HIGH-DOSE INFUSIONAL DOXORUBICIN AND CYCLOPHOSPHAMIDE - A FEASIBILITYSTUDY OF TANDEM HIGH-DOSE CHEMOTHERAPY CYCLES WITHOUT STEM-CELL SUPPORT

The purpose of this study was to determine the maximally tolerated dos e of doxorubicin administered during two cycles of intensive chemother apy with cyclophosphamide and doxorubicin without stem cell support in patients with advanced cancer and to assess the cumulative cardiac to xicity of the regimen by noninvasive radionuclide imaging and by pre- and postchemotherapy endomyocardial biopsies. Thirty-eight patients (t hirty-six with high risk or metastatic breast cancer) were treated in a dose-escalation trial using a fixed dose of i.v. cyclophosphamide (4 .2 g/m(2)) administered over 2 h on day 5 and escalating doses of doxo rubicin (50-175 mg/m(2)) given as a 96-h continuous i.v. infusion on d ays 1-4, using Filgrastim (granulocyte colony-stimulating factor) for hematological support beginning on day 6. All patients underwent pretr eatment, and 28 patients underwent postchemotherapy endomyocardial bio psies. Twenty-nine of 38 patients received two cycles of treatment (me dian number of days between cycles, 44; range, 34-62). Twenty-one pati ents had received doxorubicin previously at cumulative dose levels les s than or equal to 150 mg/m(2); all patients had pretreatment endomyoc ardial biopsy scores less than 1. One patient treated at the highest d ose level of doxorubicin (175 mg/m(2)) developed symptoms of mild cong estive heart failure following two cycles of chemotherapy. Pre- and po sttreatment radionuclide ejection fractions were 65 and 45%, respectiv ely; this patient had a posttreatment endomyocardial biopsy score of 1 (damage to <5% of myocytes). One additional patient at this dose leve l had an asymptomatic biopsy score of 1, with a decrease in ejection f raction from 62 to 43%; this recovered to 58% 5 months after completio n of chemotherapy. Six additional patients treated at lower dose level s had abnormal posttreatment endomyocardial biopsies without abnormal posttreatment ejection fractions. Nine patients received only one cycl e of chemotherapy: five patients due to decreased cardiac ejection fra ction following cycle 1 (two of these patients had normal endomyocardi al biopsies, and two patients had biopsy scores of 1); one patient sec ondary to tumor progression following cycle one; one patient due to pe rsistently detectable Clostridium difficile toxin in the stool; one pa tient refused cycle two; and one patient died following cycle one of c omplications related to sepsis. A single patient experienced a grand m al seizure associated with orthostatic hypotension, which was consider ed the dose-limiting toxicity. The median duration (over two cycles) o f granulocytopenia (absolute granulocyte count <500/mu l) at the maxim ally tolerated dose level of 150 mg/m(2) was 8.5 days (range, 5-13 day s), and the median duration of thrombocytopenia (platelets <20,000/mu l) was 2.5 days (range, 0-9 days). The median duration of hospitalizat ion including chemotherapy administration was 23 days (range, 19-36 da ys). Other toxicities included stomatitis, fever, diarrhea, and emesis . One patient developed acute leukemia 54 months posttreatment. We con clude that two courses of high-dose cyclophosphamide and doxorubicin u sing granulocyte colony-stimulating factor are feasible and safe with tolerable myocardial toxicity as evidenced by serial endomyocardial bi opsies. The dose-limiting toxicity encountered was a grand mal seizure . The recommended Phase II dose is doxorubicin 150 mg/m(2) administere d as a 96-h infusion on days 1-4, with cyclophosphamide 4.2 g/m(2) on day 5 and G-CSF 5 mu g/kg/day started on day 6 and administered until the total WBC is above 10,000/mu l for three consecutive days.