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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 mg m-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 < 0.01). 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-1 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.

The importance of the ultrafilterable platinum (fPt) fraction of cisplatin (CDDP) and carboplatin (CBDCA) for cytotoxicity and myelotoxicity was studied in vitro. By incubating CDDP or CBDCA with fetal calf serum (PCS) various fractions of fPt were prepared and determined by atomic absorption spectroscopy. A relation of % fPt fraction and incubation time (h) of 87e-1123t(r = −0.99) and 101e-o.oo87t (r = −0.99) were determined for CDDP and CBDCA, respectively. Cytotoxicity in the human small cell lung carcinoma cell line GLC4 and fPt fraction were closely related for CDDP (r = 0.99) and for CBDCA r = 0.97). However, at a similar fPt fraction the concentrations inhibiting cell survival by 50% (IC50) of CBDCA exceeded that of CDDP by a factor of 10-18 with 4 h exposure and a factor of 5 with continuous exposure. Tested in the range of peak concentrations in plasma of patients and at a clinically relevant fPt fraction of 10%, CDDP was not toxic for human bone marrow cells in the CFU-GM assay, whereas it was toxic at fPt fractions of 50% and 90%. However, CBDCA was myelotoxic at a (clinically relevant) fPt fraction of 50%, and also at 75% and 90%. The use of different fPt fractions, produced by the incubation method described in this study, permits the study of platinum drugs in vitro while approximating in vivo conditions might be used to evaluate myelotoxicity of new platinum drugs prospectively. For CDDP and CBDCA the fraction fPt determines cytotoxicity on tumor cells, and their different fPt fraction in patients account at least partly for their difference in myelotoxicity.

The chemical stability of the new anticancer platinum analogue 1,2-diaminomethyl-cyclobutane-platinum(II)-lactate (D19466) in infusion media was studied in an accelerated stability testing experiment with a selective HPLC-UV method. Variables were time, temperature, light, concentration, and infusion mixture. Mean reaction rate constants of decomposition were, respectively, 0.9555 *10−2, 2.127 *10−2, and 4.221 *10−2 hr−1 at 37, 56, and 66°C at a concentration of 200 mg/L in normal saline. From the Arrhenius equation, shelf lives (5% loss) at 4, 22, 37, and 121°C were, respectively, calculated to be 41.6, 13.2, 5.7, and 0.15 hr. Mean reaction rate constant in 5% dextrose was 3.106 * 10−2 hr−1 (200 mg/L; 56°C) and differed from that in normal saline (P 0.05). There was no influence of normal daylight on the rate of decomposition. It is recommended to prepare D19466 infusions in normal saline. Chemical stability is then maximal 12 hr at room temperature or 24 hr at 4°C. No protection against normal daylight is required. Sterilization by heat is not possible.

Earlier studies revealed that renal function is reduced in non-cancer patients with a malnutritional status. We have studied the effect of nutritional status on renal function in 46 patients with disseminated non-seminomatous testicular cancer treated with combination chemotherapy including cis-diammine dichloroplatinum (cDDP) according to the Einhorn regimen. The renal function was expressed as glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and filtration fraction (FF) measured by radioisotope infusion methods. Nutritional assessment of the patients was performed by means of three nutritional parameters: weight-for-height index (WHI), creatinine height index (CHI), and serum albumin concentration (Salb). The patients were also divided into two groups: group 1, patients with a sufficient nutritional status, defined as patients with only one abnormal nutritional parameter or none at all (n = 30); group 2, patients with an insufficient nutritional status, defined as patients with two or three abnormal nutritional parameters (n = 16). Median values of WHI, CHI and Salb in group 2 patients were significantly lower than the median values in group 1. Before treatment no correlation was found between the individual nutritional parameters and GFR, ERPF and FF respectively. The median GFR, ERPF and FF of both group 1 and group 2 did not differ significantly. Although the renal function of the total group of patients was reduced as a result of cDDP, this reduction was not influenced by the individual parameters and not higher in the group with an initially insufficient nutritional status. In this study no relation was found between nutritional status and renal function of patients with disseminated non-seminomatous testicular cancer.

With the recent development of reliable portable pumps and safe venous access systems, continuous infusion of chemotherapeutic agents on an out-patient basis has become feasible. Advantages of continuous infusion are the long-term exposure of tumour cells to the drug and the fact that most toxic effects are reduced for doxorubicin, epirubicin and mitoxantrone due to elimination of the high peak plasma levels. Preliminary data for doxorubicin suggest that its antitumour activity is maintained. Pharmacokinetic studies with epirubicin and mitoxantrone showed a linear relationship between drug dose infused and the steady-state plasma level for these drugs. The area under the curve for leukocytes drug level was higher during continuous infusion than after an equitoxic bolus injection of epirubicin and mitoxantrone. Well-randomized clinical trials will be necessary to investigate the role of continuous infusion of antracyclines and mitoxantrone in cancer chemotherapy in the future.

A prospective study with mild general analgesia and sedation together with local anesthesia during bone marrow harvest was performed. Thirty-one patients underwent 33 bone marrow collections. Pretreatment consisted of 100 mg meperidine i.m. and 20 mg diazepam i.m. 1 h before start of procedure. Eight patients got additional meperidine and diazepam during the procedure, all patients got lidocaine 1% locally. A mean volume of 1.321 was obtained with 42.5 punctures. Twenty-two patients had no complications, 4 vomited, 4 had easily correctable hypotension of short duration, one got oxygen for cyanosis of short duration. Acceptance was good in 23 patients, in 6 reasonably well, in two bad. Only one patient experienced pain problems, due to suction. Anxiety was no major problem due to good information before the procedure and mild sedation. This form of anesthesia for bone marrow collection is a safe procedure, it is generally well accepted by the patient and it can be performed on an out-patient basis.

Thirty-one patients with disseminated malignant melanoma were treated with a combination chemotherapy of bleomycin, dacarbazine and vindesine. Five complete responses, and five partial remissions occurred. One patient survived for over 2 years without evidence of disease. This combination of drugs may give better results, as far as complete recovery and long-term survival are concerned, than single-agent therapy with dacarbazine.