pSiMedica - BioSilicon

Selective Internal Radiation Therapy for
Intermediate and Advanced
Hepatocellular Carcinoma
Pierce K.H Chow
FRCSE PhD
Professor, DukeNUS Medical School Singapore
Surgical Director, Comprehensive Liver Cancer Clinic, NCC Singapore
Senior Consultant Surgeon, Singapore General Hospital
Lunch Symposium APPLE 2017
9th July 2016 Hong Kong
SGH – Surgery
Pierce Chow FRCSE PhD
What is Intermediate and Advanced HCC?
SGH – Surgery
Apple 2014 Consensus
Workshop Report
2
Pierce Chow FRCSE PhD
What is Intermediate and Advanced HCC?
SGH – Surgery
Apple 2014 Consensus
Workshop Report
3
Pierce Chow FRCSE PhD
What is Advanced HCC?
Locally Advanced HCC
Lesions confined to the liver that
are outside of the Milan criteria
with or without vascular invasion
Advanced
HCC
Metastatic HCC
• With good liver function (ChildPugh A or early B)
• With poor liver function
SGH – Surgery
Stages of Liver Cancer
Early Stage HCC
•Lesions within the Milan Criteria
•criteria:
Solitary tumour < 5cm OR < 3 tumours, each < 3cm AND No
invasion of blood vessels and no distant spread
Locally Advanced HCC
•Lesions confined to the liver that are outside of the Milan criteria
with or without vascular invasion
Metastatic HCC
• With good liver function (Child-Pugh A or early B)
• With poor liver function
National Cancer Center Singapore Guidelines on Liver Cancer
http://www.nccs.com.sg/PatientCare/ComprehensiveLiverCancerClinic/Documents/CLCC guideline Final
Ver to upload PDF 26092014.pdf
SGH – Surgery
LOCALLY ADVANCED HEPATOCELLULAR CARCINOMA
Clinical Presentation
Treatment Options
Consider Clinical Trial
Present for evaluation
by multi-disciplinary
team
Surgical resection for carefully selected cases after
multidisciplinary board evaluation
LOCOREGIONAL THERAPY
Good liver function
Locally Advanced HCC
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)
Poor liver function
 - Palliative treatment
 - Consider Clinical Trial
 - Transplant within UCSF
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
Chow et
al 2014
HCC with Portal
Vein Tumour
Thrombosis
Courtesy Kenneth Chin BSc(Hon) MD
Pierce Chow FRCSE PhD
Evidence for SIRT
in HCC with PVT
• Retrospective Studies
• Western patients
• Asian patients
• Prospective Studies
• Phase II SiRSa
• Phase III SIRveNIB
• Phase III SARAH
SGH – Surgery
Salem 2011, Hilgard 2010, Sangro 2011
Khor 2014, She 2015
Chow 2014
Chow closed
Vilgrain closed
Portal Vein Tumour Thrombosis
– Western data
Study
PVTT Status
Number of
Patients
Overall Survival (Months)
Salem et al 2010 Childs Pugh A
No PVTT
PVTT
116
81
35
17.2
22.1
10.4
Childs Pugh B
No PVTT
PVTT
122
65
57
7.7
14.9
5.6
Hilgard et al
2010
All Patients
No PVTT
PVTT
108
75
33
16.4
16.4
10.0
Sangro et al
2011
All Patients
No PVTT
PVTT
325
249
76
12.8
15.3
10.0
Courtesy Kenneth Chin MD BSc(Hon)
Survival after Y-90 Resin Microspheres in 325 patients (ENRY)
• Mainly Hepatitis C/alcohol (8 centers)
• Median Survival: 12.8 months (95% CI: 10.9-15.7)
• BCLC B: 16.9 months
• BCLC C: 10.0 months
• Failed or progressed on prior therapy
• Trans-arterial therapy
• Surgery/transplantation
• Percutaneous ablative therapy
41.5%
27.4%
18.2%
9.2%
Sangro et al. Hepatol 2011
Survival of HCC patients treated with SIR-Spheres Y-90 Resin
microspheres stratified by portal vein involvement
Survival Distribution Function
1.00
Parameter
N
Median Survival (95% CI)
Patent
Branch PVO
Main PVO
249
44
32
15.3 mo (12.4 – 18.4)
10.7 mo (7.7 – 17.1)
9.7 mo (3.9 – 11.8)
p=0.124
p<0.001
p=0.003
p<0.001
0.75
p=0.001
Patent vs. Branch PVO
Patent vs. Main PVO
Patent vs. Branch/Main PVO
Patent/Branch PVO vs. Main PVO
0.50
Western Data
Bruno 2011
0.25
0.00
N=325
0.0
N=116
0.5
N=38
N=13
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Time from Radioembolization (years)
Sangro et al. WCGIC, Ann Oncol 2011; 22 (Suppl 5): v17 Abs. O-0023.
4.5
11
Portal Vein Tumour Thrombosis
– Asian data
Study
PVTT Status
Number of
Patients
Overall Survival (Months)
Khor et al 2013
BCLC B
BCLC C
Childs Pugh A
Childs Pugh B
No PVTT
PVTT
28
71
61
39
61
41
23.8
11.8
21.7
7.1
14.4
10.1
No PVTT/HVTT
PVTT/HVTT
All Patients
No PVTT
PVTT
65
57
16
8
8
18.1
11.0
19.9
21.2
12.0
She et al
2014
Courtesy Kenneth Chin MD BSc(Hon) MD
Survival with Y-90 Resin microspheres in 103 Singapore patients
• Mainly Hepatitis B (Single Center)
• Median Survival: 14.4 months (95% CI, 11.0 – 2.2)
• BCLC B: 23.8 months
• BCLC C: 11.8 months
• Failed or progressed on prior therapy
55.4%
• Trans-arterial therapy
17.5%
• Surgery/transplantation
14.6%
• Percutaneous ablative therapy
12.6%
• Chemotherapy
10.7%
Khor et al. Hepatol Int 2014
90Y
Resin microspheres in Patients with HCC and PVT/HVT
Asian Data from Singapore
Khor 2014
• Number of SIRT administrations - single : 82.5%
Khor et al 2014
Queen Mary Hospital experience with Y-90 Resin
microspheres
• Matched cohort of 16 patients that underwent TACE
– TACE repeated every 2-3 months
– Tumour size, tumour number, presence of tumour invasion of
major branch of PV or HV
• Mainly Hep B population
Tumour characteristics
SIRT group (n=16)
TACE group (n=16)
8.4 (2.5-22)
8.0 (1.5-21.2)
1-4
9 (56.3)
10 (62.5)
>4
7 (43.8)
6 (37.5)
Presence of invasion of major branch of PV
or hepatic vein (%)
8 (50.0)
8 (50.0)
Tumour size (cm)
Tumour number (%)
She et al 2014 Hepatobiliary Surg Nutr 2014;3(4):185-193
Outcomes of Y-90 Resin microspheres
Tumour response (%)
SIRT group
(n=16)
TACE group
(n=16)
0
0
Partial response
4 (25.0)
2 (12.5)
Stable disease
5 (31.3)
5 (31.3)
Progressive disease
7 (43.8)
9 (56.3)
Complete response
19 vs 14 mths
12 vs 8 mths
OS of patients with major
vascular invasion
She et al 2014 Hepatobiliary Surg Nutr 2014;3(4):185-193
OS of all patients in the two groups
SIRTACE single Y-90 Resin
microspheres vs multiple TACE
• Pilot, open-label, randomised, prospective, cohort comparison conducted
at two European centres:
– University of Munich, Germany and Clinica Universidad de Navarra, Spain
Screening
Pre-treatment
angiography
Randomization
-30 to -1 Days
Follow-up until progression / death
Day 0
Week 6
± 1 weeks
TACE 1
6-weekly
± 2 weeks
TACE 3*
TACE n*
6-weekly assessment prior
to next procedure (as required*)
R
Baseline
assessment
TACE 2*
Week 12
± 2 weeks
Survival after
progression
or downstaging
Up to Month 60
Treatment at the
investigators’ discretion
SIRT
SIRT within 14 days of
pre-treatment work-up
• Patients received either one treatment of SIR-Spheres Y-90 resin
microspheres or a mean of 3.4 cTACE procedures
• Progression-free survival and overall survival did not differ by procedure
(p=0.374 and p=0.244, respectively)
Kolligs F, et al. Liver Int 2015
PIERCE CHOW FRCSE PHD
Portal Vein Tumour Thrombosis
18
Courtesy Kenneth MD Chin BSc(Hon)
Pierce Chow FRCSE PhD
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 . (Level B1). In this context
sorafenib may be added in patients with extra-hepatic disease.
(Level B2)
• first-line therapy in multi-focal or bilobar HCC with high
disease burden. (Level B1)
• second-line therapy in patients with multi-focal HCC who has
progressed on TACE. (Level B1)
• bridging therapy in patients on the waiting list for cadaveric
transplantation. (Level B1)
SGH – Surgery
19
Stages of Liver Cancer
Early Stage HCC
•Lesions within the Milan Criteria
•criteria:
Solitary tumour < 5cm OR < 3 tumours, each < 3cm AND No
invasion of blood vessels and no distant spread
Locally Advanced HCC
•Lesions confined to the liver that are outside of the Milan criteria
with or without vascular invasion
Metastatic HCC
• With good liver function (Child-Pugh A or early B)
• With poor liver function
National Cancer Center Singapore Guidelines on Liver Cancer
http://www.nccs.com.sg/PatientCare/ComprehensiveLiverCancerClinic/Documents/CLCC guideline Final
Ver to upload PDF 26092014.pdf
SGH – Surgery
Sequential Y-90 Resin microspheres –
Sorafenib is safe and potentially efficacious
SGH – Surgery
Chow et al 2014
Pierce Chow FRCSE PhD
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 . (Level B1). In this context
sorafenib may be added in patients with extra-hepatic disease.
(Level B2)
• first-line therapy in multi-focal or bilobar HCC with high
disease burden. (Level B1)
• second-line therapy in patients with multi-focal HCC who has
progressed on TACE. (Level B1)
• bridging therapy in patients on the waiting list for cadaveric
transplantation. (Level B1)
SGH – Surgery
22
Bilobar and/or
Large Volume HCC
Patient Outcomes According to
Suitability for TACE in the ENRY Series
Median Survival (months)
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
Survival after Y-90 Resin Microspheres in 325 patients (ENRY)
• Mainly Hepatitis C/alcohol (8 centers)
• Median Survival: 12.8 months (95% CI: 10.9-15.7)
• BCLC B: 16.9 months
• BCLC C: 10.0 months
• Failed or progressed on prior therapy
• Trans-arterial therapy
• Surgery/transplantation
• Percutaneous ablative therapy
41.5%
27.4%
18.2%
9.2%
Sangro et al. Hepatol 2011
Survival with Y-90 Resin microspheres in 103 Singapore patients
• Mainly Hepatitis B (Single Center)
• Median Survival: 14.4 months (95% CI, 11.0 – 2.2)
• BCLC B: 23.8 months
• BCLC C: 11.8 months
• Failed or progressed on prior therapy
55.4%
• Trans-arterial therapy
17.5%
• Surgery/transplantation
14.6%
• Percutaneous ablative therapy
12.6%
• Chemotherapy
10.7%
Khor et al. Hepatol Int 2014
Vascular invasion
Portal vein
Hepatic vein
Inferior vena cava
Absent
Extrahepatic metastases
Present
Absent
Child-Pugh class
A
B
C
BCLC stage
A
B
C
D
Largest tumor size (cm), mean + SD range
SGH – Surgery
32 (31.1)
6 (5.8)
3 (2.9)
62 (60.2)
12 (11.7)
24 (23.3)
Baseline
61 (59.2)
39 (37.9)
3 (2.9)
1 (1.0)
28 (27.2)
71 (68.9)
18 (17.5)
8.8 + 4.4 (1.3 – 20.0)
27
PIERCE CHOW FRCSE PHD
Bilobar/Large Volume unresectable HCC
28
Pierce Chow FRCSE PhD
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. (Level B1). In this context
sorafenib may be added in patients with extra-hepatic disease.
(Level B2)
• first-line therapy in multi-focal or bilobar HCC with high
disease burden. (Level B1)
• second-line therapy in patients with multi-focal HCC who has
progressed on TACE. (Level B1)
• bridging therapy in patients on the waiting list for cadaveric
transplantation. (Level B1)
SGH – Surgery
29
SIRTACE single Y-90 Resin
microspheres vs multiple TACE
• Pilot, open-label, randomised, prospective, cohort comparison conducted
at two European centres:
– University of Munich, Germany and Clinica Universidad de Navarra, Spain
Screening
Pre-treatment
angiography
Randomization
-30 to -1 Days
Follow-up until progression / death
Day 0
Week 6
± 1 weeks
TACE 1
6-weekly
± 2 weeks
TACE 3*
TACE n*
6-weekly assessment prior
to next procedure (as required*)
R
Baseline
assessment
TACE 2*
Week 12
± 2 weeks
Survival after
progression
or downstaging
Up to Month 60
Treatment at the
investigators’ discretion
SIRT
SIRT within 14 days of
pre-treatment work-up
• Patients received either one treatment of SIR-Spheres Y-90 resin
microspheres or a mean of 3.4 cTACE procedures
• Progression-free survival and overall survival did not differ by procedure
(p=0.374 and p=0.244, respectively)
Kolligs F, et al. Liver Int 2015
Failed/Progressed on
TACE
Patient Outcomes According to
Suitability for TACE in the ENRY Series
Median Survival (months)
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
PIERCE CHOW FRCSE PHD
Failed TACE
33
Pierce Chow FRCSE PhD
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. (Level B1). In this context
sorafenib may be added in patients with extra-hepatic disease.
(Level B2)
• first-line therapy in multi-focal or bilobar HCC with high
disease burden. (Level B1)
• second-line therapy in patients with multi-focal HCC who has
progressed on TACE. (Level B1)
• bridging therapy in patients on the waiting list for cadaveric
transplantation. (Level B1)
SGH – Surgery
34
Potential Downstaging for
Resection/Transplant
Investigator
SIR-Spheres Y-90 resin microspheres in
down-sizing primary liver cancers
Pardo ‘P4S’
Whitney
Lau
Iñarrairaegui
n
100‡
Chow
Barakat
Ettorre
44‡
71
72‡
21‡
29
1‡
1‡
Miglioresi
4‡
Gramenzi
Saxena
Coldwell
Högberg
Servajean
Gaba
63‡
25
23‡
2
1‡
1‡
of which
Tx
line
# Outcomes
Tumour Type(s)
SIR-Spheres†
≥1st
71 R0-2, 29LT 49 HCC; 7 CCC…
SIR-Spheres†
2nd–4th
4 R0
2 CCC; CRC; OeC
SIR-Spheres†
1st–2nd
4 R0
HCC
SIR-Spheres†
>1st
3 R0, 2 LT HCC
SIR-Spheres†
>1st 3 R0, 2 LT, 1 RF
UNOS stage T3
SIR-Spheres† + sorafenib >1st
2 RF, 1 LT HCC
SIR-Spheres†
1st
1 R0
HCC
SIR-Spheres†
1st
1 LT
HCC
SIR-Spheres†
1st
4 LT
HCC
SIR-Spheres†
nr
2 LT
HCC
SIR-Spheres†
>1st
1 R0
CCC
SIR-Spheres†
>3rd
1 RF
CCC
SIR-Spheres†
1st
2 R0
CCC
SIR-Spheres†
3rd
1 R0
CCC
SIR-Spheres†
2nd
1 RL
CCC
retrospective data; † SIR-Spheres Y-90 resin microspheres; R0: complete surgical resection; LT: transplant; RF:
radiofrequency ablation; RL: radiation lobectomy
‡
Pardo et al. AHPBA 2015; Abs. MO-B.02. Whitney et al. J Surg Res 2011;166:236–40. Lau et al. Int J Radiat Oncol Biol Phys 1998;40:583–92.
Iñarrairaegui et al. Int J Radiat Oncol Biol Phys 2010;77:1441‒8. Iñarrairaegui et al. Eur J Surg Oncol 2012; 38: 594-601.
Chow et al. PLoS One 2014;9:e90909. Barakat et al. World J Surg Oncol 2008;6:100. Ettorre et al. Transplantation 2010;90:930–1. Miglioresi et al. HCC2011 2011; Abs 42.
Gramenzi et al. Liver Int 2014; ePub. Saxena et al. Ann Surg Oncol 2010;251:910–6. Coldwell. WCGIC, Ann Oncol 2006;17(Suppl 6):Abs. P-102.
Högberg et al. J Radiol Protect 2012;32:439–46. Servajean et al. World J Gastroenterol 2014; 20: 5131–4. Gaba et al. J Vasc Interv Radiol 2009;20:1394–6.
Hepatic hypertrophy of contralateral lobe after Y-90 Resin
microspheres
Left-lobe hypertrophy
SGH – Surgery
mean 34.2% (SD±35.9%)
median 31.7% (range -19.0 – 106.5%)
Compensatory hypertrophy
Teo 2014
Of interest to surgeons……
1.
2.
High utility for down-staging of locally
advanced liver tumors
creates compensatory hypertrophy of contralateral lobe
…and the potential for resection/transplant
May 2012
Down-staging to resection
Feb 2014
How safe is it to resect the Liver after
down-staging liver tumours with SIRSpheres?
• Selective Internal Radiation Therapy (SIRT or
radioembolisation) is primarily used as:
• palliative treatment for inoperable primary or
metastatic liver tumours,
• SIRT can down-size or down-stage inoperable liver
tumours
• Subsequent resection appears to be serendipity
• Does radiation affect subsequent liver function?
• 4/44 patients downstaged for resection (mixed etiologies)
• Surgical therapy consisted of:
• 2 patients undergoing right hepatic lobectomy
• 1 patient - two wedge resections of segment 3
• 1 patient who had a left lateral hepatectomy with right lobe
microwave ablation.
• No evidence of liver dysfunction following resection
• None of the patients show evidence of recurrence in the liver
following resection.
2009 J Surgical Res
Safety of liver surgery following SIRT
• Matched-case analysis 840 patients: 40 patients undergoing SIRT (6), DEB*
(27) or SIRT plus DEB (7) for primary and secondary liver tumors
• Surgery performed at median 6.5 months after treatment
Limited data suggest safety if surgery is performed late
2011 HPB
PS4 Study
• Retrospective Post SIR-Spheres Surgery in
Previously Unresectable Hepatic Malignancy
Study (P4S) is an international, multicentre,
retrospective study to assess outcomes of liver
resection or transplant
• To meet the absence of robust data, the P4S data were
analysed to evaluate outcomes of liver resection or
transplantation following SIRT in patients with
unresectable hepatocellular carcinoma (HCC)
In press
PS4 Multi-site Study
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Clinica Universidad de Navarra, Pamplona, Spain: Fernando Pardo, Bruno Sangro, J Ignacio Bilbao
Klinikum Karlsruhe, Karlsruhe, Germany: Michael R Schön, Konstantinos Kouladouros
Taipei Veterans General Hospital, Taipei, Taiwan: Lee Rheun-Chuan
Newcastle Hospitals, Newcastle, UK: Derek Manas
Methodist Dallas Medical Center, Dallas TX, USA: Dhiresh Rohan Jeyarajah,
Hôpital Erasme & Institut Jules Bordet, Brussels, Belgium: Georgios Katsanos, Vincent Donckier
UZ Gasthuisberg, Leuven, Belgium: Geert Maleux
University of Bologna, Sant Orsola-Malpighi Hospital, Bologna, Italy: Antonio D Pinna, Giorgio Ercolani
St. Vincent’s Hospital, Sydney, NSW, Australia: Lourens Bester
St George Hospital, University of New South Wales, Kogarah, NSW, Australia: David L Morris,
Frances Chu
Carolinas Medical Center, Charlotte NC, USA: David Iannitti
National Cancer Center, Singapore: Pierce KH Chow
Wakefield Clinic, Wellington, New Zealand: Richard Stubbs
Austin Hospital, Heidelberg, VIC, Australia: Paul J Gow
Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy: Lucio Urbani, Caterina Vivaldi, Gianluca Masi,
Irene Bargellini
Saint Francis Hospital, Tulsa OK, USA: Kevin T Fisher
The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong: Wan-Yee Lau
Methods
• International, multi-centre retrospective study on the outcomes of liver
resection or transplantation following SIRT using SIR-Spheres 90Y
resin microspheres (Sirtex Medical; Sydney, Australia) in patients with
either:
– Primary liver cancer
•
– Metastases in the liver
• Primary endpoints:
– Peri-operative & 90-day post-operative morbidity
– 90-day post-operative mortality
•
• Secondary endpoints: – Post-operative hospital days
•
•
– Overall survival
– Timing of surgery relative to SIRT
• 16 SIRT centers in Asia-Pacific, Europe and USA
• Data were captured on baseline characteristics, prior treatment
including SIRT, liver surgery and follow-up
• Analysis used standard statistical methods
Study Design
Registered and Assessed for Eligibility
(n = 114)
Excluded from analysis
(n = 14)
• Insufficient mandatory data (n = 9)
• No liver surgery
(n = 2)
• No SIRT
(n = 1)
• <90 days follow-up
(n = 1)
†
• Transplant post-resection
(n = 1)
† included in resection sub-group only
Unresectable HCC
Non HCC 51 (HCC: 49)
± prior treatment
SIRT using
SIR-Spheres 90Y resin microspheres
± other therapies
Surgery performed
August 1998 to May 2014
Liver Resection
(HCC: 23)
Minor Resection
Major Resection
[1–2 segments resected]
[≥3 segments resected]
(HCC: 8)
(HCC: 15)
Major, but not
Extended, Resection
[3–4 segments resected]
Number of
Segments
Resected
Extended Resection
[≥5 segments resected]
(HCC: 4)
(HCC: 11)
1
2
3
4
Liver Transplantation
(HCC: 26)
5
6
Transplanted Organ
Baseline Characteristics: Disease
Characteristic
Liver Resection
(N = 23)
6 (26%)
Liver Transplant
(N = 26)
11 (42%)
Portal vein thrombosis†: PV1
PV2
PV3
PV4
1 (4%)
0
0
1 (4%)
1 (4%)
0
1 (4%)
0
Extra-hepatic metastases:
2 (8%)
0
14 (61%)
24 (92%)
3 (13%)
9 (39%)
5 (19%)
9 (35%)
Bilobar distribution:
Cirrhosis:
Viral hepatitis:
Hepatitis B
Hepatitis C
Other Treatment Prior to Surgery
Liver Resection
(N = 23)
Liver Transplant
(N = 26)
Prior liver-directed procedure:
Any:
Resection
Ablation
Vascular
Radiation to abdomen
5 (22%)
0
1 (4%)
3 (13%)
1 (4%)
7 (27%)
2 (8%)
0
6 (23%)
0
Pre-SIRT chemotherapy: None
1 line (TKI)
21 (91%)
2 (9%)
26 (100%)
0
Post-SIRT chemotherapy (TKI)
1 (4%)
0
Pre- or Post-SIRT portal vein embolisation
4 (17%)
1 (4%)
Characteristic
SIRT Prior to Surgery
Liver Resection
(N = 23)
Liver Transplant
(N = 26)
1 (4%)
21 (91%)
1 (4%)
20 (77%)
5 (19%)
1 (4%)
17 (74%)
5 (22%)
1 (4%)
23 (88%)
3 (12%)
0
5 (22%)
8 (31%)
Median total SIRT activity (IQR)
[range], GBq :
2.0 (1.7)
(0.3 – 5.0)
1.3 (1.5)
(0.3 – 3.3)
Targeted tumour burden: All
Not all
21 (91%)
2 (9%)
22 (85%)
4 (15%)
Characteristic
Intent of SIRT:
Bridge to transplant
Down-sizing
Palliative
No. of SIRT procedures: 1
2
3
SIRT to whole liver:
n (%) unless stated; SIRT: Selective Internal Radiation Therapy. GBq: gigabequerels.
Pre-Surgery Characteristics
Characteristic
ASA score:
Median (IQR)
ASA score ≥3
Total Bilirubin Grade ≥1:
Co-morbidities pre-surgery:
Any
Cardiopathy
COPD
Diabetes
Hypertension
Other
Future Liver Remnant had received SIRT:
Time from last SIRT to surgery
Median (IQR):
>6 months, n (%):
Liver Resection
(N = 23)
Liver Transplant
(N = 26)
3.0 (1.0)
14 (61%)
3.0 (1.0)
21 (81%)
4 (17%)
16 (62%)
16 (70%)
6 (26%)
1 ( 4%)
9 (39%)
13 (57%)
2 (9%)
20 (77%)
5 (19%)
1 (4%)
11 (42%)
12 (46%)
9 (35%)
5 (22%)
na
8.0 months (4.4)
16 (70%)
7.4 months (7.7)
16 (62%)
n (%) unless stated; na: not applicable; SIRT: Selective Internal Radiation Therapy.
Peri-/Post-Surgical Complications
Complication
Clavien-Dindo
(CD) grade
Liver Resection
(N = 23)
Liver Transplant
(N = 26)
Any:
CD grade ≥1
CD grade ≥3
4 (17%)
1 (4%)
13 (50%)
4 (15%)
Liver failure:
CD grade ≥1
CD grade ≥3
0
0
1 (4%)
0
Wound-specific:
CD grade ≥1
CD grade ≥3
0
0
1 (4%)
0
Cardiovascular-specific:
CD grade ≥1
CD grade ≥3
1 (4%)
0
1 (4%)
0
Pulmonary-specific:
CD grade ≥1
CD grade ≥3
0
0
1 (4%)
0
Renal-specific:
CD grade ≥1
CD grade ≥3
1 (4%)
0
2 (8%)
0
Other complications:
CD grade ≥1
CD grade ≥3
1 (4%)
1 (4%)
10 (39%)
4 (15%)
n (%) unless stated; CD: Clavien-Dindo scale;.
Outcomes for HCC in PS4 Study
Outcome
Median (IQR) duration to hospital
discharge, days:
90-day readmission rate:
All-cause mortality at:
30 days
90 days
Median follow-up from: 1st SIRT
Surgery
n (%) unless stated.
Liver Resection
(N = 23)
Liver Transplant
(N = 26)
8.0 (4.0)
11.0 (8.0)
1 (4%)
7 (27%)
0
0
0
0
38.3 months
28.5 months
43.9 months
23.7 months
Survival from surgery for HCC, stratified by procedure
Survival Distribution Function
1.00
0.75
0.50
Parameter
n
Alive
Median Survival (95% CI)
HCC Resection
HCC Transplantation
23
26
19 (83%)
24 (91%)
not calculable (42.9 – nc)
not calculable (72.1 – nc)
0.25
Censored patients
0.00
0
20
40
60
Time from First Hepatic Surgical Procedure (months)
95% CI: 95% Confidence Interval.
80
100
Conclusions
• The safety profile of post-SIRT resection and transplantation
appears consistent with published studies of hepatic resection
and transplantation
• No deaths by all-cause mortality at up to 90 days postsurgery
• Overall survival was encouraging in patients with either
hepatic resection or transplantation following SIRT using Y-90
resin microspheres
In press
Pierce Chow FRCSE PhD
Evidence for SIRT
in Intermediate and Advanced HCC
• Retrospective Studies
• Western patients
• Asian patients
• Prospective Studies
• Phase II SiRSa
• Phase III SIRveNIB
• Phase III SARAH
SGH – Surgery
Salem 2011, Hilgard 2010, Sangro 2011
Khor 2014, Teo 2014, She 2015
Chow 2014
Chow closed
Vilgrain closed
AHCC06 : SIR-Spheres Y-90 Resin microspheres versus
Sorafenib in patients with locally advanced HCC SIRveNIB
Eligibility criteria
 Locally advanced
HCC
 Child–Pugh <8 pts
 ECOG PS 0 – 1
Exclusion criteria
 Distant metastases
 Complete main
portal vein
thrombosis
Randomisation
1:1
(n=360)
Asia-Pacific, Phase III, open-labelled study
Sorafenib®
400mg b.i.d.
SIR-Spheres
Endpoints
Primary
 OS
Secondary
 TTP
 QoL
 Downstaging to
curative therapies
ECOG PS = Eastern Cooperative Oncology Group Performance Status
OS = overall survival; TTP = time to tumour progression
Eligible: Previous surgery, RFA, TACE
SGH – Surgery
Asia-Pacific HCC Trials Group 2016
SIRveNIB
Seoul,
Bundang
Ulaan Baator
Taipei
Hong Kong
Manila
Davao
Brunei
Yangon
Bangkok
Penang
Kuala Lumpur
Kuching
Singapore
Jakarta
Auckland
Bali
SGH – Surgery
27 centers 12 Countries
Pierce Chow FRCSE PhD
SIRveNIB RCT
Milan
Excludes extahepatic
metastases
SGH – Surgery
58
The SARAH Study
To determine whether SIR-Spheres Y-90 resin microspheres is
more effective on overall survival in advanced HCC than
sorafenib
Design: Prospective open-label, multi-centre, national (France) RCT
Eligible Patients:
• Unresectable HCC
• BCLC stage C or
• BCLC stage A/B:
– New lesions post-radical
therapy and unsuitable for
further radical therapy or
– No objective response after
≤2 TACE sessions
•
•
•
•
Stratify:
ECOG performance
status
Vascular invasion
Prior TACE
Institution
Randomise
1:1
n = 460
• Child-Pugh class A or B ≤7 points
• ECOG performance status 0–1
• Fit for sorafenib and SIRT
Primary endpoint:
Overall survival
Sponsor:
Assistance Publique – Hôpitaux de
Paris (AP-HP)
PI:
Prof. Valérie Vilgrain
Status:
Completed enrolment
[March 2015]
https://clinicaltrials.gov/ct2/show/NCT01482442;
SIR-Spheres
Y-90 resin
microspheres
Secondary endpoints:
sorafenib
٠ Safety and toxicity
٠ Quality of life
٠ Healthcare costs
٠ Progression-free survival (PFS)
at 6 months
Pierce Chow FRCSE PhD
Evidence and Indications for SIRT in HCC
1) For patients straddling between the intermediate and
advanced stages.
• HCC with PVT – 1st line
• Bi-lobar large volume HCC – 1st line
• Failed TACE – 2nd line
May be combined with systemic therapy sorafenib
2) For patients that are beyond the criteria for resection
with curative intent, ablation or transplantation, for
which down-staging could open the door for a radical
approach.
SGH – Surgery
60
An Expert Panel from Asia convened by
the Singapore Clinical Research Institute
• Held a one-day meeting on May 25, 2015 in the
Academia, Singapore
• A consensus view of this Panel of Experts was
reached based on the available evidence of the
literature and the Experts’ experience
SGH – Surgery
•
•
•
•
•
Wan Yee Lau, Hong Kong
Yee Leong Teoh, Singapore
Khin Maung Win, Myanmar
Rheun-Chuan Lee, Taiwan
Vanessa H de Villa,
Philippines
• Yun Hwan Joseph Kim,
Korea
• Po-Chin Liang, Taiwan
• Ramon S Santos-Ocampo,
Philippines
SGH – Surgery
• Richard Hoau Gong Lo,
Singapore
• Kieron Boon Leng Lim,
Singapore
• David Wai Meng Tai,
Singapore
• David Chee Eng Ng,
Singapore
• Farah Gillan Irani,
Singapore
• Apoorva Gogna, Singapore
• Pierce Kah-Hoe Chow,
Singapore
SGH – Surgery
Consensus: Integration of SIRT into BCLC staging system and
treatment strategy
HCC
PS 0
Child A
PS 0–2
Child A–B
PS >2
Child C
Stage 0
Very Early Stage
Stage A
Early Stage
Stage B
Intermediate Stage
Stage C
Advanced Stage
Stage D
End Stage
single <2 cm or
carcinoma in situ
single nodule or
3 nodules <3 cm
PS 0
portal vein invasion,
N1 M1 or PS 1–2
PS >2 or Child C
multinodular; PS 0
single
portal pressure;
bilirubin
normal
Resection
3 nodules <3 cm
increased
SIRT(b)
bridge no
Transplant
associated
diseases
yes
Ablation
5-yr survival 70–90% (BCLC 0); 40–70% (BCLC A)
1
()
(unless within
transplant criteria)
unilobar
bilobar
Vascular invasion. 1. Complete
fewer nodules multinodular
and/or
main PVT
smaller burden larger burden
liver-dominant; 2. EHD non
failed
bilirubin
liver dominant
TACE
<2 mg/dL;
Child A or <B7
SIRT(c)
TACE
SIRT(a)
median survival 20 mo
SIRT(d)
sorafenib
median survival 11 mo
down-staging in the context of a multi-disciplinary board decision
3 Sorafenib may be added in EHD
SGH –toSurgery
bridging
cadaveric transplant
symptomatic
survival <3 mo
Conclusion
The consensus panel agreed that SIRT can be
considered in the following HCC patients
•
•
•
•
SIRT as a treatment option to TACE
SIRT as a treatment after failed TACE
SIRT as a bridging therapy in liver transplantation
SIRT as a treatment for HCC with portal vein
tumor thrombosis
SGH – Surgery
Pierce Chow FRCSE PhD
Thank
You!
SGH – Surgery
66