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Thierry de Baere
Institut Gustave Roussy - VILLEJUIF - FRANCE
locoregional treatment of unresectable HCC
Nom du module
T. de Baere Disclosure of interest :
Grants/research supports: Galil; Terumo
Honoraria / consultation fees: AstraZenecca,
Boston sceintific, Eisai, GE Healthcare,
Guerbet, Janssen , MSD, Terumo.
Sponsored speaker’s bureau : Terumo,
Guerbet, SIRTEX, Boston sceintific
GIDEON: The Largest Global Observational Study
Completed in HCC (n = 3,202)
%AP
n=928
EU
n=1113
LA
n=90
USA
n=563
Japan
n=508
Overall
N=3202
All LRTs 67.2 43.5 27.8 49.4 84.4 57.5
TACE 60.3 33.1 13.3 37.1 71.3 47.2
Conventional
TACE (Lipiodol) *90.2 59.2 83.3 40.7 82.3 73.9
DEB-TACE * 2.9 36.1 16.7 39.7 1.7 15.9
Surgical treatment 24.2 15.5 5.6 9.4 43.3 21.1
Ablation 15.5 20.2 17.8 12.6 50.0 22.2
* For patients who received TACE: n=1511; AP=560, EU=368, LA=12, USA=209, Japan=362;
AP, Asia-Pacific; LA, Latin America; LRTs, Loco-Regional Therapies
Pre-Sorafenib Therapy for HCC by Geographical Region
Lencioni R et al. Int J Clin Pract 2014;68:609-617
(Journal of Hepatology 2018)
ESMO Guidelines for HCC - 2019
100 patients HCC < 5 cm
Microsatellites at pathology
46/100 (46%)
Mean dist tumor/satellites : 9.9 mm
TTumor < 2.5 cm
No satellites farther than 5 mm
Excepted one tumor.
Sasaki A et al. Cancer 2005;103:299-306
Ablation
local efficacy according to tumor size
• HCC complete necrosis
– Smaller than 3 cm 90%
– 3.1 to 5 cm 61%
– Greater than 5 cm 23 %
– 2cm or smaller 97.2 %
Livraghi, Radiology, 2000
2.5/3 cm 4/5 cm
Livraghi, Radiology 1999
RF ablation local efficacy :
Livraghi T, Hepatology 2007
Huang J et al. Ann Surg 2010;252:903-912
● 230 patients, 94% Child A, within Milan criteria
● Single ≤ 5 cm, up to 3 ≤ 3 cm
Feng K et al. J Hepatol 2012;57:794-802
● 168 patients, 49% Child A
● Up to 2 HCC tumors ≤ 4
cm
p = 0.342
Pompili M et al. J Hepatol 2013;59:89-97
729 consecutive single HCC <3 cm treated with surgey (n=302) or RFA (n=427)
(Peng ZW; JCO 2013. 31 426-432)
HCC : d < 7 cm (single), or n<3 & <3cm
TACE-RFA (n=94) Vs RFA (n=95)
OS : (HR=0.525; 95% CI = 0.335-0.822; P = .002 )
DFS : (HR=0.575; 95% CI = 0.374-0.897; P = .009)
OS : treatment (HR=1.87), tum. Size (HR=1.73), tum. number (HR=2.49)
Combined treatment are doing better ?
Location >>>> central vs peripheral
ESMO Guidelines for HCC - 2019
In case of long-anticipated waiting time (> 3 months), resection, local ablation or
TACE to minimise the risk of tumour progression / ‘bridge’ to transplant [III, B]
Technical recommendations on TACE from expert groups
CHINA
TAIWAN
EUROPE
AND US
INTER
NATIONAL cTACE
cTACE
DEB-
TACE
DEB-
TACE
de Baere T, et al.
Cardiovasc Intervent Radiol 2016;39:334-343
China manual for clinical practice for transarterial
chemoembolization treatment of hepatocellular carcinoma
(2018 edition)
Lencioni R, et al.
Cardiovasc Intervent Radiol 2012;35:980-985
Chang PY, et al.
Liver Cancer 2018;7:312-322
cTACE, conventional transarterial chemoembolisation; `
DEB-TACE, drug-eluting bead-transarterial chemoembolisation
Conventionallipiodol-based TACE is the standard
of care for patients with intermediate HCC,
although using DEB-TACE is an option to
minimis esystemic side effects of chemotherapy
[I, C]
Discontinue after complete response @ mRECIST
At least 2 TACE treatment before changing treatment
44% to 65% of non responders to the 1st course of TACE
demonstrated response after the 2nd course of TACE 1,2
Usually, 2 subsequent TACE 2 to 8 weeks apart are performed
• Indication for subsequent TACE
• treatment tolerance
• treatment efficacy
• need for subsequent treatment, until complete response
1. Georgiades C. Radiology 2012; 265:115-23
2. Choi J. J Hepatol 2014; 60:1212-8
Indication new TACE
• New progression in a treated location that previously responded
• New tumor foci in a non treated part of the liver
• Treatment schedule : Large Unilobar Tumors
Even if unilobar, two sessions 2-4 weeks apart
Patients with more than 50% liver replacement should be carefully
evaluated with multidisciplinary team experts in the field
• Treatment schedule : Bilobar Tumors
Separate treatment sessions for both hepatic lobes 4-8 wks apart
CT and clinical evaluation in between looking for possible complications and tolerance that
might require a longer time interval between sessions.
Liver enzymes returned to baseline before next treatment session is recommended
Treatment strategy with TACE
(Raoul JL. Cancer Treatment Reviews 72 (2019) 28–36)
STATE: selection for transarterial chemoembolization treatment; HAP: hepatoma arterial-embolisation prognostic;
ART: Assessment for Retreatment; ABCR: Alpha- foeto Protein, BCLC, Child-Pugh, Response.
Outside clinical trials, the use of therapeutic algorithms based on prognostic
scores of unknown predictive values is currently not recommended for the
selection of candidates to initial and repeated TACE [III, A]
Unresectable
early stage
Within the Milan criteria
(bridging therapy)
TACE(More evidence for cTACE)
Liver transplantation
Intermediate stage
Out of the Milan criteria
TACE
Response
In Milan criteria
1st TACE Systemic treatment
Advanced stage
Worsening liver function or
PS
2nd TACECE-CT or CE-MRI
No objective
response
Objective
response
TACE
on-demand
EHS, PVT, PD in treated area
worsening in CP or PS
New lesionsTACE or
cTACE + RFA
Scores to be
validated
Scores to be
validated
Segmental PVTT
(systemic treatment not feasible)
More evidence for cTACE
Strong evidence
Further trials required
cTACE + RFA
(Kudo M. Lancet Gastroenterol Hepatol 2018; 3: 37-46)
Median OS in patients with vascular invasion
- 13.3 months (orantinib group) / 16 months (placebo group)
Median OS in patient without vascular invasion
- 31·4 months (orantinib group) / 34·8 months (placebo group)
cTACE : lipiodol + anti-tumour drugs and embolisation materials
cTACE
Photomicrographs of doxorubicin loaded microspheres
Scale bars = 200µm
LifePearl DC Bead
Hepasphere
Tandem
(J Vasc Interv Radiol 2016. 27:1425-31)
36
37
38
39
40
41
0 0,5 1 1,5 2
Do
xo
rub
icin
Loa
de
d (
mg
/mL
bea
d)
Time (hr)
LifePearl (N=5)
DC Bead (N=5)
Tandem (N=5)
Hepasphere (N=4)
LIFEPEARL ANTHRACYCLIN REGISTRY IN SELECTIVE CHEMO-EMBOLIZATION
OF PATIENTS WITH UNRESECTABLEHEPATOCELLULAR CARCINOMA
Thierry de Baere1, Gontran Verset², Boris Guiu³, Maxime Ronot4 , Patrick Chevallier5, Géraldine Sergent6, Pierre Goffette7
Liver and Biliary damages
idarubicin (N=36)
doxorubicin (N=149)
Biloma 2.8% (1/36) 5.4% (8/149)
Portal vein thrombosis
2.8% (1/36) 6.0% (9/149)
Portal vein branch narrowing
0 1.3% (2/149)
Bile duct dilation 2.8% (1/36) 5.4% (8/149)
Global Hepatic damages
(Biloma, Portal vein thrombosis, Portal vein branch narrowing, Bile
duct dilation)
8.3% (3/36) 18.1% (27/149)
Bevacizumab/Avastin
Beyond chemotherapyFuture of drug delivery
PLGA nanoparticles
PLGA nanoparticles
Study population
•Confirmed HCC
•Unsuitable for curative
therapy,
e.g. surgical resection,
ablation, transplantation
•Disease amenable to TACE
•No extrahepatic disease
•Child-Pugh A to B7
•ECOG 0 or 1
•Exclude Vp3 and Vp4
•Exclude patients with
clinically significant
cardiovascular disease or
history of arterioembolic
event
Primary endpoint:
PFS for Arm A versus
Arm C (BICR)
Secondary
endpoints:
PFS for Arm B versus
Arm C (BICR), OS,
PROs
Other endpoints:
Safety,
immunogenicity, PK
EMERALD-1 (locoregional HCC)Phase 3, randomised, double-blind, placebo-controlled study (recruiting)
Arm C
TACE + placebo
Arm A
TACE + durvalumab
Arm B
TACE + durvalumab +
bevacizumab
R
BICR, blinded independent central review; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; OS, overall survival; PFS,
progression-free survival; PK, pharmacokinetics; PROs, patient-reported outcomes; TACE, transarterial chemoembolisation
http://clinicaltrials.gov/ct2/show/NCT03778957
N=600
Investigator-initiated studies – IO
plus TACEShort title
(NCT number)
Country
Phase
(status)Design / population HCC type Regimen
IMMUTACE
(NCT03572582)
Germany
Phase 2
(recruiting)
Estimated enrolment: N=49
(single-arm, open-label)
Key inclusion criteria:
•Confirmed intermediate-stage HCC
•Not eligible for resection or local ablation
•No prior treatment with TACE
•No prior systemic therapy
Primary endpoint: ORR
• Child-Pugh Class A
• Multinodular or large,
solitary HCC
• Tumour burden <50%
of liver volume
• TACE in combination with
nivolumab
• 4-week cycles from the
starting date of TACE
• Second TACE repeated on
Day 1 of cycle 3
• Nivolumab (240 mg IV
q2w) started 2–3 days
after first TACE, until PD
(up to 2 years)
PETAL
(NCT03397654)
United Kingdom
Phase 1/2
(recruiting)
Estimated enrolment: N=26
(single-arm, open-label)
Key inclusion criteria:
•Confirmed HCC
•Not eligible for resection or local ablation
•No extrahepatic metastasis
•No prior treatment with TACE or
systemic therapy for HCC
Primary endpoint: safety and tolerability
• Child-Pugh score <7
• ≥1 unidimensional
lesion measurable by
CT scan or MRI based
on mRECIST criteria
• TACE using doxorubicin
solution (60 mg dose) and
gelatin sponge particles
• Pembrolizumab (200 mg
q3w) 30 or 45 days after
TACE for up to 1 year
CT, computed tomography; HCC, hepatocellular carcinoma; IO, immuno-oncology; IV, intravenous; MRI, magnetic resonance imaging; ORR, objective response rate; PD,
disease progression; q2w, every 2 weeks;
q3w, every 3 weeks; TACE, transarterial chemoembolisationCourtesy of R Lencionni
Investigator-initiated studies – IO
plus TACEShort title
(NCT number)
Country
Phase
(status)Design / population HCC type Regimen
Nivolumab with
deb-TACE in
patients with liver
cancer
(NCT03143270)
United States
Early
Phase 1
(recruiting
for >1 year)
Estimated enrolment: N=14
(non-randomised, open-label)
Key inclusion criteria:
•Confirmed HCC
•Not amenable to curative surgery or
transplant
•Amenable to deb-TACE to treat all sites
of disease in one session
•No vascular invasion or extrahepatic
spread
•No prior embolisation and / or ablation
•No prior immunotherapy
Primary endpoint: safety
• Child-Pugh Class A
• Measurable disease
per RECIST v1.1
• BCLC stage B
• Deb-TACE on Day 0 (±5
days) for all cohorts
Cohort 1:
• Nivolumab (240 mg IV
q2w) will be administered 2
weeks after deb-TACE for
up to 1 year
Cohort 2:
• Nivolumab (240 mg IV
q2w) starting 4 weeks prior
to
deb-TACE (Week -4) for up
to
1 year
• No nivolumab on the day of
deb-TACE
Cohort 3:
• Nivolumab (240 mg IV
q2w) starting 4 weeks prior
to
deb-TACE (Week -4) and
continue for up to 1 yearBCLC, Barcelona Clinic Liver Cancer; deb-TACE, Drug-eluting bead TACE; HCC, hepatocellular carcinoma; IO, immuno-oncology; IV, intravenous;
q2w, every 2 weeks;
TACE, transarterial chemoembolisationCourtesy of R Lencionni
Investigator-initiated studies – IO
plus TACEShort title
(NCT number)
Country
Phase
(status)Design / population HCC type Regimen
Durvalumab and
tremelimumab
following
deb-TACE in
patients with
intermediate
HCC
(NCT03638141)
United States
Phase 2
(not yet
recruiting)
Estimated enrolment: N=30
(non-randomised, open-label)
Key inclusion criteria:
•New diagnosis of intermediate HCC
•Disease amenable to deb-TACE
•No concurrent anticancer therapy or
therapy received ≤30 days prior
to study
Primary endpoint: ORR (mRECIST)
• Measurable disease
• No diffuse HCC,
vascular invasion or
extrahepatic disease
• Main portal vein
thrombosis present
on imaging
• Four doses of
durvalumab (1500 mg
IV q4w) starting at Week
2
• At Week 15, patients
with CR will receive 9
doses of durvalumab
(1500 mg
IV q4w)
Cohort A:
• Single dose of
tremelimumab (300 mg
IV) at Week 2
Cohort B:
• Four doses of
tremelimumab (75 mg
IV q4w) starting at Week
2
CR, complete response; deb-TACE, Drug-eluting bead TACE; HCC, hepatocellular carcinoma; IO, immuno-oncology; IV, intravenous; ORR, objective
response rate; q4w, every 4 weeks; TACE, transarterial chemoembolisation
Courtesy of R Lencionni
Left radioembolization Right radioembolization
Right radioembolization
microspheres
fibrosed hepatic parenchyma
viable ADK
Fibrosis &
chronic inflammation
hepatic parenchyma
m-spheres & fibrosis
dense fibrosis
residual tumor
Sharma RA et al. J Clin Oncol 2007; 25: 1099–1106.
1000 Gy100 Gy
PS-018 | Role of 99mTc-Macroaggregated Albumin SPECT/CT based dosimetry in predicting survival and tumor response of patients with locally advanced and
inoperable HCC treated by SIRT with yttrium-90 resin microspheres, a cohort from SARAH study
Anne-Laure Hermann1, Arnaud Dieudonné2, Ronot Maxime1, Sanchez Manuel2, Pereira Helena3, Chatellier Gilles3, Castera Laurent4, Lebtahi Rachida5, Valerie Vilgrain1, Sarah Trial Group6
1 Hôpital Beaujon, Radiology, Clichy, France; 2 Hôpital Beaujon, Nuclear Medicine, Clichy, France; 3 Hôpital Européen Georges Pompidou, URC-Biostatistical Unit, Paris Cedex 15, France; 4 Hôpital Beaujon, Hepatology, Clichy, France; 2 Hôpital Beaujon, Nuclear Medicine, Clichy, France; 6 Hôpital Beaujon,
Radiology, Paris, France
5.8 months [95%CI 4.47–6.67] with 0 predictor
33.9 months [95%CI 9.46–NA] with 3 predictors
Variable HR 95% CI p
Tumour burden (%)
(> 25% vs. ≤ 25%) 1.85 1.15 – 2.97 0.0108
ALBI grade (A2 vs. A1) 1.91 1.15 – 3.20 0.0133
Tumour-absorbed dose
(< 100 Gy vs. ≥ 100 Gy) 2.70 1.72 – 4.25 < 0.0001
Courtesy of Maxime Ront
• Personalyzed dosimetry approch (PDA) vs standard dosimetry approach (SDA)
• Specific inclusion criteria : 1 tumor larger than 7 cm / Hepatic > 30%
Interim analysis of the multi-center randomized
phase 2 in advanced HCC (DOSISPHERE)
PDA :
> 205 Gy (If possible > 250-30 ) to the tumor,
Normal perfused liver Dose < 120 Gy
SDA :
120±20 Gy to the perfused liver
• Mean tumor dose (TD) was 324±131Gy (PDA) vs 221±110Gy (SDA), p=0.01.
TD = 329±145Gy for responders vs 225±110Gy for non responers p<10-3.
RRindex lesion : 71.4% (PDA) vs only 35.7% (SDA), p=0.007
Trial primary endpoint reached
Radioembolization : is it right or left ?
SIRT is not recommended as first line therapy for
patients in intermediate or advanced stage [I,E]
2 mois 4 mois 7 mois
Left radioembolization … to the right liver
7 mois
(Garlipp B, de Baere T, Seidensticker M. Hepatology 2014.59:1864-1873)
26 matched pairs
PVE : 61.5 ± 39 % after 33 [24-56] days
RE : 29 ± 28 % after 46 [27-79] days (p<0.001)
JHEP 2014
33 patients had surgery
17/33 (52%) Complete pathologic necrosis
16/33 (48%) Pathologic necrosis > 90%
Baseline Demographics (n=102)
Investigator-initiated studies – IO
plus SIRT / TAREShort title
(NCT number)
Country
Phase
(status)Design / population HCC type Regimen
NASIR-HCC
(NCT03380130)
Spain
Phase 2
(recruiting
for >1 year)
Estimated enrolment: N=40
(single-arm, open-label)
Key inclusion criteria:
•Confirmed HCC
•Patients with fibrolamellar carcinoma are
not excluded
•No history of hepatic encephalopathy
•No prior immunotherapy
Primary endpoint: safety
• Preserved liver
function (without
cirrhosis or with
compensated cirrhosis
in Child-Pugh Class
A)
• Cirrhosis absent,
non-viral or due to
hepatitis C or B virus
infection
• SIRT will be performed in
a single session using SIR-
Spheres resin
microspheres
• After 3 weeks, nivolumab
(240 mg IV q2w) will be
initiated for 8 cycles or
until PD
Y90
radioembolisation
with nivolumab in
Asians with HCC
(NCT03033446)
Singapore
Phase 2
(recruiting
for >2
years)
Estimated enrolment: N=40
(single-arm, open-label)
Key inclusion criteria:
•Confirmed HCC
•Not suitable for resection or liver
transplant
•No prior Y90 radioembolisation therapy
•No prior immunotherapy
Primary endpoint: ORR
• Child-Pugh Class A
• Measurable disease
with target lesion in
liver
(≤1 lesion >20 mm
with conventional
techniques or as >10
mm with spiral CT
scan)
• Y90 dose based on BSA
and size of liver tumour
• Dose modifications
required for percent lung
shunting between 10 and
20% on the Tc-99MMA
scan
• 21 days after
radioembolisation,
nivolumab (240 mg IV
q2w) administered over 30
minsBSA, body surface area; CT, computed tomography; HCC, hepatocellular carcinoma; IO, immuno-oncology; IV, intravenous; ORR, objective response rate; PD, disease
progression;
q2w, every 2 weeks; SIRT, selective internal radiation therapy; TARE, transarterial radioembolisation Courtesy of R Lencionni
Investigator-initiated studies – IO
plus SIRT / TAREShort title
(NCT number)
Country
Phase
(status)Design / population HCC type Regimen
Nivolumab and
Y90 in patients
with advanced
liver cancer
(NCT02837029)
United States
Phase 1
(recruiting
for >2
years)
Estimated enrolment: N=35
(single-arm, open-label)
Key inclusion criteria:
•Confirmed advanced HCC
•Not eligible for resection or liver
transplant
•No prior immunotherapy
Primary endpoint: MTD
• Child-Pugh Class A or
B
• ≥1 measurable lesion
using RECIST
guidelines
• Y90 glass microsphere
• Nivolumab administered
4 weeks after Y90, over
30–60 mins on Days 1 and
15
• Course repeated every
28 days (until PD or
unacceptable toxicity)
Nivolumab and
Y90 in patients
with liver cancer
undergoing
surgical resection
(NCT03812562)
United States
Early
Phase 1
(recruiting)
Estimated enrolment: N=12
(single-arm, open-label)
Key inclusion criteria:
•Confirmed HCC
•Eligible for resection based on preserved
hepatic function and lack of clinically
significant portal hypertension
•No prior immunotherapy
•No chemotherapy or radiotherapy ≤28
days prior to registration
Primary endpoint: Recurrence rate
• Child-Pugh Class A or
B
• Measurable disease
per RECIST v1.1
• Y90 glass microspheres
• Nivolumab administered
within 1–2 weeks after
Y90, over
30 mins on Day 1
• Treatment repeated q2w
for up to 4 doses (until PD
or unacceptable toxicity)
• If adequate FLR and at
least SD, patients will
undergo resection within 2
weeks of last dose of
nivolumab
FLR, future liver remnant; HCC, hepatocellular carcinoma; IO, immuno-oncology; MTD, maximum tolerated dose; PD, disease progression; q2w, every 2 weeks; SD, stable
disease; SIRT, selective internal radiation therapy; TARE, transarterial radioembolisationCourtesy of R Lencionni
Investigator-initiated studies – IO
plus SIRT / TAREShort title
(NCT number)
Country
Phase
(status)Design / population HCC type Regimen
Y90, ipilimumab
and nivolumab
for uveal
melanoma with
liver metastases
(NCT02913417)
United States
Phase 1/2
(recruiting
for
>2 years)
Estimated enrolment: N=18
(single-arm, open-label)
Key inclusion criteria:
•Confirmed metastatic uveal melanoma
•Liver metastasis
•≤1 prior systemic therapy
•No prior ipilimumab or CTLA-4
inhibitor
•No CNS metastases
Primary endpoint: safety and
tolerability
• Measurable disease
by RECIST
• Liver tumour
volume ≤50%
• Y90 given by injection
into the hepatic artery in
two treatments, one for
each lobe
• Four doses of concurrent
ipilimumab (3 mg/kg
q3w) and nivolumab (1
mg/kg q3w) 3–5 weeks
after Y90
• After 4 cycles,
nivolumab
(3 mg/kg q2w) given
until PD or up to 3 years
CNS, central nervous system; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; HCC, hepatocellular carcinoma; IO, immuno-oncology; PD,
disease progression; q2w, every 2 weeks; q3w, every 3 weeks; SIRT, selective internal radiation therapy; TARE, transarterial radioembolisation
Courtesy of R Lencionni
Merci