What is the role of neoadjuvant therapy in localized pancreatic carcinoma, especially for borderline resectable disease, and which regimens (e.g., FOLFIRINOX or gemcitabine + nab‑paclitaxel) are recommended for fit patients?

Role of Neoadjuvant Therapy in Localized Pancreatic Carcinoma

For borderline resectable pancreatic cancer, neoadjuvant therapy is now the preferred approach over upfront surgery, with modified FOLFIRINOX being the regimen of choice for fit patients (ECOG 0-1, age ≤75 years), and gemcitabine plus nab-paclitaxel serving as the alternative for those unable to tolerate FOLFIRINOX. 1, 2, 3

Borderline Resectable Disease: Neoadjuvant Therapy is Preferred

• Most NCCN member institutions now prefer neoadjuvant therapy over immediate surgery for borderline resectable disease, representing a paradigm shift from earlier practice patterns. 1
• Upfront resection in borderline resectable disease is no longer recommended as of 2016 NCCN guidelines. 1
• The rationale for this approach includes: selecting patients with more stable disease, treating micrometastases earlier, increasing likelihood of R0 (margin-negative) resection, and ensuring more patients receive systemic therapy (since up to 25% cannot receive postoperative therapy due to prolonged recovery). 1
• Neoadjuvant therapy can achieve resection rates of up to 68% in borderline resectable disease and 36% in locally advanced disease. 4

Recommended Neoadjuvant Regimens for Fit Patients

First Choice: Modified FOLFIRINOX

• Modified FOLFIRINOX is the preferred neoadjuvant regimen for patients with good performance status (ECOG 0-1, age ≤75 years, no major comorbidities). 2, 3
• This regimen has demonstrated superior efficacy with median overall survival of 54.4 months versus 35.0 months with gemcitabine alone in the adjuvant setting (PRODIGE 24 trial). 3
• The modified regimen consists of: irinotecan 150 mg/m² IV, oxaliplatin 85 mg/m² IV, leucovorin 400 mg/m² IV, and 5-FU 2400 mg/m² continuous infusion over 46 hours (no bolus), every 2 weeks. 3
• Important caveat: Grade 3-4 adverse events occur in approximately 76% of patients, mandating careful patient selection. 3

Alternative: Gemcitabine Plus Nab-Paclitaxel

• Gemcitabine plus nab-paclitaxel is the recommended alternative for patients who cannot tolerate FOLFIRINOX (age >75, moderate fitness, or toxicity concerns). 2, 3, 4
• This combination is particularly appropriate for patients ineligible for FOLFIRINOX and has shown R0 resection rates of 19% in borderline resectable/locally advanced disease. 5
• Nonrandomized data indicate resection rates up to 68% in borderline resectable disease with active combination regimens. 4

Resectable Disease: Clinical Trial Setting Only

• For clearly resectable disease without high-risk features, neoadjuvant therapy should only be administered within a clinical trial—the NCCN panel does not support its use outside this context. 1
• For selected resectable patients with poor prognostic features (markedly elevated CA 19-9, large primary tumors, large regional lymph nodes, excessive weight loss, extreme pain), neoadjuvant therapy can be considered after biopsy confirmation. 1

Essential Pre-Treatment Requirements

• EUS-directed biopsy is the preferred method for obtaining histologic confirmation before neoadjuvant therapy; repeat biopsy should be performed if initial results are negative. 1
• Staging laparoscopy is recommended (category 2B) before and after neoadjuvant therapy to evaluate for metastatic disease. 1
• Biliary stent placement is recommended before initiating neoadjuvant therapy in patients with jaundice. 1

Critical Restaging Protocol

• Restaging with abdominal and chest imaging is mandatory 4-6 weeks after completion of neoadjuvant therapy before committing to surgery. 1
• Repeat staging laparoscopy should be performed after neoadjuvant therapy, as 25-40% of patients will have disease progression precluding surgery. 1
• Patients who develop metastases or progress locally during neoadjuvant therapy are not candidates for surgery. 1

Timing and Duration Considerations

• Surgery should ideally be performed within 4-8 weeks after completion of neoadjuvant therapy to balance tumor regression against repopulation. 6
• Neoadjuvant therapy regimens are typically similar to those used for locally advanced disease, often involving 3-4 months of chemotherapy. 1, 5
• If surgery is achieved after neoadjuvant therapy, patients may be candidates for additional chemotherapy after multidisciplinary review. 6

Role of Radiation in Neoadjuvant Setting

• Neoadjuvant chemoradiation with gemcitabine or 5-FU has been studied, though the optimal neoadjuvant regimen combining chemotherapy and radiation has not been established. 1
• Cross-study comparisons suggest that adding preoperative chemotherapy before gemcitabine-based chemoradiation did not improve survival. 1
• Current practice often involves systemic chemotherapy followed by chemoradiation for borderline resectable disease. 1

Common Pitfalls to Avoid

• Do not proceed directly to surgery in borderline resectable disease without neoadjuvant therapy—this is outdated practice. 1
• Do not skip restaging imaging and laparoscopy after neoadjuvant therapy, as up to 40% will have progressed. 1
• Do not use neoadjuvant therapy outside clinical trials for clearly resectable disease without high-risk features. 1
• Do not delay surgery beyond 8 weeks after completing neoadjuvant therapy, as this may compromise outcomes. 6
• Do not select FOLFIRINOX for patients over 75 years or with poor performance status—use gemcitabine-based regimens instead. 2, 3

Expected Outcomes

• When R0 resection is achieved after neoadjuvant therapy, overall survival appears comparable to primarily resectable patients. 7
• Neoadjuvant therapy can induce resectability in 30-40% of locally advanced pancreatic cancer patients. 7
• Despite an approximate 10% drop in resection rates with neoadjuvant approaches, there is significant improvement in median overall survival. 4