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A Pharmacokinetic and Pharmacodynamic Rationale for Perioperative Cancer Chemotherapy in Patients with Peritoneal Carcinomatosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
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. , p. 75
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 625
Keyword [en]
Peritoneal carcinomatosis, Cytoreductive surgery, Intraperitoneal Chemotherapy, HIPEC, EPIC, Pharmacokinetics, Pharmacodynamics, Morbidity, Mortality
National Category
Surgery
Research subject
Surgery
Identifiers
URN: urn:nbn:se:uu:diva-133277ISBN: 978-91-554-7952-7 (print)OAI: oai:DiVA.org:uu-133277DiVA, id: diva2:360840
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
List of papers
1. Pharmacology of perioperative 5-fluorouracil
Open this publication in new window or tab >>Pharmacology of perioperative 5-fluorouracil
2010 (English)In: Journal of Surgical Oncology, ISSN 0022-4790, E-ISSN 1096-9098, Vol. 102, no 7, p. 730-735Article 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.

Keyword
5-fluorouracil, intraperitoneal chemotherapy, intravenous chemotherapy, pharmacokinetics, pharmacodynamics, appendiceal cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-133273 (URN)10.1002/jso.21702 (DOI)000285281300006 ()21104923 (PubMedID)
Available from: 2010-11-04 Created: 2010-11-04 Last updated: 2017-12-12Bibliographically approved
2. Pharmacokinetic Study of Perioperative Intravenous Ifosfamide
Open this publication in new window or tab >>Pharmacokinetic Study of Perioperative Intravenous Ifosfamide
2011 (English)In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, p. 185092-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. 

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-133274 (URN)10.1155/2011/185092 (DOI)
Available from: 2010-11-04 Created: 2010-11-04 Last updated: 2017-12-12Bibliographically approved
3. A pharmacologic analysis of intraoperative intracavitary cancer chemotherapy with doxorubicin
Open this publication in new window or tab >>A pharmacologic analysis of intraoperative intracavitary cancer chemotherapy with doxorubicin
2009 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 63, no 5, p. 799-805Article 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.

Keyword
Intraperitoneal chemotherapy, Intrapleural chemotherapy, Doxorubicin, Pharmacokinetics, Pharmacodynamics, Appendiceal cancer, Peritoneal mesothelioma, Pleural mesothelioma
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-103497 (URN)10.1007/s00280-008-0800-0 (DOI)000263787600006 ()18654746 (PubMedID)
Available from: 2009-05-19 Created: 2009-05-19 Last updated: 2017-12-13Bibliographically approved
4. Changes Induced by Surgical and Clinical Factors in the Pharmacology of Intraperitoneal Mitomycin C in 145 Patients with Peritoneal Carcinomatosis
Open this publication in new window or tab >>Changes Induced by Surgical and Clinical Factors in the Pharmacology of Intraperitoneal Mitomycin C in 145 Patients with Peritoneal Carcinomatosis
Show others...
2011 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 68, no 1, p. 147-156Article 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-133275 (URN)10.1007/s00280-010-1460-4 (DOI)000292048100016 ()20857115 (PubMedID)
Available from: 2010-11-04 Created: 2010-11-04 Last updated: 2017-12-12Bibliographically approved
5. Toxicity of a Uniform Combined Bidirectional Hyperthermic and Perioperative Intraperitoneal Chemotherapy Regimen after Cytoreductive Surgery in 147 Peritoneal Surface Malignancy Patients
Open this publication in new window or tab >>Toxicity of a Uniform Combined Bidirectional Hyperthermic and Perioperative Intraperitoneal Chemotherapy Regimen after Cytoreductive Surgery in 147 Peritoneal Surface Malignancy Patients
Show others...
(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:nbn:se:uu:diva-133276 (URN)
Available from: 2010-11-04 Created: 2010-11-04 Last updated: 2018-01-12Bibliographically approved

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