Transarterial Approach for HCC: New Materials & Techniqueslivercancer.or.kr/file/general/general_09_19.pdf · 2018-08-28 · HepaSphere Switching the Loaded Agent form epirubicin

가톨릭대학교 서울성모병원 영상의학과 천호종

Transarterial Approach for HCC: New Materials & Techniques

Transarterial Approaches for HCC

• TACE, conventional or drug-eluting beads (DEB)

• Radioembolization

• Intraarterial chemotherapy @ hepatic artery port

Radioembolization

• SIR-spheres (SIRTeX)

Radioembolization

• SIR-spheres (SIRTeX)

• TheraSphere (Biocompatibles)

Drug-eluting bead (DEB)

• DC beads/LC beads (Biocompatibles)

Drug-eluting bead (DEB)

• DC beads/LC beads (Biocompatibles)

• Hepasphere/Quadrasphere (Merit Medical)

• Oncozene/Embozene TANDEM (CeloNova)

TheraSphere 90Y Radiosotope

• Same isotope/mechanism with SIR-Spheres

• 100% pure beta emitter, 0.9367 MeV

No isolation or radioprotection

• Weak secondary X-ray (Bremsstrahlung) detected

• Short physical half-life: 64.2 h (2.67 days)

Decay to stable 90Zirconium

• Irradiates tissue with average range of 2.5 mm

TheraSphere vs SIR-Spheres

TheraSphere SIR-Spheres

Glass microsphere embedding 89Y Resin microsphere 90Y 89Y

89Y

89Y 89Y



Glass microsphere embedding 89Y

Activated in reactor Neutron irradiation

Resin microsphere

90Y Radiolabeling carboxyl group of polymer

90Y 89Y

89Y

89Y 89Y



Glass microsphere embedding 89Y

Activated in reactor Neutron irradiation

Resin microsphere

90Y Radiolabeling carboxyl group of polymer

90Y 90Y

90Y

90Y 90Y

90Y

90Y 90Y

90Y

90Y 89Y

89Y

89Y 89Y



Material Glass Resin

Particle size (µm) 20-30 20-60

Number of spheres/vial (million) 1.2-8 40-80

Specific gravity High (3.6 g/dL) Low (1.6 g/dL )

Activity/sphere (Bq) 2,500 40-70

Activity available (GBq) 3, 5, 7, 10, 15, 20 3

Shelf-life 12 days 24 hours (<3 days)

Dispensing /Splitting Not required/Not possible Required/Possible

30 µm

TheraSphere®

SIR-Sphere®








Less embolic effect !!





TheraSphere Less Embolic Effect


Complications Less stasis/reflux

< 1% ulcer rate

More stasis/reflux

4-29% ulcer rate

Contrast Use during Infusion

(fluoroscopy used thru’out infusion)

No contrast media used;

< 5 min infusion

Contrast medial used;

infusion 30-45 min.

Ability to Deliver Prescribed Dose > 98% delivery efficiency 1/3 unable to deliver (d/t stasis)

In Case of Portal Vein Thrombosis Available Not recommended

Tumor oxygenation Preserved;

enhancing radiation effect Impaired

Retreatment Options Retreat any time Like TACE; wait for vessels to

re-perfuse

Ischemic tumor toxicity Not expectable Expectable







Less uniform distribution of micropsheres

Inadequate tumor coverage for very large tumor ??







Shelf-life 12 days 24 hours

Activity available (GBq) 3, 5, 7, 10, 15, 20 Only 3



Shelf-life 12 days from calibration date;

treatment flexibility

24 hours from calibration date;

just in time use

Activity available (GBq) 3, 5, 7, 10, 15, 20 Only 3

Dispensing /Splitting Not required/Not possible Required/Possible

How Supplied

Ready to infuse

unit dose configuration;

standardized, reproducible

dosimetry;

arrives well in advance

Sterile water in 5 mL vial;

dose aliquoted at hospital;

more human radiation exposure

TheraSpheres Initial work-up

• Baseline CTHA or liver dynamic CT

• 99mTc MAA lung scan/Tumor SPECT

• Hepatic angiography

• Whole body PET scan

• Target Liver volume, Tumor volume

• Lung shunt fraction, T/N ratio

• Vascular mapping

• Extrahepatic metastasis

TheraSpheres Initial work-up

• Baseline CTHA or liver dynamic CT

• 99mTc MAA lung scan/Tumor SPECT

• Hepatic angiography

• Whole body PET scan

• Target Liver volume, Tumor volume

• Lung shunt fraction, T/N ratio

• Vascular mapping

• Extrahepatic metastasis

TheraSphere Dose Calculation

• Tumor volume or T/N ration is not necessary

LSF (Lung shunt fraction), R (Residual waste)

• Total Liver Volume : 1112.0 mL

• Target (Right) Liver Volume: 678.5 mL

• Tumor Volume: 113.9 mL

• Lung shunting: 3.54%

• T/N ratio: 8.81

• Anticipated residual waste: 2%






• T/N ratio: 8.81







• T/N ratio: 8.81







• T/N ratio: 8.81


• Activity Required (GBq)

= 120 Gy*678.5 mL*0.00103 Kg/mL

50*[1-0.0354]*[1-0.02]

= 1.77 GBq


Dose Calculation TheraSphere vs SIR-Spheres

• Partition model for SIR-spheres • BSA model for SIR-spheres

• TheraSphere Activity Required (GBq)

= 120 Gy*678.5 mL*0.00103 Kg/mL

50*[1-0.0354]*[1-0.02]

= 1.77 GBq

Activity

(GBq)

Mass of

Microspheres

(mg)

No. of

Microspheres

(millions)

3 27 1.2

5 45 2.0

7 63 2.8

10 90 4.0

15 135 6.0

20 180 8.0

®

TheraSphere Dose Sizes Available

TheraSphere Treatment Window Illustrator

TheraSphere Treatment Window Illustrator

TheraSphere Delivery set

TheraSphere Advantages/Limitations

• Advantages

- No physical manipulation

- Minimal embolic effects

- Can choose same activity with different numbers of spheres

• Limitations

- The low number of spheres may result in inadequate tumor

coverage for very large tumor

- High specific gravity may limit microsphere distribution

TheraSphere I

• Dose calculation이 간단함.

- Treatment Window Illustrator를 이용하여 target liver volume, lung shunt 만

있으면 필요한 치료용량과 폐선량을 계산할 수 있음.

? Large hypervascular tumor에 유효할 지?

• 다양한 단위선량 (3~20GBq)이 있음.

- 핵의학과에서 따로 분배할 필요가 없으므로 radiation hazard를 최소화 할

수 있음.

- 시술일자를 조정하면 동일한 dose에 다양한 microsphere의 용량을 선택할

수 있음

? 분배하여 다른 환자에게 시술하는 것이 불가능함.

TheraSphere II

• Microsphere 개당 activity 가 resin에 비해 50배 이상 높아 주입하는

microsphere의 수가 적고 직경도 30 µ 이하로 작음

- Embolic effect가 최소화 됨으로 PVT가 있는 HCC환자에서 보다 안전하게

시술할 수 있고 reflux나 stasis로 인한 합병증도 적음

- GDA embolization가 반드시 필요하지 않음

- 주입시간이 5분 이내로 radiation hazard가 적음

- High oxygenation이 유지되므로 방사선 치료효과가 극대화됨

? Large hypervascular tumor에 유효할 지?

• 주입시 saline을 이용

- Sterile water를 사용할 때 발생하는 혈관 합병증이 없음.

? 주입 시스템상 조영제와 번갈아 주입하는 것이 불가능함

Sangro 2011

Hepatology

Salem 2010

Gastroenterology

Higard 2010

Hepatology

Mazzaferro 2013 Hepatology

Type SIR-Spheres TheraSphere TheraSphere TheraSphere

Number of

Patients 325 291 108 52

Overall survival

(months)

14.9 (Child A)/

10.0 (Child B)

17.2 (Child A)/

7.7 (Child B)

17.2 (Child A)/

6.0 (Child B) 15

Survival of

BCLC B (mo.) 16.9 17.2 16.4 18

Survival of

BCLC C (mo.) 10.0

7.3

(10.4 Child A+PVT) 13

GI ulcers (%) 3.7% (1 fatal) 0% 0% 0%

Clinical Results TheraSphere vs SIR-Spheres

• No direct comparison data

• Similar clinical results, Less adverse events in TheraSphere

TheraSphere Future Clinical Trial in Korea

STOP-HCC trial YES-P trial

HepaSphere

• HepaSphere/Quadrasphere (Merit Medical, Medical)

• “Superabsorbent microsphere” invented by Dr. S. Hori

• Co-polymer of PVA & sodium acrylate with carboxyl groups

HepaSphere

• HepaSphere/Quadrasphere (Merit Medical, Medical)

• “Superabsorbent microsphere” invented by Dr. S. Hori

• Co-polymer of PVA & sodium acrylate with carboxyl groups

• Two drug-loading mechanism

- ion exchange : doxorubicin, irinotecan

- diffusion : cisplatin …

• Bead sizes 50-100 µm (dry) 200-400 µm (saline)

30-60 µm (dry) 120-240 µm (saline)

HepaSphere Typical imaging course

initial during TACE 1 month 3 months

Hepasphere 50-100 µm+Doxorubicin 50 mg

HepaSphere Safety & efficacy study

• Single center prospective study (2014)

- 45 patients with unresectable HCC

- 30-60 µm HepaSphere loaded with 25 mg of doxorubicin

- Tumor response at 1 months on CT/MR by mRECIST criteria

Malagari, et al. CVIR 2014;37:165-175

HepaSphere Safety & efficacy study

• Single center prospective study (2014)


- 30-60 µm HepaSphere loaded with 25 mg of doxorubicin

- Plasma doxorubicin level & Cmax

Malagari, et al. CVIR 2014;37:165-175

HepaSphere vs DC beads

• Similar pharmacokinetics



HepaSphere DC beads



• Different Characteristics

1. Drug-loading mechanism: ion exchange vs diffusion

HepaSphere can load all chemotherapeutic drugs,

esp. cisplatin.

2. “Superabsorbent” polymer microsphere

- Expansion with different rate according to absorbing fluid

- 50-100 µm (dry), 100-200 µm (contrast), 200-400 µm (saline)

More controlled calibration of the particle size


• Different Characteristics

1. Drug-loading Mechanism: ion exchange vs diffusion

2. “Superabsorbent” polymer microsphere

3. Compressible and conforming to the vessel lumen

More excellent embolic effect ?

HepaSphere


DC beads

HepaSphere Switching the Loaded Agent form epirubicin to cisplatin

• Single center retrospective study (2012)

- 85 patients with unresectable HCC refractory to epirubicin

loaded microsphere TACE

- 50-100 µm HepaSphere loaded with high-concentrated cisplatin

(1 mg/1 mg microsphere)

- Tumor response on CT by EASL criteria

- CR/PR/SD/PD (3.5/36.5/17.6/42.4%)

- Objective tumor response 40.0%

- Disease control rate 57.7%

safe, well-tolerated & efficacious salvage strategy

Seki A, et al. CVIR 2012;35:555-562

Cisplatin Less skin toxicity than doxorubicin

Non-target embolization of falciform artery with doxorubicin

Non-target embolization of intercostal artery with doxorubicin

HepaSphere Expanded indications in HCC

1. Doxorubicin-refractory HCC Cisplatin-based TACE

2. HCC supplied by cutaneous branch-containing extrahepatic

arteries

- intercostal, internal mammary, hepatic falciform arteries

3. Better tumor responses in infiltrative or vascular invasion

HCCs?

Oncozene Comparison with other drug-eluting beads


• Different characteristics

1. Smaller particles size available: 40 µm, 75 µm, 100 µm

Deeper penetration into the tumor microvasculature

Higher degree of necrosis

Useful in hypovascular or less vascular HCC

Oncozene In Vitro Loading & Release/In Vivo Pharmacokinetics

Guiu B, et al. jVIR 2014

• In vitro/In vivo prospective study (2014)


- 100 µm Oncozene with 10 mg of idarubicin

- In vitro loading/releasing profiles

Oncozene In Vitro Loading & Release/In Vivo Pharmacokinetics

Guiu B, et al. jVIR 2014

• In vitro/In vivo prospective study (2014)


- 100 µm Oncozene with 10 mg of idarubicin

- In vivo pharmacokinetics















2. High loading capacity

3. Slower release of drug

Oncozene Future Clinical Trials in Korea

• Oncozene TACE vs Sorafenib in BCLC C patients

Summary

• Drug-eluting beads TACE and radioembolization are emerging intra-

arterial treatment for the patients with unresectable HCC. Until now,

DC beads and SIR-spheres are most used materials in theses

procedures in Korea.

• Recently, new materials for DEB-TACE and radioembolization, such as

TheraSphere, HepaSphere, Oncozene are introduced. It would be

helpful to know their advantages and limitations for expanding

treatment indications and improving the therapeutic efficacy.

Documents

Transarterial Approach for HCC: New Materials & Techniqueslivercancer.or.kr/file/general/general_09_19.pdf · 2018-08-28 · HepaSphere Switching the Loaded Agent form epirubicin