Pharmacokinetics of the perioperative use of cancer chemotherapy in peritoneal surface malignancy patients

K Van der Speeten, K Govaerts, O A Stuart, P H Sugarbaker, K Van der Speeten, K Govaerts, O A Stuart, P H Sugarbaker

Abstract

Background. The peritoneal surface is an acknowledged locoregional failure site of abdominal malignancies. Previous treatment attempts with medical therapy alone did not result in long-term survival. During the last two decades, new treatment protocols combining cytoreductive surgery with perioperative intraperitoneal and intravenous cancer chemotherapy have demonstrated very encouraging clinical results. This paper aims to clarify the pharmacologic base underlying these treatment regimens. Materials and Methods. A review of the current pharmacologic data regarding these perioperative chemotherapy protocols was undertaken. Conclusions. There is a clear pharmacokinetic and pharmacodynamic rationale for perioperative intraperitoneal and intravenous cancer chemotherapy in peritoneal surface malignancy patients.

Figures

Figure 1
Figure 1
Traditional two-compartment model of peritoneal transport in which transfer of a drug from the peritoneal cavity to the blood occurs across the “peritoneal membrane.” The permeability-area product (PA) governs this transfer and can be calculated by measuring the rate of drug disappearance from the cavity and dividing by the overall concentration difference between the peritoneal cavity and the blood (or plasma). CB: the free drug concentration in the blood (or plasma); VB: volume of distribution of the drug in the body; CP: the free drug concentration in the peritoneal fluid; VP: volume of the peritoneal cavity. Modified from R. L. Dedrick, M. F. Flessner: pharmacokinetic problems in peritoneal drug administration: Tissue penetration and surface exposure [31].
Figure 2
Figure 2
Doxorubicin concentration in plasma, peritoneal fluid, tumor nodules, and normal adjacent tissues [32].
Figure 3
Figure 3
Doxorubicin levels in appendiceal tumor tissue showing diffuse peritoneal adenomucinosis (DPAM) versus peritoneal mucinous carcinomatosis (PMCA). Peritoneal fluid concentrations are also shown. TN: tumor nodule; PF: peritoneal fluid [32].
Figure 4
Figure 4
5-Fluorouracil concentrations in plasma, peritoneal fluid, and tumor nodules after intravenous administration during hyperthermic intraperitoneal chemotherapy procedure [33].

References

    1. Jayne DG, Fook S, Loi C, Seow-Choen F. Peritoneal carcinomatosis from colorectal cancer. British Journal of Surgery. 2002;89(12):1545–1550.
    1. Brodsky JT, Cohen AM. Peritoneal seeding following potentially curative resection of colonic carcinoma: implications for adjuvant therapy. Diseases of the Colon and Rectum. 1991;34(8):723–727.
    1. Chu DZJ, Lang NP, Thompson C, Osteen PK, Westbrook KC. Peritoneal carcinomatosis in nongynecologic malignancy. A prospective study of prognostic factors. Cancer. 1989;63(2):364–367.
    1. Sadeghi B, Arvieux C, Glehen O, et al. Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer. 2000;88(2):358–363.
    1. Shepherd NA, Baxter KJ, Love SB. The prognostic importance of peritoneal involvement in colonic cancer: a prospective evaluation. Gastroenterology. 1997;112(4):1096–1102.
    1. Jemal A, Murray T, Ward E, Samuels A. Cancer statistics, 2005. Ca-A Cancer Journal for Clinicians. 2005;55:10–30.
    1. Poveda A. Ovarian cancer treatment: what is new. International Journal of Gynecological Cancer. 2003;13(2):241–250.
    1. Verwaal VJ, Van Ruth S, De Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. Journal of Clinical Oncology. 2003;21(20):3737–3743.
    1. Verwaal VJ, Bruin S, Boot H, van Slooten G, van Tinteren H. 8-Year follow-up of randomized trial: cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer. Annals of Surgical Oncology. 2008;15(9):2426–2432.
    1. Elias D, Lefevre JH, Chevalier J, et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. Journal of Clinical Oncology. 2009;27(5):681–685.
    1. Glehen O, Kwiatkowski F, Sugarbaker PH, et al. Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study. Journal of Clinical Oncology. 2004;22(16):3284–3292.
    1. Glehen O, Mithieux F, Osinsky D, et al. Surgery combined with peritonectomy procedures and intraperitoneal chemohyperthermia in abdominal cancers with peritoneal carcinomatosis: a phase II study. Journal of Clinical Oncology. 2003;21(5):799–806.
    1. Yan TD, Black D, Sugarbaker PH, et al. A systematic review and meta-analysis of the randomized controlled trials on adjuvant intraperitoneal chemotherapy for resectable gastric cancer. Annals of Surgical Oncology. 2007;14(10):2702–2713.
    1. Bijelic L, Jonson A, Sugarbaker PH. Systematic review of cytoreductive surgery and heated intraoperative intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis in primary and recurrent ovarian cancer. Annals of Oncology. 2007;18(12):1943–1950.
    1. Yan TD, Welch L, Black D, Sugarbaker PH. A systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for diffuse malignancy peritoneal mesothelioma. Annals of Oncology. 2007;18(5):827–834.
    1. Yan TD, Black D, Savady R, Sugarbaker PH. A systematic review on the efficacy of cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxoma peritonei. Annals of Surgical Oncology. 2007;14(2):484–492.
    1. Yan TD, Black D, Savady R, Sugarbaker PH. Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma. Journal of Clinical Oncology. 2006;24(24):4011–4019.
    1. Elias D, Glehen O, Gilly F. Carcinose péritonéales d’origine digestive et primitive. Proceedings of the Rapport du 110 éme Congrès de l’AFC; 2008; Arnette : Wolters Kluwer France;
    1. Dedrick RL, Myers CE, Bungay PM, Devita VT. Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treatment Reports. 1978;62(1):1–11.
    1. Dedrick RL. Theoretical and experimental bases of intraperitoneal chemotherapy. Seminars in Oncology. 1985;12(3, supplement 4):1–6.
    1. Baron MA. Structure of the intestinal peritoneum in man. American Journal of Anatomy. 1941;69:439–497.
    1. Flessner M, Henegar J, Bigler S, Genous L. Is the peritoneum a significant transport barrier in peritoneal dialysis? Peritoneal Dialysis International. 2003;23(6):542–549.
    1. De Lima Vazquez V, Stuart OA, Mohamed F, Sugarbaker PH. Extent of parietal peritonectomy does not change intraperitoneal chemotherapy pharmacokinetics. Cancer Chemotherapy and Pharmacology. 2003;52(2):108–112.
    1. Van der Speeten K, Stuart OA, Chang D, Mahteme H, Sugarbaker PH. Changes induced by surgical and clinical factors in the pharmacology of intraperitoneal mitomycin C in 145 patients with peritoneal carcinomatosis. Cancer Chemotherapy and Pharmacology. 2011;68(1):147–156.
    1. Stelin G, Rippe B. A phenomenological interpretation of the variation in dialysate volume with dwell time in CAPD. Kidney International. 1990;38(3):465–472.
    1. Bettendorf U. Lymph flow mechanism of the subperitoneal diaphragmatic lymphatics. Lymphology. 1978;11(3):111–116.
    1. Bettendorf U. Electronmicroscopic studies on the peritoneal resorption of intraperitoneally injected latex particles via the diaphragmatic lymphatics. Lymphology. 1979;12(2):66–70.
    1. Katz MH, Barone RM. The rationale of perioperative intraperitoneal chemotherapy in the treatment of peritoneal surface malignancies. Surgical Oncology Clinics of North America. 2003;12(3):673–688.
    1. Dedrick RL, Myers CE, Bungay PM, Devita VT. Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treatment Reports. 1978;62(1):1–11.
    1. Flessner MF, Fenstermacher JD, Dedrick RL, Blasberg RG. A distributed model of peritoneal-plasma transport: tissue concentration gradients. American Journal of Physiology. 1985;248(3):F425–F435.
    1. Dedrick RL, Flessner MF. Pharmacokinetic problems in peritoneal drug administration: tissue penetration and surface exposure. Journal of the National Cancer Institute. 1997;89(7):480–487.
    1. Van der Speeten K, Stuart OA, Mahteme H, Sugarbaker PH. A pharmacologic analysis of intraoperative intracavitary cancer chemotherapy with doxorubicin. Cancer Chemotherapy and Pharmacology. 2009;63(5):799–805.
    1. Van der Speeten K, Stuart OA, Mahteme H, Sugarbaker PH. Pharmacology of perioperative 5-fluorouracil. Journal of Surgical Oncology. 2010;102(7):730–735.
    1. Bachur NR, Gordon SL, Gee MV, Kon H. NADPH cytochrome P-450 reductase activation of quinone anticancer agents to free radicals. Proceedings of the National Academy of Sciences of the United States of America. 1979;76(2):954–957.
    1. Elias D, Dubé P, Blot F, et al. Peritoneal carcinomatosis treatment with curative intent: the Institut Gustave-Roussy experience. European Journal of Surgical Oncology. 1997;23(4):317–321.
    1. Sugarbaker PH, Chang D. Results of treatment of 385 patients with peritoneal surface spread of appendiceal malignancy. Annals of Surgical Oncology. 1999;6(8):727–731.
    1. Barlogie B, Corry PM, Drewinko B. In vitro thermochemotherapy of human colon cancer cells with cis-dichlorodiammineplatinum(II) and mitomycin C. Cancer Research. 1980;40(4):1165–1168.
    1. Sugarbaker PH. Successful management of microscopic residual disease in large bowel cancer. Cancer Chemotherapy and Pharmacology, Supplement. 1999;43:S15–S25.
    1. Esquivel J. Technology of hyperthermic intraperitoneal chemotherapy in the United States, Europe, China, Japan, and Korea. Cancer Journal. 2009;15(3):249–254.
    1. Van Ruth S, Verwaal VJ, Zoetmulder FAN. Pharmacokinetics of intraperitoneal mitomycin C. Surgical Oncology Clinics of North America. 2003;12(3):771–780.
    1. Smeenk RM, Verwaal VJ, Zoetmulder FAN. Toxicity and mortality of cytoreduction and intraoperative hyperthermic intraperitoneal chemotherapy in pseudomyxoma peritonei—a report of 103 procedures. European Journal of Surgical Oncology. 2006;32(2):186–190.
    1. Glehen O, Osinsky D, Cotte E, et al. Intraperitoneal chemohyperthermia using a closed abdominal procedure and cytoreductive surgery for the treatment of peritoneal carcinomatosis: morbidity and mortality analysis of 216 consecutive procedures. Annals of Surgical Oncology. 2003;10(8):863–869.
    1. Sugarbaker PH, Alderman R, Edwards G, et al. Prospective morbidity and mortality assessment of cytoreductive surgery plus perioperative intraperitoneal chemotherapy to treat peritoneal dissemination of appendiceal mucinous malignancy. Annals of Surgical Oncology. 2006;13(5):635–644.
    1. Cepeda V, Fuertes MA, Castilla J, Alonso C, Quevedo C, Pérez JM. Biochemical mechanisms of cisplatin cytotoxicity. Anti-Cancer Agents in Medicinal Chemistry. 2007;7(1):3–18.
    1. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. New England Journal of Medicine. 2006;354(1):34–43.
    1. Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the gynecologic oncology group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. Journal of Clinical Oncology. 2001;19(4):1001–1007.
    1. Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. New England Journal of Medicine. 1996;335(26):1950–1955.
    1. Urano M, Kuroda M, Nishimura Y. For the clinical application of thermochemotherapy given at mild temperatures. International Journal of Hyperthermia. 1999;15(2):79–107.
    1. Stewart JH, IIII, Shen P, Russell G, et al. A phase I trial of oxaliplatin for intraperitoneal hyperthermic chemoperfusion for the treatment of peritoneal surface dissemination from colorectal and appendiceal cancers. Annals of Surgical Oncology. 2008;15(8):2137–2145.
    1. Elias DM, Sideris L. Pharmacokinetics of heated intraoperative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis. Surgical Oncology Clinics of North America. 2003;12(3):755–769.
    1. Elias D, Bonnay M, Puizillou JM, et al. Heated intra-operative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue distribution. Annals of Oncology. 2002;13(2):267–272.
    1. Jerremalm E, Hedeland M, Wallin I, Bondesson U, Ehrsson H. Oxaliplatin degradation in the presence of chloride: identification and cytotoxicity of the monochloro monooxalato complex. Pharmaceutical Research. 2004;21(5):891–894.
    1. de Somer F, Ceelen W, Delanghe J, et al. Severe hyponatremia, hyperglycemia, and hyperlactatemia are associated with intraoperative hyperthermic intraperitoneal chemoperfusion with oxaliplatin. Peritoneal Dialysis International. 2008;28(1):61–66.
    1. Piché N, Leblond FA, Sidéris L, et al. Rationale for heating oxaliplatin for the intraperitoneal treatment of peritoneal carcinomatosis: a study of the effect of heat on intraperitoneal oxaliplatin using a murine model. Annals of Surgery. 2011;254(1):138–144.
    1. Czejka M, Jäger W, Schüller J, et al. Pharmacokinetics of carboplatin after intraperitoneal administration. Archiv der Pharmazie. 1991;324(3):183–184.
    1. Los G, Verdegaal EME, Mutsaers PHA, McVie JG. Penetration of carboplatin and cisplatin into rat peritoneal tumor nodules after intraperitoneal chemotherapy. Cancer Chemotherapy and Pharmacology. 1991;28(3):159–165.
    1. Tritton TR. Cell surface actions of adriamycin. Pharmacology and Therapeutics. 1991;49(3):293–309.
    1. Lane P, Vichi P, Bain DL, Tritton TR. Temperature dependence studies of adriamycin uptake and cytotoxicity. Cancer Research. 1987;47(15):4038–4042.
    1. Jacquet P, Averbach A, Stuart OA, Chang D, Sugarbaker PH. Hyperthermic intraperitoneal doxorubicin: pharmacokinetics, metabolism, and tissue distribution in a rat model. Cancer Chemotherapy and Pharmacology. 1998;41(2):147–154.
    1. Van der Speeten K, Stuart OA, Mahteme H, Sugarbaker PH. A pharmacologic analysis of intraoperative intracavitary cancer chemotherapy with doxorubicin. Cancer Chemotherapy and Pharmacology. 2009;63(5):799–805.
    1. Johansen PB. Doxorubicin pharmacokinetics after intravenous and intraperitoneal administration in the nude mouse. Cancer Chemotherapy and Pharmacology. 1981;5(4):267–270.
    1. Ozols RF, Grotzinger KR, Fisher RI. Kinetic characterization and response to chemotherapy in a transplantable murine ovarian cancer. Cancer Research. 1979;39(8):3202–3208.
    1. Ozols RF, Locker GY, Doroshow JH. Pharmacokinetics of adriamycin and tissue penetration in murine ovarian cancer. Cancer Research. 1979;39(8):3209–3214.
    1. Ozols RF, Young RC, Speyer JL. Phase I and pharmacological studies of adriamycin administered intraperitoneally to patients with ovarian cancer. Cancer Research. 1982;42(10):4265–4269.
    1. Pestieau SR, Stuart OA, Chang D, Jacquet P, Sugarbaker PH. Pharmacokinetics of intraperitoneal gemcitabine in a rat model. Tumori. 1998;84(6):706–711.
    1. Sabbatini P, Aghajanian C, Leitao M, et al. Intraperitoneal cisplatin with intraperitoneal gemcitabine in patients with epithelial ovarian cancer: results of a phase I/II Trial. Clinical Cancer Research. 2004;10(9):2962–2967.
    1. Morgan RJ, Jr., Synold TW, Xi B, et al. Phase I trial of intraperitoneal gemcitabine in the treatment of advanced malignancies primarily confined to the peritoneal cavity. Clinical Cancer Research. 2007;13(4):1232–1237.
    1. Gamblin TC, Egorin MJ, Zuhowski EG, et al. Intraperitoneal gemcitabine pharmacokinetics: a pilot and pharmacokinetic study in patients with advanced adenocarcinoma of the pancreas. Cancer Chemotherapy and Pharmacology. 2008;62(4):647–653.
    1. Sugarbaker PH, Stuart OA, Bijelic L. Intraperitoneal gemcitabine chemotherapy treatment for patients with resected pancreatic cancer: rationale and report of early data. International Journal of Surgical Oncology. 2011;2011:7 pages.161862
    1. Alberts DS, Chen HS, Chang SY, Peng YM. The disposition of intraperitoneal bleomycin, melphalan, and vinblastine in cancer patients. Recent Results in Cancer Research. 1980;74:293–299.
    1. Glehen O, Stuart OA, Mohamed F, Sugarbaker PH. Hyperthermia modifies pharmacokinetics and tissue distribution of intraperitoneal melphalan in a rat model. Cancer Chemotherapy and Pharmacology. 2004;54(1):79–84.
    1. Sugarbaker PH, Stuart OA. Pharmacokinetic and phase II study of heated intraoperative intraperitoneal melphalan. Cancer Chemotherapy and Pharmacology. 2007;59(2):151–155.
    1. Ceelen WP, Påhlman L, Mahteme H. Pharmacodynamic aspects of intraperitoneal cytotoxic therapy. Cancer Treatment and Research. 2007;134:195–214.
    1. Sugarbaker PH, Mora JT, Carmignani P, Stuart OA, Yoo D. Update on chemotherapeutic agents utilized for perioperative intraperitoneal chemotherapy. Oncologist. 2005;10(2):112–122.
    1. Mohamed F, Sugarbaker PH. Intraperitoneal taxanes. Surgical Oncology Clinics of North America. 2003;12(3):825–833.
    1. Rietbroek RC, Katschinski DM, Reijers MHE, et al. Lack of thermal enhancement for taxanes in vitro. International Journal of Hyperthermia. 1997;13(5):525–533.
    1. Schrump DS, Zhai S, Nguyen DM, et al. Pharmacokinetics of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques. Journal of Thoracic and Cardiovascular Surgery. 2002;123(4):686–694.
    1. Cividalli A, Cruciani G, Livdi E, Pasqualetti P, Tirindelli Danesi D. Hyperthermia enhances the response of paclitaxel and radiation in a mouse adenocarcinoma. International Journal of Radiation Oncology Biology Physics. 1999;44(2):407–412.
    1. Mohamed F, Stuart OA, Glehen O, Urano M, Sugarbaker PH. Docetaxel and hyperthermia: factors that modify thermal enhancement. Journal of Surgical Oncology. 2004;88(1):14–20.
    1. Yonemura Y, Bandou E, Sawa T, et al. Neoadjuvant treatment of gastric cancer with peritoneal dissemination. European Journal of Surgical Oncology. 2006;32(6):661–665.
    1. De Bree E, Rosing H, Beijnen JH, et al. Pharmacokinetic study of docetaxel in intraoperative hyperthermic i.p. chemotherapy for ovarian cancer. Anti-Cancer Drugs. 2003;14(2):103–110.
    1. DeBree E, Rosing H, Filis D, et al. Cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy with paclitaxel: a clinical and pharmacokinetic study. Annals of Surgical Oncology. 2008;15(4):1183–1192.
    1. Speyer JL, Collins JM, Dedrick RL. Phase I and pharmacological studies of 5-fluorouracil administered intraperitoneally. Cancer Research. 1980;40(3):567–572.
    1. Jacquet P, Averbach A, Stephens AD, Anthony Stuart O, Chang D, Sugarbaker PH. Heated intraoperative intraperitoneal mitomycin C and early postoperative intraperitoneal 5-fluorouracil: pharmacokinetic studies. Oncology. 1998;55(2):130–138.
    1. Diasio RB, Lu Z. Dihydropyrimidine dehydrogenase activity and fluorouracil chemotherapy. Journal of Clinical Oncology. 1994;12(11):2239–2242.
    1. Takimoto CH. Antifolates in clinical development. Seminars in Oncology. 1997;24(5, supplement 18):S18–S40.
    1. Pestieau SR, Stuart OA, Sugarbaker PH. Multi-targeted antifolate (MTA): pharmacokinetics of intraperitoneal administration in a rat model. European Journal of Surgical Oncology. 2000;26(7):696–700.
    1. Rubin J, Clawson M, Planch A, Jones Q. Measurements of peritoneal surface area in man and rat. American Journal of the Medical Sciences. 1988;295(5):453–458.
    1. Chagnac A, Herskovitz P, Weinstein T, et al. The peritoneal membrane in peritoneal dialysis patients: estimation of its functional surface area by applying stereologic methods to computerized tomography scans. Journal of the American Society of Nephrology. 1999;10(2):342–346.
    1. Albanese AM, Albanese EF, Miño JH, et al. Peritoneal surface area: measurements of 40 structures covered by peritoneum: correlation between total peritoneal surface area and the surface calculated by formulas. Surgical and Radiologic Anatomy. 2009;31(5):369–377.
    1. Rossi CR, Deraco M, De Simone M, et al. Hyperthermic intraperitoneal intraoperative chemotherapy after cytoreductive surgery for the treatment of abdominal sarcomatosis: clinical outcome and prognostic factors in 60 consecutive patients. Cancer. 2004;100(9):1943–1950.
    1. Baratti D, Kusamura S, Martinetti A, et al. Prognostic value of circulating tumor markers in patients with pseudomyxoma peritonei treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Annals of Surgical Oncology. 2007;14(8):2300–2308.
    1. Glehen O, Schreiber V, Cotte E, et al. Cytoreductive surgery and intraperitoneal chemohyperthermia for peritoneal carcinomatosis arising from gastric cancer. Archives of Surgery. 2004;139(1):20–26.
    1. Gilly FN, Carry PY, Sayag AC, et al. Regional chemotherapy (with mitomycin C) and intra-operative hyperthermia for digestive cancers with peritoneal carcinomatosis. Hepato-Gastroenterology. 1994;41(2):124–129.
    1. Keshaviah P, Emerson PF, Vonesh EF, Brandes JC. Relationship between body size, fill volume, and mass transfer area coefficient in peritoneal dialysis. Journal of the American Society of Nephrology. 1994;4(10):1820–1826.
    1. Sugarbaker PH. Successful management of microscopic residual disease in large bowel cancer. Cancer Chemotherapy and Pharmacology, Supplement. 1999;43:S15–S25.
    1. Esquivel J. Technology of hyperthermic intraperitoneal chemotherapy in the United States, Europe, China, Japan, and Korea. Cancer Journal. 2009;15(3):249–254.
    1. Van Ruth S, Verwaal VJ, Zoetmulder FAN. Pharmacokinetics of intraperitoneal mitomycin C. Surgical Oncology Clinics of North America. 2003;12(3):771–780.
    1. Ceelen WP, Påhlman L, Mahteme H. Pharmacodynamic aspects of intraperitoneal cytotoxic therapy. Cancer Treatment and Research. 2007;134:195–214.
    1. Elias D, Bonnay M, Puizillou JM, et al. Heated intra-operative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue distribution. Annals of Oncology. 2002;13(2):267–272.
    1. Van der Speeten K, Stuart OA, Mahteme H, et al. Pharmacokinetic study of perioperative intravenous ifosfamide. International Journal of Surgical Oncology. 2011;2011:9 pages.185092

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