Paclitaxel Decreases the Interstitial Fluid Pressure and Improves Oxygenation in Breast Cancers in Patients Treated With Neoadjuvant Chemotherapy: Clinical Implications

Abstract

Purpose It has been hypothesized that tumors with high interstitial fluid pressure (IFP) and/or hypoxia respond poorly to chemotherapy (CT) because of poor drug delivery. Preclinical studies have shown that paclitaxel reduces the IFP and improves the oxygenation (pO₂) of tumors. Our aim is to evaluate the IFP and pO₂ before and after neoadjuvant CT using sequential paclitaxel and doxorubicin in patients with breast cancer tumors of ≥ 3 cm. Patients and Methods Patients were randomly assigned, according to an institutional review board–approved phase II protocol, to receive neoadjuvant sequential CT consisting of either four cycles of dose-dense doxorubicin at 60 mg/m² every 2 weeks followed by nine cycles of weekly paclitaxel at 80 mg/m² (group 1) or vice versa, with paclitaxel administered before doxorubicin (group 2). Patients were re-evaluated clinically and radiologically. The IFP (wick-in-needle technique) and pO₂ (Eppendorf) were measured in tumors at baseline and after completing the administration of the first and second drug. Results IFP and pO₂ were measured in 54 patients at baseline and after the first CT. Twenty-nine and 25 patients were randomly assigned to groups 1 and 2, respectively. Paclitaxel, when administered first, decreased the mean IFP by 36% (P = .02) and improved the tumor pO₂ by almost 100% (P = .003). In contrast, doxorubicin did not have a significant effect on either parameter. This difference was independent of the tumor size or response measured by ultrasound. Conclusion Paclitaxel significantly decreased the IFP and increased the pO₂, whereas doxorubicin did not cause any significant changes. Tumor physiology could potentially be used to optimize the sequence of neoadjuvant CT in breast cancer.