[Improvement in the regimen for combined CDDP and CPT-11 chemotherapy]

Combination therapy with cisplatin (CDDP) and irinotecan hydrochloride (CPT-11) is expected to be effective against refractory tumors. The antitumor effect of CPT-11 is believed to depend on the area under the concentration-time curve (AUC) of SN 38, which is a metabolite of the prodrug CPT-11. Of the major adverse effects of CPT-11, leukopenia is dependent on the AUC of CPT-11 and severe diarrhea is believed to be dependent on the peak concentration (Cmax) of SN 38. Considering these properties of CPT-11, we investigated the administration of a new regimen.

The subjects were patients with gynecological cancer who consented to intra-arterial [IA] infusion. The patients received CDDP (30 mg/m2 over 2 hours) concurrently with CPT-11 (40 mg/m2 over 24 hours) at 2-week intervals. Plasma concentrations of platinum and CPT-11 were measured before and after administration. To prevent binding of SN 38 to the large intestinal mucosa, we performed 1) alkalization, 2) detoxification of SN 38, and 3) clearance of the large intestine.

1) A decrease in tumor diameter or negative conversion on cytology and reduced tumor marker levels were observed in patients receiving IA infusion. 2) No serious adverse reactions occurred, except grade 3 diarrhea in one patient given infusion at the initial dose. 3) The rate of conversion from CPT-11 to SN 38 was about 10%, which was higher than the 3% rate after standard 90-minute intra-venous [i.v.] infusion. 4) In the patients treated with IA infusion, CPT-11 levels in venous blood were one thirty-third of those in arterial blood. 5) Regarding the venous blood concentration of platinum when CDDP (30 mg/m2) was administered, the AUC of free platinum in patients given IA infusion was about 2.5 times that after i.v. infusion.

The IA infusion treatment produced a good clinical response with good compliance.