Geoffrey Falkson

PURPOSE: To compare two doses of letrozole and megestrol acetate (MA) as second-line therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. PATIENTS AND METHODS: Five hundred fifty-one patients with locally advanced, locoregionally recurrent or metastatic breast cancer were randomly assigned to receive letrozole 2.5 mg (n = 174), letrozole 0.5 mg (n = 188), or MA 160 mg (n = 189) once daily in a double-blind, multicenter trial. Data were analyzed for tumor response and safety variables up to 33 months of follow-up evaluation and for survival up to 45 months. RESULTS: Letrozole 2.5 mg produced a significantly higher overall objective response rate (24%) compared with MA (16%; logistic regression, P = .04) or letrozole 0.5 mg (13%; P = .004). Duration of objective response was significantly longer for letrozole 2.5 mg compared with MA (Cox regression, P = .02). Letrozole 2.5 mg was significantly superior to MA and letrozole 0.5 mg in time to treatment failure (P = .04 and P = .002, respectively). For time to progression, letrozole 2.5 mg was superior to letrozole 0.5 mg (P = .02), but not to MA (P = .07). There was a significant dose effect in overall survival in favor of letrozole 2.5 mg (P = .03) compared with letrozole 0.5 mg. Letrozole was significantly better tolerated than MA with respect to serious adverse experiences, discontinuation due to poor tolerability, cardiovascular side effects, and weight gain. CONCLUSION: The data show letrozole 2.5 mg once daily to be more effective and better tolerated than MA in the treatment of postmenopausal women with advanced breast cancer previously treated with antiestrogens.

A randomized comparison of the relative efficacy and toxicity of daunorubicin (DNR) at 30 or 45 mg/sq m or adriamycin (ADM) at 30 mg/sq m, given on the first 3 days of a 7-day continuous infusion of cytosine arabinoside (ara-C) at 100 mg/sq m/day, shows the outcome to be dependent on anthracycline, dose, and patient age. DNR 45 is significantly better than DNR 30 or ADM 30 for inducing complete remissions (CR) in patients younger than 60 yr, (72%, 59%, 58% CRs, respectively). DNR 30 is better than DNR 45 or ADM 30 for inducing CR in patients older than 60 yr (47%, 31%, 35%, respectively). There was a corresponding shift in the induction mortality for the age, dose, and anthracycline groups. Adriamycin was significantly more toxic to the gastrointestinal tract than daunorubicin. The duration of complete remission, with cyclic courses of maintenance therapy, was independent of the patient's age, the dose, or choice of anthracycline used in induction, and of whether the maintenance courses were given every 4 wk or every 8 wk.

PURPOSE: To assess patterns of failure and how selected prognostic and treatment factors affect the risks of locoregional failure (LRF) after mastectomy in breast cancer patients with histologically involved axillary nodes treated with chemotherapy with or without tamoxifen without irradiation. PATIENTS AND METHODS: The study population consisted of 2,016 patients entered onto four randomized trials conducted by the Eastern Cooperative Oncology Group. The median follow-up time for patients without recurrence was 12.1 years (range, 0.07 to 19.1 years). RESULTS: A total of 1,099 patients (55%) experienced disease recurrence. The first sites of failure were as follows: isolated LRF, 254 (13%); LRF with simultaneous distant failure (DF), 166 (8%); and distant only, 679 (34%). The risk of LRF with or without simultaneous DF at 10 years was 12.9% in patients with one to three positive nodes and 28.7% for patients with four or more positive nodes. Multivariate analysis showed that increasing tumor size, increasing numbers of involved nodes, negative estrogen receptor protein status, and decreasing number of nodes examined were significant for increasing the rate of LRF with or without simultaneous DF. CONCLUSION: LRF after mastectomy is a substantial clinical problem, despite the use of chemotherapy with or without tamoxifen. Prospective randomized trials will be necessary to estimate accurately the potential disease-free and overall survival benefits of postmastectomy radiotherapy for patients in particular prognostic subgroups treated with presently used and future systemic therapy regimens.

In a randomized study of acute myelocytic leukemia (AML), 352 patients of all ages were treated for remission induction by one of the four regimens: 7 days of cytosine arabinoside (ara-C) by continuous intravenous (i.v.) infusion or bolus injection every 12 hr, together with daunorubicin (DNR) by rapid i.v. injection on days 1, 2, 3; or 5 days of ara-C by infusion or bolus injection and DNR for 2 days only. The regimen of 7 and 3 infusion was significantly superior to the other 3 regimens, resulting in 56% complete remission (CR). For remission maintenance, ara-C was given for 5 days every month and each month one of the following four drugs added on a cyclic rotational basis: thioguanine, cyclophosphamide, CCNU, or DNR. Although ara-C dosage each month was the same, the route of ara-C administration by random allocation was either rapid i.v. bolus or subcutaneous (s.c.) injection. The median duration of CR was significantly longer for s.c. ara-C group: 14 mo for patients less than 60 yr old (versus 8 mo for i.v.) and 31 mo for 60 or older age group (versus 9 mo for i.v.). Patients who received a combination of the best of the four induction regimens (7 and 3 infusion) and the better of the two maintenance schedules (s.c. ara-C) had a median remission duration of 22 mo and a median survival of 35 mo (the longest reported in a prospective randomized trial of therapy for AML). These results establish the validity of an intensive chemotherapy to produce rapid marrow aplasia followed by a sequential maintenance therapy for achieving prolonged disease-free survival in AML.

PURPOSE The aim of this study was to evaluate the efficacy and toxicity of gemcitabine at higher doses than had been used previously in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Eighty-four patients (65 men, 19 women; age range, 35 to 75 years; mean age, 59 years) with locally advanced or metastatic pathologically documented NSCLC were enrolled. Patients had bidimensionally measurable disease, as defined by computed tomographic (CT) scan or chest x-ray. A total of 28.6% had previously been surgically treated, while 9.5% had received radiotherapy. Fifty-three patients commenced at a dose of 1,000 mg/m2, and 31 at a dose of 1,250 mg/m2. Patients were to receive two dose escalations of 25%, provided that overall toxicity was no worse than World Health Organization (WHO) grade 1 or WHO grade 0 for platelets. Responding patients were reviewed and validated by a blinded oncology review board (ORB) of experts not involved with the study. Of the original 84 patients enrolled, 76 were assessable. RESULTS The overall response rate was 20% (95% confidence interval [CI], 11.6% to 30.8%). There were two complete responses (3%) and 13 partial responses (17%). Hematologic toxicity was negligible. WHO grade 3 WBC toxicity occurred in 0.9% of doses and WHO grade 4 in 0.1%. WHO grade 3 and 4 thrombocytopenia occurred in 0.1% and 0.1% of all doses, respectively. Nonhematologic toxicity was minor and easily controlled. Common side effects included peripheral edema, asthenia, and transient malaise. CONCLUSION The single-agent efficacy of gemcitabine is equivalent to other agents commonly used to treat NSCLC. Gemcitabine has an unusually mild side effect profile for such an active agent. The nausea and vomiting experienced with gemcitabine are mild and generally well controlled with standard antiemetics; 5-HT3 receptor antagonists are typically not required. The use of gemcitabine does not cause significant alopecia, and hematologic toxicity is modest and unlikely to require hospitalization. Gemcitabine may have a role as monotherapy in patients with inoperable NSCLC.