Abstract
Approximately 20% of pancreatic ductal adenocarcinoma (PDAC) patients have (borderline) resectable pancreatic cancer [(B)RPC] at diagnosis. Upfront resection with adjuvant chemotherapy has long been the standard of care for these patients. However, although surgical quality has improved, still about 50% of patients never receive adjuvant treatment. Therefore, recent developments have focused on a neoadjuvant approach. Directly comparing results from neoadjuvant and adjuvant regimens is challenging due to differences in patient populations that influence outcomes. Neoadjuvant trials include all patients who have (B)RPC on imaging, while adjuvant-only trials include patients who underwent a complete resection and recovered to a good performance status without any evidence of residual disease. Guidelines recommend neoadjuvant treatment for BRPC patients mainly to improve negative resection margin (R0) rates. For resectable PDAC, upfront resection is still considered the standard of care. However, theoretical advantages of neoadjuvant treatment, including the increased R0 resection rate, early delivery of systemic therapy to all patients, directly addressing occult metastatic disease, and improved patient selection for resection, may also apply to these patients. A systematic review by intention-to-treat showed a superior median overall survival (OS) for any neoadjuvant approach (19 months) compared to upfront surgery (15 months) in (B)RPC patients. A neoadjuvant approach was recently supported by three randomized controlled trials (RCTs). For resectable PDAC, neoadjuvant treatment was superior in a Japanese RCT of neoadjuvant gemcitabine with S-1 vs. upfront surgery, with adjuvant S-1 in both arms (median OS: 37 vs. 27 months, p = 0.015). A Korean trial of neoadjuvant gemcitabine-based chemoradiotherapy vs. upfront resection in BRPC patients was terminated early due to superiority of the neoadjuvant group (median OS: 21 vs. 12 months, p = 0.028; R0 resection: 52 vs. 26%, p = 0.004). The PREOPANC-1 trial for (B)RPC patients also showed favorable outcome for neoadjuvant gemcitabine-based chemoradiotherapy vs. upfront surgery (median OS: 17 vs. 14 months, p = 0.07; R0 resection: 63 vs. 31%, p < 0.001). FOLFIRINOX is likely a better neoadjuvant regimen, because of superiority compared to gemcitabine in both the metastatic and adjuvant setting. Currently, five RCTs evaluating neoadjuvant modified or fulldose FOLFIRINOX are accruing patients.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) accounts for 3% of all new cancer diagnoses, and incidence rates continue to slowly increase
Patients in neoadjuvant trials may have occult metastatic disease at surgery or may not fully recover from surgery; patients in adjuvant trials were selected after overcoming these hurdles
Despite the limited number of published randomized controlled trials (RCTs) comparing a neoadjuvant approach to upfront surgery, patients with resectabel PDAC and BRPC seem to consistently benefit from a neoadjuvant approach with regards to the R0 resection rate
Summary
Pancreatic ductal adenocarcinoma (PDAC) accounts for 3% of all new cancer diagnoses, and incidence rates continue to slowly increase. For metastatic PDAC, palliative treatment using multi-agent chemotherapy such as a combination of 5-FU, oxaliplatin, and irinotecan (FOLFIRINOX) or gemcitabine with nab-paclitaxel is the standard of care based on randomized controlled trials (RCTs) [3, 4]. These therapies have been shown to increase life expectancy with 2–4 months. For locally advanced pancreatic cancer (LAPC), no RCT has been completed, but based on a patient-level meta-analysis and the survival benefit in metastatic PDAC, FOLFIRINOX, and gemcitabine with nab-paclitaxel are the standard initial treatments [5]. The remaining 20% of PDAC patients have (borderline) resectable pancreatic cancer [(B)RPC] at diagnosis
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