Propensity score–weighted analysis of neoadjuvant therapy versus upfront surgical resection in patients with biliary tract cancers

<h2>Abstract</h2><h3>Background</h3> Bile tract cancer (BTC) is a heterogeneous and aggressive malignancy with a poor prognosis. Surgical resection is the main potentially curative treatment, but only about 20–30 % of patients present with resectable disease. The benefit of neoadjuvant chemotherapy (NAC) in BTC remains controversial. We explored outcomes of patients with BTCs receiving NAC compared to those who underwent upfront surgical resection using a propensity score weighting approach. <h3>Methods</h3> We identified patients who underwent surgical resection for stage I-III BTC between 2019 and 2023 and were evaluated at the Johns Hopkins Liver Multidisciplinary Cancer Clinic (Liver MDC). Propensity score weighting (PSW) was used to balance groups. Groups were assessed for differences in pathological response, recurrence-free survival (RFS), and overall survival (OS). Hazard ratios (HRs) were estimated using the PSW Cox proportional hazard regression model. <h3>Results</h3> Among 56 BTC patients that fit the inclusion criteria, 34 underwent upfront surgery, and 22 received NAC. Patients receiving NAC were more likely to have higher risk disease compared to patients receiving upfront resection (77.3 % vs 23.5 %, p < 0.001), including tumor size greater than 5 cm (45.5 % vs 11.8 %, p = 0.0221), lymph node involvement on staging imaging (50.0 % vs 23.5 %, p = 0.0495), and a trend towards higher mean CA19–9 at diagnosis (258.7 vs 87.7 U/mL, p = 0.179). In the univariate analysis, the NAC group showed a trend toward shorter RFS compared to the upfront surgery group (15.1 months; 95 % CI 10.3-not available (NA) versus 23.5 months; 95 % CI 15.5-NA, HR= 2.24; 95 % CI: 0.88–5.69, p = 0.082). No significant differences were seen for OS (36.5 months; 95 % CI 26.5-NA versus 48.2 months; 95 % CI 44.5-NA, HR=1.53; 95 % CI: 0.51–4.64–5.69, p = 0.448). Following PSW multivariable Cox analyses, receipt of NAC was associated with a trend toward reduced risk of recurrence (HR 0.83; 95 % CI 0.24–2.87 p = 0.7651) and death (HR 0.66; 95 % CI 0.2–2.16 p = 0.4890), although no statistically significant differences were observed. <h3>Conclusion</h3> These findings suggest that NAC may provide benefit for patients with higher-risk BTCs, achieving outcomes comparable to upfront surgical resection. The similar pathological results between the two groups further support the potential efficacy of neoadjuvant approaches. However, prospective trials are essential to definitively establish the optimal sequencing of chemotherapy and surgery in this patient population.