A Retrospective Analysis of Oxaliplatin, Irinotecan and PK-Adjusted 5-Fluorouracil Within a Neoadjuvant Multidisciplinary Approach in Locally Advanced Pancreatic Cancer (LAPC) Patients

Abstract

Introduction: Neoadjuvant therapy is an increasingly used approach in LAPC patients ( pts) but the optimal sequence remains to be defined. The aim of this study was to evaluate the feasibility and efficacy of induction chemotherapy (ICT) with pharmacokinetic (PK) monitoring, chemo-radiotherapy (CRT) and surgery. Methods: Borderline resectable and unresectable LAPC pts with EUS stages T3-4/N+ were included. Patients were scheduled to receive 4 cycles of Oxaliplatin (85mg/m2), Leucovorin (400mg/m2), Irinotecan (150mg/m2) and 5-FU (initial dose of 3200mg/m2 in 46h and subsequent doses based on PK-guided dose adjustments to reach a target range for 5 FU of 25-30 mg.h.L-1). After ICT, pts with no progressive disease received CRT (mean radiation dose of 50.4 Gy with daily concurrent Capecitabine and weekly Oxaliplatin). Surgery was planned 4 to 6 weeks after the completion of CRT. Pathological response was graded according to the CAP classification. Toxicity was recorded according to the NCI-CTCAE 4.0. Results: From November 2011 to December 2013, 17 LAPC treatment-naïve pts [M/F: 14/3, median age: 63, T4: 23.5%, N + : 53%; borderline resectable (9 pts), unresectable due to celiac abutment (2 pts), SMA and celiac encasement (1 pt), unreconstructable SMV and portal occlusion (5 pts)] were enrolled. Up to 35% of the pts required a 5-FU dose increase to achieve target levels. Grade 3-4 ICT-related toxicities were neutropenia (9 pts) and diarrhea (2 pts). Grade 3 CRT-related toxicity included neutropenia (2 pts), thrombocytopenia (2 pts), diarrhea (1 pt), anorexia (1 pt) and mucositis (1 pt); three pts required hospital admission. CRT had to be stopped in 1 pt due to cholangitis. No progressive disease was observed during preoperative treatment. Fourteen pts (82.3%) have completed the whole neoadjuvant program (three pts are still ongoing). Eleven pts proceeded to surgery with an R0 resection rate of 91%, whereas unresectability criteria remained in the other three pts. Pathological response according to CAP classification was 0 (no viable cells) and 1 (small groups of cancer cells), on an intent to treat analysis in 18.2% and 45.5% of pts respectively; ypN0 rate was 63.6%. After a median follow-up of 16 months, the 12-month actuarial PFS and OS were 83% and 90%, respectively. Conclusion: Incorporation of PK-guided dose adjustment of 5-FU with in the FOLFOXIRI schedule is feasible and provides an acceptable toxicity profile and preliminary evidence of antitumor activity. A longer follow-up is required to rule out whether 5-FU PK adjustment may contribute to a better therapeutic index in LAPC patients.