{"entity":{"id":"hcc","kind":"indication","name":"Hepatocellular carcinoma","aka":["Liver Cancer"],"tldr":"Liver cancer almost always grows in a liver already damaged by hepatitis, alcohol or fatty liver disease. It is one of the most preventable cancers, and since 2020 immunotherapy combinations have roughly doubled how long people with advanced disease live.","summary":"Hepatocellular carcinoma is the dominant primary liver cancer (~75-85%) and one of the most preventable: HBV vaccination and HCV cure have cut incidence wherever they were deployed. Its defining feature is that it arises in a diseased organ: chronic hepatitis B, hepatitis C, alcohol-related and metabolic (MASLD) cirrhosis account for most cases, so the liver's remaining function (Child-Pugh, ALBI) matters as much as tumour stage. The BCLC system integrates both and maps each stage to a treatment: ablation, resection or transplantation for early disease; TACE or radioembolisation for intermediate disease; systemic therapy for advanced disease. Surveillance of at-risk patients with six-monthly ultrasound is recommended but poorly adopted, and most patients still present beyond curative stages, which is why it remains the third leading cause of cancer death worldwide.\n\nSystemic therapy changed completely between 2018 and 2026. Sorafenib (SHARP, 2007) was the only option for a decade. Lenvatinib matched it (REFLECT), then IMbrave150 made atezolizumab plus bevacizumab the first regimen to beat sorafenib on survival (OS 19.2 vs 13.4 months). HIMALAYA's STRIDE regimen (single-dose tremelimumab plus durvalumab) followed with a doubling of five-year survival (19.6% vs 9.4%), and CheckMate 9DW's nivolumab plus ipilimumab reached a median OS of 23.7 months (approved 2025). Camrelizumab plus rivoceranib (CARES-310, OS 23.8 vs 15.2 months) is approved in China but has received three FDA complete response letters for manufacturing reasons, most recently in July 2026. Second-line options after sorafenib (regorafenib, cabozantinib, ramucirumab for AFP ≥400) lack data after immunotherapy, the setting most patients now reach.\n\nThe frontier is combining local and systemic therapy. Three phase 3 trials (EMERALD-1, LEAP-012, EMERALD-3) show that adding immunotherapy and anti-VEGF drugs to TACE prolongs progression-free survival by about 30%, but LEAP-012's final overall-survival hazard ratio of 0.98 shows PFS is a weak surrogate here, and adjuvant atezolizumab-bevacizumab (IMbrave050) lost its early benefit with follow-up. Open questions include the right therapy after first-line immunotherapy, the role of immunotherapy before transplantation, GPC3-directed cell therapy, and above all prevention: HBV vaccination and HCV cure could avert most cases, while MASLD-driven HCC in non-cirrhotic livers is rising and escapes surveillance.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Hepatocellular_carcinoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Hepatocellular_carcinoma"}],"tags":["gi","spike"],"related":[],"indications":[],"sections":[],"technologies":["radioembolisation-tare"],"targets":["gpc3","fap"],"drugs":[],"companies":["astrazeneca","bms","merck","bayer","eli-lilly","sirtex","boston-scientific"],"institutions":["mayo-clinic","mskcc"],"pathways":[],"terms":["dosimetry"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Roughly 900,000 liver cancer cases a year worldwide (GLOBOCAN), ~80% in Asia and Africa, and largely preventable: HBV vaccination and HCV cure have cut incidence in Taiwan, Japan and Egypt. Deaths are ~800,000 a year, and in the United States the death rate has risen faster than for any other cancer over the past two decades, driven by hepatitis C and fatty liver disease.","subtypes":["Viral (HBV, HCV) HCC","Alcohol-related HCC","MASLD/MASH-related HCC (often non-cirrhotic)","Fibrolamellar carcinoma (young adults, DNAJB1-PRKACA fusion)","Combined hepatocellular-cholangiocarcinoma","BCLC stages 0/A, B, C, D"],"biomarkers":["AFP","GPC3 (trials)","Child-Pugh / ALBI liver function","AFP (prognosis; ≥400 ng/mL for ramucirumab)","BCLC stage and performance status","Portal vein tumour thrombus","HBV/HCV status","AFP-L3 and DCP (GALAD score)"],"standardOfCare":[{"setting":"Early","approach":"Resection, ablation, transplant.","refs":[],"guideline":{"version":"NCCN Guidelines: Hepatocellular Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1514"}},{"setting":"Intermediate","approach":"TACE/TARE ± systemic therapy.","refs":["radioligand-therapy"],"guideline":{"version":"NCCN Guidelines: Hepatocellular Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1514"}},{"setting":"Advanced","approach":"Atezolizumab-bevacizumab, durvalumab-tremelimumab, or nivolumab-ipilimumab.","refs":["durvalumab"],"guideline":{"version":"NCCN Guidelines: Hepatocellular Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1514"}},{"setting":"Prevention","approach":"Universal HBV vaccination; antiviral suppression of HBV; direct-acting antiviral cure of HCV; alcohol and metabolic risk reduction.","refs":[],"guideline":{"nccn":"Hepatobiliary Cancers","version":"AASLD 2023 / EASL 2025"}},{"setting":"Surveillance","approach":"Six-monthly ultrasound ± AFP in cirrhosis and high-risk HBV carriers; abbreviated MRI where ultrasound is inadequate.","refs":[],"guideline":{"version":"AASLD 2023 Practice Guidance"}},{"setting":"Very early / early (BCLC 0-A)","approach":"Ablation (RFA/microwave) for ≤3 cm; resection for preserved liver function; transplantation within Milan or downstaged criteria; radiation segmentectomy as an alternative.","refs":["radioembolisation-tare"],"guideline":{"nccn":"Category 1 for resection/ablation/transplant"}},{"setting":"Intermediate (BCLC B)","approach":"TACE (conventional or DEB-TACE) or TARE; systemic therapy for high tumour burden or TACE-refractory disease; TACE + durvalumab-bevacizumab or STRIDE + lenvatinib prolong PFS (OS unproven).","refs":["radioembolisation-tare"],"guideline":{"nccn":"TACE category 1; combinations not yet standard"}},{"setting":"Advanced (BCLC C), first line","approach":"Atezolizumab + bevacizumab (IMbrave150), STRIDE tremelimumab + durvalumab (HIMALAYA), or nivolumab + ipilimumab (CheckMate 9DW); lenvatinib or sorafenib if immunotherapy is contraindicated (transplant, active autoimmune disease).","refs":["durvalumab","sorafenib"],"guideline":{"nccn":"Category 1 (preferred) for all three IO regimens","esmoMcbs":"IMbrave150 grade 5"}},{"setting":"Advanced, second line and beyond","approach":"After immunotherapy: lenvatinib, sorafenib, cabozantinib or regorafenib by extrapolation (no dedicated phase 3); ramucirumab if AFP ≥400 ng/mL; clinical trials.","refs":["cabozantinib"],"guideline":{"nccn":"Category 2A after IO"}},{"setting":"Adjuvant after resection/ablation","approach":"No approved adjuvant therapy; IMbrave050 benefit not sustained. Surveillance imaging every 3-6 months.","refs":[]},{"setting":"Portal vein tumour thrombosis","approach":"Systemic immunotherapy; Y-90 radioembolisation where TACE is contraindicated; radiotherapy to the thrombus in selected patients.","refs":["radioembolisation-tare"]}],"stateOfArt":["IO doublets first line.","GPC3 CAR-T and bispecifics emerging.","Three first-line immunotherapy regimens with overall-survival benefit over sorafenib; median OS approaching two years and five-year survival of one in five with STRIDE.","Choice of regimen is driven by bleeding risk (varices), autoimmune disease and transplant candidacy rather than a predictive biomarker.","Radioembolisation and radiation segmentectomy offer curative-intent options for small tumours and for portal vein thrombosis.","TACE plus systemic therapy prolongs PFS in intermediate-stage disease in three phase 3 trials, but overall survival is unproven (LEAP-012 OS HR 0.98).","Prevention works: HBV vaccination and HCV antivirals have cut incidence in Taiwan, Japan and Egypt; MASLD is the rising cause.","Living-donor transplantation and downstaging widen the pool of curable patients, led by Asian high-volume centres."],"history":[{"year":1941,"title":"Hepatocellular carcinoma linked to cirrhosis in large autopsy series","note":"Establishes the disease-in-a-diseased-organ paradigm.","refs":[]},{"year":1964,"title":"Hepatitis B surface antigen discovered (Blumberg)","note":"Nobel Prize 1976; leads to the vaccine.","refs":[]},{"year":1984,"title":"Taiwan begins universal HBV vaccination","note":"Childhood HCC incidence later falls ~70%.","refs":[]},{"year":1996,"title":"Milan criteria for liver transplantation","note":"Mazzaferro: ~70% five-year survival for small tumours.","refs":[]},{"year":1999,"title":"BCLC staging system published","refs":[]},{"year":2002,"title":"TACE proven to prolong survival (Llovet, Lo)","refs":[]},{"year":2007,"title":"Sorafenib: first systemic therapy","refs":[]},{"year":2007,"title":"SHARP: sorafenib, the first systemic therapy","refs":["sorafenib"]},{"year":2014,"title":"Direct-acting antivirals cure hepatitis C","note":"HCC risk falls ~70% after cure.","refs":[]},{"year":2017,"title":"RESORCE: regorafenib, first second-line benefit; SARAH/SIRveNIB negative for Y-90 vs sorafenib","refs":["sarah-sirvenib"]},{"year":2018,"title":"REFLECT: lenvatinib non-inferior first line; CELESTIAL: cabozantinib second line","refs":[]},{"year":2020,"title":"IMbrave150: atezolizumab-bevacizumab","refs":[]},{"year":2020,"title":"IMbrave150: atezolizumab + bevacizumab beats sorafenib","note":"First regimen to improve OS over sorafenib; new standard.","refs":[]},{"year":2022,"title":"HIMALAYA: STRIDE approved; BCLC update adds systemic therapy for some BCLC-B","refs":[]},{"year":2024,"title":"EMERALD-1 and LEAP-012: TACE + systemic therapy improves PFS; HIMALAYA 5-year OS 19.6%","refs":[]},{"year":2025,"title":"CheckMate 9DW approval (nivolumab + ipilimumab); second FDA CRL for camrelizumab-rivoceranib","refs":[]},{"year":2026,"title":"EMERALD-3 positive for PFS; LEAP-012 final OS HR 0.98; IMbrave050 update negative; third camrelizumab-rivoceranib CRL (23 July)","refs":[]}],"pipeline":["fapi-pet","radioembolisation-tare","gpc3","cabozantinib"],"openProblems":["Liver function limits therapy.","Surveillance uptake in cirrhosis is poor.","No predictive biomarker chooses among the three first-line immunotherapy regimens; PD-L1, TMB and viral aetiology are weak.","Second-line therapy after immunotherapy failure is extrapolated from the sorafenib era; no dedicated phase 3 has read out.","TACE combinations prolong PFS but not (yet) OS; sequencing local and systemic therapy is unresolved.","Adjuvant therapy after curative resection remains unproven; recurrence is ~70% at five years.","Surveillance uptake is below 25% and ultrasound misses early tumours in obese, steatotic livers; MASLD-HCC often arises without cirrhosis.","Immunotherapy in transplant candidates risks rejection; safe washout intervals are undefined.","Child-Pugh B patients are excluded from almost every trial yet make up a large share of real-world patients.","Global inequity: most cases occur in Asia and Africa, where HBV vaccination, HCV treatment and systemic therapy access are uneven."]},"route":"/indications/hcc/","neighbours":{"technology":[{"id":"fapi-pet","kind":"technology","name":"FAPI PET","route":"/technologies/fapi-pet/"},{"id":"quantitative-imaging-biomarkers","kind":"technology","name":"Quantitative imaging biomarkers (RECIST, PERCIST, SUV, ADC)","route":"/technologies/quantitative-imaging-biomarkers/"},{"id":"radioembolisation-tare","kind":"technology","name":"Radioembolisation (TARE / SIRT, yttrium-90)","route":"/technologies/radioembolisation-tare/"},{"id":"radioligand-therapy","kind":"technology","name":"Radioligand therapy (beta emitters)","route":"/technologies/radioligand-therapy/"}],"target":[{"id":"fap","kind":"target","name":"FAP","route":"/targets/fap/"},{"id":"gpc3","kind":"target","name":"Glypican-3","route":"/targets/gpc3/"}],"company":[{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/"},{"id":"bayer","kind":"company","name":"Bayer","route":"/companies/bayer/"},{"id":"boston-scientific","kind":"company","name":"Boston Scientific","route":"/companies/boston-scientific/"},{"id":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/"},{"id":"eli-lilly","kind":"company","name":"Eli Lilly (incl. Loxo)","route":"/companies/eli-lilly/"},{"id":"merck","kind":"company","name":"Merck & Co. (MSD)","route":"/companies/merck/"},{"id":"quirem-medical","kind":"company","name":"Quirem Medical","route":"/companies/quirem-medical/"},{"id":"sirtex","kind":"company","name":"Sirtex Medical","route":"/companies/sirtex/"}],"institution":[{"id":"pla-general-hospital","kind":"institution","name":"Chinese PLA General Hospital","route":"/institutions/pla-general-hospital/"},{"id":"mayo-clinic","kind":"institution","name":"Mayo Clinic","route":"/institutions/mayo-clinic/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"},{"id":"qst-hospital","kind":"institution","name":"QST Hospital (National Institutes for Quantum Science and Technology)","route":"/institutions/qst-hospital/"},{"id":"uk-duesseldorf","kind":"institution","name":"University Hospital Düsseldorf / CIO Düsseldorf","route":"/institutions/uk-duesseldorf/"}],"term":[{"id":"dosimetry","kind":"term","name":"Dosimetry","route":"/terms/dosimetry/"},{"id":"tare","kind":"term","name":"TARE / SIRT (radioembolisation with yttrium-90)","route":"/terms/tare/"}],"drug":[{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"donafenib","kind":"drug","name":"Donafenib","route":"/drugs/donafenib/"},{"id":"durvalumab","kind":"drug","name":"Durvalumab","route":"/drugs/durvalumab/"},{"id":"ho-166-microspheres","kind":"drug","name":"Holmium-166 microspheres","route":"/drugs/ho-166-microspheres/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"sorafenib","kind":"drug","name":"Sorafenib","route":"/drugs/sorafenib/"},{"id":"y-90-glass-microspheres","kind":"drug","name":"Yttrium-90 glass microspheres","route":"/drugs/y-90-glass-microspheres/"},{"id":"y-90-resin-microspheres","kind":"drug","name":"Yttrium-90 resin microspheres","route":"/drugs/y-90-resin-microspheres/"}],"trial":[{"id":"nct06040099","kind":"trial","name":"A US Study to Evaluate Transarterial Radioembolization (TARE) in Combination With Durvalumab and Bevacizumab Therapy in People With Unresectable Hepat","route":"/trials/nct06040099/"},{"id":"sarah-sirvenib","kind":"trial","name":"SARAH and SIRveNIB","route":"/trials/sarah-sirvenib/"},{"id":"nct06726161","kind":"trial","name":"Study of the Theranostic Pair RYZ811 (Diagnostic) and RYZ801 (Therapeutic) to Identify and Treat Subjects With GPC3+ (Glypican-3) Unresectable HCC","route":"/trials/nct06726161/"},{"id":"nct05063565","kind":"trial","name":"TheraSphere With Durvalumab and Tremelimumab for HCC","route":"/trials/nct05063565/"}],"indication":[{"id":"hcc-intermediate","kind":"indication","name":"Intermediate hepatocellular carcinoma (BCLC B)","route":"/indications/hcc-intermediate/"}],"opportunity":[{"id":"opp-gpc3-hcc-china","kind":"opportunity","name":"GPC3 imaging of the indeterminate liver nodule, led from China","route":"/opportunities/opp-gpc3-hcc-china/"}],"section":[{"id":"f-dosimetry","kind":"section","name":"Dosimetry","route":"/fronts/f-dosimetry/"},{"id":"f-radioembolisation","kind":"section","name":"Radioembolisation","route":"/fronts/f-radioembolisation/"}],"isotope":[{"id":"ho-166","kind":"isotope","name":"Holmium-166","route":"/isotopes/ho-166/"},{"id":"re-188","kind":"isotope","name":"Rhenium-188","route":"/isotopes/re-188/"},{"id":"y-90","kind":"isotope","name":"Yttrium-90","route":"/isotopes/y-90/"}],"pairing":[{"id":"tare-vs-sorafenib-caution","kind":"pairing","name":"Radioembolisation (TARE) compared with sorafenib in hepatocellular carcinoma","route":"/pairings/tare-vs-sorafenib-caution/"},{"id":"tare-plus-durvalumab-hcc","kind":"pairing","name":"Radioembolisation (TARE) with durvalumab in hepatocellular carcinoma","route":"/pairings/tare-plus-durvalumab-hcc/"}]}}