Alexei Arkhipov

PURPOSE: This phase III, double-blind, randomized, multicenter study evaluated the efficacy, pharmacodynamics, and safety of the oral aromatase inactivator exemestane (EXE) versus megestrol acetate (MA) in postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen. PATIENTS AND METHODS: A total of 769 patients were randomized to EXE 25 mg/d (n = 366) or MA (n = 403) 40 mg four times daily. Tumor response, duration of tumor control, tumor-related signs and symptoms (TRSS), quality of life (QOL), survival, and tolerability were evaluated. RESULTS: Overall objective response (OR) rates were higher in patients treated with EXE than in those treated with MA (15.0% v 12.4%); a similar trend was noted in patients with visceral metastases (13.5% v 10.5%). Median survival time was significantly longer with EXE (median not reached) than with MA (123.4 weeks; P =.039), as were the median duration of overall success (OR or stable disease > or = 24 weeks; 60.1 v 49.1 weeks; P =.025), time to tumor progression (20.3 v 16.6 weeks; P =.037), and time to treatment failure (16.3 v 15.7 weeks; P =.042). Compared with MA, there were similar or greater improvements in pain, TRSS, and QOL with EXE. Both drugs were well tolerated. Grade 3 or 4 weight changes were more common with MA (17.1% v 7.6%; P =.001). CONCLUSION: EXE prolongs survival time, time to tumor progression, and time to treatment failure compared with MA and offers a well-tolerated treatment option for postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen.

PURPOSE: To evaluate the antitumor activity and toxicity of a new steroidal aromatase inactivator, exemestane, in postmenopausal women with metastatic breast cancer who had progressive disease (PD) after treatment with a nonsteroidal aromatase inhibitor. PATIENTS AND METHODS: In this phase II trial, eligible patients were treated with exemestane 25 mg daily (n = 241) followed, at the time PD was determined, by exemestane 100 mg daily (n = 58). RESULTS: On the basis of the intent-to-treat analysis by independent review, exemestane 25 mg produced objective responses in 6.6% of patients (95% confidence interval [CI], 3.8% to 10.6%) and overall success (complete response + partial response + no change for 24 weeks or longer) in 24.3% (95% CI, 19.0% to 30.2%). The median durations of objective response and overall success were 58.4 weeks (95% CI, 49.7 to 71.1 weeks) and 37.0 weeks (95% CI, 35.0 to 39.4 weeks), respectively. Increasing the dose of exemestane to 100 mg upon the development of PD produced one partial response (1.7%; 95% CI, 0.0% to 9.2%). Both dosages were well tolerated and were discontinued because of adverse events in only 1.7% of patients. CONCLUSION: Exemestane 25 mg once daily seems to be an attractive alternative to chemotherapy for the treatment of patients with metastatic breast cancer after multiple hormonal therapies have failed.

Abstract Urinary 3-methyladenine (3-MeAde) excretion andlymphocyte DNA adduct formation was studied in 15 patients receiving methylnitrosourea (MNU) at several dose levels (250 mg, 300 mg and600 mg total dose, 143-385 mg m(-2)) as part of various combination chemotherapies for advanced tumours (malignant melanoma, lymphoblastic lymphosarcorna andHodgkin's disease). Urinary 3-MeAde levels were significantly increased over background in patients at all dose levels (p < 0.001) andthe increases were dose-dependent (r = 0.77, p < 0.01). There were large interindividual variations in the excretion of 3-MeAde at each dose of MNU. In a subset of patients, N7-methyl-2-deoxyguanosine (7-MedG) andO(6)-methyl-2'-deoxyguanosine (O(6)-WedG) levels in DNA from blood leucocytes showed dose-dependent increases, however there were no simple relationships between urinary methylated DNA bases andleucocyte DNA adducts. Levels of adducts in leucocyte DNA (7-MedG, < 17-217 μmol mol(-1) dG; O(6)-WedG, < 1.6-35 μmol mol(-1) dG) were comparable with those reported for other methylating chemotherapeutic drugs. Leucocyte DNA andurinary methyl adducts may be useful markers of individual responses to treatment with methylating drugs.