ESMO Clinical Practice Guideline Express Update on the management of metastatic pancreatic cancer
- Study type
- Clinical guideline
- Study name
- ESMO 2025
- Design
- Express Update of the 2023 ESMO clinical guideline for pancreatic cancer, on first- and second-line systemic treatment of metastatic disease
- Source
- ESMO Open · 2025
In plain words
In 2025 the European Society for Medical Oncology (ESMO) updated its recommendations for treating pancreatic cancer that has spread to other organs. For patients in good general health, two strong three-drug chemotherapy regimens, FOLFIRINOX and the newer NALIRIFOX, are recommended as the first treatment, and the combination of gemcitabine and nab-paclitaxel is also an option. If the disease grows after the first treatment, gemcitabine-based regimens can be the next treatment. The choice of regimen depends on each patient's general health, other illnesses and the side effects they can tolerate, and your doctor will suggest the best option.
Key guideline recommendations
- I, A
In patients with ECOG performance status 0 to 1, bilirubin below 1.5 times the upper limit of normal and no major comorbidity, two regimens should be recommended as first-line chemotherapy: FOLFIRINOX [I, A; ESMO-MCBS v1.1 score: 5 (versus gemcitabine)] or NALIRIFOX [I, A; ESMO-MCBS v1.1 score: 2 (versus gemcitabine–nab-paclitaxel)].
- I, B; ESMO-MCBS v1.1: 3
Gemcitabine–nab-paclitaxel (GN) can also be used in these patients.
- I, B
After FOLFIRINOX, gemcitabine–paclitaxel can be offered to patients with ECOG performance status 0 to 2 and a favourable comorbidity profile.
- III, C
Other options (after FOLFIRINOX) are gemcitabine–nab-paclitaxel (not EMA- or FDA-approved as second-line treatment) or gemcitabine alone.
- V, C
After NALIRIFOX, a gemcitabine-based regimen can be offered to patients with ECOG performance status 0 to 2 and a favourable comorbidity profile.
Study population
Patients with metastatic pancreatic cancer.
Endpoints
This article is not a trial and has no endpoints.
Safety and side effects
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Clinical significance and place in guidelines
Based on the phase 3 NAPOLI 3 trial (770 patients), this update placed NALIRIFOX alongside FOLFIRINOX as a recommended first-line treatment [I, A]: at a median follow-up of 16.1 months, median overall survival was 11.1 months with NALIRIFOX versus 9.2 months with gemcitabine–nab-paclitaxel (HR 0.83; 95% CI 0.70-0.99; P = 0.036) and median progression-free survival was 7.4 versus 5.6 months (HR 0.69; 95% CI 0.58-0.83; P < 0.0001); grade 3 or higher treatment-emergent adverse events occurred in 87% and 86% of patients, with grade 3 to 4 diarrhoea more common with NALIRIFOX (20% versus 5%) and grade 3 to 4 neutropenia less common (14% versus 25%). ESMO stresses that FOLFIRINOX and NALIRIFOX have not been compared head to head in any prospective trial and that there are no data on their relative cost-effectiveness; gemcitabine–nab-paclitaxel remains an option, particularly in patients unsuitable for triplet therapy or when gastrointestinal toxicity is a concern. For second line after FOLFIRINOX, the phase 3 GEMPAX trial (211 patients) showed that gemcitabine–paclitaxel did not significantly improve overall survival compared with gemcitabine alone (median 6.4 versus 5.9 months; HR 0.87; 95% CI 0.63-1.20; P = 0.4095), but improved progression-free survival (3.1 versus 2.0 months; HR 0.64; P = 0.0067) and objective response rate (17.1% versus 4.2%; P = 0.008), with more grade 3 or higher treatment-related adverse events (58.0% versus 27.1%). After NALIRIFOX there are no clinical trial data to guide second-line treatment, and a gemcitabine-based regimen is considered a reasonable approach for patients fit for further treatment.
Limitations
This update covers only first- and second-line systemic treatment of metastatic disease; the other recommendations of the original 2023 ESMO guideline remain valid. The recommendation for second-line treatment after NALIRIFOX is based on expert opinion (level V), as no trial data exist. FOLFIRINOX and NALIRIFOX have not been compared directly.
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.