Real-world dose reduction of standard and modified FOLFIRINOX in metastatic pancreatic cancer: a systematic review, evidence-mapping, and meta-analysis

Background: FOLFIRINOX, used in metastatic pancreatic cancer (MPC), is highly efficacious but also toxic. Various dose modifications for FOLFIRINOX have been introduced to reduce toxicity. However, these studies lack a unified pattern for `planned' dose modification, and the `actually administered' dose varied more. Objective: To map a 10-year trend for `planned' and `actual' doses of FOLFIRINOX and investigate the clinical outcomes according to dose modification. Data sources and methods: A comprehensive systematic literature search was conducted from January 2011 to September 2021. All studies for FOLFIRINOX as first-line treatment in MPC were considered. Selected studies were firstly classified according to prospective versus retrospective research, secondly standard versus modified FOLFIRINOX, and thirdly `planned' versus `actual' dose. For evidence-mapping for the trend of dose modification, we developed a web-based interactive bubble-plot program (www.RDI-map.com). Objective response rate (ORR) and hematologic toxicity were set as endpoints for the comparison of clinical outcomes according to dose modification. Results: A total of 37 studies were identified for evidence-mapping (11 prospective and 26 retrospective studies). There were 12 different types of `planned' dose modification in FOLFIRINOX ranging 75-100% oxaliplatin, 75-100% irinotecan, 0-100% 5-fluorouracil (5-FU) bolus, and 75-133% 5-FU continuous injection. The `actual' dose further decreased to 54-96%, 61-88%, 0-92%, and 63-98%, respectively. For the standard versus modified FOLFIRINOX, the ORR was 28.2% (95% CI: 22.5-33.9%) and 33.8% (95% CI: 30.3-37.3%), respectively (p = 0.100), and the incidence of febrile neutropenia was 11.6% (95% CI: 0-16.0%) and 5.5% (95% CI: 0-8.9%), respectively (p = 0.030). Conclusions: RDI-map.com enables multifactorial evidence-mapping for practical FOLFIRINOX dose reduction. The pattern of dose modification was not consistent across studies, and there was a significant gap between the `planned' and `actual' doses. Modified FOLFIRINOX showed similar efficacy to the standard regimen with reduced incidence of febrile neutropenia.