What is the preferred first‑line systemic therapy for metastatic pancreatic adenocarcinoma in a relatively fit adult (Eastern Cooperative Oncology Group performance status 0‑1) with normal organ function, and what alternative regimen is recommended for older or frail patients?

Primary Treatment for Metastatic Pancreatic Adenocarcinoma

For fit patients (ECOG 0-1) with metastatic pancreatic adenocarcinoma, FOLFIRINOX or gemcitabine plus nab-paclitaxel are the two preferred first-line regimens, while older or frail patients (ECOG 2) should receive gemcitabine monotherapy. 1

First-Line Treatment Algorithm Based on Performance Status

For Fit Patients (ECOG 0-1, Age ≤75, Bilirubin ≤1.5× ULN)

FOLFIRINOX is the preferred regimen for patients with a favorable comorbidity profile, delivering median overall survival of approximately 11 months. 1, 2 This regimen consists of leucovorin, fluorouracil, irinotecan, and oxaliplatin. 1

Gemcitabine plus nab-paclitaxel is the alternative first-line option for patients with an adequate (but not necessarily favorable) comorbidity profile. 1 This combination demonstrated statistically significant improvements in overall survival, progression-free survival, and response rates versus gemcitabine alone. 2

The choice between these two regimens should be based on:

• Patient preference and available support system for managing toxicity 1
• Comorbidity profile: FOLFIRINOX requires more favorable baseline health 1
• Access to infusion services: FOLFIRINOX requires chemotherapy port and infusion pump management 1

For Patients with Moderate Performance Status (ECOG 2)

Gemcitabine monotherapy at 1000 mg/m² over 30 minutes, weekly for 3 weeks every 28 days, is the recommended treatment. 1 This is a Category 1 recommendation. 1

Optional additions to gemcitabine for ECOG 2 patients include:

• Capecitabine (may be added to gemcitabine) 1
• Erlotinib (may be added to gemcitabine) 1

For Patients with Poor Performance Status (ECOG ≥3)

Cancer-directed therapy should be offered only on a case-by-case basis; supportive care should be emphasized. 1 Best supportive care is the typical recommendation for ECOG 3-4 patients. 3

Alternative First-Line Regimens (Category 1 or 2B)

For patients who cannot tolerate the preferred regimens, additional options include:

• Gemcitabine plus erlotinib: Category 1 acceptable combination 1, 2
• Gemcitabine plus capecitabine: Category 1 acceptable combination 1, 2
• Gemcitabine plus cisplatin: Category 1 preferred specifically for patients with germline BRCA1/2 or other DNA-repair mutations 2
• GTX regimen (fixed-dose-rate gemcitabine, docetaxel, capecitabine): Category 2B 1, 2
• Fluoropyrimidine plus oxaliplatin: Category 2B 1, 2
• Capecitabine monotherapy: Category 2B 1, 2

Critical Pre-Treatment Requirements

Before initiating systemic therapy:

• Perform multiphase CT scan of chest, abdomen, and pelvis 1
• Evaluate baseline performance status and comorbidity profile 1
• Ensure bilirubin ≤1.5× ULN before starting combination chemotherapy 2, 4
• Refer to palliative care at first visit 1
• Discuss goals of care and patient preferences before treatment initiation 1, 2

Special Population: DNA-Repair Deficient Tumors

For patients with germline BRCA1/2 or other DNA-repair mutations, platinum-based regimens (gemcitabine plus cisplatin or FOLFIRINOX containing oxaliplatin) should be strongly considered due to heightened sensitivity to DNA-damaging agents. 2 This is a Category 1 recommendation. 2

Toxicity Management and Dose Modifications

FOLFIRINOX Modifications

Omit the bolus 5-FU in most patients to lessen toxicity while preserving efficacy. 2 This is a Category 1 recommendation. 2 Monitor closely for:

• Neutropenia
• Diarrhea
• Neuropathy 2

Gemcitabine Plus Nab-Paclitaxel Dosing

Standard dosing is gemcitabine 1000 mg/m² plus nab-paclitaxel 125 mg/m² on days 1,8,15 of each 28-day cycle. 2 This is Category 1. 2

Common Pitfalls to Avoid

Do not delay initiation of systemic chemotherapy in patients with adequate biliary drainage and recovered organ function; early treatment is critical for disease control. 2 This is a Category 1 recommendation. 2

Do not combine gemcitabine with 5-FU/capecitabine, irinotecan, or platinum agents as first-line therapy in metastatic disease (outside specific contexts such as BRCA-mutated tumors); large phase III trials showed no survival benefit. 2

Do not use routine chemoradiation in the metastatic setting without prior systemic chemotherapy; the FFCD-SFRO trial demonstrated inferior 1-year overall survival (32% vs 53% with gemcitabine alone; P = 0.006) due to toxicity limiting subsequent systemic therapy. 2

Treatment Duration

Continue first-line chemotherapy until disease progression, unacceptable toxicity, or completion of the planned course (typically 4-6 months for locally advanced disease before considering consolidation). 2 This is a Category 1 recommendation. 2

Evidence Quality Considerations

The recommendations for FOLFIRINOX and gemcitabine plus nab-paclitaxel are both Category 1 (based on high-level evidence and uniform NCCN consensus), making them equally valid choices from an evidence standpoint. 1 The ASCO 2016 guideline, which represents the most comprehensive systematic review of this topic, explicitly states both regimens should be offered to ECOG 0-1 patients based on patient preference and comorbidity profile. 1

Swiss expert consensus data from 2020 confirms that FOLFIRINOX is preferred for younger patients (age <65) with good performance status, while there is a trend toward gemcitabine plus nab-paclitaxel for patients with increasing age and reducing performance status. 3