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

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 within 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.