1. No category

Tratamiento del Hepatocarcinoma Avanzado
Bruno Sangro
Clínica Universidad de Navarra. CIBERehd. IdiSNA
Pamplona, Spain
Sumario
• Definición del HCC avanzado
• Indicación de tratamiento
• Decisiones difíciles
–
–
–
–
Opciones multiples
Pacientes con insuficiencia hepática
Cambio de tratamiento
Interrupción de tratamiento
• Perspectivas de futuro
Cancer Staging
Define subgroups of patients in order to:
• Establish prognosis (natural history of the disease)
• Select the best treatment option
Tumor Stages in HCC
Very Early ‐ 0
Early ‐ A
Advanced ‐ C
Early ‐ A
Intermediate ‐ B
Advanced ‐ C
Sumario
• Definición del HCC avanzado
• Indicación de tratamiento
• Decisiones difíciles
–
–
–
–
Opciones multiples
Pacientes con insuficiencia hepática
Cambio de tratamiento
Interrupción de tratamiento
• Perspectivas de futuro
Tumor Features Impact On Tx Efficiency
METASTASES
ECOG > 0
PVT
SYSTEMIC
NO
NO
NO
RE or SIRT
YES *
POSSIBLY **
NO
TACE
YES *
LIKELY **
YES
* The impact of lymph node or limited bone metastases on the long‐term outcome of patients treated by RE or TACE is largely unknown
** Patients with altered performance status may more likely have subclinical disease
Safety of TACE and RE in patients with PVT
TACE
RE
Risk of liver toxicity among patients with PVT
Early liver toxicity among 20 patients with PVT
Variable
Variable
Odds Ratio
p value
AST (IU/L)
1.008
0.008
Na (mmol/L)
0.932
0.026
Albumin (g/dL)
0.547
0.028
Bilirubin
3
3
6
Bilirubin (mg/dL)
1.486
0.035
Prothrombin
1
1
1
Log AFP (ng/mL)
1.095
0.002
Ascites
0
0
1
PVT > 1st branch
2.075
0.003
Encephalopathy
0
1
0
G2‐G3 toxicity Day Month Month 0
1
2
Min YW, et al. Liver Int 2013;33:197. Inarrairaegui M, et al. J Vasc Intervent Radiol. 2010;8:1205 Sorafenib consistently increases overall survival in different global patient populations
SHARP
Sorafenib (n=299)
1.00
Sorafenib (n=150)
1.00
Median OS: 10.7 months
Placebo (n=303)
Median OS: 7.9 months
0.75
0.50
0.25
0.00
0
2
4
6
8
10
Months
HR = 0.69
12
14
16
18
Survival probability
Survival probability
Asia‐Pacific
Median OS: 6.5 months
Placebo (n=76)
Median OS: 4.2 months
0.75
0.50
0.25
0.00
0
2
4
6
8
10
12
14
16
18
20
22
Months
HR = 0.68
Llovet JM et al. N Engl J Med 2008;359:378–90. Cheng A, et al. Lancet Oncol 2009;10:25–34.
Sorafenib for Advanced Stage Patients
SHARP
Asia–Pacific
Sorafenib (n=150)
1.00
Median OS: 6.5 months
Survival probability
Placebo (n=76)
Median OS: 4.2 months
0.75
0.50
0.25
0.00
0
2
4
6
8
10
12
14
16
18
20
22
Months
Bruix J, et al. J Hepatol. 2012;57:821‐9. Cheng AL, et al. Eur J Cancer. 2012;48:1452‐65. A Subgroup Analysis of the SHARP Trial
Bruix J, et al. J Hepatol. 2012;57:821‐9.
Sumario
• Definición del HCC avanzado
• Indicación de tratamiento
• Decisiones difíciles
–
–
–
–
Opciones multiples
Pacientes con insuficiencia hepática
Cambio de tratamiento
Interrupción de tratamiento
• Perspectivas de futuro
Contraindications to TACE Absolute contraindications
Relative contraindication
Related to cirrhosis
Decompensated cirrhosis (Child–Pugh B ≥ 8):
‐ Jaundice, encephalopathy, refractory ascites or hepatorenal syndrome
Untreated varices at high risk of bleeding Related to tumor burden
Extensive tumor with massive replacement of both entire lobes
Tumor size ≥ 10 cm
Portal vein invasion
Related to technique
Non‐tumoral PVT or severely reduced portal vein flow
Untreatable AV fistula
Renal insufficiency (creatinine ≥ 2 mg/dL) Comorbidities with clinically significant compromised organ function
Bile‐duct occlusion or incompetent papilla due to stent or surgery
Modified from Raoul J‐L, et al. Cancer Treat Rev. 2011;37:212
Treatment options in intermediate‐stage HCC
An expert consensus opinion
BCLC
substage
B1
B2
B3
B4
IN
OUT
OUT
ANY
CPT score
5–6–7
5–6
7
8–9*
ECOG PS
0
0
0
0–1
NO
NO
NO
NO
TACE
TACE or RE
LT or
TACE + ABL
SOR
Beyond Milan
Within Up‐to‐7
PVT
1st treatment option
Alternative
treatment
*
BSC
Research or
TACE
LT**
*With severe/refractory ascites and/or jaundice; **Only if up‐to‐7 IN and PS 0; Bold options are supported by highest scientific evidence.
% of pts
mOS (mo)
41%
35%
7%
17%
34
24
15
12
Bolondi L, et al. Semin Liver Dis 2012;32:348. Piscaglia F, et al. EASL Annual Meeting 2013. Abstr. 109.
Median Overall Survival (months)
Survival Reported Across Different Studies
Among HCC Patients With PVT
Child A
Sorafenib
Radioembolization
Hilgard, et al. Hepatology. 2010;52:1741‐9. Salem, et al. Gastroenterology. 2010;138:52‐64 Cheng, et al. Eur J Cancer. 2012;48:1452‐65. Bruix, et al. J Hepatol. 2012;57:821‐9.
Mazzaferro, et al. Hepatology. 2013;57:1826‐37. Iñarrairaegui M, et al. J Vasc Interv Radiol. 2010;21:1205–12
RE for Advanced Stage Patients with PVT 70% of patients showed objective response
Mazzaferro V, et al. Hepatology 2012 epub ahead of print
Sumario
• Definición del HCC avanzado
• Herramientas terapéuticas
– Terapias sistémicas, intraarteriales y procedimientos
complementarios
• Decisiones fáciles (opción única)
• Decisiones difíciles
–
–
–
–
Opciones multiples
Pacientes con insuficiencia hepática
Cambio de tratamiento
Interrupción de tratamiento
• Perspectivas de futuro
Sorafenib in Child B Patients
297 patients
– 79% CP‐A
– 15% CP‐B7
– 5% CP‐B8
Child
Median OS
A
10
B
3.8
35 % PVI & 20% EHD
G3‐4 Toxicity
–
–
–
–
Fatigue Diarrhea
HFSR Cachexia
16% vs. 11%
15% vs. 13%
12% vs. nr
nr vs. 9.5%
Pressiani T, et al. Ann Oncol 2012
Sumario
• Definición del HCC avanzado
• Herramientas terapéuticas
– Terapias sistémicas, intraarteriales y procedimientos
complementarios
• Decisiones fáciles (opción única)
• Decisiones difíciles
–
–
–
–
Opciones multiples
Pacientes con insuficiencia hepática
Cambio de tratamiento
Interrupción de tratamiento
• Perspectivas de futuro
SCORES
ABCR score
ART score
Sieghart W, et al. Hepatology 2013;57:2261‐2273. Adhoute X, et al. J Hepatol 2015, 62:855–862.
Poor Prognosis Does Not Mean Lack Of Benefit
RCTs supporting the use of TACE
A Treatment Algorithm For TACE First TACE
CR
Liver decompensation always contraindicates TACE
SD
PD
Second TACE
CR
Follow‐up / 3 months
PR
PR
SD
PD
New lesion
Growth of
existing lesion
Vascular Invasion
Consider new TACE
Consider
RE or SOR
Modified from Raoul J‐L, et al. Cancer Treat Rev. 2011;37:212‐20.
RE for Intermediate to Advanced HCC
TACE Failures
After 2 TACE sessions
RE through segmental artery
After 2 TACE sessions
4 years after RE
3 years after RE
Sumario
•
•
•
•
Definición del HCC avanzado
Indicación de tratamiento
Decisiones fáciles (opción única)
Decisiones difíciles
–
–
–
–
Opciones multiples
Pacientes con insuficiencia hepática
Cambio de tratamiento
Interrupción de tratamiento
• Perspectivas de futuro
• Intolerancia
• Progresión (si EECC)
• Descompensación
Sumario
•
•
•
•
Definición del HCC avanzado
Indicación de tratamiento
Decisiones fáciles (opción única)
Decisiones difíciles
–
–
–
–
Opciones multiples
Pacientes con insuficiencia hepática
Cambio de tratamiento
Interrupción de tratamiento
• Perspectivas de futuro
Ongoing Clinical Trials of RE in Intermediate to Advanced HCC
YES‐P1
SIRveNIB2
SARAH3
SORAMIC4
STOP5
No. Patients
328
360
400
665
400
Control Arm
SOR
SOR
SOR
SOR
SOR
Exp. Arm
RE
RE
RE
RE + SOR
RE + SOR
Endpoint
OS
OS
OS
OS
OS
US – EU
Asia‐Pacific
France
EU
Global
Area
1. http://clinicaltrials.gov/ct2/show/NCT 01887717;
2. http://clinicaltrials.gov/ct2/show/NCT01135056; 3. http://clinicaltrials.gov/ct2/show/NCT001482442;
4. http://clinicaltrials.gov/ct2/show/NCT01126645; 5. http://clinicaltrials.gov/ct2/show/NCT01556490.
Systemic Therapies Tested in HCC
Antiangiogenic Agents
Non‐antiangiogenic Agents
Agent
Molecular target
Agent
Molecular target
Brivanib
VEGFR/FGFR
Cetuximab
EGFR
Pazopanib
PDGFR, VEGFR
Sandostatin
SST
Erlotinib
VEGFR, EGFR
Everolimus
m‐TOR
Sunitinib
PDGFR, VEGFR, SCR, FLT3
Bortezomib
Proteasome Bevacizumab
VEGFR
Cixutumumab
IGF1‐R
Linifanib
VEGF, PDGF, PDGFR, CSF1R
Ispinesib
kinesin
Cediranib
VEGFR
Dasatinib
SRC
Vandetanib
VEGFR, EGFR
Belinostat
Histone deacetylase
Ramucirumab
VEGFR
Lapatinib
EGFR, ErbB‐2
Regorafenib
VEGFR, TIE‐2
Tivantinib
c‐met
Cabozantinib
c‐met, VEGFR
Tigatuzumab
TRAIL‐R2
Tremelimumab
CTLA‐4
Nivolumab
PD‐1