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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 CyberKnife in Hepatocellular carcinoma [email protected]

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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

[email protected]

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

[email protected]

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

[email protected]

Role of RT in HCC

- Radical radiation therapy / SBRT

- ‘Bridge to transplant’

- Palliative intent RT

- SBRT along with systemic therapy

[email protected]

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

[email protected]

3-D Conformal RT

IMRT

Radiosurgery

Modern SBRT Systems

SynchronyTM

Fiducial based tracking along with respiratory motion tracking

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

[email protected]

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 [email protected]

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

[email protected]

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 [email protected]

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 [email protected]

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

[email protected]

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

[email protected]

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

[email protected]

CK planning

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)[email protected]

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)[email protected]

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)[email protected]

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)[email protected]

Patient selectionNOT only the size, site of lesion also matters

[email protected]

Outcome depends not ONLY on planning BUT also on execution

Need internal fiducial based intra-fraction tracking system

To treat liver tumour

[email protected]

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

[email protected]

Challenges: evaluation for local controlNO suitable imaging method to assess response after CK,

need to evaluate efficacy only with Survival Function

[email protected]

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

[email protected]

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 [email protected]

‘Bridge to transplant’

• Patient eligible for transplant but need to wait >3months• Non-invasive option• Evaluate response to radiation therapy

[email protected]

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. [email protected]