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- 1. - CyberKnife isan option in inoperable or medically not suitable for surgery & in patient with progression / not tolerating systemic therapy - Initial results are impressive with low toxicity, good response rate - Pts with small tumour, no prior treatment with good performance treated with high dose have significantly better survival - Dose >45 Gy; 15Gy/# and small vol tumour (<50cc) have better prognosis - There is minimal toxicity with CyberKnife in liver tumours - Addition of chemotherapy along with CyberKnife will be the future CyberKnife in Hepatocellular carcinoma
- 2. HCC: Facts - 70%of pts present with advanced disease (Stage BCLC C) - Majority have background hepatitis B/C with cirrhosis - Nodal involvement common - Majority have impaired liver function Curative intent surgery/ transplant possible only 30% patients
- 3. Inoperable HCC: Sorafinib(Chemotherapy) Study Type N Result Llovet JM* (2008) Multi-centric Ph III 602 Median OS: 10.7 vs 7.9 mo (P<0.001). Symptomatic progression : 4.1 vs. 4.9 mo, (P=0.77). Radiologic progression: 5.5 vs 2.8 mo (P<0.001). 3 month survival benefit Abou-Alfa GK^ (2006) Ph II 137 Median TTP: 4.2 mo & OS: 9.2 mo. Grade 3/4 toxicities: Fatigue (9.5%), diarrhea (8.0%), & hand- foot skin reaction (5.1%). Muszbek N# (2008) Ph III Economic analysis - LYG was longer for sorafenib. (1.52 vs. 1.03 LYG/pt for sorafenib & BSC). Lifetime total costs: $47,51 for sorafenib & $10,376 for BSC ICER: $75,821/LYG. Cheng AL^^ (2009) Multi-centric Ph III 271 Median OS: 6.5 vs 4.2 mo(p=0.014). Median TTP :2.8 vs1.4 mo (p=0.0005). *N Engl J Med. 2008 ;359(4):378-90. ^J Clin Oncol. 2006 ;24(26):4293-300. #Curr Med Res Opin. 2008 ;24(12):3559-69. ^^Lancet Oncol. 2009 Jan;10(1):25-34 Median survival 10.7 months: Grade 3/4 toxicity: 10%
- 4. Llovet. J ofHepatology 2008 HCC treatment: Based on low level of evidence
- 5. Role of RTin HCC - Radical radiation therapy / SBRT - ‘Bridge to transplant’ - Palliative intent RT - SBRT along with systemic therapy
- 6. Why RT isnot the initial choice in HCC - HCC considered ‘radio-resistant’ - Usually late presentation: large tumour- ONLY palliative care - Liver is relative radiosensitive; low tolerance - ‘Radiation induced liver disease (RILD)’: ‘anicteric hepatitis’ - Difficult to deliver high dose!! - Liver moves with respiration: need 3-4 cm margin- difficult to spare liver - Technology not available to deliver precise radiation therapy
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- 11. Synchrony TM Fiducial based trackingalong with respiratory motion tracking
- 12. Radical RT/ SBRT •Early stage (0-A) disease • Few occasions even in multifocal lesions (Stage B) • Cirrhotic background- surgery is difficult • Medically inoperable or comorbidities • Technically ‘difficult to do surgery’ (subdiaphragamatic, porta) • Patient not willing for surgery
- 13. Study Type nDose Median FU (Mo) LC (%) OS Toxicity Mendez (2006) Ph I/II 8 25Gy/%# 30Gy/3# 13 82 1-Yr: 75% 2-Yr: 40% Gr-3/4: 1 pt Choi (2006) Ph II 20 50Gy/5-10# 23 NR 1-Yr: 70% Gr-3: Nil Tse (2008) Ph I 31 36Gy/6# 17.6 65 Median OS: 11.6 mo 1-Yr: 48% Gr-3: 8 pt Choi (2008) Ph II 31 30-36Gy/3# 10.5 72 At 11 mo: 72% Gr-3: Nil Yang (2009) Ph II 40 50Gy/10# 35 65 1-Yr: 73% Gr-3: Nil Cardenes (2010) Ph I 6 12-16 Gy/2-3# 24 100 1 Yr: 75% 2-Yr: 60% Gr-3: 3 pt Louis (2010) Ph II 25 45Gy/3# 12.7 95% 1-Yr OS: 79% Gr-3: 2 pt Early studies: SBRT for HCC All recurrent / resistant HCCs Local control / survival function: impressive
- 14. HCC: Recent studies AuthorJour n Study criteria FU Outcome Price TR Cancer 2012 26 Awaiting for liver transplant 13 CR-4 PR-15 Resp rate 73% CTCAE Gr-3: Nil Ibarra RA Acta Oncol 2012 21 Inoperable HCC 12.9 TTP=6.3 mo 1-Yr OS 87% 2-Yr OS 55% Facciuto ME J Surg Oncol 2012 39 Post TACE residual Progressive CR 30% Stable 57% Prog 7% Excellent response rate with SBRT
- 15. HCC: Recent studies AuthorJour n Study criteria FU (mo) Outcome Goyal HPB 2012 17 Recurrent Dose 35Gy 8 Vol reduction: 44% LC 82% Seo YS J Surg Oncol 2010 38 Inoperable HCC , 10 cm / post-TACE Dose 45Gy High dose indepent prog factor 2-Yr OS 61.4% Kwow JH BMC 2010 42 Post TACE residual Progressive Dose 39 Gy 1-Yr OS 92.9% 3-Yr OS 58.6% High dose RT independent prognostic factor
- 16. Recurrent/ progressive HCC(n=174) Recurrent progressive HCC SBRT= 42 No SBRT= 138 Median FU= 20 months Dose= 37Gy Local control 1-Yr: 87.6% 2-Yr: 75.1% Overall survival 2-Yr: 64% Median Survival: 8 mo Independent prognostic factor: 1.SBRT 2.T<4 cm 3.Stage I 4.Child Pugh A 2-Yr OS p-value SBRT 72.6% 0.013NO SBRT 42.1% Huang WY et al, IJROBP 2012
- 17. HCC: TACE VsTACE+SBRT Evaluated 365 HCC pts (<3 cm) n CR P-value DFS (mo) p-value CTCAE Gr- 3 TACE 38 29/30(96%) 0.001 15.7 0.029 - TACE+ SBRT 30 1/88 (3%) 4.2 Nil Kimura HY et al, J Gasteroenterol Hepatol 2013 n Respons e after 6 mo 2-Yr LC 2-Yr OS CTCAE Gr-3 SBRT 4 7 CR-38% PR-38% 94% 68.8% 6% Kang JK et al, Cancer 2012
- 18. SBRT: Prognostic factors Evaluated153 HCC pts HCC= 48 pts Median FU= 15 mo Dose= 45Gy/3# T= 33 mm Local Control- 1-Yr: 84% 2-Yr: 74.6% Factors influencing outcome: T<50 mm (p=0.019) TD>45Gy (p=0.001) D/Fr >15Gy (p=0.019) Dewas S et al, Radiat Oncol 2012
- 19. TACE+ SBRT inunresectable HCC Study n RT Dose Results Yoshikawa (1990) 31 48 Gy 5-Yr: 35% Guo (2003) 107 55 Gy 3-Yr: 28.4% 5-Yr: 15.8% Wu (2004) - - 1-Yr: 93.6% 2-Yr: 53.8% 3-Yr: 25.9% MS: 25 mo Marelli (2006) Meta-analysis 7 RCT - Improves survival with TACE+SRT Zhou 50 - 1-Yr: 60% 2-Yr: 38% 3-Yr: 28% MS: 17 mo TACE + SRT is a safe an effective palliation treatment in unresectable HCC
- 20. Liver tumour: CyberKnife:ASH protocol Liver tumour prior to CK evaluated by hepatic surgeon Inoperable or not willing for surgery counseled for CK Assessed with triphasic 320 slice CT scan Vacloc preparation MRI scan of liver as per CK protocol Fiducial placement under USG/CT scan guidance Wait for 3-5 days for fiducial stabilization CT scan with vacloc as per CK protocol Treatment with fiducial tracking on Syncrony 21-45 Gy/3# treatment as per critical structure constraints
- 21. Planning & treatmentexecution Contouring: CT scan & MRI scan fusion Occasionally PET scan fusion Target (GTV) & critical structures contoured (liver, duodenum, small intestine, kidney) PTV margin ≅ 2 mm Planning done: on Multiplan Plan approved as per: 1.Target coverage 2.Critical structure dose 3.Nodes / beamlets / MU / time Critical structure constraints as per protocol
- 22. CK planning: Normaltissue constraints Organ/ Critical structure Dose Constraints Liver V21<33% Spinal cord Dmax 22 Gy Kidney V15< 33% Stomach V21< 5 cm3 Intestine V16<5 cm3; Dmax < 27 Gy Duodenum D15 < 5cm3; Dmax < 24 Gy Timmerman et al, Sem Oncol 2008 At least 800 cc of liver <10Gy
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- 24. All ptHCC Mets Age(yr) Mean (range) 57.5 (35-81) 60.3 (45-71) 51.2 (35-61) Gender Male Female 14 (82) 3(18) 9(100) 0 2(50) 2(50) Child Pugh A B C 1(6) 10(58) 6(36) 0 6(67) 3(33) 1(25) 2(50) 1(25) KPS 70-80 90-100 13(76) 4(24) 6(67) 3(33) 3(75) 1(25) Hepatitis No Yes 9(54) 8(46) 1(12) 8(88) 4(100) 0 Hepatitis B C 4(50) 4(50) 4(50) 4(50) - Liver status Normal/fatty liver Diffuse cirrhosis 12(72) 5(28) 4(40) 5(60) 4(100) 0 No of lesions 1 2 3 12(72) 3 (18) 2 (10) 7 (77) 2 (23) 0 1(25) 1(25) 2(50) Tumour Vol <10cc 11-90cc >90cc 3(18) 8 (48) 6 (34) 3(33) 3(33) 3(33) 0 3(75) 1(25) Prior treatment No treatment Treatment done TACE Chemotherapy 4 (24) 13 (76) 5(30) 8 (70) 3(33) 6(67) 0 6(100) 0 4(100) 3(75) 1(25) Demographic profile (n=17) Mean age: 57.5 yrs Male: 82% Child Pugh A & B: 64% KPS>80: 24% Hepatitis: 46% Single lesion: 72% Tumour vol <90cc: 66% Prior Rx: 76% Dutta et al ESTRO 2013 (Abstr)
- 25. All ptHCC Mets PTV (Target) Mean vol (cc) Range (cc) Max dose (Gy) Mean dose (Gy) Prescription isodose (%) Target Coverage (%) Mean CI Mean nCI Mean HI 192 (10- 710) 36.3 33.3 84 94 1.13 1.28 1.19 196 (10- 710) 39 35.7 84 94 1.06 1.26 1.18 200 (50.7-628) 36 33.5 84 92 1.21 1.31 1.19 Liver Mean volume (cc) Mean dose (Gy) 20Gy Vol (cc) 10Gy Vol (cc) 800cc liver dose (Gy) 1197 4.7 111 357 8.2 1143 4.3 92.9 313.7 7.5 1582 7 182.5 532 10.2 Small intestine Mean dose (Gy) 2% volume dose (Gy) 3.4 10.6 2.8 8.9 3.2 9.9 Dosimetry Mean target Vol: 192 cc Pres Isodose: 84% Target coverage: 94% Mean dose: 33 Gy Dose Range: 21-45Gy Fractions: 3 Mean liver dose: 4.7 Gy 800 cc liver: < 8.2 Gy 2% Small Intestine: 10.6 Gy Dutta et al ESTRO 2013 (Abstr)
- 26. All ptHCC Mets Median OS (mo) 10.1 10.1 9.0 Mean OS (mo) Range 11.3 1.9-26.5 11.9 2.1-26.5 8.3 1.9-13.3 Status at LFU Local control Progression Metastasis* Dead Alive 7 (41) 7 (41) 3 (18) 12 (70) 5 (30) 3 (35) 4 (40) 2 (25) 6 (67) 3 (33) 1 (25) 2 (50) 1 (25) 3 (75) 1 (25) Toxicity profile GI Toxicity Gr- I-II Gr-III-IV Other^ 5 (29) 0 1 (12) 1 (11) 0 1 (11) 2 (50) 0 0 Fiducial related toxicity Pain 2 (24) 1 (11) 1 (25) *One pt with HCC had brain metastasis at 2 yrs FU. One HCC pt had extensive mets at 7 mo post-CK. ^One pt had anicteric ascites, pedal oedema, high alk phos 3 mo post-CK, resolved with supportive care Survival function Dutta et al ESTRO 2013 (Abstr)
- 27. Survival function p-value: NS MedianSurvival: HCC: 10.1 mo Mets: 9.0 mo 1yr Survival: HCC: 45% Mets: 30% Dutta et al ESTRO 2013 (Abstr)
- 28. Factors Median OS (mo) p-value^ KPS 70-808.3 0.034 90-100 15.4 Child Pugh A/B 13.3 0.039 C 4.9 Cirrhosis No 13.3 0.005 Yes 9.4 Prior Rx yes 8.3 0.006 No 16.6 Hepatitis No 10.5 0.977 yes 9.5 Dose <39Gy 9.5 0.02 >39Gy 15.4 Volume <10cc 15.7 0.011 >90cc 7.2 Factors influence outcome 1) Higher KPS, 2) Favourable Child Pugh, 3) No corrhosis, 4) No prior Rx, 5) Dose>39Gy 6) Small volume disease patients have significantly better survival ^Log Rank test Dutta et al ESTRO 2013 (Abstr)
- 29. Our Survival functiondata: HCC Study Type n Survival (mo) Toxicity (Gr-3/4) Llovet JM* (2008) Ph III 602 10.7 Abou-Alfa GK^ (2006) Ph II 137 9.2 Fatigue (5%), diarrhea (8.0%), hand-foot dis (5.1%) Cheng AL (2009) Ph III 271 6.5 Our study (2013) Retro 17 10.1 1 pt with anecteric hepatitis Our pt cohort is heavily pre-treated (76%), Progression on chemotherapy and high viral load (Hep B/C) Dutta et al ESTRO 2013 (Abstr)
- 30. Patient selection NOT onlythe size, site of lesion also matters
- 31. Outcome depends notONLY on planning BUT also on execution
- 32. Need internal fiducialbased intra-fraction tracking system To treat liver tumour
- 33. Single vs multiplefiducial No difference in survival function, BUT difference in T Time Multiple fiducials Single fiducial Survival: 15.6 vs 10.4 mo No difference in survival function, BUT difference in T Time
- 34. Challenges: evaluation forlocal control NO suitable imaging method to assess response after CK, need to evaluate efficacy only with Survival Function
- 35. Survival Function in SmallVol (<10cc), CP A, Single lesion, No prior Rx p-value: 0.001 Median survival Vol<10 cc, KPS>80, No Prior Rx: 19.2 months Vol>90cc, KPS<80, Prior Rx: 6.4 months
- 36. ‘Palliative SBRT’ • Inoperable •Progressive/ Recurrent disease • Not responding to chemotherapy • Not able to tolerate chemotherapy • Poor GC: no systemic therapy • Aim: symptom palliation
- 37. Phase II Trial:Palliative RT for HCC (n=42) Purpose Evaluate feasibility & response of liver radiotherapy (RT) in improving symptoms QOL Patients and Methods Pts unsuitable for or refractory to standard therapies, with an index symptom of pain, abdominal discomfort, nausea, or fatigue. The Brief Pain Inventory (BPI), Functional Assessment of Cancer Therapy–Hepatobiliary (FACT-Hep), and EORTC QLQ-C30 were completed by pts at baseline and each follow- up. Primary outcome: % of pts with a clinically significant change at 1 mo BPI subscale of symptom Results At 1 mo, 48% had an improvement in symptom on average in the past wk. 52% had improvement in symptom at its worst, 37% at its least, and 33% now. Improvements FACT-G & hepatobiliary subscale in 23% and 29%. Improvements in EORTC QLQ-C30 functional (range, 11% to 21%) and symptom (range, 11% to 50%) domains. Conclusion Improvements in symptoms were observed at 1 month in a substantial proportion of patients. Soliman H et al JCO 2013
- 38. ‘Bridge to transplant’ •Patient eligible for transplant but need to wait >3months • Non-invasive option • Evaluate response to radiation therapy
- 39. Bridge to transplant:literature Median Follow up: 62 months Patients: 10 Median SBRT dose: 51 Gy (33-54Gy) All patients had orthotropic transplant Pathological response: 27% CR 73% PR No progression after SBRT (CK) At 5 yr disease free survival: 100% 4 pts had acute toxicities (all grade I) (nausea, abdominal discomfort, fatigue) O’Connor JK et al, Liver Transpl Mar 2012
- 47. Conclusions - Robotic radiosurgeryis an option in inoperable or medically not suitable for surgery and in patient with progression / not tolerating systemic therapy - Initial results are impressive with low toxicity, good response rate - Pts with small tumour, no prior treatment with good performance treated with high dose have significantly better survival - Dose >45 Gy; 15Gy/# and small vol tumour (<50cc) have better prognosis - Need multi-centric prospective studies.