Phase II randomized multicenter trial | Alliance Cooperative Group | n = 126 | BR-PDAC | JAMA Oncology 2022 **Katz et al.** Matthew H. G. Katz Published in JAMA Oncology, 2022 Enrollment: 2016–2018 [PubMed Link](https://pubmed.ncbi.nlm.nih.gov/35834226/) --- ### Essential Takeaway ALLIANCE A021501 demonstrated that neoadjuvant mFOLFIRINOX alone produced favorable outcomes in borderline resectable PDAC, while routine addition of hypofractionated radiation did not improve survival or surgical outcomes. The trial reinforced mFOLFIRINOX as a modern neoadjuvant backbone and accelerated movement toward selective rather than routine RT in BR-PDAC. --- ### Clinical Question In borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC), does adding hypofractionated radiation after neoadjuvant mFOLFIRINOX improve outcomes compared with chemotherapy alone? --- ### Population - Borderline resectable PDAC - Borderline criteria based on Alliance consensus vascular involvement definitions - No metastatic disease - Adequate performance status for multi-agent chemotherapy --- ### Study Design #### Arm 1 — Chemotherapy Alone - 8 cycles neoadjuvant mFOLFIRINOX - Restaging after cycle 4 - Surgery 4–8 weeks later - 4 cycles adjuvant FOLFOX #### Arm 2 — Chemotherapy + Radiation - 7 cycles neoadjuvant mFOLFIRINOX - Restaging after cycle 4 - Hypofractionated RT/SBRT - Surgery 4–8 weeks later - 4 cycles adjuvant FOLFOX --- ### Endpoints #### Primary Endpoint 18-month overall survival (OS) #### Secondary Endpoints - Event-free survival (EFS) - R0 resection rate - Pathologic complete response (pCR) - Toxicity/adverse events #### EFS Definition Time from randomization to: - disease progression - R2 resection - recurrence after surgery - death --- ### Key Results #### Major Finding The radiation arm failed to improve outcomes and was closed early for futility. --- ### Overall Survival - mFOLFIRINOX alone met the predefined survival threshold - Addition of RT did not improve survival --- ### Resection Outcomes - Higher proportion of patients ultimately underwent surgery in the chemotherapy-alone arm - High R0 resection rates observed with systemic therapy alone --- ### Additional Findings #### Strong Outcomes with Modern Systemic Therapy The chemotherapy-alone arm demonstrated: - favorable survival - high rates of successful resection - encouraging R0 resection outcomes These findings reinforced systemic therapy as the dominant therapeutic component in BR-PDAC. #### Selective Rather Than Routine RT The trial did not prove RT has no role in pancreatic cancer. Instead, it challenged routine incorporation of radiation for all borderline resectable patients after induction chemotherapy. --- ### Interpretation ALLIANCE A021501 became one of the most influential modern neoadjuvant PDAC trials because it demonstrated that intensive systemic therapy alone can achieve strong outcomes in BR-PDAC without mandatory addition of radiation. The study accelerated movement toward: - mFOLFIRINOX-based neoadjuvant paradigms - selective rather than routine RT - systemic disease control as the primary therapeutic focus - biologic selection before surgery --- ### Important Limitations #### Phase II Design - Not definitive phase III evidence #### Small Sample Size - Relatively limited enrollment #### Radiation Heterogeneity - Multiple RT approaches permitted - SBRT and hypofractionated RT both allowed #### Does Not Exclude a Role for RT Selected patients may still benefit from RT, including: - persistent vascular involvement - local control concerns - pain symptoms - biologically favorable localized disease --- ### Practice Impact ALLIANCE A021501 reinforced neoadjuvant mFOLFIRINOX as a modern standard backbone for BR-PDAC and substantially reduced enthusiasm for routine addition of radiation after induction chemotherapy. The trial helped shift many centers toward: - chemotherapy-first strategies - selective RT use - biology-driven operative decision making - prioritization of systemic disease control before surgery