J. G. McVie

Pharmacokinetics of carboplatin after intraperitoneal administration

SummaryThe phamacokinetics of carboplatin, ultrafilterable platinum, and total platinum after intraperitoneal (i. p.) administration were studied in peritoneal fluid, plasma, red blood cells (RBCs), and urine during a phase-I trial in patients with minimal, residual ovarian cancer. Samples were collected from 7 patients who had recived carboplatin (200–500 mg/m2) in 21 dialysis fluid. The fluid was withdrawn after a 4-h dwell. Platinum concentrations were measured by flameless atomic absorption spectrometry, and intact carboplatin was determined by HPLC with electrochemical detection. Peak concentrations of carboplatin in plasma were obtained 2 h after the end of instillation. The mean ratio of peak concentrations of carboplatin in instilled fluid and plasma was 24±11. The peritoneal clearance of carboplatin was 8±3 ml/min, which was 12 times less than the plasma clearance (93±32 ml/min). Due to this clearance ratio, the AUCs for the peritoneal cavity were about 10 times higher than those for plasma. On average, 34%±14% of the dose was still present in the instillation fluid that had been withdrawn after a dwell time of 4 h. In plasma, the mean value of AUC/Dnet (Dnet=Dose — amount recovered from the peritoneal cavity) after i.p. administration was comparable with that of AUC/D after i.v. administration. This means that unrecovered carboplatin (66%) was completely absorbed from the peritoneal cavity. It may be expected from this bioavailability that the maximum tolerated dose (MTD) of i.p.-administered carboplatin with a 4-h dwell is around 1.5 times higher than that after i.v. administration. Overall pharmacokinetic parameters of carboplatin and platinum in plasma were comparable after i.p. and i.v. administration.

Dose-Finding Studies with Carboplatin, Ifosfamide, Etoposide and Mesna in Non-Small Cell Lung Cancer

Carboplatin, a clinically active analogue of cisplatin, was added to a regimen containing ifosfamide and etoposide, two agents with proven activity in non-small cell lung cancer (NSCLC). From August 1986 until November 1988, 43 consecutive patients (29 men and 14 women), mean age 57 years, performance status of 2 or less, with symptomatic, inoperable NSCLC were accrued and received carboplatin 100 mg/m2 on days 1, 3, and 5, or 300 or 350 mg/m2 on day 1; ifosfamide 1,500 mg/m2 and etoposide 60 or 100 mg/m2 every 4 weeks. Thirty-four patients were previously untreated, nine had been irradiated before, and two had also received previous chemotherapy. So far, 154 courses have been administered; 19 patients have received four or more courses. With the combination of 350 mg/m2 carboplatin and 100 mg/m2 etoposide, myelosuppression was dose-limiting; nephrotoxicity and neurotoxicity did not occur. Evaluation of response after two or four courses in 40 patients showed an objective response in 40%, whereas 30% progressed during therapy. Carboplatin added to etoposide and ifosfamide is a feasible combination that warrants further study in a randomized fashion.

Clinical Experience with 1, 1-Diaminomethylcyclohexane (Sulphato) Platinum (II) (TNO-6)

Cis-diamminodichloroplatinum II (cisplatin) is the first member of a group of platinum coordination complexes, which were shown to possess antitumor activity (1). With the introduction of cisplatin into the clinic the spectrum of tumors which can be treated effectively with chemotherapy has broadened (2). This agent is increasingly utilized in first-line regimens against testicular cancer, ovarian cancer, head and neck cancer, bladder cancer, while results in squamous cell cancer of the uterine cervix and in some childhood solid tumors like neuroblastoma and osteogenic sarcoma have been most promising. However, the use of the drug is hampered by some serious side effects. Its major clinical disadvantages are intense nausea and vomiting and renal impairment (3,4). Nausea and vomiting are much more distressing than found with other cytostatic drugs and cannot be effectively prevented. Adequate hydration and attention paid to optimal urinary flow results in a decrease in the incidence and the severity of nephrotoxicity. Nevertheless, substantial decrease in glomerular filtration rate and effective renal plasma flow can be found, which may be at least partially irreversible (5,6). Other toxicities include neurotoxicity, ototoxicity, myelosuppression, diarrhea and occasional liver function test abnormalities, electrolyte imbalances and occasional anaphylactic-like reactions (7). Although nephrotoxicity is generally considered as the major dose limiting toxicity, methods to overcome this toxicity have created the possibility to administer multiple courses of the drug. With prolonged treatment other toxicities may become dose-limiting. Recognition of these limitations has stimulated a widespread search for alternative platinum complexes with equal or greater antitumor activity but with decreased toxicities.

Phase II study of ACNU in non-small-cell lung cancer: EORTC study 08872.

SummaryA total of 62 patients with metastatic or locally advanced non-small-cell lung cancer were entered in a phase II study of ACNU. Initially, the drug was given i. v. at a dose of 100 mg/m2 every 6 weeks, but due to observed haematological side effects in chemotherapy-pretreated patients, the dose was lowered in this group to 75 mg/m2. We observed one complete response in a subject exhibiting multiple lung metastases and a partial response in two patients, one showing brain metastases and one who experienced local disease recurrence. The toxicity of ACNU mainly consisted of bone marrow suppression especially thrombocytopenia, with one toxic death occurring due to intracerebral haemorrhage. We concluded that at this dose and on this schedule, ACNU has limited activity in non-small-cell lung cancer.

A NEW INTRAPERITONEAL TUMOR MODEL IN THE RAT

SummaryA new tumour model that is particularly suitable for testing intraperitoneal chemotherapy is described. Single tumours were induced to grow in the mesentery of rats by the implantation of small pieces taken from subcutaneous tumours. Tumour growth was monitored by repeated laparotomies at which the tumour size was measured with calipers. In this way, growth curves of treated and untreated tumours could be defined. The diameter of untreated intraperitoneal tumours increased linearly with time [diameter (mm)=0.39 t (days) +2.4]. Tests using different numbers of laparotomies showed that the procedure itself had little influence on growth. Cell kinetic studies of 6-mm tumours showed a mean labelling index of 31% and a volume-doubling time of 3.9 days, resulting in cell-loss factors probably in excess of 70%. The model was tested by assessing the effect of the chemotherapeutic agent cisplatin. Regression and regrowth could be satisfactorily followed, leading to estimates of growth delay. This model therefor provides a quantitative way to assess the response of intraperitoneal tumours to chemotherapy.

Platinum Coordination Derivatives by the Intraperitoneal Route: Pharmacokinetics and Clinical Results

Notwithstanding improvement of treatment results in ovarian cancer, even the patient who achieved a complete remission may face a relapse. The seven year follow-up figures of the study performed in the Netherlands (1), which compared cisplatin containing combination chemotherapy CHAP-5 (cyclophosphamide, hexamethylmelamine, adriamy-cin and cisplatin) with HexaCAF (hexamethylmelamine, cyclophosphamide, adriamycin and 5-flourouracil) show a steadily decrease of the number of disease free patients upto 60–70% of those formerly in complete remission. Therefore even for patients in complete remission as a result of cisplatin based combination chemotherapy new treatment strategies seem warranted. For the other, not reaching a complete remission this counts the more. Late intensification by an increased dose of cisplatin for instance could offer such a new treatment avenue, based on the theory of Goldie and Coldman (2). Such an increased dose might overcome acquired cisplatin resistance of remaining tumorcells.