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Neutrophil Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin

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Abstract

Background and Objective

Peritoneal carcinomatosis is an abdominal metastatic manifestation of a life-threatening tumour progression requiring standard palliative surgery and/or chemotherapy treatment. The aim of this study was to characterize the immediate neutrophilia response induced by cytoreductive surgery (CRS) and the myelosuppression effect of hyperthermic intraperitoneal oxaliplatin (HIO) in peritoneal carcinomatosis patients.

Methods

Absolute neutrophil counts (ANCs) from 45 patients treated with CRS and HIO diluted in isotonic 4 % icodextrin (cohort A), 21 patients undergoing CRS followed by HIO diluted in isotonic 5 % dextrose (cohort B) and 18 patients treated with CRS without HIO (cohort C) were used to estimate the system-related parameters [baseline ANC (Circ0), mean transit time (MTT) and feedback on proliferation (γ)] and drug-specific (α) parameters of a modified Friberg’s model that accounts for the surgical stress-induced neutrophilia. The plasma oxaliplatin concentrations, C p, were assumed to reduce the proliferation rate of the progenitor cells according to the function α × C p. Model evaluation and simulations were undertaken to evaluate the effect of the dose, treatment duration and carrier solution on the incidence of severe neutropenia.

Results

The typical values [between-subject variability, expressed in coefficient of variation values (%)] of the Circ0, MTT, γ and α were estimated to be 3.58 × 109 cells/L (41.2 %), 144 h (70.9 %), 0.155 and 0.066 L/mg (134.9 %), respectively. Surgical stress induced a maximal 3.37-fold increase in the proliferation rate that was attenuated with a half-life of 10 days, and a maximal 68 % reduction in the MTT that was attenuated with a half-life of 28 days. Age, body surface area, sex, total proteins and carrier solution did not impact the model parameters. The model evaluation evidenced an accurate prediction of the incidence of neutropenia grade ≥2 and/or ≥3. Simulations indicated that (i) the neutropenia was reversible and short-lasting; and (ii) the HIO dose and treatment duration were the main determinants of the severity and duration of neutropenia.

Conclusion

The time course of neutropenia was well characterized by the model that was developed, which simultaneously accounts for the acute-immediate neutrophilia response induced by CRS and the HIO myelosuppressive effect produced in the bone marrow. This model suggests that higher doses than those evaluated to date could be used in peritoneal carcinomatosis patients without substantially increasing the risk of severe neutropenia.

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Acknowledgments

The authors would like to thank the patients and the medical, nursing and laboratory staff of the Hospital Quirón Torrevieja who participated in the present study. The authors would like to thank Dr. Ricardo Nalda for his valuable help during the simulation exercise. This work was supported by Consellería de Sanidad of Comunidad Valenciana (grant GE-079/11). The authors also like to thank the peer reviewers of this manuscript for their valuable comments, which helped to improve the quality of the work and Dr. Ricardo Nalda-Molina for his comments and support at the beginning of this project.

Conflict of interest

Carlos Pérez-Ruixo, Belén Valenzuela, José Esteban Peris, Pedro Bretcha-Boix, Vanesa Escudero-Ortiz, José Farré-Alegre and Juan José Pérez-Ruixo have indicated no potential conflicts of interest, other than those reflected in their affiliations.

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The views expressed in this article are the personal view of the authors, reflecting their scientific knowledge of this topic, and should not be understood or quoted as being made on behalf of the companies where the authors work.

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Authors and Affiliations

  1. Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain

    Carlos Pérez-Ruixo & José Esteban Peris

  2. Platform of Oncology, Hospital Quirón Torrevieja, Partida de la Loma s/n, 03184, Torrevieja, Alicante, Spain

    Belén Valenzuela, Pedro Bretcha-Boix, Vanesa Escudero-Ortiz & José Farré-Alegre

  3. Pharmacokinetics and Drug Metabolism, AMGEN, Valencia, Spain

    Juan José Pérez-Ruixo

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  1. Carlos Pérez-Ruixo
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Correspondence to Belén Valenzuela.

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Pérez-Ruixo, C., Valenzuela, B., Peris, J.E. et al. Neutrophil Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin. Clin Pharmacokinet 52, 1111–1125 (2013). https://doi.org/10.1007/s40262-013-0092-3

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