Adriamycin chemotherapy—efficacy, safety, and pharmacologic basis of an intermittent single high-dosage schedule

Abstract

A study designed to correlate clinical and pharmacologic observations was undertaken in 96 patients treated with adriamycin. The basic dosage schedule was 60 mg/m2 I.V. q 3 weeks. Pharmacokinetic studies showed a prolonged plasma half-life, low urinary excretion, and undetectable levels in CSF. Patients with significantly impaired liver function had marked elevation and prolongation of plasma drug levels associated with severe toxicity unless dosage was reduced by 50-7596. Of the 82 evaluable patients, 10/25 with sarcomas, 9/31 with carcinomas, and 15/26 with hematologic malignancies have achieved complete or partial remission. An additional 22/48 have improved. Six patients with solid tumors had progressive CNS disease while responding systemically. Adriamycin can he used with relative safety and high efficacy in a dosage schedule that resulted from pharmacologic studies. Dosage reduction in patients with liver disease is essential to avoid life-threatening toxicity.

Dependence of the cytostatic effect of adriamycin on drug concentration and exposure time in vitro

“…Cell cultures.-Experiments were carried out with the following cell lines: B14F28 Chinese hamster cells, a lung fibroblast line (Born 1974) with an average cell-cycle time of 11-14 h and HeLa S3 cells, supplied by Flow Laboratories, Irvine, Scotland, and adapted to our culture conditions (mean cellcycle time 24 h). Monolayer cultures of both cell lines were cultured in Eagle's minimum essential medium (MEM) supplemented with 10% calf serum, 0 01 % neomycin and 0.035% NaHCO3.…”

“…Although a number of empirical dosage schedules are used in the treatment with Adriamycin (Carter et al, 1972), there is controversy about optimum schedule and dosage. Benjamin et al (1974) correlating clinical and pharmacological observations proposed the intermittent single high-dose application of Adriamycin, suggesting that its effectiveness appeared to be related to schedule, rather than dose.…”

An evaluation of hepatic extraction and clearance of doxorubicin

“…Some studies suggest that DOX-induced toxicity correlates with deranged hepatic function as measured by bromsulphophthalein time, serum bilirubin concentration or indocyanine green clearance (Benjamin et al, 1974;Benjamin, 1975;Doroshow and Chan, 1982;Brenner et al, 1984). Hepatic dysfunction is common in cancer patients owing to factors such as hepatic metastases, drug-induced toxicity and viral and bacterial infections.…”

Randomized trial comparing protracted infusion of 5-fluorouracil with weekly doxorubicin and cyclophosphamide with a monthly bolus FAC regimen in metastatic breast carcinoma (SPM90)

“…For all of these parameters, there was no significant difference when adjusted for chemotherapy modality group. Although anthracyclines are the most active single agents in patients with breast cancer, toxicity can be severe in patients with impaired liver function and reduced hepatic clearance (Benjamin et al, 1974). In patients with a poor performance status or low bone marrow reserve, massive liver involvement or lymphangitic pulmonary metastases, weekly administration of 15-20 mg m-2 doxorubicin is associated with fewer complications without a reduction in its effectiveness compared with the conventional dose of 50-75 mg m-2 every 3 weeks, as shown by Scheithauer et al (1985).…”