Revisiting resectability of biliary tract cancers, in the triplet drug therapy era with immune checkpoint inhibitors.

Biliary tract cancers (BTCs) include intrahepatic, perihilar, distal cholangiocarcinoma, gallbladder cancer, and sometimes papillary Vater cancer. The incidence of BTCs varies worldwide (0.3-85.0/100,000 population). In Japan, the incidence is lowest, but it is increasing (22,000 cases/ year). The 5-year overall survival (OS) in patients with localized BTC is approximately 60%, which is better than that in liver or pancreatic cancer, but is < 5% in patients with metastatic cancers. Surgery requires liver and pancreas surgery with vascular reconstruction, and is associated with a high perioperative mortality rate (> 2%) relative to other cancer surgeries (< 1%). As an adjuvant therapy, fluorouracil prodrugs are effective for improving OS (hazard ratio [HR] 0.69-0.81); however, in patients who receive major hepatectomy, the completion rate is reportedly low (60%). Since 2010, gemcitabine + cisplatin (GC) has become the first-line therapy for unresectable lesions. Subsequently, in 2023-2024 three triplet regimens were reported: GC + S-1(tegafur-gimeracil-oteracil), GC + durvalumab (an anti-PD-L1 antibody), and GC + pembrolizumab (an anti-PD-1 antibody). HRs for OS were 0.79-0.83, objective response rates were 27-42% (GC, 15-29%), and tumor control rates were 75-85% (GC, 62-83%) with small increases in adverse events. In this review, considering the eligibility criteria of currently ongoing neoadjuvant studies, we report two borderline resectable cases with a discussion on resectability. Owing to the high-risk nature of the surgery and to avoid early recurrence due to subclinical metastasis during postoperative recovery, these three triplet regimens for unresectable tumors may change the concept of resectability in BTC.