Randomized multicenter phase II/III study with adjuvant gemcitabine versus neoadjuvant/adjuvant FOLFIRINOX in resectable pancreatic cancer: The NEPAFOX trial.
Authors: Al-Batran Salah-Eddin , Reichart Alexander , Bankstahl Ulli Simone , Pauligk Claudia , Kraus Thomas Werner , Bechstein Wolf Otto , Trojan Jorg , Behrend Matthias , Potenberg Jochem , Homann Nils , Venerito Marino , Bohle Wolfram , Varvenne Michael , Bolling Claus , Behringer Dirk M. , Kratz-Alber Karsten , Siegler Gabriele Margareta , Hozaeel Wael , Goetze Thorsten Oliver 
Published: January 2021

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Background: The outcome of pancreatic cancer remains poor. Few patients (pts) can be assigned to surgery and 80% of resected pts experience a relapse. Currently, adjuvant ctx is standard, but prognosis remains poor. FOLFIRINOX (FFX) is a SOC in metastatic and meanwhile in the adjuvant setting and may represent a valuable neoadjuvant option in resectable and borderline resectable stages. We initiated the NEPAFOX– trial in Germany to explore the efficacy of perioperative FFX. Methods: This is a multicenter randomized phase II/III trial. Recruitment of the trial was stopped after 40 patients (pts) due to poor accrual. Pts with resectable or borderline resectable adenocarcinoma of the pancreas without metastases were eligible. Eligible pts were randomized to (arm A) upfront surgery followed by adjuvant gemcitabine (1000 mg/m2) for 6 months or (arm B) perioperative FFX (irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, 5-FU 400mg/m² bolus, 5-FU 2400 mg/m², sodium folinate 400 mg/m2) 4-6 cycles (8-12 weeks) pre and further 4-6 cycles post surgery. The primary endpoint is OS. Secondary endpoints include PFS, perioperative morbidity, mortality, and others. Results: 40 pts (42.5% female) were randomized over 3 years (05.03.2015 FPI - 23.03.2018 LPI), 21 in arm A, 19 in arm B. Age range was 46-84y, median age 64y.Before randomization, 76.2% of the pts in Arm A and 78.9% in Arm B were classified as primarily resectable the remaining pts as borderline resectable. Patients received in median 3 cycles in Arm A (range: 0-6) and 6 in Arm B (range: 1-12). Surgery was performed in 18 pts (85.7%) in Arm A and 11 (57.9%) in Arm B. Reasons for not conducting surgery were for Arm A patient´s wish (1 pt) and inoperability (2 pts), for Arm B early progressive disease (4 pts), death (1 pt), pneumonia (1 pt), and toxicities (1 pt). 13 (Arm A) and 5 (Arm B) pts had a R0-Resection. Perioperative morbidity occurred in 72.2% of operated pts in Arm A and 45.5% in Arm B. Median OS was 25.68 months in Arm A (6 events of death) and 10.03 months in Arm B (14 events) with HR 0.366 and p = 0.0337. Median PFS was 9.8 months in Arm A (12 events) and 6.64 months in Arm B (16 events) with HR 0.722 and p = 0.4099. Conclusions: Due to low pt numbers, the analyses for primary and secondary endpoints are not robust and only descriptive. Median OS for Gemcitabine- arm was in the line with literature data and better than for FFX, but pt/event numbers are too for conclusion. Only 11 out of 19 FFX pts underwent surgery, only 9 pts had pancreatic resection, indicating that pts should be extremely good selected before starting a neoadjuvant approach. According to CT or MRI pts of arm B were not more advanced regarding tumor staging. Nevertheless, there were no safety issues in the FFX arm regarding surgical complications, so neoadjuvant/ perioperative treatment approach seems to be feasible, subjected to the small number of pts in the study. Clinical trial information: NCT02172976.