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A pharmacologic analysis of intraoperative intracavitary cancer chemotherapy with doxorubicin
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
2009 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 63, no 5, 799-805 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: A pharmacologic analysis of intracavitary doxorubicin in the treatment of patients with intracavitary cancer dissemination was performed to further evaluate the possible benefits of this treatment modality. METHODS: Twenty appendiceal malignancy patients with peritoneal carcinomatosis (PC), three appendiceal malignancy patients with direct extension into the pleural cavity, 20 patients with peritoneal mesothelioma and one patient with pleural mesothelioma were available for pharmacologic monitoring. After intraperitoneal or intrapleural administration of doxorubicin, plasma and peritoneal fluid samples were obtained at 15, 30, 45, 60 and 90 min in all patients. After intrapleural administration, plasma and pleural fluid samples were collected at similar intervals. Tumor and normal tissues were obtained when available. Doxorubicin concentrations were determined by high-performance liquid chromatography (HPLC). RESULTS: Intraperitoneal doxorubicin showed a prolonged retention in the peritoneal cavity. Doxorubicin concentrations in tumor tissue were consistently elevated above intraperitoneal concentrations from 30 through 90 min. For appendiceal malignancy, the concentrations of doxorubicin were significantly higher in minimally aggressive mucinous tumors. Pleural chemotherapy solutions retained doxorubicin to a greater extent than peritoneal fluid. CONCLUSIONS: Doxorubicin shows characteristics favorable for intracavitary administration with sequestration of doxorubicin in cancer nodules.

Place, publisher, year, edition, pages
2009. Vol. 63, no 5, 799-805 p.
Keyword [en]
Intraperitoneal chemotherapy, Intrapleural chemotherapy, Doxorubicin, Pharmacokinetics, Pharmacodynamics, Appendiceal cancer, Peritoneal mesothelioma, Pleural mesothelioma
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-103497DOI: 10.1007/s00280-008-0800-0ISI: 000263787600006PubMedID: 18654746OAI: oai:DiVA.org:uu-103497DiVA: diva2:218339
Available from: 2009-05-19 Created: 2009-05-19 Last updated: 2017-12-13Bibliographically 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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