Total Neoadjuvant Therapy Versus Standard Neoadjuvant Chemoradiotherapy for Borderline Resectable Pancreatic Cancer:...

The optimal neoadjuvant strategy for borderline resectable pancreatic cancer (BRPC) remains uncertain. Total neoadjuvant therapy (TNT) combines extended induction chemotherapy with radiotherapy before surgery. Whether TNT improves oncologic outcomes over standard neoadjuvant chemoradiotherapy (NACRT) is unclear; the incremental benefit of the radiotherapy component itself has also been questioned. A systematic search of PubMed, Embase, Cochrane CENTRAL, Web of Science and Scopus identified comparative studies of TNT vs standard NACRT in BRPC published between January 2005 and May 2026. Randomized controlled trials and observational comparative studies were included. Random-effects meta-analysis using the DerSimonian-Laird method was performed. Primary outcomes were overall survival and R0 resection rate. Secondary objectives assessed the independent survival benefit of radiotherapy and the influence of chemotherapy backbone selection. Twenty-three studies met inclusion criteria for qualitative synthesis. Nineteen primary studies comprising 9,219 patients contributed to data extraction. TNT was associated with superior R0 resection rates (94%-95% vs. 78%-80%) and higher pathological complete response (pCR) rates (5.8%-13.0% vs. 2.1%-6.0%) compared to standard NACRT. TNT was associated with improved overall survival in the largest available database analysis (hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.72-0.94), though a smaller cohort showed no difference. The radiotherapy component did not confer an independent survival benefit when added to systemic chemotherapy (PREOPANC-2 BRPC subgroup HR 0.80, 95% CI 0.53-1.21, P = 0.30). PAXG demonstrated superior event-free survival over mFOLFIRINOX (HR, 0.63; P = 0.0018). Grade 3 to 4 adverse events were frequent (60%-67%), but surgical morbidity was comparable across treatment arms. Findings suggest that TNT improves pathologic response and margin-negative resection rates compared to standard NACRT in BRPC. There appears to be modest improvement in survival but is not uniformly reproduced. The survival advantage appears driven primarily by extended systemic chemotherapy rather than the radiotherapy component. The choice of chemotherapy backbone significantly influences event-free survival.