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

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• 作者：Carlos Pez-Ruixo (1)
  Bel Valenzuela (2)
  JosEsteban Peris (1)
  Pedro Bretcha-Boix (2)
  Vanesa Escudero-Ortiz (2)
  JosFarrAlegre (2)
  Juan JosPez-Ruixo (3)
  
• 刊名：Clinical Pharmacokinetics
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：52
• 期：12
• 页码：1111-1125
• 全文大小：
• 作者单位：Carlos Pez-Ruixo (1)
  Bel Valenzuela (2)
  JosEsteban Peris (1)
  Pedro Bretcha-Boix (2)
  Vanesa Escudero-Ortiz (2)
  JosFarrAlegre (2)
  Juan JosPez-Ruixo (3)
  
  1. Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain
  2. Platform of Oncology, Hospital Quir Torrevieja, Partida de la Loma s/n, 03184, Torrevieja, Alicante, Spain
  3. Pharmacokinetics and Drug Metabolism, AMGEN, Valencia, Spain
  
• ISSN：1179-1926

文摘

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 (] and drug-specific ( parameters of a modified Friberg 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 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, and were estimated to be 3.58109 cells/L (41.2%), 144 h (70.9%), 0.155 and 0.066L/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 28days. 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 and/or . 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.