title: Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications.
abstract: OBJECTIVE
  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 (pO(2)) of tumors. Our aim is to evaluate the IFP and pO(2) before and after neoadjuvant CT using sequential paclitaxel and doxorubicin in patients with breast cancer tumors of >/= 3 cm.
  
  
  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/m(2) every 2 weeks followed by nine cycles of weekly paclitaxel at 80 mg/m(2) (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 pO(2) (Eppendorf) were measured in tumors at baseline and after completing the administration of the first and second drug.
  
  
  RESULTS
  IFP and pO(2) 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 pO(2) 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.
  
  
  CONCLUSIONS
  Paclitaxel significantly decreased the IFP and increased the pO(2), whereas doxorubicin did not cause any significant changes. Tumor physiology could potentially be used to optimize the sequence of neoadjuvant CT in breast cancer.
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. ataghian@partners.org
authors.forename: Alphonse G
authors.initials: AG
authors.lastname: Taghian
authors.forename: Rita
authors.initials: R
authors.lastname: Abi-Raad
authors.forename: Sherif I
authors.initials: SI
authors.lastname: Assaad
authors.forename: Adrian
authors.initials: A
authors.lastname: Casty
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.forename: Eren
authors.initials: E
authors.lastname: Yeh
authors.forename: Peryhan
authors.initials: P
authors.lastname: Molokhia
authors.forename: Khaled
authors.initials: K
authors.lastname: Attia
authors.forename: Timothy
authors.initials: T
authors.lastname: Sullivan
authors.forename: Irene
authors.initials: I
authors.lastname: Kuter
authors.forename: Yves
authors.initials: Y
authors.lastname: Boucher
authors.forename: Simon N
authors.initials: SN
authors.lastname: Powell
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D045604:Extracellular Fluid / Q000187:drug effects; D005260:Female; D006801:Humans; D008593:Menopause; D008875:Middle Aged; D010101:Oxygen Consumption / Q000187:drug effects; D017239:Paclitaxel / Q000008:administration & dosage
chemical_list: D004317:Doxorubicin; D017239:Paclitaxel