Stereotactic Ablative RT in HCC Mi-Sook Kim, MD, PhD Department of Radiation Oncology Korea Institute of Radiological and Science
Nov 27, 2014
Stereotactic Ablative RTin HCC
Mi-Sook Kim, MD, PhDDepartment 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)
ToxicityTable 4. Grade 3 or 4 Toxicities According to the Common Toxicity Cri-teria for Adverse Events Version 3.0 Grading Scalea
ToxicityGrade 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 ulcercGastric ulcer perforation.
Retrospective Analysis Dose escalation
studyNo constraint
(n=38)
86 pa-tients
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 studyConstraint (n=47)
Tx according to proto-cols
But no enrollment in studies (n=23)
J Surg Oncol 2010;102:209Cancer 2012;118:5424
Survival outcome anaylsis (n=82)
Size > 7.0 cm (n=4)
30 40 50 60 70 0
20
40
60
80
100 R² = 0.808988615555813
2-year local control
Overall survival (OS) as SABR Dose
Simple correlation (82 patients with 95 le-sions)
SABR dose (Gy)
SABR dose (Gy)
Overa
ll s
ur-
viv
al
Local con
trol
30 40 50 60 70 0
20
40
60
80
100
R² = 0.884165554567678
2 year overall survival
TCP by SABR doseTu
mor
Con
trol Pro
babili
ty (
TCP)
SABR dose (Gy)
Lesions with LD ≤ 7 cmTCP50=34.9 Gy, γ50=1.22Dose 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Unpublished data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 frac-tions
0 12 24 36 48 600
20
40
60
80
100
Time from SBRT (months)
0 12 24 36 48 600
20
40
60
80
100
Time from SBRT (months)
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 12 24 36 48 600
20
40
60
80
100
Time from SBRT (months)
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 12 24 36 48 600
20
40
60
80
100
Time from SBRT (months)
>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 12 24 36 48 600
20
40
60
80
100
Time from SBRT (months)
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 ofhepatic toxicity
Probability of toxicity %Volume to receive
<15 GyVolume to receive
<17 Gy
≥700 cc <700 cc ≥700 cc <700 cc
5N=45
Hepatic toxicity*≥grade 2 3 (1/39) 0 2 (1/43) 0
The progression of CP class 0 0 0 0
A worsening of MELD score>5 0 0 0 0
Non-classic RILD 0 0 0 0Classic RILD 0 0 0 0
6-8N=15
Hepatic toxicity*≥grade 2 33 (3/9) 83 (5/6) 45 (5/11) 75 (3/4)
The progression of CP class 11 (1/9) 67 (4/6) 27 (3/11) 50 (2/4)
A worsening of MELD score>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 con-straint
Yes No Unknown Total0
10
20
30
40
50
3/5
0/26
2/16
5/47
Severe GI ...
Preexisting GI ulcer before SABR
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 -> ITVGTV = visible tumor on CTPTV = 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
NCT0182582460 Gy/3 Fx
NCT0185066745~60 Gy/3 Fx
NCT01850368
40 Gy/4 Fx
No Clinical Trials
Debulking SBRT
Sum ≤ 5 cm & 3 cm from GI tract
Sum ≤10 cm
Yes
No Yes
No
Normal Liver Dose-ConstraintsrV15<700 ml (CP A5), rV17<700 ml (CP A6-
B7)
No
Incomplete TACE
Complete TACE
Observation
Thank you
Thank you
Follow-up
Initially or Recurrent HCCUnsuitable for Op, TPL, RFA
BCLC 0/A/B (1-3 nodules≤7 cm)
TACE #1-2
Eligibility CheckInformed 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 Evalua-tion at 6 mo
Repetitive TACE or other therapy
Non PD PD
EGD at 2 monthsCBC, Admission panel, PT, AFP
EGD within 6 monthsCBC, 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 dis-ease • 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 radiotherapy/hepatic arte-rial Yttrium therapy
Inclusion
Exclusion
Estimated Enrollment: 73 patientsEstimated primary completion date: 2012.6 – 2014.06
Estimated Enrollment: 54 patientsEstimated primary completion date: 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• Normal liver volume ≥ 1000 ml• Incomplete response after TACE of 1-5 sessions• A single lesion or multiple lesions including portal vein thrombosis included in radi-ation field with one or con-secutive sessions of SABR• No extrahepatic metas-tases or malignant nodes • No liver cirrhosis related complication• No severe other co-morbid-ity
Exclusion• Direct tumor extension into the esophagus, stomach, duodenum, small bowel or large bowel• Prior radiotherapy to upper Abd
Follow-up
TACE #1-5
Eligibility CheckInformed Consent
SABR (60 Gy in 3 fractions)Within 14 days (Time b/w fx`s
≥ 48 hrs)
Response evaluation at 2 mo
Non PD PD
2nd Response Evalua-tion at 6 mo
Repetitive TACE or other therapy
Non PD PD
EGD at 2 monthsCBC, Admission panel, PT, AFPPET at 6 months as possible
EGD within 6 monthsCBC, Admission panel, PT, AFP
4wks after TACE
Inclusion
Exclusion
Initially or Recurrent HCCUnsuitable for Op, TPL, RFA
NCT01825824KROG 12-02KCT0000422
Estimated Enrollment: 28 patientsEstimated primary completion date: 2012.10 – 2013.12
Inclusion• Age≥18 years• Initially or Recurrent HCC • ECOG PS 0-1• HCC with major portal vein tumor thrombosis (tumor thrombosis in the main por-tal 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 bur-den and potentially treat-able with RT, chemotherapy and target agent etc; • Patient survival is expected to be as least 6 months
Exclusion• Prior TACE ≥ 4 after diag-nosis of major portal vein tumor thrombosis• Severe complication caused by liver cirrhosis• Uncontrolled inter-current illness except liver cirrhosis
±AdditionalTreatment
TACE #0-3
Eligibility CheckInformed Consent
SABR (40 Gy in 4 fractions)Within 28 days (Time b/w fx`s
≥ 48 hrs)
Response evaluation at 2 mo
Follow-up at 4, 6 mo,
then at every 3 months
EGD within 6 monthsCBC, Admission panel, PT, AFP
4wks after TACE
Inclusion
Exclusion
HCC with major portal vein thrombosis(Main or 1st branch portal vein)
NCT01850368KROG 13-02KCT0000542
EGD at 2 months as possibleCBC, Admission panel, PT, AFP
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 - multi-variate
Clinical parameters for pro-gression of CP class after
SABRParameters
No.ofpatients
No. of the progres-sion of CP class
P_valueNo. of a worsening of MELD score>5
P_value
Age ≤60 years>60 years
3130
14
0.19504
0.053
Sex MaleFemale
4318
32
0.62713
0.073
ECOG PS 12
574
41
0.29640
1.000
Liver cirrhosis NoYes
853
05
1.00004
1.000
Viral hepatitis NoYes
1249
23
0.25204
0.576
Previous treatment† ≤2>3
2536
14
0.64013
0.638
Initial CP score 56/7/8
4610/3/2
05/0/0
0.0010
3/1/00.003
Pre-MELD score ≤8>8
538
41
0.51831
0.439
SABR duration 3 days≥4 days
3526
32
1.00031
0.629
PTV ≤28 cc>28 cc
2734
05
0.06004
0.122
Normal liver volume ≤1,000 cc>1,000 cc
1645
41
0.01531
0.052
V15G ≤700 cc>700 cc
1348
41
0.00631
0.028
V17Gy ≤700 cc>700 cc
754
23
0.09622
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 Inaccessible to RFA TACE#1 → Partial uptake 60 Gy/ 3 fractions
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 Inaccessible to RFA TACE#1 → Compact in S7, No uptake in S1 51 Gy/ 3 fractions
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 TACE#1 → Partial uptake 42 Gy/ 3 fractions
Pre-SABRSABR, 27 Gy/ 3 fractionsPost-SABR 2MPost-SABR 8MPost-SABR 1Y 4M
F/50 10.2 cm right hepatic mass CP A5 TACE#1 → Partial uptake 27 Gy/ 3 fractions
Treatment based BCLC Stage
Llovet et al. J Hepatology 2012;56:908–943
BCLC Stage based Treatment
Inoperable Inac-ces.
BCLC Stage based Treatment
Inoperable Inac-ces.
TACE
BCLC Stage based Treatment
Inoperable Inac-ces.
Incomplete TACE → Sorafenib alone ???
BCLC Stage based Treatment: SABR Role
Inoperable Inac-ces.
Curative SABR ( size < 7cm)
Incom-plete
BCLC stage based Eligibility
Unsuitable for Op, TPL, RFA
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
Treat-ment as guide-
line
1 - 3 nodules D sum ≤ 10 cm
Yes
No
Eligibility check
BCLC Stage based Treatment
Inoperable Inac-ces.
SABR
Incom-plete
SABR or 3D-CRT
BCLC Stage based Treatment
Inoperable Inac-ces.
SABR
Incom-plete
SABR or 3D-CRT
Palliative RT
Ongoing Multicenter Phase II study of SABR for HCC ≦5 cm
1. 처음 진단된 원발성 혹은 재발성 간세포암 환자2. 숙련된 외과의에 의해 판단된 절제 불가능한 간세포암 3. Child-Pugh class A or 7 점 이상인 환자4. 전신수행도 (ECOG score) 가 0 또는 1 인 환자5. 단일 혹은 다발성 종양의 크기의 총 합이 5 cm 이하인 환자6. 위장관에서 최소 3 cm 이상 떨어진 종양7. 종양을 제외한 정상간용적이 1000ml 이상인 환자8. 1 회에서 5 회의 경동맥화학색전술 후 잔존 종양이 남은 환자9. 다발성 종양인 경우 1 회의 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 Ko-rea
Proposal of phase II trial in IAEA
Study Machine Setup, mode MarginDose, prescrip-
tionSize(cm
)Out-come
Toxicity
1Louis, Belgium(n=25)
Cy-berknife
CT-partial exhale
Real-time track-ing
GTV+10mm=CTVCTV+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%
2An-dolino,
Indiana U(n=60)
LINAC(Elekta)
CT-not reported
Abdominal com-pression
GTV+5(axial), 10(S-I)mm=PTV
48Gy/3fx
80% isodose
3.1(1.0-6.5)
2y-LC 87
2y-OS 47
IncreasedCP class, 20%
Current(n=82)
Cy-berknife, RapidArc
CT-slow (3sec)
Abdominal com-pression
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
IncreasedCP 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 Prescrip-tiondose
Cover-age
(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
PTVVolume
(ml)
PTV_Belgium93.5
PTV_Indiana U49.3
PTV_Current28.8
PTVVolume
(ml)Dose
PrescriptionCover-
age
PTV_Belgium93.5 45Gy 65%
PTV_Indiana U 49.3 48Gy 93%
PTV_Current28.8 60Gy 98%
PTVVolume
(ml)
Prescrip-tiondose
Cover-age
(V100)V95 CI
PTV_Belgium 93.5 45Gy 65% 70% 0.66
PTV_Indiana U 49.3 48Gy 93% 95% 1.12
PTV_Current28.8 60Gy 98%
100%
1.15
PTV_Belgium
PTV_Indiana U
PTV_Current
Rati
o o
f To
tal S
tru
ctu
re V
ol-
um
e [
%]
Study, yearStud
ytype
Number(#)
Tumor size(cm)
LocalControl
(%)
Overallsurvival
(%)Toxicity
Lin 2004 RCT 52 Mean 2.9 82 74 (3yr) 7.6%
Lu 2005Retr
o87 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 2010Retr
o88 2.0 95.2 70 (5yr) 5.7%
Li 2010Retr
o117 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 2012Retr
o1170 2.0 96.8 60 (5yr) 2.2%
CurrentRetr
o
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
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 Ko-rea
Proposal of phase II trial in IAEA
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 Abla-tive Radiotherapy for Hepatocellular Carcinoma ≦ 5 (NCT01825824, KROG 12-02, KCT0000422)
(3) Stereotactic ablative radiotherapy for hepatocel-lular carcinoma with major portal vein invasion: A phase II study (NCT01850368, KROG 13-02, KCT0000542)
Ongoing SABR trials in Korea
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
Ongoing SABR trials in Korea
Multicenter Phase II study of Stereotactic Ablative Radiotherapy for Hepatocellular Carcinoma ≦ 5 cm
NCT01825824, KROG 12-02, KCT0000422 Estimated Enrollment: 54 Study Start Date: 2012.6 Estimated Primary Completion Date: 2013.12 Current Enrollment: 19
Ongoing SABR trials in Korea
Stereotactic ablative radiotherapy for hepatocel-lular carcinoma with major portal vein invasion: A phase II study
NCT01850368, KROG 13-02, KCT0000542 Estimated Enrollment: 28 Study Start Date: 2012.10 Estimated Primary Completion Date: 2013.12 Current Enrollment: 2
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 Ko-rea
Proposal of phase II trial in IAEA
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 BCLC 0/A/B (1-3 nodules≤7 cm) 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)
Objective1) 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 sur-vival
(5) To evaluate treatment-related toxicity
BCLC stage based Treatment
Bruix J et al, Hepatology 2011;53:1020
Patient selection (Inclu-sion)
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 ad-
equate 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 con-straints
– The minimal planned prescription dose to PTV is 42 Gy
– Delivered within 14D – The time between fractions ≥ 48 hours
Radiation therapy - DoseNormal Liver Con-
straint Prescription Dose
Child-PughScore
Reserved Liver Vol-ume (cc)
PlannedPrescription
Dose
If the rV17Gy or rV15Gy is lessthan 700cc at this planed
dose
A5 rV17Gy >700
54Reduce to 48 Gy and re-
evaluation
48Reduce to 45 Gy and re-
evaluation
45Reduce to 42 Gy and re-
evaluation42 Ineligible
A6-B7 rV15Gy >700
54Reduce to 48 Gy and re-
evaluation
48Reduce to 45 Gy and re-
evaluation
45Reduce to 42 Gy and re-
evaluation42 Ineligible
Image acquisition (Plan CT)
CT – Multi-phasic IV contrast is recommended – Axial acquisitions with gantry 0 degrees will be re-
quired 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
contrast enhanced CT and/or MRI ITV – The union of GTV delineations on all breathing
phases – Alternatively from contouring on a maximum in-
tensity projection (MIP) CT dataset – The volume constructed to encompass the full
range of tumor motion seen at maximum inspira-tory and expiratory phases
PTV – ITV to PTV margins considering set-up uncertain-
ties – ITV + 0.2 cm
Thank you
Thank you
Incomplete TACE
SBRT after Incomplete TACE in In-operable 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 12 24 36 48 600
20
40
60
80
100
Time from SBRT (months)
Ov
era
ll s
urv
iva
l (%
)
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
NormalLiver
Volume(cc)
RNV15Gy
(cc)
CP scoreMELDScore
Hepatictoxicity*
Clinical manifestations ofdeterioration of hepatic function
Pre Post Pre Post Pre Post
1 M/50 1191 999 5 6 9 12 1 2 Hyperbilirubinemia
2 M/59 1108 972 6 6 13 14 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
5 M/61 842 655 6 8 3 10 1 2 Hypoalbuminemia, Ascites
6 M/73 914 693 6 8 6 6 1 2 Hypoalbuminemia, Ascites
7 F/62 889 697 6 10 8 14 1 3 Hyperbilirubinemia, Hepatic encephalopathy
8 F/67 724 574 7 8 8 10 1 2 Hyperbilirubinemia
9 F/66 1104 804 7 8 9 15 1 2 Hyperbilirubinemia*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
PatientSex/Age
NormalLiver
Volume(cc)
RNV15Gy
(cc)
CP scoreMELDScore
Hepatictoxicity*
Clinical manifestations ofdeterioration of hepatic function
Pre Post Pre Post Pre Post
1 M/50 1191 999 5 6 9 12 1 2 Hyperbilirubinemia
2 M/59 1108 972 6 6 13 14 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
5 M/61 842 655 6 8 3 10 1 2 Hypoalbuminemia, Ascites
6 M/73 914 693 6 8 6 6 1 2 Hypoalbuminemia, Ascites
7 F/62 889 697 6 10 8 14 1 3 Hyperbilirubinemia, Hepatic encephalopathy
8 F/67 724 574 7 8 8 10 1 2 Hyperbilirubinemia
9 F/66 1104 804 7 8 9 15 1 2 Hyperbilirubinemia*Grade according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0
Study, Inst.Year Type # Size Dose Outcome (%)
Choi, CMC2008 Retro 31 Median 25.2 ml
(3.6-57.3) 30-39Gy/3fx MS 11.5mos
Kwon, CMC2010 Retro 42 Median 15.4 ml
(3.0-81.8) 30-39Gy/3fx 3Y-LC 683Y-OS 59
Seo, KIRAMS2010 Phase 1 38 Median 40.5 ml
(11-464) 33-57Gy/3-4fx 3Y-LC 663Y-OS 40
Kang, KIRAMS2012 Phase 2 47 Median 2.9 cm
(1.3-7.8 cm) 42-60Gy/3fx 3Y-LC 94.63Y-OS 68.7
Shin, KIRAMS2010 Retro 6 >10 cm 32-40Gy/4fx PFS 6mos
MS 10mosBae, 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 HCC
StudyDesign# of pts
Dose/Fx(Median)
Size or Vol-ume
(Median)
F/U Dura-tion
(Median)
Re-sponse
(%)
2Y LC(%)
2Y OS (%)
Toxicity
TsePMH2008
Phase I31
24-54/6(36/6)
9-1913 cc (173 cc)
11-39(18)
CR 5PR 44
65 (1Y) 48 (1Y) Increased CTP, 16%
BujoldPMH2013
Phase I/II& Phase
II102
24-54/6(36/6)
1-1913 cc (117 cc)
14-231 mm (72 mm)
17CR 11PR 43
87 (1Y) 55 (1Y)
CTP class, 29% (3M), 6% (12M)
Gr 3, 27%; Gr 4, 3%; Gr 5 7%
KwonCMC2010
Retro42
30-39/3(33/3)
3-82 cc (15 cc)8-49(29)
CR 60PR 26
68 (3Y) 59 (3Y) Gr4 liver toxicity, 2%
CardenesIndiana U
2010
Phase I17
36-48/3 (CP A)
40/5 (CP B)
8-95 cc (34 cc)20-60 mm (40
mm)
10-42(24)
CR 25PR 56
100 60RILD, 12%
(All CP B pts)
AndolinoIndiana U
2011
Phase I/II(Interim)
6024-48/3-5
2-112 cc (29cc)10-65 mm (31
mm)
2-52(27)
CR 30PR 40
90 67 Increased CTP, 20%
LouisBelgium
2010
Retro25
45/318-100 mm (45
mm)1-24(13)
CR 57PR 29
95 52Gr3 liver toxicity, 4%
Gr3 liver pain, 4%DU, 4%
SeoKIRAMS2010
Phase I38
33-57/311-464 cc (41
cc)3-47(15)
CR 3PR 61
66 61 Gr 3 toxicity, 3%
KangKIRAMS2012
Phase II47
42-60/3(57/3)
2-214 cc (14 cc)13-78 mm (29
mm)
6-38(17)
CR 38PR 38
95 69Ascites, 9%
GI toxicity, 11%Increased CTP, 13%
Protocol (continuing)
Patient selection (Exclu-sion)
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 ac-ceptable forms of contraception
Use of regular phenytoin, carbamzepine, hypericum perfo-ratum 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, duode-
num, small or large bowel > 0.5 cm Documentation of liver disease, including cirrho-
sis, 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 al-
lowed 3D-CRT(a minimum of 5 beam angles), IMRT IGRT – mandatory Positioning (Immobilization) – Immobilization may vary with departmental pro-
tocol – 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, Stom-
ach, 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 re-sponse or progressive disease
– PD : an increase of at least 20% in the sum of the di-ameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since the treat-ment started; the appearance of one or more new le-sions
Lencioni R et al, Semin Liver Dis 2010;30:52
Pretreatment Response evaluation Follow-up
Baseline 3-4 weeks after TACE2 months, 6 months af-
ter SABRRepetitive TACE or other
therapyWritten consent XEligibility checklist XRegistration XMedical history X X X XPhysical examina-tion
X X X X
ECOG performance X X X XChild-Pugh classifi-cation
X X X X
Vital sign X X X XLaboratory evalua-tion
CBC X X X XAdmission panel X X X XCoagulation panel X X X XSerology (HBV/
HCV)X
Tumor markerAFP level X X X XPIVKA II a X a X a X a X a
Tumor assessmentDynamic liver CT X X X XDynamic 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
EGDX: within the past 6
monthsX : 2 months after RT X a
Survival status X
a: optional study or when appropriate for symptoms or findings.; b: investigators discretion (chemotherapy or radiotherapy)
Thank you
Thank you
Lesson from phase I, II and Retrospective analy-
sis Radiation dose affect LC and OS Radiation induced liver deterio-
ration 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 ne-
glected
• 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 control by pre-
cise technique and hypofractional biological bene-
fit
IMRT
CyberKnife
Tomotherapy
VMAT
TrueBeam2D
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 Statis-
tics, 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 unsuit-able for local ablative therapy) patients with large/multifocal HCC who do not have vascu-lar invasion or extrahepatic spread, but TACE alone rarely produced a complete response.
Introduction• Radiotherapy has typically not been consid-
ered 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 favor-able 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 Clinical-trial.gov
Clinicaltrial.gov (2013.5.10) 142 studies found for: hepatocellular carcinoma | radiotherapy 25 studies found for: hepatocellular carcinoma | radiotherapy |
stereotactic
Trials registered Clinical-trial.gov
142 studies found for: hepatocellular car-cinoma | radiotherapy
Trials registered Clinical-trial.gov
25 studies found for: hepatocellular carci-noma | radiotherapy | stereotactic
Ongoing SABR trials (HCC)
Trial # Design Institution Dis-ease
CP scor
e
Size(cm)
Start Esti-matedCom-plete
En-roll
Com-ment
NCT00152906
Phase 1/2
Princess Mar-garet Hospital
HCC, IHC, Mets
A NA 2003.6 NA 140
NCT00243841
Phase 1/2
Indiana Uni-versity
HCC A-B NA 2004.5 2014.12
60
NCT00914355
Phase 2
Princess Mar-garet Hospital
HCC A-B8 ≤ 15-CP A
≤ 10-CP B
2007.8 2013.8 47
NCT00607828
Phase 1
University of Nebraska
HCC A-B ≤ 8 2007.11
2009.10
28
NCT01347333
NA St. John's Mercy Re-
search Insti-tute
HCC, IHC, Mets
NA ≤ 6 2008.9 2015.9 50
NCT01528878
Phase 1
University of North Carolina
HCC, Mets
A-B NA 2009.4 2014.4 40
NCT00746655
Phase 1
University of Pittsburgh
HCC A-B ≤ 180 ml
2009.7 2012.6 12 +TACE
From clinicaltrial.gov (2013.5.10)
Ongoing SABR trials (HCC)
Trial # Design Institution Dis-ease
CP scor
e
Size(cm)
Start Esti-matedCom-plete
En-roll
Com-ment
NCT01668134
Phase 1
Washington University
HCC, IHC
A-B7 NA 2009.9 2015.12
40
NCT01668134
Phase 1
Washington University
HCC, IHC
A-B7 NA 2009.9 2015.12
40
NCT01522937
Phase 2
University of Michigan
HCC, Mets
NA NA 2009.10
2014.1 70
NCT01005875
Phase 1
University of Alabama
HCC A-B7 ≤ 6 2009.11
2012.12
5 +So-rafenib
NCT01213758
NA University of Aarhus, Den-
mark
Liver NA NA 2010.6 2013.1 20
NCT01194206
Phase 2
Seidman Can-cer Center
HCC A-B NA 2010.8 2012.3 NA
NCT01247298
Phase 0
(Pilot)
University of Alabama
HCC A-B ≤ 8 2010.10
2014.12
20 +TACEFrom clinicaltrial.gov (2013.5.10)
Ongoing SABR trials (HCC)
Trial # Design Institution Dis-ease
CP scor
e
Size(cm)
Start Esti-matedCom-plete
En-roll
Com-ment
NCT01167374
Phase 1
University Hospital Hei-
delberg
HCC NA NA 2011.8 2013.1 33 Carbon Ion
NCT01850667
Phase 2
Korea Cancer Center Hospi-
tal
HCC A-B7 < 10 2012.1 2014.9 71 +TACE
NCT01825824
Phase 2
Korea Cancer Center Hospi-
tal
HCC A-B7 ≤ 5 2012.6 2014.12
54 +TACE
NCT01850368
Phase 2
Korea Cancer Center Hospi-
tal
HCC A-B7 NA 2012.10
2014.3 28 +TACE
NCT01730937
Phase 3
Princess Mar-garet Hospital
RTOG 1112
HCC A ≤ 15 2013.1 2016.6 368 Sorafenib±SABR
NCT01801163
Phase 1b
Indiana Uni-versity
HCC A ≤ 6 2013.2 2014.8 14 +So-rafenib
From clinicaltrial.gov (2013.5.10)
0 12 24 36 48 600
20
40
60
80
100
Time from SABR (months)
0 12 24 36 48 600
20
40
60
80
100
Time from SABR (months)
Local control as SABR dose
p=0.0340
> 54 Gy (n=21)
≤ 54 Gy (n=29)
0 12 24 36 48 600
20
40
60
80
100
Time from SABR (months)
> 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 patients1) This phase 2 study aims to target a 2-year over-all 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 Design
MinMax De-sign
First Stage Sample Size (n1) 15 24
Upper Limit For 1st Stage Rejection of Drug (r1) 9 15
Maximum Sample Size (n) 43 36
Upper Limit for 2nd Stage Rejection of Drug (r) 28 24
Expected Sample Size If Response Prob-ability = 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 BCLC 0/A/B (1-3 nodules≤7 cm) 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)
Estimated Enrollment: 71 patientsEstimated primary completion date: 2012.1 – 2013.12
Follow-up
TACE #1-5
Eligibility CheckInformed Consent
SABR (45-60 Gy in 3 fractions)Within 14 days (Time b/w fx`s
≥ 48 hrs)
Response evaluation at 2 mo
Non PD PD
2nd Response Evalua-tion at 6 mo
Repetitive TACE or other therapy
Non PD PD
EGD at 2 monthsCBC, Admission panel, PT, AFPPET at 6 months as possible
EGD within 6 monthsCBC, Admission panel, PT, AFP
4wks after TACE
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 < 10 cm• Normal liver volume ≥ 1000 ml• Incomplete response after TACE of 1-5 sessions• A single lesion or multiple lesions including portal vein thrombosis included in radi-ation field with one or con-secutive sessions of SABR• No extrahepatic metas-tases or malignant nodes • No liver cirrhosis related complication• No severe other co-morbid-ity
Exclusion• Direct tumor extension into the esophagus, stomach, duodenum, small bowel or large bowel• Prior radiotherapy to upper Abd
Inclusion
Exclusion
NCT01850667KCT0000454
Initially or Recurrent HCCUnsuitable for Op, TPL, RFA