Clinical trialPhase 2Pancreatic cancer

Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial

Lancet Gastroenterol Hepatol · 2024140 patients (77 neoadjuvant FOLFIRINOX, 63 upfront surgery)

Labori KJ, Bratlie SO, Andersson B, et al. Lancet Gastroenterol Hepatol. 2024. 9:205-217

Study type: Clinical trial
Study name: NORPACT-1
Phase: Phase 2
Design: Open-label, multicentre randomised trial in 12 hospitals in Denmark, Finland, Norway and Sweden (3:2 randomisation before October 2018 and 1:1 thereafter); EudraCT: 2015-001635-21
Sample size: 140 patients (77 neoadjuvant FOLFIRINOX, 63 upfront surgery)
Source: Lancet Gastroenterol Hepatol · 2024
Trial registration: NCT02919787

In plain words

An important question in pancreatic cancer that can be operated on is whether it is better to have chemotherapy before the operation, or surgery first followed by chemotherapy. In the NORPACT-1 study in the Nordic countries, one group first received 4 cycles of FOLFIRINOX chemotherapy and then had surgery, while the other group went straight to surgery; both groups also had chemotherapy after surgery. In this study, chemotherapy before the operation did not help people live longer, and that group's results were even numerically worse, although the study was small. So for tumours that can clearly be removed, immediate surgery followed by chemotherapy remains a standard approach; your treatment team will make the final decision based on your situation.

Key results

60% vs 73%

18-month survival (intention to treat)

Neoadjuvant FOLFIRINOX vs upfront surgery; p=0.032

25.1 months vs 38.5 months

Median overall survival (intention to treat)

HR 1.52 (95% CI 1.00-2.33); log-rank p=0.050

57% vs 70%

18-month survival (per protocol)

p=0.14

23.0 months vs 34.4 months

Median overall survival (per protocol)

HR 1.46 (95% CI 0.99-2.17); log-rank p=0.058

61 of 77 patients (79%)

Received neoadjuvant treatment in the FOLFIRINOX group

82% vs 89%

Resection performed

63/77 vs 56/63; p=0.24

Drugs in this study:Capecitabine (Xeloda)Fluorouracil (5-FU)Gemcitabine (Gemzar)Irinotecan (Camptosar)Oxaliplatin (Eloxatin)

Dose and schedule cards

Neoadjuvant FOLFIRINOX (PREOPANC-2)

Resectable or borderline resectable pancreatic cancer; WHO performance status 0–1Cycle length: Every 14 daysOn the page “Pancreatic cancer” · Adjuvant (postoperative) and neoadjuvant (preoperative) therapy

Resectable or borderline resectable pancreatic cancer; WHO performance status 0–1

Drug	Dose	Route	Schedule
Oxaliplatin	85 mg/m²	IV over 2 hours	Day 1
Irinotecan	180 mg/m²	IV over 90 minutes	Day 1
Leucovorin	400 mg/m²	IV over 2 hours	Day 1
Fluorouracil (bolus)	400 mg/m²	IV bolus	Day 1
Fluorouracil (infusion)	2400 mg/m²	IV, 46-hour continuous infusion	Starting Day 1

Cycle length: Every 14 days
Duration: 8 cycles, then surgery; no adjuvant therapy after surgery

Doses and schedule from PREOPANC-2; infusion durations per the FDA labels. In resectable disease without high-risk features, the benefit of neoadjuvant therapy has not been established.

On the page “Pancreatic cancer” · Adjuvant (postoperative) and neoadjuvant (preoperative) therapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Neoadjuvant FOLFIRINOX

Four cycles of neoadjuvant FOLFIRINOX (on day 1 of each 14-day cycle): oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m² and fluorouracil (5-FU) 400 mg/m² bolus followed by 2400 mg/m² over 46 hours; then surgery and adjuvant chemotherapy (4 cycles of gemcitabine + capecitabine, or after the protocol amendment 8 cycles of modified FOLFIRINOX).

2Upfront surgery (control group)

Surgery followed by adjuvant chemotherapy: initially gemcitabine 1000 mg/m² over 30 minutes on days 1, 8 and 15 with capecitabine 830 mg/m² twice daily for 3 weeks followed by 1 week of rest, in each 28-day cycle (6 cycles); after the protocol amendment, modified FOLFIRINOX was also allowed (oxaliplatin 85, irinotecan 150, leucovorin 400 and fluorouracil 2400 mg/m² over 46 hours on day 1 of each 14-day cycle; 12 cycles).

Source of the regimen details: Abstract of the paper

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 18 or older with WHO performance status zero or 1 and a resectable tumour of the pancreatic head highly suspicious for pancreatic adenocarcinoma on imaging. Enrolment from 8 February 2017 to 21 April 2021.

Endpoints

Primary endpoint: overall survival at 18 months (analysed in the intention-to-treat and per-protocol populations). Safety was assessed in all randomised patients who received at least one cycle of treatment before or after surgery.

Safety and side effects

In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or higher adverse event. One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. During adjuvant chemotherapy, the most common grade 3 or higher adverse event was neutropenia (11 [22%] in the neoadjuvant FOLFIRINOX group and 5 [11%] in the upfront surgery group).

Clinical significance and place in guidelines

NORPACT-1, comparing neoadjuvant FOLFIRINOX with upfront surgery in resectable pancreatic head cancer, showed no survival benefit for neoadjuvant treatment; 18-month survival and median overall survival were numerically better in the upfront surgery group. This result supports continuing upfront surgery followed by adjuvant chemotherapy as the standard approach for clearly resectable tumours, and neoadjuvant treatment in this group remains a subject of research.

Limitations

Phase 2 trial with a small number of patients (140) and no masking; the randomisation ratio changed during the study (3:2 to 1:1), the adjuvant chemotherapy regimen changed with a protocol amendment, and the proportion receiving adjuvant modified FOLFIRINOX differed between groups (25% vs 43%). Only 79% of patients in the FOLFIRINOX group received neoadjuvant treatment, and some patients ultimately did not have pancreatic ductal adenocarcinoma. Confidence intervals are wide and results should be interpreted with caution.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.