Postmenopausal Women who Progress on Fulvestrant ('Faslodex') Remain Sensitive to Further Endocrine Therapy Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. Equivalent single-dose pharmacokinetics of two different dosing methods of prolonged-release fulvestrant ('Faslodex') in postmenopausal women with advanced breast cancer Final Overall Survival: Fulvestrant 500mg vs 250mg in the Randomized CONFIRM Trial Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. Adjuvant oral 5-fluorouracil for cervical cancer: Japanese Gynecologic Oncology Group report. 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. Fulvestrant in women with advanced breast cancer after progression on prior aromatase inhibitor therapy: North Central Cancer Treatment Group Trial N0032. Adjuvant docetaxel for high-risk, node-negative breast cancer. Results of a phase II study comparing three dosing regimens of fulvestrant in postmenopausal women with advanced breast cancer (FINDER2) Three dose regimens of fulvestrant in postmenopausal Japanese women with advanced breast cancer: results from a double-blind, phase II comparative study (FINDER1). A retrospective analysis of the proportion of patients responding for > 1 year in two phase III studies of fulvestrant vs. anastrozole. Oral metronomic cyclophosphamide and methotrexate plus fulvestrant in advanced breast cancer patients: a mono-institutional case-cohort report. DEGRO practical guidelines for radiotherapy of breast cancer V Bicalutamide (Casodex) 150 mg as immediate therapy in patients with localized or locally advanced prostate cancer significantly reduces the risk of disease progression. Pharmacokinetic Profile of Intramuscular Fulvestrant in Advanced Breast Cancer Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114.
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 PURPOSE We compared fulvestrant 500 mg regimen with the approved dose of fulvestrant 250 mg per month for treatment of postmenopausal women with estrogen receptor-positive advanced breast cancer who experienced progression after prior endocrine therapy . PATIENTS AND METHODS Comparison of Faslodex in Recurrent or Metastatic Breast Cancer ( CONFIRM ) is a double-blind , parallel-group , multicenter , phase III study . Patients were r and omly assigned to fulvestrant 500 mg ( 500 mg intramuscularly [ IM ] on day 0 , then 500 mg IM on days 14 and 28 and every 28 days thereafter ) or 250 mg every 28 days . Primary end point was progression-free survival ( PFS ) . Secondary end points included objective response rate , clinical benefit rate ( CBR ) , duration of clinical benefit ( DoCB ) , overall survival ( OS ) , and quality of life ( QOL ) . RESULTS PFS was significantly longer for fulvestrant 500 mg ( n = 362 ) than 250 mg ( n = 374 ) ( hazard ratio [ HR ] = 0.80 ; 95 % CI , 0.68 to 0.94 ; P = .006 ) , corresponding to a 20 % reduction in risk of progression . Objective response rate was similar for fulvestrant 500 mg and 250 mg ( 9.1 % v 10.2 % , respectively ) . CBR was 45.6 % for fulvestrant 500 mg and 39.6 % for fulvestrant 250 mg . DoCB and OS were 16.6 and 25.1 months , respectively , for the 500-mg group , whereas DoCB and OS were 13.9 and 22.8 months , respectively , in the 250-mg group . Fulvestrant 500 mg was well tolerated with no dose-dependent adverse events . QOL was similar for both arms . CONCLUSION Fulvestrant 500 mg was associated with a statistically significant increase in PFS and not associated with increased toxicity , corresponding to a clinical ly meaningful improvement in benefit versus risk compared with fulvestrant 250 mg 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 Background At the time of the initial analysis of overall survival ( OS ) for the Comparison of Faslodex in Recurrent or Metastatic Breast Cancer ( CONFIRM ) r and omized , double-blind , phase III trial , approximately 50 % of patients had died . A final analysis of OS was subsequently planned for when 75 % of patients had died . Methods Patients were r and omly assigned 1:1 to fulvestrant 500 mg administered as two 5-mL intramuscular injections on days 0 , 14 , and 28 and every 28 ( ±3 ) days thereafter or fulvestrant 250 mg administered as two 5-mL intramuscular injections ( one fulvestrant and one placebo [ identical in appearance to study drug ] ) on days 0 , 14 ( two placebo injections only ) , and 28 and every 28 ( ±3 ) days thereafter . OS was analyzed using an unadjusted log-rank test . No adjustments were made for multiplicity . Serious adverse events ( SAEs ) and best response to subsequent therapy were also reported . All statistical tests were two-sided . Results In total , 736 women ( median age = 61.0 years ) were r and omly assigned to fulvestrant 500 mg ( n = 362 ) or 250 mg ( n = 374 ) . At the final survival analysis , 554 of 736 ( 75.3 % ) patients had died . Median OS was 26.4 months for fulvestrant 500 mg and 22.3 months for 250 mg ( hazard ratio = 0.81 ; 95 % confidence interval = 0.69–0.96 ; nominal P = .02 ) . There were no clinical ly important differences in SAE profiles between the treatment groups ; no clustering of SAEs could be detected in either treatment group . Type of first subsequent therapy and objective responses to first subsequent therapy were well balanced between the two treatment groups . Conclusions In patients with locally advanced or metastatic estrogen receptor – positive breast cancer , fulvestrant 500 mg is associated with a 19 % reduction in risk of death and a 4.1-month difference in median OS compared with fulvestrant 250 mg . Fulvestrant 500 mg was well tolerated , and no new safety concerns were identified PURPOSE The third-generation nonsteroidal aromatase inhibitors ( AIs ) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal , hormone receptor-positive ( HR+ ) breast cancer . Because many patients subsequently experience progression or relapse , it is important to identify agents with efficacy after AI failure . MATERIAL S AND METHODS Evaluation of Faslodex versus Exemestane Clinical Trial ( EFECT ) is a r and omized , double-blind , placebo controlled , multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR+ advanced breast cancer ( ABC ) progressing or recurring after nonsteroidal AI . The primary end point was time to progression ( TTP ) . A fulvestrant loading-dose ( LD ) regimen was used : 500 mg intramuscularly on day 0 , 250 mg on days 14 , 28 , and 250 mg every 28 days thereafter . Exemestane 25 mg orally was administered once daily . RESULTS A total of 693 women were r and omly assigned to fulvestrant ( n = 351 ) or exemestane ( n = 342 ) . Approximately 60 % of patients had received at least two prior endocrine therapies .  Median TTP was 3.7 months in both groups ( hazard ratio = 0.963 ; 95 % CI , 0.819 to 1.133 ; P = .6531 ) . The overall response rate ( 7.4 % v 6.7 % ; P = .736 ) and clinical benefit rate ( 32.2 % v 31.5 % ; P = .853 ) were similar between fulvestrant and exemestane respectively . Median duration of clinical benefit was 9.3 and 8.3 months , respectively . Both treatments were well tolerated , with no significant differences in the incidence of adverse events or quality of life . Pharmacokinetic data confirm that steady-state was reached within 1 month with the LD schedule of fulvestrant . CONCLUSION Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteroidal AI Japanese women with low-stage cervical cancer receiving radical hysterectomy and radiotherapy  have a good 5-year survival rate . However , women with risk factors such as nodal metastasis may benefit from adjuvant chemotherapy , which was studied in women having surgery alone or surgery plus radiotherapy .  Patients having surgery alone ( S ) ( n=623 ) or surgery and radiotherapy ( SR ) ( n=919 ) were r and omly assigned to receive or not receive oral 5-fluorouracil ( 5-FU ) for 1 year . The effect of various factors on survival was studied by multivariate analysis . Patients who received S obtained no benefit from 5-FU , whereas 5-FU-treated SR patients had significantly better 5-year survival than those not receiving chemotherapy ( P=0.043 ) . The SR patients without nodal metastases had a better survival rate if they received 5-FU ( P<0.001 ) , whereas those with nodal metastases did not . Oral 5-FU after radical hysterectomy with radiotherapy appears useful for patients with low-stage cervical cancer who have some risk factors but not for those with pelvic lymph node metastases 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 PURPOSE Fulvestrant is an antiestrogen that leads to estrogen receptor degradation and has demonstrated efficacy in breast cancer patients who have had disease recurrence or progression after tamoxifen . This study was design ed to examine the efficacy and toxicity of fulvestrant in patients with disease progression on a third-generation aromatase inhibitor ( AI ) .  PATIENTS AND METHODS A one-stage phase II trial was conducted in postmenopausal women with measurable disease by Response Evaluation Criteria in Solid Tumors criteria who experienced disease progression after treatment with a third-generation AI and , at most , one additional hormonal agent .  Tumors must have been estrogen receptor and /or progesterone receptor positive . The primary end point was objective response rate , and secondary end points were time to disease progression , survival , duration of response , and toxicity . RESULTS Eighty patients were enrolled , and three were ineligible . Characteristics of the 77 eligible patients included median age of 68 years , performance score of 0 or 1 in 91 % of patients , visceral dominant disease in 88 % of patients , two prior hormonal treatments in 73 % of patients , and prior chemotherapy for metastatic disease in 32 % of patients . Eleven patients ( 14.3 % ) achieved a partial response , and 16 patients ( 20.8 % ) had stable disease for at least 6 months , for a clinical benefit rate of 35 % . Antitumor activity seemed to be higher in women with prior treatment with AI alone compared with women whose prior treatment also included tamoxifen . Median time to progression was 3 months , and median survival time was 20.2 months . Fulvestrant was well tolerated . CONCLUSION Fulvestrant is a well-tolerated treatment and has efficacy against breast cancers that have progressed after therapy with a third-generation AI BACKGROUND A regimen of docetaxel , doxorubicin , and cyclophosphamide ( TAC ) is superior to a regimen of fluorouracil , doxorubicin , and cyclophosphamide ( FAC ) when used as adjuvant therapy in women with node-positive breast cancer . The value of taxanes in the treatment of node-negative disease has not been determined . METHODS We r and omly assigned 1060 women with axillary-node-negative breast cancer and at least one high-risk factor for recurrence ( according to the 1998 St. Gallen criteria ) to treatment with TAC or FAC every 3 weeks for six cycles after surgery . The primary end point was disease-free survival after at least 5 years of follow-up . Secondary end points included overall survival and toxicity . RESULTS At a median follow-up of 77 months , the proportion of patients alive and disease-free was higher among the 539 women in the TAC group ( 87.8 % ) than among the 521 women in the FAC group ( 81.8 % ) , representing a 32 % reduction in the risk of recurrence with TAC ( hazard ratio , 0.68 ; 95 % confidence interval [ CI ] , 0.49 to 0.93 ; P=0.01 by the log-rank test ) . This benefit was consistent , regardless of hormone-receptor status , menopausal status , or number of high-risk factors . The difference in survival rates  ( TAC , 95.2 % ; FAC , 93.5 % ) was not significant ( hazard ratio , 0.76 ; 95 % CI , 0.45 to 1.26 ) ; however , the number of events was small ( TAC , 26 ; FAC , 34 ) . Rates of grade 3 or 4 adverse events were 28.2 % with TAC and 17.0 % with FAC ( P<0.001 ) . Toxicity associated with TAC was diminished when primary prophylaxis with granulocyte colony-stimulating factor was provided . CONCLUSIONS As compared with adjuvant FAC , adjuvant TAC improved the rate of disease-free survival among women with high-risk , node-negative breast cancer . ( Funded by GEICAM and Sanofi-Aventis ; Clinical Trials.gov number , NCT00121992 . ) The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive advanced breast cancer (FINDER)2 study evaluated the efficacy , safety , and pharmacokinetics ( PK ) of three fulvestrant dosing regimens . FINDER2 enrolled Western postmenopausal women recurring or progressing after prior endocrine therapy . Primary endpoint : objective response rate ( ORR ) ; secondary endpoints : time to progression ( TTP ) , clinical benefit rate ( CBR ) , tolerability , and PK parameters .  Patients were r and omized to receive fulvestrant : 250 mg/month ( approved dose [ AD ] ) ; 250 mg plus loading dose ( loading dose [ LD ] ; 500 mg on day 0 , 250 mg on days 14 , 28 , and monthly thereafter ) ; or 500 mg ( high dose [ HD ] ; 500 mg/month plus 500 mg on day 14 of Month 1 ) . Treatment continued until disease progression or discontinuation . 144 patients were r and omized : fulvestrant AD ( n = 47 ) ; LD ( n = 51 ) ; HD ( n = 46 ) . ORRs were : 8.5 % ( 95 % confidence interval [ CI ] : 2.4 , 20.4 % ) , 5.9 % ( 1.2 , 16.2 % ) , and 15.2 % ( 6.3 , 28.9 % ) in the AD , LD , and HD arms , respectively . CBRs were : 31.9 % ( 95 % CI : 19.1 , 47.1 % ) , 47.1 % ( 32.9 , 61.5 % ) , and 47.8 % ( 32.9 , 63.1 % ) for the AD , LD , and HD arms , respectively . Median TTP ( months ) was numerically longer for HD ( 6.0 ) and LD ( 6.1 ) versus AD ( 3.1 ) . Tolerability was similar across dosing regimens . Steady-state plasma fulvestrant concentrations were predictable and achieved earlier with LD and HD . While there appeared to be a trend toward improved efficacy with HD and LD versus AD , no significant differences could be shown . A parallel study ( FINDER1 ) has reported similar findings in Japanese patients BACKGROUND FINDER1 compared efficacy , tolerability and pharmacokinetics ( PK ) of three fulvestrant dose regimens in postmenopausal Japanese women with estrogen receptor (ER)-positive locally advanced/metastatic breast cancer recurring or progressing after prior endocrine therapy . PATIENTS AND METHODS The primary end point of this r and omised , multicentre , phase II study was objective response rate ( ORR ) and the secondary end points included time to progression ( TTP ) , clinical benefit rate ( CBR ) , PK profiles and tolerability .  Postmenopausal women with ER-positive advanced breast cancer were r and omised to 28-day cycles of fulvestrant approved dose ( AD ) , loading dose ( LD ) or high dose ( HD ) until disease progression . RESULTS Hundred and forty-three patients ( median age 61 years ) received fulvestrant AD ( n = 45 ) , LD ( n = 51 ) or HD ( n = 47 ) . ORR was similar across dose regimens : 11.1 % , 17.6 % and 10.6 % for AD , LD and HD , respectively , with overlapping confidence intervals . TTP and CBR were also similar between groups ( median TTP : 6.0 , 7.5 and 6.0 months , respectively ; CBR : 42.2 % , 54.9 % and 46.8 % for AD , LD and HD , respectively ) . C(max ) and area under the plasma concentration-time curve were dose proportional and PK steady state was reached earlier with LD and HD than with AD . All three doses were well tolerated , with a similar adverse-event profile and no emerging safety concerns . CONCLUSION Fulvestrant AD , LD and HD had similar efficacy and tolerability profiles in postmenopausal Japanese women with ER-positive advanced breast cancer 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 ] Fulvestrant is effective in postmenopausal women with estrogen receptor-positive advanced breast cancer ( ABC ) . So far , no published data exist on fulvestrant combined with chemotherapy . We retrospectively assessed the role of combining oral metronomic cyclophosphamide and methotrexate ( CM ) to fulvestrant in two cohorts ( A and B ) of heavily pre-treated estrogen receptor-positive advanced ABC patients . From October 2006 to September 2009 , 33 postmenopausal patients received  fulvestrant 250 mg via i.m . injection q28 days . In A , 20 patients added metronomic cyclophosphamide ( 50 mg p.o . daily ) and methotrexate ( 2.5 mg p.o . twice daily on day 1 and day 4 weekly ) after disease progression , continuing fulvestrant at the same dose . In B , 13 patients started fulvestrant plus metronomic CM upfront . Thirty-two patients were evaluable for response . Clinical benefit ( partial response + stable disease > 24 months ) for A + B was 56 % ( 95 % CI 38 - 74 % ) . The addition of metronomic CM did not determine relevant toxicities . Treatment with  fulvestrant plus metronomic CM  was effective in advanced ABC and was minimally toxic providing long-term disease control in a high proportion of patients . The prolonged clinical benefit , often desirable in such patients , supports this regimen as an additional and useful therapeutic tool Aim The purpose of this work is to give practical guidelines for radiotherapy of locally advanced , inflammatory and metastatic breast cancer at first presentation . Methods A comprehensive survey of the literature using the search phrases “ locally advanced breast cancer ” , “ inflammatory breast cancer ” , “ breast cancer and synchronous metastases ” , “ de novo stage IV and breast cancer ” , and “ metastatic breast cancer ” and “ at first presentation ” restricted to “ clinical trials ” , “ r and omized trials ” , “ meta- analysis ” , “ systematic review ” , and “ guideline ” was performed and supplemented by using references of the respective publications . Based on the German interdisciplinary S3 guidelines , up date d in 2012 , this publication addresses indications , sequence to other therapies , target volumes , dose , and fractionation of radiotherapy . Results International and national guidelines are in agreement that locally advanced , at least if regarded primarily unresectable and inflammatory breast cancer should receive neoadjuvant systemic therapy first , followed by surgery and radiotherapy . If surgery is not amenable after systemic therapy , radiotherapy is the treatment of choice followed by surgery , if possible . Surgery and radiotherapy should be administered independent of response to neoadjuvant systemic treatment . In patients with a de novo diagnosis of breast cancer with synchronous distant metastases , surgery and radiotherapy result in considerably better locoregional tumor control . An improvement in survival has not been consistently proven , but may exist in subgroups of patients . Conclusion Radiotherapy is an important part in the treatment of locally advanced and inflammatory breast cancer that should be given to all patients regardless to the intensity and effect of neoadjuvant systemic treatment and the extent of surgery . Locoregional radiotherapy in patients with primarily distant metastatic disease should be prescribed on an individual basis . ZusammenfassungZielZiel der Arbeit ist die Entwicklung von Praxis-Leitlinien zur Strahlentherapie des lokal fortgeschrittenen einschließlich des inflammatorischen Mammakarzinoms sowie zur lokalen Therapie bei synchroner Fernmetastasierung . Method enEs erfolgte eine Literaturübersicht basierend auf den Suchbegriffen „ locally advanced breast cancer “ , „ inflammatory breast cancer “ , „ breast cancer and synchronous metastases “ , „ de novo stage IV and breast cancer “ und „ metastatic breast cancer “ sowie „ at first presentation “ . Stratifiziert wurde nach „ clinical trials “ , „ r and omized trials “ , „ meta- analysis “ , „ systematic review “ und „ guideline “ , ergänzt von kürzlich veröffentlichten Abstract s. Ergänzend zu den Stellungnahmen der deutschen interdisziplinären S3-Leitlinie der Deutschen Krebsgesellschaft und der AWMF zum Mammakarzinom von 2012 bezieht diese Publikation Stellung zu den Indikationen , zur zeitlichen Abfolge mit and eren Therapien , zum Zielvolumen sowie zur Dosis und Fraktionierung der Strahlentherapie . ErgebnisseInternationale und nationale Leitlinien stimmen darin überein , dass Patientinnen mit einem lokal fortgeschrittenen , zumindest primär als irresektabel eingestuften , sowie Patientinnen mit einem inflammatorischen Mammakarzinom zunächst eine neoadjuvante Systemtherapie erhalten sollen , gefolgt von einer Operation und einer Strahlentherapie . Falls nach der Systemtherapie eine Operation nicht durchführbar ist , sollte zunächst eine Radiotherapie erfolgen und anschließend noch einmal die Möglichkeit einer Operation bedacht werden . Operation und Bestrahlung erfolgen unabhängig vom Ansprechen auf die neoadjuvante Systemtherapie . Bei Patientinnen mit primärer Fernmetastasierung führt die lokale Beh and lung mittels Operation und/oder Strahlentherapie zur besseren lokalen Tumorkontrolle . Ein Überlebensvorteil besteht wohl nicht , möglicherweise aber doch für einige Subgruppen der Patientinnen . SchlussfolgerungEine Strahlentherapie ist wichtiger Best and teil der Beh and lung lokal fortgeschrittener und inflammatorischer Mammakarzinome für alle betroffenen Patientinnen , unabhängig von der Intensität und dem Ergebnis der neoadjuvanten systemischen Therapie und des Ausmaßes einer eventuellen Chirurgie . Bei Patientinnen mit primärer Fernmetastasierung muss i m Tumorboard die Indikation zur lokoregionären Strahlentherapie individuell gestellt werden OBJECTIVES To investigate the efficacy and tolerability of bicalutamide ( Casodex ) as immediate therapy , either alone or as adjuvant to treatment of curative intent , in patients with localized or locally advanced ( T1b-T4 , any nodal status , M0 ) prostate cancer . METHODS This was a multicenter , prospect i ve , r and omized , double-blind , placebo-controlled trial in Europe , South Africa , Australia , and Mexico and is part of the Casodex Early Prostate Cancer program . RESULTS A total of 3603 men were r and omized to receive bicalutamide ( n = 1798 ) or placebo ( n = 1805 ) . The patient demographics were well balanced between the two groups . Prior therapy of curative intent had been given to 64 % of the patients ( prostatectomy [ 44 % ] , radiotherapy [ 18 % ] , and prostatectomy and radiotherapy [ 2 % ] ) and 36 % had been monitored with watchful waiting . After a median follow-up of 2.6 years and a median exposure to the study drug of 2.2 years , a significant 43 % reduction in the risk of objective progression was observed for the bicalutamide group compared with the placebo group ( hazard ratio 0.57 , 95 % confidence interval 0.48 to 0.69 , P < < 0.0001 ) . The time to prostate-specific antigen doubling was significantly delayed for the bicalutamide group compared with the placebo group ( hazard ratio 0.37 , 95 % confidence interval 0.32 to 0.43 , P < < 0.001 ) . The survival data were immature , with 7.2 % overall mortality . The most frequently reported adverse events with bicalutamide were gynecomastia alone ( 17.4 % ) , breast pain alone ( 17.6 % ) , and gynecomastia with breast pain ( 47.5 % ) . CONCLUSIONS Bicalutamide 150 mg daily as immediate therapy , alone or as adjuvant to treatment of curative intent , significantly reduced the risk of disease progression in patients with localized or locally advanced prostate cancer . Longer follow-up is underway to assess any benefit in overall survival 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 PURPOSE The combination of radiation therapy with fluorouracil (5-FU)-based chemotherapy is generally accepted as appropriate postoperative therapy for patients with adenocarcinomas of the rectum that extend through the bowel wall or with lymph nodes positive for tumor . We attempted to determine whether the efficacy of this postoperative therapy could be improved by the addition of leucovorin and /or levamisole . METHODS A total of 1,696 patients were r and omized and eligible for treatment with one of four treatment schemes . All patients received two cycles of bolus 5-FU-based systemic chemotherapy followed by pelvic radiation therapy with chemotherapy and two more cycles of the same systemic chemotherapy . Chemotherapy was either 5-FU alone , 5-FU with leucovorin , 5-FU with levamisole , or 5-FU with leucovorin and levamisole . RESULTS With a median follow-up duration of 48 months , there is no statistically significant advantage to any of the treatment regimens compared with bolus 5-FU alone . There is evidence of increased gastrointestinal toxicity with the three-drug combination compared with bolus 5-FU alone . Statistical analysis suggests it is very unlikely that either levamisole-containing combination will be shown to be of value with further follow-up evaluation . CONCLUSION There is no evidence at present for a beneficial effect of levamisole in the adjuvant treatment of rectal cancer . Definitive evaluation of the effect of the addition of leucovorin to 5-FU and pelvic radiation will require further follow-up evaluation
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 .
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 .