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Improvement in intraperitoneal intraoperative cisplatin exposure based on pharmacokinetic analysis in patients with ovarian cancer

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Abstract

Ovarian cancer is the leading cause of gynecological cancer-related death in Western countries. The present treatment standards for ovarian cancer are based on the association of debulking surgery with platinum-based chemotherapy. Another strategy that could be further investigated is intraperitoneal chemotherapy (IP). We previously described that the 2-h administration of intraoperative IP cisplatin did not reach satisfactory concentrations. In the present study, we present the results of a pharmacokinetic analysis performed after two consecutive 1-h IP 30 mg/l cisplatin administrations. Twenty-seven patients with advanced epithelial cancer classified FIGO stage IIIC were included in the study. Blood and IP samples were taken over a 24-h period, during and after IP treatment. Both total and ultrafiltered (Uf) platinum (Pt) concentration levels were analyzed. Biological and clinical toxicities were also recorded. With this strategy, IP Pt concentrations stayed above the target concentration (10 mg/l) for a satisfactory length of time. The serum Pt concentrations were higher than those observed with the “one-bath” protocol and they induced the occurrence of recoverable renal toxicities (3 grade 1, 7 grade 2 and 4 grade 3). The best predictive parameter for renal failure was the total Pt 24-h Area Under the Curve (AUC) with a threshold value of 25 mg h/l RR = 0.31 (95% CI 0.13 − 0.49, P < 0.01). Administration of an increased amount of cisplatin is feasible and a satisfactory level of IP Pt concentrations is obtained. However, this improvement is associated with an increase in serum Pt levels and resulting renal toxicities. An attractive solution would be to decrease Pt transfer from peritoneum to bloodstream. A phase 1 study using intraoperative IP epinephrine in order to decrease this transfer is presently being carried out.

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Acknowledgments

The authors are very grateful to the staff of the pharmacology department for their help in samples management. This work was supported by a grant from the Ligue Contre le Cancer du Doubs. The authors of this manuscript also state that they have no conflict of interest in the present study.

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Authors and Affiliations

  1. Laboratoire de Pharmacologie Clinique, CHU Jean Minjoz, 3 bvd Fleming, 25030, Besancon CEDEX, France

    Bernard Royer, Damien Montange & Jean-Pierre Kantelip

  2. Service de Chirurgie Viscérale et Oncologique, CHU Jean Minjoz, Besançon, France

    Delphine Delroeux & Bruno Heyd

  3. Service d’Oncologie, CHU Jean Minjoz, Besançon, France

    Emmanuel Guardiola & Xavier Pivot

  4. Département d’Anesthésie, CHU Jean Minjoz, Besançon, France

    Marielle Combe

  5. Laboratoire de Pharmacologie, CHU Maison Blanche, Reims, France

    Guillaume Hoizey

  6. Faculté de Médecine, Unité INSERM 517, Dijon, France

    Bruno Chauffert

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  1. Bernard Royer
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  2. Delphine Delroeux
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  3. Emmanuel Guardiola
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  7. Jean-Pierre Kantelip
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  8. Bruno Chauffert
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  9. Bruno Heyd
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  10. Xavier Pivot
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Correspondence to Bernard Royer.

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Royer, B., Delroeux, D., Guardiola, E. et al. Improvement in intraperitoneal intraoperative cisplatin exposure based on pharmacokinetic analysis in patients with ovarian cancer. Cancer Chemother Pharmacol 61, 415–421 (2008). https://doi.org/10.1007/s00280-007-0484-x

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  • DOI: https://doi.org/10.1007/s00280-007-0484-x

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