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Drug-Eluting Beads Chemoembolization (DEBDOX) for Hepatocellular Carcinoma in 2011: The Case for a Treatment Standard. JF Geschwind, MD Professor Radiology, Surgery, and Oncology Director, Vascular and Interventional Radiology Johns Hopkins University School of Medicine Baltimore, Maryland.
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Drug-Eluting Beads Chemoembolization (DEBDOX) for Hepatocellular Carcinoma in 2011:The Case for a Treatment Standard JF Geschwind, MD Professor Radiology, Surgery, and Oncology Director, Vascular and Interventional Radiology Johns Hopkins University School of Medicine Baltimore, Maryland
1. Why Drug-elutingTechnology? • Clear Rationale: • Maximize drug delivery • Consistent (scientifically reproducible) • Long lasting effect/slow release (sustained) • Tumor effect vs. systemic side effectsWE HAVE COME A LONG WAY!
Symptomatictreatment BCLC staging system and treatment strategy HCC Stage 0PS 0, Child–Pugh A Stage A–CPS 0–2, Child–Pugh A–B Stage DPS >2, Child–Pugh C Very early stage (0) 1 HCC <2cmCarcinoma in situ Early stage (A) 1 HCC or 3 nodules<3cm, PST 0 Intermediate stage (B) Multinodular,PST 0 Advanced stage (C)Portal invasion, N1, M1, PST 1–2 End stage (D) 1 HCC 3 nodules ≤3cm Portal pressure/bilirubin Increased Associated diseases Normal No Yes Resection Liver transplantation PEI/RFA TACE Sorafenib Curative treatments Randomised controlled trials HCC = hepatocellular carcinoma; BCLC = Barcelona Clinic Liver CancerPEI = percutaneous ethanol injection; RFA = radiofrequency ablationTACE = transarterial chemoembolisation; PST = performance status Llovet JM, et al. J Natl Cancer Inst 2008;100:698–711
Chemoembolization of Hepatocellular Carcinoma With Drug-Eluting Beads: Efficacy and Doxorubicin Pharmacokinetics 1000 DEB-TACE • 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) 800 600 Doxorubicin at serum, ng/mL 400 200 0 baseline 5 min 20 min 40 min 60 min 2 h 6 h 24 h 48 h 7 d Time Post-Procedure 1000 Conventional TACE 800 600 Doxorubicin at serum, ng/mL 400 200 0 baseline 5 min 20 min 40 min 60 min 2 h 6 h 24 h 48 h 7 d Time Post-Procedure DEBDOX: DC Bead®, Drug-Eluting Bead doxorubicin Varela M et al. J Hepatology. 2006; 46(3):474-481.
Single Center Phase II Trial of DEBDOX in Patients with Unresectable HCC Reyes D et al. Cancer J. 2009
Kaplan-Meier Survival Curves 100 OS PFS 80 60 Survival Probability % 40 20 0 40 0 10 20 30 Time Months Reyes D et al. Cancer J. 2009
PRECISION V: Overall 6-month Tumor Response Rates p = 0.11 Disease Control = Objective Response + Stable Disease Objective Response = Complete Response + Partial Response
6-month Response in More Advanced Patients DC Bead®demonstrated statistically significant advantage in advanced patients Objective Response (p=0.038) and Disease Control (p=0.026) P < 0.05
PRECISION V trial1: DC Bead® was associated with a significantly lower incidence of doxorubicin-related AEs than cTACE DC Bead® cTACE 35 30 25 20 15 10 5 0 Alopecia Marrow suppression Mucositis Skin discoloration p=0.012* Incidence of doxorubicin-related AEs (%) DC Bead® is approved in 40 countries worldwide, including the USA (as LC Bead™) and Europe2 DC Bead® cTACE *p=0.0001 for analysis with assumption of independence of events 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010;44:41–52 2. http://www.biocompatibles.com/media/press-releases/2009/06-08-2009.aspx AE = adverse event
Prospective Randomized Comparison of Chemoembolization with Doxorubicin-Eluting Beads and Bland Embolization with Bead Block for Hepatocellular Carcinoma Malagari et al, Cardiovasc Intervent Radiol. 2009 Nov 24 • 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
Clinical Evidence *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
Conclusions DEBDOX: Proven Rationale Extension of cTACE Excellent PK profile Minimal toxicities Efficacy: Tumor response 75-85% EASL Survival: ~26 months BCLC B-C
2. How?Technical Considerations: Towards a Standardized Protocol • Drug delivery not embolotherapy! • 1. Choice of particle size • 2. Choice of drug: doxorubicin vs. irinotecan3. Catheter placement4. Actual delivery (how? Contrast or not?)5. End point (?)
1. Optimizing Drug Delivery: Importance of Particle Size
IA Therapy for Vx-2 Liver Tumor:Iron-oxide Labeled Microspheres 300-500µm 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 100-300µm
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):259-67 Dreher M et al. GEST 2010
1. Optimizing Drug Delivery: Importance of Particle Size SMALL
Complete necrosis on MR imaging DC Bead® [DEBDOX] in Patients with HCC
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
Histopathology: Extensive necrosis + no viable tumor cells DEB within necrotic tumor
2. Optimizing Drug Delivery: What drug? Doxorubicin: HCC, NET Irinotecan: CRC (?), No data
3. Catheter Placement Selective? YES 1.Better control 2.Minimize reflux 3.Better visualization of beads
Pre-treatment Post-treatment #1: Residual viable tumor
MRI Post-treatment #2 No recurrence 29 months post initial treatment
4. Actual Delivery 1. Must use microcatheter 2. Use cone beam CT for targeting 3. Visibility of beads critical 4. Mix with contrast (4:1) 5. Inject slowly (1 ml/min)
Usefulness of Cone Beam CT Imaging: Research and Clinical Use • Visualize the tumor • Target the tumor (drug delivery) • Proof of success = predicting response: • Tumor perfusion • Tumor segmentation
5. End Points 1. Entire planned dose administered 2. Stop before stasis!! 3. No need for further bland embolization
Conclusions Drug-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
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