Dr Apoorva Gogna MBBS FRCR FAMS Consultant Interventional Radiology Center Department of Diagnostic Radiology SingaporeGeneral Hospital MULTI-DISCIPLINARY MANAGEMENT OF INTERMEDIATE STAGE HCC
CASE HISTORY 67 year old male No PMHx HCV cirrhosis AFP 8283 μg/l Child-Pugh A ECOG PS 0 Tbili 17μmol/L PT 11.2s PLT 172 X10 9 /L Alb 39 g/l Segment 7 lesion 4.8cm Four phase CT: Multifocal HCC Segments 7 (4.8 cm) Segment 6 (1.0 cm) and Segment 4A (2.1 cm)
CASE HISTORY 67 year old male No PMHx HCV cirrhosis AFP 8283 μg/l Child-Pugh A ECOG PS 0 Tbili 17μmol/L PT 11.2s PLT 172 X10 9 /L Alb 39 g/l Segment 6 lesion 1.0cm Four phase CT: Multifocal HCC Segments 7 (4.8 cm) Segment 6 (1.0 cm) and Segment 4A (2.1 cm)
CASE HISTORY 67 year old male No PMHx HCV cirrhosis AFP 8283 μg/l Child-Pugh A ECOG PS 0 Tbili 17μmol/L PT 11.2s PLT 172 X10 9 /L Alb 39 g/l Segment 4A lesion 2.1cm Four phase CT: Multifocal HCC Segments 7 (4.8 cm) Segment 6 (1.0 cm) and Segment 4A (2.1 cm)
CASE HISTORY 67 year old male No PMHx HCV cirrhosis AFP 8283 μg/l Child-Pugh A ECOG PS 0 Tbili 17μmol/L PT 11.2s PLT 172 X10 9 /L Alb 39 g/l Segment 7 lesion 4.8cm Four phase CT: Multifocal HCC Segments 7 (4.8 cm) Segment 6 (1.0 cm) and Segment 4A (2.1 cm) ICG 15: 15.4% FLR (incl S4): 0.32
POSSIBLE TREATMENT OPTIONS 1. Liver Transplant (beyond Milan, UCSF) 2. Extended right (seg 4-8) + S4 hemihepatectomy 3. Right hemihepatectomy (seg 5-8) + S4 RFA 4. TACE 5. DC Bead therapy 6. SIRT (Y-90 Sir-Sphere Therapy) 7. Some other combination
BCLC STAGING AND TREATMENT STRATEGY HCC Stage 0 PS 0, Child-Pugh A Stage A-C PS 0-2, Child-Pugh A-B Stage D PS > 2, Child-Pugh C Very early stage (0) Single < 2 cm Carcinoma in situ Early stage (A) Single or 3 nodules < 3 cm, PS 0 Intermediate stage (B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1, M1, PS 1-2 Terminal stage (D) Single Portal pressure/bilirubin Increased 3 nodules 3 cm Associated diseases Normal No Yes Resection Liver transplantation RFA Curative treatments (30%); 5-yr survival: 40%-70% (SIRT) TACE Sorafenib Palliative; 3-yr survival: 10%-40% Symptomatic (20%); survival < 3 mos Forner A, et al. Semin Liver Dis 2010; 30:61-74 Llovet JM, et al. Journal of the National Cancer Institute. 2008;100:698-711.
LIMITATIONS TO SURGERY Small left lobe Marginal functional reserve Indocyanine green retention test: 15.4% at 15 min sflr [Future Liver Remnant/Total Estimated Liver Volume] = 0.32 Target sflr = 0.40 0.50
PVE PRIOR TO SURGERY FOR HCC
LOCAL ABLATIVE TECHNIQUES RFA Distribution of Tumours According to Size, and Effect of Tumour Size on Outcome of Radiofrequency Ablation Maximum diameter of tumour (n = 82) Less than 3.0 to 5.0 Greater than 3.0 cm cm 5.0 cm Number of tumours 55 24 3 Number of tumours 48 (87.3%) 18 (75.0%) 0 (0%) showing complete ablation after 1 ablation Number of tumours 5 (9.1%) 2 (8.3%) 0 (0%) showing complete ablation after 2 ablations 96.4% 83.3% Ref: Image-Guided Radio-frequency Ablation of Liver Malignancies : Experience at Singapore General Hospital. CS Low, RHG Lo, TN Lau, London PJ Ooi, CK Ho, BS Tan, AYF Chung, WH Koo, PKH Chow. Ann Acad Med Singapore 2006 (Dec); Vol 35(12):851-857
LOCAL ABLATIVE TECHNIQUES RFA Overall survival Post resection 5 year OS 65.0 59.5% Ref: Lencioni R et al. Abdom Imaging 2009; 34:547-556 1) Lencioni R, et al. Radiology. 2005;234:961-967 2) Tateishi R, et al. Cancer. 2005;103:1201-1209. 3) Choi D, et al. Eur Radiol. 2007;17:684-692.
Probability of Survival RANDOMIZED TRIAL OF RFA VS RESECTION N = 168 HCC < 4 cm and up to 2 nodules 85% positive for viral hepatitis (77% with HBV) 1.0 0.8 0.6 0.4 0.2 OS Resection group Radiofrequency ablation group Censored 0 0 6 12 18 24 30 36 Mos Pts at Risk, n RES group 84 75 70 66 63 55 52 RFA group 84 73 67 64 58 50 46 Feng K, et al. J Hepatol. 2012;57:794-802.
RIGHT PVE + RFA S4 Right posterior PV Left PV Right anterior PV Coils Catheter in main PV Catheter in main PV
6 WEEKS AFTER PVE sflr = 0.46 New 0.8cm segment 2 lesion ICG R15 = 45.6% Segment 6 and 7 lesions stable Tbili 23umol/L Alb 34g/L PRE POST
POSSIBLE TREATMENT OPTIONS 1. Liver Transplant (beyond Milan, just beyond UCSF) 2. Right hemihepatectomy (S5-8)+ S2 RFA 3. TACE 4. DC Bead therapy 5. SIRT (Y-90 Sir-Sphere Therapy) 6. Some other combination
COMPARATIVE MEDIAN SURVIVAL (MTHS) Study AHCC05 Khor 2014 Cheng 2009 Sangro 2011 Salem 2010 Phase II MC Y90 + Sorafenib Retrospec Y90 Prospectv Sorafenib arm only Retrospec Y90 Prospectv Y90 Cohort Asian Asian Asian European US BCLC B 20.3 23.8 14.3 16.9 17.2 BCLC C 8.6 11.8 5.6 10.0 7.3 Khor AY et al Hepatology International. 2014; 8: 395-404. Sangro B et al. Hepatology 2011 Sept 2; 54(3):868-878
TC99M-MAA SCAN Segment VII tumour Ant branch PV coils Segment VI tumour Post branch Y-90 Liver-lung shunt 6.1% T/N ratio 1.6
SIRT Y-90 therapy 2 weeks later (right lobe) Uneventful Planned dose fraction 120Gy to tumour, 73Gy to normal liver, 3Gy to lung (partition modeling) Total of 0.9 GBq SIRTEX SirSpheres superselectively infused into ant. br (0.3 GBq) and post. br (0.6 GBq) of the right HA
POST-Y90 mrecist: Segment 7: PR 4.8cm 2.0cm. 50% decreased enhancement Segment 6: CR Segment 4A: PR local recurrence Segment 2: (not treated)
RFA was performed on the segment 4A, 7 and segment 2 lesions RFA POST-RFA
15 months post RFA follow up No residual or recurrent tumour at segment 7 ablation site
DISCUSSION Radioembolisation can be safely achieved after PV embolisation Little non-target embolisation risk due to few collaterals TACE is relatively contraindicated in PV thrombosis 1, but radioembolisation is safe (case series) Relatively minimal embolization effect 2 Potential for continued research 1 Llovet JM, Bruix J (2003) Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37(2):429 442 2Sato K, Lewandowski RJ, Bui JT et al (2006) Treatment of unresectable primary and metastatic liver cancer with yttrium-90 microspheres (TheraSphere): assessment of hepatic arterial embolization. Cardiovasc Intervent Radiol 29(4):522 529
DISCUSSION Radioembolisation offers possibility of tumour down-sizing for subsequent curative therapy Most HCC patients not suited for conventional curative therapy 3 Radio-embolisation + RFA a potentially curative treatment option for a non-surgical candidate Patient remained disease-free 15 months post-rfa 3 Raoul JL, Sangro B, Forner A et al (2011) Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization. Cancer Treat Rev 7(3):212 220
DISCUSSION Is ctace/ DC Bead therapy feasible in portal vein thrombosis? Yes No Is ctace/ DC Bead therapy feasible after portal vein embolization? Yes No
TACE PRIOR TO PVE Theoretical benefits: More cirrhotic liver needed for safe resection Cirrhotic liver does not regenerate as much/ as fast Inflammatory response greater hypertrophy HCC derives blood supply from arterial tree Hepatic artery buffer response may lead to increased tumor growth Arterioportal shunts within HCC can decrease effect of PVE
TACE PRIOR TO PVE P=0.022
TAE PRIOR TO PVE Yoo et al 2011 n=135 patients 71 TAE+ PVE (av. 1.2 mo after TAE) 64 PVE only Higher mean increase in FLR 7.3% vs 5.8% (p=0.035) Recurrence free survival at 5 years: 61% vs 38% Yoo H et al Ann Surg Onc 2011; 18:1251-57
ASIAN TACE IN PVTT CASE-CONTROL STUDY Segmental PVT TACE median OS 10.2months Conservative median OS 5.2months Main PVT TACE median OS 5.3months Conservative median OS 3.4months Luo et al Ann Surg Onc 2011
HEPATIC EMBOLIZATION AFTER PVE Inadequate FLR hypertrophy Hepatic artery embolization Adds component of inflammation and necrosis Nagino et al 2000 Two cases of cholangioca Negligible FLR hypertrophy after PVE TAE done for 50% of intended resection area Outcome: Liver abscess requiring drainage (n=1) Prolonged abnormal LFT. Returned to baseline after 2 weeks.
fa JVIR 2008; 19:1513-1517
SIRT FOR FLR HYPERTROPHY Vouche M, Salem R et al J Hepatol 2013 N=83 HCC (n=67), CholangioCA (n=8), met CRC (n=8) FLR hypertrophy noted at 1 month Median FLR hypertrophy of 45% after 9 months Right lobectomy HCC (HCC n=3, 4%), (CRC n=1), (Cholangio n=1). Transplant HCC (n=6, 9%)
CONCLUSION Multi-modality therapy for HCC is feasible/ ideal in intermediate stage HCC PVE for borderline resection candidates Combination therapy in PVE should be explored Consensus strategies for management of disease progression after PVE are needed
THANK YOU Acknowledgements: A/Prof Tay Kiang Hiong Prof Pierce Chow Dr Richard Lo Dr Farah Irani Dr Mark Burgmans Dr Gideon Ooi Apoorva.gogna@sgh.com.sg