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Welcome. The CLDF would like to thank our supporter, Bristol Myers Squibb, for providing an educational grant for this initiative.

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(1)
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Welcome

The CLDF would like to thank our supporter,

Bristol Myers Squibb

, for providing an

(3)
(4)

BCLC

Over 50% of HCC patients

are intermediate or

advanced stage

– Should every intermediate

stage patient get TACE?

– Should every

advanced stage patient

get sorafenib?

There may be room for

a more individualized

treatment strategy

(5)
(6)

Transarterial Chemoembolization

Conventional TACE

• Chemotherapy (doxorubicin or cisplatin)

emulsified with ethiodized oil is administered into tumor-bearing artery

– Selective killing of tumor, which is supplied

only by the hepatic artery

– Normal liver survives, due to dual blood

supply with portal vein

• Proven by RCTs to improve survival in

intermediate HCC

– Patient selection: ECOG 0-2, Child A or B, no

extrahepatic spread

– Repeated treatments often necessary

• Post-embolization syndrome

– Pain, nausea, low-grade fever, fatigue

– 1-2 day hospitalization

3-year survival:

26-29% with TACE

3-17% with supportive care

Meta-analysis:

2-year mortality significantly

reduced with TACE (OR 0.54)

Camma C, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma:meta-analysis of randomized controlled trials.

(7)

Transarterial Chemoembolization

Drug-eluting Bead TACE

Similar to conventional TACE, but

beads rather than ethiodized oil

carry the chemotherapy

Simultaneous chemotherapy

and embolization

Small beads = more effective

tumor kill (?)

Slower elution = fewer systemic

side effects (?)

(52%)56

47

(44%)

24

(22%)

59

(63%)

48

(52%)

25

(27%)

Complete Response Objective Response

DC Bead cTACE

Disease Control

0 10 20 30 40 50 60 70

% Patients

(8)

Transarterial Radioembolization

Y90

• Transarterial administration of radioactive

microspheres (Yttrium-90)

– Very high local radiation dose

(100-1000 Gy or more)

– 40x higher dose to tumor than external

beam radiation

– Not dependent on flow occlusion

• Two-step procedure

– Initial mapping angiogram

• Check for arteries in treatment area going to stomach or bowel

• Test dose of Tc-MAA to measure shunt fraction to lungs

– 1-2 weeks later, Y90 delivery performed

• Mild side effect profile

– Less post-embolization syndrome

– Can treat entire lobe at one time (large

lesions, multiple lesions)

– Fully outpatient procedure

Salem, et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology. 2011.

(9)

Transarterial Radioembolization

Radiation Segmentectomy

Superselective Y90 delivery into one

hepatic segment

Radioembolization was traditionally

performed in lobar fashion

– Large tumors

– Multifocal disease

Radiation segmentectomy can be

employed in treatment of localized

tumors

– Deliver entire lobar dose into one

segment (ablative dose)

– Radiation damage is limited to the

segment treated

High complete response rates with

(10)
(11)

Conventional TACE

The Latest Data

101 articles including over

10,000 patients

Objective response rate 52.5%

Overall survival 70% at 1 year,

32% at 5 years

Median OS was 19 months

Mortality rate 0.6%

6 months 1 year 2 years 3 years 5 years

10 20 30 40 50 60 70 80 90 100

%

Fig. 2. OS rates after lipiodol TACE for HCC. Data based on a systematic review of 101 clinical studies including 10,108 subjects. Bars show 95% CIs

About 1/3 of patients do poorly with TACE (<1 year survival)

About 1/3 of patients do OK with TACE (1-5 year survival)

About 1/3 of patients do very well with TACE (>5 year survival)

(12)

Conventional TACE

Predictors of 5-year survival

TACE outcomes are poor in 3 groups

• Very large tumors

• Widely multifocal disease • Portal vein invasion

Number of lesions

• 1 = 33%

• 2-3 = 24%

• 4 or more = 16%

Largest tumor size

• Up to 2 cm = 39%

• 2.1-3 cm = 28%

• 3.1-5 cm = 23%

• >5 cm = 16%

PV invasion

• None = 28%

• Branch = 12%

• Main = 0%

Takayasu K, et al. Prospective Cohort Study of Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma in 8510 Patients.

(13)

Drug-eluting Bead TACE

The Latest Data

• 177 patients randomized to DEB-TACE or cTACE

• No difference in objective response rates

• No difference in median survival

– 28 months for cTACE

– 29 months for DEB-TACE

• Significant adverse events rare in both

groups (<7%)

– Abdominal pain more frequent with cTACE

• Conventional TACE and DEB TACE are equivalent

}

P=0.949 cTACE

DC bead

0 0.2 0.4 0.6 0.8 1.0

6 12 18 24

(14)

Transarterial Radioembolization

The Latest Data

459 patients in 25 French centers

– 237 treated with single SIR-Spheres treatment

– 222 treated with sorafenib 400 mg BID

Objective response rate better for Y90 (19% vs 12%)

Overall survival not significantly different

(8 vs 9.9 months)

SAE more common with sorafenib (63% vs 41%)

Y90 produces better response rate, better QoL and

fewer SAE than sorafenib

0 6

p=0.18

12 18 24 30 36 42 48

0 20 40 60 80 100

Time since randomisation (months)

A Overall survival

SIRT Sorafenib

(15)

0 6 p=0.18

12 18 24 30 36 42 48 0 20 40 60 80 100

Time since randomisation (months)

A Overall survival

SIRT Sorafenib

0 6 p=0.18

12 18 24 30 36 42 48 0 20 40 60 80 100

Time since randomisation (months)

A Overall survival

SIRT Sorafenib

Transarterial Radioembolization

The Latest Data

459 patients in 25 French centers

– 237 treated with single SIR-Spheres treatment

– 222 treated with sorafenib 400 mg BID

Objective response rate better for Y90 (19% vs 12%)

Overall survival not significantly different

(8 vs 9.9 months)

SAE more common with sorafenib (63% vs 41%)

Y90 produces better response rate, better QoL and

fewer SAE than sorafenib

Limitations…

45% of patients had previous failed TACE 33% of patients had main portal vein invasion

Centers were not skilled or experienced with Y90

(16)

Transarterial Radioembolization

The Latest Data

Largest cohort of HCC patients treated with Y90

152 patients were BCLC B (intermediate HCC)

– Median survival 25 months if Child class A

– Median survival 15 months if Child class B

541 patients were BCLC C (advanced HCC)

– Median survival 15 months if Child class A

– Median survival 8 months if Child class B

Time (Months) BCLC C Censored Overall Survival

Child Pugh Class

A

P < 0.0001

B 0 0 10 20 30 40 50 60 70 80 90 100

12 24 36 48 60 72 84 96 108 120 132 144 A

Time (Months) BCLC B Censored Overall Survival

Child Pugh Class

A

P = 0.037

B 0 0 10 20 30 40 50 60 70 80 90 100

12 24 36 48 60 72 84 96 108 A

(17)

Largest cohort of HCC patients treated with Y90

152 patients were BCLC B (intermediate HCC)

– Median survival 25 months if Child class A

– Median survival 15 months if Child class B

541 patients were BCLC C (advanced HCC)

– Median survival 15 months if Child class A

– Median survival 8 months if Child class B

Time (Months) BCLC C Censored Overall Survival

Child Pugh Class

A

P < 0.0001

B 0 0 10 20 30 40 50 60 70 80 90 100

12 24 36 48 60 72 84 96 108 120 132 144 A

Time (Months) BCLC C Censored Overall Survival

Child Pugh Class

A P < 0.0001

B 0 0 10 20 30 40 50 60 70 80 90 100

12 24 36 48 60 72 84 96 108 120 132 144

A

Time (Months) BCLC B Censored Overall Survival

Child Pugh Class

A

P = 0.037

B 0 0 10 20 30 40 50 60 70 80 90 100

12 24 36 48 60 72 84 96 108

A

Time (Months) BCLC B Censored Overall Survival

Child Pugh Class

A P = 0.037

B 0 0 10 20 30 40 50 60 70 80 90 100

12 24 36 48 60 72 84 96 108

A

BCLC B

Y90 median survival 15-25 months Compare to 19 months for TACE

BCLC C

Y90 median survival 8-15 months Compare to 8-10 months for sorafenib

Transarterial Radioembolization

The Latest Data

(18)

185 patients with HCC and PVT treated with Y90

– 42% main PVT, 23% segmental, 35% branch

Median survival 13.9 months for CP-A, 6.9

months for CP-B7

Some patients had long-term survival

Low toxicity

Lobar vs. branch PVT similar

Y90 is effective for CP-A patients with HCC

and PVT

Overall Survival

Months from Treatment

0

51 44 31 19 11 7 5 3 3 3 2 1 1 23 15 8 5 5 4 3 3 2 1 1 0 0

Number at risk

Group: Lobar or Segmental Branch Group: Main PVT

0 10 20 30 40 50 60 70 80 90 100

5 10 15 20 25 30 35 40 45 50 55 60

Lobar or Segmental Branch Main PVT

PVT extent

P=0.49

28 18 8 4 3 3 3 3 2 1 0 23 14 7 4 2 1 0 0 0 0 0

Number at risk

Group: Lobar or Segmental Branch Group: Main PVT

Overall Survival

Months from Treatment

0 0 10 20 30 40 50 60 70 80 90 100

5 10 15 20 25 30 35 40 45 50

Lobar or Segmental Branch Main PVT PVT extent P=0.87 A B7

Transarterial Radioembolization

The Latest Data

(19)

Overall Survival

Months from Treatment

0

51 44 31 19 11 7 5 3 3 3 2 1 1 23 15 8 5 5 4 3 3 2 1 1 0 0

Number at risk

Group: Lobar or Segmental Branch Group: Main PVT

0 10 20 30 40 50 60 70 80 90 100

5 10 15 20 25 30 35 40 45 50 55 60

Lobar or Segmental Branch Main PVT

PVT extent

P=0.49

28 18 8 4 3 3 3 3 2 1 0 23 14 7 4 2 1 0 0 0 0 0

Number at risk

Group: Lobar or Segmental Branch Group: Main PVT

Overall Survival

Months from Treatment

0 0 10 20 30 40 50 60 70 80 90 100

5 10 15 20 25 30 35 40 45 50

Lobar or Segmental Branch Main PVT

PVT extent

P=0.87

185 patients with HCC and PVT treated with Y90

– 42% main PVT, 23% segmental, 35% branch

Median survival 13.9 months for CP-A, 6.9 months

for CP-B7

Some patients had long-term survival

Low toxicity

Lobar vs. branch PVT similar

My take: Y90 gives hope in HCC with PVT. 10%

long-term survival is better than 0.

A

B7

Transarterial Radioembolization

The Latest Data

(20)

Radiation Segmentectomy

The Latest Data

102 patients with HCC up to 5 cm not

amenable to RFA

Treated with radiation segmentectomy

– Complete response in 47%

– Partial response in 39%

Median overall survival 34 months (!)

33 patients had OLT

– All had >90% tumor necrosis on path

No major complications

Table 3. Pathological Outcome by Radiation Dose

PN CPN Total

<190 Gy 9 3 12

>190 Gy 7 14 21

Total 16 17 33

(21)
(22)

Comparisons Between Therapies

Conventional TACE vs Drug-eluting Bead TACE

DEB-TACE expected to improve response rates and

reduce side effects

2016 meta-analysis

Four RCTs, 8 observational studies

• DEB-TACE with doxorubicin vs. conventional TACE with

varied chemotherapy

1449 patients

Liver function and tumor stage comparable between

the groups

No significant difference in 1-year, 2-year and

3-year survival

No difference in objective response rates

No difference in adverse events

No significant difference between DEB-TACE and

conventional TACE

Hazard Ratio Exp[(O-E) / V], Fixed, 95% Cl

Favours DEB-TACE Favours cTACE

0.01 0.1 1 10 100

0.01 0.1 1 10 100

Favours cTACE Favours DEB-TACE Odds Ratio

M-H, Random, 95% CI Survival

Response rate

Facciorusso, et al. Drug-eluting beads versus conventional chemoembolization for the treatment of unresectable hepatocellular carcinoma: a meta-analysis. Digestive and Liver Disease. 2016.

(23)

Comparisons Between Therapies

TACE vs Radioembolization (Y90)

245 comparable patients with

unresectable intermediate-stage

HCC and no PVT

123

underwent TheraSphere Y-90

vs.

122

had TACE

Response rate 49% vs. 36%

(p=0.104)

Time to progression 13 vs. 8 months (p=0.046)

– Overall median survival 20 vs. 17

months (ns)

– Less abdominal pain and LFT increase

with Y90

Time (month)

0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

5 10 15 20 25 30 35 40 45 50 Radioembolization Chemoembolization

(24)

Comparisons Between Therapies

Radiation Segmentectomy vs. TACE

Retrospective study of segmental TACE vs

segmental Y90 for localized HCC

– TACE patients (n=77) had worse performance status

and worse Child class

– Y90 patients (n=101) had larger tumors, more

infiltrative tumors, more PVI

Complete response rate better for Y90

(92% vs 74%)

Index tumor progression rate better for Y90

(15% vs 42%)

Segmental Y90 (radiation segmentectomy) yields

better local response rate than segmental TACE

0 180 365 548 730

Days after Treatment

# at Risk

Radio-embolization Chemo-embolization

131

103 69 36 16 5 98 50 29 13

Radioembolization Chemoembolization

(25)

Comparisons Between Therapies

Radiation Segmentectomy vs. TACE+ablation

• 121 matched patients with solitary HCC < 3 cm

– 41 had radiation segmentectomy

– 80 had TACE followed by MWA

• No difference in CR rate, 83% (RS) vs 82%

(TACE/MWA)

• No difference in TTP (11 vs 12 months)

• No difference in overall survival

• 90-day mortality rate 0% in both groups

• Radiation segmentectomy can effectively cure small HCC

100

80

60

40

20

0

0 6 12 18 24

Time (months)

Treatment

TACE-MWA RS

Figure

Fig. 2. OS rates after lipiodol TACE for HCC. Data based on a  systematic review of 101 clinical studies including 10,108  subjects
Table 3. Pathological Outcome by Radiation Dose

References

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