Teaching pack: Hepatocellular carcinoma

Hepatocellular carcinoma is the dominant primary liver cancer (~75-85%) and the third leading cause of cancer death worldwide. 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.

Systemic 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.

• 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).

1. 1941Hepatocellular carcinoma linked to cirrhosis in large autopsy series
2. 1964Hepatitis B surface antigen discovered (Blumberg)
3. 1984Taiwan begins universal HBV vaccination
4. 1996Milan criteria for liver transplantation
5. 1999BCLC staging system published
6. 2002TACE proven to prolong survival (Llovet, Lo)
7. 2007Sorafenib: first systemic therapy
8. 2007SHARP: sorafenib, the first systemic therapy
9. 2014Direct-acting antivirals cure hepatitis C
10. 2017RESORCE: regorafenib, first second-line benefit; SARAH/SIRveNIB negative for Y-90 vs sorafenib

• FAPI PET (technology)
• Camrelizumab + rivoceranib (product)
• EMERALD-3 (trial)
• TACE + immunotherapy/anti-VEGF (pairing)
• Radioembolisation (TARE / SIRT, yttrium-90) (technology)
• Glypican-3 (target)
• CAR-T cell therapy (technology)
• Immunotherapy downstaging to transplant with a safe washout (idea)
• Blood-based HCC surveillance to replace six-monthly ultrasound (idea)
• HCC surveillance in cirrhosis (ultrasound + AFP) (technology)
• Multi-cancer early detection (MCED) (technology)
• Cabozantinib (product)

• HIMALAYA (phase 3, n=1,171): Overall survival: 16.4 months vs 13.8 months, HR 0.78
• SHARP (phase 3, n=602): Overall survival: 10.7 months vs 7.9 months, HR 0.69
• IMbrave150 (phase 3, n=501): Overall survival (updated): 19.2 months vs 13.4 months, HR 0.66
• REFLECT (phase 3, n=954): Overall survival: 13.6 months vs 12.3 months, HR 0.92
• CELESTIAL (phase 3, n=707): Overall survival: 10.2 months vs 8 months, HR 0.76
• CheckMate 9DW (phase 3, n=668): Overall survival: 23.7 months vs 20.6 months, HR 0.79

• 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.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. Which drug beat pembrolizumab head to head on progression-free survival in lung cancer?
   Answer

   Ivonescimab, a PD-1×VEGF bispecific (Akeso/Summit): PFS 11.1 vs 5.8 months in PD-L1-positive first-line NSCLC (HARMONi-2, China).
3. What was the first cancer drug approved on the basis of a blood test for leftover disease?
   Answer

   Atezolizumab for ctDNA-positive muscle-invasive bladder cancer after cystectomy (IMvigor011, using Signatera), approved Q2 2026; DFS HR 0.64, OS HR 0.59.
4. What fraction of advanced melanoma patients on nivolumab plus ipilimumab are alive at ten years?
   Answer

   About 43% overall survival (CheckMate 067), with melanoma-specific survival around 52%.
5. What is CAR-T and which cancers is it approved for?
   Answer

   A patient's T cells are engineered with a synthetic receptor, multiplied, and returned. Approved CD19 products treat B-cell lymphomas and leukaemias; BCMA products treat multiple myeloma; the first solid-tumour approval (Claudin 18.2, gastric) is in China.
6. What were the first checkpoint inhibitor and the first ADC ever approved?
   Answer

   Ipilimumab (2011) was the first checkpoint inhibitor; gemtuzumab ozogamicin (Mylotarg, 2000) was the first ADC, withdrawn in 2010 and re-approved in 2017.

• Wikipedia: https://en.wikipedia.org/wiki/Hepatocellular_carcinoma
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1514