/7
Mean tumor size in cm (range) 6.9 (1.9-16.2)
Number Tumors (1,1+, Multifocal)
10/6/4
Portal vein thrombosis (Y/N) 4/16
AFP (ng/ml) 1215Reyes D et al. Cancer J. 2009
6
Kaplan-Meier Survival Curves
Time Months403020100
100
80
60
40
20
0
Sur
viva
l Pro
babi
lity
%
OSPFS
Reyes D et al. Cancer J. 2009
7
PRECISION V: Overall 6-month Tumor Response Rates
p = 0.11
Disease Control = Objective Response + Stable Disease Objective Response = Complete Response + Partial Response
8
6-month Response in More Advanced Patients
DC Bead® demonstrated statistically significant advantage in advanced patientsObjective Response (p=0.038) and Disease Control (p=0.026)
P < 0.05
9
p=0.012*
Inci
den
ce o
f d
oxo
rub
icin
-rel
ated
AE
s (%
)
35
30
25
20
15
10
5
0 DC Bead® cTACE
Alopecia
Marrow suppression
Mucositis
Skin discoloration
DC Bead® cTACE
PRECISION V trial1: DC Bead® was associated with a significantly lower incidence of doxorubicin-related AEs than cTACE
AE = adverse event1. Lammer J, et al. Cardiovasc Intervent Radiol 2010;44:41–52
2. http://www.biocompatibles.com/media/press-releases/2009/06-08-2009.aspx
*p=0.0001 for analysis with assumption of independence of events
DC Bead® is approved in 40 countries worldwide, including the
USA (as LC Bead™) and Europe2
10
Prospective Randomized Comparison of Chemoembolization with Doxorubicin-Eluting Beads and Bland Embolization with Bead Block for Hepatocellular Carcinoma
• Evaluate the added role of a chemotherapeutic in TACE of intermediate-stage HCC
• Group A (n = 41) DEBDOX• Group B (n = 43) bland embolization• EASL criteria and AFP
• At 6 month:DEBDOX CR 27% PR 46%Bland embo CR 14% PR 42%
• Tumor Recurrence:Bland embolization >> DEBDOX (78% vs. 46% at 12 months)
• TTP: DEBDOX >>Bland embolization 42 +/- 9.5 vs. 36 +/- 9.0 weeks, p = 0.008
Malagari et al, Cardiovasc Intervent Radiol. 2009 Nov 24
11
Clinical EvidenceInvestigator Level of
evidenceNumber patients
CP score CR and PR Survival *
Varela (2007) 3iiDiii 27 A 75% (EASL) 2YR 89%
Geschwind (2009) 3iiiDiii 20 A(15)/B(5) 89% (RECIST)
95% (EASL)
26 months
Poon (2007) 3iiDiii 35 A 50% (RECIST)
70% (EASL)
N/A
Grosso (2008) 3iiiDiii 50 A(46)/B (4) 74.8 % (EASL) N/A
Malagari (2008) 3iiDiii 71 A (27)/B (44) 80.6 % (EASL) 2YR 91%
Forner (2008) 27 A 50% (RECIST) N/A
Lammer (2008) 3iiDiii 30 A (26)/B (4) 40% (RECIST)
44% (EASL)
N/A
Lencioni-PRECISION V (2010)
1iiDiii 212 (102 DEB)
A (77)/B (16) 52% (RECIST) 63% (EASL)
N/A
*Survival data on DEBDOX are restricted to less than 4 years and longer term follow-up results will be published soon.**DEB vs TACE: p=0.11. DEB advantage for CP B/ECOG 1/bilobar or recurrence: p= 0.038. Fewer dox side effects: p=0.0001
12
Conclusions
DEBDOX: Proven Rationale Extension of cTACE Excellent PK profile Minimal toxicities
Efficacy: Tumor response 75-85% EASL Survival: ~26 months BCLC B-C
13
2. How? Technical Considerations: Towards a Standardized Protocol
Drug delivery not embolotherapy!Drug delivery not embolotherapy!
1. Choice of particle size2. Choice of drug: doxorubicin vs. irinotecan3. Catheter placement4. Actual delivery (how? Contrast or not?)5. End point (?)
15
Distribution of iron oxide-containing Embosphere particles after transcatheter arterial embolization in an animal model of liver cancer: evaluation with MR imaging and implication for therapy.Lee KH, Liapi E, Vossen JA, Buijs M, Ventura VP, Georgiades C, Hong K, Kamel I, Torbenson MS, Geschwind JF. J Vasc Interv Radiol. 2008 Oct;19(10):1490-6.
IA Therapy for Vx-2 Liver Tumor:Iron-oxide Labeled Microspheres 300-500µm
17
Drug-Eluting Beads for liver embolization: Concentration of doxorubicin in tissue and in beads in a pig model
100-300μm or 700-900μm loaded with 37.5 mg dox/mL Livers analyzed 28 or 90 days after embolization DEBs eluted 43% of their initial drug load after 28 days and
89% after 90 days Drug detected at distances as far as 600μm from bead
edge 100-300μm induced more necrosis than 700-900μm
beads (p= .0036)
MicroCT analysis: Small beads distal arteries + homogeneous distribution
Doxorubicin concentration declines with increasing distances from the bead edge (still enough to be cytotoxic in vitro)
Namur J et al. J Vasc Interv Radiol. 2010 Feb;21(2):259-67Dreher M et al. GEST 2010
20
Histological findings and tumor response 48 y/o female, right lobe lesion, s/p 3 treatments with DEBDOX
Gross specimen after resection showing complete necrosis
23
3.
Catheter Placement
Selective?
YES
1.Better control
2.Minimize reflux
3.Better visualization of beads
28
4.Actual Delivery
1. Must use microcatheter2. Use cone beam CT for targeting3. Visibility of beads critical4. Mix with contrast (4:1)5. Inject slowly (1 ml/min)
29
Usefulness of Cone Beam CT
Imaging: Research and Clinical Use
1. Visualize the tumor2. Target the tumor (drug delivery)3. Proof of success = predicting response:
Tumor perfusionTumor segmentation
31
5.
End Points
1. Entire planned dose administered
2. Stop before stasis!!
3. No need for further bland embolization
32
ConclusionsDrug-Eluting Beads in 2011: Why, how and when?
WHY? Rationale ESTABLISHED HOW? Technical considerations NEARING CONSENSUS
(panel of experts) Bead size: Nearly there! SMALL >>large Drug: Doxorubicin (YES) vs. irinotecan (NO) Catheter position: SELECTIVE End point: FULL DOSE (no stasis) Unknown: Frequency treatment/dosing
WHEN? HCC: Good data
NET: On-going studies, CRC: On-going studies
33
DISCLOSURES
Grant support:
Genentech, Bayer Healthcare, Nordion, Biocompatibles, Abdulmalik Research Fund, Alice Pratt Liver Cancer Fund, NIH/NCI, DOD, RSNA, SIR
Consultant:
Philips Medical System, Bayer Healthcare, Nordion, Biocompatibles, Guerbet, PreScience
Patent:
Use of 3-BrPA as an anti-cancer agent Founder: PreScience Pharma