The Role of Interventional Radiology (Locoregional

Transcription

1 The Role of Interventional Radiology (Locoregional therapies) in HCC Richard Owen MB, MRCP, FRCR Interventional Radiology, Associate Professor University of Alberta Aldo Montana-Loza MD, FRCPC Hepatology Assistant Professor University of Alberta Western Canadian Gastrointestinal Cancer Consensus Conference - Winnipeg Disclosure Received honorarium, research support, summer student support, consulted for Cook Inc, Covidian, Gore Inc, Boston Scientific, Site PI for a MDT STOP HCC trial of Sorafanib +/- Therasphere 1

2 What are the Locoregional therapies? Radio Frequency Ablation (RFA) Percutaneous Ethanol Injection (PEI) Cryotherapy (Similar Principles to RFA) Trans Arterial Chemo Embolization (TACE) Drug eluting bead/traditional Selective Internal Radiation Treatment (SIRT) Therasphere Where do Locoregional treatments fit in? SIRT RFA TACE 2

3 The problem with the Liver in HCC Advanced tumours at presentation Life expectancy 7.9mths (Sorafanib trial Control arm) Advanced liver disease at presentation Majority have underlying Cirrhosis Adverse tumor characteristics (portal vein invasion) Non sensitive to traditional external beam radiation Poor response to systemic chemotherapy Sorafanib Max 3/12 improvement Up to 50% cannot tolerate Rx MELD Score Measures of CLD Developed in 1994 to asses risk for patients undergoing TIPPS procedures 3.8 x log (e) (bilirubin mg/dl) x log (e) (I) log (e) (creatinine mg/dl) Actually is What is the risk of dying with liver disease in the next 3 months Child Pugh score 2 year survival A = 85% B = 57% C = 35% 3

4 Radio Frequency ablation (RFA) A radio frequency generator provides a source of radiofrequency An active electrode (needle) is inserted into the body (liver), the dispersive electrode is on the skin surface (grounding pad) An electric field is produced around the electrodes, the needle has a much higher field around it than the grounding electrode The RF causes charged ions to oscillate and friction causes the tissues to heat. Temperatures above 45 c cause irreversible cell damage and apoptosis Needle tip temperatures are recorded as a reflection of the tissue temperatures RFA Impedance may also be used to measure tissue dessication and indirectly temperature Temperature of >90 are undesirable as charring and gas formation occur and inhibit needle function Day case procedure, usually under sedation only Ultrasound usual guidance modality May use CT 4

5 Principles of Treatment Zone of ablation exceeds diameter of lesion (ie surgical margin) Adjacent tissues (both inside and outside liver) must be considered when zone of ablation is planned RFA is non specific (ie will kill all tissues including the ones you want to preserve within the heat radius of 45 degrees) Principles of Treatment 5

6 Principles of Treatment Different tissues and materials conduct heat differently Heat sink effect of flowing blood may preserve tissue viability within the kill zone (ie adjacent to IVC) RFA Pre and Post 6

7 Contraindications Uncorrectable coagulopathy Inability to image the lesion (position) Subcapsular and Exophytic Hilar Adjacent to large vessels (IVC/Major Portal vein) Immediately adjacent to the gall bladder >5cm diameter Complications of RFA 3554 lesions in 2320 patients Procedure related mortality (0.3%) Major complications (2.2%) Bleeding, tract seeding, infection Minor Complications (4.7%) Burns, biloma, gallbladder injury Livraghi et al Radiology Treatment of Focal Liver Tumors with Percutaneous Radio-Frequency Ablation: Complications in a MultiCenter study. 7

8 Trans Arterial Embolization +/- Chemo o The occlusion of tumor blood supply to induce infarction, with or without the addition of chemotherapy o Embolization induces ischaemia and may increase the effectiveness of some chemo drugs and increase the inter tumoral concentrations o Liver has dual blood supply protecting against infarction and severe liver injury o Tumor blood supply primarily from hepatic artery, there may be a solitary feeder o Tumor hypervascular c/w background parenchyma Trans Arterial Embolization +/_ Chemo (TACE) Bland Embolization Particulate embolics Polyvinyl alcohol (contour etc) PLGA Acrylic co polymer (Embospheres Conventional TACE (lipiodol emulsion) Introduced intra arterially via catheter Feeding vessels occluded with particulate emboli 50 mg Doxyrubricin (Cisplatin/Mitomycin) Drug Eluting Bead technology (DEB TACE) 8

9 Exclusion Criteria for TACE Age > 80 years Advanced liver disease (Childs C) Bili >34 µmol/l* Main portal vein occlusion* Extrahepatic spread or Metastatic disease Renal failure (Creatinine >250 µmol/l)* * Absolute Contra-indication DEB (Drug Eluting Beads) DC Beads/Hepaspheres Chemo Drug (Doxorubricin or Irinotecan) contained within polymer beads Drug added few hours prior to Rx Diffuses into bead (diffuses out) 9

10 Drug Eluting Beads c/w Conventional TACE Advantages Decreased systemic and hepatic toxicity (Day case procedure) Improved Tumor response* Embolic agent combined More predictable endpoint Easier to detect recurrence, easier to RF Disadvantages Expensive ($1495/vial) Different complications and endpoint Visualization of Rx zones more difficult *Level 2 Safety Profile of DEB 237 Patients 37.5 mg/ml 30 day mortality 1.26% Grade 4 complications 5.48% PES 86.5% Cholecystitis 5.48% Grade 2 liver function deterioration 4.2% Athens Dec CVIR 10

11 11 Jan 10 AFP Normal Creat Norm Bili vial DC Beads 2 nd and 3 rd Bead Rx Feb 9, Mar 24, Jun Vials Total ( x3, x 2) No Bilirubin change CT s after 1 st and 2 nd Rx 11

12 Selective Internal Radiation Therapy (SIRT) with Y 90 (Therasphere) Radioembolization with Yttrium-90 is a novel form of liver-directed brachytherapy Radiolabeled glass beads 30-50µm in diameter are injected into the hepatic artery, become trapped at the precapillary level, and emit lethal internal radiation (Beta emitter T 1/ hours.9367 MeV); limiting exposure to the surrounding normal parenchyma, and allowing higher dose delivery than with an external beam Tumor cells sensitive to radiation doses of >100 Gy, Material made by placing Yttrium 89 in a nuclear reactor and adding a Neutron, decays to stable Zirconium 90 Appropriate Patients Advanced HCC not amenable to other treatments Bridge to transplantation Downstaging to resection, transplant or RFA Large or multifocal tumours Portal vein involvement 12

13 Advantages of Therasphere over TACE (and other palliative treatments) Outpatient procedure Better tolerated than TACE (Esp in elderly) Wider indications Large tumours (up to 70% liver volume) Portal vein thrombus Can be used in patients with worse synthetic function (bilirubin up to 50 µm/l) Single treatment per lobe (c/w multiple TACE procedures) Follow up CT s at 4,7 and 10 months 13

14 Adverse Events (121Rx) Transient Elevation in Bilirubin (23%) Severe (7%) GI tract Ulceration (4.1%) Cholecystitis (1.7%) Hepatic Failure (1.7%) Hepatic Abscess (<1%) Barcelona Clinic Liver Cancer Staging Classification (BCLC) Stage 0 PST 0, Child-Pugh A Stage A-C PST 0-2, Child-Pugh A-B Stage D PST >2, Child-Pugh C Very early stage (0) Single <2 cm Carcinoma in situ Early stage (A) Single or 3 nodules <3 cm, PST 0 Intermediate stage (B) Multinodular, PST 0 Advanced stage (C) Portal invasion, N1, M1, PST 1 2 Terminal stage (D) Single Portal pressure / bilirubin Increased 3 nodules <3 cm Associated diseases Portal invasion, N1, M1 Normal No Yes Resection Liver transplantation (CLT/LDLT) PEI/RFA Chemoembolization Sorafenib Curative treatments Target: 30-40% Median OS >60 months; 5 years survival 40-70% Target: 20% OS: 20 months (SD 14-45) Target: 40% OS: 11 months (SD 6-14) CLT/LDLT = cadaveric liver transplantation/living donor liver transplantation; PST = Performance Status Test Best Supportive Care Target: 10% OS: <3 months Bruix J, et al. Hepatology 2011;51:1020 Llovet JM et al. Nat Rev Gastroenterol Hepatol 2013;10:34 14

15 Locoregional Therapies for Hepatocellular Carcinoma BCLC Staging System Survival Probability Log Rank A vs. B P <.0001 B vs. C P =.04 C vs. D P =.01 A B D 0 C Time (Months) No at Risk: Stage A Stage B Stage C Stage D Marrero JA, et al. Hepatology 2005;41:707 Barcelona Clinic Liver Cancer Staging Classification (BCLC) Stage A-C PST 0-2, Child-Pugh A-B Early stage (A) Single or 3 nodules <3 cm, PST 0 Intermediate stage (B) Multinodular, PST 0 3 nodules <3 cm Associated diseases Yes PEI/RFA Chemoembolization TACE/DEB/TARE Curative treatments 50%-75% at 5 years Randomized controlled trials 40%-50% at 3 years vs 10% at 3 years CLT/LDLT = cadaveric liver transplantation/living donor liver transplantation; PST = Performance Status Test Bruix J, et al. Hepatology 2011;51:

16 RCT and and Meta-Analyses Comparing RFA versus PEI Author Lencioni RA, et al. Radiology 2003 Lin SM, et al. Gastroenterology 2004 Shiina S, et al. Gastroenterology 2005 Lin SM, et al. Gut 2005 Brunello F, et al. Scand J Gastroenterol 2008 Orlando A, et al. Am J Gastroenterol 2009 Treatment (n) PEI: 50 RFA: 52 PEI:52 PEI-HD: 53 RFA: 52 PEI: 114 RFA: 118 PEI: 62 PAI: 63 RFA: 62 PEI: 69 RFA: 70 PEI: 347 RFA: 354 Overall Survival 88% 98% At 2 years P= % 55% 74% At 3 years **P< % 74% At 4 years P= % 53% 74% At 3 years *P= % 58.9% At 3 years P=0.47 OR= ) RFA vs. PEI Local Recurrence 62% 96% At 2 years P= % 33% 18% At 3 years **P< % 1.7% At 4 years P= % 31% 14% At 3 years *P=0.01 Complete Response 82% 91% 88% 92% 96% 88.1% 92.4% 96.1% 36.2% 65.7% At 1 year P= OR=0.29 ( ) RFA vs. PEI OR=2.28 ( ) RFA vs. PEI Prognostic Factors For recurrence: Treatment (RFA vs. PEI) Tumor size ( 3 vs. <3cm) Bilirubin level 34.2 vs. <34.2 μmol/l For survival and recurrence: Tumor size ( 3 vs. <3cm) Tumor differentiation (I vs. II-III) Treatment (RFA vs. PEI/PEI-HD) For survival: Treatment (RFA vs.pei ) For local recurrences: Treatment (RFA vs. PEI ) Cirrhosis vs. chronic hepatitis Prothrombin time ( 80 vs. >80) Tumor number (multiple vs. single) Tumor grade (I vs. II-III) For survival and recurrence: Tumor size ( 2 vs. <2 cm) Differentiation grade (III-IV vs. I-II) Treatment (RFA vs. PEI/PAI) For survival: Child-Pugh B Age Locoregional Therapies for Hepatocellular Carcinoma Summary for Ablation Therapy RFA standard percutaneous ablation treatment for pts with lesions 3cm (single or up to 3 lesions), and single lesion 5cm Not candidates for liver resection or liver transplant Well preserved liver function (Child-Pugh A or B) and good performance status (BCLC Stage A-C) Recommendation grade A PEI should be reserved only when RFA is not available or not technically possible (pericholecystic and subcapsular lesions and lesions near the hilum) Recommendation grade B 16

17 Randomized Control Trails and Meta-Analyses of TACE Author Lin DY, et al. Gastroenterology 1988 Pelletier G, et al. J Hepatol 1990 Trinchet JC, et al. N Engl J Med 1995 Bruix J, et al Hepatology 1998 Pelletier G, et al. J Hepatol 1998 Lo CM, et al. Hepatology 2002 Llovet JM, et al. Lancet 2002 Llovet JM, et al. Hepatology 2003 Pts (n) Treatment TAE TAE+IV 5FU IV 5FU TACE-Dox 50mg Conservative tx TACE-Cis 70mg Conservative treatment TAE Conservative treatment TACE-Cis 2mg/kg+Tam Tam TACE-Cis 30mg Conservative treatment TAE TACE-Dox 25-75mg/m2 Conservative treatment Treatment group Control group Mean (n) Sessions Overall, 1 and 2 years survival 42 and 25% 20 and 20% 13 and 13% 2 24% 33% and 38% 43 and 26% and 49% 72 and 50% and 24% 55 and 26% and 31% 32 and 11% P= and 50% 82 and 63% 63 and 27% P= % 27% Response Rates (%) Prognostic Factors for Survival -TACE: RR of death: 0.49 ( ); P = Portal vein obstruction RR of death 2.71 ( ); P= TACE OR: 0.45 ( ), P=0.02 -Treatment response OR: 0.59 ( ), P= Locoregional Therapies for Hepatocellular Carcinoma Trans-Arterial Chemoembolization Survival (%) Median survival after first TACE 19.4±3.8 mo (95% CI, ) Probability of survival at 6-mo and 1-yr was 77%, and 69% Follow-up (mo) Pt followed (no.) Sawhney S, et al. Can J Gastroenterol 2011;25:426 17

18 TACE with Drug-Eluting Bead Author Varela M, et al. J Hepatol 2007 Poon RT, et al. Clin Gastroenterol Hepatol 2007 Malagari K, et al. Cardiovasc Intervent Radiol 2008 Sadick M, et al. Onkologie 2010 Patients (n) Study phase Treatments / Dose Overall Survival Objective Response** Prognostic Factors 27 II 2 / 150mg At 1 year: 66.6% (EASL) 92.5% At 2 year: 88.9% 30 II 2 / 150mg 42.9% (RECIST +necrosis) 62 II 3 / 150mg 70.8% (EASL) 24 II 2-3 / 160mg At 30months: 42% Lammer J, et al. Cardiovasc Intervent Radiol 2010 Dhanasekaran R, et al. J Surg Oncol III 3 / TACE 50-75mg/m 2 3 / DC Bead 150mg III 1.46/ TACE 50 mg/m / DC Bead 75 mg *Maximum doxorubicin dose per treatment. **Objective response: complete + partial response 284 days (4-563) 610 days ( ) P= % 51.6% (EASL) P=0.11 Better tumor response: Child-Pugh B Bilobar or recurrent disease P=0.02 Grade 5 clinical toxicity was similar Locoregional Therapies for Hepatocellular Carcinoma Summary for TACE and DC Bead Conventional TACE standard treatment for solitary lesions <8 cm or multinodular tumors (>3 lesions), with no evidence of extrahepatic disease (visceral or lymph node metastasis), Well preserved liver function (Child-Pugh A and early B) and performance status (BCLC A-C) Recommendation grade A TACE with drug eluting-beads may be an option, particularly in pts with more advanced liver disease (Child Pugh B, BCLC C, bilobar or recurrent disease) or pts with mild-moderate cardiac failure Recommendation grade B 18

19 Phase II Trials Using SIRT for Unresectable HCC Author N #Treatments / dose* Kulik LK, et al. Hepatology 2008 Vente MA, et al. Eur Radiol % had 1 tx 31% had 2 tx PVT: Gy No PVT: Gy Overall Survival No PVT: 15.6 mo Branch PVT: 10 mo Main PVT: 4.5 mo P= Response rates PR: 70% (EASL) PR: 42% (WHO) SD: 35% (WHO) months PR: 16-72% SD: Prognostic factors Salem R, et al. Gastroenterology 2010 Salem R, et al. Gastroenterology No tx 1.8 / 103 Gy Child-Pugh A: 17.2 mo Child-Pugh B: 7.7 mo P =0.002 TACE 245 TARE (IQR 1 3) 1 (IQR 1 2) Median survival times not statistically different (20.5 vs 17.4 mo, P =.232 PR: 57% (EASL) PR: 42% (WHO) Time-to-progression longer following TARE (13.3 vs 8.4 mo, P =.046) Age <65, PS 0 Absence of PHT Solitary lesions Bilirubin <2mg/dL Albumin >3.5mg/L AFP <200ng/ml Tumor response Post hoc analyses of sample size indicated that randomized study with > 1000 pts would be required to establish equivalence of survival times between pts treated with these two therapies Phase II Trials Using SIRT for Unresectable HCC Author N #Treatments / dose* Sangro S, et al. J Clin Oncol 2010 Mazzaferro V, et al. Hepatology 2013 Moreno-Luna LE, et al. Cardiovasc Intervent Radiol 2013 Overall Survival Response rates Prognostic factors GBq 14.1 months Extrahepatic disease Bilirubin level # nodules CLIP classification Gy median OS was 15 months (95% confidence interval [CI], months) 61 TARE matched 55 TACE 120 Gy 15.0 mo TARE 14.4 mo TACE (P = 0.47) Five complete responses occurred (9.6%), Objective response was 40.4 Complete tumor response more common after TARE (12 %) TACE (4 %) (p = 0.17) tumor response was the sole variable affecting TTP (P < 0.001) and the second affecting survival (after Child-Pugh class) 59 (97 %) TARE pts received outpatient treatment 53 (98 %) TACE pts were hospitalized for 1 day (P < 0.001) 19

20 Trans-arterial Chemoembolization for Hepatocellular Locoregional Therapies for Hepatocellular Carcinoma Cancer Features at Accession in Patients Receiving SIRT Pre-treatment Features n (%) or mean ± SE Age (years) 62 ± 2 Male: Female 64: 7 Etiology of HCC Alcohol HBV HCV NASH Others* 10 (14) 11 (16) 23 (32) 9 (13) 18 (25) Bilirubin (μmol/l) 28±7 I 1.2±0.07 Child-Pugh Classification A B C 39 (55) 27 (38) 5 (7) Child-Pugh (Points) 7±0.2 MELD Score 10±1 BCLC Staging Classification B C D 44 (62) 22 (31) 5 (7) Montano-Loza AJ, et al. J Hepatol 2013;58:S112 Trans-arterial Chemoembolization for Hepatocellular Locoregional Therapies for Hepatocellular Carcinoma Cancer Tumor Characteristics in Patients Receiving SIRT Tumor Characteristics n (%) or mean ± SE Location of the Tumors Right Lobe Left Lobe Both 34 (48) 12 (17) 25 (35) Maximum Diameter (cm) 8±1 Tumor Largest Diameter >8 cm 28 (39) Number of Tumors 3.1±0.5 Single Tumor 38 (54) 3 Tumors 19 (27) Portal vein thrombosis 22 (31) AFP (μg/l) 1280±480 Montano-Loza AJ, et al. J Hepatol 2013;58:S112 20

21 Trans-arterial Chemoembolization for Hepatocellular Locoregional Therapies for Hepatocellular Carcinoma Cancer Tumor Response Assessment after SIRT in Patients with HCC Type of Tumor Response WHO Criteria RECIST Criteria EASL Criteria Complete Response (12) Partial Response 4 (7) 7 (12) 25 (43) Stable Disease 45 (78) 41 (71) 26 (45) Progressive Disease 9 (15) 10 (17) 0 WHO = World Health Organization; RECIST = Response Evaluation Criteria in Solid Tumors; EASL = European Association for the Study of the Liver Criteria Montano-Loza AJ, et al. J Hepatol 2013;58:S112 Locoregional Therapies for Hepatocellular Carcinoma Survival (%) Median survival 12±2 mo (95% CI, 9-15) Follow-up (mo) Pt followed (no.) Montano-Loza AJ, et al. J Hepatol 2013;58:S112 21

22 Features Associated with Mortality after TARE by Univariate Cox Analysis Features Associated Death Alive HR 95% CI P-value (n=43) (n=28) Age (years) 62±2 61± Gender (M: F) 37: 6 27: Ascites 20 (47) 4 (14) Encephalopathy 4 (9) 1 (4) <0.001 Creatinine (nl, μmol/l) 87±5 80± I (nl, ) 1.3± ± Albumin (nl, g/l) 36±1 37± Bilirubin (nl, <20 μmol/l) 31±11 23± Sodium (nl, mmol/l) 138±1 138± MELD Score 10±1 9± <0.001 MELD 13 points 11 (26) 2 (7) Child-Pugh (A/B/C) 22/18/3 18/8/ <0.001 Child-Pugh (points) 7±0.5 6± Child-Pugh 8 points 12 (28) 4 (14) BCLC Classification (B/C/D) 26/14/3 18/8/ Tumor Largest Dimension (cm) 7±1 8± Tumor Largest Diameter >8 cm 14 (33) 14 (50) Number of Tumors 2.8± ± Tumors 13 (30) 6 (21) Alpha fetoprotein (ng/l) 993± ± Portal vein thrombosis 14 (33) 8 (29) Montano-Loza AJ, et al. J Hepatol 2013;58:S112 Features Associated with Mortality by Multivariate Cox Analysis First Model Death Alive HR 95% CI P-value (n=43) (n=28) MELD Score 10±1 9± Child-Pugh (A/B/C) 22/18/3 18/8/ Second Model Ascites 20 (47) 4 (14) Encephalopathy 4 (9) 1 (4) I (nl, ) 1.3± ± Albumin (nl, g/l) 36±1 37± Bilirubin (nl, <20 μmol/l) 31±11 23± Montano-Loza AJ, et al. J Hepatol 2013;58:S112 22

23 Locoregional Therapies for Hepatocellular Carcinoma Survival (%) MELD 12 MELD 13 Log Rank, P= Pt followed Follow-up (mo) Montano-Loza AJ, et al. J Hepatol 2013;58:S112 Locoregional Therapies for Hepatocellular Carcinoma Survival (%) Child-Pugh 7 Child-Pugh 8 Log Rank, P= Follow-up (mo) Pt followed (no.) Montano-Loza AJ, et al. J Hepatol 2013;58:S112 23

24 Locoregional Therapies for Hepatocellular Carcinoma Summary for TARE TARE promising results in phase II trials for locally advanced HCC RCT in comparison to conventional TACE/drug-eluting beads are needed TARE therapy appears to be safe in more advanced disease including portal vein invasion and larger tumors Recommendation grade B Randomized Control Trials Comparing TACE versus TACE + Other Local Therapies Author Koda M, et al. Cancer 2001 Bartolozzi C, et al. Radiology 1995 Becker G, et al. World J Gastroenterol 2005 Patient s (n) Treatment TACE+PEI PEI TACE TACE+PEI TACE TACE+PEI Treatmen ts (n) Tumor Size <3cm <3cm 4.8cm 5.1cm >5cm: 63% >5cm: 68% Overall Survival 80.8 and 40.4% 65.9 and 37.7% P= and 43.4% 86.7 and 72.2% P> and 38.7% 62.9 and 18% P=0.04 Tumor Recurrence 39.3 and 39.3% 19.3 and 19.3% P= and 70.1% 35.6 and 48.4% P<0.05 Prognostic Factors Tumors <2cm Okuda I Akamatsu M, et al. Liver Int TAE+PEI/RFA PEI / RFA 100 and 82.4% 95.5 and 82.2% P=0.6 0% 25% P=0.04 Marelli L, et al. Cancer Treat Rev TACE+PEI/RF A vs. TACE or PEI/RFA - - OR, ( ) P=

25 Algorithm of Treatment for Patients with Hepatocellular Carcinoma Candidates for Locoregional Treatment Locoregional Treatment for HCC Child-Pugh A or B, Single 3 cm, but up to 5 cm or 3 nodules 3 cm Child-Pugh A or B, Multinodular tumors (>3 lesions) Solitary Lesion >5 cm <8 cm Pericholecystic, Subcapsular Lesions or Lesions Near the Hilum Patients with more Advance Liver Disease or Heart Failure Portal Vein Thrombosis or Portal Vein invasion Larger Tumors Radiofrequency Ablation Percutaneous Ethanol Injection Conventional Transarterial Chemoembolization TACE with DC Bead Transarterial Radioembolization Meza-Junco J, et al. Cancer Treat Rev 2011;38:54 25