Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy - a multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study)

Abstract

BackgroundAt time of diagnosis, less than 10% of patients with pancreatic adenocarcinomas (PDAC) are considered to be immediately operable (i.e. resectable). Considering their poor overall survival (OS), only tumours without vascular invasion (NCCN 2017) should be considered for resection, i.e. those for which resection with disease-free margins (R0) is theoretically possible in absence of presurgery treatment. With regard to high R1 rates and undetectable locoregional and/or metastatic spreading prior to surgery explain (at least in part) the observed 1-year relapse and mortality rates of 50 and 25%, respectively. Today, upfront surgery followed by adjuvant chemotherapy is the reference treatment in Europe. The main limitation of the adjuvant approach is the low rate of completion of the full therapeutic sequence. Indeed, only 47 to 60% patients received any adjuvant therapy after resection compared to more than 75% for neoadjuvant therapy. No previous prospective study has compared this approach to a neoadjuvant FOLFIRINOX or FOLFOX chemotherapy for resectable PDAC.MethodsPANACHE01-PRODIGE48 is a prospective multicentre controlled randomized non comparative Phase II trial, evaluating the safety and efficacy of two regimens of neo-adjuvant chemotherapy (4 cycles of mFOLFIRINOX or FOLFOX) relative to the current reference treatment (surgery and then adjuvant chemotherapy) in patients with resectable PDAC. The main co-primary endpoints are OS rate at 12 months and the rate of patients undergoing the full therapeutic sequence.DiscussionThe “ideal” cancer treatment for resectable PDAC would have the following characteristics: administration to the highest possible proportion of patients, ability to identify fast-progressing patients (i.e. poor candidates for surgery), a low rate of R1 resections (through optimisation of local disease control), and an acceptable toxicity profile. The neoadjuvant approach may meet all these criteria. With respect to published data on the efficacy of FOLFOX and mFOLFIRINOX, these two regimens are potential candidates for neoadjuvant use in the aim to optimising oncological outcomes in resectable PDAC.Trial registrationClinicalTrials.gov, NCT02959879. Trial registration date: November 9, 2016.

Neoadjuvant Therapy for Resectable and Borderline Resectable Pancreatic Cancer: A Meta-Analysis of Randomized Controlled Trials

“…Nevertheless, the best chemotherapy regimen has not been established, and it is unlikely that the chemotherapy regimens used in the PACT-15 (Cisplatin, Epirubicin, Gemcitabine, Capecitabine) or Prep-02/JSAP-05 (gemcitabine, S-1) will be widely adopted [34,35]. Given that most patients currently receive either gemcitabine/nab-paclitaxel or mFOLFIRINOX, the ongoing NEONAX [44], NEPAFOX [45], NORPACT-1 [46], PANACHE01-PRODIGE48 [47], PREOPANC-2 [48], ESPAC-5 [49], and SWOG S1505 [50] trials as well as the upcoming Alliance A021806 trial, which incorporate one of these regimens, should improve our understanding of the preferred preoperative regimen.…”

Neoadjuvant Treatment in Patients With Resectable and Borderline Resectable Pancreatic Cancer

“…This study uses R0 resection rate as primary endpoint. The PANACHE01-PRODIGE48 is a three-arm trial with 2:2:1 allocation to 4 cycles of neoadjuvant mFOLFIRINOX (arm A) or FOLFOX (arm B), both followed by 8 cycles of adjuvant chemotherapy, or upfront surgery followed by 12 cycles of adjuvant chemotherapy (arm C) (NCT02959879) (61). The choice of adjuvant chemotherapy regimen will be left to the medical teams, according to guidelines during the recruitment period.…”

Implications of Prolonged Time to Pancreaticoduodenectomy After Neoadjuvant Chemoradiation

“…[2][3][4] Recent guidelines have recognized neoadjuvant chemoradiotherapy for localized pancreatic adenocarcinoma as the preferred treatment strategy with borderline resectable cancer and an acceptable treatment option for patients with potentially resectable cancer. [5][6][7][8][9] Proposed benefits of this approach include the selection of patients with favorable tumor biology, early treatment of micrometastatic disease, facilitation of a margin-negative resection, and maximal delivery of all components of multimodality therapy. [10][11][12][13] According to the NCCN guidelines for pancreatic adenocarcinoma, surgery is ideally performed 4 to 8 wk after completion of neoadjuvant chemoradiation (CR) therapy.…”