Summary In phase I studies. lobaplatin showed activity in ovarian cancer patients pretreated with platinum. A phase II trial with lobaplatin was performed in patients with refractory or relapsed ovarian cancer to define activity and pharmacokinetics. Twenty-two patients were treated with lobaplatin administered as an intravenous bolus every 4 weeks. Dependent on creatinine clearance (CRCL) patients received 30 or 50 mgm-2 lobaplatin as the starting dose. Twenty-two patients received 78 courses (median 3, range 1-6). In eight patients total platinum (TPt) in plasma and urine, free platinum (FPt) in plasma ultrafiltrate (both measured by atomic absorption spectrometry) and lobaplatin in plasma ultrafiltrate measured (by high-performance liquid chromatography) were measured. Toxicity was confined to mild nausea and vomiting, mild leucocytopenia (WHO grade 3 in 18% of the courses), and renal function-related thrombocytopenia (WHO grade 3 4 in 53% of the courses). A correlation was found between CRCL and reduction in platelet count (r = -0.77; P<0.0l). No renal toxicity was encountered. Five of 21 evaluable patients (24%) achieved a response (four complete remissions and one partial remission). Remissions occurred mainly in patients who relapsed more than 6 months after primary treatment. The median survival from start of lobaplatin treatment was 8 months. The mean areas under the curve (AUCs) were 4.2 ± 0.5, 3.0 ± 0.6. and 3.2 ± 1.1 h mgl-' for TPt, FPt and lobaplatin respectively. The free platinum fraction (FPt TPt) was initially very high, indicating low protein binding. FPt was essentially present as intact lobaplatin. Four hours after infusion 54 ± 5% and 24 h after infusion 74 ± 3% of the lobaplatin dose was excreted in the urine. In conclusion. lobaplatin is a platinum compound with anti-tumour activity in patients with relapsed ovarian cancer, especially in those who have platinum-sensitive tumours. The main toxicity of lobaplatin is thrombocytopenia and its dose should be corrected according to renal function.Keyword: ovarian cancer; phase II; lobaplatin Over the last decade, treatment of patients with ovarian cancer has been dominated by cisplatin-containing regimens (Neijt et al., 1984;Williams et al., 1985; Omura et al., 1986). Combinations of cisplatin with one single alkylating agent give equivalent results to three-or four-drug schedules, but appear to be less toxic (Neijt et al., 1987). In recent years, the development of new drugs has been directed towards the development of platinum analogues that are equipotent but less toxic than the parent compound. Carboplatin has emerged as leading analogue in this respe-t with reduced nephrotoxicity, gastointestinal toxicity and neurotoxicity (Calvert et al., 1982;Evans et al., 1983). Myelotoxicity, especially thrombocytopenia. has been found to be the doselimiting toxicity of carboplatin. Especially in ovarian cancer, carboplatin appears to have equivalent activity to cisplatin (Alberts et al., 1992;Swenerton et al., 1992).An important direction in current r...

Summary Patients receiving high-dose chemotherapy (HD-CT) are at risk of severe mucositis. Most prevention studies evaluate the degree of mucositis on clinical, and therefore subjective, measurements. The aim of this study was to develop an objective in vitro assay of chemotherapy-induced mucositis. Twelve patients with locally advanced breast carcinoma received HD-CT followed by peripheral stem cell reinfusion. Before and twice weekly after HD-CT, the mucosa was evaluated by an oral washing, a buccal smear and the World Health Organization (WHO) toxicity grading; furthermore, blood leucocyte levels were determined. For the oral washings, the percentage of viable epithelial cells was determined by trypan blue dye exclusion and leucocytes were counted by fluorescence microscopy after incubation with acridine orange. Maturity of buccal cells was assessed by staining buccal smears for morphology according to Papanicolaou (Whitacker D and Williams V, 1994). Eight healthy volunteers served as controls. The mean percentage (± s.e.m.) of viable oral epithelial cells was stable in controls (44 ± 2%). In patients, they increased after HD-CT, which was significant after day 7 compared with pretreatment (P < 0.05). In addition, a shift from mature to immature epithelial cells in buccal smears was observed. Oral leucocyte levels were closely correlated with the blood leucocyte counts. The WHO score followed the results of these other evaluations with some delay. The viability of buccal cells obtained by oral washings increases after HD-CT. This is possibly because of desquamation of the upper oral mucosa layer, with a shift from mature to more immature cells. These data can be quantitated, and this assay may therefore be useful in studies aimed at prevention of mucositis.Keywords: mucositis; in vitro assay; quantitation Mucositis is a common, always unpleasant, sometimes unbearable toxic side-effect of chemotherapy. In particular, in patients receiving high-dose chemotherapy followed by bone marrow or peripheral stem cell transplantation, mucositis can be dose limiting. Chemotherapy causes a direct toxic effect on the rapidly dividing cells of the basal oral epithelium, which can result in mucosal atrophy, erythema and ulceration. The severe stages of mucositis with disruption of the oral mucosal barrier can lead to mucosal ulcers and secondary infection. In addition, it can provide a portal of entry for micro-organisms into the systemic circulation, which can lead to life-threatening septicaemia in myelosuppressed patients. Mucositis causes major discomfort, such as pain requiring intensive analgesia, and may restrict or even prohibit normal oral feeding and drug intake (Sonis, 1989;Sonis et al, 1990;Toth et al, 1990;Peterson, 1992; Woo et al, 1993).Grading of mucositis is necessary to document its degree and to evaluate the effect of measures for prevention or intervention. Most available scoring systems are based on a combination of objective changes in the mucosa (e.g. erythema, ulceration), subjective complaints (e.g....

Summary Etoposide phosphate is a water-soluble prodrug of etoposide. The plasma pharmacokinetics of etoposide following oral administration of etoposide phosphate or oral etoposide were compared. Seventeen patients with solid tumours were enrolled to receive oral etoposide phosphate 125 mg m-2 on days 1-5 every 3 weeks, with escalation to 175 mg m-2 from course 3 when possible. Patients were randomized to receive oral etoposide phosphate or oral etoposide on day 1 of course 1 and the alternative compound on day 1 of course 2.Fifteen patients received two or more courses and were evaluable for pharmacokinetic comparisons. The median AUCinf (area under the concentration vs time curve from zero to infinity) of etoposide was 77.7 mg 1-1 h after etoposide phosphate (95% Cl 61.3-100.5) and 62.0 mg 1-1 h after oral etoposide (95% Cl 52.2-76.9). The difference in favour of etoposide phosphate was borderline significant: median 9.9 mg 1-1 h (95% Cl 0.1-32.8 mg 1-1 h; P = 0.05). However, the inter-patient variability of etoposide AUCinf was not improved (coefficients of variation 42.3% and 48.4%). Etoposide phosphate was undetectable in plasma after oral administration. Toxicities of oral etoposide phosphate were not different from those known for etoposide. In conclusion, oral etoposide phosphate does not offer a clinically relevant benefit over oral etoposide.Keywords: etoposide; etoposide phosphate; oral; pharmacokinetics; toxicity Etoposide, a podophyllotoxin derivative, is incorporated in standard chemotherapy for treatment of small-cell lung cancer (SCLC) and germ cell tumours, as well as in second-line treatment for haematological and many other malignancies . Activity is improved considerably when the dose is divided over several days, and therefore oral administration is attractive (Slevin et al, 1989a). It has been shown that oral etoposide monotherapy, usually with the dose divided over 5 days or longer periods, is an effective treatment in patients with SCLC and refractory malignant lymphomas . In small studies, prolonged oral etoposide treatment showed remarkable activity in relapsed or refractory breast and ovarian cancers (response rates up to 35% and 25% respectively) (Hoskins and Swenerton, 1994;Martin et al, 1994). Patient convenience is an important additional reason for choosing the oral route. However, pharmacokinetic studies have shown that oral etoposide also has disadvantages. Bioavailability is incomplete, probably decreasing with dose, and is reported to be below 50% for doses above 200 mg. Bioavailability shows wide inter-and intra-patient variability (Hande et al, 1993;Harvey et al, 1985;Slevin et al, 1989b). The consequences are considerable risks of underdosing and unpredictable toxicity.The water-soluble prodrug etoposide phosphate was synthesized because use of intravenous etoposide administration is Received 30 September 1996 Revised 19 December 1996 Accepted 20 December 1996 Correspondence to: EGE de Vries, Division of Medical Oncology, Department of Internal Medicine, University Hos...

The administration of platinum-based chemotherapy induces serotonin release from the enterochromaffin cells, causing nausea and vomiting. This study was conducted to evaluate parameters of serotonin metabolism following platinum-based chemotherapy given in combination with the serotonin type-3 antagonist tropisetron as an antiemetic agent. In nine chemotherapy-naive patients with disseminated germ-cell tumors, parameters of serotonin metabolism in both blood and urine were evaluated during two consecutive courses of platinum-based chemotherapy. Serotonin concentrations in platelet-rich plasma and platelet-poor plasma as well as urinary 5-hydroxyindoleacetic acid (5-HIAA) and serotonin levels were measured during the full length of the courses. By means of comparison with the antiemetic agent chlorpromazine, used on day 1 of the first course only, the effect of the serotonin type-3 antagonist tropisetron, the antiemetic agent used during the rest of the courses, on these parameters was studied. Clinical effects were also recorded. No change in the parameters of serotonin metabolism could be demonstrated during either course by the serotonin type-3 antagonist tropisetron. Also in vitro, no effect of tropisetron on the active serotonin uptake by platelets was found. Serotonin levels in platelets showed no correlation with emetic response. However, the platelet serotonin content decreased significantly between the first and the second course (P < 0.01). The significant reduction in platelet serotonin content observed between the first and the second course indicates a depletion of total body serotonin. The role of a serotonin type-3 antagonist might be affected by the altered serotonin equilibrium during later courses of chemotherapy.

The cytotoxic action of two morpholino anthracyclines, methoxymorpholino anthracycline (MRA-MT, FCE 23,762) and cyanomorpholino anthracycline (MRA-CN), was compared with the cytotoxicity of doxorubicin (DOX), the topoisomerase II inhibitor etoposide (VP-16), the topoisomerase I inhibitor camptothecin, methotrexate, and cisplatin in GLC4, a human small-cell lung-cancer cell line, in GLC4-Adr, its P-glycoprotein (Pgp)-negative, multidrug-resistant (MDR; 100-fold DOX-resistant) subline with overexpression of the MDR-associated protein (MRP) and a lowered topoisomerase II activity, and in GLC4-CDDP, its cisplatin-resistant subline. GLC4-Adr was about 2-fold cross-resistant for the morpholino anthracyclines and GLC4-CDDP was, relative to GLC4, more resistant for the morpholino anthracyclines than for DOX. Overall, MRA-CN was about 2.5-fold more cytotoxic than MRA-MT. The cytotoxicity profile of the morpholino anthracyclines in these cell lines mimicked that of camptothecin.