Atualização das Recomendações da Sociedade Brasileira de Hepatologia para o Tratamento Sistêmico do Carcinoma Hepatocelular

CHAGAS, Aline Lopes; LEAL, Cassia Regina Guedes; MELLO, Vivianne Barreto de; BARROS, Fábio Marinho Do Rego; BITTENCOURT, Paulo Lisboa; MATTOS, Angelo A; AROUCHA, Dayse; FONSECA, Leonardo G da; SILVA, Joyce Roma Lucas de; DOTTORI, Mariana Fonseca; TEIXEIRA, Rosangela; MENDES, Liliana Sampaio Costa; REZENDE, Rosamar Eulira Fontes; FILGUEIRA, Norma Arteiro; COUTINHO, Anelisa K; ARAÚJO NETO, João Marcello de; COELHO, Henrique Sergio Moraes; PESSOA, Mario Guimarães; CHEINQUER, Hugo; PARISE, Edison Roberto; FRANÇA, Alex; ÁLVARES-DA-SILVA, Mário Reis; CARRILHO, Flair José; CORAL, Gabriela P; PINTO, Paulo de Tarso Aparecida; PEREIRA, Leila M M Beltrão; PARANÁ, Raymundo; ALVES, Rogério Camargo Pinheiro; BRANDÃO-MELLO, Carlos Eduardo

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ORIGINAL ARTICLE • Arq. Gastroenterol. 60 (1) • Jan-Mar 2023 • https://doi.org/10.1590/S0004-2803.202301000-14 copiar

Atualização das Recomendações da Sociedade Brasileira de Hepatologia para o Tratamento Sistêmico do Carcinoma Hepatocelular

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO

O carcinoma hepatocelular (CHC) é uma das principais causas de mortalidade relacionada a câncer no Brasil e no mundo. A Sociedade Brasileira de Hepatologia (SBH) publicou em 2020 a atualização das recomendações da SBH para o diagnóstico e tratamento do CHC. Desde então, novas evidências científicas sobre o tratamento sistêmico do CHC foram relatadas na literatura médica, incluindo novos medicamentos aprovados que não estavam disponíveis na época do último consenso, levando a diretoria da SBH a promover uma reunião monotemática on-line para discutir e rever as recomendações sobre o tratamento sistêmico do CHC. Um grupo de experts foi convidado para realizar uma revisão sistemática da literatura e apresentar uma atualização, baseada em evidências científicas, sobre cada tópico relacionado ao tratamento sistêmico e a apresentar os dados e recomendações resumidas durante a reunião. Todos os painelistas se reuniram para discutir os tópicos e elaborar as recomendações atualizadas. O presente documento é a versão final do manuscrito revisado, contendo as recomendações da SBH, e seu objetivo é auxiliar os profissionais de saúde, formuladores de políticas e planejadores no Brasil e na América Latina na tomada de decisões sobre o tratamento sistêmico de pacientes com CHC.

Palavras-chave:
Carcinoma hepatocelular; tumores malignos do fígado; tratamento sistêmico

Class of Recommendation	Definition	Suggested wording
I	There was consensus. More than 90% of the panel agreed	Is recommended
IIa	There was general preference in favor. Between 70-90% of the panel agreed	Should be considered
IIb	The majority -(50-70%) of the panel agreed	May be considered
III	There was agreement that the intervention is not recommended	Is not recommended

Level of evidence	Definition
A	Data derived from multiple randomized clinical trials or meta-analysis
B	Data derived from a single randomized clinical trial or large non-randomized studies
C	Consensus of experts’ opinion and/or small studies, retrospective studies, or registries

Pivotal phase III study	Sharp (n=602)	Reflect (n=954)	IMbrave (n=501)
Drug	Sorafenib	Lenvatinib	Atezolizumab + Bevacizumab
Drug class	Multi-kinase inhibitor targeting VEGFR 2-3, PDGFR, and RAF kinase	Multi-kinase inhibitor targeting VEGFR 1-3, PDGFR, FGFR 1-4, KIT, and RET	Atezo: Immune checkpoint inhibitor, anti-PD-L1 Beva: anti-VEGF
Eligible patients	Patients with advanced stage HCC ineligible/after progression to surgical or locoregional therapies, Child Pugh A, ECOG PS 0-2, with no prior systemic therapy	Patients with unresectable HCC, BCLC B or C, Child Pugh A, ECOG PS 0-1 with no prior systemic therapy. Ps: excluded patients with >50% liver involvement, invasion of the bile duct, or invasion of the main portal vein	Patients with locally advanced or metastatic and/or unresectable HCC, with no prior systemic therapy. Child Pugh A, ECOG PS 0-1
Overall survival (months) (95%CI)	Drug: 10.7 (9.4-13.3)	Lenvatinib: 13.6 (12.1-14.9)	Atezo + Beva: 19.2 (17-23.7)
	Placebo: 7.9 (6.8-9.1)	Sorafenib: 12.3 (10.4-13.9)	Sorafenib: 13.4 (11.4-16.9)
	HR: 0.69 (0.55-0.87), P<0.0001	HR: 0.92 (0.79-1.06)	HR: 0.66 (0.52-0.85), P=0.0009
PFS/TTP (months)	Drug: 5.5 (4.1-6.9)	Lenvatinib: 7.4 (6.9-8.8)	Atezo + Beva: 6.9 (5.7-8.6)
	Placebo: 2.8 (2.7-3.9)	Sorafenib: 3.7 (3.6-4.6)	Sorafenib: 4.3 (4-5.6)
	HR: 0.58 (0.45-0.74), P<0.0001	HR: 0.66 (0.57-0.77), P<0.0001	HR: 0.65 (0.53-0.81), P=0.0001
Overall response rate - RECIST (%)	Sorafenib: ORR: 2% CR: 0% PR:2% SD:71% DCR:43%	Lenvatinib: ORR: 18.8% CR: <1% PR: 18% SD: 54% PD: 18% DCR: 72.8%	Atezo + Beva: ORR: 30% CR: 8% PR: 22% SD: 44% DCR: 74% PD: 19%
		Sorafenib: ORR: 6.5%	Sorafenib: ORR: 11%
		CR: < 1% PR: 6% SD: 53% PD: 32% DCR: 59%	CR: <1% PR: 11% SD: 43% DCR: 55% PD: 25%
Overall response rate - mRECIST (%)	NA	Lenvatinib: ORR: 24.1% CR: 1% PR: 23% SD: 51% PD: 15% DCR: 75.5%	Atezo + Beva: ORR: 35% CR: 12% PR: 23% SD: 37% DCR: 73% PD: 20%
		Sorafenib: ORR: 9.2% CR: <1% PR: 9% SD: 51% PD: 31% DCR: 60.5%	Sorafenib: ORR: 14% CR: 3% PR: 11% SD: 41% DCR: 55% PD: 25%
Adverse events, any grade	Diarrhea (39%), fatigue (22%), HFSR (21%), anorexia (14%), hypertension (5%), bleeding (7%)	Hypertension (42%), diarrhea (39%), anorexia (34%), decreased weight (31%), fatigue (30%), HFSR (27%), proteinuria (25%)	Hypertension (29.8%), fatigue (20.4%), proteinuria (20.1%), pruritus (19.5%), AST increase (19.5%), diarrhea (18.8%), anorexia (17.6%)
Adverse events grade 3 or 4	HFSR (8%), diarrhea (8%), fatigue (4%), hypertension (2%), bleeding (1%)	Hypertension (23%), decreased weight (8%), anorexia (5%), diarrhea (4%), fatigue (4%), HFSR (3%)	Hypertension (15.2%), AST increase (7%), ALT increase (3.6%), proteinuria (3%);
Dose schedule and route of administration	400 mg of sorafenib (two	≥60 kg: 12 mg/day (three 4-mg tablets taken orally once a day)	Intravenous infusion of 1200 mg atezolizumab + 15 mg/kg
	200-mg tablets) taken orally twice daily	<60 kg: 8 mg/day (two 4-mg tablets taken orally once a day)	bevacizumab every 3 weeks
Approved for HCC	Europe, USA, Brazil	Europe, USA, Brazil	Europe, USA, Brazil

Pivotal phase III study	RESORCE (n=573)	CELESTIAL (n=707)	REACH-2 (n=292)
Drug	Regorafenib	Cabozantinib	Ramucirumab
Drug class	Multi-kinase inhibitor targeting VEGFR1-3, PDGFR, RAF kinase, and FGFR1-2	Multi-kinase inhibitor with potent activity against VEGFR 1-3, AXL, and MET	IgG1 recombinant monoclonal antibody, antagonist of VEGFR2, which blocks VEGF activation
Eligible patients	Patients previously treated with sorafenib who tolerated at least 400 mg/d of the drug. Child Pugh A, ECOG PS 0-1	Patients previously treated with sorafenib or up to two systemic treatments for HCC. Child Pugh A, ECOG PS 0-1	Patients with AFP ≥400 ng/mL previously treated with sorafenib, Child Pugh A, ECOG PS 0-1
Overall survival (months) (95%CI)	Drug: 10.6 (9.1-12.1)	Drug: 10.2 (9.1-12.0)	Drug: 8.5 (7.0-10.6)
	Placebo: 7.8 (6.3-8.8)	Placebo: 8.0 (6.8-9.4)	Placebo: 7.3 (5.4-9.1)
	HR: 0.63 (0.50-0.79), P<0.0001	HR: 0.76 (0.63-0.92), P=0.0005	HR: 0.71 (0.53-0.94), P=0.0199
PFS (months)	Drug: 3.1 (2.8-4.2)	Drug: 5.2 (4.0-5.5)	Drug: 2.8 (2.8-4.1)
	Placebo: 1.5 (1.4-1.6)	Placebo: 1.9 (1-9-1.9)	Placebo: 1.6 (1.5-2.7)
	HR: 0.46 (0.37-0.56), P<0.0001	HR: 0.44 (0.36-0.52), P<0.0001	HR: 0.45 (0.33-0.60), P=0.0001
Adverse events grade 3 or 4	Hypertension (15%), hand-foot syndrome (13%), fatigue (9%), and diarrhea (3%)	Hand-foot syndrome (17%), hypertension (16%), increased AST (12%), fatigue (10%), and diarrhea (10%)	Hypertension (13%), hyponatremia (6%), and increased AST (3%)
Dose schedule and route of administration	four coated tablets containing 40 mg each (160 mg regorafenib) taken orally once daily, with food, in a single dose, for 3 weeks followed by 1 week without therapy	60 mg taken orally once daily in a single dose, not with food (administer ≥2 h after and ≥1 h before eating)	Intravenous infusion of 8 mg/kg every 2 weeks
Approved for HCC	Europe, USA, Brazil	Europe, USA, Brazil	Europe, USA, Brazil

Atezolizumab + Bevacizumab	Tyrosine kinase inhibitors - Lenvatinib or Sorafenib
Patients at high risk of bleeding:	Patients at high risk of bleeding:
Thrombocytopenia with platelets <75 x 10⁹/L	Thrombocytopenia with platelets <75 x 10⁹/L
Untreated or treated gastric or esophageal varices with high risk of bleeding	Gastric or esophageal varices that require treatment
Bleeding diathesis or significant coagulopathy	Bleeding or thrombotic disorders
Recent GI bleeding or hemoptysis	Recent GI bleeding or hemoptysis
Serious, non-healing or dehiscing wound, active ulcer or untreated bone fracture
Severe chronic hepatitis with AST, ALT >5 xULN	Severe chronic hepatitis with AST, ALT >5 xULN
Autoimmune diseases and conditions requiring immunosuppression:	Absence of contraindication in patients with autoimmune diseases or conditions requiring immunosuppression.
Current or past autoimmune disease
Exceptions: hypothyroidism, type 1 diabetes, skin diseases with limited involvement
Any condition that requires chronic systemic immunosuppression
Cardiovascular diseases:	Cardiovascular diseases:
Inadequately controlled blood pressure	Inadequately controlled blood pressure or need of
History of hypertensive crisis or hypertensive encephalopathy	>1 antihypertensive medication
Chronic heart failure (NYHA class >1), myocardial infarction or stroke in the last 3 months	Chronic heart failure (NYHA class > II)
Unstable angina	Unstable angina, myocardial infarction or stroke in the last 6 months
Unstable arrhythmia	Arrhythmia requiring medical treatment
Significant vascular disease (including recent peripheral arterial thrombosis) in the last 6 months	QTc >480 ms
Populations with unknown benefit:	Populations with unknown benefit:
HBV-HCV coinfection	HIV infection
HIV infection	ECOG >1
ECOG >1	Child-Pugh class B or C
Child-Pugh class B or C	Liver transplantation
Current moderate to severe ascites or any history of hepatic encephalopathy	HCC with ≥50% liver involvement, invasion into the bile duct, or invasion of the main portal branch (only for lenvatinib)
Liver transplantation	Brain or leptomeningeal metastasis
Brain or leptomeningeal metastasis
Fibrolamellar HCC, sarcomatoid HCC or mixed cholangiocarcinoma and HCC

Drug	Targets	Condition	Phase	Primary endpoint	Clinical trial
Atezolizumab plus Lenvatinib or Sorafenib	PD-L1 + VEGFRs, FGFRs, RAF RET, KIT	Second-line	III	OS	NCT04770896
SHR-1210 plus Apatinib	PD-1 + VEGFR-2	First-line	III	OS PFS	NCT03764293
Nivolumab plus Sorafenib	PD-1 + VEGFRs, KIT, RAF PDGFRs	First-line	II	MTD ORR	NCT03439891
Nivolumab plus Ipilimumab	PD-1 + CTLA-4	First-line	III	OS	NCT04039607
Durvalumab plus Bevacizumab	PD-L1 + VEGFA	Second-line	III	RFS	NCT03847428
Cabozantinib plus Atezolizumab	PD-L1 + VEGFR, MET, RET, KIT, AXL	First-line	III	OS PFS	NCT03755791

Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia e Outras Especialidades - IBEPEGE. Rua Dr. Seng, 320, 01331-020 São Paulo - SP Brasil, Tel./Fax: +55 11 3147-6227 - São Paulo - SP - Brazil
E-mail: secretariaarqgastr@hospitaligesp.com.br

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[1] Corresponding author: Aline Lopes Chagas. E-mail: aline.chagas@hc.fm.usp.br