Faculty Bibliography

Daunomycin, like its anthracycline analog adriamycin, is a cardiotoxic antitumor antibiotic. Reports on 5,613 patients receiving daunomycin were reviewed for cardiotoxicity. Two distinct patterns of cardiotoxicity were defined, congestive heart failure (cardiomyopathy) and electrocardiographic changes. Dose-response curves were constructed using the percent incidence of cardiomyopathy versus the total dose of daunomycin in mg/m2. There was a dose-response relationship between the total dose of daunomycin and the development of cardiomyopathy, both in children and adults. The children seem more susceptible to the drug-induced cardiomyopathy. The electrocardiographic changes in the children and adults did not show a dose-dependent relationship, were present consistently even at the lowest dosage levels, and did not predict for subsequent development of cardiomyopathy. The dose-response curves constructed enable the clinician to judge the relative risk of developing cardiomyopathy at a given total dosage level and allows comparison of the human experience with the experimental animal model data.

Clinical studies involving 5-azacytidine, a ring analogue of cytidine, began in Europe in 1967 and the United States in 1970, and we review available preclinical and clinical studies here. The drug possesses cytotoxic, antimicrobial, antineoplastic, abortive, and mutagenic activity in various biological systems. 5-Azacytidine is thought to exert its antineoplastic effect through interference with nucleic acid metabolism. The dose-limiting toxicities are nausea, vomiting, and leukopenia, while the incidence of thrombocytopenia is low. Hepatic toxicity ranges from abnormal findings in liver function tests to hepatic coma. Clinical results in solid tumors are not encouraging, but 5-azacytidine shows consistent antitumor activity in patients with acute myelogenous leukemia resistant to previous treatment. An overall response rate of 36%, with 20% complete remissions, was achieved in 200 previously treated patients with acute myelogenous leukemia. Further studies must define the role of 5-azacytidine alone and in combination for the first-line treatment of acute myelogenous leukemia.

This report describes a de novo development of Kaposi's sarcoma in a Puerto-Rician man 9 months after a cadaveric renal transplant. Progression of the disease was observed despite local irradiation, while the patient remained immunosuppressed with prednisone and azathioprine. This was accompanied by depressed immunologic tests. Discontinuation of azathioprine and addition of chemotherapy (bleomycin and vincristine), while continuing prednisone to maintain functional survival of renal allograft, has led in this patient to regression of extensive cutaneous and suspected pulmonary Kaposi's sarcoma lesions. The possible importance of a depressed immunosurveillance mechanism and activation of latent oncogenic virus by the presence of an allograft in the de novo appearance of Kaposi's sarcoma in transplant recipients is briefly discussed.

Two hundred and fifty-eight patients with small cell carcinoma and 185 patients with adenocarcinoma were centrally randomized to receive either cyclophosphamide (1000 mg/m2 every 3 weeks) iv or cyclophosphamide (700 mg/m2 every 3 weeks) iv plus CCNU (70 mg/m2 every 6 weeks) orally. Those patients who were initially treated with the single agent were then treated with CCNU (130 mg/m2 every 6 weeks) at the time of cyclophosphamide failure. Objective tumor regression occurred more frequently with the combination regimen in patients with small cell carcinoma (43% vs 22%, P = 0.002), but no difference in response rates was apparent in patients with adenocarcinoma. In both cell types patients survived somewhat longer following treatment with the combination. The overall incidence of severe toxicity was equal for the two regimens in both cell types; however, the therapeutic index of the combination was superior to that of the single agent in small cell carcinoma. Severe drug toxicity was more frequent in small cell carcinoma patients with extensive disease, and survival was reduced in both cell types with extensive disease. Survival was better for ambulatory patients in both cell types and women survived longer than men. In women with small cell carcinoma, ambulatory status also was associated with a higher incidence of tumor regression. In patients with small cell carcinoma those who had prior lung surgery survived longer than those without prior surgery. Previous radiation therapy was associated with a reduced incidence of objective regression in men with small cell carcinoma. In both cell types patients with tumor regression lived longer than nonresponders; however, objective disease stability was associated with improved survival only in patients with adenocarcinoma. Stratification in future studies should consider extent of disease, performance status, sex, and prior therapy.