RFA-based Combination Therapy 肝病研究中心, 肝臟科 林口長庚醫院, 長庚醫學大學 (CHANG GUNG MEMORIAL HOSPITAL, LINKUO) 林成俊 (CHEN-CHUN LIN)

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1 RFA-based Combination Therapy 肝病研究中心, 肝臟科 林口長庚醫院, 長庚醫學大學 (CHANG GUNG MEMORIAL HOSPITAL, LINKUO) 林成俊 (CHEN-CHUN LIN)

2 CONTENTS Introduction RFA-based Combination Therapy Ethanol injection (PEI) Saline perfusion Transarterial (chemo)embolization (TACE/TAE) Sorafenib New advance in RFA alone

3 RADIOFREQUENCY ABLATION (RFA) 5- YEAR SURVIVAL RATES RFA is effective for HCC 3 cm and has 5-year survival rate about 50%. Long term survival for early HCC after RFA 51% (Child A) (Lencioni, et al, 2005) 63% (Child A) (Tateishi, et al, 2005) 64% (Child A) (Choi, et al, 2007) 76% (BCLC resectable) (N Kontchou et al, 2009) 3

4 Initial complete necrosis rate Initial Complete Response after Local Ablation Independently related to Tumor Size 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% P = % 78% 57% 45% 46% <2cm cm cm >5cm Multinodular Total 282 cirrhotic HCC patients 2.1cm to 5.0cm: several insertions, mean insertion, 2.1 ± 1.2 > 5cm: TAE followed by PEI BCLC group data Sala, 2004, Hepatology

5 LIMITATION OF RFA: ABLATION SIZE 3CM Perfusion-mediated cooling effect Hepatic vessel/sinusoid perfusion Temperature cooling (heat sink phenomenon) Charring formation High impedance Reduce electric current (energy deposition)

6 RFA-BASED COMBINATION THERAPY Combination with percutaneous ethanol injection (PEI)

7 PEI + RFA in a rat breast tumor model RFA alone PEI alone PEI RFA RFA PEI Diameter of coagulation necrosis (mm) * Effect of ethanol prior to RFA (P<0.005) Reduced current required to achieve 70 C tip temperature 71.1 ma vs ma (P <0.003) Greater tissue impedance during subsequent RF ablation ohms vs ohms (P < 0.01) Goldberg, et al. Radiology 2000

8 Combined PEI and RFA for large HCC (< 4cm) Vallone, et al. Cardiovasc Intervent Radiol, 2006

9 RFA + PEI vs. RFA alone (RCT study) Improve survival (only HCC sized 3-5 cm) All patients HCC < 3 cm HCC > 5 cm HCC 3-5 cm Zhang, et al. 2007, Radiology

10 HCC near portal vein RFA tip PEI tip

11 PEIT prior to RFA HCC near portal vein No any recurrence and survival > 8 years Post RFA 1 month Post RFA 1 year

12 HCC near the Gallbladder RFA tip PEI tip RFA, plan for 1 st direction RFA, plan for 2 nd direction PE injection RF 1 st direction ablation RF 2 nd direction ablation

13 HCC near the Gallbladder 1-day after RFA 1-month after RFA 1-year after RFA Complete Ablation without Recurrence

14 PEI + RFA Long-term cohort study 54 patients (72 tumors) 3-4cm = 2-3cm Long-term OS High-risk = Non-high-risk Year MS OS (3-4cm) 95% 68% 68% 63.1M OS (2-3cm) 92% 77% 58% 62.8M P = Year MS OS (HRL) 93% 71% 61% 62.8M OS (NHRL) 89% 89% 71% 66.7M P = Lin JW, Lin CC, Lin SM, 2014, Kaohsiung J Med Sci

15 Advantage PEI + RFA (Summary) Easily perform and low cost Reduce perfusion-mediated cooling effect (Goldberg, 2000, Radiology) Improve OS for medium-sized HCC (RCT) (Zhang, 2007, Radiology) Safe and effective HRL HCC (Lin, 2014, KJMS) Disadvantage More severity of pain (Kurokohchi, 2008, WJG) Possible increase risk of biliary tree injury (Cha, 2013, KJR) Induced high impedance (Lee JM, 2004, CVIR) Reduce predictability of RFA (Lee JM, 2004, CVIR)

16 RFA-BASED COMBINATION THERAPY Combination with saline

17 Hypertonic saline (HS) Control the growth of VX2 carcinoma cell (Rabbit animal study) Concentration of saline Necrotic area of tumor Concentration of saline Viability of VX2 cancer cells Rabbit survival Hypertonic inj: days Control group: days P < Lin YC, et al. 2005, AJR

18 Wet RFA (Saline + RFA) Group A: standard dry RF ablation, Group B: RFA + 5% NaCl (11ml) preinjection, Group C: RFA + 5% NaCl (11ml) at a rate of 1 ml/min Group D: RFA + 36% NaCl (6ml) preinjection, Group E: RFA + 36% NaCl (6ml) at a rate of 0.5 ml/min. (ex vivo bovine liver) Wet RFA Perfusion NaCl 5% or 36% Impedance before RFA Impedance rise Current during RFA Gr. A: RFA alone Gr. C: RFA + 5% NaCl perfusion Gr. D: RFA + 36% NaCl pre-inj Lee JM et al. 2004, KJR

19 Lee JM et al. 2004, KJR Gr A: dry RF ablation V = cm 3 (4.9*2.4*2.4 cm 3 ) Gr B: RFA + 5% NaCl pre-inj V = cm 3 (4.4*2.4*2.2 cm 3 ) Gr C: RFA + 5% NaCl perfusion V = cm 3 (6.1*5.1*5.2 cm 3 ) P < 0.05 Gr D: RFA + 36% NaCl pre-inj V = cm 3 (4.9*4.3*4.2 cm 3 ) Gr E: RFA + 36% NaCl perfusion V = cm 3 (6.0*5.1*5.4 cm 3 ) P < 0.05 Efficiency in creating a large ablation zone: Wet RFA (Nacl perfusion) > RFA + Nacl pre-inj > RFA alone

20 Wet RFA (Saline + RFA) enlarge ablation size Animal study (dogs) Gr A: IC (internally cooled) Gr B: ICW (internally cooled wet, 0.9% saline, 0.7mL/min) Gr C: Pringle maneuver (occlusion of hepatic perfusion) Gr B and Gr C effectively expand ablation zone Gr B vs. Gr C a larger ablation with easy handling V = 0.48 V = 1.82 V = 1.22 Park MH, 2012, Gut Liver

21 Saline + RFA (Summary) High concentration of saline tumor necrosis Wet RFA (ICW, internally cooled wet) Avoid high impedance deposit more energy Perfusion with chilled 0.9% saline during RFA Large coagulation volume Easy handle Need more clinical data Possible complication: unclear

22 RFA-BASED COMBINATION THERAPY Combination with Transarterial (chemo)embolization TACE/TAE

23 Occlusion of tumor blood supply by balloon catheter RFA increase ablation size TAE for HA Balloon catheter 40 patients Gelatin sponge patients HCC cm, mean 4.7cm Results: All complete necrosis (after 1-2 sessions RFA) No major complication Rossi, 2000,Radiology

24 TACE followed 15 min later by RFA enlarge coagulation volume TACE + RFA RFA alone 3.4 cm coagulation area Surrounded by reddish infarct tissue Hyperthermia + local chemotherapy effect 3.0 cm x 2.2 cm coagulation area Surrounded by normal liver parenchyma Rabbit VX2 hepatic tumors 2008, Mostafa, JVIR

25 TACE-RFA was superior to TACE alone or RFA alone in improving survival for Patients with hepatocellular carcinoma larger than 3 cm. 2008, Cheng, JAMA

26 Shibata et al, 2009, Radiology LTP TACE + RFA RFA alone TACE + RFA vs. RFA alone OS TACE + RFA RFA alone equivalent effectiveness for the treatment of small (3 cm) HCCs Combination treatment may not be necessary

27 Solitary intermediate-size HCC ( cm) Local tumor progression P = Overall survival NS, P = Extending ablated area in fewer treatment sessions Decreasing the local tumor progression 2010, Morimoto, Cancer

28 Meta-analysis for RFA + TACE RFA+TACE was obviously associated with higher survival rates OR1-year = 2.06, 95 % CI , P < 0.001; OR3-year = 1.93, 95 % CI , P = 0.009; OR5-year = 1.87, 95 % CI , P = The combination of TACE with RFA can improve the overall survival rate and provides better prognosis for patients with HCC, but more randomized controlled trials using large sample sizes are needed to provide sufficient evidence. Yan, et al Dig Dis Sci

29 HCC < or = 7 cm, number 1-3 Overall survival Recurrence-free survival Peng ZW et al, 2013, JCO

30 Interim analysis of the efficacy of switching multiple-electrode of radiofrequency ablation alone or combined with transarterial chemoembolization for treating hepatocellular carcinoma sized 3-7cm (a prospective randomize-controlled study) Chen-Chun Lin ( 林成俊 ), Shi-Ming Lin ( 林錫銘 ), Wei-Ting Chen ( 陳威廷 ), Division of Hepatology, Liver Research Unit, Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital; Chang Gung University

31 RFA + TACE vs. RFA alone (Summary) Animal studies Reduce perfusion-mediated cooling effect. Chemotherapy may increase infarct area Clinical evidences (RCT) Small HCC: May not have additional benefit Intermediate-size HCC: Decrease risk of local tumor progression HCC (< 7cm, N=1~3): Better overall survival and recurrence-free survival HCC (3-7 cm, N = 1-3, TACE+SWC) Comparable PTE, LTP, and OS but more complications

32 RFA-BASED COMBINATION THERAPY Combination with Sorafenib

33 Sorafenib Targets Tumor Cell Proliferation and Angiogenesis Adapted from Wilhelm S, et al. Cancer research 2004; 64: and Whittaker S, et al. Oncogene 2010; 29:

34 Sorafenib Suppress Rapid Progress of HCC after RFA (in vivo) RFA Tumor volume: RFA + Sorafenib < RFA alone, P < RFA alone < Control group, P = RFA + Sorafenib vs RFA: Significantly decrease HIF-1a and VEGFA P = RFA vs control: Significantly increased HIF-1a and VEGFA P < , Xu, et al, Acta Radiol

35 HCC < 3cm, PSM study RFA + Sorafenib RFA direction no. = 2 23x20mm 55x53mm RFA alone RFA direction no. = 4 18x18mm 25x25mm

36 STORM (OP or RFA + Sorafenib) Randomized, Double-blind, Placebo-controlled trial Pathology-proven Complete Removal of tumor - surgical resections Patients with CR after surgical resection or completion of local ablation treament (RFA or PEI) ECOG PS: 0 Child-Pugh A and B Sorafenib 400mg twice daily Matching placebo twice daily Primary endpoint: Recurrence Free Survival (RFS) Secondary endpoint: Time to recurrence (TTR) Overall Survival (OS) Approximately Countries 1: 1

37 Recurrence Overall survival P = 0.12 P = 0.48

38 P=0.036 P=0.047 Feng X et.al AJG 2014

39 Randomized study: RFA + Sorafenib vs. RFA alone Sorafenib 400mg bid starts after 4-7 days after RFA Recurrences rates at 1-, 2-, 3- year RFA + Sorafenib: 36.7%, 43.3%, 56.7% RFA alone: 62.5%, 78.1%, 87.5% p < 0.01 TTP RFA + Sorafenib: 17.0 months RFA alone: 6.1 months P < 0.05 Kan, et al Eur Rev Med Pharmacol Sci

40 Sorafenib + RFA Summary Sorafenib Anti-proliferation ( growth factors) Anti-angiogenesis ( perfusion-mediated cooling effect) Sorafenib + RFA HCC (< 3cm): Increase ablation size HCC (BCLC 0-B1): Low recurrence Better OS HCC (HBV-HCC, Medium-sized) Decrease recurrence and prolong TTP

41 RFA ALONE NEW ADVANCE SWC-RFA

42 Medium-sized HCC Local tumor progression: SWC < S-RFA Before PSM After PSM P = Tumors at risk SWC S-RFA HR: % C.I.: Actual local tumor progression: SWC: 9/82 (11.1%) S-RFA: 21/54 (41.2%) P = Tumors at risk SWC S-RFA HR: % C.I.: LTP for intermediate-size HCC on reference SWC = 10% (2012, Lee, KJR) RFA = 39% (2010, Morimoto, Cancer) RFA = 76% (2011, Kim, An Surg Oncol)

43 CONCLUSIONS RFA-BASED COMBINATION RFA could combine with PEI, TACE or sorafenib safely These combinations have potential efficacy to broaden the RFA treatment scope on the HCC therapy.

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