Liposomal irinotecan pre-emptive dose reduction in patients with pancreatic ductal adenocarcinoma: 667 patients’ experience within a population-based study

Abstract

Background: Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is currently the standard second-line treatment for patients with pancreatic ductal adenocarcinoma (PDAC) after previous failed gemcitabine-based therapy. This population-based study aimed to evaluate the efficacy and safety of nal-IRI + 5-FU/LV and the association of pre-emptive nal-IRI dosing with treatment outcomes in patients with PDAC. Methods: We retrospectively enrolled a total of 667 consecutive patients with PDAC who received nal-IRI plus 5-FU/LV treatment between August 2018 and November 2020 at 9 medical centers in Taiwan. Patients were allocated into groups according to pre-emptive nal-IRI dosing (⩾75%, 50–74%, <50%) for comparison of treatment efficacy and safety. Results: The median overall survival (OS) and time to treatment failure (TTF) were 5.9 months [95% confidence interval (CI), 5.3–6.5] and 2.8 months (95% CI, 2.6–3.0), respectively. The median OS was 6.5 months (95% CI, 5.7–6.7), 5.0 months (95% CI, 3.4–6.5), and 4.1 months (95% CI, 2.7–5.6), respectively, among the ⩾75%, 50–74%, and <50% pre-emptive nal-IRI dosing groups, whereas the median TTF of the three groups was 3.0 months (95% CI, 2.6–3.4), 2.6 months (95% CI, 2.3–2.9), and 1.9 months (95% CI, 1.6–2.2), respectively. Pre-emptive nal-IRI dosing <50% was an independent negative prognostic factor for OS and TTF in multivariate analyses. The most common severe adverse events were neutropenia (22.9%), anemia (21.1%), and hypokalemia (15.4%). Patients in the <50% pre-emptive nal-IRI dosing group had a significantly lower incidence of neutropenia and non-neutropenic infection than those in the other groups. Conclusion: Our results support the use of nal-IRI + 5-FU/LV as standard clinical practice for treating patients with PDAC based on this large population-based study. Our findings encourage physicians to provide adequate doses of nal-IRI in order to achieve better outcomes without compromising safety profiles.

Effect of previous conventional irinotecan treatment in patients with pancreatic cancer being treated with liposomal irinotecan plus 5‐fluorouracil and leucovorin

“…Our previous study reported that previous conventional irinotecan treatment was a poor prognostic factor for survival outcome in Taiwanese patients with mPDAC treated with nal‐IRI+5‐FU/LV. However, this variable was insignificant in the multivariate model after adjusting for other confounding factors 18 . This finding indicated that the effect of nal‐IRI on survival outcome in mPDAC patients might be relevant to clinical factors other than prior conventional irinotecan treatment.…”

“…However, this variable was insignificant in the multivariate model after adjusting for other confounding factors. 18 This finding indicated that the effect of nal-IRI on survival outcome in The subgroup analysis in the NAPOLI-1 study showed that the hazard ratio of OS in patients previously treated with conventional irinotecan favored the 5-FU/LV treatment compared to the nal-IRI+5-FU/LV treatment. 19 This analysis has been criticized as a post-hoc univariate analysis which did not balance the basic characteristics of patients previously treated with conventional irinotecan.…”

A real-world analysis on the efficacy and tolerability of liposomal irinotecan plus 5-fluorouracil and folinic acid in metastatic pancreatic ductal adenocarcinoma in Belgium

“… 14 , 21 This might be explained by the fact that dose reductions were used to manage adverse effects, as such preventing treatment discontinuation and allowing patients to remain on the treatment longer. 22 Indeed, limiting treatment toxicities using dose modifications improved the efficacy of nab-paclitaxel + gemcitabine. 23 – 25 All this indicates that improving the tolerability of the chemotherapy with dose modifications might lead to a better quality of life, without compromising the efficacy and even results in increased time on treatment.…”

Emerging Trends and Research Foci in Tumor Microenvironment of Pancreatic Cancer: A Bibliometric and Visualized Study

“…Recent data suggest that early intervention with nal-IRI in the treatment modality significantly improves median OS and PFS in pancreatic cancer. Onivyde (intravenous liposomal irinotecan injection) is approved for use in combination with 5-fluorouracil and leucovorin (5-FU/LV) in patients with metastatic pancreatic adenocarcinoma that has progressed following gemcitabine-based therapy and was developed to overcome the pharmacological and clinical limitations of nonliposomal irinotecan ( 60 – 62 ). Vactosertib (a selective small-molecule inhibitor of the TGF-β type I receptor kinase ALK5) in combination with paclitaxel constructs nanoliposome complexes to increase drug solubilization while overcoming the barriers to drug penetration by PDAC matrix utilization and reducing side effects ( 63 ).…”