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

From the Department of Radiation Oncology, Department of Medicine, Division of Hematology-Oncology, and Department of Radiology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA

Address reprint requests to Alphonse Taghian, MD, PhD, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; e-mail: ataghian{at}partners.org

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.

Supported by a grant from Massachusetts Department of Public Health, an Investigator Initiated grant from Bristol-Myers-Squibb, the Massachusetts General Hospital Cancer Center, the Susan and Michael Schechter Research Fund, Jane Mailloux Research Fund, and the National Cancer Institute (NCI)/Avon supplement to NCI Specialized Programs of Research Excellence (SPORE) award, P50 CA89393, entitled "Dana-Farber SPORE in Breast Cancer."

Presented in part at the International Conference of Radiation Research, Brisbane, Australia, August 17-21, 2003, and at the 23rd Annual Meeting of the European Society of Therapeutic Radiology and Oncology, Amsterdam, Netherlands, October 24-28, 2004.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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