cancersCancer

Advanced hepatocellular carcinoma (BCLC C)

aka Advanced-stage HCC, Unresectable hepatocellular carcinoma, Metastatic hepatocellular carcinoma, HCC with portal vein invasion, BCLC C

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.

Part ofHepatocellular carcinoma

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.

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.

Red cards

From the labels and guidelines behind the standard of care. Your team's thresholds win.

Emergency services now
Bowel perforation
Sudden severe abdominal pain, a hard or very tender abdomen, or abdominal pain with vomiting and fever. Boxed warning for gastrointestinal perforation on bevacizumab.
Bevacizumab Cabozantinib Lenvatinib Ramucirumab Regorafenib Sorafenib source
Emergency services now
Hypophysitis or adrenal crisis
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
Atezolizumab Durvalumab Ipilimumab Nivolumab Tremelimumab source
Emergency services now
Fainting or palpitations
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Cabozantinib Lenvatinib Regorafenib Sorafenib source
Check before combining
Food and drink: Cabozantinib
Tablets: take on an empty stomach (no food 2 hours before or 1 hour after). Avoid grapefruit.
Cabozantinib source
Check before combining
Food and drink: Regorafenib
Take with a low-fat breakfast (under 30% fat).
Regorafenib source
Check before combining
Food and drink: Sorafenib
Take without food (1 hour before or 2 hours after).
Sorafenib source

See all on the product pages:Atezolizumab Bevacizumab Cabozantinib Durvalumab Ipilimumab Lenvatinib Nivolumab Ramucirumab Regorafenib Sorafenib Tremelimumab·Printable cards in the navigator

Anatomy and lymph node drainage

Liver: subsites and node stations · wireframe schematic, not to scale

Organ atlas →

Hepatocellular carcinoma grows in a cirrhotic liver and spreads first inside it and into the portal vein, so staging depends on liver function and vascular invasion as much as on size.

Subsites

Right lobe (segments V-VIII)Advanced HCC in hepatitis B carriers (antiviral cover during treatment)
Left lobe (segments II-IV)
Portal vein (macrovascular invasion)HCC with portal vein invasion (macrovascular invasion, BCLC C)
Capsule and diaphragm surface

Regional lymph nodes

hepatic hilar
coeliac
paracaval

Same organ: Hepatocellular carcinoma, Early hepatocellular carcinoma (BCLC 0 and A), Intermediate hepatocellular carcinoma (BCLC B), Hepatoblastoma

Who gets it and what has changed

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.

Group

gastrointestinal

Cases by country

Cases by country · GLOBOCAN 2022

All countries →

No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.

Standard of care

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Lines of therapy by subgroup →Staging and risk scores →

Decisions you may face

4 with more than one option · full decision page →

One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.

First line6 First line when immunotherapy is unsuitable2 Second line and beyond5 Portal vein tumour thrombus2 Liver disease during treatment

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 HIMALAYA CheckMate 9DWAtezolizumabBevacizumabDurvalumabTremelimumabNivolumabIpilimumabChild-Pugh score

First line when immunotherapy is unsuitable

Lenvatinib (REFLECT) or sorafenib (SHARP), for example after liver transplantation or with active autoimmune disease.

REFLECT SHARPLenvatinibSorafenib

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 CELESTIALRegorafenibCabozantinibRamucirumabLenvatinibSorafenibAlpha-fetoprotein (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)SBRT / SABR (stereotactic radiotherapy)Radioembolisation (TARE / SIRT, yttrium-90)

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 Child-Pugh score

Subtypes & biomarkers

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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 clinicians test

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

How often this target appears

History

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2008SHARP: sorafenib is the first drug to extend survival in advanced HCC
SHARPSorafenib
2017RESORCE: regorafenib works after sorafenib
RESORCERegorafenib
2018REFLECT: lenvatinib non-inferior to sorafenib; CELESTIAL: cabozantinib in later lines
REFLECTLenvatinibCELESTIALCabozantinib
2020IMbrave150: atezolizumab plus bevacizumab beats sorafenib
IMbrave150AtezolizumabBevacizumab
2022HIMALAYA: durvalumab plus tremelimumab (STRIDE) beats sorafenib
HIMALAYADurvalumabTremelimumab
2025CheckMate 9DW: nivolumab plus ipilimumab beats lenvatinib or sorafenib
CheckMate 9DWNivolumabIpilimumab

What changed

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Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.

All 14 changes by month →

FollowWatch this cancer and Saved shows what changed since you last looked.Follow by feed

In development

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What is in development for Advanced hepatocellular carcinoma (BCLC C), drawn from the whole corpus: 12 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.

Drugs in phase 3 · 2

Phase 3antibody (INN stem -mab; form not stated in the registry record)

Livmoniplimab

Phase 3antibody (INN stem -mab; form not stated in the registry record)

Cobolimab

Technologies being tested · 2

Angiogenesis and vascular normalisation models TIM-3 blockade

Trials reported · 7

CheckMate 9DW · phase 3 · 2024 · positive
CELESTIAL · phase 3 · 2018 · positive
HIMALAYA · phase 3 · 2022 · positive
IMbrave150 · phase 3 · 2020 · positive
REFLECT · phase 3 · 2018 · positive
RESORCE · phase 3 · 2017 · positive
SHARP · phase 3 · 2008 · positive

Targets under investigation · 1

Glypican-3

Open problems and what is being done

No trial has defined the best drug after progression on immunotherapy.
What is being done about this
Resistance to treatment
and how the field plans to fix it →
Available now
CabozantinibApproved
In trials
Nothing recorded yet.
Ideas and roadmaps
Nothing recorded yet.
Also on OnCo: Resistance atlas · Lines of therapy.
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.

Trials

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Trials recruiting now

Recruiting trials near you · live from ClinicalTrials.gov

Advanced hepatocellular carcinoma (BCLC C)

condition: Advanced hepatocellular carcinoma

Open on ClinicalTrials.gov →

within

Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.

Landmark trials

CELESTIAL CheckMate 9DW HIMALAYA IMbrave150 REFLECT RESORCE SHARP

Expert centres

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Where the expertise is

Expert centres

121 centres in 29 countries · 0 with a trial for this cancer on record · second-opinion finder →

Choose a region from the globe in the header to mark centres near you.

121 centres


Memorial Sloan Kettering Cancer Center New York · cancer center	United States	NCI comprehensive	5,100	94,456	Comprehensive genomic profiling CAR-T cell therapy Digital pathology & AI	#1
Stanford Health Care / Stanford Cancer Institute Stanford · university	United States	NCI comprehensive	3,000	50,162	CAR-T cell therapy SBRT / SABR (stereotactic radiotherapy)CyberKnife robotic radiosurgery Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)+1	#30
Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences Tianjin · hospital	China	none recorded	4,959	62,355	CAR-T cell therapy	-
Abramson Cancer Center, University of Pennsylvania Philadelphia · cancer center	United States	NCI comprehensive	3,148	54,267	CAR-T cell therapy In vivo CAR-T PARP PET Personalised neoantigen (mRNA) vaccines +2	-
Zhongshan Hospital, Fudan University Shanghai · hospital	China	none recorded	2,872	31,534	Liquid biopsy (ctDNA)Thermal ablation (RFA, microwave, cryo)Robotic & minimally invasive surgery	-
Tongji Hospital, Huazhong University of Science and Technology Wuhan · hospital	China	none recorded	2,478	31,527	HPV & HBV vaccination Patient-derived organoids Immune checkpoint inhibitors CAR-T cell therapy	-
University College London Hospitals / UCL Cancer Institute London · hospital	United Kingdom	none recorded	2,376	28,940	Proton therapy CAR-T cell therapy Liquid biopsy (ctDNA)Whole-exome & whole-genome sequencing +5	-
Fred Hutchinson Cancer Center Seattle · cancer center	United States	NCI comprehensive	2,123	29,954	CAR-T cell therapy Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems	-
Department of Biotechnology, Government of India New Delhi · government	India	none recorded	2,028	15,043	CAR-T cell therapy HPV & HBV vaccination Point-of-care and decentralised cell manufacturing	-
Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Dallas, TX · cancer center	United States	NCI comprehensive	1,744	19,757	SBRT / SABR (stereotactic radiotherapy)STING & innate immune agonists Metabolic therapy: starving the tumour of a nutrient	-
City of Hope Duarte, CA · cancer center	United States	NCI comprehensive	1,546	20,319	CAR-T cell therapy Biology-guided radiotherapy (RefleXion X1, SCINTIX)	-
Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine Houston, TX · cancer center	United States	NCI comprehensive	1,488	18,490	CAR-T cell therapy Allogeneic (off-the-shelf) cell therapy Whole-exome & whole-genome sequencing Endocrine therapy (SERMs, AIs, SERDs)	-
UMC Utrecht Cancer Center Utrecht · cancer center	Netherlands	none recorded	1,422	20,323	MR-guided adaptive radiotherapy Patient-derived organoids Functional (ex vivo) drug testing IMRT / IGRT (modern external beam)+1	-
Peking University Cancer Hospital Beijing · cancer center	China	none recorded	1,344	18,195	CAR-T cell therapy Immune checkpoint inhibitors Antibody-drug conjugate (ADC)	-
NCI Center for Cancer Research (intramural programme) Bethesda, MD · government	United States	none recorded	1,312	26,262	TIL therapy TCR-T cell therapy CAR-T cell therapy HPV & HBV vaccination +1	-

(showing the first 15)

These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with Advanced hepatocellular carcinoma but is thinly recorded here will look small.

Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.

Seeking a second opinion: ask your oncologist for a referral to a high-volume centre; most accept records and pathology by mail or telehealth. In the US, use the NCI's Find a Cancer Center tool or the nonprofit Cancer Commons, which navigates options for advanced cancers at no cost. The second-opinion finder explains how referral works in your country.

Questions to ask

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Bring to your appointment

Questions to ask your oncologist about Advanced hepatocellular carcinoma

Generated from this cancer's standard of care, biomarkers, and pipeline · 20 questions

Newly diagnosed

What is my exact diagnosis, stage, and grade, and which tests established them?
Why: Everything else follows from an accurate stage and subtype.
Which biomarkers have been tested on my tumour (for example Child-Pugh A and ALBI grade, Alpha-fetoprotein 400 or above, Portal vein tumour thrombus extent, Varices on endoscopy before bevacizumab, Hepatitis B DNA and antiviral cover), and what were the results?
Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
Which subtype is my cancer, and does that change the recommended treatment?
Why: Recognised subtypes for this cancer include HCC with portal vein invasion, HCC with extrahepatic spread, Symptomatic HCC with preserved liver function.
Is germline (inherited) genetic testing recommended for me or my family?
Why: Inherited variants can change treatment and matter for relatives.

First line

For my situation (first line), which of the standard options do you recommend and why?
Why: Guideline options include: 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.
Am I a candidate for Atezolizumab, Bevacizumab, Durvalumab or related drugs, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of IMbrave150 and HIMALAYA apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

First line when immunotherapy is unsuitable

For my situation (first line when immunotherapy is unsuitable), which of the standard options do you recommend and why?
Why: Guideline options include: Lenvatinib (REFLECT) or sorafenib (SHARP), for example after liver transplantation or with active autoimmune disease.
Am I a candidate for Lenvatinib, Sorafenib, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of REFLECT and SHARP apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Second line and beyond

For my situation (second line and beyond), which of the standard options do you recommend and why?
Why: Guideline options include: Lenvatinib or sorafenib after immunotherapy; regorafenib (RESORCE), cabozantinib (CELESTIAL) or ramucirumab when alpha-fetoprotein is 400 or above, all proven after sorafenib.
Am I a candidate for Regorafenib, Cabozantinib, Ramucirumab or related drugs, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of RESORCE and CELESTIAL apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Portal vein tumour thrombus

For my situation (portal vein tumour thrombus), which of the standard options do you recommend and why?
Why: Guideline options include: Radiotherapy or radioembolisation to the thrombus alongside systemic therapy; hepatic artery infusion chemotherapy in Asian centres.

Liver disease during treatment

For my situation (liver disease during treatment), which of the standard options do you recommend and why?
Why: Guideline options include: Antiviral therapy for hepatitis B, variceal management and monitoring of liver function, which decides whether further lines are possible.

Any stage

Are there clinical trials I could join, for example of CheckMate 9DW, Camrelizumab + rivoceranib, Ivonescimab, Livmoniplimab?
Why: Trials are how the next standard of care is set; asking early keeps options open.
Would a second opinion at a high-volume centre change anything, and can you help arrange it?
Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?
Why: Supportive care improves quality of life and helps patients complete treatment.
I read that “No trial has defined the best drug after progression on immunotherapy”. How does that affect my plan?
Why: Open problems are where trials and second opinions matter most.
I read that “Patients with Child-Pugh B liver function are excluded from trials yet make up a large share of the clinic”. How does that affect my plan?
Why: Open problems are where trials and second opinions matter most.