Discussion
toxicity, ototoxicity, tumour
ADVERSE EVENTS, CAVITY, TUMOUR, OTOTOXICITY, PERIPHERAL NEUROPATHY
This study demonstrates that intraperitoneal administration of 100 mg/mSystemic exposure to unbound cisplatin is closely correlated with tumour response [The high systemic exposure to ultrafiltered cisplatin after intraperitoneal administration might be caused by higher fraction of complexed cisplatin to low weight molecules in the ultrafiltered part. When absorbed from the peritoneal cavity to the systemic compartment, cisplatin crosses epithelial barriers. A fraction of diaquaplatin, the active intermediate formed from cisplatin, is likely to be complexed to low-molecular weight molecules such as glutathione, cysteine and methionine before it reaches the blood stream. This complexed cisplatin is considered as inactive drug, but still contribute to the total amount of ultrafiltered cisplatin measured in plasma. Therefore the AUCTaking into account the high systemic exposure to ultrafiltered cisplatin after intraperitoneal administration, it is remarkable that the phase III studies supporting the use of intraperitoneal cisplatin uses equal [High systemic exposure to ultrafiltered cisplatin is expected to cause increased incidence of systemic adverse events like peripheral neuropathy, haematological toxicity and ototoxicity [In contrast to cisplatin, a large water insoluble drug like paclitaxel is very slowly absorbed from the peritoneal compartment. It has been demonstrated that the pharmacological advantage, very slow peritoneal clearance and a high peritoneal-plasma AUC ratio of 996 [Soundness of this study are its prospective nature, rich cisplatin blood sampling and the accurate time information for the blood samples. This is essential to accurately determine the pharmacokinetic parameters. The comparison with systemic exposure data after intravenous administration is helpful to place the findings of the study in perspective. Although this study yielded new insights in intraperitoneal drug delivery, there are some shortcomings that need to be addressed. First, since patients were allowed to leave the hospital after administration of paclitaxel, few paclitaxel samples could be collected beyond 12 h. Since paclitaxel is very slowly absorbed from the peritoneal compartment sampling at later timepoints is recommended for an accurate estimation of the systemic exposure. Second, since only one intraperitoneal fluid sample was collected, it was not possible to determine total exposure in the peritoneal compartment. Also peritoneal sampling through the PAC turned out to be more challenging than expected. The tube was often blocked while drawing up intraperitoneal fluid making it impossible to collect an intraperitoneal sample for the majority of patients. However the high CThe results of this study together with earlier findings in literature shed a new light on intraperitoneal chemotherapy administration. The importance of systemic exposure of intraperitoneal administrated drugs is often underestimated. We showed that the assumption that systemic exposure after intraperitoneal therapy remains low does not apply for all cytotoxic drugs and in some circumstances can be very high, as is the case for intraperitoneal administered cisplatin. The chemotherapy schedule used in this study is the GOG-172 regimen that demonstrated a 16-month improvement in median overall survival [Intraperitoneal administration of 100 mg/m