Neoadjuvant chemotherapy does not improve survival in pancreatic cancer


In the NORPACT-1 study, adjuvant FOLFORINOX shows no additional benefit compared to upfront surgery in patients with resectable pancreatic ductal adenocarcinoma

Neoadjuvant chemotherapy with combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) shows no survival benefit compared with upfront surgery in pancreatic ductal adenocarcinoma, as reported by the exploratory multicentre, randomised, phase 2 NORPACT-1 trial (Lancet Gastroenterol Hepatol. 2024 Jan 15:S2468-1253(23)00405-3).

Systemic therapy options are limited for this difficult-to-treat malignancy. Currently, the standard of care for fit patients with resectable pancreatic ductal adenocarcinoma and without medical contraindications is upfront surgery followed by six months of adjuvant chemotherapy, preferably with modified FOLFIRINOX.

In the NORPACT-1 study, 140 patients were randomly assigned either to the neoadjuvant FOLFIRINOX group or the upfront surgery followed by adjuvant chemotherapy group in the period between February 2017 and April 2021. Neoadjuvant treatment consisted of four cycles (2 months) of FOLFIRINOX, and patients were treated in twelve hospitals in Norway, Sweden, Denmark and Finland. The primary endpoint was overall survival (OS) at 18 months after the date of randomisation. The follow up was based on physical examination, and blood samples taken 6, 12, 18, and 24 months after surgery and every year thereafter until disease recurrence, or at 5 years postoperatively in patients without relapse.

In the neoadjuvant group median OS was 25.1 months (95% CI 17.2-34.9) compared with 38.5 months (27.6-not reached) in the upfront surgery group. No significant differences in median OS were found in intention-to-treat (ITT) and pre-protocol populations, as part of secondary endpoints. The ITT median OS in the neoadjuvant group was 25.1 months (95% CI 17.2–34.9) versus 38.5 months (27.6–not reached) in the upfront surgery group (HR 1.52 [95% CI 1.00–2.33], log-rank p=0·050), while the pre-protocol median OS of 23.0 months (95% CI 16.2–34.9) versus 34.4 months (19.4–not reached; HR 1.46 [95% CI 0.99–2.17], log-rank p=0.058).

Although results of this trial do not support neoadjuvant FOLFIRINOX as standard of care in resectable pancreatic ductal adenocarcinoma, a comment accompanying the publication of the study results on The Lancet Gastroenterology & Hepatology highlights some study design aspects that may have impacted on the final outcomes. For instance, only 61% of patients in the neoadjuvant FOLFORINOX group completed all four cycles due to toxicity, decline in performance status or early death, while others receiving a suboptimal dose of chemotherapy. Also, a histological confirmation of resectable pancreatic ductal adenocarcinoma was only required in the neoadjuvant FOLFIRINOX group, and “although the number of patients who were found not to have pancreatic ductal adenocarcinoma was balanced between groups, this confirmation and the need for management of biliary obstruction could potentially have disadvantaged patients receiving neoadjuvant chemotherapy,” stated the experts commenting on the study.

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