Download - 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
Dutta et al ESTRO 2013 (Abstr)
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
Dutta et al ESTRO 2013 (Abstr)
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)
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
Dutta et al ESTRO 2013 (Abstr)
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)
Dutta et al ESTRO 2013 (Abstr)
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