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Toxicity of a Uniform Combined Bidirectional Hyperthermic and Perioperative Intraperitoneal Chemotherapy Regimen after Cytoreductive Surgery in 147 Peritoneal Surface Malignancy Patients
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.
Washington Cancer Institute, Washington DC, USA.
Washington Cancer Institute, Washington DC, USA.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background

Currently, the treatment of peritoneal surface malignancy is managed in selected patients by the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The chemotherapy agents utilized are selected from response rates in the treatment of gross disease and from pharmacologic studies. These agents are then subjected to morbidity/mortality studies to establish the safety of the treatment. The aim of this study was to analyze the morbidity and mortality of a new bidirectional hyperthermic and perioperative intraperitoneal chemotherapy regimen used after cytoreductive surgery.

Materials and Methods

Patients (n=147) with peritoneal surface malignancy received a uniform treatment of cytoreductive surgery combined with intraoperative chemotherapy. HIPEC with mitomycin C and doxorubicin was supplemented with intravenous 5-fluorouracil and leucovorin. In 65 patients, additional early postoperative intraperitoneal (EPIC) 5-fluorouracil was added to the HIPEC for the first four postoperative days. The clinical factors were cataloged prospectively and any adverse events (AE) were tabulated. 

Results

In 85% of patients, complete cytoreduction was achieved. There was an increase in grade IV AE in patients with incomplete cytoreduction (p<0.04) and in patients receiving fresh frozen plasma (p<0.001). For both grades III and IV AE, a right colon resection increased morbidity (p<0.02) and chemotherapy treatment HIPEC plus EPIC increased morbidity, compared to HIPEC alone (p<0.05). The overall morbidity (grades I-IV) was 64% and mortality was 0.6%.

Conclusion

The new bidirectional hyperthermic and perioperative intraperitoneal chemotherapy regimen used after CRS can be safely applied in peritoneal carcinomatosis patients.

National Category
Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-133276OAI: oai:DiVA.org:uu-133276DiVA: diva2:360828
Available from: 2010-11-04 Created: 2010-11-04 Last updated: 2013-05-27Bibliographically 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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