In the largest international multicentre study to date, including 742 patients after resection for localised pancreatic adenocarcinoma following preoperative (m)FOLFIRINOX, compared to no adjuvant chemotherapy, both adjuvant (m)FOLFIRINOX and other multiagent adjuvant regimens were associated with prolonged overall survival (OS), whereas an adjuvant single agent regimen was not.
The impact of adjuvant chemotherapy on OS may be lower in subgroups such as patients with 8 or more preoperative cycles of (m)FOLFIRINOX, those having radiological response, and those with ypN0 disease according to Drs. Thomas F. Stoop, Marc G. Besselink of the Amsterdam UMC in Amsterdam, the Netherlands and colleagues from the Scientific Committee of the European-African Hepato-Pancreato-Biliary Association and International Collaboration on Advanced Pancreatic Cancer, who published the findings on 23 January 2025 in the JAMA Oncology.
The authors wrote in the background that current data suggest that adjuvant chemotherapy after preoperative chemotherapy is associated with prolonged OS, either in all patients or exclusively in those with presence of certain characteristics, e.g. depending on preoperative CA-19.9, lymph node involvement (either ypN0 or ypN1-2), larger tumour size, perineural invasion, and/or positive resection margin. Particularly, evidence about ypN status as an indicator for adjuvant chemotherapy is conflicting.
However, these studies are limited by the lack of adjustment for the number of preoperative chemotherapy cycles and specific adjuvant chemotherapy regimens used. Clinicians specifically doubt the value of adjuvant therapy if patients have already received 8 or more cycles of (m)FOLFIRINOX preoperatively.
This international observational study investigated the association of adjuvant chemotherapy with OS in patients with localised pancreatic adenocarcinoma (e.g. primary resectable, borderline resectable, and locally advanced pancreatic cancer) who underwent resection after preoperative (m)FOLFIRINOX, taking into account the number of preoperative chemotherapy cycles and the adjuvant chemotherapy regimen.
This retrospective cohort study included patients with localised pancreatic adenocarcinoma treated with 2 to 11 cycles of preoperative (m)FOLFIRINOX followed by resection across 48 centres in 20 countries from 2010 to 2018. Patients who died within 3 months after surgery were excluded (landmark). Data were analyzed from 1 February to 31 December 2023. The primary outcome was OS, calculated from the 3-month landmark. Cox regression analysis, including interaction analyses, was performed to investigate the association of adjuvant chemotherapy with OS.
Overall, 767 patients were included after resection of pancreatic adenocarcinoma with median (IQR) age of 62 (55-67) years, 404 (52.7%) were male. Adjuvant chemotherapy was independently associated with prolonged OS (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.49-0.87), confirmed by adjusted OS curves.
The interaction analysis to assess estimated treatment effect across subgroups was not statistically significant. The forest plot and interaction test suggest that the association of adjuvant chemotherapy was lower among patients receiving 8 or more cycles of preoperative (m)FOLFIRINOX, those who had radiological response, and those with ypN0 disease.
Compared to no adjuvant chemotherapy, both adjuvant (m)FOLFIRINOX (HR 0.57, 95% CI 0.40-0.80) and other multiagent adjuvant regimens (HR 0.61, 95% CI 0.41-0.92) were associated with prolonged OS, whereas single-agent adjuvant chemotherapy was not (HR 0.75, 95% CI 0.55-1.03).
The authors commented that association of adjuvant chemotherapy with OS seemed to attenuate after approximately 30 months. Importantly, it cannot be ruled out that the association of adjuvant chemotherapy with OS is weaker or even absent in certain subgroups, which deserves further study. Randomised clinical trials are needed to give a definite answer on the value of adjuvant chemotherapy, particularly in subgroups such as those receiving 8 or more cycles of (m)FOLFIRINOX preoperatively, those with radiological response following preoperative therapy, and those with ypN0 disease.
Furthermore, the optimal number of cycles of perioperative chemotherapy should be addressed in future randomised clinical trials. A noninferiority design could be considered, randomising for receiving adjuvant chemotherapy or not in patients after resection following 8 cycles preoperative (m)FOLFIRINOX. Moreover, the value of adjuvant chemotherapy after resection following preoperative gemcitabine and nab-paclitaxel and NALIRIFOX should be investigated.
Considering the major limitations of histopathological tumour burden assessment as a surrogate marker for the sensitivity of the preoperatively administered chemotherapy, the use of alternatives such as liquid biopsies and organoids to assess the chemotherapy sensitivity may be of value. Moreover, promising results from molecular and genomic profiling should be integrated into these trials. Finally, the potential of total neoadjuvant chemotherapy should be assessed according to the authors.
Reference
Stoop TF, Sugawara T, Oba A, et al. for the Scientific Committee of the European-African Hepato-Pancreato-Biliary Association (E-AHPBA) and International Collaboration on Advanced Pancreatic Cancer. Adjuvant Chemotherapy After Resection of Localized Pancreatic Adenocarcinoma Following Preoperative FOLFIRINOX. JAMA Oncology; Published online 23 January 2025. doi:10.1001/jamaoncol.2024.5917