Dutta liver (1)

------------------------ HCC ?

Radiosurgery in liver tumours: Recent updates

Worldwide Incidence of Hepatocellular Carcinoma

High (> 30:100,000)

Low or data unavailable (< 3:100,000)Intermediate (3-30:100,000)

Worldwide Incidence of Hepatocellular Carcinoma

HCC Epidemiology

El-Serag HB, Gastroenterology 2004

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

Inoperable HCC: SorafinibStudy Type N ResultLlovet 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

Median survival 10.7 months: Grade 3/4 toxicity: 10%

Where is radiation ?

Bruix et al Lancet 2009

Llovet. J of Hepatology 2008

HCC treatment: Based on low level of evidence

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

Sonaki N et al, W J Gastro 2015

HCC Management

Role of Radiosurgery in HCC is established

Role of RT in HCC

- Radical radiation therapy / SBRT

- ‘Bridge to transplant’

- Palliative intent RT

- SBRT along with systemic therapy

3-D Conformal RT

IMRT

Radiosurgery

Modern SBRT Systems

Modern SBRT Accuracy

• Mechanical Accuracy = 0.2 mm

• Total Clinical Accuracy – Stationary lesions: 0.95 mm– Moving lesions: 1.5 mm

Total Clinical

Accuracy

CyberKnifeTotal Clinical Accuracy

Chang et al.Neurosurgery, 2003

Murphy MJ et al. Int J Radiat Oncol Biol Phys. 2003

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

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 SBRT

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

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-valueSBRT 72.6%

0.013NO SBRT 42.1%

Huang WY et al, IJROBP 2012

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

TACE+ SBRT in unresectable HCC

Study n RT Dose ResultsYoshikawa (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

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

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

CK planning

Demographic profile (n=50)

Mean age: 57.5 yrsMale: 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 MetsPTV (Target)

Mean vol (cc)Range (cc)

Max dose (Gy)Mean dose (Gy)

Prescription isodose (%)Target Coverage (%)

Mean CIMean nCI

Mean 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


All pt (n=31)

HCC(n=13)

Mets(n=18)

Median OS (mo) 9 10.5 6.5Mean OS (mo)

Range12.4

1.9-44.618.4

2.1-44.68.2

1.9-24.6Status at LFU

Local controlProgressionMetastasis*

DeadAlive

9 (29)

15 (48)6 (19)

19 (61)12 (39)

2 (15)7 (53)3 (23)

10 (77)3 (23)

7 (39)8 (44)3 (17)9 (50)9 (50)

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


Survival function

p-value: NS

Median Survival:HCC: 10.1 moMets: 9.0 mo

1yr Survival:HCC: 45%Mets: 30%


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>39Gy6) Small volume disease patients

have significantly better survival

^Log Rank test


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 (2015) Retro 50 10.4 1 pt with anecteric hepatitis

Our pt cohort is heavily pre-treated (76%),Progression on chemotherapy and high viral load (Hep B/C)


Patient selectionNOT only the size, site of lesion also matters

Outcome depends not ONLY on planning BUT also on execution

Liver movement (n=51 snaps)Liver movement is more erratic than we think

Snap1 Snap2 Snap3

Lat shift 1.8 1.04 1.2Ant Shift 1.2 1.28 1.91Sup shift 2.9 3.3 2.84

Need internal fiducial based intra-fraction tracking system

To treat liver tumour

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

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

need to evaluate efficacy only with Survival Function

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

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

‘Bridge to transplant’

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

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

CLOCC study

Presented By Theo Ruers at 2015 ASCO Annual Meeting ASC0 2015 Abstr

Overall Survival

Presented By Theo Ruers at 2015 ASCO Annual Meeting ASC0 2015 Abstr

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.

www.radiosurgery-india.com [email protected]

Oscar Lambart Centre. Nice, FranceDr Eric LatigoDr Mirabel

Lille CyberKnife Centre, FranceDr Bondiaue

Munich CyberKnife Centre, GermanyDr Alex MuciavicDr Barnad Wowra

Apollo Hospitals teamLiver transplant teamMedical & Surgical gastroentrologistMedical OncologistRadiologistMedical Physicists

Acknowledgements

http://www.radiosurgery-india.com/

Health & Medicine

Dutta liver (1)