What is a recommended neoadjuvant therapy regimen for a patient with resectable pancreas cancer?

Neoadjuvant Therapy for Resectable Pancreatic Cancer

For patients with resectable pancreatic cancer, neoadjuvant therapy with sequential nab-paclitaxel plus gemcitabine followed by modified FOLFIRINOX is now supported by the highest-quality evidence and should be strongly considered, particularly for patients with good performance status. 1

Primary Recommendation Based on Most Recent Evidence

The 2025 randomized phase 3 trial (324 patients) demonstrated that sequential neoadjuvant nab-paclitaxel plus gemcitabine followed by modified FOLFIRINOX significantly improved event-free survival (15.3 vs 10.9 months, HR 0.71, p=0.0136) and overall survival (35.4 vs 27.2 months, HR 0.73, p=0.0477) compared to upfront surgery. 1 This represents the most definitive evidence for neoadjuvant therapy in truly resectable disease.

Current Guideline Framework

The National Comprehensive Cancer Network guidelines create a nuanced framework:

• For clearly resectable disease without high-risk features: Neoadjuvant therapy should only be performed within clinical trials 2
• For resectable disease with poor prognostic features: Selected patients may be considered for neoadjuvant therapy after biopsy confirmation 2
• For borderline resectable disease: Neoadjuvant chemotherapy is recommended to downsize tumors and improve resectability 2

However, the 2025 trial evidence 1 now challenges the restriction on neoadjuvant therapy for standard resectable disease, showing clear survival benefits.

Recommended Neoadjuvant Regimens

First-Line Options (in order of preference):

1. Sequential nab-paclitaxel plus gemcitabine followed by modified FOLFIRINOX - supported by the highest quality 2025 phase 3 trial 1

   • Nab-paclitaxel 75 mg/m² plus gemcitabine 600 mg/m² on days 1,8,15 of 28-day cycles (dose level 1 from phase I data) 3
   • Followed by modified FOLFIRINOX
   • Grade ≥3 adverse events occurred in 47.6% of patients 1

2. FOLFIRINOX - acceptable neoadjuvant regimen for fit patients 2

3. Gemcitabine/nab-paclitaxel - acceptable alternative 2

4. Gemcitabine/cisplatin - specifically for patients with BRCA1/2 or other DNA repair mutations 2

Patient Selection Criteria

Ideal candidates for neoadjuvant therapy:

• Good performance status (able to tolerate combination chemotherapy) 2
• Histologic confirmation via EUS-directed biopsy (preferred method) 2
• Treatment coordinated through or at a high-volume center 2

Patients who may not be candidates:

• Advanced age (>75-80 years) with significant comorbidities 4
• Poor performance status precluding intensive chemotherapy 5

Treatment Algorithm

1. Obtain tissue diagnosis via EUS-directed biopsy 2

2. Administer neoadjuvant chemotherapy:

   • Sequential nab-paclitaxel/gemcitabine followed by modified FOLFIRINOX (preferred based on 2025 trial) 1
   • Alternative: FOLFIRINOX or gemcitabine/nab-paclitaxel alone 2

3. Restaging after neoadjuvant therapy to assess resectability

4. Surgical resection if disease remains resectable or has downstaged

5. Adjuvant chemotherapy (4 cycles, preferably gemcitabine plus capecitabine) 1

   • Patients who received neoadjuvant therapy may be candidates for additional chemotherapy after surgery and multidisciplinary review 4, 2

Key Advantages of Neoadjuvant Approach

• Improved survival outcomes: Median OS 35.4 months vs 27.2 months with upfront surgery 1
• Higher R0 resection rates: 63% vs 31% in PREOPANC-1 trial 6
• Early systemic therapy delivery: All patients receive chemotherapy, not just the 50% who complete adjuvant therapy 6
• Better patient selection: Identifies rapidly progressive disease before major surgery 7, 6
• Addresses occult metastatic disease: Treats micrometastases present at diagnosis 7, 6

Important Caveats

• The 2025 trial included 50% of patients with pancreatic body or tail tumors, which may have different biology than head tumors 1
• Neoadjuvant strategies may delay potentially curative surgery in some patients with truly resectable disease 2
• Grade ≥3 adverse events are higher with neoadjuvant therapy (47.6%) compared to upfront surgery (30.7%) 1
• Dose-limiting toxicity (neutropenia, anemia, thrombocytopenia, liver injury) occurred in 44.4% at the recommended dose level 3

Post-Neoadjuvant Considerations

After neoadjuvant therapy and resection, patients should receive adjuvant chemotherapy:

• Preferably gemcitabine plus capecitabine for 4 cycles 1
• Modified FOLFIRINOX is the preferred adjuvant regimen for fit patients who did not receive it neoadjuvantly 4
• Adjuvant chemoradiation may be offered to patients with R1 resection and/or positive lymph nodes after completing 4-6 months of systemic chemotherapy 4