What is the role of neo-adjuvant (pre-surgical) chemotherapy in the treatment of pancreatic cancer?

Role of Neoadjuvant Chemotherapy in Pancreatic Cancer

Neoadjuvant chemotherapy is strongly recommended for borderline resectable pancreatic cancer to downsize tumors and improve resectability, but should only be used within clinical trials for clearly resectable disease without high-risk features. 1

Indications for Neoadjuvant Therapy

Borderline Resectable Disease

• Neoadjuvant chemotherapy or chemoradiotherapy is recommended for patients with borderline resectable pancreatic cancer (tumors with vessel encasement) to achieve tumor downsizing and potentially convert unresectable tumors to resectable status 1
• This approach may benefit patients by increasing the likelihood of R0 resection (negative margins) 2
• Neoadjuvant gemcitabine plus nab-paclitaxel (GnP) has shown promising results in borderline resectable disease, with significantly higher R0 resection rates (100% vs 77%) compared to upfront surgery 2

Resectable Disease

• For patients with clearly resectable pancreatic cancer without high-risk features, neoadjuvant chemotherapy should only be performed within clinical trials 1
• Selected patients with resectable disease but poor prognostic features (markedly elevated CA 19-9 levels, large primary tumors, large regional lymph nodes, excessive weight loss, extreme pain) may be considered for neoadjuvant therapy after biopsy confirmation 1

Potential Benefits of Neoadjuvant Approach

• Increases the likelihood that a higher proportion of patients will receive chemotherapy (compared to only ~50% of patients who complete adjuvant therapy after surgery) 1
• Potential to downsize tumors to increase likelihood of margin-free resection 1
• Ability to select patients with more stable disease or disease responsive to therapy for surgery 1
• Treatment of micrometastases at an earlier stage 1
• Facilitates surgical procedures with shorter operation time and less blood loss 2

Recommended Regimens

• Acceptable neoadjuvant regimens include FOLFIRINOX, gemcitabine/albumin-bound paclitaxel, and gemcitabine/cisplatin (for patients with BRCA1/2 or other DNA repair mutations) 1
• Chemoradiation after chemotherapy is sometimes included in the neoadjuvant setting 1
• Patient-derived organoid (PDO)-based neoadjuvant chemotherapy shows promising resection rates in borderline resectable pancreatic cancer patients 3

Patient Selection and Monitoring

• Neoadjuvant therapy should preferably be administered at or coordinated through a high-volume center 1
• EUS-directed biopsy is the preferred method of obtaining histologic confirmation before administering neoadjuvant therapy 1
• Staging laparoscopy is recommended before and after neoadjuvant therapy to evaluate for metastatic disease 1
• Patients who develop metastases during neoadjuvant chemotherapy or who progress locally are not candidates for secondary surgery 1
• Abdominal and chest imaging should be repeated after neoadjuvant therapy 1

Evidence on Survival Outcomes

• Recent data show improved survival in patients who received neoadjuvant therapy compared to upfront surgery 1
• In borderline resectable disease, neoadjuvant gemcitabine plus nab-paclitaxel has shown significantly longer disease-free survival and overall survival compared to upfront surgery 2
• However, a recent meta-analysis of randomized controlled trials found that neoadjuvant treatment in resectable pancreatic cancer does not improve disease-free survival or overall survival compared to upfront surgery followed by adjuvant treatment 4

Post-Neoadjuvant Considerations

• Patients who have received neoadjuvant chemoRT or chemotherapy may be candidates for additional chemotherapy after surgery and multidisciplinary review 1
• When additional chemotherapy is given after surgery, the choice of regimen may be based on the observed response to neoadjuvant therapy and other clinical considerations 1
• Treatment should ideally be initiated within 4 to 8 weeks after surgery 1

Caveats and Limitations

• No randomized phase III trials have compared neoadjuvant therapy in borderline resectable disease versus surgery without initial therapy 1
• Most studies evaluating neoadjuvant chemotherapy have used gemcitabine-based regimens; trials with more active combined regimens including modified FOLFIRINOX are ongoing 4
• Neoadjuvant strategies may delay potentially curative surgery in some patients with resectable disease 1
• The optimal neoadjuvant regimen has not been definitively established 1, 5