As of January 2023, the Food and Drug Administration (FDA) has approved nivolumab, pembrolizumab, ramucirumab, nivolumab/ipilimumab, atezolizumab/ bevacizumab, and tremelimumab/durvalumab as firstor second-line monoclonal antibodies (mAbs) for unresectable hepatocellular carcinoma (HCC) in the USA (1). In Japan, atezolizumab/bevacizumab was approved in 2020, and it became the regimen of choice for first-line treatment. Durvalumab/tremelimumab was approved as first-line treatment in 2023. In total, 6 or 7 regimens are available for HCC in Japan as of January 2024. The recent dramatic progress in systemic therapy for HCC provides the possibility of a combination of surgery and systemic therapy; i.e., adjuvant, neoadjuvant, or conversion settings.
Adjuvant systemic therapyThe first type of combination is the adjuvant setting: systemic therapy after liver resection. Tumor recurrence is known to be very common even after curative liver resection. The reported 5-yr recurrence rate was as high as 70 to 80% (2). There are two peaks for recurrence-free survival (RFS) hazard after liver resection. The first peak is recurrence because of residual micro metastases. The second peak may be because of so-called multi-centric carcinogenesis. Adjuvant therapy is targeted to lower the first wave of recurrence.There have been several trials on adjuvant therapy to solve this issue. Takayama's adaptive immunotherapy was probably one of the oldest and milestone studies which indicated the impact of adaptive immunotherapy as reported by the National Cancer Center Japan (3). They used autologous lymphocytes activated in vitro with recombinant interleukin-2 and antibodies against CD3. After culturing for two weeks, they obtained enough T cells with CD3, 4, and 8 markers. The primary endpoint was met, and this immunotherapy significantly reduced the risk of tumor recurrence after resection. However, this adjuvant therapy was not feasible in daily practice (P1)