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Pharmacokinetic Study of Perioperative Intravenous Ifosfamide
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
Washington Cancer Institute, Washington D.C., USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
Washington Cancer Institute, Washington D.C., USA.
2011 (English)In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, 185092- p.Article in journal (Refereed) Published
Abstract [en]

Background

The use of cancer chemotherapy as part of a surgical procedure in the management of patients with peritoneal carcinomatosis has gained prominence in recent years with selected patients showing benefit. Various combinations of intraperitoneal and systemic chemotherapy used with moderate hyperthermia constitute the cytotoxic component of this therapy.  Ifosfamide, being a heat synergized drug, may be an important chemotherapy agent to use when attempting to optimize this treatment strategy. 

Materials and methods

16 Patients with peritoneal surface malignancy following cancer resection were treated with intraperitoneal hyperthermic (41.5 - 42.5°C) cisplatin and doxorubicin combined with the infusion of systemic ifosfamide chemotherapy.  Using high pressure liquid chromatography (HPLC) the concentrations of ifosfamide and 4-hydroxyifosfamide were determined in plasma, peritoneal fluid, urine, and when possible, within small tumor nodules less than 1 cm.

Results

Urine ifosfamide and 4-hydroxyifosfamide concentrations exceeded those within the plasma and peritoneal fluid throughout the 90 minutes of drug infusion.  Plasma concentrations of ifosfamide exceeded peritoneal fluid levels of ifosfamide during the 90 minutes of chemotherapy infusion; however, at 60 minutes after infusion ceased, the peritoneal fluid and plasma concentrations were equivalent.  Both ifosfamide and 4-hydroxyifosfamide could be recovered from peritoneal tumor nodules throughout the 90 minutes of ifosfamide continuous infusion and exceeded plasma concentrations.

Conclusions

Clear understanding of the pharmacology of perioperative intraperitoneal hyperthermia combined with systemic chemotherapy may provide important information for the design of treatment regimens.  4-hydroxyifosfamide within cancerous tissue suggested a favorable pharmacologic endpoint in the study of ifosfamide administered in the operating room. 

Place, publisher, year, edition, pages
2011. 185092- p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-133274DOI: 10.1155/2011/185092OAI: oai:DiVA.org:uu-133274DiVA: diva2:360824
Available from: 2010-11-04 Created: 2010-11-04 Last updated: 2017-12-12Bibliographically approved
In thesis
1. A Pharmacokinetic and Pharmacodynamic Rationale for Perioperative Cancer Chemotherapy in Patients with Peritoneal Carcinomatosis
Open this publication in new window or tab >>A Pharmacokinetic and Pharmacodynamic Rationale for Perioperative Cancer Chemotherapy in Patients with Peritoneal Carcinomatosis
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Peritoneal carcinomatosis (PC) is a common manifestation of both gastrointestinal and gynecologic malignancies. Until recently, this condition was considered beyond curative intent treatment. Since the 1980s, new treatment strategies combining cytoreductive surgery (CRS) with perioperative intraperitoneal and intravenous chemotherapy have emerged. The underlying hypothesis considers CRS responsible for the removal of the macroscopic disease and that perioperative chemotherapy should address the residual microscopic disease. These new treatment regimens have presented encouraging clinical results that contrast with prior failure. The parameters for perioperative chemotherapy are mainly extrapolated from literature on peritoneal dialysis and data from systemic chemotherapy. The overall aim of this thesis was to provide a pharmacokinetic and pharmacodynamic rationale for perioperative intraperitoneal (IP) and intravenous (IV) chemotherapy in PC patients and, to assess its toxicity. After intraoperative IV administration of 5-fluorouracil or ifosfamide, substantial levels of these drugs were found inside the peritoneal fluid and tumor nodules (Papers I and II). This created a pharmacologically advantageous situation whereby a normothermic administered IV drug was subject to the effect of the local hyperthermia in the peritoneal fluid and tumor nodule. High levels of 5-fluouracil, ifosfamide and doxorubicin were observed inside the tumor nodules (Papers I, II and III) and, the identical pharmacokinetic advantage (expressed as Area Under the Curve (AUC) IP/IV ratios)) resulted in different drug levels of doxorubicin according to the density of the tumor nodules (Paper III). These data stressed the importance of pharmacodynamic variables such as tumor nodule density, size, and, vascularity. Therefore, the tumor nodule is proposed as a more appropriate pharmacological endpoint than AUC ratios. After IP Mitomycin C administration in PC patients with a contracted abdomen, mitomycin clearance from the abdomen decreased (Paper IV), which indicated  these patients at risk of under-treatment. Consequently, these pharmacologic data indicate a change in dosimetry for these treatment protocols might be warranted according to the diffusion area. Although diffusional vectors are viewed the main driving force for these treatment protocols, only pharmacokinetic variables such as dose, volume and duration are considered. As pharmacodynamic variables are equally important in the pharmacological assessment of cytotoxic effect, the tumor nodule was proposed as the center of a new conceptual model (Paper I). Mitomycin C data on non-metabolizers ( Paper IV) indicated the cytotoxicity of these cancer chemotherapy protocols is at the level of the individual tumor nodules. The morbidity and mortality of a new bidirectional intraoperative chemotherapy regimen in PC patients was analyzed (Paper V) which provided a means for identifying subsets of patients at risk for increased toxicity. This thesis provides pharmacokinetic and pharmacodynamic guidance for improving perioperative chemotherapy treatment strategies in PC patients and reports its toxicity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 75 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 625
Keyword
Peritoneal carcinomatosis, Cytoreductive surgery, Intraperitoneal Chemotherapy, HIPEC, EPIC, Pharmacokinetics, Pharmacodynamics, Morbidity, Mortality
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:uu:diva-133277 (URN)978-91-554-7952-7 (ISBN)
Public defence
2010-12-17, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2010-11-26 Created: 2010-11-04 Last updated: 2011-01-13Bibliographically approved

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