Quantifying the impact of metronomic chemotherapy chemo-switch regimen and the sequencing of chemotherapy and radiotherapy on pancreatic ductal adenocarcinoma treatment.

Abstract

Metronomic chemotherapy (MCT) is a novel chemotherapy approach characterized by a high-frequency, low-dose administration strategy. The "chemo-switch" regimen involves the sequential use of two dosing strategies: maximum tolerated dose (MTD) chemotherapy and MCT. For patients with pancreatic ductal adenocarcinoma (PDAC), selecting novel chemotherapy regimens appropriately according to their physical conditions may help address the challenges associated with MTD chemotherapy, such as excessive toxicity, prolonged tumor recovery, and suboptimal efficacy. There is currently limited research on mathematical models related to novel chemotherapy regimens and PDAC, as well as on the impact of different drug administration strategies and the sequence of chemoradiotherapy in combined treatment. To address these gaps, we propose a two-dimensional multiscale mathematical model. Initially, we model the individual effects of MTD chemotherapy, antiangiogenic therapy, and radiotherapy. Subsequently, we analyze the anti-tumor effects of various chemotherapy regimens and their underlying mechanisms. Furthermore, we assess how different drug administration regimens and the sequencing of chemotherapy and radiotherapy affect treatment outcomes. Simulation results indicate that, compared to standard MTD chemotherapy, using the MCT regimen or introducing MCT during MTD chemotherapy (chemo-switch regimen) demonstrates better anti-tumor efficacy and sustained tumor perfusion, enhancing drug accumulation within tumor regions. Combined therapy exhibits superior efficacy compared to monotherapy. Placing radiotherapy after anti-angiogenic therapy and chemotherapy suggests more effective in suppressing tumor growth and sustaining tumor perfusion. It is noteworthy that while this study focuses on PDAC treatment, its findings can be extrapolated to other fibrotic tumors, thereby facilitating similar analyses across different tumor types.