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Background: Therapy with high-dose cyclophosphamide, cisplatin, and carmustine (BCNU) plus autologous bone marrow transplantation has been extensively studied as treatment for patients with stage II or III breast cancer who have a 70% or greater risk of developing metastatic disease. This therapy is being used in a cooperative intergroup phase III clinical trial. In the cyclophosphamide-cisplatin-BCNU regimen, cyclophosphamide and BCNU, but not cisplatin, have been reported to cause acute lung injury, suggesting that either cyclophosphamide or BCNU may contribute to this injury. Purpose: The purpose of this study was to analyze clinical and pharmacokinetic data from our ongoing phase II trials and to determine whether there is an association between BCNU pharmacokinetics and acute lung injury following cyclophosphamide-cisplatin-BCNU therapy. Methods: We performed a retrospective study of 38 patients treated following induction therapy or relapse, 29 with stage II-IV breast cancer and nine with intermediate and high-grade stage III-IV non-Hodgkin's lymphoma. These patients received therapy with cyclophosphamide at a dose of 1875 [mu]g/[m.sup.2] daily as a 1-hour intravenous infusion for 3 days, cisplatin at 55 mg/[m.sup.2] per day as a 72-hour continuous intravenous infusion, and BCNU at 600 mg/[m.sup.2] as a 2-hour infusion immediately following completion of the cisplatin infusion. Data from analysis of blood samples were used to calculate pharmacokinetic parameters for BCNU, and acute lung injury was determined on the basis of pulmonary function test results and histologic examination of lung biopsy specimens. Results: Our analysis showed that 20 (53%) of the 38 patients developed pulmonary injury following treatment. Twelve (60%) of the 20 had values for area under the curve (AUC) for BCNU concentration x time that exceeded 600 ([mu]g/mL) x minute, whereas only two (11%) of the 18 without pulmonary injury had values above this level (P

Metastatic breast cancer is a malignancy of the breast tissue associated with the spreading of cancer cells to other body sites. Because this disease is not considered curable, most treatment methods are designed only to reduce symptoms and disease severity. An intensive dose schedule of the anticancer agent doxorubicin produced complete remission for longer than 18 months in only three of 26 patients treated and caused toxic effects on the heart. Treatment with the anticancer agents cyclophosphamide, cisplatin, and carmustine with bone marrow support to maintain marrow function produced complete remission in 15 percent of patients for longer than 18 months. Because relapses occurred in tissues with a large amount of tumor, it was suggested that a reduction in tumor size may improve responses to treatment. The effectiveness of the combined use of these treatment approaches was assessed in 45 patients with metastatic breast cancer. The drug regimen consisted of doxorubicin, 5-fluorouracil, methotrexate, and a method to maintain bone marrow function called 'folinic acid (or leucovorin) rescue' (AFM), and was designed to shrink the tumor rapidly and extensively before treating patients with high doses of alkylating-type anticancer agents and bone marrow support. Ninety-one percent of the patients responded to treatment, and complete clinical response was achieved in 38 percent after an average of 70 days of treatment. These findings show that AFM is effective in producing remission in patients with metastatic breast cancer. However, the considerable toxicity of the regimen must be considered in its routine use for breast cancer. (Consumer Summary produced by Reliance Medical Information, Inc.)

Carmustine, also called BCNU, is a powerful anticancer agent which is used for both solid tumors and lymphomas. BCNU has serious side effects, however, including bone marrow suppression, liver toxicity, lung disease, and progressive kidney failure. Recently, attempts to use high doses of BCNU have been combined with autologous bone marrow transplantation. In this procedure, bone marrow taken from the patient is replaced later to supplant the bone marrow that has been crippled by the chemotherapeutic treatment. While this procedure permits the use of higher doses of BCNU, it also results in high rates of other side effects besides bone marrow suppression. While many of the side effects have been well studied, researchers have now found that myocardial ischemia is a side effect which has been previously overlooked. Myocardial ischemia is the inadequate supply of oxygen to the heart muscle resulting from obstructed blood flow. This same phenomenon is common in the form of angina pectoris, and, if the oxygen deprivation is severe enough, may result in a heart attack. The condition most often results from disease of the blood vessels supplying the heart. Three patients receiving infusions of BCNU developed chest pain and racing heart beats during or immediately after the infusion. Electrocardiograms (ECGs) taken of the three cancer patients revealed physiological changes indicative of myocardial ischemia. The oldest of the three patients was 41, and none had previous histories of cardiovascular disease. Angina pectoris is normally treated with drugs which relax the blood vessels to the heart; this treatment proved effective in these cancer patients as well. Myocardial ischemia is known to be a side effect of 5-fluorouracil, which is unrelated in molecular structure to BCNU. Although the cause of the myocardial ischemia in patients treated with high-dose BCNU is not understood, these cases illustrate that this side effect must be considered as a possibility in patients receiving this treatment. (Consumer Summary produced by Reliance Medical Information, Inc.)