Neoadjuvant Chemotherapy in Resectable Biliary Tract Cancer: A Systematic Review and Metanalysis
Pereira, R. A., Barcellos, G., Lenz, G., Pereira, A. A. L., & Biachi de Castria, T. (2025). Neoadjuvant Chemotherapy in Resectable Biliary Tract Cancer: A Systematic Review and Metanalysis. Journal of surgical oncology, 10.1002/jso.70169. Advance online publication. https://doi.org/10.1002/jso.70169IF: 1.9 Q2
Neoadjuvant Chemotherapy in Resectable Biliary Tract Cancer: A Synthesis of Findings
Executive Summary
This briefing document synthesizes the findings of a comprehensive systematic review and meta-analysis on the use of neoadjuvant chemotherapy for resectable biliary tract cancer (BTC). The analysis, encompassing 23 studies and 11,344 patients, compared outcomes between patients receiving neoadjuvant chemotherapy followed by surgery and those undergoing upfront surgery. The primary conclusion is that neoadjuvant chemotherapy is associated with a significant improvement in overall survival, corresponding to a 31% relative reduction in the risk of death. Furthermore, this preoperative approach does not increase the risk of major postoperative complications and is linked to a significantly lower rate of 30-day postoperative mortality. While the analysis showed a positive trend toward achieving higher rates of complete tumor removal (R0 resection), this finding did not reach statistical significance. The evidence strongly suggests that neoadjuvant chemotherapy is a beneficial treatment strategy that can improve survival and surgical outcomes for select patients with resectable BTC.
1. Background and Context
Biliary tract cancers (BTC)—a group of aggressive malignancies including gallbladder cancer (GBC), extrahepatic cholangiocarcinoma (ECC), and intrahepatic cholangiocarcinoma (ICC)—are characterized by a poor prognosis. Surgical resection is the only potentially curative treatment, with the current standard of care often involving adjuvant chemotherapy with capecitabine following surgery. However, a significant number of patients are unable to complete this adjuvant therapy due to postoperative complications, performance status decline, or early disease recurrence.
Neoadjuvant chemotherapy, administered before surgery, has emerged as a promising strategy to improve outcomes. Its potential benefits include:
Early treatment of micrometastatic disease.
Tumor downstaging to improve resectability.
Better selection of patients who are most likely to benefit from surgery.
Increased rates of margin-negative (R0) resections.
Despite these theoretical advantages, the role of neoadjuvant therapy in resectable BTC remains controversial, and current clinical guidelines are cautious about its routine use due to a lack of high-quality prospective data.
2. Study Overview: A Systematic Review and Meta-Analysis
The source of this briefing is a systematic review and meta-analysis by Pereira et al., published in the Journal of Surgical Oncology in 2025. The study was conducted to clarify the impact of neoadjuvant chemotherapy on key clinical outcomes in patients with resectable BTC.
Scope: The analysis included 23 studies, comprising one randomized controlled trial (the GAIN trial) and 22 observational studies, for a total of 11,344 patients.
Population: Adult patients with non-metastatic, resectable (Stage I–III/IVa) biliary tract cancers.
Intervention: Neoadjuvant systemic chemotherapy followed by curative-intent surgery.
Comparator: Upfront surgery, with or without adjuvant chemotherapy.
Primary Outcome: Overall Survival (OS).
Secondary Outcomes: Recurrence-free survival (RFS), R0 resection rate, postoperative complications, and short-term mortality.
3. Key Findings on Clinical Outcomes
The meta-analysis produced several critical findings regarding the efficacy and safety of neoadjuvant chemotherapy in this patient population.
Summary of Main Outcomes
Detailed Outcome Analysis
Overall Survival (OS)
The most significant finding was a clear survival advantage for patients receiving neoadjuvant chemotherapy. The pooled analysis showed a Hazard Ratio (HR) of 0.69, indicating a 31% relative reduction in the risk of death compared to the upfront surgery group.
This survival benefit was consistent in subgroup analyses for specific cancer types:
Intrahepatic Cholangiocarcinoma (iCCA): HR = 0.65 (p = 0.0002)
Gallbladder Cancer (GBC): HR = 0.59 (p = 0.0003)
Surgical and Safety Outcomes
R0 Resection Rate: There was a positive trend toward higher rates of complete tumor removal (margin-negative resection) in the neoadjuvant group (OR = 1.30), though this result did not reach statistical significance (p=0.07). This suggests neoadjuvant therapy may aid in achieving better surgical clearance.
Postoperative Safety: The preoperative treatment did not increase surgical risk.
There was no statistically significant difference in the rate of major postoperative complications.
Notably, the neoadjuvant approach was associated with a significantly lower risk of 30-day postoperative mortality (OR = 0.52).
Treatment Course and Recurrence
Recurrence-Free Survival (RFS): Based on the three studies that reported this outcome, there was no significant difference in RFS between the two groups. The authors note that the impact on RFS remains uncertain with currently available data.
Adjuvant Therapy Completion: Patients who received neoadjuvant chemotherapy were significantly more likely to complete their planned course of adjuvant therapy after surgery. This suggests that administering systemic therapy preoperatively may better preserve a patient's fitness for completing a full multi-modal treatment plan.
4. Methodological Considerations and Limitations
The authors acknowledge several limitations that provide context for interpreting the results:
Study Quality: The analysis was dominated by retrospective observational studies (22 of 23), which inherently carry a risk of selection bias and residual confounding. The single included randomized controlled trial (GAIN) was assessed as having a low risk of bias.
Risk of Bias: Using the ROBINS-I tool, 17 of the 22 non-randomized studies were judged to have a "serious" overall risk of bias, primarily due to potential confounding factors in how patients were selected for neoadjuvant treatment versus upfront surgery.
Heterogeneity: Biliary tract cancers are biologically distinct entities. The analysis noted significant statistical heterogeneity for certain outcomes (e.g., R0 resection rate), reflecting variability in cancer subtypes, chemotherapy regimens, and patient populations across the included studies. The authors emphasize the need for disease-specific trials rather than a "one-size-fits-all" approach.
Publication Bias: Visual inspection of funnel plots suggested a moderate potential for publication bias or small-study effects, where smaller studies with more favorable results may be more likely to be published.
5. Conclusions and Implications
This systematic review and meta-analysis provides compelling evidence that neoadjuvant chemotherapy is associated with a significant overall survival benefit for patients with resectable biliary tract cancer, without increasing the risk of major surgical complications. The findings support the use of neoadjuvant chemotherapy as a viable and potentially superior treatment strategy for select patients, particularly those with high-risk features or marginally resectable disease.
The results strongly advocate for a shift in the treatment paradigm and should guide the planning of future prospective randomized trials. Such trials are needed to definitively confirm these findings, identify the patient subgroups most likely to benefit, and establish optimal chemotherapy regimens.
