Carboplatin

Abstract

Carboplatin is a ‘second-generation’ platinum compound advocated for use in the treatment of patients with ovarian cancer and it has also shown promise in small cell lung cancer, squamous cell carcinomas of the head and neck, and seminomas. Overall, it would appear to have a similar qualitative spectrum of activity to cisplatin. There have been few comparative trials with carboplatin, either alone or in combination with other chemotherapeutic agents, but the limited data suggest comparable efficacy with cisplatin in ovarian cancer. Importantly, the toxicity profile of carboplatin is markedly different from that of cisplatin, with nephrotoxicity, neurotoxicity and ototoxicity occurring only infrequently with carboplatin. As with cisplatin, nausea and vomiting occur in many patients after carboplatin administration, but symptoms are usually delayed for several hours and are mild to moderate in severity — dose-limiting nausea and vomiting are infrequent with carboplatin. The dose-limiting toxicity of carboplatin is myelosuppression, with severe thrombocytopenia and less often leucopenia, which may be more severe in older patients or in those with renal impairment or those who have had previous chemotherapy. Thus, preliminary data suggest that carboplatin is a therapeutically equivalent alternative to cisplatin, but with a differing toxicity profile that should offer advantages over cisplatin in many patients. Carboplatin is a cytotoxic platinum complex structurally related to cisplatin, and the antitumour activity of carboplatin in laboratory studies is qualitatively similar to that of cisplatin. Like cisplatin, carboplatin reacts with nucleophilic sites on DNA, causing intrastrand and interstrand crosslinks and DNA-protein crosslinks. However, these crosslinks are formed later with carboplatin than with cisplatin. In vitro tests have shown that carboplatin potentiates the effects of radiation on tumour growth and inhibits recovery from radiation-induced potentially lethal damage. Carboplatin cytotoxicity is greatly enhanced by an increase in temperature to 41.8°C. In vivo studies show that, alone among 9 platinum complexes tested (including cisplatin), carboplatin causes an increase in tumour phosphorylation without an associated increase in healthy kidney and/or liver tissue phosphorylation, indicating greater tumour selectivity. Carboplatin is usually administered intravenously and plasma concentrations and AUC increase proportionally with the dose. Tissue distribution is similar to that seen with cisplatin, with highest concentrations of platinum in the liver, kidney, skin and tumours. In lung and liver tumours, concentrations appear to be higher in the tumours than in the normal surrounding organ tissue. After an intravenous dose of carboplatin 20 to 1600 mg/m² in patients with cancer, the distribution half-life is 83 to 96 minutes. The volume of distribution is 16 to 20L. In contrast to cisplatin which is extensively protein-bound, carboplatin is not extensively bound to plasma proteins, at least in the initial hours following administration although this fraction does increase with time. Estimations of protein binding of less than 10 to 24% have been made by various authors, although higher values have been reported at the end of a continuous 24-hour infusion or 24 hours after a 1-hour infusion. It is suggested that degradation products or metabolites of carboplatin are irreversibly bound to plasma proteins as time passes following administration. The main route of excretion of carboplatin is via renal clearance. About 50 to 75% of the total platinum administered as carboplatin is excreted in the urine in the first 24 hours. Tubular secretion is probably not involved, in which carboplatin again differs from cisplatin. Total body clearance of free platinum is 75 to 147 ml/min after doses of 20 to 1600 mg/m². The elimination half-life of carboplatin in patients with malignancies is 180 minutes, that of free platinum is 354 to 366 minutes, and that of total platinum is 399 to greater than 1440 minutes. Renal clearance and total body clearance of platinum from carboplatin are reduced in patients with impaired renal function, necessitating reduced dosage in these patients. Carboplatin 300 to 800 mg/m² intravenously, given alone, has produced response rates (complete or partial remissions) of 25 to 28% for up to 13+ months in previously treated patients with advanced ovarian cancer and 85% in one study of previously untreated patients. With carboplatin 150 to 400 mg/m², in combination with other cytotoxic agents, the response rate was 30 to 83% in previously untreated patients and 48 to 69% in previously treated patients. Some patients seemingly resistant to previous cisplatin treatment respond to carboplatin but whether they had received optimum doses of cisplatin was not always clear. Nevertheless, this encouraging finding merits further study. Comparative trials of carboplatin and cisplatin, alone or in combination, have shown similar response rates in patients with ovarian cancer (33 to 78% and 32 to 92%, respectively). Carboplatin has also been studied extensively in the treatment of lung cancer. In patients with small cell lung cancer, carboplatin alone has produced response rates of 50 to 60% in previously untreated patients, but much lower success rates of 0 to 19% in previously treated patients. When combined with other cytotoxic drugs (usually including etoposide) overall response rates of 58 to 100% have been achieved. In non-small cell cancer, however, much lower success rates are seen, with only 0 to 20% showing objective responses to carboplatin alone or in combination with etoposide, although 52 to 56% of such patients treated with carboplatin, etoposide and ifosfamide responded. In patients with squamous cell carcinomas of the head and neck, carboplatin alone has produced objective response in 24 to 26% of patients, and in 48 to 92% of patients when combined with 5-fluorouracil or other therapies. Several studies have confirmed the poor efficacy of carboplatin alone in patients with advanced gastrointestinal cancer, with responses occurring in only 0 to 10% of patients. In these patients higher response rates are seen when carboplatin is combined with 5-fluorouracil. In testicular cancer, carboplatin has been associated with 84 to 93% response rates in patients with advanced seminomas, but in only 5 to 15% of patients with non-seminomatous germ cell cancers. Some activity has been observed in a few studies in patients with primary brain tumour (12 to 35% response rate) and urinary tract tumours (6 to 28%) but overall these results are not impressive. In other types of tumour only occasional studies have been reported, mostly with disappointing results, including patients with metastatic breast cancer, malignant lymphoma, leukaemias, renal cancer, malignant melanoma, bone and soft tissue sarcomas and mesothelioma. As predicted by preclinical toxicology studies, the tolerability profile of carboplatin differs from that of cisplatin. Severe nephrotoxicity is usually not seen, although reversible indications of reduced renal function have been reported occasionally. Similarly, neurotoxicity and ototoxicity, which occur frequently with cisplatin, appear to be infrequent and mild following carboplatin administration. Gastrointestinal toxicity occurs in most patients receiving carboplatin, but nausea and vomiting appear to be considerably less severe than in patients receiving cisplatin, are delayed 6 to 12 hours after drug administration, and seldom continue for longer than 24 hours. Nausea and vomiting are not usually dose-limiting with carboplatin therapy. The dose-limiting toxicity of carboplatin is dose-related myelosuppression, predominantly thrombocytopenia. Leucopenia and anaemia also occur but are less severe. Approximately 37% of patients receiving carboplatin 400 mg/m² experience thrombocytopenia (platelets less than 100,000/mm³), although the incidence may be higher in the elderly, patients with renal impairment or those who have undergone previous cytotoxic therapy. Platelet nadirs occur from 14 to 28 days after administration. Little is yet known of the effects of repeated courses of carboplatin on myelosuppression, although there is some evidence that thrombocytopenia and leucopenia may be cumulative. Prevention of carboplatin-induced myelosuppression has been investigated in animal studies using ‘priming’ doses of cyclophosphamide or combination treatment with diethyldithiocarbamate. While clearly very preliminary, these interesting findings merit further study. The recommended dose of intravenous carboplatin varies with the treatment schedule, and the age and renal function of the patient. Moreover, the dose should be lower in patients who have undergone prior chemotherapy compared with previously untreated patients. The following is a list of treatment schedules which have been employed: a bolus injection in the range 240 to 270 (350 to 450 in previously untreated patients) mg/ m² every 4 weeks; weekly bolus injections of 240 (320 in previously untreated patients) mg/m² for 4 consecutive weeks with 2 weeks’ rest; a bolus of 77 (100 in previously untreated patients) mg/m² for 5 consecutive days every 4 to 6 weeks; a 24-hour continuous infusion of 240 (320 in previously untreated patients) mg/m² every 4 to 5 weeks. Children require slightly higher doses, namely 560 mg/m² every 4 weeks or 175 mg/m²/ week for 4 weeks with 2 weeks’ rest. Preliminary studies suggest that continuous infusion offers no great advantage and also requires either hospitalisation or the use of cumbersome equipment. Unlike cisplatin, carboplatin does not require concurrent forced hydration and may therefore be given on an outpatient basis.