Intensive 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), NSC #4366650 and cryopreserved autologous marrow transplantation for refractory cancer. A phase I-II study.
One hundred forty-three patients with refractory cancer were treated with intensive BCNU (600-2850 mg/m2) and autologous marrow transplantation to determine the maximum tolerated dose and antitumor effects of this regimen. Recovery from severe pancytopenia in less than 4 weeks after transplantation occurred in 92.8% of evaluable patients, suggesting the efficacy of the autologous marrow in limiting the prolonged myelosuppression anticipated with intensive BCNU. Serious extramedullary toxicity was encountered at BCNU 1200 mg/m2, where a 9.5% incidence of fatal interstitial pneumonitis and a 3.0% incidence of fatal hepatic necrosis was observed. Higher BCNU doses, 1500 to 2850 mg/m2, were associated with a 35.3% incidence of fatal hepatotoxicity. Fatal encephalomyelopathy was encountered in two patients given BCNU 2250 and 2850 mg/m2. One patient who received the highest cumulative dose of BCNU (3450 mg/m2 in 2 courses) died of cardiac necrosis. Other serious extramedullary toxicities were not encountered, even in the 14 patients who survived from 1 to nearly 5 years after BCNU therapy. Antitumor responses occurred in 40.0% of evaluable patients; a dose effect could not be evaluated due to patient heterogeneity. The BCNU doses associated with acceptable toxicity, 600 to 1200 mg/m2, produced a 37.5% total and an 11.3% complete response (CR) rate, including five patients with prolonged CRs of 1 to nearly 5 years. Notable among the CRs was the 25.0% CR rate in previously untreated metastatic melanoma, and the production of CRs in malignant disease in the central nervous system (CNS) including melanoma, lung cancer, adenocarcinoma of unknown primary, acute leukemia and glioblastoma multiforme. It is concluded that augmented doses of BCNU can be given when autologous marrow transplantation is used to limit myelosuppression. Lung and liver toxicity prevent the use of BCNU doses greater than 1200 mg/m2; neurotoxicity, and perhaps cardiotoxicity, are manifestations of the highest doses used in this study. The antitumor activity of BCNU 600 to 1200 mg/m2 remains to be determined for most neoplasms; these results suggest improved results in melanoma and CNS malignancy compared to conventional-dose BCNU therapy.
D000293:Adolescent; D000328:Adult; D000368:Aged; D016026:Bone Marrow Transplantation; D001932:Brain Neoplasms / Q000556:secondary / Q000628:therapy; D002330:Carmustine / Q000008:administration & dosage* / Q000009:adverse effects / Q000633:toxicity; D002493:Central Nervous System Diseases / Q000139:chemically induced; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007223:Infant; D008171:Lung Diseases / Q000139:chemically induced; D008297:Male; D008545:Melanoma / Q000628:therapy; D008875:Middle Aged; D009369:Neoplasms / Q000401:mortality / Q000628:therapy*
D002330:Carmustine