Pancreas
Lancet Gastroenterol Hepatol. 2023;8(2):157–68
Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): A 4-arm, multicenter, randomized, phase 2 trial
Background: Patients with borderline resectable pancreatic ductal adenocarcinoma have relatively low resection rates and poor survival despite the use of adjuvant chemotherapy. The aim of this study was to establish the feasibility and efficacy of 3 different types of short-course neoadjuvant therapy compared with immediate surgery.
Methods: ESPAC5 (formerly known as ESPAC-5f) was a multicenter, open label, randomized controlled trial done in 16 pancreatic centers in 2 countries (UK and Germany). Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, biopsy-proven pancreatic ductal adenocarcinoma in the pancreatic head, and were staged as having a borderline resectable tumor by contrast-enhanced computed tomography (CT) criteria following central review. Participants were randomly assigned by means of minimization to 1 of 4 groups: immediate surgery; neoadjuvant gemcitabine and capecitabine (gemcitabine 1000 mg/m² on days 1, 8, and 15, and oral capecitabine 830 mg/m² twice a day on days 1–21 of a 28-day cycle for 2 cycles); neoadjuvant FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², folinic acid given according to local practice, and fluorouracil 400 mg/m² bolus injection on days 1 and 15 followed by 2400 mg/m² 46 h intravenous infusion given on days 1 and 15, repeated every 2 weeks for 4 cycles); or neoadjuvant capecitabine-based chemoradiation (total dose 50.4 Gy in 28 daily fractions over 5.5 weeks [1.8 Gy per fraction, Monday to Friday] with capecitabine 830 mg/m² twice daily [Monday to Friday] throughout radiotherapy). Patients underwent restaging contrast-enhanced CT at 4–6 weeks after neoadjuvant therapy and underwent surgical exploration if the tumor was still at least borderline-resectable. All patients who had their tumor resected received adjuvant therapy at the oncologist’s discretion. Primary end points were recruitment rate and resection rate. Analyses were done on an intention-to-treat basis.
Findings: Between September 3, 2014, and December 20, 2018, from 478 patients screened, 90 were randomly assigned to a group (33 to immediate surgery, 20 to gemcitabine plus capecitabine, 20 to FOLFIRINOX, and 17 to capecitabine-based chemoradiation); 4 patients were excluded from the intention-to-treat analysis (1 in the capecitabine-based chemoradiotherapy group withdrew consent before starting therapy and 3 [2 in the immediate surgery group and 1 in the gemcitabine plus capecitabine group] were found to be ineligible after randomization). 44 of 55 patients (80%) completed neoadjuvant therapy. The recruitment rate was 25.92 patients per year from 16 sites; 21 of 31 patients (68%) in the immediate surgery and 30 of 55 patients (55%) in the combined neoadjuvant therapy groups underwent resection (p = 0.33). R0 resection was achieved in 3 of 21 patients (14%) in the immediate surgery group and 7 of 30 (23%) in the combined neoadjuvant therapy groups (p = 0.49). Surgical complications were observed in 29 of 68 patients (43%) who underwent surgery; no patients died within 30 days. 46 of 55 patients (84%) receiving neoadjuvant therapy were available for restaging. Six of 46 patients (13%) had a partial response. Median follow-up time was 12.2 months (95% confidence interval [CI]: 12.0–12.4). One-year overall survival was 39% (95% CI: 24–61) for immediate surgery, 78% (95% CI: 60–100) for gemcitabine plus capecitabine, 84% (95% CI: 70–100) for FOLFIRINOX, and 60% (95% CI: 37–97) for capecitabine-based chemoradiotherapy (p = 0.0028). One-year disease-free survival from surgery was 33% (95% CI: 19–58) for immediate surgery and 59% (95% CI: 46–74) for the combined neoadjuvant therapies (hazard ratio = 0.53, 95% CI: 0.28–0.98, p = 0.016). Three patients reported local disease recurrence (2 in the immediate surgery group and 1 in the FOLFIRINOX group). 78 patients (91%) were included in the safety set and assessed for toxicity events. 19 of 78 patients (24%) reported a grade 3 or worse adverse event (2/28 patients [7%] in the immediate surgery group and 17/50 patients [34%] in the combined neoadjuvant therapy groups), the most common of which were neutropenia, infection, and hyperglycemia.
Interpretation: Recruitment was challenging. There was no significant difference in resection rates between patients who underwent immediate surgery and those who underwent neoadjuvant therapy. Short-course (8 week) neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX had the best survival compared with immediate surgery. These findings support the use of short-course neoadjuvant chemotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma.