title: Randomized clinical trial design for assessing noninferiority when superiority is expected. Pharmacokinetic Profile of Intramuscular Fulvestrant in Advanced Breast Cancer A retrospective analysis of the proportion of patients responding for > 1 year in two phase III studies of fulvestrant vs. anastrozole. Postmenopausal Women who Progress on Fulvestrant ('Faslodex') Remain Sensitive to Further Endocrine Therapy Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. A randomised trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. Equivalent single-dose pharmacokinetics of two different dosing methods of prolonged-release fulvestrant ('Faslodex') in postmenopausal women with advanced breast cancer Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma 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. Sensitivity to further endocrine therapy is retained following progression on first-line fulvestrant 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. A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Arimidex Study Group. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. 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. Anastrozole (Arimidex) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results. 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. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. Active-control clinical trials to establish equivalence or noninferiority: methodological and statistical concepts linked to quality. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment.
abstract: The r and omized clinical trial ( RCT ) is the gold st and ard for definitive evaluation of new therapies . RCTs design ed to show that the therapeutic efficacy of a new therapy is not unacceptably inferior to that of st and ard therapy are called noninferiority trials . Traditionally , noninferiority trials have required very large sample sizes . Sometimes , a new treatment regimen with a favorable toxicity and /or tolerability profile is also expected to have some modest improvement in efficacy . In such specialized setting s we describe a hybrid trial- design approach that requires a dramatically smaller sample size than that of a st and ard noninferiority design . This hybrid design can naturally incorporate a formal test of superiority as well as noninferiority Objective To characterise the pharmacokinetics of a long-acting formulation of fulvestrant following intramuscular administration of single and multiple doses . Study design : Pharmacokinetic investigations of single and multiple doses of fulvestrant were conducted within two global phase III efficacy studies that compared intramuscular fulvestrant with oral anastrozole in postmenopausal women with hormone-sensitive advanced breast cancer ( study 0020 , conducted in Europe , Australia and South Africa , and study 0021 , conducted in North America ) . Methods Patients received once-monthly intramuscular injections of fulvestrant 250 mg ( 1 × 5mL for ≤21 months in study 0020 ; 2 × 2.5mL for ≤30 months in study 0021 ) . Serial blood sample s were collected for the first 28 days after the initial dose and immediately prior to all subsequent monthly doses . Plasma fulvestrant concentrations were determined by high-performance liquid chromatography-t and em mass spectrometry . Patients Twenty-six ( study 0020 ) and 193 ( study 0021 ) postmenopausal women , comprising the pharmacokinetic subgroups of the phase III efficacy trials , were studied . Patients had shown disease progression or recurrence following previous hormonal therapy for advanced disease or had relapsed after adjuvant endocrine therapy with a nonsteroidal antiestrogen . Outcome measures and results For single-dose fulvestrant 250 mg , area under the concentration-time curve from time zero to 28 days ( AUC28 ) , maximum observed plasma concentration ( Cmax ) , minimum observed plasma concentration at 28 days ( Cmin ) and time to maximum plasma concentration ( tmax ) were determined . For multiple-dose fulvestrant 250 mg once monthly , steady-state trough concentrations ( Ctrough ) were determined . Plasma fulvestrant concentrations reached a peak at a median of 7 days ( range 2–8 days ) postdose , and declined biexponentially with a slower phase commencing approximately 2–3 weeks postdose . Intersubject variability in Cmax and AUC28 was approximately 6-fold and 4-fold , respectively . Mean parameters for single-dose fulvestrant were : AUC28 , 148 μg · day/L ; Cmax , 8.2 μg/L ; Cmin , 2.6 μg/L ; tmax , 7.0 days . Geometric mean Ctrough increased from 2.57 to 6.15 μg/L ( study 0020 ) and from 2.38 to 6.52 μg/L ( study 0021 ) over the first 6 months , reaching steady-state concentrations of approximately 6–7 μg/L ( study 0020 ) or 9 μg/L ( study 0021 ) . Preliminary pharmacokinetic analysis , using a naive pooled data approach , suggests that observed single- and multiple-dose plasma profiles can be adequately described with a two-compartment kinetic model . Model-generated steady-state AUC28 values were approximately 300 μg · day/L. Conclusions The intramuscular formulation of fulvestrant displays predictable kinetics and approximately 2-fold accumulation on administration once monthly . At the proposed therapeutic dosage ( 250 mg once monthly ) , plasma fulvestrant concentrations are maintained within a narrow range throughout the administration interval , thus ensuring stable systemic drug exposure during long-term treatment 737 Background : Fulvestrant ( Faslodex ) is an estrogen receptor antagonist with no agonist effects . Two phase III trials have compared the efficacy of fulvestrant 250 mg ( once-monthly , intramuscular injection ) and anastrozole ( 1 mg/daily , p.o . ) in patients with advanced breast cancer progressing on prior endocrine therapy .  Fulvestrant was at least as effective as anastrozole for the primary endpoint of time to progression and the secondary endpoint of objective response ( OR ) . Here , we report a retrospective analysis of duration of response ( DOR ) by categorical time period ( ≥1 year ) in patients experiencing an OR ( complete [ CR ] or partial response [ PR ] ) or clinical benefit ( CB ; CR + PR + stable disease [ SD ] ≥24 weeks ) in these two trials . METHODS Duration of OR and CB was calculated from r and omization until disease progression and percentages were calculated using the total number of patients per treatment group as the denominator ( fulvestrant n=428 ; anastrozole n=423 ) . RESULTS Median follow-up was 22.1 months . A total of 186 patients receiving fulvestrant had CB ( CR : n=20 ; PR : n=62 ; SD ≥24 weeks : n=104 ) compared with 173 patients receiving anastrozole ( CR : n=11 ; PR : n=59 ; SD ≥24 weeks : n=103 ) . A numerically greater proportion of patients receiving fulvestrant achieved OR and CB for ≥1 year than those receiving anastrozole . CONCLUSION Fulvestrant has benefits in terms of the numbers of patients with prolonged duration of response . These data support the initial DOR findings in these trials . [ Figure : see text ] [ Table : see text ] Abstract Purpose . This retrospective evaluation of data from two r and omized , multicenter trials examined whether tumor responses to further endocrine therapy were seen in postmenopausal women with advanced breast cancer who had progressed on both initial endocrine therapy , usually tamoxifen , and on the estrogen receptor ( ER ) antagonist fulvestrant ( ' Faslodex ' ) . Patients and methods . A combined total of 423 patients received fulvestrant 250 mg as a monthly intramuscular injection . After progression on fulvestrant , some patients received another endocrine therapy . Responses to subsequent endocrine therapy were assessed using a question naire sent to the trial investigators . Best responses were classified as a complete or partial response ( CR or PR ) , stable disease ( SD ) lasting ≥24 weeks , or disease progression . Results . Follow-up data were available for 54 patients who derived clinical benefit ( CB , defined as CR , PR or SD ) from fulvestrant and who received subsequent endocrine therapy  , result ing in a PR in 4 patients , SD in 21 patients , and disease progression in 29 patients . Data were available for 51 patients who derived no CB from fulvestrant and who received further endocrine therapy , result ing in a PR in 1 patient , SD in 17 patients , and disease progression in 33 patients . Aromatase inhibitors were used as subsequent endocrine therapy in > 80 % of patients . Conclusions . After progression on fulvestrant , patients may retain sensitivity to other endocrine agents . Fulvestrant provides an additional option to existing endocrine therapies for the treatment of advanced or metastatic breast cancer in postmenopausal women , and may provide the opportunity to extend the sequence of endocrine regimens before cytotoxic chemotherapy is required The CONSORT ( Consoli date d St and ards of Reporting Trials ) Statement , including a checklist and a flow diagram , was developed to help authors improve their reporting of r and omized controlled trials . Its primary focus was on individually r and omized trials with 2 parallel groups that assess the possible superiority of one treatment compared with another but is now being extended to other trial design s. Noninferiority and equivalence trials have method ological features that differ from superiority trials and present particular difficulties in design , conduct , analysis , and interpretation . Although the rationale for such trials occurs frequently , those design ed and described specifically as noninferiority or equivalence trials appear less commonly in the medical literature . The quality of reporting of those that are published is often inadequate . In this article , we present an adapted CONSORT checklist  for reporting noninferiority and equivalence trials and provide illustrative examples and explanations for those items amended from the original CONSORT checklist . The intent is to improve reporting of noninferiority and equivalence trials , enabling readers to assess the validity of their results and conclusions The aim of this study was to compare the efficacy and tolerability of the new aromatase inhibitor ' ARIMIDEX ' ( anastrozole ) with megestrol acetate in the treatment of advanced breast cancer in postmenopausal women .  Anastrozole is a new potent and highly selective non-steroidal aromatase inhibitor . We conducted a prospect i ve r and omised trial comparing two doses of anastrozole ( 1 and 10 mg orally once daily ) with megestrol acetate ( 40 mg orally four times daily ) in postmenopausal patients with advanced breast cancer who progressed after prior tamoxifen therapy . All patients were analysed for efficacy as r and omised ( intention to treat ) and for tolerability as per treatment received . Of the 378 patients who entered the study , 135 were r and omised to anastrozole 1 mg , 118 to anastrozole 10 mg , and 125 patients to megestrol acetate .  After a median follow-up of 192 days , response rate which included complete response , partial response and patients who had disease stabilisation for 6 months or more was 34 % for anastrozole 1 mg , 33.9 % for anastrozole 10 mg and 32.8 % for megestrol acetate . There were no statistically significant differences between either dose of anastrozole and megestrol acetate in terms of objective response rate , time to objective progression of disease or time to treatment failure . The three treatments were generally well tolerated , but more patients on megestrol acetate reported weight gain , oedema and dyspnoea as adverse events while more patients on anastrozole reported gastro-intestinal disorders , usually in the form of mild transient nausea . Patients on anastrozole did not report higher incidences of oestrogen withdrawal symptoms .  Anastrozole is an effective and well tolerated treatment for postmenopausal patients with advanced breast cancer . The higher 10 mg dose did not result in additional clinical benefit , but was well tolerated reflecting the good therapeutic margin with anastrozole . Based on this data , anastrozole 1 mg should be the recommended therapeutic dose PURPOSE To compare the efficacy and tolerability of tamoxifen with that of letrozole , an oral aromatase inhibitor , with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer . PATIENTS AND METHODS Nine hundred seven patients were r and omly assigned  letrozole 2.5 mg once daily ( 453 patients ) or tamoxifen 20 mg once daily ( 454 patients ) . Patients had estrogen receptor- and /or progesterone receptor-positive tumors , or both receptors were unknown . Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment . One prior chemotherapy regimen for metastatic disease was allowed . The primary end point was time to progression ( TTP ) . Secondary end points included overall objective response rate ( ORR ) , its duration , rate and duration of clinical benefit , time to treatment failure ( TTF ) , overall survival , and tolerability . RESULTS TTP was significantly longer for letrozole than for tamoxifen ( median , 41 v 26 weeks ) . Treatment with letrozole reduced the risk of progression by 30 % ( hazards ratio , 0.70 ; 95 % confidence interval , 0.60 to 0.82 , P = .0001 ) . TTP was significantly longer for letrozole irrespective of dominant site of disease , receptor status , or prior adjuvant antiestrogen therapy . Similarly , TTF was significantly longer for letrozole ( median , 40 v 25 weeks ) . ORR was higher for letrozole ( 30 % v 20 % ; P = .0006 ) , as was the rate of clinical benefit ( 49 % v 38 % ; P = .001 ) . Survival data are currently immature and not reported here . Both treatments were well tolerated . CONCLUSION Letrozole was significantly superior to tamoxifen in TTP , TTF , ORR , and clinical benefit rate . Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer Purpose To compare the pharmacokinetics of two different dosing methods of fulvestrant ( ' Faslodex ' ) , an estrogen receptor antagonist with no known agonist activity , for the treatment of advanced breast cancer . Methods Postmenopausal women with advanced breast cancer were r and omly assigned to receive a single 5-ml intramuscular injection of 250 mg fulvestrant , or two 2.5-ml intramuscular injections with a total of 250 mg fulvestrant .  Blood sample s were taken for pharmacokinetic analysis up to 28 days after injection . Results Plasma concentrations of fulvestrant were measurable up to 28 days after both dosing methods . The concentration-time profiles were relatively shallow , spanning an approximate threefold range from 3 h after dosing to Cmin measured on day 28 . Peak plasma concentrations ( Cmax ) of fulvestrant occurred between 1 and 11 days after dosing , with mean Cmax values of 6.0 and 6.2 ng/ml following one 5-ml injection and two 2.5-ml injections , respectively . The plasma concentration-time profiles were very similar in terms of duration and concentration , and overall exposure to fulvestrant was similar in both dosing groups ( the ratio of the AUC0–28 of the single-injection group to that of the double-injection group was 1.01 ; 95 % confidence interval 0.68–1.51 ) . Conclusion This study found no evidence of any pharmacokinetic difference between one 5-ml injection and two 2.5-ml injections . The two methods can be used interchangeably , depending on which is more convenient in any particular clinical setting Fulvestrant is an estrogen receptor antagonist with no agonist effects . In the second‐line treatment of advanced breast carcinoma , fulvestrant was shown previously to be as effective as the third‐generation aromatase inhibitor , anastrozole , in terms of time to disease progression and objective response rates . The authors reported the overall survival results from these studies 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 r and omized , 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 r and omized 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 Summary There is a need for new endocrine agents that lack cross-resistance with currently available treatments to extend the endocrine treatment window and delay the need for cytotoxic chemotherapy . This retrospective analysis evaluated the response of postmenopausal patients with previously untreated metastatic/locally advanced breast cancer to further endocrine treatment following progression on first-line fulvestrant or tamoxifen .  Patients received fulvestrant 250 mg ( intramuscular injection every 28 days ) plus matching tamoxifen placebo ( once daily ) , or tamoxifen 20 mg ( orally once daily ) plus matching fulvestrant placebo ( every 28 days ) in a double-blind , r and omized , phase III trial . Treatment continued until disease progression or withdrawal , when further endocrine therapy was initiated ( at the treating physician ’s discretion ) . Information regarding subsequent therapies and responses was obtained by follow-up question naire . Two-hundred- and -forty-five question naires were returned ( from 587 patients ) , 149 of which yielded follow-up data on patients receiving second-line endocrine therapy following fulvestrant ( n=83 ) and tamoxifen ( n=66 ) . Second-line therapy produced objective responses ( OR ) in 6/44 ( 13.6 % ) and clinical benefit ( CB ) in 25/44 ( 56.8 % ) patients who had CB with fulvestrant and produced OR in 5/41 ( 12.2 % ) patients and CB in 27/41 ( 65.8 % ) patients who had CB with first-line tamoxifen . For patients deriving no CB from trial therapy , second-line therapy produced OR in 3/39 ( 7.7 % ) and CB in 15/39 ( 38.5 % ) patients in the fulvestrant group and OR in 4/25 ( 16.0 % ) and CB in 12/25 ( 48.0 % ) patients in the tamoxifen group . Results from this question naire-based study suggest that postmenopausal women with advanced breast cancer who respond to first-line fulvestrant or tamoxifen retain sensitivity to subsequent endocrine therapy 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 , r and omized trial , patients with metastatic/locally advanced breast cancer previously untreated for advanced disease were r and omly 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 prospect ively 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 BACKGROUND Anastrozole is a new oral aromatase inhibitor with highly potent and selective activity for the aromatase enzyme . In a Phase III trial , the efficacy and tolerability of anastrozole , given in doses of 1 and 10 mg orally once daily , and megestrol acetate , given in doses of 40 mg orally 4 times daily , were compared in 386 postmenopausal women with advanced breast carcinoma who progressed after tamoxifen therapy . METHODS The trial was r and omized , double blind for anastrozole , open label for megestrol acetate , parallel group , and multicenter . Patients were r and omly assigned to receive anastrozole , 1 mg ( n = 128 ) ; anastrozole , 10 mg ( n = 130 ) ; or megestrol acetate ( n = 128 ) . The primary efficacy measures were time to progression and tumor response ; secondary measures were time to treatment failure , duration of response , quality of life , and time to death . RESULTS With a median duration of follow-up of 6 months , there was no statistical evidence of a difference between either 1 or 10 mg doses of anastrozole and megestrol acetate for any efficacy endpoint . According to rigid response criteria , 10 % , 6 % , and 6 % of patients in the anastrozole 1 mg , anastrozole 10 mg , and megestrol acetate groups , respectively , had an objective response ( complete response or partial response ) and 27 % , 24 % , and 30 % of patients in the respective groups had stable disease for a duration of 24 weeks or longer . Quality -of-life assessment s revealed that anastrozole in a 1-mg dose was associated with better physical scores and anastrozole in a 10-mg dose with better psychologic scores than megestrol acetate . Both anastrozole and megestrol acetate were generally well tolerated . Among anticipated adverse events , gastrointestinal disturbance was more common among patients in the anastrozole groups , whereas weight gain occurred more frequently among patients in the megestrol acetate groups . Weight increases of 5 % or more and 10 % or more were more common among megestrol acetate-treated patients ; moreover , patients in this group continued to gain weight over time . CONCLUSIONS Anastrozole , given in doses of 1 and 10 mg once daily , represents a well tolerated and effective therapeutic option for the treatment of postmenopausal women with advanced breast carcinoma who progress after tamoxifen treatment PURPOSE This phase III , double-blind , r and omized , 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 r and omized 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 compare the efficacy and tolerability of anastrozole ( 1 and 10 mg once daily ) , a selective , oral , nonsteroidal aromatase inhibitor , and megestrol acetate ( 40 mg four times daily ) , in postmenopausal women who progressed following tamoxifen treatment . PATIENTS AND METHODS Two r and omized , double-blind for anastrozole , open-label for megestrol acetate , parallel-group , multicenter trials were conducted in 764 patients . Because both trials were identical in design , an analysis of the combined results was performed to strengthen interpretation of results from each trial . RESULTS The median follow-up duration was approximately 6 months . The estimated progression hazards ratios were 0.97 ( 97.5 % confidence interval [ CI ] , 0.75 to 1.24 ) for anastrozole 1 mg versus megestrol acetate and 0.92 ( 97.5 % CI , 0.71 to 1.19 ) for anastrozole 10 mg versus megestrol acetate . The overall median time to progression was approximately 21 weeks . Approximately one third of patients in each group benefited from treatment . Twenty-seven patients ( 10.3 % ) in the anastrozole 1-mg group , 22 ( 8.9 % ) in the anastrozole 10-mg group , and 20 ( 7.9 % ) in the megestrol acetate group had a complete or partial response , and 66 ( 25.1 % ) , 56 ( 22.6 % ) , and 66 ( 26.1 % ) patients , respectively , had stable disease for > or = 24 weeks . For all end points , individual trial results were similar to the results of the combined analysis . Anastrozole and megestrol acetate were well tolerated . Gastrointestinal disturbance was more common among patients in the anastrozole groups than the megestrol acetate group ; the difference between the anastrozole 10 mg and megestrol acetate groups was significant ( P = .005 ) . Significantly fewer patients in the anastrozole 1-mg ( P < .0001 ) and 10-mg ( P < .002 ) groups had weight gain than in the megestrol acetate group . More than 30 % of megestrol acetate-treated patients had weight gain > or = 5 % , and 10 % of patients had weight gain > or = 10 % . Patients who received megestrol acetate continued to gain weight over time . CONCLUSION Anastrozole , 1 and 10 mg once daily , is well tolerated and as effective as megestrol acetate in the treatment of postmenopausal women with advanced breast cancer who progressed following tamoxifen treatment . Moreover , anastrozole therapy avoids the weight gain associated with megestrol acetate treatment PURPOSE To compare the efficacy and tolerability of fulvestrant ( formerly ICI 182,780 ) with anastrozole in the treatment of advanced breast cancer in patients whose disease progresses on prior endocrine treatment . PATIENTS AND METHODS In this double-blind , double-dummy , parallel-group study , postmenopausal patients were r and omized to receive either an intramuscular injection of fulvestrant 250 mg once monthly or a daily oral dose of anastrozole 1 mg . The primary end point was time to progression ( TTP ) . Secondary end points included objective response ( OR ) rate , duration of response ( DOR ) , and tolerability . RESULTS Patients ( n = 400 ) were followed for a median period of 16.8 months . Fulvestrant was as effective as anastrozole in terms of TTP ( hazard ratio , 0.92 ; 95.14 % confidence interval [ CI ] , 0.74 to 1.14 ; P = .43 ) ; median TTP was 5.4 months with fulvestrant and 3.4 months with anastrozole . OR rates were 17.5 % with both treatments . Clinical benefit rates ( complete response + partial response + stable disease > or = 24 weeks ) were 42.2 % for fulvestrant and 36.1 % for anastrozole ( 95 % CI , -4.00 % to 16.41 % ; P = .26 ) . In responding patients , median DOR ( from r and omization to progression ) was 19.0 months for fulvestrant and 10.8 months for anastrozole . Using all patients , DOR was significantly greater for fulvestrant compared with anastrozole ; the ratio of average response duration s was 1.35 ( 95 % CI , 1.10 to 1.67 ; P < 0.01 ) . Both treatments were well tolerated . CONCLUSION Fulvestrant was at least as effective as anastrozole , with efficacy end points slightly favoring fulvestrant . Fulvestrant represents an additional treatment option for postmenopausal women with advanced breast cancer whose disease progresses on tamoxifen therapy PURPOSE To analyze overall survival ( OS ) and up date 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 r and omly 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 up date s 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 r and omized letrozole arm ( 34 v 30 months , respectively ) . Although this difference in OS is not significant , survival was improved in the r and omized 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 We present an initial survival analysis and an up date of the safety data of the North American and Tamoxifen or Arimidex R and omized Group Efficacy and Tolerability ( TARGET ) double-blind , r and omised , multicentre studies which compared anastrozole with tamoxifen as first-line treatment in postmenopausal patients with oestrogen receptor and /or progesterone receptor-positive ( ER+/PR+ ) or receptor-unknown advanced breast cancer ( ABC ) . At a median follow-up of 43.7 months , 56.0 % of patients in the anastrozole group and 56.1 % of patients in the tamoxifen group had died . The proportion of patients dead at 2 years was 31.1 and 32.0 % in the anastrozole and tamoxifen groups , respectively . In the ER+/PR+ subgroup , 55.1 and 55.9 % of patients had died and median time to deaths ( TTD ) were 40.8 and 41.3 months in the anastrozole and tamoxifen groups , respectively . Both agents remained well tolerated , with fewer reports of vaginal bleeding  ( anastrozole versus tamoxifen , 1.0 % versus 2.5 % ) and thromboembolic events ( anastrozole versus tamoxifen , 5.3 % versus 9.0 % ) in the anastrozole group versus the tamoxifen group . Hot flushes and vaginal dryness were reported marginally less in the tamoxifen group compared with the Anastrozole group . Although no improvement in survival was observed , the favourable profile of anastrozole with respect to efficacy ( TTP ) and tolerability [ Cancer 92 ( 2001 ) 2247 ] support the use of anastrozole in advance of tamoxifen as the first-line therapy choice in postmenopausal women with ABC 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 r and omized , double-blind , multicenter study was design ed 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 This report presents the results of a survival up date based on the combined data from two studies that compared the efficacy and tolerability of anastrozole ( 1 or 10 mg once daily ) , a selective , nonsteroidal aromatase inhibitor administered orally , and megestrol acetate ( 40 mg 4 times daily ) in the treatment of postmenopausal women with advanced breast carcinoma whose disease had progressed after treatment with tamoxifen 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 r and omly 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 The r and omized , double-blind , placebo-controlled trial is the optimum method for clinical evaluation of new treatments , as assessed by clinicians and statisticians . However , if a known st and ard of therapy exists , it may be difficult to prove that a new therapy is superior . Equivalence and noninferiority clinical trial design s are now frequently utilized in clinical medical research . This article review s the statistical differences between superiority , equivalence , and noninferiority design schemes , which pose specific ethical questions and have important implication s for interpretation and clinical application of trial results . A guideline is proposed as a st and ard approach for reporting to facilitate qualitative assessment of the methodology of these trials PURPOSE To compare the efficacy and tolerability of fulvestrant ( formerly ICI 182,780 ) and anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment . PATIENTS AND METHODS Patients ( n = 451 ) with advanced breast cancer were r and omized to receive fulvestrant 250 mg as a once-monthly ( one x 5 mL ) intramuscular injection or an oral dose of anastrozole 1 mg in this open , parallel-group , multicenter trial . The primary end point was time to progression ( TTP ) . Secondary end points included objective response ( OR ) rates , defined as complete response ( CR ) or partial response ( PR ) , duration of response ( DOR ) , and tolerability . RESULTS Patients were followed for a median period of 14.4 months . In terms of TTP , fulvestrant was as effective as anastrozole ( hazard ratio , 0.98 ; confidence interval [ CI ] , 0.80 to 1.21 ; P = .84 ) . Median TTP was 5.5 months for fulvestrant and 5.1 months for anastrozole . OR rates showed a numerical advantage for fulvestrant ( 20.7 % ) over anastrozole ( 15.7 % ) ( odds ratio , 1.38 ; CI , 0.84 to 2.29 ; P = .20 ) . Clinical benefit rates ( CR + PR + stable disease > or = 24 weeks ) were 44.6 % for fulvestrant and 45.0 % for anastrozole . Median DOR was 14.3 months for fulvestrant and 14.0 months for anastrozole . Both treatments were well tolerated , with 3.2 % and 1.3 % of fulvestrant- and anastrozole-treated patients , respectively , withdrawn from treatment because of an adverse event . CONCLUSION Fulvestrant was as effective as anastrozole . These data confirm that fulvestrant is an additional , effective , and well-tolerated treatment for advanced breast cancer in postmenopausal women whose disease progressed on prior endocrine therapy
target: Fulvestrant can therefore be considered as alternative therapy to anastrozole or exemestane in postmenopausal women with locally advanced or metastatic breast cancer that has recurred on prior adjuvant endocrine therapy or progressed on prior endocrine therapy for advanced disease .
background: A systematic review was undertaken to examine all available evidence to develop and support clinical recommendations regarding the use of fulvestrant ( Faslodex ® ) as systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women .