Cystic fluid-platinum kinetics in ovarian cancer patients: relevance to cis-dichlorodiammine platinum (II) sensitivity testing in vitro.

Cystic fluid-platinum kinetics in ovarian cancer patients: Relevance to cis -dichlorodiammine platinum (II) sensitivity testing in vitro

cis-dichlorodimmineplatinum (CDDP) leads to tumour regression in 50% of patients with advanced ovarian cancer (Gershenson et al, 1981;Adams et al, 1984). The number of treatment failures, coupled with the drug-induced host toxicities in this condition, have prompted studies on the human tumour stem cell assay (Salmon & Von Hoff;1982) in which CDDP, or other cytotoxic agents, are incubated with cultured biopsy material and the extent of cell kill in vitro used to predt the sensitivity of an individual patient's tumour to the drug. The potential clinical usefulness of this test has been discussed (Von Hoff, 1983) and a number of practial problems assocated with the assay have been described (Von Hoff & Weisenthall, 1980). One difficulty concerns the lack of precise knowledge on the interpatient variability of CDDP levels surrounding tumour cells, and has led to the use of a wide range of drug concentrations and exposure times for sensitivity testing in vitro (Alberts et al., 1981;Wilson & Neal, 1981;Morasca et al., 1983). For this reason we have studied the time-course of both total and non-protein bound (ultrafilterable) platinum in plasma and the cystic fluid associated with tumour cells in patients with cystadenocarcinoma of the ovary receiving i.v. infusions of CDDP. The results show that tumour exposure to total drug concentration in this condition is variable between patients and it is suggested that the availability of potentially active platinum species is less than was often previously anticipated.
Three patients were diagnosed at primary laparotomy as having Stage l, cystadenocarcnoma of the ovary. They had a tumour burden >Ocm in diameter and multiple peritoneal metastases were present. Debulking of the tumour mass was not feasible. The malignant cysts were multilocular with solid tumour elements and consequently it was not possible to obtain meaningful estimates of total Correspondence: R-G. Fish.
Received 31 January 1985; and in revised form, 29 March 1985. cystic fluid volume. Approximately 4 weeks after the primary surgery, the 3 patients were given a 6h i.v. infusion of CDDP. Before drug therapy, serum urea, creatinine, eklctrolytes and birubin were within the normal range. Twenty-four hours prior to, and following CDDP infusion, 21 respectively of 5% dextrose-normal saline and normal saline were admini i.v. A bolus of mannitol (12.5g) was given immiately before CDDP. The cytotoxic drug was admini in 21 of normal saline containing 25 g of mannitol.
Plasma samples were taken at intervals for 24h after the initiation of drug therapy. Fluid from within the malignant cyst was aspirated under local anesthetic using a 21 gauge needle. Collctions of cystic fluid were obtained before, during, at the end of CDDP therapy and post-infusion at 3 and 24h. Aliquots of plasma and cystic fluid were imfmdiately ultrafiltered by means of Amicon Centriflo CF 25 cones. The ultrafiltrates were used for the determination of the free (non-protein bound) platinum concentrations. The orginal plasma, cystic fluids and ultrafiltrates were stored at -20°C before analysis. Platinum levels were measured by flamekss atomic absorption spectrophotometry as descnbed previously (FLsh et al., 1984). Plasma and cystic fluid samples containing CDDP were evaluated using pre-infusion fluids spiked with drug, to overcome any matrix interference. The area under the concentration x time curve (AUC) for platinum in plasma and cystic fluid was measured by the trapezoidal method.
The time-course of total platinum in plasma and cystic fluid for the three patients is shown in Figure  1. In both fluids, peak platinum levels occurred at the end of drug infusion, and after 24h, the total plasma platinum level had fallen to -80% of the peak values. The maximum total platinum concentration achieved and the calclated AUCs in cystic fluid were variable between patients (Table X).
It is known that CDDP or its metabolites bind firmly to plasma proteins (Vermorken et al., 1984). These macromolecular complexes appear to have little demonstrable cytotoxicity in vitro (Holdener et al., 1983) and therefore, it would seem that the M.D. SHELLEY et al.  Plasma, ultrafilterable platinum 207 220 3.10 Cystic, ultrafilterable platinum 1.15 1.50 1.60 direct use of pharmacokinetic data based upon the total achievable plasma platinum levels in patients is inappropriate as a reflection of tumour exposure to active platinum species.
The mean concentration changes for the nonprotein bound platinum species in the 3 patients are shown in Figure 2. Peak platinum levels were similar in both fluids and between patients. The AUCs for ultrafilterable platinum in the cystic fluids were -50% of those for plasma (Table I), although more frequent sampling of this fluid may have provided a better estimate. In both fluids, the non-protein bound platinum declined rapidly during the post-infusion period and was below detection after 3 h.
In these patients, platinum species rapidly diffused into cystic fluid and, with the present dosing schedule, peak levels ranging from 0.38-0.48 ug ml-1 and a tumour exposure (AUC) of 1.15-1.60pgmlI-h-1 were obtained for the pharmacologically active non-protein bound platinum in this fluid. It is concluded that the free platinum concentration is similar in the cystic fluid of all 3 patients, as is that in the plasma. The data support the idea of using only 10% of the peak plasma concentration of total platinum as a reasonable in vitro assay concentration (Alberts et al, 1981).