LA TERAPIA DELL’EPATOCARCINOMA OGGI
Giuseppe Cabibbo GI & Liver Unit, PROMISE University of Palermo, Italy [email protected]
Ø high rate of mortality;
Ø strictly associated with chronic liver disease, mainly cirrhosis;
Ø well-known risk factors. Dominant role of HBV and HCV;rising role of NASH, obesity; and diabetes;
Ø biological and clinical heterogeneity and wide prognosis.
Hepatocellular carcinoma (HCC): Introduction
CabibboG.etal.LivInt2017
PooledActuarialRecurrenceRate-6months:7.4%(Range:0-12.5%)-24months:47%(Range:32-100%)
PooledSurvivalRecurrenceRate-3years:80%(Range:65.3-95%)-5years:59%(Range:47-78%)
Recurrence OverallSurvival
Rangeat5yr:47-78%
Meta-analysis of aggregate data (MA-AD): HCV-untreated arms of studies after curative treatments
Rangeat24months:32-100%
Cabibbo et al. Hepatology 2010
Range 0 – 75% Range 0 – 50%
p for heterogeneity < 0.0001
Untreatedcontrolgroupsof30RCTs
17.5% 7.3%
The Barcelona Clinic Liver Cancer (BCLC) Staging Classification for HCC
Llovet JM et al. J Gastroenterol 2005; 40: 225-235
BCLC stage Performance
status Tumor volume,
number and invasiveness Child-Pugh
0 Very early 0 Single < 2 cm A
A Early 0 Single or 3 nodules < 3 cm A – B
B Intermediate 0 Large/Multinodular A – B
C Advanced 1 – 2 Portal invasion and/or Extrahepatic spread N1M1 A – B
D Terminal > 2 Any of above C
Il grande assente….
CabibboG.etal,onbehalfITA.LI.CA.Group.JHep2017
Predictor of Survival HR 95%CI P-value
Early recurrence 2.5 1.2-5.1 0.01
Early hepatic decompensation 7.5 4.2-13.5 <0.0001
Time dependent Cox model (MV analysis)
CabibboG.etal,onbehalfRESIST-HCV&ITA.LI.CA.JHep2019
Improvementinoverallsurvivalseemsduetosignificantreductioninhepaticdecompensation He
paticdecom
pensation
Survival
Iavarone, Cabibbo et al. Hepatology 2015
Predictors of Survival of Patients with Advanced HCC Who Permanently
Discontinued Sorafenib
Conclusions: 1) The survival following sorafenib discontinuation is significantly influenced by reason for drug withdrawal, i.e. adverse effects, liver impairment and tumour progression pattern.
2) In patients eligible to 2nd line trials, survival is determined by reason of sorafenib discontinuation, performance status and extrahepatic tumor burden.
3) In real life practice, these results are keys in prognostic prediction and design/analysis of second line trials.
EASLClinicalPracticeGuidelines:Managementofhepatocellularcarcinoma2018
EuropeanAssociationfortheStudyoftheLiver,JHepatol2018
Surgical Resection
Ø Optimal candidates: Ø BCLC stage 0 or A
Ø Child-Pugh A
Ø Performance status 0 Ø Single tumors Ø Normal portal pressure
Ø Normal bilirubin Ø Excellent functional reserve
5-year survival 60-70%
High recurrence rate
50% at 3 years 70% at 5 years
Bruix J et al. Hepatology 2005; Llovet JM. J Gastroenterol 2005; Forner A et al Nat Rev Clin Oncol 2014
Therapeutic Options
- Too restrictive in real life: > 50% are above….
Child A patients 5-yr survival Multiple (126) 58% Single (308) 68%
Child A patients 5-yr survival PTH (136) 56% No PTH (250) 71%
Ishizawa T, et al. Gastroenterology 2008
AblationTherapy
Ablation Therapies Therapeutic Options
– Radiofrequency ablation (RFA); MW ablation – Percutaneous ethanol injection (PEI)
RFA or PEI 5-year survival 40-50%
High recurrence rate
50% at 3 years 70% at 5 years
• Llovet JM. J Gastroenterol 2005; 40 : 225-235; Bruix J, Sherman M. Hepatology 2005; 42: 1208-1236; Bruix J et al. J Hepatol 2001; 35: 421-430
RFA
Optimalcandidates:
n BCLCStageAdisease(Novascularinvasionormetastases)
n Child-PughAorBn Singlenodule<2cm(feasiblealsoforsolitarytumor<5cm
or≤ 3nodules<3cm
Advantage Minimally invasive, easily repeatable
Disadvantage Higher recurrence risk with respect to resection
• TuttiipazienticonHCCsingoloefunzioneepaticapreservatavannoconsideratiperuntrattamentocurativo(chirurgiaoablazione),scegliendoloinbasealledimensionidellalesione:
Ø HCC≤2cm:seapprocciabileinsicurezzacontrattamentiinterstizialipercutaneiolaparoscopici,latermoablazionevaconsideratailtrattamentodiprimalinea,seeseguitaincentriesperti.
Ø HCCdi2.1–3cm:lasceltatrachirurgiaetermoablazionedeveesserefattacasopercasoemultidisciplinarmente,ancheselaresezione(anatomica)èiltrattamentopreferibileperradicalità.
Ø HCC>3cm:laresezioneepaticaèiltrattamentodiprimascelta.
Terapia HCC singolo
RFA Resection TACE
Relevanceoftumorlocation
5-year survival 70% Recurrence rate < 15%
• Bruix J, Sherman M. Hepatology 2005; Llovet JM. J Gastroenterol 2005; • Mazzaferro V et al. N Engl J Med 1996; Mazzaferro V. et al. Lancet 2009
Optimal candidates: n BCLC Stage A disease
n No vascular invasion
n No metastases
n Fulfill the Milan criteria
– Solitary tumor < 5 cm or – ≤ 3 nodules < 3 cm
Advantage Removal of the diseased liver together with the tumor
Disadvantage Long waiting lists
Liver Transplantation Therapeutic Options
…butorganshortageandtoostrictcriteria(UCSF,up-to-sevenAFP,…)
Considerazioneorganizzativagenerale
Pertuttiipazientiinetàtrapiantologicaeadaltopotenzialedibeneficiodatrapianto,lastrategiaterapeuticadovrebbe
esserecondivisaprecocemente(ancheinrete)conuncentrotrapianti,alfinediottimizzarel’iterterapeutico.
Trapianto
HCC BRIDGE study 18,031 pts (67% from Asia, 20% from Europe and 13% from North America)
Liver Int. 2015
Curativetherapiesaresuperiortostandardofcare(TACE)forintermediatestagehepatocellularcarcinoma
Survivalbytreatmentof456BCLC-Bpatients
Curativetreatments
Othertreatments
BSC
Sorafenib
TACE
Overallsurvival
Months
TreatmentchoicewasanindependentprognosticfactorforBCLCBptsafteradjustmentforotherpredictors.
n.145
n.233
n.39
n.18
n.21
PecorelliAetal.,forITA.L.ICA,LiverInt2016Aug27.doi:10.1111/liv.13242[Epubaheadofprint]
J Clin Oncol 2012
TACE-RFA was superior to RFA alone in improving survival for patients
with HCC less than 7 cm.
Radioembolizzazione(TARE)
• E’unabrachiterapia(isotopoβ-emittenteIttrio90)nellaqualelasorgenteradioattivavieneinseritanella
retevascolaretumorale.
• E’costosa,complessaeconpotenzialeelevatatossicitàepatica,gastro-duodenaleepolmonare.Pertanto,
dovrebbeesserepraticatasoloneicentridiriferimentoperlemalattieneoplasticheepaticheeconuna
grandeesperienzainmerito.
• Datochelemicrosferehannouneffettoembolizzanteminimo,puòessereeffettuatainsicurezzaanche
nelpazientecontrombosiportale(troncoeramiintraepatici).
TARE:(potenziali)Indicazioni
• PazienticoncontroindicazioniallaTACE(trombosiportale);
• PazientigiàtrattaticonTACE,senzarispostacompleta;
• Pazienticontumoridigrandidimensioni,conpatterninfiltrante,tumoriipovascolari;
• Pazientiintollerantialsorafenib;
• Down-staging(pre-OLT)eterapia“ponte”periltrapianto
TARE:openissuesPro
• Significativovantaggioneldiseasecontrolratevssorafenib(RCT)(1,2);SignificativovantaggioinTimeto
ProgressionvsTACE(RCT)(3).
Contro
• NonevidenzadiguadagnodisopravvivenzainRCTs:
vsTACEnelpazienteintermedio(3);vssorafenibnelpazienteavanzato(1,2).
• Pochidatisullasafetyconadeguatofollow-up.
1.VilgrainetalLancetOnc2017;2.ChowetalJCO2018;3SalemetalGastroenterology2016
vsTACE
vsSora
EASLClinicalPracticeGuidelines:Managementofhepatocellularcarcinoma2018
EuropeanAssociationfortheStudyoftheLiver,JHepatol2018
SHARP1 Asia–Pacific2
SHARP Asia–Pacific Median, sorafenib 10.7 months 6.5 months Median, placebo 7.9 months 4.2 months Hazard ratio (95% CI) 0.69 (0.55–0.87) 0.68 (0.50–0.93)
Sorafenib improved overall survival in HCC patients
1. Llovet JM, et al. N Engl J Med. 2008;359:378-90. 2. Cheng A-L, et al. Lancet Oncol. 2009;10:25-34.
§ Iavarone, Cabibbo et al. Hepatology 2011.
Survival according to sorafenib dose
--- Half-dose No. = 77 --- Full dose No. = 219
P = 0.0006
Confirmed by MV analysis
* Iavarone, Cabibbo et al. Hepatology 2011 Reiss K, et al. JCO 2017
- All pts started at full dose
- Prospective study
SOFIA study* RDS, reduced starting dose
SDS, Standard starting dose
- Retrospective Study
- Propensity score maching
Ten Years Later
First line systemic therapy (positive phase III trial) - Sorafenib (2008) - Lenvatinib (2018) - nivolumab (?)
Second line systemic therapy (positive phase III trial) - Regorafenib (2017) - Cabozantinib (2018) - Ramucirumab (2019) - nivolumab (?)
Drug Target Sorafenib RAF/MEK/ERK
pathway VEGFR/PDGFR
Lenvatinib VEGFR Regorafenib VEGF1/VEGF2/
VEGF3/ PDGFR/FGFR/KIT/RET/RAF-1/ BRAF
Cabozantinib MET/VEGFR2/FLT3/c-KIT/ RET
Ramucirumab VEGFR2 Nivolumab PD-1
Kudo M. et al. Lancet 2018
- Non-inferiority trial
- No patients with > 50%liver occupation, bile duct occupation, or invasion of the main portal vein
Bruix J et al. Lancet 2017
- Sorafenib intolerant patients non included in the study.
OS:10.6mosvs7.8mos
Randomization2:1
Abou-Alfa G.K. et al. NEJM 2018
- Approximately 30% of patients received 2 prior systemic regimens.
Randomization2:1
Zhu AX, et al. Lancet Oncol. 2019.
OverallSurvival(%
)
Outcome Ramucirumab(n=197)
Placebo(n=95) HR(95%CI)
MedianOS,mos 8.5 7.3 0.71(0.531-0.949)P=.0199
12-mosurvival,% 36.8 30.3 0.2930
18-mosurvival,% 24.5 11.3 0.0187
100
80
60
40
20
00 3 6 9 12 15 18 21 24 27
MonthsPatientsatRisk,n
RamucirumabPlacebo
19795
17276
12150
8736
5619
3712
264
141
40
00
baseline AFP ≥ 400 ng/mL
Randomization 2:1
Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-
controlled, phase 3 trial.
OverallSurvival(%
)
100
80
60
40
20
00 3 6 9 12 15 18 21 24 27
MonthsPatientsatRisk,n
RamucirumabPlacebo
19795
17276
12150
8736
5619
3712
264
141
40
00
baseline AFP ≥ 400 ng/mL
The target population was enriched by recruiting
patients with increased alpha-fetoprotein (AFP) > 400
ng/mL so that is the first positive phase III study
conducted in a biomarker-selected population.
Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-
controlled, phase 3 trial.
Randomization 2:1 Zhu AX, et al. Lancet Oncol. 2019.
Which (and how) HCC patients can be treated after sorafenib?
- Regorafenib Progressor but tolerant to sorafenib
Patients with advanced HCC prior treated with sorafenib, with good liver function
- Cabozantinib Progressor and/or intolerant to sorafenib
- Ramucirumab Progressor and/or intolerant to Sorafenib with AFP > 400
1) No direct comparison;
2) Indirect comparisons are not feasible.
KudoM.LiverCancer2017
Sequential Therapy for HCC
Keymessage:RuolodelTeamMultidisciplinare
IpazienticonHCCdovrebberoessereriferitiadunTeamMultidisciplinarechedovrebbe
includere:
ü epatologo
ü oncologo
ü radiologo(diagnosticoeinterventista)
ü chirurgospecializzatoinpatologiadelfegato
ü anatomo-patologo
ü …
chedovrebberoavereunruoloattivonellacuradiquestipazienti.