Neoadjuvant therapy or upfront surgery for resectable and borderline resectable pancreatic cancer: A meta-analysis of randomised controlled trials
van Dam, J. L., Janssen, Q. P., Besselink, M. G., Homs, M. Y. V., van Santvoort, H. C., van Tienhoven, G., de Wilde, R. F., Wilmink, J. W., van Eijck, C. H. J., Groot Koerkamp, B., & Dutch Pancreatic Cancer Group (2022). Neoadjuvant therapy or upfront surgery for resectable and borderline resectable pancreatic cancer: A meta-analysis of randomised controlled trials. European journal of cancer (Oxford, England : 1990), 160, 140–149. https://doi.org/10.1016/j.ejca.2021.10.023
Executive Summary
This briefing document synthesizes the findings of a meta-analysis of seven randomized controlled trials (RCTs) involving 938 patients, comparing neoadjuvant therapy with upfront surgery for resectable and borderline resectable pancreatic cancer. The analysis demonstrates a significant overall survival benefit for patients receiving neoadjuvant therapy, increasing the median overall survival from 19 months to an estimated 29 months (Hazard Ratio [HR] 0.66).
The benefit is most pronounced and statistically confirmed for patients with borderline resectable pancreatic cancer (HR 0.61). For patients with resectable pancreatic cancer, the analysis did not find a statistically significant improvement in survival, indicating that more evidence is required for this subgroup.
Pathologically, neoadjuvant therapy was associated with significantly higher rates of microscopically complete (R0) resections and negative lymph node (N0) resections. There was no statistically significant difference in the overall resection rate or the frequency of major surgical complications between the two approaches. A critical limitation of this meta-analysis is that the included trials predominantly utilized older, gemcitabine-based chemotherapy regimens; none employed the current standard of care, adjuvant FOLFIRINOX. This context is essential when interpreting the findings and underscores the need for ongoing trials with modern therapeutic agents.
Introduction and Background
Pancreatic cancer is a highly lethal malignancy, ranking as the third leading cause of cancer-related death in the United States and the fourth in Europe, with a 5-year survival rate of just 10%. For non-metastatic disease, treatment strategy hinges on the tumor's classification as resectable, borderline resectable, or locally advanced, based on vascular involvement.
The standard treatment paradigms under investigation are:
Upfront Surgery: Involves surgical resection of the tumor followed by adjuvant (post-operative) chemotherapy. This is the standard of care for resectable pancreatic cancer.
Potential Benefits: Avoids the need for biliary stenting, eliminates the risk of clinical deterioration during chemotherapy, and prevents surgical delays for tumors that may not respond to neoadjuvant treatment.
Key Disadvantage: Population-based studies show that only about 50% of patients who undergo surgery successfully receive the intended adjuvant therapy due to poor post-operative recovery or early disease progression.
Neoadjuvant Therapy: Involves administering chemotherapy or chemoradiotherapy before surgery. This is recommended by NCCN guidelines for borderline resectable cancer but only in a clinical trial context by NICE guidelines.
Potential Benefits: Guarantees the early delivery of systemic chemotherapy, may increase the likelihood of a microscopically complete (R0) resection, and helps identify patients with rapidly progressive disease, thereby preventing futile surgery.
Methodology of the Meta-Analysis
This analysis synthesized data from high-quality studies to provide a robust comparison of the two treatment strategies.
Study Design: A systematic review and meta-analysis of seven randomized controlled trials (RCTs).
Patient Population: A total of 938 patients with resectable and/or borderline resectable pancreatic cancer were included (471 assigned to upfront surgery, 467 to neoadjuvant therapy).
Interventions: All included trials featured at least one gemcitabine-based neoadjuvant chemo(radio)therapy arm. Notably, none of the trials used adjuvant FOLFIRINOX or adjuvant gemcitabine plus nab-paclitaxel, which are more modern regimens.
Primary Outcome: Overall Survival (OS), analyzed by intention-to-treat.
Secondary Outcomes: Resection rate, R0 resection rate, N0 resection rate, and major surgical complications.
Evidence Assessment: The certainty of evidence was formally assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. The evidence for the primary outcome of Overall Survival was rated as high.
Core Findings: Overall Survival (OS)
Neoadjuvant therapy demonstrated a clear and statistically significant improvement in overall survival compared to upfront surgery across the combined patient population.
Subgroup Analysis by Resectability Status
The survival benefit was driven primarily by patients with borderline resectable disease.
Borderline Resectable Pancreatic Cancer: Neoadjuvant therapy was associated with superior OS (HR 0.61, 95% CI 0.44–0.85; P=0.004).
Resectable Pancreatic Cancer: No statistically significant difference in OS was observed between the two approaches (HR 0.77, 95% CI 0.53–1.12; P=0.18).
Subgroup Analysis by Treatment Type
Improved survival was observed with both neoadjuvant chemotherapy and chemoradiotherapy.
Neoadjuvant Chemotherapy: HR 0.54 (95% CI 0.34–0.87; P=0.01)
Neoadjuvant Chemoradiotherapy (CRT): HR 0.74 (95% CI 0.58–0.95; P=0.02)
Core Findings: Surgical and Pathological Outcomes
While neoadjuvant therapy did not increase the overall percentage of patients undergoing surgery, it significantly improved the quality and effectiveness of the resections that were performed.
Limitations and Contextual Considerations
The strengths of this meta-analysis include its large patient cohort, focus on high-quality RCTs, and use of intention-to-treat analysis. However, several limitations must be considered:
Outdated Regimens: The primary limitation is that the included trials used gemcitabine-based regimens. They were designed before the PRODIGE 24/CCTG PA.6 trial established FOLFIRINOX as a superior adjuvant therapy, which is now the standard of care in the upfront surgery arm of ongoing trials.
Heterogeneity of Trials: The studies varied in their specific neoadjuvant treatment protocols and their definitions for resectability, which complicates the pooling of data.
Trial Accrual Challenges: Four of the seven included RCTs were terminated early due to slow patient accrual or because regimens became outdated, highlighting the inherent difficulty in conducting such research.
Data Availability: Two of the seven included trials were only available as conference abstracts at the time of the meta-analysis publication.
Conclusions and Future Directions
This meta-analysis provides high-quality evidence that neoadjuvant therapy improves overall survival compared to upfront surgery in patients with borderline resectable pancreatic cancer. The results also show that neoadjuvant therapy leads to higher rates of complete (R0) and lymph node-negative (N0) resections without increasing surgical complications.
Uncertainty remains regarding the benefit of neoadjuvant therapy for patients with resectable pancreatic cancer, for whom a survival advantage was not statistically demonstrated.
Future research, including several ongoing RCTs, should address the following critical questions:
Is the neoadjuvant approach also superior for patients with clearly resectable pancreatic cancer when compared against modern adjuvant therapies like FOLFIRINOX?
In the neoadjuvant setting, is a FOLFIRINOX-based regimen superior to the gemcitabine-based treatments analyzed in these trials?
Does adding (chemo)radiotherapy after neoadjuvant chemotherapy further improve survival outcomes?
