季匡華 Kwan-Hwa Chi, M.D. Chairman, Section of Radiation Therapy and Oncology Shin Kong Wu Ho-Su Memorial Hospital, Taiwan Professor, School of Medicine National Yang-Ming University

1. Angiogenic blockade and
Tomotherapy in hepatocellular
carcinoma
季匡華 Kwan-Hwa Chi, M.D.
Chairman, Section of Radiation Therapy and Oncology
Shin Kong Wu Ho-Su Memorial Hospital, Taiwan
Professor, School of Medicine
National Yang-Ming University

2. Hepatoma Treatment Option
Surgery 15-29%
TAE/TACE 40-70%
PEIT
RFA
5→25%
Radiotherapy 2→6%
Background

4.  The Ideal Radiotherapy Facility for Hepatoma
Treatment
1. Proton Therapy
2. Tomotherapy
3. Cyberknife
Background

5.  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 )

7. 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).

8. Moderate fractionation
250-500cGy/fx
10-20fx
( Proton, Tomot
herapy)
Conventional
fractionation
200cGy/fx 25-35fx
Extreme
fractionation (SBRT)
< 8fx, > 600cGy/fx
Background

9. The difference of SBRT vs Tomotherapy
SBRT
1. effective with HCCs ≦6cm
2. not close to critical organs
3. Stringent immobilization
Tomotherapy with moderate fractionation
1. No size limitation
2. Multiple targets
3. SIBRT
4. Conventional immobilization

10. 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

11. Retrospectively reviewing our clinical
experience of combined anti-
angiogeneics and hypofractionated
tomotherapy for patients with
hepatoma.
(Shin-Kong Memorial Hospital)

12.  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

13. Our antiangiogeneics protocol
Before 2009
Sunitinib 1# Bid ± maintenance
After 2010
Sorafenib 1# Bid concomitant plus 3# maintenance (if
Insurance Reimburse)
Metronomic chemotherapy
Cyclophosphamide 1# Qod
Hydroxyurea 1# Qod (if no insurance)

15. 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.

16. 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

17. Response to Treatment in Assessable Patients (n=23)
Outcome
Targeted Therapy Plus Multiple-Target Tomotherapy
(in field response)
Number %
Radiological CR 2 8.6
Radiological PR 15 65.4
Stable Disease 5 21.7

18. Univariate and Multivariate Cox Analysis of Survival
Factor
Univariate Multivariate
HR 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

19. Overall
Sunitinib
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

20. 1
10
100
1000
10000
100000
1000000
-14 0 14 28 42 56 70 84 98 112
Day
AFP(ng/ml)

21. 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%)

22. Images fusion under abdomen compression

23. Image Fusion
Fusion based on R’t lobe
liver
Fusion based on L’t lobe
liver

24. Tomo plan
 Plan parameter:
 Jaw: 2.5 cm
 Pitch: 0.287
 Modulation Factor(Actual) : 2.7 (1.732)
 Tx time: 258 sec

25. 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

26. 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

28. 50% dose is comformal

29. Coronal Sagittal

30. 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

31. DVH
Normal liver
R’t kidney
L’t kidney
cord

32. Stage No. Median(m)
Overall survival
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

33. No. Median
(m)
Overall survival
89 13.4 57.5 33.2 17.7 15.5 3.9
Overall survival

34. Prior No. Median
(m)
Overall survival
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

35. 1
10
100
1000
10000
100000
-100 100 300 500 700 900 1100 1300
AFPconc.(ng/ml)
Days
謝**
葉**
游**
詹**
楊**
陳**
洪**
莊林**

36. 2007/04/12 2007/07/11
(pre-treat) (post-treat)
(1+ months later)

37. 2007/04/15 2007/07/19
(pre-treat) (post-treat)
(3+ months later)

38. 2007/12/31 2008/05/01
(pre-treat) (post-treat)

39. 2008/02/13 2008/05/21
(pre-treat) (post-treat)

40. 2008/02/18 2008/05/07
(pre-treat) (post-treat)

41. 2008/03/11 2008/07/09
(pre-treat) (post-treat)

42. 2008/04/11 2008/07/07
(pre-treat) (post-treat)

43. 2007/03/26 2007/06/22 2008/06/26
(pre-treat) (post-treat) (post-treat)
(1+ months later) (15+ months later)

44. 2007/04/11 2007/07/10 2007/09/05
(pre-treat) (post-treat) (post-treat)
(1+ months later) (4+ months later)

45. 2007/05/06 2007/07/06 2007/09/04
(pre-treat) (post-treat) (post-treat)
(1+ months later) (3+ months later)

46. 2007/05/24 2007/08/29 2007/10/30
(pre-treat) (post-treat) (post-treat)
(1+ months later) (3+ months later)

47. 2007/09/05 2007/11/26 2009/06/20
(pre-treat) (post-treat) (post-treat)
(2+ months later) (21+ months later)

48. 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.

49. 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.

50. 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.

52. The End
Thanks!