Pharmacodynamic aspects of intraperitoneal cytotoxic therapy

Abstract

The pharmacokinetic (PK) properties of cytotoxic drugs, described by parameters such as plasma half live and distribution volume, are generally well studied and have implications for toxicity and development of dosage regimens. The PK rationale for intraperitoneal (ip) cytotoxic drug therapy is discussed in chapter 8. In order to exert their anticancer effects, drugs have to gain access to tumour cells by penetrating into tissue. The available data on tumour tissue distribution of cytotoxic drugs and their relation with antitumour efficacy are limited, and mainly stem from in vitro multicellular models such as tumour spheroids (spherical tumour aggregates; diameter approximately 1 mm) and multilayered cell cultures [1]. Tissue penetration in these models is studied following incubation in a medium containing anticancer drugs, and generally the results show a very limited cytotoxic drug penetration. Since abstraction is made of vascular drug supply and the geometry of drug penetration is from the periphery towards the centre, the results of these models apply even more to ip chemotherapy than to intravenous administration. On the other hand, the renewed interested in ip chemotherapy in the management of peritoneal surface malignancy generated data relating specifically to tissue penetration of ip administered cytotoxic drugs, combined or not with locoregional hyperthermia. This chapter provides a summary of the available data concerning the pharmacodynamics of cytotoxic drug administration with an emphasis on drugs used clinically during hyperthermic intraperitoneal chemoperfusion (HIPEC).