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- CyberKnife is an 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
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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
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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 IIIEconomic 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 BSCICER: $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
*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%
Llovet. J of Hepatology 2008
HCC treatment: Based on low level of evidence
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Role of RT in HCC
- Radical radiation therapy / SBRT
- ‘Bridge to transplant’
- Palliative intent RT
- SBRT along with systemic therapy
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Why RT is not 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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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
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Study Type n Dose 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 mo1-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
HCC: Recent studies
Author Jour n Study criteria FU Outcome
Price TR Cancer 2012
26 Awaiting for liver transplant
13 CR-4PR-15Resp rate 73%CTCAE Gr-3: Nil
Ibarra RA Acta Oncol2012
21 Inoperable HCC 12.9 TTP=6.3 mo1-Yr OS 87%2-Yr OS 55%
Facciuto ME
J Surg Oncol 2012
39 Post TACE residualProgressive
CR 30%Stable 57%Prog 7%
Excellent response rate with SBRTcopyright@www.radiosurgery-india.com
HCC: Recent studies
Author Jour n Study criteria FU (mo)
Outcome
Goyal HPB 2012 17 RecurrentDose 35Gy
8 Vol reduction: 44%LC 82%
Seo YS J Surg Oncol 2010
38 Inoperable HCC ,10 cm / post-TACEDose 45Gy
High dose indepent prog factor2-Yr OS 61.4%
Kwow JH BMC 2010
42 Post TACE residualProgressiveDose 39 Gy
1-Yr OS 92.9%3-Yr OS 58.6%
High dose RT independent prognostic factor
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Recurrent/ progressive HCC (n=174)
Recurrent progressive HCCSBRT= 42No SBRT= 138Median FU= 20 monthsDose= 37Gy
Local control1-Yr: 87.6%2-Yr: 75.1%
Overall survival2-Yr: 64%Median Survival: 8 mo
Independent prognostic factor:1.SBRT2.T<4 cm3.Stage I4.Child Pugh A
2-Yr OS p-value
SBRT 72.6% 0.013NO SBRT 42.1%
Huang WY et al, IJROBP 2012
HCC: TACE Vs TACE+SBRTEvaluated 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 Response after 6 mo
2-Yr LC
2-Yr OS CTCAE Gr-3
SBRT 47
CR-38%PR-38%
94% 68.8% 6%
Kang JK et al, Cancer 2012 copyright@www.radiosurgery-india.com
SBRT: Prognostic factorsEvaluated 153 HCC pts
HCC= 48 ptsMedian FU= 15 moDose= 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 copyright@www.radiosurgery-india.com
TACE+ SBRT in unresectable 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-analysis7 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
Liver tumour: CyberKnife: ASH protocolLiver 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
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Planning & treatment execution
Contouring:CT scan & MRI scan fusionOccasionally 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 coverage2.Critical structure dose3.Nodes / beamlets / MU / time
Critical structure constraints as per protocol
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CK planning: Normal tissue 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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All pt HCC Mets Age(yr) Mean
(range)57.5
(35-81)60.3
(45-71)51.2
(35-61)Gender Male
Female14 (82)3(18)
9(100)0
2(50)2(50)
Child Pugh A
BC
1(6)10(58)6(36)
06(67)3(33)
1(25)2(50)1(25)
KPS 70-8090-100
13(76)4(24)
6(67)3(33)
3(75)1(25)
Hepatitis NoYes
9(54)8(46)
1(12)8(88)
4(100)0
Hepatitis BC
4(50)4(50)
4(50)4(50) -
Liver status Normal/fatty liverDiffuse cirrhosis
12(72)5(28)
4(40)5(60)
4(100)0
No of lesions 123
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)
03(75)1(25)
Prior treatmentNo treatment
Treatment doneTACE
Chemotherapy
4 (24)13 (76)5(30)8 (70)
3(33)6(67)
06(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)
All pt HCC Mets
PTV (Target) Mean vol (cc)
Range (cc)Max dose (Gy)
Mean dose (Gy)Prescription isodose (%)
Target Coverage (%)Mean CI
Mean nCIMean HI
192(10-710)36.333.38494
1.131.281.19
196(10-710)39
35.78494
1.061.261.18
200(50.7-628)
3633.58492
1.211.311.19
Liver Mean volume (cc)
Mean dose (Gy)20Gy Vol (cc)10Gy Vol (cc)
800cc liver dose (Gy)
11974.71113578.2
11434.3
92.9313.7
7.5
1582
7182.553210.2
Small intestineMean dose (Gy)
2% volume dose (Gy)
3.4
10.6
2.88.9
3.29.9
Dosimetry
Mean target Vol: 192 ccPres Isodose: 84%Target coverage: 94%
Mean dose: 33 GyDose Range: 21-45GyFractions: 3
Mean liver dose: 4.7 Gy800 cc liver: < 8.2 Gy
2% Small Intestine: 10.6 Gy
Dutta et al ESTRO 2013 (Abstr)
All pt HCC Mets Median OS (mo) 10.1 10.1 9.0
Mean OS (mo)Range
11.31.9-26.5
11.92.1-26.5
8.31.9-13.3
Status at LFULocal controlProgressionMetastasis*
DeadAlive
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 profileGI Toxicity Gr- I-II
Gr-III-IVOther^
5 (29)
01 (12)
1 (11)0
1 (11)
2 (50)00
Fiducial related toxicityPain 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)copyright@www.radiosurgery-india.com
Survival function
p-value: NS
Median Survival:HCC: 10.1 moMets: 9.0 mo
1yr Survival:HCC: 45%Mets: 30%
Dutta et al ESTRO 2013 (Abstr)copyright@www.radiosurgery-india.com
Factors Median OS
(mo) p-value^
KPS70-80 8.3
0.03490-100 15.4
Child PughA/B 13.3
0.039C 4.9
CirrhosisNo 13.3
0.005Yes 9.4
Prior Rxyes 8.3
0.006No 16.6
HepatitisNo 10.5
0.977yes 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)copyright@www.radiosurgery-india.com
Our Survival function data: 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)copyright@www.radiosurgery-india.com
Patient selectionNOT only the size, site of lesion also matters
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Need internal fiducial based intra-fraction tracking system
To treat liver tumour
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Single vs multiple fiducialNo 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
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Challenges: evaluation for local controlNO suitable imaging method to assess response after CK,
need to evaluate efficacy only with Survival Function
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Survival Function in Small Vol (<10cc), CP A, Single lesion, No prior Rx
p-value: 0.001 Median survivalVol<10 cc, KPS>80, No Prior Rx: 19.2 months
Vol>90cc, KPS<80, Prior Rx: 6.4 months
‘Palliative SBRT’
• Inoperable• Progressive/ Recurrent disease• Not responding to chemotherapy• Not able to tolerate chemotherapy• Poor GC: no systemic therapy• Aim: symptom palliation
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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 2013copyright@www.radiosurgery-india.com
‘Bridge to transplant’
• Patient eligible for transplant but need to wait >3months• Non-invasive option• Evaluate response to radiation therapy
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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
Conclusions- Robotic radiosurgery is 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. copyright@www.radiosurgery-india.com
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