Stereotactic Ablative RT in HCC

Stereotactic Ablative
RT
in HCCMi-Sook Kim, MD, PhD
Department of Radiation Oncology
Korea Institute of Radiological and Science

Contents
• Published Phase II study
• Retrospective Analysis (published or under
review)
• Our methodology for HCC treatment

SABR for HCC: Phase 2 trial
(Kang, Kim et al, Cancer 2012;118:5424-31)

Inclusion criteria for HCC
• Inoperable, without metastatic lesion
• 1 – 3 lesions
• Not indication for RFA d/t location, invisible
in Sono etc
• TACE #1 – 5 : Incomplete response
• Cumulative longitudinal diameter < 10 cm
• Child-Pugh class A - B7

Survival outcomes
LCR* : 95%
OSR† : 69%
DFSR‡ : 34%
* Local control rate
†Overall survival rate
‡Disease free survival rate
• Total 47 pts are enrolled(2008-2011)
• Tumor size : 3 (1.3-8 cm)

Toxicity
Table 4. Grade 3 or 4 Toxicities According to the Common Toxicity Criteria for
Adverse Events Version 3.0 Grading Scalea
Toxicity
Grade 3 Grade 4
No. of
Patients
%
No. of
Patients
%
Hyperbilirubinemia 2 4.3 - -
Thrombocytopenia 5 10.6 - -
Ascites 2 4.3 - -
Gastrointestinal ulcer 3b 6.4 2c 4.3
a The Child-Turcott-Pugh class increased from A to B in 6 patients (12.8%) and
reduced from B to A in 1 patient (2.1%).
bGastroduodenal ulcer or colonic ulcer
cGastric ulcer perforation.

Retrospective Analysis
Dose escalation study
No constraint (n=38)
86 patients
Toxicity analysis
(n=61)
4 fractionations (n=22)
Intrahepatic progression (n=15)
Follow-up loss (n=7)
Previous RT history (n=1)
Two course SABR (n=1)
Planning data loss (n=1)
Phase II study
Constraint (n=47)
Tx according to protocols
But no enrollment in studies
(n=23)
J Surg Oncol 2010;102:209 Cancer 2012;118:5424
Survival outcome
anaylsis (n=82)
Size > 7.0 cm (n=4)

R² = 0.809
0
20
40
60
80
100
30 40 50 60 70
2-year local control
Overall survival (OS) as SABR
DoseSimple correlation (82 patients with 95 lesions)
SABR dose (Gy) SABR dose (Gy)
Overall
survival
Localcontrol
R² = 0.884
0
20
40
60
80
100
30 40 50 60 70
2 year overall survival

TCP by SABR dose
TumorControlProbability(TCP)
SABR dose (Gy)
Lesions with LD ≤ 7 cm
TCP50=34.9 Gy, γ50=1.22
Dose at 90% of TCP
=54.8 Gy (95% CI, 51.2~58.4)
Dose at 80% of TCP
=46.4 Gy (95% CI, 43.3~49.5)
Unpublished data
Proposed SABR
dose
: 54 Gy/ 3 fractions

0
20
40
60
80
100
0 12 24 36 48 60
Time from SBRT (months)
0
20
40
60
80
100
0 12 24 36 48 60
Local control as SBRT dose
- Stratification as Longest diameter(LD) -
p=0.0340
55.5-60 Gy (n=21)
33-54 Gy (n=29)
0
20
40
60
80
100
0 12 24 36 48 60
55.5-60 Gy (n=15) 55.5-60 Gy (n=1)
33-54 Gy (n=18) 33-54 Gy (n=11)
p=0.0758 p=0.5194
LD ≤ 30 mm 30 mm< LD ≤ 50 mm LD > 50 mm

Independent Prognostic factor
affecting OS
0
20
40
60
80
100
0 12 24 36 48 60
>54 Gy
(n=32)
<45 Gy
(n=10)
2yr :
71%
2yr :
30%
p=0.001
2yr :
64%
45-54 Gy
(n=40)
5yr :
39%
0
20
40
60
80
100
0 12 24 36 48 60
BCLC A
(n=43)
BCLC B,C
(n=39)
2yr :
74%
2yr :
51%
p=0.012
5yr :
58%
5yr :
21%
By SABR dose By BCLC stage
Multivariate (total pts No :82)

Normal liver constraint
Initial
CP
score
End points of
hepatic toxicity
Probability of toxicity %
Volume to receive <15
Gy
Volume to receive <17
Gy
≥700 cc <700 cc ≥700 cc <700 cc
5
N=45
Hepatic toxicity*≥grade 2 3 (1/39) 0 2 (1/43) 0
The progression of CP clas
s
0 0 0 0
A worsening of MELD scor
e>5
0 0 0 0
Non-classic RILD 0 0 0 0
Classic RILD 0 0 0 0
6-8
N=15
Hepatic toxicity*≥grade 2 33 (3/9) 83 (5/6) 45 (5/11) 75 (3/4)
The progression of CP clas
s
11 (1/9) 67 (4/6) 27 (3/11) 50 (2/4)
A worsening of MELD scor
e>5
11 (1/9) 50 (3/6) 18 (2/11) 50 (2/4)
Non-classic RILD 0 50 (3/6) 18 (2/11) 25 (1/4)
Classic RILD 0 0 0 0
 At least 700 ml of normal liver ≤ 17 Gy (CP A5)
≤ 15 Gy (CP A6-B7)
Unpublished data

Liver dose prescription: From 60 Gy
672cc
17 Gy 60Gy/3 fx’s17 Gy
693cc
57 Gy/3 fx’s
710cc
17 Gy 54 Gy/3 fx’s

Gastroduodenum constraint
3/5
0/26
2/16
5/47
0
10
20
30
40
50
Preexisting GI ulcer before
SABR
Severe GI…
Bae et al, Int J Radiat Oncol Biol Phys 2012;84:e469, Kang et al, Cancer 2012;118:5424
 Ulcer by EGD (–) : Dmax ≤ 35
Gy
(+) : Dmax ≤ 28 Gy

SABR technique in
KIRAMS
Slow CT +conventional helical CT -> ITV
GTV = visible tumor on CT
PTV = GTV(=ITV)+2 mm
95-98% of PTV is covered by prescribed
dose

OAR (mandatory)
OAR Dose-constraints
Normal liver (rV) rV17≥700 (CP A5)
rV15≥700 (CP A6-B7)
Esophagus (Dmax) 27 Gy
Stomach (Dmax) Ulcer(+) 28 Gy, Ulcer(–) 35 Gy
Duodenum (Dmax) Ulcer(+) 28 Gy, Ulcer(–) 35 Gy
Small bowel (Dmax/V25) Dmax 30 Gy, V25≤20 ml
Large bowel (Dmax/V25) Dmax 30 Gy, V25≤20 ml
Spinal cord (Dmax/D0.25 ml) Dmax 22 Gy, D0.25 ml18 Gy

Unsuitable for Op, TPL, RFA
TACE 1-5 sessions
NCT01825824
60 Gy/3 Fx
NCT01850667
45~60 Gy/3 Fx
NCT01850368
40 Gy/4 Fx
No Clinical
Trials
Debulking
SBRT
Sum ≤ 5 cm & 3 cm from GI
tract
Sum ≤10 cm
Ye
s
No Ye
s
No
Normal Liver Dose-Constraints
rV15<700 ml (CP A5), rV17<700 ml (CP A6-B7) No
Incomplete TACE
Complete TACE Observation

Follow-up
Initially or Recurrent HCC
BCLC 0/A/B (1-3 nodules≤7 cm)
TACE #1-2
Eligibility Check
Informed Consent
SABR (42-54 Gy in 3 fractions)
Within 14 days (Time b/w fx`s ≥ 48
hrs)
Response evaluation at 2 mo
Non PD PD
2nd Response Evaluation at
6 mo
Repetitive TACE or other
therapy
Non PD PD
EGD at 2 months
CBC, Admission panel, PT, AFP
EGD within 6 months
CBC, Admission
panel, PT, AFP
4wks after TACE
Inclusion
• Diagnosis of HCC (Patho-
, Radio-)
• BCLC 0, A, B (within 14D)
• CP score A-B7 (within 14D)
• Age≥18 years
• ECOG PS 0-2
• Measureable hepatic disease
• Unsuitable for resection,
transplant, or local ablation
(eg, RFA, PEI)
• Unsuitable or refractory to
TACE of 1-2 sessions
• Normal liver volume ≥ 800 ml
Exclusion
• Sum of longest diameter > 7
cm
• # of lesions > 3 (nodules)
• Extrahepatic metastases or
malignant nodes
• Direct tumor extension into the
stomach, duodenum, small
bowel or large bowel
• Prior radiotherapy to upper
abdomen
• Prior internal
Inclusion
Exclusion
Estimated Enrollment: 73 patients
Estimated primary completion date
: 2012.6 – 2014.06

: 2012.6 – 2013.12
Inclusion
• Age≥18 years
• Initially or Recurrent HCC
• Unsuitable for
resection, transplant,
or local ablation (eg, RFA, PEI)
• CP score A-B7
• ECOG PS 0-1
• Sum of longest diameter ≤ 5
cm
• HCC with 3 cm apart from GI
tract
• Incomplete response after
• A single lesion or multiple
lesions including portal vein
thrombosis included in radiation
field with one or consecutive
sessions of SABR
• No extrahepatic metastases or
malignant nodes
• No liver cirrhosis related
complication
• No severe other co-morbidity
ExclusionFollow-up
TACE #1-5
Eligibility Check
Informed Consent
SABR (60 Gy in 3 fractions)
hrs)
Non PD PD
6 mo
therapy
Non PD PD
EGD at 2 months
PET at 6 months as possible
EGD within 6 months
CBC, Admission
panel, PT, AFP
4wks after TACE
Inclusion
Exclusion
NCT01825824
KROG 12-02
KCT0000422

: 2012.10 – 2013.12
Inclusion
• Age≥18 years
• ECOG PS 0-1
• HCC with major portal vein
tumor thrombosis (tumor
thrombosis in the main portal
vein or 1st branch of portal
vein)
• CP score A-B7
• Patients can have extra-
hepatic disease; provided the
hepatic disease is the highest
burden, the extra-hepatic
disease is low burden and
potentially treatable with
RT, chemotherapy and target
agent etc;
• Patient survival is expected to
be as least 6 months
Exclusion
• Prior TACE ≥ 4 after diagnosis
of major portal vein tumor
thrombosis
• Severe complication caused by
liver cirrhosis
±Additional
Treatment
TACE #0-3
Eligibility Check
Informed Consent
SABR (40 Gy in 4 fractions)
hrs)
Follow-up at 4, 6 mo,
then at every 3
months
EGD within 6 months
CBC, Admission
panel, PT, AFP
4wks after TACE
Inclusion
Exclusion
HCC with major portal vein thrombosis
(Main or 1st branch portal vein)
NCT01850368
KROG 13-02
KCT0000542
EGD at 2 months as possible

SABR technique in KIRAMS
 Simulation CT: slow CT and conventional helical CT
 Fusion of slow CT and conventional helical CT
 Gross tumor volume (GTV) = visible tumor on CT
 Planning target volume (PTV) = GTV(=ITV)+2/4 mm

OAR (not mandatory)
OAR Dose-constraints
Heart (Dmax) 30 Gy
Great vessel (Dmax) 45 Gy
Skin (Dmax) 32 Gy
Chest wall (Dmax) 35 Gy
Gall bladder (Dmax) 43 Gy
Common bile duct (Dmax) 40 Gy
Both Kidney (rV) rV14≥200
Both Lung (V20/rV) V20≤10%, rV10≥1500 , rV11≥1000

Variable
Local control (n=95) Overall survival (n=82)
p-value p-value
Age (≤60 vs. >60 years) 0.026 NS
Gender (male vs. female) NS NS
Diagnosis history at SBRT (initially vs.
recurrence)
NS NS
aFP (≤14 vs. >14 IU/ml) NS NS
Child-Pugh class (A vs. B) NS NS
BCLC (A vs. B, C) NS 0.015
No. of previous TACE sessions (≤2 vs. >2) NS NS
Portal vein tumor thrombosis (yes vs. no) NS NS
Longest diameter (≤50 vs. >50 mm) NS NS
SBRT dose (Gy) 0.027 0.005
Prognostic factors - multivariate

Clinical parameters for
progression of CP class after
SABRParameters
No.of
patients
No. of the progressi
on of CP class
P_value
No. of a worsening
of MELD score>5
P_value
Age ≤60 years
>60 years
31
30
1
4
0.195
0
4
0.053
Sex Male
Female
43
18
3
2
0.627
1
3
0.073
ECOG PS 1
2
57
4
4
1
0.296
4
0
1.000
Liver cirrhosis No
Yes
8
53
0
5
1.000
0
4
1.000
Viral hepatitis No
Yes
12
49
2
3
0.252
0
4
0.576
Previous treatment† ≤2
>3
25
36
1
4
0.640
1
3
0.638
Initial CP score 5
6/7/8
46
10/3/2
0
5/0/0
0.001
0
3/1/0
0.003
Pre-MELD score ≤8
>8
53
8
4
1
0.518
3
1
0.439
SABR duration 3 days
≥4 days
35
26
3
2
1.000
3
1
0.629
PTV ≤28 cc
>28 cc
27
34
0
5
0.060
0
4
0.122
Normal liver volume ≤1,000 cc
>1,000 cc
16
45
4
1
0.015
3
1
0.052
V15G ≤700 cc
>700 cc
13
48
4
1
0.006
3
1
0.028
V17Gy ≤700 cc
>700 cc
7
54
2
3
0.096
2
2
0.061

Pre-SABRSABR 60 Gy/ 3 fractionsPost-SABR 3MPost-SABR 6MPost-SABR 10M
 M/56
 S5 3.6 cm, close to GB
 CP B7
 Poor ICG
 Inaccessible to RFA
 TACE#1 → Partial uptake
 60 Gy/ 3 fractions

Pre-SABRSABR, 60 Gy/3 fractionsPost-SABR 1MPost-SABR 6MPost-SABR 3Y
 F/54
 Single, S4 2.5 cm, close to heart
 CP A5
 Poor ICG

Pre-SABRSABR, 51 Gy/ 3 fractionsPost-SABR 1MPost-SABR 3MPost-SABR 4Y
 M/47
 Two lesion, S1 1.0 cm, S7 1.0 cm, clse to stomach, duodenum
 CP A5
 Recurrence after LLS & S6 segmentectomy
 TACE#1 → Compact in S7, No uptake in S1

Pre-SABR, aFP 867.8 IU/mlSABR, 42 Gy/ 3 fractionsPost-SABR 3M, aFP 74.07 IU/mlPost-SABR 9M, aFP 4.14 IU/mlPost-SABR 1Y 3M, aFP 2.92 IU/ml
 M/46
 5.7 cm with Rt post IHBD, PV
 CP A5

Pre-SABRSABR, 27 Gy/ 3 fractionsPost-SABR 2MPost-SABR 8MPost-SABR 1Y 4M
 F/50
 10.2 cm right hepatic mass
 CP A5

Treatment based BCLC Stage
Llovet et al. J Hepatology 2012;56:908–943

BCLC Stage based Treatment
Inoperable Inacces.

Inoperable Inacces.
TACE

Inoperable Inacces.
Incomplete TACE → Sorafenib alone ???

: SABR Role
Inoperable Inacces.
Curative SABR ( size < 7cm)
Incomplete

BCLC stage based Eligibility
TACE of 1-2 sesstions
Complete Incomplete
Observation SABR(cure aim)
CP score A-B7
Normal liver volume ≥ 800
ml
HCC
BCLC Stage
0
BCLC Stage
B
BCLC Stage
A
Treatment
as
guideline
1 - 3 nodules D sum
≤ 10 cm
Ye
s
No
Eligibility
check

Inoperable Inacces.
SABR
Incomplete
SABR or 3D-CRT

Inoperable Inacces.
SABR
Incomplete
SABR or 3D-CRT Palliative
RT

Ongoing Multicenter Phase II study
of SABR for HCC ≦5 cm
1. 처음 진단된 원발성 혹은 재발성 간세포암 환자
2. 숙련된 외과의에 의해 판단된 절제 불가능한 간세포암
3. Child-Pugh class A or 7점 이상인 환자
4. 전신수행도 (ECOG score)가 0 또는 1인 환자
5. 단일 혹은 다발성 종양의 크기의 총 합이 5 cm 이하인 환자
6. 위장관에서 최소 3 cm 이상 떨어진 종양
7. 종양을 제외한 정상간용적이 1000ml 이상인 환자
8. 1회에서 5회의 경동맥화학색전술 후 잔존 종양이 남은 환자
9. 다발성 종양인 경우 1회의 방사선 조사야 내에 모두 포함되거나 연속적인 방사선 치료로 모두
포함되는 경우

Contents
Our KIRMAS experience of SABR for
HCC
Phase II study (single institue)
Retrospective result for optimal tumor
dose
Retrospective result for constraint for
normal liver and GI
Ongoing phase II Multicenter trial in
Korea

Study Machine Setup, mode Margin Dose, prescription Size(cm) Outcome Toxicity
1Louis,
Belgium
(n=25)
Cyberknife
CT-partial exhale
Real-time tracking
GTV+10mm=CTV
CTV+1.5mm=PTV
45Gy/3fx
80% isodose
4.5
(1.8-10.0)
2y-LC 95
2y-OS 52
Liver pain, 4%
Liver toxicity, 4%
DU, 4%
2Andolino,
Indiana U
(n=60)
LINAC
(Elekta)
CT-not reported
Abdominal
compression
GTV+5(axial),
10(S-I)mm=PTV
48Gy/3fx
80% isodose
3.1
(1.0-6.5)
2y-LC 87
2y-OS 47
Increased
CP class, 20%
Current
(n=82)
Cyberknife,
RapidArc
CT-slow (3sec)
Abdominal
compression
GTVslow+2(axial),
4(S-I)mm=PTV
60Gy/3fx
70-80%
isodose(CK)
92-98%
isodose(RA)
3.0
(1.0-7.0)
2y-LC 87
2y-OS 63
Increased
CP class, 13%
GI toxicity, 7%
Compare with other studies
1. Louis et al. Technol Cancer Res Treat. 2010 Oct;9(5):479-87.
2. Andolino et al. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):e447-53.

PTV Volume
(ml)
Min-Max dose Prescription
dose
Coverage
(V100)
V95 CI
PTV_Belgium 93.5 1080-6634 45Gy 65% 70% 0.66
PTV_Indiana U 49.3 2755-6634 48Gy 93% 95% 1.12
PTV_Current 28.8 5612-6634 60Gy 98% 100% 1.15
Compare with other studies

PTV
Volume
(ml)
PTV_Belgium
93.5
PTV_Indiana U
49.3
PTV_Current
28.8

PTV
Volume
(ml)
Dose
Prescription
Coverage
PTV_Belgium
93.5 45Gy 65%
PTV_Indiana U
49.3 48Gy 93%
PTV_Current
28.8 60Gy 98%

PTV
Volume
(ml)
Prescription
dose
Coverage
(V100)
V95 CI
PTV_Belgium
93.5 45Gy 65% 70% 0.66
PTV_Indiana U
49.3 48Gy 93% 95% 1.12
PTV_Current
28.8 60Gy 98% 100% 1.15
PTV_Belgiu
m
PTV_Indiana U
PTV_Current
RatioofTotalStructureVolume[%]

Study, year
Study
type
Number
(#)
Tumor size
(cm)
Local
Control (%)
Overall
survival (%)
Toxicity
Lin 2004 RCT 52 Mean 2.9 82 74 (3yr) 7.6%
Lu 2005 Retro 87 2.5 94.2 56 (5yr) 3.9%
Shiina 2005 RCT 118 2.2 98.3 74 (4yr) 5.1%
Bouza 2009 Meta 396 Mean 2.6 93 62 (4yr) 4.1%
Waki 2010 Retro 88 2.0 95.2 70 (5yr) 5.7%
Li 2010 Retro 117 2.4 91.5 40 (5yr) 24.1% (fever 12.5%)
Feng 2012 RCT 84 Mean 2.6 96.4 67 (3yr) 9.5%
Shiina 2012 Retro 1170 2.0 96.8 60 (5yr) 2.2%
Current Retro
82
(Rec 66%)
3.2 82 39 (5yr)
GI 6.1%, non-GI 6.1%
CP score+2 7%
Current
(Dose>54 Gy)
Retro
32
(Rec 53%)
3.0 100 68 (4.5yr)
GI 3.1%, non-GI 3.1%
CP score+2 9%
Compare with RFA studies
Abbreviations: RCT = randomized control study; Retro = retrospective; Rec=recurrence; GI =
gastrointestinal; CP = child-pugh

Ongoing SABR trials in Korea
(1) Phase II multicenter study of Stereotactic Body
Radiation Therapy for Hepatocellular Carcinoma: toxicity
and outcome (NCT01850667, KCT0000454)
(2) Multicenter Phase II study of Stereotactic Ablative
Radiotherapy for Hepatocellular Carcinoma ≦ 5
(NCT01825824, KROG 12-02, KCT0000422)
(3) Stereotactic ablative radiotherapy for hepatocellular
carcinoma with major portal vein invasion: A phase II
study (NCT01850368, KROG 13-02, KCT0000542)

 Phase II multicenter study of Stereotactic Body Radiation
Therapy for Hepatocellular Carcinoma: toxicity and
outcome
 NCT01850667, KCT0000454
 Estimated Enrollment: 71
 Study Start Date: 2012.1
 Estimated Primary Completion Date: 2013.12
 Current Enrollment: 31

 Multicenter Phase II study of Stereotactic Ablative
Radiotherapy for Hepatocellular Carcinoma ≦ 5 cm
 NCT01825824, KROG 12-02, KCT0000422

 Stereotactic ablative radiotherapy for hepatocellular
carcinoma with major portal vein invasion: A phase II
study
 NCT01850368, KROG 13-02, KCT0000542

Outline of Proposal
 Objective – 2-year overall survival
 Design – International multicenter phase 2
 Eligibility – Unsuitable for Op, TPL, or RFA
Unsuitable or refractory to TACE#1~2
CP score A-B7, Normal liver ≥ 800 ml
 CT – 4D CT, Slow CT, Conventional helical CT
 Planning – ITV+2 mm=PTV, V100%⊃95% of
PTV
 Techniques – AC, DIBH, Gating, Tracking
 Dose – 42~54 Gy/3 fx
(Reduce by normal liver dose-constraint)

Objective
1) Primary objective:
To evaluate 2-year overall survival
2) Secondary objectives:
(1) To evaluate 6-month response
(2) To evaluate time to local progression
(3) To evaluate time to progression
(4) To evaluate 2-year progression free survival
(5) To evaluate treatment-related toxicity

BCLC stage based Treatment
Bruix J et al, Hepatology 2011;53:1020

Patient selection (Inclusion)
 Initially or recurrent diagnosis of HCC (Patho-, Radio-) (within 180D)
 Measureable hepatic disease (within 28D)
 Zubrod Performance Status 0-2 (within 28D)
 Age ≥ 18 years
 BCLC 0, A, or B (within 14D)
 Child-Pugh score A5, A6, or B7 (within 14D)
 Normal liver volume ≥ 800 ml
 Unsuitable for resection, transplant, or local ablation (eg, RFA, PEI)
 Unsuitable or refractory to TACE or DEB of 1-2 sessions
 All blood work obtained within 14 days prior to study entry with
adequate organ marrow function
 Women of childbearing potential and male participants must agree
to practice adequate contraception while on study and for at least 6
months following the last dose of RT.
 Study-specific informed consent prior to study entry

Radiation therapy - Dose
 Our proposal
– 54, 51, 48, 45, 42 Gy/3 fx
– The highest allowable prescription dose to
PTV, while respecting normal tissue constraints
– The minimal planned prescription dose to PTV is 42
Gy
– Delivered within 14D
– The time between fractions ≥ 48 hours

Radiation therapy - Dose
Normal Liver Constrai
nt
Prescription Dose
Child-Pug
h
Score
Reserved Liv
er Volume (c
c)
Planned
Prescription D
ose
If the rV17Gy or rV15Gy is less
than 700cc at this planed dose
A5 rV17Gy >700
54
Reduce to 48 Gy and re-evaluat
ion
48
ion
45
ion
42 Ineligible
A6-B7 rV15Gy >700
54
ion
48
ion

Image acquisition (Plan CT)
 CT
– Multi-phasic IV contrast is recommended
– Axial acquisitions with gantry 0 degrees will be required
with spacing ≤ 0.3 cm between scans.
– 4D CT, Slow CT (≥3 sec per slice), Conventional (helical)
CT
– If contraindications to IV CT contrast exist, contrast
multiphase MR can be used to define GTV. Diagnostic
imaging can be imported to the planning system to aid in
target delineation.
– Exhale breath hold CT or average phase CT (from 4D
CT or Slow CT) may be used as the baseline CT for
radiation therapy planning.

Target
 GTV
– All parenchymal and vascular HCC visualized on contra
st enhanced CT and/or MRI
 ITV
– The union of GTV delineations on all breathing phases
– Alternatively from contouring on a maximum intensity pr
ojection (MIP) CT dataset
– The volume constructed to encompass the full range of
tumor motion seen at maximum inspiratory and expirator
y phases
 PTV
– ITV to PTV margins considering set-up uncertainties
– ITV + 0.2 cm

Incomplete TACE
SBRT after Incomplete TACE in
Inoperable HCCFirst TACE (2006-2008)
Pts satisfied eligibility
(1) Single tumor
(2) BCLC stage 0 or A
(3) Tumor size ≤10 cm
(4) No extrahepatic mets
(5) Child-Pugh score ≤7
(6) No major vessel invasion
(7) ECOG ≤2
n=497
Complete TACE
n=19 n=85
Additional SBRT
n=39
Without SBRT
n=46
Inclusion criteria
(1) Multiple tumors
(2) Diffuse infiltrative tumor type
(3) Tumor > 2/3 of liver volume
(4) LC associated complications
(5) Severe co-morbidity
(6) Previous RT to upper abdomen
(7) Other malignancies within 5 yrs
Exclusion criteria
Pts Not satisfied eligibility
n=393
Not assessed
n=104
1-8(2)
1-9(3) 1-11(2)

TACE vs TACE+SABR
0
20
40
60
80
100
0 12 24 36 48 60
Overallsurvival(%)
Addition of SABR to
Incomplete TACE
(n=39)
Incomplete TACE (n=46)
2yr : 84%
2yr : 46%
5yr : 47%
2yr : 77%
Complete TACE (n=19)
5yr : 68%
5yr : 28%
Total : 104 pts

The progression of CP class
after SABR
Patient
Sex
/Age
Normal
Liver
Volume
(cc)
RNV15Gy
(cc)
CP score
MELD
Score
Hepatic
toxicity* Clinical manifestations of
deterioration of hepatic function
Pre Post Pre Post Pre Post
1 M/50 1191 999 5 6 9 12 1 2 Hyperbilirubinemia
3 F/69 717 527 6 7 1 7 0 2 Hyperbilirubinemia
4 M/49 1167 737 6 7 11 12 0 2 Hypoalbuminemia, Ascites
7 F/62 889 697 6 10 8 14 1 3 Hyperbilirubinemia, Hepatic encephalopathy
*Grade according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0
5 pts/total 61 pts

Worsening of MELD score > 5
Patient
Sex
/Age
Normal
Liver
Volume
(cc)
RNV15Gy
(cc)
CP score
MELD
Score
Hepatic
toxicity* Clinical manifestations of
deterioration of hepatic function
Pre Post Pre Post Pre Post
7 F/62 889 697 6 10 8 14 1 3 Hyperbilirubinemia, Hepatic encephalopathy
*Grade according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0

Study, Inst.
Year
Type # Size Dose Outcome (%)
Choi, CMC
2008
Retro 31
Median 25.2 ml
(3.6-57.3)
30-39Gy/3fx MS 11.5mos
Kwon, CMC
2010
Retro 42
Median 15.4 ml
(3.0-81.8)
30-39Gy/3fx
3Y-LC 68
3Y-OS 59
Seo, KIRAMS
2010
Phase 1 38
Median 40.5 ml
(11-464)
33-57Gy/3-4fx
3Y-LC 66
3Y-OS 40
Kang, KIRAMS
2012
Phase 2 47
Median 2.9 cm
(1.3-7.8 cm)
42-60Gy/3fx
3Y-LC 94.6
3Y-OS 68.7
Shin, KIRAMS
2010
Retro 6 >10 cm 32-40Gy/4fx
PFS 6mos
MS 10mos
Bae, KIRMAS
2013
Retro 35 BCLC C 30-60Gy/3fx 2 Y-OS 23
Publications of SABR result for HCC in Korea

Consistent result of SABR to
HCCStudy
Design
# of pts
Dose/Fx
(Median)
Size or Volume
(Median)
F/U Duration
(Median)
Respons
e
(%)
2Y LC
(%)
2Y OS
(%)
Toxicity
Tse
PMH
2008
Phase I
31
24-54/6
(36/6)
9-1913 cc (173 cc)
11-39
(18)
CR 5
PR 44
65 (1Y) 48 (1Y) Increased CTP, 16%
Bujold
PMH
2013
Phase I/II
& Phase II
102
24-54/6
(36/6)
1-1913 cc (117 cc)
14-231 mm (72
mm)
17
CR 11
PR 43
87 (1Y) 55 (1Y)
CTP class, 29% (3M), 6%
(12M)
Gr 3, 27%; Gr 4, 3%; Gr 5 7%
Kwon
CMC
2010
Retro
42
30-39/3
(33/3)
3-82 cc (15 cc)
8-49
(29)
CR 60
PR 26
68 (3Y) 59 (3Y) Gr4 liver toxicity, 2%
Cardenes
Indiana U
2010
Phase I
17
36-48/3 (CP A)
40/5 (CP B)
8-95 cc (34 cc)
20-60 mm (40 mm
)
10-42
(24)
CR 25
PR 56
100 60
RILD, 12%
(All CP B pts)
Andolino
Indiana U
2011
Phase I/II
(Interim)
60
24-48/3-5
2-112 cc (29cc)
10-65 mm (31 mm)
2-52
(27)
CR 30
PR 40
90 67 Increased CTP, 20%
Louis
Belgium
2010
Retro
25
45/3
18-100 mm (45 m
m)
1-24
(13)
CR 57
PR 29
95 52
Gr3 liver toxicity, 4%
Gr3 liver pain, 4%
DU, 4%
Seo
KIRAMS
2010
Phase I
38
33-57/3 11-464 cc (41 cc)
3-47
(15)
CR 3
PR 61
66 61 Gr 3 toxicity, 3%
Kang
KIRAMS
2012
Phase II
47
42-60/3
(57/3)
2-214 cc (14 cc)
13-78 mm (29 mm
)
6-38
(17)
CR 38
PR 38
95 69
Ascites, 9%
GI toxicity, 11%
Increased CTP, 13%

Patient selection (Exclusion)
 Sum of longest diameter > 7 cm
 # of lesions > 3 (nodules)
 Extrahepatic metastases or malignant nodes
 Direct tumor extension into the stomach, duodenum, small bowel or
large bowel
 Prior radiotherapy to upper abdomen
 Prior internal radiotherapy/hepatic arterial Yttrium therapy
 Prior invasive malignancy
 Severe, active co-morbidity
 Pregnancy or women of childbearing potential and men who are
sexually active and not willing/able to use medically acceptable
forms of contraception
 Use of regular phenytoin, carbamzepine, hypericum perforatum or
rifampin
 Use of combination anti-retroviral therapy for HIV

PreTx Evaluations/Mx
 For all patients, the following criteria calculated from
baseline CT or MR scans should be met:
– Liver volume minus intrahepatic GTV ≥ 800 ml
– Minimal distance from GTV to
stomach, duodenum, small or large bowel > 0.5 cm
 Documentation of liver disease, including
cirrhosis, hepatitis history
 Alfa-feto protein (AFP), LFT, Electrolyte, Ca/P (within
28D)
 Bhcg (within 14D)
 Esophagogastroduodenoscopy (EGD) within 6 months

Technique (1)
 Only photon (X-ray, at least 6MV)
– by LINAC, Betatron, or Microtron
– Cobalt-60 and charged particle beams are not allowed
 3D-CRT(a minimum of 5 beam angles), IMRT
 IGRT – mandatory
 Positioning (Immobilization)
– Immobilization may vary with departmental protocol
– Custom immobilization is recommended (e.g. vacuum
immobilization, patient positioning boards, knee cushions

Technique (2)
 Breathing (Internal organ motion) control
– Reliable abdominal compression, active breath-holding
techniques, accelerator beam gating with the respiratory
cycle, tumor tracking (GTV does not deviate beyond the
confines of the PTV)
– Measurement of target/liver breathing motion is required,
unless breath hold is to be used for liver immobilization.
Motion may be assessed using 4D CT, fluoroscopy and/or
cine MR.
 Localization (Verification)
– Planar kV imaging devices, an in-room helical CT device,
tomotherapy helical CT, cone-beam CT equipment,
standard EPID imaging

Planning
 V100%⊃95% of PTV
 V100%⊃100% of ITV
 Dmax within PTV ≤ 150%
 Dmax outside PTV ≤ 120%
 Normal tissue – Liver, Esophagus, Stomach,
Duodenum, Small bowel, Large bowel, Spinal
cord, Heart, Great vessel, Skin, Chest wall, Gall
bladder, Common bile duct, Kidney, Lung

Other therapy
 All supportive therapy for optimal medical care
 Anticoagulants are not to be used to treat HCC
related vascular thrombosis

Patient assessments
 Response – mRECIST
– CR : the disappearance of any intratumoral arterial
enhancement in all target lesions
– PR : at least a 30% decrease in the sum of diameters of
viable (contrast enhancement in the arterial phase) target
lesions, taking as reference the baseline sum of the diameters
of target lesions
– SD : any cases that do not qualify for either partial response
or progressive disease
– PD : an increase of at least 20% in the sum of the diameters
of viable (enhancing) target lesions, taking as reference the
smallest sum of the diameters of viable (enhancing) target
lesions recorded since the treatment started; the appearance
of one or more new lesions
Lencioni R et al, Semin Liver Dis 2010;30:52

Pretreatment Response evaluation Follow-up
Baseline 3-4 weeks after TACE
2 months, 6 months after SA
BR
Repetitive TACE or other ther
apy
Written consent X
Eligibility checklist X
Registration X
Medical history X X X X
Physical examination X X X X
ECOG performance X X X X
Child-Pugh classificatio
n
X X X X
Vital sign X X X X
Laboratory evaluation
CBC X X X X
Admission panel X X X X
Coagulation panel X X X X
Serology (HBV/HCV) X
Tumor marker
AFP level X X X X
PIVKA II a X a X a X a X a
Tumor assessment
Dynamic liver CT X X X X
Dynamic liver MRI a X a X a X a X a
Ultrasonography a X a X a X a X a
Liver angiography a X a X a X a X a
Chest x-ray X X X a X a
Chest CT a X a X a X a X a
WBBS a X a X a X a X a
PET scan a X a X a X a X a
TACE X X b
Other therapy b X b
Adverse event X X
EGD
X: within the past 6 month
X : 2 months after RT X aa: optional study or when appropriate for symptoms or findings.; b: investigators discretion (chemotherapy or radiotherapy)

Lesson from phase I, II and
Retrospective analysis
Radiation dose affect LC and OS
Radiation induced liver deterioration is
very low incidence in SABR group
CP class progression after SABR is
associated with initial C-P sore and
normal liver volume

HCC SABR in KIRAMS
 Immobilization – Wing board or Vacuum cushion
 Abdominal compression with 2 or 4 belts
 Slow CT (3 sec per slice)
 Fusion of slow CT and conventional helical CT
 GTV(=ITV)+2/4 mm = PTV
 60 Gy in 3 fractions (Reduce by normal liver dose-
constraints)
 100% Dose ⊃95% of PTV
 RapidArc (AAA) or Cyberknife (Ray Tracing)
 Verification – CBCT or Orthovoltage X-ray (using
fiducial or lipiodol )

Introduction
• Previously, role of RT for HCC has long been
neglected
• Now, HCC is challengeable in Radiation
oncology field
• Why ? HCC is revealed to radiosensitive tumor
• SBRT (stereotactic body RT) or SABR
(Stereotactic Ablative RT) would increase local

IMRT
CyberKnife
Tomotherapy
VMAT
TrueBeam
2D
3D-CRT
GammaKnife
Evolving RT machine for 2 decades

Indication for
curative aim SABR
 Liver function (CP score ≤ 7)
 No direct invasion to stomach or bowel wall
 Normal liver volume > 700 cc
 Visible mass by enhanced CT or fusion
imaging, not diffuse
 No. of lesions < 5
 Vessel invasion, GB invasion, close to bowel :
Not contraindication for SABR

Introduction
 According to the 2011 Global Cancer Statistics, an
estimated 748,300 new liver cancer cases and
695,900 cancer deaths occurred worldwide in 2008.
 TACE had been widely used as first line non-
curative therapy for non-surgical (and unsuitable for
local ablative therapy) patients with large/multifocal
HCC who do not have vascular invasion or
extrahepatic spread, but TACE alone rarely
produced a complete response.

Introduction
• Radiotherapy has typically not been considered a
frontline treatment for HCC because of the low
efficacy of radiation for tumor control in HCC and the
much lower tolerance of the whole liver to RT than
the tumoricidal dose
• However, recent studies have reported favorable
outcomes for HCC using 3-D conformal radiotherapy
either alone or in combination with other
interventional modalities.

Introduction
 SABR is an external beam radiation therapy method
used to very precisely deliver a high dose of
radiation to an extracranial target within body, using
either a single dose or a small number of fractions.
 Specialized treatment planning results in high target
dose and steep dose gradients beyond the target.

Trials registered
Clinicaltrial.gov
 Clinicaltrial.gov (2013.5.10)
 142 studies found for:
hepatocellular carcinoma | radiotherapy
 25 studies found for:
hepatocellular carcinoma | radiotherapy |
stereotactic

Trials registered
Clinicaltrial.gov
 142 studies found for: hepatocellular carcinoma |
radiotherapy

Trials registered
Clinicaltrial.gov
 25 studies found for: hepatocellular carcinoma |
radiotherapy | stereotactic

Ongoing SABR trials (HCC)
Trial # Design Institution Diseas
e
CP
scor
e
Size
(cm)
Start Estimat
ed
Complet
e
Enro
ll
Comment
NCT
00152906
Phase
1/2
Princess
Margaret
Hospital
HCC,
IHC,
Mets
A NA 2003.6 NA 140
NCT
00243841
Phase
1/2
Indiana
University
HCC A-B NA 2004.5 2014.12 60
NCT
00914355
Phase 2 Princess
Margaret
Hospital
HCC A-B8 ≤ 15-CP A
≤ 10-CP
B
2007.8 2013.8 47
NCT
00607828
Phase 1 University of
Nebraska
HCC A-B ≤ 8 2007.11 2009.10 28
NCT
01347333
NA St. John's Mercy
Research
Institute
HCC,
IHC,
Mets
NA ≤ 6 2008.9 2015.9 50
NCT
01528878
North Carolina
HCC,
Mets
A-B NA 2009.4 2014.4 40
NCT
00746655
Pittsburgh
HCC A-B ≤ 180 ml 2009.7 2012.6 12 +TACE
From clinicaltrial.gov (2013.5.10)

e
CP
scor
e
Size
(cm)
Start Estimat
ed
Complet
e
Enro
ll
Comment
NCT
01668134
Phase 1 Washington
University
HCC,
IHC
A-B7 NA 2009.9 2015.12 40
NCT
01668134
Phase 1 Washington
University
HCC,
IHC
A-B7 NA 2009.9 2015.12 40
NCT
01522937
Michigan
HCC,
Mets
NA NA 2009.10 2014.1 70
NCT
01005875
Alabama
HCC A-B7 ≤ 6 2009.11 2012.12 5 +Sorafeni
b
NCT
01213758
NA University of
Aarhus,
Denmark
Liver NA NA 2010.6 2013.1 20
NCT
01194206
Phase 2 Seidman Cancer
Center
HCC A-B NA 2010.8 2012.3 NA
NCT
01247298
Phase 0
(Pilot)
University of
Alabama
HCC A-B ≤ 8 2010.10 2014.12 20 +TACE

e
CP
scor
e
Size
(cm)
Start Estimat
ed
Complet
e
Enro
ll
Comment
NCT
01167374
Phase 1 University
Hospital
Heidelberg
HCC NA NA 2011.8 2013.1 33 Carbon
Ion
NCT
01850667
Phase 2 Korea Cancer
Center Hospital
HCC A-B7 < 10 2012.1 2014.9 71 +TACE
NCT
01825824
Center Hospital
HCC A-B7 ≤ 5 2012.6 2014.12 54 +TACE
NCT
01850368
Center Hospital
HCC A-B7 NA 2012.10 2014.3 28 +TACE
NCT
01730937
Phase 3 Princess
Margaret
Hospital
RTOG 1112
HCC A ≤ 15 2013.1 2016.6 368 Sorafenib
±SABR
NCT
01801163
Phase
1b
Indiana
University
HCC A ≤ 6 2013.2 2014.8 14 +Sorafeni
b

0
20
40
60
80
100
0 12 24 36 48 60
Time from SABR (months)
0
20
40
60
80
100
0 12 24 36 48 60
Local control as SABR dose
p=0.0340
> 54 Gy (n=21)
≤ 54 Gy (n=29)
0
20
40
60
80
100
0 12 24 36 48 60
> 54 Gy (n=15) > 54 Gy (n=1)
≤ 54 Gy(n=18) ≤ 54 Gy(n=11)
p=0.0758 p=0.5194
LD ≤ 3.0 cm 3.0 cm< LD ≤ 5.0
cm
LD > 5.0 cm
- Stratification as Longest diameter(LD) -
Unpublished data

Sample size
 Multicenter phase 2 trial, Single arm
 Required sample size : 48 patients
1) This phase 2 study aims to target a 2-year overall
survivalof 55% (P1 = 55%). Local control at 2 years of
75% is considered unacceptable (P0 = 75%).
2) The sample size was calculated with Simon’s two stage
optimal design at a significance level of 0.05 and 80%
statistical power.
3) Sample size – 43 by Simon`s optimal two-stage design
for phase 2 clinical trial
4) Adjusting the number of cases for in eligible or
unanalyzable cases by 10%, 48 patients are needed.
Richard Simon, Controlled Clinical Trials 1980;10:1

Sample size calculation
Optimal Two Stage Design
Optimum Desi
gn
MinMax Desi
gn
First Stage Sample Size (n1) 15 24
Upper Limit For 1st Stage Rejection of Drug (r
1)
9 15
Maximum Sample Size (n) 43 36
Upper Limit for 2nd Stage Rejection of Drug (r) 28 24
Expected Sample Size If Response Probability
= P0
22.30 26.08
Probability of Early Termination at P0 0.74 0.83
Richard Simon, Controlled Clinical Trials 1980;10:1

Outline of Protocol
 Objective – 2-year overall survival
 Design – International multicenter phase 2
 Eligibility – Unsuitable for Op, TPL, or RFA
Unsuitable or refractory to TACE#1~2
CP score A-B7, Normal liver ≥ 800 ml
 CT – 4D CT, Slow CT, Conventional helical CT
 Planning – ITV+2 mm=PTV, V100%⊃95% of
PTV
 Techniques – AC, DIBH, Gating, Tracking
 Dose – 42~54 Gy/3 fx
(Reduce by normal liver dose-constraint)

TCP as SBRT Dose
Clinical TCP curve for all lesions (n=95)

: 2012.1 – 2013.12
Follow-up
TACE #1-5
Eligibility Check
Informed Consent
SABR (45-60 Gy in 3 fractions)
hrs)
Non PD PD
6 mo
therapy
Non PD PD
EGD at 2 months
PET at 6 months as possible
EGD within 6 months
CBC, Admission
panel, PT, AFP
4wks after TACE
Inclusion
• Age≥18 years
• Unsuitable for
resection, transplant,
or local ablation (eg, RFA, PEI)
• CP score A-B7
• ECOG PS 0-1
• Sum of longest diameter < 10
cm
• Incomplete response after
• A single lesion or multiple
lesions including portal vein
thrombosis included in radiation
field with one or consecutive
sessions of SABR
• No extrahepatic metastases or
malignant nodes
• No liver cirrhosis related
complication
• No severe other co-morbidity
Exclusion
• Direct tumor extension into the
esophagus, stomach, duodenu
Inclusion
Exclusion
NCT01850667
KCT0000454

Stereotactic Ablative RT in HCC

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