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Changes Induced by Surgical and Clinical Factors in the Pharmacology of Intraperitoneal Mitomycin C in 145 Patients with Peritoneal Carcinomatosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
Washington Cancer Institute, Washington D.C., USA.
Westat, Rockville, MD, USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
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2011 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 68, no 1, 147-156 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are a combined treatment modality considered for selected patients with peritoneal carcinomatosis from colorectal and appendiceal cancer. Mitomycin C is a drug often used in this clinical setting. The surgical and clinical factors that may influence the pharmacokinetics of hyperthermic intraperitoneal chemotherapy should be further elucidated.

MATERIALS AND METHODS: The patients included were 145 who had colorectal or appendiceal carcinomatosis resected using cytoreductive surgery prior to treatment with hyperthermic intraperitoneal chemotherapy with mitomycin C as part of a multidrug regimen. The effect of clinical and surgical factors on drug distribution after single intraperitoneal bolus administration with mitomycin C was determined.

RESULTS: The pharmacokinetics of 145 patients treated with intraperitoneal mitomycin C showed a 27 times greater exposure to peritoneal surfaces when compared to plasma. At 90 min, 29% of the drug remained in the chemotherapy solution, 62% was retained in the body, and 9% was excreted in the urine. The extent of peritonectomy increased the clearance of mitomycin C from the peritoneal space (p = 0.051). A major resection of visceral peritoneal surface and a contracted peritoneal space reduced drug clearance. A contracted peritoneal space significantly reduced (p = 0.0001) drug concentrations in the plasma.

CONCLUSIONS: Surgical and clinical factors may require modifications of drug dose or timing of chemotherapy administration. A large visceral resection and a contracted peritoneal space caused a reduced mitomycin C clearance. Total diffusion surface is an important determinant of mitomycin C pharmacokinetics.

Place, publisher, year, edition, pages
2011. Vol. 68, no 1, 147-156 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-133275DOI: 10.1007/s00280-010-1460-4ISI: 000292048100016PubMedID: 20857115OAI: oai:DiVA.org:uu-133275DiVA: diva2:360825
Available from: 2010-11-04 Created: 2010-11-04 Last updated: 2015-07-23Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 625
Peritoneal carcinomatosis, Cytoreductive surgery, Intraperitoneal Chemotherapy, HIPEC, EPIC, Pharmacokinetics, Pharmacodynamics, Morbidity, Mortality
National Category
Research subject
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)
Available from: 2010-11-26 Created: 2010-11-04 Last updated: 2011-01-13Bibliographically approved

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