Intra-arterial Therapy in Management of HCC: ctace, DEB-TACE, and Y90 Radioembolization

Transcription

1 Intra-arterial Therapy in Management of HCC: ctace, DEB-TACE, and Y90 Radioembolization Department of Radiology, National Cancer Center In Joon Lee

2 Contents Conventional TACE Role of TACE in management of HCC Hepatocarcinogenesis and hemodynamic change Basic concept of selective TACE with Lipiodol New platform of Intra-arterial Therapies Drug-eluting bead Y90 Radioembolization

3 Llovet JM et al. J Hepatol 2012; 56: EASL-EORTC Guidelines for HCC Levels of Evidence vs. Grade of Recommendation

4 BCLC Staging System TACE

5 Treatment Stage Migration Global Patterns of Liver Cancer Management - The first multiregional, large-scale, observational study to document real-world HCC patient experience from diagnosis to death Park JW et al. Liver Int 2015; 35:

6 Park JW et al. Liver Int 2015; 35: Treatment Stage Migration Global Patterns of Liver Cancer Management 1 Site 1 Site 1 Site

7 Park JW et al. Liver Int 2015; 35: Treatment Stage Migration Global Patterns of Liver Cancer Management

8 Normal Liver Perfusion Blood supply Hepatic artery : 50% Portal vein : 50% Venous drainage Hepatic vein CVIR 1991;14:158. Hepatology 2000; 31:

9 Hepatocarcinogegesis & Hemodynamic Change Hemodynamic change Abdom Imaging 2011;36: Radiology 2009;252: Portal vein Feeding vessel for early HCC Drainage vein for moderately HCC

10 Hepatocarcinogegesis & Hemodynamic Change Microsatellite lesions Pathological analysis of 100 small tumors (<5cm) 46/100 tumors had microsatellite lesions around the tumor. Tumor size and distance to the microsatellite were significantly correlated. Cancer 2005;103:

11 Lipiodol in Conventional TACE Lipiodol Iodized poppy seed oil Lymphangiography ( 1920s ~ ) Contrast media cheap!!! TACE for HCC (1980s ~) Uptake in HCC Occlusion of hepatic arteriole at 10um level

12 Lipiodol in Conventional TACE Lipiodol as a drug-delivery system Mixed with Adriamycin/CDDP/MMC Water-in-oil emulsion Doxorubicin (water) in Lipiodol (oil) droplet Water-in-oil emulsion

13 Lipiodol in Conventional TACE Lipiodol as a drug-delivery system Mixed with Adriamycin/CDDP/MMC Water-in-oil emulsion Doxorubicin (water) in Lipiodol (oil) droplet Drug delivery vehicles!!! Water-in-oil droplet Hepatic artery - water -

14 Lipiodol in Conventional TACE To increase stability of emulsion in NCC Doxorubicin 10mg/contrast media 0.5cc Contrast media : Visipaque 270 Gravity of Visipaque 270 Lipiodol (Radiology 1989;170: ) Volume : Lipiodol 2cc/contrast media 0.5cc 4 : 1 Water-in-oil emulsion Water-in-oil emulsion Oil-in-water emulsion

15 PLoS ONE 2014; 9(12): e doi: /journal.pone Lipiodol in Conventional TACE 1:1 4:1 Lipiodol : CM = 4:1 DEB Lipiodol : CM = 1:1 Lipiodol : NS = 4:1 Lipiodol : NS = 1:1

16 Conventional TACE Lipiodol : semi-fluid embolic material

17 Conventional TACE Lipiodol : semi-fluid embolic material Hepatic artery peribiliary vascular plexus and tumor drainage portal vein Particles

18 Conventional TACE Dual embolization!!! Medical hepatectomy effect Angiographical subsegmentectomy Necrosis

19 Ultra-selective TACE with Lipiodol JVIR 2007; 18:

20 Ultra-selective TACE with Lipiodol Ultra-selective TACE: chemo < ischemic effect!!! Ultra-selection of tumor feeder Minimizing ischemic area Decreasing normal parenchyma injury Aggressive chemoembolization Maximizing ischemic effect!!! Increasing therapeutic efficacy

21 Ultra-selective TACE with Lipiodol Technical advancement for TACE Non-selective TACE of the whole liver parenchyma Subsegment approach with microcatheter Conventional 2D angiography guidance 3D imaging navigation with CBCT angiography

22 Ultra-selective TACE with Lipiodol M/60 with 1cm HCC Immediate 13 months

23 Ultra-selective TACE with Lipiodol M/55 with 10.6cm HCC #1 TACE ( ) #1 TACE 시행 1 개월 : AFP : ng/ml TACE #2 ( ) #2 TACE 시행 1 개월 : AFP : ng/ml

24 Ultra-selective TACE with Lipiodol Extended right hemihepatectomy: Totally necrotic nodule with 1) post-chemoembolization status with no residual tumor 2) size: 8.0x7.5x7.0cm 3) clear resection margin (safety margin: 0.8cm)

25 Ultra-selective TACE with Lipiodol M/61 with multiple nodules

26 Ultra-selective TACE with Lipiodol M/61 with multiple nodules A4

27 Ultra-selective TACE with Lipiodol M/61 with multiple nodules A3

28 Ultra-selective TACE with Lipiodol M/61 with multiple nodules A8

29 A6 Ultra-selective TACE with Lipiodol M/61 with multiple nodules

30 Ultra-selective TACE with Lipiodol M/61 with multiple nodules A1

31 Ultra-selective TACE with Lipiodol M/61 with multiple nodules

32 DEB-TACE Drug-eluting bead (DEB) Hydrophilic polymer backbone Negative charges to ionically bind positively charged drugs Loading and release of the drug

33 DEB-TACE Pharmacokinetics of DEB-TACE Increased therapeutic efficacy Decreased systemic toxicity J Hepatol 2007; 46:

34 DEB-TACE Efficacy of DEB-TACE compared to ctace PRECISION V (CVIR 2010; 33: 41-52) No difference in 6-month tumor response P = 0.11

35 DEB-TACE Efficacy of DEB-TACE compared to ctace Facciorusso A et al. (Dig Liver Dis 2016 ;48: ) P = 0.51 P = 0.10 Objective response rate Patient survival

36 DEB-TACE DEB vs. bland embolization No difference in tumor response and overall survival J Clin Oncol. 2016; 34:

37 DEB-TACE Safety Advantage in abdominal pain and postembolic syndrome Shorter hospitalization Controversy over the advantage in systemic side effect

38 DEB-TACE ctace vs. DEB-TACE ctace DEB-TACE

39 DEB-TACE Where are the DEB relatively to the tumor? Irie et al. (Hepatol Res 2016; 46:E ) Mean diameter of HCC: 2.0cm Mean diameter of feeder: 410um Significant correlation between HCC diameter and its feeder Namur et al. (J Hepatol 2011; 55: ) 1 patient explanted 8hr after DEB-TACE with um Tumor size: 3.9cm Occlusion of intratumoral (42%) and peri-tumoral (58%) vessels Peri-tumoral Intra-tumoral + Peri-tumoral Intratumoral 800 um 400 um 100 um

40 DEB-TACE Where are the DEB relatively to the tumor? Lower penetration than Lipiodol Less capsular irrigation, less pain Cannot reach to portal vein Disadvantage of early HCC (dual supply from HA and PV) Difficulty of injection through fine feeder Disadvantage of small HCC JVIR 2017; 28:

41 DEB-TACE 4cm HCC, DC bead vial

42 DEB-TACE 1.3 cm HCC, DC bead vial Initial MR 1 months 4 months Courtesy of KM Kim, Severance Hospital of Yonsei University, Seoul

43 DEB-TACE Size of DEB PRECISION V (CVIR 2010; 33:41-52) DC-Bead um, um Lencioni et al. (CVIR 2012; 35: ) Technical recommendation for DEB-TACE DC-bead um Prajapati et al. (AJR 2014; 203:W ) TACE with um sized DEB is associated with significantly higher survival rate and lower complications than TACE with and um sized DEB

44 DEB-TACE Current products DC-Bead (BTG, 2003) 100 to 700 um HepaSphere (Merit Medical, 2007) 120 to 800 um DC-Bead M1 (BTG) um TANDEM (Boston Scientific, 2012) 40 to 100 um LifePearl (Terumo, 2015) 100 to 400 um

45 Y90 Radioembolization Radioembolization Transarterial Radioembolization (TARE) Selective Internal Radiation Therapy (SIRT) Microsphere Brachytherapy Implantation

46 Y90 Radioembolization Liver tolerance/ tumor sensitivity to radiation External Radiotherapy Radiation-Induced Liver Disease Y90: 100 ~ 3,000 Gy Gy Curative Doses: Adenocarcinoma

47 Y90 Radioembolization Radiation therapy External Beam RT Internal RT = Brachytherapy

48 Y90 Radioembolization Radioembolization Pre-treatment Radioembolization Misnomer... No Embolization!!! Selective Internal Radiation Therapy (SIRT) Microsphere Brachytherapy Implantation 45 day post-treatment Radiographics 2008;28: 81-99

49 Y90 Radioembolization Y-90 (Yttrium) microsphere micron 100% pure beta emitter Decays to 90 Zirconium Tissue penetration Average: 2.5mm Maximum: 11mm Half-life: 64.1 hr 94% of radiation delivered within 11 days

50 Y90 Radioembolization Mechanism of action ctace & DEB-TACE: Chemoembolization, tumor ischemia/hypoxia Radioembolization: Brachytherapy, high dose tumor radiation ctace DEB-TACE Radioembolization Salem R. Clin gastroentero hepatol 2013;11:

51 Y90 Radioembolization Radioembolization vs. ctace Salem R et al. (Gastroenteology 2011; 140: ) Time to progression: 13.3 vs 8.4 months, P = Median survival: 20.5 vs 17.4 months, P = For intermediate stage: 17.5 vs months, P = Less post embolization syndrome For early stage HCC Radiation subsegmentectomy Stronger local anti-tumor effect than ctace (western style) vs. ultraselective TACE??? RCT: PREMIERE (Estimated completion date: Aug. 2018)

52 Y90 Radioembolization Ideal HCC candidate Non-infiltrative tumor type < 50% tumor burden < 70% bulk disease or tumor nodules that are not too numerous to count No ascites Normal bilirubin Albumin 3g/dL Salem et al. JVIR 2006;17(8):

53 Y90 Radioembolization In Korea Mainly performing for advanced disease Because of very expensive Bilobar diseases are 63/165 (38.1%) in Korea data collection Courtesy of KM Kim, Severance Hospital of Yonsei University, Seoul

54 Y90 Radioembolization HCC patients to recommend radioembolization Old age > 65 Single Treatment Branch portal vein invasion Large tumor, over 7cm in diameter

55 Y90 Radioembolization Usefulness for large HCC Radiation lobectomy Salem R. Hepatology 2013; 58: months Total necrosis confirmed by surgical specimen Courtesy of KM Kim, Severance Hospital of Yonsei University, Seoul

56 Y90 Radioembolization Products SIR-Spheres Resin Size: microns Activity/Sphere: 50 Bq Dose size: 3 GBq Distilled water TheraSphere Glass Size: microns Activity/Sphere: 2500 Bq Dose size: 3, 5, 7, 10, 15, 20 GBq Normal saline

57 Y90 Radioembolization Process 1) Pre-therapy simulation with 99mTc-MAA Intervention room angiography w/u Nuclear medicine - Lung shunt scan 2) Target liver volume analysis 3) Treatment approach 4) Dosimetry 5) Product order considering treatment window 6) Radioembolization (Treatment) 7) Post-treatment imaging 1~2 weeks complex pre-treatment preparation

58 Y90 Radioembolization 1. Pre-therapy simulation with 99mTc-MAA Intervention room angiography w/u CTHA, CBCT hepatic arteriography, repeated angiography Preprocedure coil embolization GDA, non-hepatic artery originated from hepatic artery Unifocalization of the tumor feeder Simulation of Y90 radioembolization using 99mTc-MAA

59 Y90 Radioembolization 1. Pre-therapy simulation with 99mTc-MAA Nuclear medicine - Lung shunt scan <10% No dose reduction 10-15% 20% dose reduction 15-20% 40% dose reduction More than 20% Impossible for Y-90

60 Y90 Radioembolization 2. Volume analysis CT imaging Measurement of target liver volume - not tumor volume!!! Salem et al. JVIR 2006;17(8):

61 Y90 Radioembolization 3. Treatment approach Whole liver Bi-lobar sequential (CVIR2012; 35: ) Lobar Radiation lobectomy Segmental/selective Radiation subsegmentectomy Early stage HCC

62 Y90 Radioembolization 4. Dosimetry Optimal therapeutic radiation dose Considering liver volume and lung shunt fraction Recommended Dose: Gy (nominal 120 Gy) Dose could be adjusted based on Tumor vascularity, liver function, and performance status Amount of radioactivity required to deliver the dose to the target liver volume is: Activity Required = (GBq) [Desired Dose (Gy)] [Liver Mass* (kg)] 50 (1-LSF)(1-R) Accounts for lung shunt fraction (LSF) as measured by Tc-99m MAA & estimated the percent residual (R) in the administration system

63 Y90 Radioembolization 4. Dosimetry Physical decay of Y-90 and resulting activity at time of Tx Order to dose vial and treatment time window Activity (+10% GBq) No. of Microspheres (millions)*

64 Y90 Radioembolization Dose Planning Spreadsheet Calculated Activity with 1% residual waste Possible Treatment Window and Dose Vial

65 Y90 Radioembolization 5. Radioembolization Catheter positioning Same location as the simulation using 99mTc-MAA Infusion of Y-90 microsphere

66 Y90 Radioembolization 6. Post-treatment imaging Bremsstrahlung scan, Y90 PET (better resolution) JVIR 2013;24:

67 Y90 Radioembolization Complication of radioembolization Hepatic dysfunction Radiation induced liver disease 0~4%, 4~8 wks after radioembolization Strong anti-tumor effect in lobar treatment Increase of parenchymal damage Decrease of liver function Worsening patient s survival Sequential lobar (CVIR2012; 35: ) Possibility of disease progression during interval period Segmental or subsegmental approach

68 Y90 Radioembolization Complication of radioembolization Radiation pneumonitis Major complication of radioembolization Related to lung shunting Possibility of patient s death Complication by infusing through non-hepatic artery Invisible during injection possibility of reflux Radiation gastroduodenitis, radiation cholecystitis Preprocedure coil embolization, anti-reflux catheter

69 Take Home Massage Conventional TACE Pros: high evidence, cheap, dual-embolization effect Cons: pharmacokinetics, pain DEB-TACE Pros: pharmacokinetics, less pain Cons: therapeutic efficacy?? Y90 Radioembolization Pros: strongest anti-tumor effect, no post embolization syndrome Cons: High cost, complex pre-treatment preparation, radiation pneumonitis

70 Center for Liver Cancer, National Cancer Center Thank you for your attention.