# Advanced hepatocellular carcinoma (BCLC C)

Source: https://onco.cc/cancers/hcc-advanced/  
OnCo record `hcc-advanced` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Advanced hepatocellular carcinoma has invaded the liver's veins or spread beyond it. Sorafenib was the only drug for a decade; now the combination of the immunotherapy atezolizumab with the anti-angiogenic antibody bevacizumab, or the two-antibody regimen durvalumab with tremelimumab, is standard first line, and several further drugs follow it.

## Summary

BCLC stage C is defined by macrovascular invasion, extrahepatic spread or cancer-related symptoms in a patient with preserved liver function (Child-Pugh A) and good performance status; patients with decompensated cirrhosis are stage D and are treated for the liver disease alone. Diagnosis by imaging is usual, but biopsy is increasingly taken for trials and to exclude combined hepatocellular-cholangiocarcinoma. Because outcomes depend on the liver as much as the tumour, ALBI grade, portal hypertension, varices and hepatitis B control are assessed before any drug is started.

Sorafenib, a multikinase inhibitor, was the first drug to extend survival: SHARP (NEJM 2008) improved median overall survival from 7.9 to 10.7 months, and nothing beat it for ten years until lenvatinib proved non-inferior in REFLECT (Lancet 2018) with a median of 13.6 against 12.3 months. IMbrave150 (NEJM 2020) then showed that atezolizumab with bevacizumab beat sorafenib, with a median overall survival of 19.2 months against 13.4 in the updated analysis, and it became the first-line standard; endoscopy for varices is required before starting because bevacizumab raises bleeding risk. HIMALAYA (NEJM Evidence 2022) showed that a single priming dose of tremelimumab with durvalumab (the STRIDE regimen) also beat sorafenib, with a median of 16.4 against 13.8 months and about one in five patients alive at five years, giving a chemotherapy-free option for patients who cannot have bevacizumab. CheckMate 9DW (Lancet 2025) added nivolumab with ipilimumab, which beat lenvatinib or sorafenib with a median of 23.7 against 20.6 months, and in China camrelizumab with rivoceranib beat sorafenib in CARES-310.

After first-line therapy the evidence is thinner, because the second-line drugs were tested after sorafenib: regorafenib (RESORCE, 10.6 against 7.8 months), cabozantinib (CELESTIAL, 10.2 against 8.0 months) and ramucirumab for patients with alpha-fetoprotein of 400 or above (REACH-2, 8.5 against 7.3 months). Lenvatinib or sorafenib is commonly given after immunotherapy, and trials now test the sequence properly. Radiotherapy or radioembolisation to a portal vein tumour thrombus, hepatic artery infusion chemotherapy in Asia and treatment of bone or brain metastases are added as needed, with liver function the constant limit.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: Advanced-stage HCC; Unresectable hepatocellular carcinoma; Metastatic hepatocellular carcinoma; HCC with portal vein invasion; BCLC C
- Tags: subtype-page
- Group: gastrointestinal
- Burden: Hepatocellular carcinoma that has invaded the portal or hepatic veins, spread outside the liver or caused symptoms, while liver function is still preserved; the stage most patients reach in countries without surveillance, and the one where drug therapy has changed most in the last decade.
- Subtypes: HCC with portal vein invasion (macrovascular invasion, BCLC C); HCC with extrahepatic spread (lung, bone, nodes); Symptomatic HCC with preserved liver function; Advanced HCC after progression on immunotherapy; Advanced HCC in hepatitis B carriers (antiviral cover during treatment)
- Biomarkers: Child-Pugh A and ALBI grade (eligibility for all trials); Alpha-fetoprotein 400 or above (ramucirumab); Portal vein tumour thrombus extent; Varices on endoscopy before bevacizumab; Hepatitis B DNA and antiviral cover; Aetiology (viral versus non-viral) as a possible modifier of immunotherapy benefit

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/hcc-advanced/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/hcc-advanced/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/hcc-advanced/#what-it-is [5 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/hcc-advanced/#finding-it [6 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/hcc-advanced/#treating-it [5 settings, 4 decisions with options]
- Trials and papers (own page): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/hcc-advanced/evidence/ [48 trials, 5 key papers, 6 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/hcc-advanced/#science [10 targets]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/hcc-advanced/where-you-are/
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/hcc-advanced/#living-with-it [20 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/hcc-advanced/coming/ [15 medicines, 48 trials, 3 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/hcc-advanced/data/ [114 connected records]

## Standard of care

- First line: Atezolizumab with bevacizumab (IMbrave150) after endoscopic assessment of varices, or durvalumab with a single dose of tremelimumab (HIMALAYA); nivolumab with ipilimumab (CheckMate 9DW) where approved. ([IMbrave150](https://onco.cc/trials/imbrave150/), [HIMALAYA](https://onco.cc/trials/himalaya/), [CheckMate 9DW](https://onco.cc/trials/checkmate-9dw/), [Atezolizumab](https://onco.cc/drugs/atezolizumab/), [Bevacizumab](https://onco.cc/drugs/bevacizumab/), [Durvalumab](https://onco.cc/drugs/durvalumab/), [Tremelimumab](https://onco.cc/drugs/tremelimumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Child-Pugh score](https://onco.cc/terms/child-pugh/))
- First line when immunotherapy is unsuitable: Lenvatinib (REFLECT) or sorafenib (SHARP), for example after liver transplantation or with active autoimmune disease. ([REFLECT](https://onco.cc/trials/reflect/), [SHARP](https://onco.cc/trials/sharp/), [Lenvatinib](https://onco.cc/drugs/lenvatinib/), [Sorafenib](https://onco.cc/drugs/sorafenib/))
- Second line and beyond: Lenvatinib or sorafenib after immunotherapy; regorafenib (RESORCE), cabozantinib (CELESTIAL) or ramucirumab when alpha-fetoprotein is 400 or above, all proven after sorafenib. ([RESORCE](https://onco.cc/trials/resorce/), [CELESTIAL](https://onco.cc/trials/celestial/), [Regorafenib](https://onco.cc/drugs/regorafenib/), [Cabozantinib](https://onco.cc/drugs/cabozantinib/), [Ramucirumab](https://onco.cc/drugs/ramucirumab/), [Lenvatinib](https://onco.cc/drugs/lenvatinib/), [Sorafenib](https://onco.cc/drugs/sorafenib/), [Alpha-fetoprotein (AFP)](https://onco.cc/terms/afp/))
- Portal vein tumour thrombus: Radiotherapy or radioembolisation to the thrombus alongside systemic therapy; hepatic artery infusion chemotherapy in Asian centres. ([Portal vein tumour thrombus (macrovascular invasion)](https://onco.cc/terms/portal-vein-tumour-thrombus/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/), [Radioembolisation (TARE / SIRT, yttrium-90)](https://onco.cc/technologies/radioembolisation-tare/))
- Liver disease during treatment: Antiviral therapy for hepatitis B, variceal management and monitoring of liver function, which decides whether further lines are possible. ([Hepatitis B and C as cancer causes](https://onco.cc/terms/hbv-hcv/), [Child-Pugh score](https://onco.cc/terms/child-pugh/))

## State of the art

- Immunotherapy combinations have roughly doubled median survival compared with the sorafenib era and produce a tail of long-term survivors.
- Four positive first-line regimens now exist, and the choice rests on bleeding risk, autoimmune disease and transplant history.
- Every second-line drug was proven after sorafenib, so sequencing after immunotherapy is guided by inference rather than trials.

## Open problems

- No trial has defined the best drug after progression on immunotherapy.
- Patients with Child-Pugh B liver function are excluded from trials yet make up a large share of the clinic.
- Non-viral (metabolic) HCC may benefit less from immunotherapy, and the reason is unclear.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Hepatocellular_carcinoma
- SHARP (NEJM 2008): https://www.nejm.org/doi/full/10.1056/NEJMoa0708857
- IMbrave150 (NEJM 2020): https://www.nejm.org/doi/full/10.1056/NEJMoa1915745
- HIMALAYA (NEJM Evidence 2022): https://evidence.nejm.org/doi/full/10.1056/EVIDoa2100070
- Wikipedia: https://en.wikipedia.org/wiki/Hepatocellular_carcinoma

## Connected records

- cancers: [Early hepatocellular carcinoma (BCLC 0 and A)](https://onco.cc/cancers/hcc-early/), [Hepatocellular carcinoma](https://onco.cc/cancers/hcc/), [Intermediate hepatocellular carcinoma (BCLC B)](https://onco.cc/cancers/hcc-intermediate/)
- trials: [4SC-201 (Resminostat) and Sorafenib in Advanced Hepatocellular Carcinoma](https://onco.cc/trials/nct00943449/), [A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors](https://onco.cc/trials/nct07636785/), [A Phase I/II Study to Evaluate AZD5851 in GPC3+ Advanced/Recurrent Hepatocellular Carcinoma](https://onco.cc/trials/nct06084884/), [A Phase Ib/II Trial to Evaluate the Efficacy and Safety of HH-009 for the Treatment of FGF19-positive Advanced or Unresectable HCC](https://onco.cc/trials/nct07547553/), [A Phase II Clinical Study of AK104/AK112 in Combination With TT-00420 Tablet for Advanced HCC.](https://onco.cc/trials/nct07052253/), [A Phase II Clinical Study to Evaluate HLX43 in Patients With Locally Advanced or Metastatic HCC Failed or Intolerance to Standard Therapy](https://onco.cc/trials/nct06742892/), [A Study Evaluating Atezolizumab and Bevacizumab, With or Without Tiragolumab, in Participants With Untreated Locally Advanced or Metastatic Hepatocell](https://onco.cc/trials/nct05904886/), [A Study Evaluating Atezolizumab, With or Without Bevacizumab, in Participants With Unresectable Hepatocellular Carcinoma and Child-pugh B7 and B8 Cirr](https://onco.cc/trials/nct06096779/), [A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Li](https://onco.cc/trials/nct04524871/), [A Study of AK112 in Patients With Advanced Hepatocellular Carcinoma (HCC)](https://onco.cc/trials/nct06530251/), [A Study of Durvalumab or Tremelimumab Monotherapy, or Durvalumab in Combination With Tremelimumab or Bevacizumab in Advanced Hepatocellular Carcinoma](https://onco.cc/trials/nct02519348/), [A Study of Nofazinlimab (CS1003) in Subjects With Advanced Hepatocellular Carcinoma](https://onco.cc/trials/nct04194775/), [A Study of TTI-101 as Monotherapy and in Combination in Participants With Locally Advanced or Metastatic, and Unresectable Hepatocellular Carcinoma](https://onco.cc/trials/nct05440708/), [A Study to Assess the Dose, Adverse Events, and Change in Disease Activity of Livmoniplimab as an Intravenous (IV) Solution in Combination With Budigalimab as an IV Solution in Adult Participants With Hepatocellular Carcinoma (HCC)](https://onco.cc/trials/nct06109272/), [A Study to Evaluate C-CAR031 in Glypican-3 (GPC3)+ Advanced/Recurrent Hepatocellular Carcinoma (HCC)](https://onco.cc/trials/nct06590246/), [A Study to Evaluate the Efficacy and Safety of IBI310 and Sintilimab Combination Therapy in Patients With Hepatocellular Carcinoma as First-line Treatment](https://onco.cc/trials/nct07490262/), [A Study to Evaluate the Safety and Tolerability of Pumitamig Alone or In Combination With Ipilimumab in Participants With First-Line Advanced or Unres](https://onco.cc/trials/nct07291076/), [A Study to Explore the Reasonable Dosage and Evaluate the Efficacy, Safety and Tolerability of HLX10 and HLX04 with or Without HLX53 in Untreated, Locally Advanced or Metastatic Hepatocellular Carcinoma Patients.](https://onco.cc/trials/nct06349980/), [A Trial of Casdozokitug in Combination With Toripalimab Plus Bevacizumab in Participants With Unresectable and/or Locally Advanced or Metastatic Hepat](https://onco.cc/trials/nct06679985/), [ABSK-011+BSC vs. Placebo+BSC in Previously Treated Advanced HCC With FGF19 Overexpression](https://onco.cc/trials/nct07327034/), [CELESTIAL](https://onco.cc/trials/celestial/), [CheckMate 9DW](https://onco.cc/trials/checkmate-9dw/), [CVM-1118 in Combination With Nivolumab for Unresectable Advanced Hepatocellular Carcinoma](https://onco.cc/trials/nct05257590/), [Dual-Target GPC3/B7-H3 CAR-NK Cells for Advanced HCC](https://onco.cc/trials/nct07500220/), [Durvalumab and Tremelimumab as First Line Treatment in Participants With Advanced Hepatocellular Carcinoma (HCC)](https://onco.cc/trials/nct05883644/), [Durvalumab and Tremelimumab With Lenvatinib as First-line Treatment in Patients With Unresectable Hepatocellular Carcinoma](https://onco.cc/trials/nct07081633/), [Durvalumab Plus Tremelimumab as First-line Treatment in Chinese Patients With uHCC](https://onco.cc/trials/nct05557838/), [GPC3-Targeted T-Cell Therapy (ECT204) in Adults With Advanced HCC](https://onco.cc/trials/nct04864054/), [HIMALAYA](https://onco.cc/trials/himalaya/), [IMbrave150](https://onco.cc/trials/imbrave150/), [MRG006A Combination Therapy for Advanced Hepatocellular Carcinoma (Phase I/II)](https://onco.cc/trials/nct07479485/), [Namodenoson in the Treatment of Advanced Hepatocellular Carcinoma in Patients With Child-Pugh Class B7 Cirrhosis](https://onco.cc/trials/nct05201404/), [Ori-C101Chimeric Antigen Receptor (CAR) Modified T Cells for the Treatment of HCC](https://onco.cc/trials/nct05652920/), [Phase IIb Study of AST-3424 in Patients With AKR1C3-high Expressing Advanced Hepatocellular Carcinoma](https://onco.cc/trials/nct07310173/), [Phase III Study of Rilvegostomig in Combination With Bevacizumab With or Without Tremelimumab as First-line Treatment of Hepatocellular Carcinoma](https://onco.cc/trials/nct06921785/), [REACH-2](https://onco.cc/trials/reach-2/), [REFLECT](https://onco.cc/trials/reflect/), [RESORCE](https://onco.cc/trials/resorce/), [SHARP](https://onco.cc/trials/sharp/), [Study of ADI-PEG 20 Versus Placebo in Subjects With High Arginine Level and Unresectable Hepatocellular Carcinoma](https://onco.cc/trials/nct05317819/), [Study of Cabozantinib in Combination With Atezolizumab Versus Sorafenib in Participants With Advanced Hepatocellular Carcinoma (HCC) Who Have Not Rece](https://onco.cc/trials/nct03755791/), [Study of RP2 in Combination With Second-line Therapy in Patients With Locally Advanced or Metastatic HCC](https://onco.cc/trials/nct05733598/), [Study of the Theranostic Pair RYZ811 (Diagnostic) and RYZ801 (Therapeutic) to Identify and Treat Subjects With GPC3+ (Glypican-3) Unresectable HCC](https://onco.cc/trials/nct06726161/), [Study of ZG005 Combined With Bevacizumab Versus Sintilimab Combined With Bevacizumab in Advanced Hepatocellular Carcinoma](https://onco.cc/trials/nct06558227/), [Study to Evaluate Adverse Events, and Change in Disease Activity, When Intravenously (IV) Infused With Livmoniplimab in Combination With IV Infused Bu](https://onco.cc/trials/nct05822752/), [Symbiotic-GI-13: A Study to Learn About Study Medicine Called PF-08634404 as a Single Treatment and Combination Treatment in Adult Participants With a](https://onco.cc/trials/nct07227012/), [Visugromab, Nivolumab and Lenvatinib Compared to Double Placebo and Lenvatinib in Unresectable or Metastatic Hepatocellular Carcinoma Post Anti-PD-(L)](https://onco.cc/trials/nct07219459/), [Yttrium Y 90 Glass Microspheres and Capecitabine in Treating Patients With Liver Cholangiocarcinoma or Liver Metastases](https://onco.cc/trials/nct00858429/)
- key papers: [BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update](https://onco.cc/key-papers/paper-bclc-2022-reig-j-hepatol-2022/), [HIMALAYA: tremelimumab plus durvalumab in unresectable hepatocellular carcinoma](https://onco.cc/key-papers/paper-himalaya-nejm-evidence-2022/), [IMbrave150: atezolizumab plus bevacizumab replaces sorafenib as first treatment for advanced liver cancer](https://onco.cc/key-papers/paper-imbrave150-nejm-2020/), [REFLECT: lenvatinib versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma](https://onco.cc/key-papers/paper-reflect-lenvatinib-lancet-2018/), [SHARP: sorafenib in advanced hepatocellular carcinoma](https://onco.cc/key-papers/paper-sharp-sorafenib-nejm-2008/)
- drugs: [Atezolizumab](https://onco.cc/drugs/atezolizumab/), [Bevacizumab](https://onco.cc/drugs/bevacizumab/), [Cabozantinib](https://onco.cc/drugs/cabozantinib/), [Camrelizumab + rivoceranib](https://onco.cc/drugs/camrelizumab-rivoceranib/), [Cobolimab](https://onco.cc/drugs/cobolimab/), [Durvalumab](https://onco.cc/drugs/durvalumab/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Ivonescimab](https://onco.cc/drugs/ivonescimab/), [Lenvatinib](https://onco.cc/drugs/lenvatinib/), [Livmoniplimab](https://onco.cc/drugs/livmoniplimab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Ramucirumab](https://onco.cc/drugs/ramucirumab/), [Regorafenib](https://onco.cc/drugs/regorafenib/), [Sorafenib](https://onco.cc/drugs/sorafenib/), [Tremelimumab](https://onco.cc/drugs/tremelimumab/)
- targets: [Glypican-3](https://onco.cc/targets/gpc3/)
- technologies: [CAR-T cell therapy](https://onco.cc/technologies/car-t/), [Radioembolisation (TARE / SIRT, yttrium-90)](https://onco.cc/technologies/radioembolisation-tare/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/)
- terms: [Alpha-fetoprotein (AFP)](https://onco.cc/terms/afp/), [Child-Pugh score](https://onco.cc/terms/child-pugh/), [Hepatitis B and C as cancer causes](https://onco.cc/terms/hbv-hcv/), [LI-RADS (Liver Imaging Reporting and Data System)](https://onco.cc/terms/li-rads/), [Portal vein tumour thrombus (macrovascular invasion)](https://onco.cc/terms/portal-vein-tumour-thrombus/)
- people: [Andrew X. Zhu](https://onco.cc/people/andrew-zhu/), [Jordi Bruix](https://onco.cc/people/jordi-bruix/)

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JSON: https://onco.cc/api/v1/entities/hcc-advanced.json