LA TERAPIA DELL’EPATOCARCINOMA OGGI

Giuseppe Cabibbo GI & Liver Unit, PROMISE University of Palermo, Italy giuseppe.cabibbo78@gmail.com

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.