Stereotactic Ablative RT in HCC

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

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)

Local con

30 40 50 60 70 0

R² = 0.884165554567678

2 year overall survival

TCP by SABR doseTu

trol Pro

babili

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Unpublished data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

Time from SBRT (months)

0 12 24 36 48 600

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

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

>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

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

End points ofhepatic toxicity

Probability of toxicity %Volume to receive

<15 GyVolume to receive

<17 Gy

≥700 cc <700 cc ≥700 cc <700 cc

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

17 Gy 60Gy/3 fx’s17 Gy

57 Gy/3 fx’s

17 Gy 54 Gy/3 fx’s

Gastroduodenum con-straint

Yes No Unknown Total0

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

No Yes

Normal Liver Dose-ConstraintsrV15<700 ml (CP A5), rV17<700 ml (CP A6-

Incomplete TACE

Complete TACE

Observation

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

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

SABR (60 Gy in 3 fractions)Within 14 days (Time b/w fx`s

≥ 48 hrs)

Non PD PD

EGD at 2 monthsCBC, Admission panel, PT, AFPPET at 6 months as possible

4wks after TACE

Inclusion

Exclusion

NCT01825824KROG 12-02KCT0000422

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

SABR (40 Gy in 4 fractions)Within 28 days (Time b/w fx`s

≥ 48 hrs)

Follow-up at 4, 6 mo,

then at every 3 months

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

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)

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)

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)

Portal vein tumor thrombosis (yes vs. no)

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

0.19504

Sex MaleFemale

0.62713

ECOG PS 12

0.29640

Liver cirrhosis NoYes

1.00004

Viral hepatitis NoYes

0.25204

Previous treatment† ≤2>3

0.64013

Initial CP score 56/7/8

4610/3/2

05/0/0

0.0010

3/1/00.003

Pre-MELD score ≤8>8

0.51831

SABR duration 3 days≥4 days

1.00031

PTV ≤28 cc>28 cc

0.06004

Normal liver volume ≤1,000 cc>1,000 cc

0.01531

V15G ≤700 cc>700 cc

0.00631

V17Gy ≤700 cc>700 cc

0.09622

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.

Incomplete TACE → Sorafenib alone ???

BCLC Stage based Treatment: SABR Role

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

BCLC Stage 0

BCLC Stage B

BCLC Stage A

Treat-ment as guide-

1 - 3 nodules D sum ≤ 10 cm

Eligibility check

Incom-plete

SABR or 3D-CRT

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%

Compare with other studies

PTVVolume

PTV_Belgium93.5

PTV_Indiana U49.3

PTV_Current28.8

PTVVolume

(ml)Dose

PrescriptionCover-

PTV_Belgium93.5 45Gy 65%

PTV_Indiana U 49.3 48Gy 93%

PTV_Current28.8 60Gy 98%

PTVVolume

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%

PTV_Belgium

PTV_Indiana U

PTV_Current

Study, yearStud

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

82(Rec 66%)

3.2 82 39 (5yr)GI 6.1%, non-GI

6.1%CP score+2 7%

Current(Dose>54 Gy)

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 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)

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 Estimated Enrollment: 54 Study Start Date: 2012.6 Estimated Primary Completion Date: 2013.12 Current Enrollment: 19

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

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

If the rV17Gy or rV15Gy is lessthan 700cc at this planed

A5 rV17Gy >700

54Reduce to 48 Gy and re-

evaluation

evaluation42 Ineligible

A6-B7 rV15Gy >700

evaluation

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

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

Complete TACE

n=19 n=85

Additional SBRT

Without SBRT

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

Not assessed

1-8(2)

1-9(3) 1-11(2)

TACE vs TACE+SABR

0 12 24 36 48 600

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

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

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

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

CP scoreMELDScore

Hepatictoxicity*

Clinical manifestations ofdeterioration of hepatic function

Pre Post Pre Post Pre Post

7 F/62 889 697 6 10 8 14 1 3 Hyperbilirubinemia, Hepatic encephalopathy

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

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

Phase I17

36-48/3 (CP A)

40/5 (CP B)

8-95 cc (34 cc)20-60 mm (40

10-42(24)

CR 25PR 56

100 60RILD, 12%

(All CP B pts)

AndolinoIndiana U

Phase I/II(Interim)

6024-48/3-5

2-112 cc (29cc)10-65 mm (31

2-52(27)

CR 30PR 40

90 67 Increased CTP, 20%

LouisBelgium

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

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/

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

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

• 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-

CyberKnife

Tomotherapy

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

142 studies found for: hepatocellular car-cinoma | radiotherapy

25 studies found for: hepatocellular carci-noma | radiotherapy | stereotactic

Ongoing SABR trials (HCC)

Trial # Design Institution Dis-ease

CP scor

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

NCT00914355

Phase 2

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

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)

CP scor

Size(cm)

En-roll

Com-ment

NCT01668134

Phase 1

Washington University

HCC, IHC

A-B7 NA 2009.9 2015.12

NCT01668134

Phase 1

Washington University

HCC, IHC

A-B7 NA 2009.9 2015.12

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-

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)

CP scor

Size(cm)

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-

HCC A-B7 < 10 2012.1 2014.9 71 +TACE

NCT01825824

Phase 2

HCC A-B7 ≤ 5 2012.6 2014.12

54 +TACE

NCT01850368

Phase 2

HCC A-B7 NA 2012.10

2014.3 28 +TACE

NCT01730937

Phase 3

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

Time from SABR (months)

0 12 24 36 48 600

Local control as SABR dose

p=0.0340

> 54 Gy (n=21)

≤ 54 Gy (n=29)

0 12 24 36 48 600

> 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)

Follow-up

TACE #1-5

SABR (45-60 Gy in 3 fractions)Within 14 days (Time b/w fx`s

≥ 48 hrs)

Non PD PD

EGD at 2 monthsCBC, Admission panel, PT, AFPPET at 6 months as possible

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

Stereotactic Ablative RT in HCC

course sabr n

sabr duration

ns ns sbrt dose gy

gy3 fractionspostsabr

curative sabr size

fractionations n

studies n

sabr dosesimple correlation

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