Is early-stage pancreatic adenocarcinoma truly early: stage migration on final pathology with surgery-first vs. neoadjuvant therapy sequencing

Abstract

Introduction: Neoadjuvant therapy (NT) remains controversial in early-stage pancreatic ductal adenocarcinoma (PDAC), defined as clinical (c) Stage I-II. Our aim was to analyze rates of pathologic upstaging/downstaging for resectable PDAC treated with surgery-first (SF) vs. NT. Methods: Utilizing the National Cancer Data Base (NCDB), patients with cStage I–II PDAC who underwent pancreaticoduodenectomy in 2006–2013 were pathologically staged using the AJCC 8th edition and compared by treatment sequencing. Results: Among 13,871 patients, 15.3% received NT. Despite higher pre-treatment T-stage (cT2: 71.9% vs. 56.3%, p < 0.001), NT patients had lower rates of pathologic nodal metastases (46.2% vs. 69.2% in SF, p < 0.001), suggesting higher rates of pathologic downstaging. For cStage II treated with NT, 40.1% were downstaged to pathologic Stage I. When cStage II underwent SF, only 18.3% were downstaged to pathologic Stage I. In cStage II, 31.8% were upstaged to stage III after SF, vs. only 12.8% after NT. In cStage I, 65.3% were upstaged following SF, vs. 46.0% after NT (all p < 0.001). On multivariate analysis, preoperative CA19-9 > 37 U/ml (OR-1.34), and more nodes examined (OR-8.86) were associated with increased upstaging, whereas NT was associated with decreased upstaging (OR-0.18, all p < 0.001). Using Cox regression, patients with NT (HR-0.77, p < 0.001) or downstaging (HR-0.80, p < 0.001) had improved OS. Conclusions: NT is associated with reduction in unexpected upstaging, reduction in nodal positivity, and improved survival, compared to SF approach in early-stage PDAC. Because clinical staging underestimates the underlying disease burden in resectable PDAC, patients with cStage I-II should be considered for NT.