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

Abstract

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 (PLT 0 ), 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 PLT 0 , 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.

Thrombin generation and platelet activation in cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy - A prospective cohort study

“…Platelet dynamics were previously described by Perez Ruixo, indicating a model based time course of platelet counts, which simultaneously accounts for the acute-immediate thrombocytopenia response induced by the CRS and the hyperthermic intraperitoneal oxaliplatin effects in bone marrow, as well as the subsequent thrombocytosis due to the natural defence mechanism to prevent major bleedings [ 31 ]. Our measurements revealed that during CRS and 30 minutes of chemotherapy, platelet count did not significantly change, however it decreased to non-critical levels on day 1 and 3.…”

Hyperthermic intraperitoneal chemotherapy with oxaliplatin for peritoneal carcinomatosis: a clinical pharmacological perspective on a surgical procedure

“…Few studies have investigated the PD of oxaliplatin during HIPEC [34,39,68,69]. These studies use PK/PD models to find associations between PK parameters and PD toxicities of the treatment.…”

“…It has been demonstrated that HIPEC‐induced neutropenia largely depends on the duration of the HIPEC procedure and the oxaliplatin concentration in the perfusate, which is related to systemic concentrations . It has been predicted that each 400 mg l −1 increase in initial oxaliplatin concentration causes a 28% decrease in the absolute neutrophil count (ANC) at day 7 . Extending the duration of HIPEC from 30 min to 60 min is predicted to result in a 23% decrease in ANC at day 7 .…”

“…It has been predicted that each 400 mg l −1 increase in initial oxaliplatin concentration causes a 28% decrease in the absolute neutrophil count (ANC) at day 7 . Extending the duration of HIPEC from 30 min to 60 min is predicted to result in a 23% decrease in ANC at day 7 . This is relevant because postoperative infectious complications can be expected within the first week after surgery.…”

“…This is relevant because postoperative infectious complications can be expected within the first week after surgery. the main determinants for the duration and severity of HIPEC‐induced thrombocytopenia are the initial oxaliplatin concentration and the duration of the HIPEC procedure .…”