human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    
agent
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 .
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    