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Pharmacology of perioperative 5-fluorouracil
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.
2010 (English)In: Journal of Surgical Oncology, ISSN 0022-4790, E-ISSN 1096-9098, Vol. 102, no 7, 730-735 p.Article in journal (Refereed) Published
Abstract [en]

Background

The purpose of this study was to analyze our current pharmacologic data regarding the perioperative use of 5-fluorouracil in the treatment of peritoneal surface malignancies.

Methods

Twenty-nine patients with peritoneal carcinomatosis from appendiceal malignancy were included in this pharmacological study.

Results

In the nine patients who received early postoperative intraperitoneal chemotherapy, the area under the curve for intraperitoneal 5-fluorouracil was 43,000 (+20,300) µg/ml x minutes and for intravenous 5-fluorouracil was 157 (+99) µg/ml x minutes.  The area under the curve ratio was 422 (+360). In 20 patients who received intravenous 5-fluorouracil in the operating room intraperitoneal 5-fluorouracil levels maintained a higher level as compared to the intravenous drug level over the 90 minutes of drug sampling. The area under the curve ratio of peritoneal fluid to plasma was 2.3 (+1.3). The area under curve ratio of peritoneal fluid to tumor nodules was 9.9 (+9.8).  The area under the curve ratio of plasma to tumor nodules was 5.2 (+4.7).

Conclusions

By modulating the route or timing of administration of 5-fluorouracil, it becomes a pharmacologic advantageous molecule in patients with peritoneal carcinomatosis of an appendiceal malignancy. 5-fluorouracil remains the cornerstone of the perioperative management of peritoneal carcinomatosis of gastrointestinal origin.

Place, publisher, year, edition, pages
2010. Vol. 102, no 7, 730-735 p.
Keyword [en]
5-fluorouracil, intraperitoneal chemotherapy, intravenous chemotherapy, pharmacokinetics, pharmacodynamics, appendiceal cancer
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-133273DOI: 10.1002/jso.21702ISI: 000285281300006PubMedID: 21104923OAI: oai:DiVA.org:uu-133273DiVA: diva2:360823
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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Van der Speeten, KurtMahteme, Haile

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