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Stereotactic Ablative RT in HCC

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Mi-Sook Kim, MD, PhD …

Mi-Sook Kim, MD, PhD
Department of Radiation Oncology
Korea Institute of Radiological and Science

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  • 1. Stereotactic Ablative RT in HCCMi-Sook Kim, MD, PhD Department of Radiation Oncology Korea Institute of Radiological and Science
  • 2. Contents • Published Phase II study • Retrospective Analysis (published or under review) • Our methodology for HCC treatment
  • 3. SABR for HCC: Phase 2 trial (Kang, Kim et al, Cancer 2012;118:5424-31)
  • 4. 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
  • 5. 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)
  • 6. 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.
  • 7. 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)
  • 8. 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
  • 9. 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
  • 10. 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 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 20 40 60 80 100 0 12 24 36 48 60 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
  • 11. Independent Prognostic factor affecting OS 0 20 40 60 80 100 0 12 24 36 48 60 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 20 40 60 80 100 0 12 24 36 48 60 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)
  • 12. 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
  • 13. 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
  • 14. 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
  • 15. 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
  • 16. 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
  • 17. 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
  • 18. Thank you Thank you
  • 19. Follow-up Initially or Recurrent HCC Unsuitable for Op, TPL, RFA 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
  • 20. Estimated Enrollment: 54 patients Estimated 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 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) 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 PET at 6 months as possible EGD within 6 months CBC, Admission panel, PT, AFP 4wks after TACE Inclusion Exclusion Initially or Recurrent HCC Unsuitable for Op, TPL, RFA NCT01825824 KROG 12-02 KCT0000422
  • 21. Estimated Enrollment: 28 patients Estimated 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 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) 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 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 CBC, Admission panel, PT, AFP
  • 22. 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
  • 23. 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
  • 24. 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
  • 25. 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
  • 26. 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
  • 27. 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
  • 28. 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
  • 29. 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
  • 30. 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
  • 31. Treatment based BCLC Stage Llovet et al. J Hepatology 2012;56:908–943
  • 32. BCLC Stage based Treatment Inoperable Inacces.
  • 33. BCLC Stage based Treatment Inoperable Inacces. TACE
  • 34. BCLC Stage based Treatment Inoperable Inacces. Incomplete TACE → Sorafenib alone ???
  • 35. BCLC Stage based Treatment : SABR Role Inoperable Inacces. Curative SABR ( size < 7cm) Incomplete
  • 36. 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 Treatment as guideline 1 - 3 nodules D sum ≤ 10 cm Ye s No Eligibility check
  • 37. BCLC Stage based Treatment Inoperable Inacces. SABR Incomplete SABR or 3D-CRT
  • 38. BCLC Stage based Treatment Inoperable Inacces. SABR Incomplete SABR or 3D-CRT Palliative RT
  • 39. 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
  • 40. 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
  • 41. 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.
  • 42. 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
  • 43. PTV Volume (ml) PTV_Belgium 93.5 PTV_Indiana U 49.3 PTV_Current 28.8
  • 44. 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%
  • 45. 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[%]
  • 46. 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
  • 47. 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
  • 48. 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)
  • 49. 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
  • 50. 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
  • 51. Ongoing SABR trials in Korea  Stereotactic ablative radiotherapy for hepatocellular 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
  • 52. 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
  • 53. 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)
  • 54. 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
  • 55. BCLC stage based Treatment Bruix J et al, Hepatology 2011;53:1020
  • 56. 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
  • 57. 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
  • 58. 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 Reduce to 45 Gy and re-evaluat ion 45 Reduce to 42 Gy and re-evaluat ion 42 Ineligible A6-B7 rV15Gy >700 54 Reduce to 48 Gy and re-evaluat ion 48 Reduce to 45 Gy and re-evaluat ion
  • 59. 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.
  • 60. 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
  • 61. Thank you Thank you
  • 62. 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)
  • 63. TACE vs TACE+SABR 0 20 40 60 80 100 0 12 24 36 48 60 Overallsurvival(%) Time from SBRT (months) 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
  • 64. 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 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
  • 65. 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 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
  • 66. 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
  • 67. 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%
  • 68. Protocol (continuing)
  • 69. 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
  • 70. 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
  • 71. 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
  • 72. 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
  • 73. 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
  • 74. Other therapy  All supportive therapy for optimal medical care  Anticoagulants are not to be used to treat HCC related vascular thrombosis
  • 75. 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
  • 76. 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)
  • 77. Thank you Thank you
  • 78. 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
  • 79. 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 )
  • 80. 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
  • 81. IMRT CyberKnife Tomotherapy VMAT TrueBeam 2D 3D-CRT GammaKnife Evolving RT machine for 2 decades
  • 82. 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
  • 83. 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.
  • 84. 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.
  • 85. 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.
  • 86. Trials registered Clinicaltrial.gov  Clinicaltrial.gov (2013.5.10)  142 studies found for: hepatocellular carcinoma | radiotherapy  25 studies found for: hepatocellular carcinoma | radiotherapy | stereotactic
  • 87. Trials registered Clinicaltrial.gov  142 studies found for: hepatocellular carcinoma | radiotherapy
  • 88. Trials registered Clinicaltrial.gov  25 studies found for: hepatocellular carcinoma | radiotherapy | stereotactic
  • 89. 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 Phase 1 University of North Carolina HCC, Mets A-B NA 2009.4 2014.4 40 NCT 00746655 Phase 1 University of Pittsburgh HCC A-B ≤ 180 ml 2009.7 2012.6 12 +TACE From clinicaltrial.gov (2013.5.10)
  • 90. Ongoing SABR trials (HCC) Trial # Design Institution Diseas 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 Phase 2 University of Michigan HCC, Mets NA NA 2009.10 2014.1 70 NCT 01005875 Phase 1 University of 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 From clinicaltrial.gov (2013.5.10)
  • 91. Ongoing SABR trials (HCC) Trial # Design Institution Diseas 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 Phase 2 Korea Cancer Center Hospital HCC A-B7 ≤ 5 2012.6 2014.12 54 +TACE NCT 01850368 Phase 2 Korea Cancer 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 From clinicaltrial.gov (2013.5.10)
  • 92. 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 Time from SABR (months) 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 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
  • 93. 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
  • 94. 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
  • 95. 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)
  • 96. TCP as SBRT Dose Clinical TCP curve for all lesions (n=95)
  • 97. Estimated Enrollment: 71 patients Estimated primary completion date : 2012.1 – 2013.12 Follow-up TACE #1-5 Eligibility Check Informed 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 Evaluation at 6 mo Repetitive TACE or other therapy Non PD PD EGD at 2 months CBC, Admission panel, PT, AFP PET at 6 months as possible EGD within 6 months CBC, 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 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 Initially or Recurrent HCC Unsuitable for Op, TPL, RFA