Alliance A021501: Preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated radiation therapy (RT) for borderline resectable (BR) adenocarcinoma of the pancreas.

Abstract

377 Background: Neoadjuvant therapy has been associated with a median overall survival (OS) of 18 – 23 months (mo) in patients (pts) with BR pancreatic ductal adenocarcinoma (PDAC). To establish reference regimens to which novel treatments can be compared in future studies, we evaluated neoadjuvant mFOLFIRINOX with or without RT in BR PDAC in a phase II National Clinical Trials Network (NCTN) trial. Methods: Pts with ECOG PS 0-1 and BR PDAC confirmed by central real-time radiographic review after pre-registration were randomized to either arm A: 8 cycles of neoadjuvant mFOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours), or arm B: 7 cycles of mFOLFIRINOX followed by stereotactic body RT (SBRT, 33-40 Gy in 5 fractions [fx]) or hypofractionated image guided RT (HIGRT, 25 Gy in 5 fx). Pts in either arm without disease progression underwent pancreatectomy, then 4 cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours). The primary endpoint, 18-mo OS rate, of each arm was compared to a historical control of 50%. Planned interim analysis mandated closure of either arm in which <11 of first 30 accrued pts underwent R0 resection. Results: 155 pts pre-registered and 126 pts were enrolled to arm A (N=70; 54 randomized, 16 following closure of arm B) or arm B (N=56; closed at interim analysis, all pts randomized prior to closure). Median age (A: 63y, B: 67y), median CA 19-9 level (A: 171 U/ml, B: 248 U/ml) and ECOG PS (A: 51% PS 0, B: 57% PS 0) of registered pts were similar between arms (p > 0.05). Treatment detailed in Table. The 18-mo OS rate based on Kaplan Meier estimates was 67.9% (95%CI: 54.6 – 78.0) in arm A and 47.3% (95%CI: 33.7 – 59.7) in arm B. Among pts who underwent pancreatectomy, 18-mo OS rate was 93.1% (95%CI: 84.3 – 100) and 78.9% (95%CI: 62.6 – 99.6) in arm A and B, respectively. With median follow-up of 27 and 31 mo, median OS was 31.0 (95%CI: 22.2 – NE) mo and 17.1 (95%CI: 12.8 – 24.4) mo in arm A and B, respectively. Conclusions: Neoadjuvant mFOLFIRINOX was associated with favorable OS relative to historical data in pts with BL PDAC in this phase II NCTN trial. mFOLFIRINOX with hypofractionated RT did not improve OS compared to historical data. mFOLFIRINOX represents a reference regimen in this setting and a backbone on which to add novel agents. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org Clinical trial information: NCT02839343. [Table: see text]

Multimodality standard of care treatment of resectable and borderline resectable pancreatic cancer

“…The resection rates were 49% with mFOLFIRINOX and 35% for mFOLFIRINOX plus chemoradiotherapy and the median (95% CI) overall survival was 31.0 (22.2-NE) months and 17.1 (12.8-24.4) months respectively (7). Thus, both ESPAC-5F and the Alliance A021501 randomized trials showed that chemoradiotherapy (as in the advanced and adjuvant settings) was inferior to chemotherapy alone (6,7).…”

“…Randomized studies using a mixture of resectable, borderline resectable and locally advanced disease have tended to produce a confused picture. Two recent trials focusing only on borderline resectable disease, however, have a produced more consistent conclusion (6,7). The ESPAC-5F trial has shown that using neoadjuvant therapy was superior to upfront surgery (6).…”

“…In the Alliance A021501 trial 110 patients with borderline resectable pancreatic cancer were randomized to either arm eight cycles of neoadjuvant mFOLFIRINOX, or to seven cycles of mFOLFIRINOX followed by stereotactic body radiotherapy (with 5 fractions of either 33-40 Gy of stereotactic body radiation or 25 Gy hypofractionated image guided radiotherapy followed by four cycles of adjuvant mFOLFOX6 after resection (7). The resection rates were 49% with mFOLFIRINOX and 35% for mFOLFIRINOX plus chemoradiotherapy and the median (95% CI) overall survival was 31.0 (22.2-NE) months and 17.1 (12.8-24.4) months respectively (7). Thus, both ESPAC-5F and the Alliance A021501 randomized trials showed that chemoradiotherapy (as in the advanced and adjuvant settings) was inferior to chemotherapy alone (6,7).…”

Neoadjuvant therapy for pancreatic ductal adenocarcinoma: Opportunities for personalized cancer care

“…The Alliance A021501 trial, randomized patients with BR PDAC to either 8 cycles of FOLFIRINOX or 7 cycles of FOLFIRINOX followed by hypofractionated radiation before surgery. Patients who received radiation therapy were less likely to undergo surgical resection and experienced shorter OS[ 32 ]. In summary, NT with systemic chemotherapy with selective use of preoperative radiation is currently the preferred approach for BR PDAC.…”

AGITG MASTERPLAN: a randomised phase II study of modified FOLFIRINOX alone or in combination with stereotactic body radiotherapy for patients with high-risk and locally advanced pancreatic cancer

“…The combination of chemotherapy and SBRT, while promising, remains unpublished in a randomised setting. At the time of this publication results from the A021501 Alliance Trial have just been presented, although not published, warranting comparison of trial methodologies [ 35 , 36 ]. The chemotherapy regimens included in MASTERPLAN are included as accepted standard of care, during a time when standard of care is controversial and often institutional dependent.…”