Guidelines for SIRT in HCC An Evolution

Guidelines for SIRT in HCC An Evolution 2 nd Asia Pacific Symposium on Liver- Directed Y-90 Microspheres Therapy 1st November 2014, Singapore

The challenge of HCC Surgery is potentially curative in early HCC But 80% are inoperable at time of diagnosis Median survival of untreated inoperable HCC 3 8 months High recurrence rates after surgical resection 2

LOCALLY ADVANCED HEPATOCELLULAR CARCINOMA Clinical Presentation Treatment Options Consider Clinical Trial Locally Advanced HCC Good liver function Poor liver function Present for evaluation by multi-disciplinary team - Palliative treatment - Consider Clinical Trial - Transplant within UCSF Surgical resection for carefully selected cases after multidisciplinary board evaluation LOCOREGIONAL THERAPY No Vascular Invasion* Transarterial chemoembolisation (TACE) + DC-Beads [32,33] (level 1b) Selective Internal Radiation Therapy (SIRT) [34-36] (level 2b) External beam RT (alone or as part of combined modality) Sorafenib [32-35] (level 1b) With Vascular Invasion Sorafenib [37-40] (level 1b) Selective Internal Radiation Therapy (SIRT) [34-36] (level 2b) External beam RT (alone or as part of combined modality) [41,42] (level 2a) Transplantation is a consideration for HCC within the USCF expanded criteria (single tumours < 6.5cm or 2-3 tumours < 4.5cm at the most, with a total tumour diameter < 8cm) after assessment by a multidisciplinary tumour board [43,44] (level 2b) *Sorafenib may also be considered when local regional therapy is not feasible or fails [40] (level - 2b) National Cancer Center Singapore Consensus Guidelines on Liver Cancer http://www.nccs.com.sg/patientcare/comprehensivelivercancerclinic/documents/clcc guideline Final Ver to upload PDF 26092014.pdf

Main Loco-regional Therapies Trans-arterial chemo-embolisation (TACE): widely used - disease control approx 40% used mainly in HCC, NETs (includes DC Beads) Selective Internal Radiation Therapy (SIRT): higher disease control (approx 80%) SIR-Sphere, Thera-Sphere 4

Hepatology 2008; 47(1): 71-81

Guidelines for SIRT 1) ESMO Guidelines 2) NCCN Guidelines 3) APPLE Guidelines 4) National Cancer Center Guidelines 6

European Society of Medical Oncology 7

ESMO Guidelines (2010) BCLC Staging for HCC Summary of Treatment Options and Recommendations according to BCLC S. Jelic, 2010 8

ESMO Guidelines (2010) Yttrium-90 microsphere radioembolization is a recently FDAapproved, non-surgical procedure used to treat inoperable HCC 9

ESMO Guidelines (2012) C.Verslype, 2012 10

Hepatocellular carcinoma: ESMO ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up Annals of Oncology 23 (Supplement 7): vii41 vii48, 2012 11

National Comprehensive Cancer Network 12

NCCN Guidelines (2009) Pierce Chow FRCS, PhD

NCCN Guidelines (2009) Pierce Chow FRCS, PhD randomized, controlled studies on the use of radioembolization therapy in the treatment of patients with HCC are needed..

NCCN Guidelines (2012)

NCCN Guidelines (2012) may be amenable to embolization (chemoembolization, bland embolization, radioembolization) provided that the arterial blood supply to the tumor may be isolated.

NCCN Guidelines (2014) 17

NCCN Guidelines (2014) *Arterially directed therapies include transarterial embolization (TAE), chemoembolization (transarterial chemoembolization[tace] and TACE with drug-eluting beads [DEB-TACE] )and radioembolization with yttrium-90 microspheres. 18

Pierce Chow FRCS, PhD Asia-Pacific Primary Liver Cancer Expert (APPLE) conference 2014 19

Pierce Chow FRCS, PhD APPLE 2014 Consensus Workshop Apple 2014 Consensus Workshop Report 20

APPLE recommendations for SIRT 2014 first- line therapy in Advanced HCC with vascular invasion and/or which are liver dominant with bilirubin <2 mg/dl and which are Child-Pugh A or <B7 1-3. (Level B1). In this context sorafenib may be added in patients with extra-hepatic disease4. (Level B2) first-line therapy in multi-focal or bilobar HCC with high disease burden5,6. (Level B1) second-line therapy in patients with multi-focal HCC who has progressed on TACE1-3. (Level B1) bridging therapy in patients on the waiting list for cadaveric transplantation7,8. (Level B1) 21

90 Y microspheres in Patients with HCC and PVT

90 Y microspheres in Patients with HCC and PVT Data from SGH/NCC Number of SIRT administrations - single : 82.5% Khor et al 2014

Chow et al 2014

Comparative Median Survival Study AHCC05 2014 (Phase II multicenter study) Asian Patients Khor 2013 (Retrospec tive study) Cheng 2009 (Prospective Study) European Patients Sangro 2011 (Retrospective study) US Patients Salem 2010 (Prospective study) Y-90 + Sorafenib Y-90 Sorafenib Placebo Y-90 Y-90 BCLC B 20.3mo 23.8mo 14.3 mo 8 mo 16.9 mo 17.2 mo BCLC C 8.6mo 11.8mo 5.6 mo 4.1 mo 10.0 mo 7.3 mo SIRSA 1 patient down-staged to transplantation, 2 to RFA

Median Survival (months) Patient Outcomes According to Suitability for TACE in the ENRY Series No difference not reached n = 52 n = 32 n = 39 n = 55 n = 48 n = 31 (unresectable) Candidates for TACE Poor Candidates for TACE Failed TACE Sangro et al., Hepatology 2011;54:868-878

Overall Survival by BCLC Stage Data from SGH/NCC Number of SIRT administrations - single : 82.5%

Pierce Chow FRCS, PhD Downstaging for HCC: Chemoembolization VS Y90 SIRT Downstaged patients stratified according to size/distribution Table for follow-up/survivals Lewandowski, 2009 30

Tumor size changes after 3 months T3 to T2 30 20 PD 10 0-10 SD -20-30 -40-50 -60 PR +32 mo +8 mo -70 Retrospective analysis of 86 UNOS T3 patients (2000-2008; indication by MDT) TACE (43) RE (43) TACE (43) RE (43) Portal HT 77% 74% Single 53% 47% Child A 53% 56% BCLC B 85% 79% Selective Treat 56% 46% G3/4 Bil Toxicity 26% 7% MELD Pre/Post 9/9 8/9.5 Ds T3 T2 31% 58% Med. time to prog 12.8 33.3 Transplanted 26% 21% RFA 23% 42% Med Surv (cens) 18.7 35.7 Med Surv (uncens) 19.2 41.6 Recurrence 18% 22% Lewandowski, RJ, et al. Am J Transpl. 2009;9:1920-8.

SIR-Spheres microspheres in down-sizing primary liver cancers to resection, ablation or radiation lobectomy Investigator n Tx line # Outcomes Tumour Type(s) Whitney 44 SIR-Spheres 2 nd 4 th 4 R0 2 CCC; CRC; OeC Lau 71 SIR-Spheres 1 st 2 nd 4 R0 HCC Iñarrairaegui 72 SIR-Spheres >1 st 3 R0, 2 LT HCC of which 21 SIR-Spheres >1 st 3 R0, 2 LT, 1 RF UNOS stage T3 Chow 29 SIR-Spheres + sorafenib >1 st 2 RF, 1 LT HCC Barakat 1 SIR-Spheres 1 st 1 R0 HCC Ettorre 1 SIR-Spheres 1 st 1 LT HCC Miglioresi 4 SIR-Spheres 1 st 4 LT HCC Gramenzi 63 SIR-Spheres nr 2 LT HCC Saxena 25 SIR-Spheres >1 st 1 R0 CCC Coldwell 23 SIR-Spheres >3 rd 1 RF CCC Högberg 2 SIR-Spheres 1 st 2 R0 CCC Gaba 1 SIR-Spheres 2 nd 1 RL CCC retrospective data; SIR-Spheres microspheres; R0: complete surgical resection; LT: transplant; RF: radiofrequency ablation; RL: radiation lobectomy

Pierce Chow FRCS, PhD APPLE 2014 Consensus Workshop Apple 2014 Consensus Workshop Report 34

National Cancer Center Singapore 35

Thank You! 37