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

Abstract

The aim of the study was to characterize the platelet count (PLT) dynamics in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal oxaliplatin (HIO). Data from patients treated with CRS alone (N = 18) or CRS and HIO (N = 62) were used to estimate the baseline platelet count (PLT0), rate constants for platelet maturation (k tr ) and platelet random destruction (k s ), feedback on progenitor cell proliferation (γ), and the drug-specific model parameters (α, β). Plasma oxaliplatin concentrations, C p , reduced the proliferation rate of progenitor cells (k prol) according to a power function α × C p (β) . The surgery effect on k prol and k s was explored. The typical values (between subject variability) of the PLT0, k tr , k s , γ, α, and β were estimated to be 237 × 10(9) cells/L (32.9%), 7.09 × 10(-3) h(-1) (47.1%), 8.86 × 10(-3) h(-1) (80.0%), 0.621, 0.88 L/mg (56.9%), and 2.63. Surgery induced a maximal 2.09-fold increase in k prol that was attenuated with a half-life of 8.42 days. Splenectomy decreased k s by 47.5%. Age, sex, body surface area, sex, total proteins, and HIO carrier solution did not impact the model parameters. The model developed suggests that, following CRS and HIO, thrombocytopenia and thrombocytosis were reversible and short-lasting; the severity of the thrombocytopenia and thrombocytosis was inversely correlated, with splenectomized patients having thrombocytopenia of lower severity and thrombocytosis of higher severity; and the HIO dose and treatment duration determine the severity and duration of the thrombocytopenia. Higher HIO dose or longer treatment duration could be used without substantially increasing the risk of major hematological toxicity.

Keywords: cytoreductive surgery; hyperthermic intraperitoneal chemotherapy (HIPEC); oxaliplatin; peritoneal carcinomatosis; population pharmacokinetic pharmacodynamic modeling; thrombocytopenia; thrombocytosis.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

Schematic of the platelet dynamics model

Fig. 2

Goodness-of-fit plots for the platelet dynamics model

Fig. 3

Prediction-corrected visual predictive check (upper panels), and representative individual time course of platelet counts and the corresponding model predictions for non-splenectomized (middle panels) and splenectomized patients (lower panels) stratified by cohort

Fig. 4

Influence of surgery-specific parameters SPmax and kp on platelet profiles

Fig. 5

Effect of initial oxaliplatin concentrations on the peritoneum, treatment duration, and carrier solution on platelet dynamics in non-splenectomized and splenectomized patients. The solid lines represent HIO diluted in icodextrin 4% while the dashed lines represent HIO diluted in dextrose 5%

Fig. 6

Effect of initial oxaliplatin concentrations in the peritoneum, treatment duration, and carrier solution in the incidence of thrombocytopenia and thrombocytosis in non-splenectomized and splenectomized patients