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: BACKGROUND A r and omized phase III trial in high-risk breast cancer patients was conducted , to further explore the impact of dose-density in the adjuvant treatment for breast cancer . The safety analysis is presented . PATIENTS AND METHODS From October 2000 until June 2005 , 1121 node-positive patients were r and omized to sequential dose-dense epirubicin 110 mg/m(2 ) and paclitaxel ( Taxol , Bristol Myers-Squibb , Princeton , New Jersey , USA ) 250 mg/m(2 ) ( group A ) , or concurrent epirubicin 83 mg/m(2 ) and paclitaxel 187 mg/m(2 ) ( group B ) , both followed by three cycles of ' intensified ' combination chemotherapy with cyclophosphamide , methotrexate and fluorouracil ( CMF ) . Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments . RESULTS Median dose intensity of epirubicin and paclitaxel was double in group A , as design ed , with significantly less cycles administered at full dose ( P < 0.001 ) . Median cumulative dose of all drugs and total treatment duration , however , were identical between groups . Severe taxane-related toxic effects were more frequent in group A , while severe thrombocytopenia was low and present only in group A. There were no differences in the rates of other hematological toxic effects , including febrile neutropenia . The rates of secondary malignancies were low . CONCLUSION Both regimens as used in the present study are well tolerated and safe . The rates of severe taxane-related toxic effects and thrombocytopenia , although low overall , are significantly increased with the dose-dense sequential regimen Introduction The Preoperative Chemotherapy in Primary Operable Breast Cancer ( POCOB ) study was design ed to compare preoperative with postoperative chemotherapy in patients with early breast cancer concerning breast conserving therapy ( BCT ) procedures ,  disease free survival ( DFS ) and overall survival ( OS ) . Methods Patients ( n = 698 ) with early breast cancer were enrolled between 1991 and 1999 and r and omized between  preoperative versus postoperative chemotherapy ( four cycles of fluorouracil , epirubicin , and cyclophosphamide ) . Endpoints were BCT procedures , DFS , OS , and tumor response to preoperative chemotherapy .  In addition , tumor tissue was collected for translational research and the following markers were examined : ER , PgR , HER2 , p21 , p53 , and bcl-2 expression . Results With a median follow-up of 10 years , there was no statistically significant difference between the two treatment arms for OS ( HR = 1.09 ; 95%CI 0.83–1.42 ; P = 0.54 ) , DFS ( HR = 1.12 ; 95%CI 0.90–1.39 ; P = 0.30 ) , or locoregional recurrences ( LRR , HR = 1.16 ; 95%CI 0.77–1.74 ) . Preoperative chemotherapy was associated with an increase in BCT rates . BCT in part feasible due to tumor downsizing after preoperative chemotherapy was not correlated with higher LRR or worse OS compared to BCT which was feasible without downsizing of the tumor . Using available tumor material , only tumor stage , nodal stage , and grade were independent prognostic factors for overall survival . Conclusions Preoperative chemotherapy does not result in a difference in OS or DFS compared to postoperative chemotherapy in patients with early breast cancer . Moreover , it increases BCT rates with no significant increase of LRR . This implies that preoperative chemotherapy is a safe procedure for patients with early breast cancer , even after a follow-up period of 10 years Purpose : There are currently no vali date d factors predictive of response to taxanes in patients with breast cancer . We analyzed specimens from patients included in the Breast Cancer International Research Group ( BCIRG ) 001 trial , a r and omized study which showed the superiority of docetaxel/doxorubicin/cyclophosphamide over fluorouracil/doxorubicin/cyclophosphamide as adjuvant therapy for node-positive operable breast cancer in terms of disease-free survival ( DFS ) and overall survival ( OS ) . Experimental Design : Immunohistochemical assessment of biological markers included histologic grade , tumor size , estrogen and progesterone receptors , lymph node status , HER2 , MUC1 , Ki-67/MIB-1 , p53 , Bcl-2 , Bax , Bcl-XL , BAG-1 , β-tubulin isotypes II , III and IV , τ protein , and detyrosinated α tubulin . Associations between selected parameters and survival were tested through univariate analyses , then completed with multivariate analyses and a bootstrap resampling technique . Results : In univariate analysis histologic grade , tumor size , number of involved nodes , estrogen and progesterone receptor status , p53 , Ki-67 , tubulin III , and τ protein were associated both with DFS and with OS . In multivariate analysis estrogen and progesterone receptors , tumor size , number of involved nodes , and Ki-67 protein were associated both with DFS and with OS , whereas τ protein levels were correlated with DFS and tubulin III and P53 were correlated with OS . No interaction was observed between Ki-67 and treatment allocation . Conclusions : We conclude that the expression in primary tumors of Ki-67 and p53 protein , as well as of the microtubule-related parameters τ protein and tubulin III , are independent prognostic factors in patients receiving adjuvant chemotherapy  for node-positive breast cancer but are not predictive of benefit from docetaxel-containing adjuvant chemotherapy . Clin Cancer Res ; 16(15 ) ; 3988–97 . © 2010 AACR PURPOSE Capecitabine is an active agent in the treatment of breast cancer . It is not known whether integration of capecitabine into an adjuvant regimen that contains a taxane , an anthracycline , and cyclophosphamide improves outcome in early breast cancer . PATIENTS AND METHODS Women with axillary node-positive or high-risk node-negative breast cancer were r and omly assigned to receive either three cycles of docetaxel and capecitabine ( TX ) followed by three cycles of cyclophosphamide , epirubicin , and capecitabine ( CEX ; n = 753 ) or three cycles of docetaxel ( T ) followed by three cycles of cyclophosphamide , epirubicin , and fluorouracil ( CEF ; n = 747 ) . The primary end point was recurrence-free survival ( RFS ) . RESULTS During a median follow-up time of 59 months , 214 RFS events occurred ( local or distant recurrences or deaths ; TX/CEX , n = 96 ; T/CEF , n = 118 ) . RFS was not significantly different between the groups ( hazard ratio [ HR ] , 0.79 ; 95 % CI , 0.60 to 1.04 ; P = .087 ; 5-year RFS , 86.6 % for TX/CEX v 84.1 % for T/CEF ) . Fifty-six patients assigned to TX/CEX died during the follow-up compared with 75 of patients assigned to T/CEF ( HR , 0.73 ; 95 % CI , 0.52 to 1.04 ; P = .080 ) . In exploratory analyses , TX/CEX improved breast cancer-specific survival ( HR , 0.64 ; 95 % CI , 0.44 to 0.95 ; P = .027 ) and RFS in women with triple-negative disease and in women who had more than three metastatic axillary lymph nodes at the time of diagnosis . We detected little severe late toxicity . CONCLUSION Integration of capecitabine into a regimen that contains docetaxel , epirubicin , and cyclophosphamide did not improve RFS significantly compared with a similar regimen without capecitabine Background Adjuvant treatment decision-making based on conventional clinical /pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades . Response to therapy is currently not considered in the decision-making procedure . ADAPT is one of the first new generation (neo)adjuvant trials dealing with individualization of (neo)adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers , e.g. , Ki-67 , for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment . Methods / design The prospect i ve , multi-center , controlled , non-blinded , r and omized , investigator initiated phase II/III ADAPT trial has an innovative “ umbrella ” protocol design . The “ umbrella ” is common for all patients , consisting of dynamic testing of early therapy response .  ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany ; 4,000 patients with hormone receptor positive ( HR+ ) and HER2 negative disease will be included in the ADAPT HR+/HER2- sub-trial , where treatment decision is based on risk assessment and therapy response to induction therapy , and 380 patients will be included in ADAPT HER2+/HR+ . A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative . These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting . Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy , as reported by local/ central pathology for HR and HER2 status . Discussion Recent trials , such as the GeparTrio , have shown that response-guided therapy using clinical response may improve outcome . For chemotherapy or HER2-targeted treatment , pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome . For endocrine therapy , response to short induction treatment – as defined by decrease in tumor cell proliferation – strongly correlates with outcome . ADAPT now aims to combine static prognostic and dynamic predictive markers , focusing not just on single therapeutic targets , but also on general markers of proliferation and cell death . Biomarker analysis will help to optimize selection of subtype-specific treatment . Trial registration Clinical Trials.gov : ADAPT Umbrella : NCT01781338 ; ADAPT HR+/HER2- : NCT01779206 ; ADAPT HER2+/HR+ : NCT01745965 ; ADAPT HER2+/HR- : NCT01817452 ; ADAPT TN : NCT01815242 PURPOSE This study was design ed to determine whether increasing the dose of doxorubicin in or adding paclitaxel to a st and ard adjuvant chemotherapy regimen for breast cancer patients would prolong time to recurrence and survival . PATIENTS AND METHODS After surgical treatment , 3,121 women with operable breast cancer and involved lymph nodes were r and omly assigned to receive a combination of cyclophosphamide ( C ) , 600 mg/m(2 ) , with one of three doses of doxorubicin ( A ) , 60 , 75 , or 90 mg/m(2 ) , for four cycles followed by either no further therapy or four cycles of paclitaxel at 175 mg/m(2 ) . Tamoxifen was given to 94 % of patients with hormone receptor-positive tumors . RESULTS There was no evidence of a  doxorubicin dose effect . At 5 years , disease-free survival was 69 % , 66 % , and 67 % for patients r and omly assigned to 60 , 75 , and 90 mg/m(2 ) , respectively . The hazard reductions from adding paclitaxel to CA were 17 % for recurrence ( adjusted Wald chi(2 ) P = .0023 ; unadjusted Wilcoxon P = .0011 ) and 18 % for death ( adjusted P = .0064 ; unadjusted P = .0098 ) . At 5 years , the disease-free survival ( + /- SE ) was 65 % ( + /- 1 ) and 70 % ( + /- 1 ) , and overall survival was 77 % ( + /- 1 ) and 80 % ( + /- 1 ) after CA alone or CA plus paclitaxel , respectively . The effects of adding paclitaxel were not significantly different in subsets defined by the protocol , but in an unplanned subset analysis , the hazard ratio of CA plus paclitaxel versus CA alone was 0.72 ( 95 % confidence interval , 0.59 to 0.86 ) for those with estrogen receptor-negative tumors and only 0.91 ( 95 % confidence interval , 0.78 to 1.07 ) for patients with estrogen receptor-positive tumors , almost all of whom received adjuvant tamoxifen . The additional toxicity from adding four cycles of paclitax 
    Output:
    
agent
In general , single-agent chemotherapy is not recommended for the adjuvant treatment of breast cancer in any patient population .
Anthracycline-taxane-based polychemotherapy regimens are , overall , considered superior to earlier-generation regimens and have the most significant impact on patient survival outcomes .
Regimens with varying anthracycline and taxane doses and schedules are options ; in general , paclitaxel given every 3 weeks is inferior .
Evidence does not support the use of bevacizumab in the adjuvant setting ; other systemic therapy agents such as metformin and vaccines remain investigatory .
***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: BACKGROUND A r and omized phase III trial in high-risk breast cancer patients was conducted , to further explore the impact of dose-density in the adjuvant treatment for breast cancer . The safety analysis is presented . PATIENTS AND METHODS From October 2000 until June 2005 , 1121 node-positive patients were r and omized to sequential dose-dense epirubicin 110 mg/m(2 ) and paclitaxel ( Taxol , Bristol Myers-Squibb , Princeton , New Jersey , USA ) 250 mg/m(2 ) ( group A ) , or concurrent epirubicin 83 mg/m(2 ) and paclitaxel 187 mg/m(2 ) ( group B ) , both followed by three cycles of ' intensified ' combination chemotherapy with cyclophosphamide , methotrexate and fluorouracil ( CMF ) . Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments . RESULTS Median dose intensity of epirubicin and paclitaxel was double in group A , as design ed , with significantly less cycles administered at full dose ( P < 0.001 ) . Median cumulative dose of all drugs and total treatment duration , however , were identical between groups . Severe taxane-related toxic effects were more frequent in group A , while severe thrombocytopenia was low and present only in group A. There were no differences in the rates of other hematological toxic effects , including febrile neutropenia . The rates of secondary malignancies were low . CONCLUSION Both regimens as used in the present study are well tolerated and safe . The rates of severe taxane-related toxic effects and thrombocytopenia , although low overall , are significantly increased with the dose-dense sequential regimen Introduction The Preoperative Chemotherapy in Primary Operable Breast Cancer ( POCOB ) study was design ed to compare preoperative with postoperative chemotherapy in patients with early breast cancer concerning breast conserving therapy ( BCT ) procedures ,  disease free survival ( DFS ) and overall survival ( OS ) . Methods Patients ( n = 698 ) with early breast cancer were enrolled between 1991 and 1999 and r and omized between  preoperative versus postoperative chemotherapy ( four cycles of fluorouracil , epirubicin , and cyclophosphamide ) . Endpoints were BCT procedures , DFS , OS , and tumor response to preoperative chemotherapy .  In addition , tumor tissue was collected for translational research and the following markers were examined : ER , PgR , HER2 , p21 , p53 , and bcl-2 expression . Results With a median follow-up of 10 years , there was no statistically significant difference between the two treatment arms for OS ( HR = 1.09 ; 95%CI 0.83–1.42 ; P = 0.54 ) , DFS ( HR = 1.12 ; 95%CI 0.90–1.39 ; P = 0.30 ) , or locoregional recurrences ( LRR , HR = 1.16 ; 95%CI 0.77–1.74 ) . Preoperative chemotherapy was associated with an increase in BCT rates . BCT in part feasible due to tumor downsizing after preoperative chemotherapy was not correlated with higher LRR or worse OS compared to BCT which was feasible without downsizing of the tumor . Using available tumor material , only tumor stage , nodal stage , and grade were independent prognostic factors for overall survival . Conclusions Preoperative chemotherapy does not result in a difference in OS or DFS compared to postoperative chemotherapy in patients with early breast cancer . Moreover , it increases BCT rates with no significant increase of LRR . This implies that preoperative chemotherapy is a safe procedure for patients with early breast cancer , even after a follow-up period of 10 years Purpose : There are currently no vali date d factors predictive of response to taxanes in patients with breast cancer . We analyzed specimens from patients included in the Breast Cancer International Research Group ( BCIRG ) 001 trial , a r and omized study which showed the superiority of docetaxel/doxorubicin/cyclophosphamide over fluorouracil/doxorubicin/cyclophosphamide as adjuvant therapy for node-positive operable breast cancer in terms of disease-free survival ( DFS ) and overall survival ( OS ) . Experimental Design : Immunohistochemical assessment of biological markers included histologic grade , tumor size , estrogen and progesterone receptors , lymph node status , HER2 , MUC1 , Ki-67/MIB-1 , p53 , Bcl-2 , Bax , Bcl-XL , BAG-1 , β-tubulin isotypes II , III and IV , τ protein , and detyrosinated α tubulin . Associations between selected parameters and survival were tested through univariate analyses , then completed with multivariate analyses and a bootstrap resampling technique . Results : In univariate analysis histologic grade , tumor size , number of involved nodes , estrogen and progesterone receptor status , p53 , Ki-67 , tubulin III , and τ protein were associated both with DFS and with OS . In multivariate analysis estrogen and progesterone receptors , tumor size , number of involved nodes , and Ki-67 protein were associated both with DFS and with OS , whereas τ protein levels were correlated with DFS and tubulin III and P53 were correlated with OS . No interaction was observed between Ki-67 and treatment allocation . Conclusions : We conclude that the expression in primary tumors of Ki-67 and p53 protein , as well as of the microtubule-related parameters τ protein and tubulin III , are independent prognostic factors in patients receiving adjuvant chemotherapy  for node-positive breast cancer but are not predictive of benefit from docetaxel-containing adjuvant chemotherapy . Clin Cancer Res ; 16(15 ) ; 3988–97 . © 2010 AACR PURPOSE Capecitabine is an active agent in the treatment of breast cancer . It is not known whether integration of capecitabine into an adjuvant regimen that contains a taxane , an anthracycline , and cyclophosphamide improves outcome in early breast cancer . PATIENTS AND METHODS Women with axillary node-positive or high-risk node-negative breast cancer were r and omly assigned to receive either three cycles of docetaxel and capecitabine ( TX ) followed by three cycles of cyclophosphamide , epirubicin , and capecitabine ( CEX ; n = 753 ) or three cycles of docetaxel ( T ) followed by three cycles of cyclophosphamide , epirubicin , and fluorouracil ( CEF ; n = 747 ) . The primary end point was recurrence-free survival ( RFS ) . RESULTS During a median follow-up time of 59 months , 214 RFS events occurred ( local or distant recurrences or deaths ; TX/CEX , n = 96 ; T/CEF , n = 118 ) . RFS was not significantly different between the groups ( hazard ratio [ HR ] , 0.79 ; 95 % CI , 0.60 to 1.04 ; P = .087 ; 5-year RFS , 86.6 % for TX/CEX v 84.1 % for T/CEF ) . Fifty-six patients assigned to TX/CEX died during the follow-up compared with 75 of patients assigned to T/CEF ( HR , 0.73 ; 95 % CI , 0.52 to 1.04 ; P = .080 ) . In exploratory analyses , TX/CEX improved breast cancer-specific survival ( HR , 0.64 ; 95 % CI , 0.44 to 0.95 ; P = .027 ) and RFS in women with triple-negative disease and in women who had more than three metastatic axillary lymph nodes at the time of diagnosis . We detected little severe late toxicity . CONCLUSION Integration of capecitabine into a regimen that contains docetaxel , epirubicin , and cyclophosphamide did not improve RFS significantly compared with a similar regimen without capecitabine Background Adjuvant treatment decision-making based on conventional clinical /pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades . Response to therapy is currently not considered in the decision-making procedure . ADAPT is one of the first new generation (neo)adjuvant trials dealing with individualization of (neo)adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers , e.g. , Ki-67 , for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment . Methods / design The prospect i ve , multi-center , controlled , non-blinded , r and omized , investigator initiated phase II/III ADAPT trial has an innovative “ umbrella ” protocol design . The “ umbrella ” is common for all patients , consisting of dynamic testing of early therapy response .  ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany ; 4,000 patients with hormone receptor positive ( HR+ ) and HER2 negative disease will be included in the ADAPT HR+/HER2- sub-trial , where treatment decision is based on risk assessment and therapy response to induction therapy , and 380 patients will be included in ADAPT HER2+/HR+ . A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative . These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting . Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy , as reported by local/ central pathology for HR and HER2 status . Discussion Recent trials , such as the GeparTrio , have shown that response-guided therapy using clinical response may improve outcome . For chemotherapy or HER2-targeted treatment , pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome . For endocrine therapy , response to short induction treatment – as defined by decrease in tumor cell proliferation – strongly correlates with outcome . ADAPT now aims to combine static prognostic and dynamic predictive markers , focusing not just on single therapeutic targets , but also on general markers of proliferation and cell death . Biomarker analysis will help to optimize selection of subtype-specific treatment . Trial registration Clinical Trials.gov : ADAPT Umbrella : NCT01781338 ; ADAPT HR+/HER2- : NCT01779206 ; ADAPT HER2+/HR+ : NCT01745965 ; ADAPT HER2+/HR- : NCT01817452 ; ADAPT TN : NCT01815242 PURPOSE This study was design ed to determine whether increasing the dose of doxorubicin in or adding paclitaxel to a st and ard adjuvant chemotherapy regimen for breast cancer patients would prolong time to recurrence and survival . PATIENTS AND METHODS After surgical treatment , 3,121 women with operable breast cancer and involved lymph nodes were r and omly assigned to receive a combination of cyclophosphamide ( C ) , 600 mg/m(2 ) , with one of three doses of doxorubicin ( A ) , 60 , 75 , or 90 mg/m(2 ) , for four cycles followed by either no further therapy or four cycles of paclitaxel at 175 mg/m(2 ) . Tamoxifen was given to 94 % of patients with hormone receptor-positive tumors . RESULTS There was no evidence of a  doxorubicin dose effect . At 5 years , disease-free survival was 69 % , 66 % , and 67 % for patients r and omly assigned to 60 , 75 , and 90 mg/m(2 ) , respectively . The hazard reductions from adding paclitaxel to CA were 17 % for recurrence ( adjusted Wald chi(2 ) P = .0023 ; unadjusted Wilcoxon P = .0011 ) and 18 % for death ( adjusted P = .0064 ; unadjusted P = .0098 ) . At 5 years , the disease-free survival ( + /- SE ) was 65 % ( + /- 1 ) and 70 % ( + /- 1 ) , and overall survival was 77 % ( + /- 1 ) and 80 % ( + /- 1 ) after CA alone or CA plus paclitaxel , respectively . The effects of adding paclitaxel were not significantly different in subsets defined by the protocol , but in an unplanned subset analysis , the hazard ratio of CA plus paclitaxel versus CA alone was 0.72 ( 95 % confidence interval , 0.59 to 0.86 ) for those with estrogen receptor-negative tumors and only 0.91 ( 95 % confidence interval , 0.78 to 1.07 ) for patients with estrogen receptor-positive tumors , almost all of whom received adjuvant tamoxifen . The additional toxicity from adding four cycles of paclitax 
    Output:
    