ACUTE LUNG INJURY FOLLOWING TREATMENT WITH HIGH-DOSE CYCLOPHOSPHAMIDE, CISPLATIN, AND CARMUSTINE - PHARMACODYNAMIC EVALUATION OF CARMUSTINE

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 mg/m daily as a 1-hour intravenous infusion for 3 days, cisplatin at 55 mg/m2 per day as a 72-hour continuous intravenous infusion, and BCNU at 600 mg/m2 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<.03). Thus, 12 (86%) of 14 patients with BCNU AUC greater than 600 (mug/mL) x minute developed lung injury. Conclusions: These results suggest that BCNU exposure greater than 600 (mug/mL) minute is associated with increased risk of acute lung injury after cyclophosphamide-cisplatin-BCNU therapy and may be a major cause of pulmonary drug injury following this regimen. Implications: Strategies aimed at more uniform drug exposure or selective neutralization of chlorethylisocyanate, one of the two major hydrolysis products of BCNU, might reduce the incidence of acute lung injury following this regimen without major compromise of antitumor effect.