# 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

## 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

- trials: [CELESTIAL](https://onco.cc/trials/celestial/), [CheckMate 9DW](https://onco.cc/trials/checkmate-9dw/), [HIMALAYA](https://onco.cc/trials/himalaya/), [IMbrave150](https://onco.cc/trials/imbrave150/), [REFLECT](https://onco.cc/trials/reflect/), [RESORCE](https://onco.cc/trials/resorce/), [SHARP](https://onco.cc/trials/sharp/)
- 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/), [Portal vein tumour thrombus (macrovascular invasion)](https://onco.cc/terms/portal-vein-tumour-thrombus/)
- cancers: [Hepatocellular carcinoma](https://onco.cc/cancers/hcc/)

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