How to select the most appropriate adjuvant treatment after neoadjuvant treatment and resection for locally advanced pancreatic cancer?

Abstract

Adjuvant chemotherapy (ACT) significantly improves survival of patients undergoing upfront surgery for resectable pancreatic cancer. After introducing the concept of neoadjuvant therapy (NAT) with potent chemotherapy regimens, long term survival has been achieved even in patients with borderline and locally advanced pancreatic cancer (BR/LAPC) following radical resection. The observed pathologic tumor response is strongly predictive of survival and provides a unique opportunity to visualize to what extent the cancer has been sensitive to the administered chemotherapy regimen and may potentially give hint how to personalize further oncologic treatment. Current literature provides only limited and heterogeneous data as to whether and what type of ACT is beneficial after NAT and resection for BR/LAPC. Larger studies suggest that ACT may bring survival advantage and should be attempted particularly in node-positive disease and preferably with more potent regimen such as FOLFIRINOX, if tolerable. In case of complete pathologic response, particularly after FOLFIRINOX, it does not seem beneficial to deescalate the treatment during ACT, but whether continuation on the same regimen is worthwhile needs to be further examined. In case of gemcitabine-based treatment as NAT, continuation with more cycles seems to be of value unless tumor biology proves to be too aggressive, with high lymph node ratio. Whether switch to a different regimen should be sought, if tolerability allows it, needs to be further studied. Whether it is the exact treatment sequence (NAT, ACT or both) of the potent chemotherapy regimens like FOLFIRINOX and gemcitabinenab-paclitaxel or the total dose of chemotherapy that has impact on survival in BR/LAPC, is unknown.

The benefit of adjuvant chemotherapy following pancreaticoduodenectomy for pancreatic adenocarcinoma depends on response to neoadjuvant therapy

“…However, study completion is not anticipated until approximately 2030 13 . In the meantime, a variety of retrospective studies have attempted to determine which patients may ultimately derive the most benefit from AT after NAT and resection 11 . The lymph node ratio (LNR), the ratio of nodes harboring metastatic disease among all resected, has been studied in PDAC as a predictor of survival.…”

“…However, results of follow‐up studies with larger cohorts are conflicting and are challenging to compare due to differences in cohort classification (e.g., addition of patients with N0 disease among those with a low LNR) 16,17 . Similarly, studies investigating the benefit of AT after NAT and resection in which patients are stratified by node‐positive or ‐negative disease disagree on the survival advantage of additional treatment 11,17–19 . These conflicting results call for a better method of assessing AT benefit after NAT, potentially incorporating dynamic response of a tumor to therapy, such as tumor regression, CA19‐9 response 20,21 or, as in our study, with downstaging 22 …”

“…Response to therapy may be a selection marker for those with suspicion for disseminated disease (e.g., highly elevated CA19‐9) 9 . While use of NAT is increasingly common, no randomized trial data currently exists to guide treatment decisions regarding administration of adjuvant therapy (AT) after NAT and resection for PDAC 10,11 . As a result, decision‐making for those being considered for AT after NAT currently relies upon expert consensus based on extrapolation of existing AT studies and retrospective analyses with heterogeneous regimens and discordant conclusions 5,11 .…”

“…9 While use of NAT is increasingly common, no randomized trial data currently exists to guide treatment decisions regarding administration of adjuvant therapy (AT) after NAT and resection for PDAC. 10,11 As a result, decision-making for those being considered for AT after NAT currently relies upon expert consensus based on extrapolation of existing AT studies and retrospective analyses with heterogeneous regimens and discordant conclusions. 5,11 Currently, the American Society of Clinical Oncology recommends AT for resected patients who received any preoperative treatment for a total of 6 months of therapy, whereas the National Comprehensive Cancer Network suggests the consideration of AT after NAT without more specific recommendations.…”

“…10,11 As a result, decision-making for those being considered for AT after NAT currently relies upon expert consensus based on extrapolation of existing AT studies and retrospective analyses with heterogeneous regimens and discordant conclusions. 5,11 Currently, the American Society of Clinical Oncology recommends AT for resected patients who received any preoperative treatment for a total of 6 months of therapy, whereas the National Comprehensive Cancer Network suggests the consideration of AT after NAT without more specific recommendations. 3,5 We performed a retrospective review of the National Cancer Database (NCDB) to specifically analyze which patients may benefit from AT following NAT and pancreaticoduodenectomy for PDAC, with a primary outcome of overall survival (OS).…”