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Angiogenic blockade and Tomotherapy in
hepatocellular carcinoma
季匡華 Kwan-Hwa Chi, M.D.Chairman, Section of Radiation Therapy and OncologyShin Kong Wu Ho-Su Memorial Hospital, TaiwanProfessor, School of Medicine National Yang-Ming University
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Hepatoma Treatment Option
Surgery 15-29%
TAE/TACE 40-70%
PEITRFA
5→25%
Radiotherapy 2→6%
Background
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The Ideal Radiotherapy Facility for Hepatoma Treatment
1. Proton Therapy
2. Tomotherapy
3. Cyberknife
Background
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Local control at 5 years 86.9% for all 192 tumor patients
with median 72Gy/16fx. T<5cm 87.8% with out portal vein thrombosis T ≥5cm 82.1%
Overall survival 53.5% for child A of patient with
solitary tumor. All case is 23.5% at 5 years.
Proton Therapy: TsuKuba University
(Clinical Cancer Research 2005;11(10):3799-805 )
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Major determinants for clinical results interpretation
1. Not only the stage, but also the number of targets (patient selections).
2. Underlying liver function (patient selections).
3. Salvage treatment or primary treatment.
4. Concomitant treatment, adjunctive treatment (TACE, antiangiogeneic, maintenance AA, anti-viral treatment).
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Moderate fractionation
250-500cGy/fx
10-20fx
( Proton, Tomotherapy)
Conventional fractionation200cGy/fx 25-35fx
Extreme fractionation
(SBRT)< 8fx, > 600cGy/fx
Background
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The difference of SBRT vs Tomotherapy
SBRT 1. effective with HCCs 6cm ≦2. not close to critical organs3. Stringent immobilization
Tomotherapy with moderate fractionation4. No size limitation5. Multiple targets6. SIBRT7. Conventional immobilization
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Figure 1 Cumulative dose-volume histograms (cDVH) of normal liver for IMRT plans (solid line) and SSPT plans (dashed line).(a) cDVH for patients with nominal diameter of GTV (a) 5.1cm, (b) 7.8cm and (c) 16.1 cm. Triangles in each figure were dose constrains for one-third and for two-thirds of the volume of the normal liver.
Proton Therapy vs IMRT
Radiation Oncology 2013, 8:48
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Retrospectively reviewing our clinical experience of combined anti-angiogeneics and hypofractionated tomotherapy for patients with hepatoma.
(Shin-Kong Memorial Hospital)
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Tumor response to radiation is determined not only by tumor cell phenotype but also by microvascular sensitivity. (Garacia-Barros et al. Science 2003)
Drugs that neutralize VEGF signaling generate a window for tumor vasculature normalization within a few weeks. Then, hypoxia may followed.
(Cancer Cell 2004)
Radiotherapy to liver may result in the outgrowth of previously dormant micro- tumor not in the irradiated field due to a surge of VEGF. A maintenance AA is important to prevent rebound.
。
Rationale of Combined AA and HRT
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Our antiangiogeneics protocol
Before 2009Sunitinib 1# Bid ± maintenance
After 2010Sorafenib 1# Bid concomitant plus 3# maintenance (if Insurance Reimburse)Metronomic chemotherapy
Cyclophosphamide 1# QodHydroxyurea 1# Qod (if no insurance)
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Methods & Materials
1. Immobilized, diaphragm compression.
2. GTVs, 56Gy in 16 fractions initially planned by tomotherapy.
3. Ceiling on mean liver dose 18-20Gy.
4. Both intrahepatic and extrahepatic lesions are treatment simultaneously.
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1. Sunitinib 25mg p.o. at least one wk before, during and at least 2wk after RT.
2. Encouraged to maintenance use of sunitinib 2-3 tab/day till progression.
3. Lamivudine prophylactic treatment for HBV carriers.
Methods & Materials
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Response to Treatment in Assessable Patients (n=23)
OutcomeTargeted Therapy Plus Multiple-Target Tomotherapy
(in field response)
Number %
Radiological CR 2 8.6
Radiological PR 15 65.4
Stable Disease 5 21.7
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Univariate and Multivariate Cox Analysis of SurvivalFactor
Univariate MultivariateHR 95% CI P HR 95% CI P
Target:1 v>1 0.64 0.16-2.615 0.534
In-field recurrence:No v Yes 0.18 0.04-0.80 0.024 0.36 0.08-1.70 0.194
Outside-field recurrence:No v Yes 0.68 0.08-5.61 0.718
Target size:< 5cm v >5cm 0.30 0.04-2.42 0.256
Vessel invasion:No v Yes 0.47 0.06-3.9 0.485
Maintenance sunitinib:No v Yes 3.96 0.92-17.14 0.065 12.04 1.19-121.64 0.035
Extrahepatic targets:No v Yes 0.68 0.14-3.42 0.642
Child classification:A v B 1.10 0.22-5.45 0.909
AFP level:< 400 v >400 0.58 0.14-2.43 0.455
NTD dose Gy2 (α/β=3 )
< 60Gy v 60Gy ≧ 3.83 0.90-16.22 0.069 9.10 0.96-86.23 0.054
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OverallSunitinib maintenance
No maintenance
1-year survival 70% 89% 42%
1-year progression survival
12% 22% 0%
Median survival 16m > 20m 9m
Median TTP 7m 10m 4m
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1
10
100
1000
10000
100000
1000000
-14 0 14 28 42 56 70 84 98 112
Day
AF
P (
ng/m
l)
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Table 1: Characteristics of all patients
Characteristics n = 89
Age, years, median (range) 61(37-85)
Gender
Male 74 (83%)
Female 15 (17%)
Previous local treatment
Yes 37 (42%)
No 52 (58%)
Stage
I 3 (3%)
II 19(22%)
III IV
49(55%)18(20%)
Combined antiangiogenic treatment
Sunitinib 39 (44%)
Sorafenib 5 (5.6%)
Metronomic chemotherapy
39 (44%)
No antiangiogenic agent 6 (6.7%)
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Images fusion under abdomen compression
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Image Fusion
Fusion based on R’t lobe liver
Fusion based on L’t lobe liver
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Tomo plan
Plan parameter: Jaw: 2.5 cm Pitch: 0.287 Modulation Factor(Actual) : 2.7 (1.732) Tx time: 258 sec
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Tomo plan tip First Use 2.5 cm jaw instead of 1.0 cm jaw
Reduce motion effect Higher modulation factor:
Modulation Factor(Actual) : 2.7 (1.732) Split normal liver into two parts
To reduse dose in healthy liver 1cm beyond PTV Normal liver (out) : normal Liver – (PTV+1-2cm)
Higher importance than normal liver (in) to reduce the dose in healthy liver
Try to lower the volume of 10% prescription dose lower mean liver dose
Normal liver (in) : normal Liver – Normal liver (out) Try to lower the volume of high dose make dose drop quickly
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Tomo plan tip
Set constrain to normal-liver-out dose 1.5cGy/ml hepatocyte, mean normal liver dose 18-20Gy depended on Child class
Lower the coverage of target to get lower liver dose
Then increase the coverage of target the liver dose doesn’t increase too much
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50% dose is comformal
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Coronal Sagittal
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Tx plan Prescription Dose :
GTV- PVT (34.5 c.c.): 200 cGy x 20 = 40 Gy GTV-left lobe (168.3 c.c.): 200 cGy x 20 = 40 Gy
Normal liver Dose Normal liver = liver – PTV Targets+1 cm margins determine normal-liver-out or in Mean dose: 1916 cGy Volume: 1475 c.c.
Normal-liver-out (893 c.c.) mean dose is 1066 cGy
Normal-liver-in (539 c.c.) mean dose is 3226 cGy
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DVH
Normal liver
R’t kidneyL’t kidney
cord
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Stage No. Median(m)Overall survival
1 year 2 year 3 year 4 year 5 year
I 3 29.8 100 66.7 0 0 0
II 19 23.1 72.2 48.9 27.2 27.2 0
III 49 10.5 40.9 18.7 11.2 7.5 0
IV 18 22.3 70.8 45.1 24.1 24.1 24.1
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No. Median(m)
Overall survival
1 year 2 year 3 year 4 year 5 year
89 13.4 57.5 33.2 17.7 15.5 3.9
Overall survival
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Prior No.
Median(m)
Overall survival
1 year 2 year 3 year 4 year 5 year
Yes 37 18.2 64.7 37.0 31.7 25.4 12.7
No 52 12 49.8 30.1 10.0 10.0 -
P=0.078
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-100 100 300 500 700 900 1100 13001
10
100
1000
10000
100000
謝 **
葉 **
游 **
詹 **
楊 **
陳 **
洪 **
莊林 **
Days
AF
P c
on
c.(
ng
/ml)
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2007/04/12 2007/07/11 (pre-treat) (post-treat) (1+ months later)
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2007/04/15 2007/07/19
(pre-treat) (post-treat)
(3+ months later)
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2007/12/31 2008/05/01
(pre-treat) (post-treat)
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2008/02/13 2008/05/21
(pre-treat) (post-treat)
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2008/02/18 2008/05/07
(pre-treat) (post-treat)
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2008/03/11 2008/07/09
(pre-treat) (post-treat)
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2008/04/11 2008/07/07
(pre-treat) (post-treat)
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2007/03/26 2007/06/22 2008/06/26
(pre-treat) (post-treat) (post-treat) (1+ months later) (15+ months later)
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2007/04/11 2007/07/10 2007/09/05
(pre-treat) (post-treat) (post-treat)
(1+ months later) (4+ months later)
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2007/05/06 2007/07/06 2007/09/04
(pre-treat) (post-treat) (post-treat)
(1+ months later) (3+ months later)
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2007/05/24 2007/08/29 2007/10/30
(pre-treat) (post-treat) (post-treat)
(1+ months later) (3+ months later)
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2007/09/05 2007/11/26 2009/06/20
(pre-treat) (post-treat) (post-treat) (2+ months later) (21+ months later)
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Summary Antiangiogenics is not curative. The combination
of antiangiogenics and radiotherapy may be curative.
Highly conformal tomotherapy may provide high quality plan for advanced HCC. High RR and AFP response not amenable to other treatment .
Prolong use of antiangiogenics can result in decreased microvascular density and increase tumor hypoxia and decrease radiosensitivity. Early use of radiotherapy may be mandatory.
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Summary: Hepatoma are prone to develop progressive
disease outside the radiation fields. Combination of angiogenesis inhibitors seem able to prevent out-field surge of dormant tumor re-growth.
Hypofractionated schedule appears more promising than conventional schedule. Whether HRT is better than SBRT is unknown, but more user friendly.
RILD incidence seems not to be affected by the concomitant use of AA and anti-viral agents.
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Summary: Respiration motion control is a must be in era of
HCC high conformal therapy.
More effective systemic treatment by combination of multi-angiogenics targets such as sorafenib, proteosome inhibitor, metronomic chemotherapy, zolendrotic acid, axitinib for a total blockage.
High quality images such as primovist MRI may be needed.
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The End
Thanks!