{"entity":{"id":"hcc-advanced","kind":"cancer","name":"Advanced hepatocellular carcinoma (BCLC C)","aka":["Advanced-stage HCC","Unresectable hepatocellular carcinoma","Metastatic hepatocellular carcinoma","HCC with portal vein invasion","BCLC C"],"tldr":"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.\n\nSorafenib, 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.\n\nAfter 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.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Hepatocellular_carcinoma","links":[{"label":"SHARP (NEJM 2008)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa0708857"},{"label":"IMbrave150 (NEJM 2020)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa1915745"},{"label":"HIMALAYA (NEJM Evidence 2022)","url":"https://evidence.nejm.org/doi/full/10.1056/EVIDoa2100070"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Hepatocellular_carcinoma"}],"tags":["subtype-page"],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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"],"standardOfCare":[{"setting":"First line","approach":"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.","refs":["imbrave150","himalaya","checkmate-9dw","atezolizumab","bevacizumab","durvalumab","tremelimumab","nivolumab","ipilimumab","child-pugh"]},{"setting":"First line when immunotherapy is unsuitable","approach":"Lenvatinib (REFLECT) or sorafenib (SHARP), for example after liver transplantation or with active autoimmune disease.","refs":["reflect","sharp","lenvatinib","sorafenib"]},{"setting":"Second line and beyond","approach":"Lenvatinib or sorafenib after immunotherapy; regorafenib (RESORCE), cabozantinib (CELESTIAL) or ramucirumab when alpha-fetoprotein is 400 or above, all proven after sorafenib.","refs":["resorce","celestial","regorafenib","cabozantinib","ramucirumab","lenvatinib","sorafenib","afp"]},{"setting":"Portal vein tumour thrombus","approach":"Radiotherapy or radioembolisation to the thrombus alongside systemic therapy; hepatic artery infusion chemotherapy in Asian centres.","refs":["portal-vein-tumour-thrombus","sbrt","radioembolisation-tare"]},{"setting":"Liver disease during treatment","approach":"Antiviral therapy for hepatitis B, variceal management and monitoring of liver function, which decides whether further lines are possible.","refs":["hbv-hcv","child-pugh"]}],"stateOfArt":["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."],"history":[{"year":2008,"title":"SHARP: sorafenib is the first drug to extend survival in advanced HCC","refs":["sharp","sorafenib"]},{"year":2017,"title":"RESORCE: regorafenib works after sorafenib","refs":["resorce","regorafenib"]},{"year":2018,"title":"REFLECT: lenvatinib non-inferior to sorafenib; CELESTIAL: cabozantinib in later lines","refs":["reflect","lenvatinib","celestial","cabozantinib"]},{"year":2020,"title":"IMbrave150: atezolizumab plus bevacizumab beats sorafenib","refs":["imbrave150","atezolizumab","bevacizumab"]},{"year":2022,"title":"HIMALAYA: durvalumab plus tremelimumab (STRIDE) beats sorafenib","refs":["himalaya","durvalumab","tremelimumab"]},{"year":2025,"title":"CheckMate 9DW: nivolumab plus ipilimumab beats lenvatinib or sorafenib","refs":["checkmate-9dw","nivolumab","ipilimumab"]}],"pipeline":["checkmate-9dw","camrelizumab-rivoceranib","ivonescimab","livmoniplimab","cobolimab","gpc3","car-t","cabozantinib"],"openProblems":["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."],"parent":"hcc"},"route":"/cancers/hcc-advanced/","neighbours":{"trial":[{"id":"celestial","kind":"trial","name":"CELESTIAL","route":"/trials/celestial/"},{"id":"checkmate-9dw","kind":"trial","name":"CheckMate 9DW","route":"/trials/checkmate-9dw/"},{"id":"himalaya","kind":"trial","name":"HIMALAYA","route":"/trials/himalaya/"},{"id":"imbrave150","kind":"trial","name":"IMbrave150","route":"/trials/imbrave150/"},{"id":"reflect","kind":"trial","name":"REFLECT","route":"/trials/reflect/"},{"id":"resorce","kind":"trial","name":"RESORCE","route":"/trials/resorce/"},{"id":"sharp","kind":"trial","name":"SHARP","route":"/trials/sharp/"}],"drug":[{"id":"atezolizumab","kind":"drug","name":"Atezolizumab","route":"/drugs/atezolizumab/"},{"id":"bevacizumab","kind":"drug","name":"Bevacizumab","route":"/drugs/bevacizumab/"},{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"camrelizumab-rivoceranib","kind":"drug","name":"Camrelizumab + rivoceranib","route":"/drugs/camrelizumab-rivoceranib/"},{"id":"cobolimab","kind":"drug","name":"Cobolimab","route":"/drugs/cobolimab/"},{"id":"durvalumab","kind":"drug","name":"Durvalumab","route":"/drugs/durvalumab/"},{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/"},{"id":"ivonescimab","kind":"drug","name":"Ivonescimab","route":"/drugs/ivonescimab/"},{"id":"lenvatinib","kind":"drug","name":"Lenvatinib","route":"/drugs/lenvatinib/"},{"id":"livmoniplimab","kind":"drug","name":"Livmoniplimab","route":"/drugs/livmoniplimab/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"ramucirumab","kind":"drug","name":"Ramucirumab","route":"/drugs/ramucirumab/"},{"id":"regorafenib","kind":"drug","name":"Regorafenib","route":"/drugs/regorafenib/"},{"id":"sorafenib","kind":"drug","name":"Sorafenib","route":"/drugs/sorafenib/"},{"id":"tremelimumab","kind":"drug","name":"Tremelimumab","route":"/drugs/tremelimumab/"}],"target":[{"id":"gpc3","kind":"target","name":"Glypican-3","route":"/targets/gpc3/"}],"technology":[{"id":"car-t","kind":"technology","name":"CAR-T cell therapy","route":"/technologies/car-t/"},{"id":"radioembolisation-tare","kind":"technology","name":"Radioembolisation (TARE / SIRT, yttrium-90)","route":"/technologies/radioembolisation-tare/"},{"id":"sbrt","kind":"technology","name":"SBRT / SABR (stereotactic radiotherapy)","route":"/technologies/sbrt/"}],"term":[{"id":"afp","kind":"term","name":"Alpha-fetoprotein (AFP)","route":"/terms/afp/"},{"id":"child-pugh","kind":"term","name":"Child-Pugh score","route":"/terms/child-pugh/"},{"id":"hbv-hcv","kind":"term","name":"Hepatitis B and C as cancer causes","route":"/terms/hbv-hcv/"},{"id":"portal-vein-tumour-thrombus","kind":"term","name":"Portal vein tumour thrombus (macrovascular invasion)","route":"/terms/portal-vein-tumour-thrombus/"}],"cancer":[{"id":"hcc","kind":"cancer","name":"Hepatocellular carcinoma","route":"/cancers/hcc/"}]}}