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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.
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.
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.
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.
Same organ: Hepatocellular carcinoma, Early hepatocellular carcinoma (BCLC 0 and A), Intermediate hepatocellular carcinoma (BCLC B), Hepatoblastoma
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.
Lenvatinib (REFLECT) or sorafenib (SHARP), for example after liver transplantation or with active autoimmune disease.
Lenvatinib or sorafenib after immunotherapy; regorafenib (RESORCE), cabozantinib (CELESTIAL) or ramucirumab when alpha-fetoprotein is 400 or above, all proven after sorafenib.
Radiotherapy or radioembolisation to the thrombus alongside systemic therapy; hepatic artery infusion chemotherapy in Asian centres.
Antiviral therapy for hepatitis B, variceal management and monitoring of liver function, which decides whether further lines are possible.
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.
The targets of this cancer's medicines and the ones linked to it directly.
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.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Sudden severe abdominal pain, a hard or very tender abdomen, or abdominal pain with vomiting and fever. Boxed warning for gastrointestinal perforation on bevacizumab.
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Tablets: take on an empty stomach (no food 2 hours before or 1 hour after). Avoid grapefruit.
Take with a low-fat breakfast (under 30% fat).
Take without food (1 hour before or 2 hours after).
See all on the product pages:AtezolizumabBevacizumabCabozantinibDurvalumabIpilimumabLenvatinibNivolumabRamucirumabRegorafenibSorafenibTremelimumab·Printable cards in the navigator
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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.
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