title: Neutrophil dynamics in peritoneal carcinomatosis patients treated with cytoreductive surgery and hyperthermic intraperitoneal oxaliplatin.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Pérez-Ruixo
authors.forename: Belén
authors.initials: B
authors.lastname: Valenzuela
authors.forename: José Esteban
authors.initials: JE
authors.lastname: Peris
authors.forename: Pedro
authors.initials: P
authors.lastname: Bretcha-Boix
authors.forename: Vanesa
authors.initials: V
authors.lastname: Escudero-Ortiz
authors.forename: José
authors.initials: J
authors.lastname: Farré-Alegre
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Pérez-Ruixo
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003131:Combined Modality Therapy; D013505:Digestive System Surgical Procedures; D006801:Humans; D006979:Hyperthermia, Induced; D007958:Leukocyte Count; D008954:Models, Biological; D009503:Neutropenia / Q000139:chemically induced; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin