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

Hepatoma Treatment Option

Surgery 15-29%

TAE/TACE 40-70%

PEITRFA

5→25%

Radiotherapy 2→6%

Background

The Ideal Radiotherapy Facility for Hepatoma Treatment

1. Proton Therapy

2. Tomotherapy

3. Cyberknife

Background

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 )

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).

Moderate fractionation

250-500cGy/fx

10-20fx

( Proton, Tomotherapy)

Conventional fractionation200cGy/fx 25-35fx

Extreme fractionation

(SBRT)< 8fx, > 600cGy/fx

Background

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

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

Retrospectively reviewing our clinical experience of combined anti-angiogeneics and hypofractionated tomotherapy for patients with hepatoma.

(Shin-Kong Memorial Hospital)

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

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)

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.

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

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

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

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

1

10

100

1000

10000

100000

1000000

-14 0 14 28 42 56 70 84 98 112

Day

AF

P (

ng/m

l)

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%)

Images fusion under abdomen compression

Image Fusion

Fusion based on R’t lobe liver

Fusion based on L’t lobe liver

Tomo plan

Plan parameter: Jaw: 2.5 cm Pitch: 0.287 Modulation Factor(Actual) : 2.7 (1.732) Tx time: 258 sec

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

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

50% dose is comformal

Coronal Sagittal

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

DVH

Normal liver

R’t kidneyL’t kidney

cord

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

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

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

-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)

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

2007/04/15 2007/07/19

(pre-treat) (post-treat)

(3+ months later)

2007/12/31 2008/05/01

(pre-treat) (post-treat)

2008/02/13 2008/05/21

(pre-treat) (post-treat)

2008/02/18 2008/05/07

(pre-treat) (post-treat)

2008/03/11 2008/07/09

(pre-treat) (post-treat)

2008/04/11 2008/07/07

(pre-treat) (post-treat)

2007/03/26 2007/06/22 2008/06/26

(pre-treat) (post-treat) (post-treat) (1+ months later) (15+ months later)

2007/04/11 2007/07/10 2007/09/05

(pre-treat) (post-treat) (post-treat)

(1+ months later) (4+ months later)

2007/05/06 2007/07/06 2007/09/04

(pre-treat) (post-treat) (post-treat)

(1+ months later) (3+ months later)

2007/05/24 2007/08/29 2007/10/30

(pre-treat) (post-treat) (post-treat)

(1+ months later) (3+ months later)

2007/09/05 2007/11/26 2009/06/20

(pre-treat) (post-treat) (post-treat) (2+ months later) (21+ months later)

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.

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.

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.

The End

Thanks!