A randomised study of CGS 16949A (fadrozole) versus tamoxifen in previously untreated postmenopausal patients with metastatic breast cancer

BACKGROUND:: Fadrozole, a potent, highly specific inhibitor of aromataseactivity, has only been used as second-line therapy in treatmentof post-menopausal women with advanced breast cancer. A prospectivelyrandomised study was therefore undertaken to compare relativeclinical efficacy of fadrozole as first-line treatment to thatof tarnoxifen. PATIENTS AND METHODS:: Eighty postmenopausal women who had not received prior treatmentfor advanced/metastatic breast cancer were randomised to receiveeither fadrozole, 1 mg twice daily, or tamoxifen, 20 mg daily. RESULTS:: Toxicity was not statistically different on the two treatmentarms. Only mild to moderate toxicity was documented: hot flashesin 37%, headaches in 6.5%, mild fatigue in 2.6%. There werealso no statistically significant differences in objective responserates, survival or time to treatment failure (TTF). Objectiveresponse rate on fadrozole was 50% (complete response (CR) 8.3%and partial response (PR) 42%). On tamoxifen objective responsewas 44.7% (CR 21% and PR 24%). Median TTF was 4.9 months onfadrozole and 5 months on tamoxifen. Median survival was 22.7months on fadrozole and 27.5 months on tamoxifen. CONCLUSION:: While response rates, survival and TTF were not statisticallysignificantly different, there were more complete responseson tamoxifen and duration of objective response (CR + PR) wassignificantly longer in the patients treated with tamoxifen. breast cancer, fadrozole, postmenopausal, tamoxifen     

Primary endocrine therapy for advanced breast cancer: To start with tamoxifen or with medroxyprogesterone acetate?

BACKGROUND:: The availability of compounds effective against metastatic diseaseand at the same time excellently tolerated even in long-termadministration has determined the choice of tamoxifen as primarytreatment for palliation in metastatic breast cancer. Otherdrugs or other hormonal approaches were hardly tested againsttamoxifen, especially as first-line treatment. PATIENTS AND METHODS:: 119 patients with metastatic breast cancer and no prior endocrinetherapy were randomized to receive either tamoxifen (TAM) 20mg/day orally (64 patients), or medroxyprogesterone acetate(MAP) lg/day i.m. 5 days/week for 4 weeks and then 500 mg twicea week (55 patients). The subsequent endocrine therapy was alsoprospectively defined at study entry. RESULTS:: A total of 111 events, contributing to the end-point ‘timeto progression’ have so far been observed: a study ofsimilar size would have a 90% power to detect a hazard ratioof 1.85. Initial MAP was associated with a significantly higherremission rate (50% versus 30% for tamoxifen; p – 0.023)and a marginally significantly longer median time to progression(8.8 versus 5.4 months; p = 0.051). Overall survival was alsolonger for the MAP group (28 versus 20 months; p – 0.384).The use of MAP was associated with a significantly higher toxicity,mainly hypertension, weight gain and tremor. CONCLUSIONS:: The implications of these results are that initial endocrinetherapy in postmenopausal patients with metastatic disease shouldbe MAP if the patient is willing to accept the side effectsof high-dose progestins. Progestins should be tested in theadjuvant setting for postmenopausal women, especially thosewith no tendency to hypertension or obesity.     

Risk of new primaries after chemotherapy and/or tamoxifen treatment for early breast cancer

BACKGROUND:: Both chemotherapy and tamoxifen are widely used either aloneor in combination as adjuvant treatment following mastectomy.Despite the fact that both of them exhibit carcinogenic propertiesin experimental models, detailed reports on the incidence ofnew primaries following chemotherapy and/or tamoxifen in patientswith early breast cancer are limited. PURPOSE:: To investigate the incidence of new primaries (including oppositebreast tumors and skin cancers) in untreated patients and inpatients treated with either tamoxifen or chemotherapy or withboth modalities. PATIENTS AND METHODS:: A total of 1696 patients with early breast cancer, 1286 of whomwere treated with either CMF-based adjuvant chemotherapy (n= 410), tamoxifen (n = 656) or with a combination of the two(n = 220) were considered for the present analysis. Patientswere operated on between November 1983 and December 1991 andwere followed up to June 1994. Detailed information about secondmalignancies were available for all patients. RESULTS:: Overall, 53 new primaries, 19 of them opposite breast tumors,occurred in 53 patients. The actuarial cumulative incidencerates at 5 years were: 3.1% (95% CI: 1.4%– 4.8%) in untreatedpatients; 1.7% (95% CI: 0.0%–3.5%) in tamoxifen-treatedpatients; 4.2% (95% CI: 1.3%–7.1%) in chemotherapy-treatedpatients and 2.6% (95% CI: 0.0%%5.2%) in the chemo-tamoxifengroup (all groups: P = n.s.; chemotherapy-treated versus tamoxifen-treated:P = 0.01). The corresponding figures, after exclusion of thepatients with opposite-breast and skin tumors, were: untreatedpatients: 2% (95% CI: 0.6%–3.4%); tamoxifen-treated patients0.95% (95% CI: 0.0%–2.4%); chemotherapy-treated patients:2.6% (95% CI: 0.4%–4.8%); chemotherapy plus tamoxifen:1.65% (95% CI: 0.4%–3.8%); (all groups: P = n.s.; CT versusTAM P = 0.05). Chemotherapy-treated patients showed a risk thatwas about two-fold that of the one to be expected in the generalpopulation. By contrast, a decrease in the total risk was observedin patients treated with tamoxifen. Patients who received chemotherapyand tamoxifen as well as those in the no-treatment group showeda risk which was comparable to that of the general population. CONCLUSIONS:: Adjuvant chemotherapy appears to increase the risk of secondmalignancies. By contrast, tamoxifen seems to exert an overallprotective effect in this regard, and it also appears to counteract,at least partially, the carcinogenic effect of chemotherapy. IMPLICATIONS:: While there is plenty of evidence that the benefit achievedby adjuvant chemotherapy considerably exceeds the risk of secondmalignancies, the indiscriminate use of chemotherapy shouldbe avoided, particularly in patients with a low risk of relapse.Moreover, it seems reasonable to prefer tamoxifen over chemotherapyfor patients likely to obtain comparable therapeutic benefitfrom antiestrogenic treatment. adjuvant chemotherapy, adjuvant tamoxifen, adjuvant chemo-tamoxifen therapy, early breast cancer, second malignancies     

A study of fadrozole, a new aromatase inhibitor, in postmenopausal women with advanced metastatic breast cancer.

PURPOSE: The study investigated the therapeutic effects of fadrozole (CGS 16949A), a new aromatase inhibitor, in women who had received prior treatment for metastatic breast cancer. MATERIALS AND METHODS: Eighty postmenopausal women who had received prior treatment for metastatic breast cancer were randomized to receive fadrozole 1 mg/d or 4 mg/d per day orally. Seventy-eight patients were assessable for toxicity and response. RESULTS: Toxicity was limited to mild (grade 1) to moderate (grade 2) hot flashes in 28%, nausea and vomiting in 13%, fatigue in 8%, and mild loss of appetite in 5% of patients. No electrolyte or unanticipated hormonal changes occurred. The overall response was 23% (complete response, 10%; partial response, 13%). In addition, 45% of the patients had a no change status. There was no difference in response rate between the patients randomized to the two different doses of fadrozole. Only dominant site of metastases significantly affected response. The median time to treatment failure (TTF) was 4.4 months (4.7 months on 1 mg/d and 3.7 months on 4 mg/d). The median survival was 22.6 months (17.5 months on 1 mg/d; median survival has not been reached in patients on 4 mg/d). The response and survival in patients with estrogen receptor (ER)-positive and ER-unknown disease were not significantly different. CONCLUSIONS: Fadrozole has good therapeutic effect as a second-line treatment in postmenopausal women with metastatic breast cancer. In this study there was no significant difference in toxicity or response between 1 mg/d and 4 mg/d. Further trials comparing fadrozole to other hormone treatment are indicated.     

Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group.

PURPOSE: To analyze overall survival (OS) and update efficacy data for letrozole versus tamoxifen as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: This multicenter phase III trial randomly assigned 916 patients with hormone receptor-positive or unknown tumors letrozole 2.5 mg (n = 458) or tamoxifen 20 mg (n = 458) daily until disease progression. Optional cross-over was permitted at the treating physician's discretion. This report updates efficacy at a median follow-up of 32 months. RESULTS: The superiority of letrozole to tamoxifen was confirmed for time to progression (median, 9.4 v 6.0 months, respectively; P <.0001), time to treatment failure (median, 9 v 5.7 months, respectively; P <.0001), overall objective response rate (32% v 21%, respectively; P =.0002), and overall clinical benefit. Median OS was slightly prolonged for the randomized letrozole arm (34 v 30 months, respectively). Although this difference in OS is not significant, survival was improved in the randomized letrozole arm over the first 2 years of the study. Approximately one half of the patients in each arm crossed over. Total duration of endocrine therapy ("time to chemotherapy") was significantly longer (P =.005) for patients initially on letrozole (median, 16 months) than for patients initially on tamoxifen (median, 9 months). Time to worsening of Karnofsky performance score was significantly delayed with letrozole compared with tamoxifen (P =.001). CONCLUSION: This study documents the superiority of letrozole over tamoxifen in first-line endocrine therapy in postmenopausal women with advanced breast cancer.     

Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study.

PURPOSE: To compare the efficacy and tolerability of anastrozole (Arimidex; AstraZeneca, Wilmington, DE, and Macclesfield, United Kingdom) with that of tamoxifen as first-line therapy for advanced breast cancer (ABC) in postmenopausal women. PATIENTS AND METHODS: This randomized, double-blind, multicenter study evaluated the efficacy of anastrozole 1 mg once daily relative to tamoxifen 20 mg once daily in patients with tumors that were hormone receptor-positive or of unknown receptor status who were eligible for endocrine therapy. The primary end points were time to progression (TTP), objective response (OR), and tolerability. RESULTS: A total of 668 patients (340 in the anastrozole arm and 328 in the tamoxifen arm) were randomized to treatment and followed-up for a median of 19 months. Median TTP was similar for both treatments (8.2 months in patients who received anastrozole and 8.3 months in patients who received tamoxifen). The tamoxifen:anastrozole hazards ratio was 0.99 (lower one-sided 95% confidence limit, 0.86), demonstrating that anastrozole was at least equivalent to tamoxifen. Anastrozole was also as effective as tamoxifen in terms of OR (32.9% of anastrozole and 32.6% of tamoxifen patients achieved a complete response [CR] or partial response [PR]). Clinical benefit (CR + PR + stabilization of > or = 24 weeks) rates were 56.2% and 55.5% for patients receiving anastrozole and tamoxifen, respectively. Both treatments were well tolerated. However, incidences of thromboembolic events and vaginal bleeding were reported in fewer patients treated with anastrozole than with tamoxifen (4.8% v 7.3% [thromboembolic events] and 1.2% v 2.4% [vaginal bleeding], respectively). CONCLUSION: Anastrozole satisfied the predefined criteria for equivalence to tamoxifen. Together with the lower observed incidence of thromboembolic events and vaginal bleeding, these findings indicate that anastrozole should be considered as first-line therapy for postmenopausal women with ABC.     

A phase III randomized trial of dacarbazine and carboplatin with and without tamoxifen in the treatment of patients with metastatic melanoma

BACKGROUND: Metastatic melanoma is a disease associated with a poor prognosis, and dacarbazine is still the reference agent. The authors conducted a randomized trial to test the benefit of adding tamoxifen to dacarbazine and carboplatin chemotherapy for previously untreated patients with metastatic melanoma. METHODS: Eligible patients with histologically confirmed, measurable metastatic melanoma were randomized to carboplatin 300 mg/m2 and dacarbazine 1 g/m2 administered intravenously on Day 1 with or without tamoxifen 20 mg/day administered orally throughout the treatment period (C + D +/- T). Chemotherapy was repeated in 28-day treatment cycles for a minimum of 2 cycles or until disease progression. The study was designed to be stopped after accrual of 28 patients per treatment arm based on 80% power to detect an improvement in response from 20% to 40% among patients treated with tamoxifen. RESULTS: A total of 56 patients were randomized; all were evaluable for response and survival. The 2 treatment groups were well balanced for various prognostic factors; 75% of patients had predominant visceral disease. Complete and partial responses combined were 10.7% in the C + D arm and 14.3% in the C + D + T arm (P=1.0). Median survival was 7 months for C + D and 4.6 months for C + D + T (the difference was not significant). The median time to disease progression was worse for the patients treated with tamoxifen (P=0.03). Toxicity was similar in the two groups, with no episodes of deep venous thrombosis. CONCLUSIONS: The addition of tamoxifen did not improve the response rate, time to progression, or survival compared with chemotherapy with dacarbazine and carboplatin in unselected patients with metastatic melanoma.     

Intensive therapy and autotransplant for patients with an incomplete response to front-line therapy for lymphoma

BACKGROUND:: Patients with Hodgkin's disease (HD) and intermediate or high-gradenon-Hodgkin's lymphoma (NHL) who fail to achieve a completeremission (CR) with standard induction therapy have a poor prognosiswith conventional-dose salvage therapy alone. We examined therole of subsequent intensive therapy and autologous bone marrowtransplantation (ABMT) in patients who demonstrated a responseto conventional-dose salvage therapy. PATIENTS AND METHODS:: Sixty-six patients with either HD (n = 30) or NHL (n = 36) underwentintensive therapy with etoposide (60 mg/kg), intravenous melphalan(160–180 mg/m²) followed by infusion of unpurged autologousbone marrow and/or blood cells. All patients had advanced stageor bulky disease at diagnosis and failed to achieve a CR afteran anthracycline-containing front-line chemotherapy regimen(NHL) or ABVD or equivalent regimen (HD). Patients who achieveda CR after involved-field radiotherapy were excluded. All patientsdemonstrated sensitivity to conventionaldose salvage treatmentbefore advancing to intensive therapy and ABMT. RESULTS:: The CR, partial response (PR) and overall response rate (RR)following ABMT for HD patients was 48%, 17% and 65%, respectively.At a median follow-up of 35 months, the predicted three-yearoverall survival (OS) is 51% (95% CI: 44%–60%) and event-freesurvival (EFS) is 34% (95% CI: 26%–54%). For patientswith NHL, the CR, PR and RR were 68%, 9% and 77%, respectively.At a median follow-up of 28 months, the predicted three-yearOS is 51% (95% CI: 35%–66%) and EFS is 39%(95% CI: 21%–57%). CONCLUSIONS:: Intensive therapy with etoposide and melphalan followed by ABMTresults in prolonged survival in selected patients with lymphomawho fail to achieve a complete remission to front-line chemotherapy.Based on our previous studies of outcome to conventionaldosesalvage chemotherapy, we estimate that of all patients failinginduction therapy, 28% with HD and 15% with NHL will be eventfreeat three years after ABMT. induction failure, Hodglun's disease, non-Hodgkin's lymphoma, refractory lymphoma     

A case of advanced breast cancer successfully treated with primary endocrine therapy

We present a case of a premenopausal woman with advanced hormone-sensitive breast cancer who was successfully treated with primary endocrine therapy consisting of ovarian ablation followed by a combined endocrine regimen of the aromatase inhibitor fadrozole 2 mg daily and tamoxifen 20 mg daily. During the 5 months treatment period, PR evaluation of the loco-regional lesions was performed The patient then underwent mastectomy with axillary lymph node dissection followed by fadrozole and tamoxifen therapy. Throughout the treatment course, no adverse events were encountered and the patient has been enjoying a favorable quality of life. As shown by this case, primary endocrine therapy is a promising treatment option for hormonesensitive breast cancer. However, this modality should be continued to be regarded as experimental.     

High-dose oral medroxyprogesterone acetate or tamoxifen as adjuvant hormone therapy for node-negative early-stage breast cancer: randomized trial with 7-year update

A randomized adjuvant trial compared tamoxifen 20 mg daily for 5 years with high-dose oral medroxyprogesterone acetate (MPA) 1 g orally for 9 months. One hundred ninety-four patients with histologically proven primary node-negative breast carcinoma were enrolled between December 1990 and October 1996, with 98 patients randomized into the tamoxifen arm and 96 into the MPA arm. At a median follow-up of 86 months, 25 relapses and 13 deaths were recorded. The relapse-free survival rate at 7 years in the tamoxifen arm was 93%, versus 81% in the MPA arm (P = 0.02). The difference was observed in patients with stage T2 disease (100% in the tamoxifen group vs. 64% in the MPA group; P = 0.01), in younger and/or premenopausal patients (in patients < 50 years of age, 100% in the tamoxifen arm vs. 81% in the MPA arm [P = 0.02], and in patients > or = 50 years of age, 90% in the tamoxifen arm vs. 82% in the MPA arm [P = 0.16]). Also, the overall survival rate at 7 years was lower in women < 50 years of age (P = 0.04).     

Phase II study of prolonged oral etoposide in patients with ovarian cancer refractory to or relapsing within 12 months after platinum-containing chemotherapy

PATIENTS AND METHODS:: Twenty-eight patients with ovarian cancer refractory to or relapsingwithin 12 months after cis-platin-containing chemotherapy weretreated with etoposide 50 mg/m² daily for 21 days, followedby a 7-day break. RESULTS:: Of 25 evaluable patients, 4 achieved partial responses (16%,95% confidence interval 5%–36%) of 4, 4, 7, and 10 months'duration. The platinum treatment-free intervals for these patientswere 2, 9, 7, and 10 months, respectively. Etoposide in thisschedule was generally well tolerated,with myelosuppressionas the major toxicity, resulting in a median dose intensityover all cycles of 83% (range 47%–100%). CONCLUSION:: Prolonged oral etoposide is moderately active both in relapsedand platinum-refractory ovarian cancer, and a schedule of 50mg/m² days 1–21, every 4 weeks is fairly well toleratedin this usually heavily pretreated and elderly patient population. etoposide, ovarian cancer     

Low-dose continuous intravenous infusion of 5-fluorouracil for metastatic breast cancer

BACKGROUND:: Third-line chemotherapies for advanced breast cancer are difficultto tailor to the individual patient because of reduced toleranceand significant toxicity. Treatment with a continuous intravenousinfusion of low-dose 5-fluorouracil (FU-LDCI) is generally welltolerated and thus, a reasonable option for heavily pretreatedpatients. PATIENTS AND METHODS:: From 1989 to 1995,106 consecutive patients with advanced breastcancer were treated with FU-LDCI. 5-Fluorouracil was given atan initial daily dose of 250 mg/m² administered continuouslywith the aid of an elastomer, non-electronic pump through apermanent central venous line for 21 days followed by a 7-dayrest. The median age was 56 years (range, 30–82), themedian ECOG Performance Status was 1 (range 0–4) and themedian number of metastatic sites was 2 (range 1–4). Sixty-onepercent of the patients had previously received more than 2chemotherapy regimens which in 81% included adriamycin, andin 90% 5-fluorouracil. RESULTS:: Eighty patients were evaluable for objective response: 17 ofthem had partial responses (21%, 95% CI: 14%–31%) and23 stable disease (29%, 95% CI: 20%–40%). One-hundredfive patients were evaluable for subjective response, with 46reporting improvement (44%,95% CI: 35%–54%). Previoustreatments with either 5-fluorouracil or adriamycin did notpredict response to FU-LDCI. Median time to progression forpatients with a partial response or stable disease was 259 days(range 82–737). The overall survival for the populationsas a whole was 274 days (range 13–2264), and the mediandose received was 1904 mg/week (range 753–4329). The maintoxic effects were grades I and II mucositis, and nausea andvomiting (observed in 31% and 28%, respectively). Grade IIItoxicities were uncommon: mucositis in 3%, nausea and vomitingin 3%, anemia, thrombocytopenia and hepatitis in 2%, and skintoxicity (hand-foot syndrome) in 1%. Catheter-related thrombosiswas observed in 2% of the patients, and there were no pump failures.A questionnaire concerning the impact of the treatment uponquality of life was completed by all of the 13 patients whowere alive at the time of evaluation of the results, and allof them rated FU-LDCI as easy to tolerate. The monthly costof FU-LDCI (USS1,051.00 in Switzerland) was lower than the costof weekly low-dose adriamycin (USS1,483.00 in Switzerland),a treatment which is often used as a palliative regimen in similarcircumstances. CONCLUSIONS:: FU-LDCI is a useful, cost-effective third-line treatment forpatients with metastatic breast cancer who need palliation withcytotoxic drugs. advanced breast cancer, chemotherapy, 5-fluorouracil infusion, financial costs, low-dose continuous, palliative therapy, quality of life     

Phase II, randomized, double-blind study of two dose levels of arzoxifene in patients with locally advanced or metastatic breast cancer.

PURPOSE: To select a daily dose of arzoxifene (LY353381), a selective estrogen receptor modulator, for use in future studies in women with locally advanced or metastatic breast cancer who are either potentially tamoxifen sensitive (TS) or tamoxifen refractory (TR). PATIENTS AND METHODS: This trial was a randomized, double-blind, phase II study of arzoxifene 20 mg (n = 55) and 50 mg (n = 57) in women with advanced or metastatic breast cancer. Patients were randomly assigned to balance for number of metastatic disease sites, prior tamoxifen therapy, and estrogen receptor status. The primary end point was tumor response rate (RR). Secondary end points included clinical benefit rate (CBR), time to progression (TTP), and toxicity. RESULTS: Forty-nine patients were TS and 63 were TR. According to independent review, among TS patients, RR was higher in the 20-mg arm than the 50-mg arm (26.1% v 8.0%), with a longer TTP (8.3 v 3.2 months; P >.05). Among the TR patients, response rate was the same in the 20-mg and 50-mg arms (10.3%) with similar TTP (2.7 and 2.8 months, respectively; P >.05). CBR was higher in the 20-mg arm than in the 50-mg arm among TS patients (39.1% v 20.0%) and TR patients (13.8% v 10.3%). Arzoxifene was well tolerated. Dose-dependent toxicity was not demonstrated. There were no deaths during study. CONCLUSION: Arzoxifene is effective in the treatment of TS and TR patients with advanced or metastatic breast cancer at the 20-mg and 50-mg dose levels. Toxicities are minimal, and the therapy is tolerated. The 20-mg dose seems to be at least as effective as the 50-mg dose. Accordingly, arzoxifene 20 mg/d was selected for further study in patients with breast cancer.     

Dose-intensive chemotherapy with doxorubicin, cyclophosphamide and GM-CSF fails to improve survival of metastatic breast cancer patients

BACKGROUND: A dose response relationship for doxorubicin and cyclophosphaniidehas been suggested. In a previous dose finding study we treatedadvanced breast cancer padents with escalating doses of doxorubicinand cyclophos phaniide lit combination with GM-CSF. The aimof this study is to further define the acute and cumulativetoxicity of this treatment in relation to its antitumor activity. PATIENTS AND METHODS: Twenty-eight patients with metastatic breast cancer were treatedwith doxorubiciri (90 mg/ m and cyclophosphamide (1000 mg/mat 3-week intervals. Dose reductions of 10% were applied inthe second and fourth cycles. On the second day GM-CSF was startedat 250 sg/m daily for 10 days. The intention was to give 6 cycles,but when a complete remission was reached earlier only one morecycle was given as consolidation. RESULTS: The median number of cycles was 5 (range 2–6). Twenty—threepatients responded (82%, 95% CI 69%–97%), with 9 of themachieving a complete response (3 2%, 95% CL 14%–50%).For the 18 patients evaluable for time to progression and survivalthe median time to progression was 8 months and the median survival14.5 months. Toxicity was substantial: grades 3 or 4 neutropeniaoccurred in 95% of cycles and grades 3–4 thrombocytopeniain 49% of cycles. Grade 3–4 mucositis was present in 13%of the cycles. Weakness and fatigue were always present andwere cumula tive. Four patients had a decline In the left ventricularejection fraction (LVEF). These side effects were the reasonfor discontinuing therapy in 9 of the 28 patients (3 2%). CONCLUSION: This treatment has a high response rate in comparison with conventional-dosechemotherapy but does not prolong time to progression or survival.The toxicity makes this protocol unsuitable for use as paffiativetreatment. breast cancer, chemotherpy, dose intensity, GM-CSF     

Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma.

BACKGROUND: Two randomized, double-blind trials have compared tamoxifen 20 mg daily and the selective, nonsteroidal aromatase inhibitor anastrozole 1 mg daily as first-line therapy for advanced breast carcinoma (ABC) in postmenopausal women. The trials were prospectively designed to allow for combined data analyses. METHODS: The combined study population included 1021 postmenopausal women (median age, 67 years [range, 30-92]) with ABC whose tumors were either estrogen and/or progesterone receptor positive or of unknown receptor status. Primary endpoints were time to progression (TTP), objective response, and tolerability. RESULTS: At a median duration of follow-up of 18.2 months, anastrozole was at least equivalent to tamoxifen in terms of median TTP (8.5 and 7.0 months, respectively; estimated hazard ratio [tamoxifen relative to anastrozole], 1.13 [lower 95% confidence level, 1.00]). In a retrospective subgroup analysis, anastrozole was superior to tamoxifen with respect to TTP (median values of 10.7 and 6.4 months for anastrozole and tamoxifen, respectively, two-sided P = 0.022) in patients with estrogen and/or progesterone receptor positive tumors (60% of combined trial population). In terms of objective response, 29.0% of anastrozole and 27.1% of tamoxifen patients achieved either a complete response (CR) or a partial response (PR). Clinical benefit (CR + PR + stabilization of > or = 24 weeks) rates were 57.1% and 52.0% for anastrozole and tamoxifen, respectively. Both anastrozole and tamoxifen were well tolerated. Anastrozole led to significantly fewer venous thromboembolic (P = 0.043; not adjusted for multiple comparisons) events, and vaginal bleeding was reported in fewer patients treated with anastrozole than with tamoxifen. CONCLUSIONS: In postmenopausal women with hormonally sensitive ABC, anastrozole should be considered as the new standard first-line treatment.     

Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group.

PURPOSE: The efficacy and tolerability of anastrozole (Arimidex; AstraZeneca, Wilmington, DE, and Macclesfield, United Kingdom) and tamoxifen were compared as first-line therapy for advanced breast cancer in 353 postmenopausal women. PATIENTS AND METHODS: The randomized, double-blind, multicenter study was designed to evaluate anastrozole 1 mg once daily relative to tamoxifen 20 mg once daily in patients with hormone receptor-positive tumors or tumors of unknown receptor status who were eligible for endocrine therapy. Primary end points were objective response (OR), defined as complete (CR) or partial (PR) response, time to progression (TTP), and tolerability. RESULTS: Anastrozole was as effective as tamoxifen in terms of OR (21% v 17% of patients, respectively), with clinical benefit (CR + PR + stabilization > or = 24 weeks) observed in 59% of patients on anastrozole and 46% on tamoxifen (two-sided P =.0098, retrospective analysis). Anastrozole had a significant advantage over tamoxifen in terms of TTP (median TTP of 11.1 and 5.6 months for anastrozole and tamoxifen, respectively; two-sided P =.005). The tamoxifen:anastrozole hazards ratio was 1.44 (lower one-sided 95% confidence limit, 1.16). Both treatments were well tolerated. However, thromboembolic events and vaginal bleeding were reported in fewer patients who received anastrozole compared with those who received tamoxifen (4.1% v 8.2% [thromboembolic events] and 1.2% v 3.8% [vaginal bleeding], respectively). CONCLUSION: Anastrozole satisfied the predefined criteria for equivalence to tamoxifen. Furthermore, we observed both a significant increase in TTP and a lower incidence of thromboembolic events and vaginal bleeding with anastrozole. These findings indicate that anastrozole should be considered as first-line therapy for postmenopausal women with advanced breast cancer.     

Phase II randomized study of dacarbazine, carmustine, cisplatin and tamoxifen versus dacarbazine alone in advanced melanoma patients

This randomized phase II trial was performed to define the activity and toxicity of the combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin (DDP) and tamoxifen (DBDT regimen) versus DTIC alone in patients with metastatic melanoma. Sixty patients with metastatic melanoma were randomly assigned to receive BCNU 150 mg/m2 intravenously (i.v.) on day 1, cisplatin 25 mg/m2 i.v. daily on days 1 to 3, DTIC 220 mg/m2 i.v. daily on days 1 to 3 and tamoxifen 160 mg orally daily for 7 days prior to chemotherapy (DBDT arm; arm A). Treatment cycles were repeated every 28 days, while BCNU was given every two cycles. The DTIC arm (arm B) patients received DTIC alone 1200 mg/m2 i.v. on day 1, repeated every 21 days. Patients were evaluated every two cycles; responding patients continued the treatment for a maximum of 12 cycles. The overall response rate was 26% in the DBDT arm and 5% in the DTIC arm. Complete responses were 2.5% for DBDT and 0% for DTIC. The median progression-free survival and the median survival were 4 and 9 months, respectively for DBDT, and 2 and 7 months for DTIC. DBDT was associated with significant haematological toxicity: 33% of the patients experienced a grade III or IV neutropenia and 28% a grade III or IV thrombocytopenia. In conclusion, the overall response rate obtained with DBDT was greater than that obtained with DTIC alone; however, this combination increases toxicity with limited impact on overall survival.     

Double-blind randomised trial comparing the non-steroidal aromatase inhibitors letrozole and fadrozole in postmenopausal women with advanced breast cancer.

BACKGROUND: To compare the efficacy, safety and tolerability of letrozole, an advanced non-steroidal aromatase inhibitor, and fadrozole hydrochloride, an older-generation drug in this class, we conducted a randomised double-blind trial in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: One hundred and fifty-seven postmenopausal women with advanced breast cancer were enrolled and randomly assigned to receive letrozole or fadrozole in a multicentre, randomised double-blind trial in Japan. One hundred and fifty-four eligible patients were treated with either letrozole 1.0 mg once daily (n = 77) or fadrozole 1.0 mg twice daily (n = 77), for a minimum of 8 weeks. RESULTS: Letrozole showed a significantly higher overall objective response rate [complete response (CR) + partial response (PR)] than fadrozole (31.2% and 13.0%, respectively; P = 0.011, Fisher's exact test). Clinical benefits defined as CR, PR and stable disease (no change in status for more than 24 weeks) were also higher in patients treated with letrozole (50.6%) than fadrozole (35.1%). Letrozole was significantly superior to fadrozole in terms of the dominant lesion in soft tissue, bone and viscera (P = 0.011, stratified Mantel-Haenszel test). Median time to progression was 211 days in the letrozole group and 113 days in the fadrozole group with no significant difference (P = 0.175, log-rank test). Letrozole markedly reduced the estradiol, estrone and estrone sulfate levels in peripheral blood within 4 weeks. The suppressive effect of fadrozole on these hormone levels was insufficient. Adverse drug reactions were observed in 35.9% of the patients treated with letrozole and in 39.5% of those treated with fadrozole with no significant difference between the two groups (P = 0.74, Fisher's exact test). Most of the adverse drug reactions were rated as grade 1 or 2. CONCLUSIONS: The results show letrozole at a dose of 1.0 mg once daily to be more effective in treating postmenopausal women with advanced breast cancer than fadrozole at 1.0 mg twice daily, with similar safety and tolerability profiles.     

Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial.

PURPOSE: To evaluate the efficacy and tolerability of fulvestrant (Faslodex; AstraZeneca Pharmaceuticals LP, Wilmington, DE), a new estrogen receptor (ER) antagonist that downregulates ER and has no agonist effects, versus tamoxifen, an antiestrogen with agonist and antagonist effects, for the treatment of advanced breast cancer in postmenopausal women. PATIENTS AND METHODS: In this multicenter, double-blind, randomized trial, patients with metastatic/locally advanced breast cancer previously untreated for advanced disease were randomly assigned to receive either fulvestrant (250 mg, via intramuscular injection, once monthly; n = 313) or tamoxifen (20 mg, orally, once daily; n = 274). Patients' tumors were positive for ER (ER+) and/or progesterone receptor (PgR+), or had an unknown receptor status. RESULTS: At a median follow-up of 14.5 months, there was no significant difference between fulvestrant and tamoxifen for the primary end point of time to progression (TTP; median TTP, 6.8 months and 8.3 months, respectively; hazard ratio, 1.18; 95% CI, 0.98 to 1.44; P =.088). In a prospectively planned subset analysis of patients with known ER+ and/or PgR+ tumors ( approximately 78%), median TTP was 8.2 months for fulvestrant and 8.3 months for tamoxifen (hazard ratio, 1.10; 95% CI, 0.89 to 1.36; P =.39). The objective response rate for the overall population was 31.6% with fulvestrant and 33.9% with tamoxifen, and 33.2% and 31.1%, respectively, in the known hormone receptor-positive subgroup. Both treatments were well tolerated. CONCLUSION: In the overall population, between-group differences in efficacy end points favored tamoxifen, and statistical noninferiority of fulvestrant could not be demonstrated. However, in patients with hormone receptor-positive tumors, fulvestrant had similar efficacy to tamoxifen and was well tolerated.     

Efficacy of first-line letrozole versus tamoxifen as a function of age in postmenopausal women with advanced breast cancer

PURPOSE: To compare the efficacy, in regard to time to progression (TTP) and objective response rate (ORR), of letrozole (Femara; Novartis Pharma AG; Basel Switzerland), an oral aromatase inhibitor, with that of tamoxifen (Tamofen; Leiras OY; Turku, Finland) as first-line therapy in younger (<70 years) and older (>/=70 years) postmenopausal women with advanced breast cancer. MATERIALS AND METHODS: Nine hundred seven patients with advanced breast cancer were randomly assigned to receive 2.5 mg letrozole (n = 453) or 20 mg tamoxifen (n = 454) once daily in a double-blind, multicenter, international trial. Among the prospectively planned analyses were analyses of TTP and ORR by age (<70 and >/=70 years). The results of these prospectively planned analyses are reported here. RESULTS: Letrozole was as effective in older postmenopausal women (>/=70 years of age) as it was in younger postmenopausal women (<70 years of age). The overall ORR in the older subgroup was significantly higher in patients treated with letrozole (38%) than in patients treated with tamoxifen (18%). In the younger subgroup of postmenopausal patients, the ORRs were not significantly different (letrozole, 26%; tamoxifen, 22%). TTP was significantly longer for letrozole than for tamoxifen in both age groups (younger: letrozole median TTP, 8.8 months; tamoxifen, 6.0 months; older: letrozole median TTP, 12.2 months; tamoxifen, 5.8 months). Although age was independently prognostic of TTP, there was no significant effect of age on ORR in the presence of other factors. CONCLUSION: The data show that letrozole, 2.5 mg once daily, is as effective in older, postmenopausal women as it is in younger postmenopausal women with advanced breast cancer. In addition, letrozole was more effective than tamoxifen in both younger and older patients.