Evaluation of paclitaxel in adjuvant chemotherapy for patients with operable breast cancer: preliminary data of a prospective randomized trial. Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer:National Surgical Adjuvant Breast and Bowel Project Protocol B-27. Randomised trial: survival benefit and safety of adjuvant dose-dense chemotherapy for node-positive breast cancer Sequential epirubicin-docetaxel-CMF as adjuvant therapy of early breast cancer: Results of the Taxit216 multicenter phase III trial. A feasibility study evaluating docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer. Weekly docetaxel versus CMF as adjuvant chemotherapy for elderly breast cancer patients: safety data from the multicentre phase 3 randomised ELDA trial. Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by Paclitaxel for early breast cancer. Feasibility and Tolerability of Sequential Doxorubicin/Paclitaxel Followed by Cyclophosphamide, Methotrexate, and Fluorouracil and Its Effects on Tumor Response as Preoperative Therapy Adjuvant docetaxel for node-positive breast cancer. Multicenter, randomized phase III study of adjuvant chemotherapy for axillary positive breast cancer (APBC) comparing 6 cycles (cy) of FEC vs 4 cy of FEC followed by 8 weekly paclitaxel (T) administrations: Safety analysis of GEICAM 9906 trial. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. Epirubicin plus tamoxifen versus tamoxifen alone in node-positive postmenopausal patients with breast cancer: A randomized trial of the International Collaborative Cancer Group. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. Prophylactic growth factor (GF) support with adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) for node-negative breast cancer (BC): An interim safety analysis of the GEICAM 9805 study. Intensive dose-dense compared with high-dose adjuvant chemotherapy for high-risk operable breast cancer: Southwest Oncology Group/Intergroup study 9623. Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. Life-threatening sepsis associated with adjuvant doxorubicin plus docetaxel for intermediate-risk breast cancer. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. Concurrent doxorubicin plus docetaxel is not more effective than concurrent doxorubicin plus cyclophosphamide in operable breast cancer with 0 to 3 positive axillary nodes: North American Breast Cancer Intergroup Trial E 2197.
PURPOSE Paclitaxel has significant antitumor activity in patients with metastaticbreast cancer who have been previously treated with or exposed to anthracycline-containing chemotherapy .  In this prospect i ve r and omized trial , the role of paclitaxel was evaluated in an adjuvant setting to determine its impact on reducing the risk of recurrence in patients with operable breast cancer . EXPERIMENTAL DESIGN Five hundred twenty-four patients were r and omized to be treated either with 4 cycles of paclitaxel followed by 4 cycles of combination therapy with 5-fluorouracil , Adriamycin , and cyclophosphamide ( Pac/FAC ) or with 8 cycles of FAC alone .  Patients with intact primary breast cancer received the initial 4 cycles of paclitaxel or 4 cycles of FAC in a neoadjuvant setting . Planned duration of therapy was the same in all patients . After completion of 8 cycles of chemotherapy , those patients who were > or = 50 years and whose tumors were positive for estrogen receptors received tamoxifen for 5 years . RESULTS Ninety-two patients have had a recurrence after a median follow-up of 60 months with a range of 5 - 89 months . Estimated disease-free survival at 48 months was 0.83 for FAC and 0.86 for Pac/FAC group . The difference between the two groups was not statistically significant ( P = 0.09 ) . The overall estimated hazard ratio for Pac/FAC compared with FAC derived by fitting the Cox regression model and incorporating terms for prognostic factors was 0.66 . CONCLUSION Preliminary results suggest that the addition of paclitaxel to a FAC regimen of adjuvant or neoadjuvant therapy may further reduce the risk of disease recurrence ; however , differences were not statistically significant . At the time of this analysis , there have been 47 deaths . The survival data are too preliminary to permit meaningful evaluation of the impact of paclitaxel on mortality BACKGROUND The aim of the study was to analyse the toxicity and health related quality of life ( HRQoL ) of breast cancer patients treated with FAC ( 5-fluorouracil , doxorubicin , cyclophosphamide ) and TAC ( docetaxel , doxorubicin , cyclophosphamide ) with and without primary prophylactic G-CSF ( PPG ) .  PATIENTS AND METHODS This was a phase III study to compare FAC and TAC as adjuvant treatment of high-risk node-negative breast cancer patients . After the entry of the first 237 patients , the protocol was amended to include PPG in the TAC arm due to the high incidence of febrile neutropenia . A total of 1047 evaluable patients from 49 centres in Spain , two in Pol and and four in Germany were included in the trial .  Side-effects and the scores of the EORTC QLQ-C30 and QLQ BR-23 question naires were compared in the three groups ( FAC , TAC pre-amendment and TAC post-amendment ) . RESULTS The addition of PPG to TAC significantly reduced the incidence of neutropenic fever , grade 2 - 4 anaemia , asthenia , anorexia , nail disorders , stomatitis , myalgia and dysgeusia . Patient QoL decreased during chemotherapy , more with TAC than FAC , but returned to baseline values afterwards . The addition of PPG to TAC significantly reduced the percentage of patients with clinical ly relevant Global Health Status deterioration ( 10 or more points over baseline value ) at the end of chemotherapy ( 64 % versus 46 % , P<0.03 ) . CONCLUSIONS The addition of PPG significantly reduces the incidence of neutropenic fever associated with TAC chemotherapy as well as that of some TAC-induced haematological and extrahaematological side-effects . The HRQoL of patients treated with TAC is worse than that of those treated with FAC but improves with the addition of PPG , particularly in the final part of chemotherapy treatment 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 paclitaxel was generally modest . CONCLUSION The addition of four cycles of paclitaxel after the completion of a st and ard course of CA improves the disease-free and overall survival of patients with early breast cancer PURPOSE This study was design ed to determine the effect of adding docetaxel ( T ) to preoperative doxorubicin and cyclophosphamide ( AC ) on  breast cancer response rates and disease-free survival ( DFS ) and overall survival ( OS ) . PATIENTS AND METHODS Women with operable breast cancer ( N = 2,411 ) were r and omly assigned to receive preoperative AC followed by surgery , AC followed by T and surgery , or AC followed by surgery and then T. Tamoxifen was initiated concurrently with chemotherapy . Median time on study for 2,404 patients with follow-up was 77.9 months . RESULTS Addition of T to AC did not significantly impact DFS or OS . There were trends toward improved DFS with addition of T. The addition of T reduced the incidence of local recurrences as first events ( P = .0034 ) . Preoperative T , but not postoperative T , significantly improved DFS in patients who had a clinical partial response after AC ( hazard ratio [ HR ] = 0.71 ; 95 % CI , 0.55 to 0.91 ; P = .007 ) . Pathologic complete response , which was doubled by addition of preoperative T , was a significant predictor of OS regardless of treatment ( HR = 0.33 ; 95 % CI , 0.23 to 0.47 ; P < .0001 ) . Pathologic nodal status after chemotherapy was a significant predictor of OS ( P < .0001 ) . CONCLUSION The addition of preoperative or postoperative T after preoperative AC did not significantly affect OS , slightly improved DFS , and decreased the incidence of local recurrences . The sample size of this study was not sufficient to yield significance for the moderate DFS improvement . Concurrent use of tamoxifen may have limited the impact of adding We evaluated the survival benefit , safety , feasibility , and tolerability of dose-dense ( DD ) adjuvant chemotherapy with epirubicin and paclitaxel for women with node-positive primary breast cancer . R and omised patients ( n=216 ) received DD or conventional-schedule ( CS ) chemotherapy . Dose-dense regimen patients ( n=108 ) received epirubicin 90 mg m−2 plus paclitaxel 175 mg m−2 in four 14-day cycles , then cyclophosphamide 600 mg m−2 , methotrexate 40 mg m−2 , and fluorouracil 600 mg m−2 ( CMF 600/40/600 ) in three 14-day cycles , plus filgrastim 5 μg kg day−1 as growth support in every cycle . Conventional-schedule regimen patients ( n=108 ) received epirubicin 90 mg m−2 plus cyclophosphamide 600 mg m−2 in four 21-day cycles , then CMF 600/40/600 in three 21-day cycles , plus filgrastim if required . After a median follow-up of 38.4 months , 71 patients ( 33 % ) relapsed or died : DD , 33 patients ( 15 deaths ) ; CS , 38 patients ( 22 deaths ) . Dose dense showed a trend for improved disease-free survival ( DFS ) and overall survival ( OS ) . Four-year rates of DFS and OS were 64 and 85 % for DD , and 58 and 75 % for CS . All seven cycles were administered to 208 patients ( 96 % ) . Rates of cycle delay , discontinuation , dose reduction , and adverse events were similar in both groups . Dose-dense sequential chemotherapy with epirubicin/paclitaxel then CMF , supported by filgrastim , is safe and improves survival for patients with node-positive breast cancer LBA520 Background : Docetaxel is among the most active drugs for advanced breast cancer and it has recently shown efficacy in the adjuvant setting too . This trial is aim ed at comparing the efficacy and tolerability of a sequential approach of a chemotherapy combination regimen containing docetaxel to a st and ard anthracycline-based regimen as adjuvant therapy in node-positive ( N+ ) early breast cancer . METHODS Between July 1998 and July 2002 , 972 N+ early breast cancer patients were r and omized to either arm A ( E→CMF ) :  Epirubicin ( E ) 120 mg/m2 iv d1 q21 × 4 cycles followed by Cyclophosphamide 600 mg/m2 iv , Methotrexate 40 mg/m2 iv and Fluorouracil 600 mg/m2 iv ( CMF ) d1,8 q28 × 4 cycles ; or armB ( E→T→CMF ) in which Docetaxel 100 mg/m2 iv ( T ) d1 q21 × 4 cycles was administered after the 4th cycle of E and before the 1st cycle of CMF . Treatment allocation was performed by a computer program using a dynamic balancing algorithm . Balancing factors were : center , lymph node involvement ( 1 to 3 , 4 to 9 , > 10 ) , estrogen receptor status ( negative/positive/unknown ) , menopausal status ( pre/post ) . During chemotherapy pts were subjected to physical examination and blood chemistry tests every 3 wks , hematology was repeated weekly . At the completion of treatment pts were followed up every 3 months for the first 2 years , every 6 months for years 3 - 5 and every 12 months for years 6 - 10 . Primary endpoint was disease free survival ( DFS ) and secondary endpoints were tolerability and overall survival ( OS ) . The study was design ed to detect a hazard ratio of 0.70 , assuming an α of 0.05 ( two sided ) , a power of 0.80 and an expected DFS in Arm A of 0.65 at 5 years . This required 480 pts per Arm and 250 events . RESULTS As of March 27th 2006 , 486 pts were enrolled in arm A and 486 in arm B , 252 primary events were recorded and the median follow up was 53 months . DFS at 5 years was 0.67 in arm A vs 0.74 in arm B with an estimated Hazard Ratio ( HR ) of 0.80 ( 95 % CI : 0.62 - 1.03 , p = 0.079 ) . After adjustement by predefined balancing factors ( ER , Nodal and menopausal status ) the HR was 0.78 ( 95 % CIs : 0.61 - 1.00 ; p = 0.05 ) . As for OS , 117 deaths were observed with HR of 0.74 ( 95 % CIs : 0.51 - 1.07 , p = 0.10 ) . CONCLUSIONS Sequential E→T→CMF yields a borderline significant improvement of DFS . Follow up up date is still ongoing . [ Table : see text ] BACKGROUND AND PURPOSE Docetaxel is an active agent in the treatment of metastatic breast cancer . We evaluated the feasibility of docetaxel-based sequential and combination regimens as adjuvant therapies for patients with node-positive breast cancer . PATIENTS AND METHODS Three consecutive groups of patients with node-positive breast cancer or locally-advanced disease , aged < or = 70 years , received one of the following regimens : a ) sequential A-->T-->CMF : doxorubicin 75 mg/m2 q 3 weeks x 3 , followed by docetaxel 100 mg/m2 q 3 weeks x 3 , followed by i.v . CMF days 1 + 8 q 4 weeks x 3 ; b ) sequential accelerated A-->T-->CMF : A and T were administered at the same doses q 2 weeks ; c ) combination therapy : doxorubicin 50 mg/m2 + docetaxel 75 mg/m2 q 3 weeks x 4 , followed by CMF x 4 . When indicated , radiotherapy was administered during or after CMF , and tamoxifen started after the end of CMF . RESULTS Seventy-nine patients have been treated . Median age was 48 years . A 30 % rate of early treatment discontinuation was observed in patients receiving the sequential accelerated therapy ( 23 % during A-->T ) , due principally to severe skin toxicity . Median relative dose-intensity was 100 % in the three treatment arms . The incidence of G3-G4 major toxicities by treated patients , was as follows : skin toxicity a : 5 % ; b : 27 % ; c : 0 % ; stomatitis a : 20 % ; b : 20 % ; c : 3 % . The incidence of neutropenic fever was a : 30 % ; b : 13 % ; c : 48 % . After a median follow-up of 18 months , no late toxicity has been reported . CONCLUSIONS The accelerated sequential A-->T-->CMF treatment is not feasible due to an excess of skin toxicity . The sequential non accelerated and the combination regimens are feasible and under evaluation in a phase III trial of adjuvant therapy Within an ongoing multicentre phase 3 r and omised trial ( ELDA , cancertrials.gov ID : NCT00331097 ) , early breast cancer patients , 65 - 79 years old , with average to high risk of recurrence , are r and omly assigned to receive CMF ( cyclophosphamide 600 mg/m2 , methotrexate 40 mg/m2 , fluorouracil 600 mg/m2 , days 1 - 8 ) or docetaxel ( 35 mg/m2 days 1 - 8 - 15 ) , every 4 weeks . Here we report an unplanned safety analysis prompted by an amendment introducing creatinine clearance as a tool to adjust methotrexate dose . Before such change , 101 patients with a median age of 70 were r and omly assigned CMF  ( 53 patients ) or docetaxel ( 48 patients ) . At least one grade s 3 - 4 toxic event of any type was reported in 40 ( 75.5 % ) and 19 ( 39.6 % ) patients with CMF and docetaxel , respectively ( p=0.0002 ) . Grade s 3 - 4 hematological events were observed in 37 ( 69.8 % ) vs. 4 ( 8.3 % ) cases ( p<0.0001 ) and grade s 3 - 4 non-hematological toxicity in 12 ( 22.6 % ) vs. 15 ( 31.2 % ) patients ( p=0.11 ) , with CMF and docetaxel , respectively . A higher incidence of anemia , neutropenia , thrombocytopenia and febrile neutropenia was reported with CMF .  Constipation , mucositis , nausea and vomiting were more common with CMF ;  diarrhoea , abdominal pain , dysgeusia , neuropathy and liver toxicity were more frequent with docetaxel . No significant interaction was found between the occurrence of severe toxicity and baseline variables , including creatinine clearance and geriatric activity scales . In conclusion , weekly docetaxel appears to be less toxic than CMF in terms of hematological toxicity PURPOSE The aim of this study was to explore the effect of dose-dense sequential chemotherapy with or without paclitaxel primarily on disease-free survival ( DFS ) and secondarily on overall survival ( OS ) in patients with high-risk operable breast cancer . PATIENTS AND METHODS From June 1997 until November 2000 , 604 patients with T1 - 3N1M0 or T3N0M0 tumors were r and omized to three cycles of epirubicin 110 mg/m2 followed by three cycles of paclitaxel 250 mg/m2 followed by three cycles of ' intensified ' CMF ( cyclophosphamide 840 mg/m2 , methotrexate 47 mg/m2 and fluorouracil 840 mg/m2 ) ( group A ) , or to four cycles of epirubicin followed by four cycles of CMF , as in group A ( group B ) . All cycles were given every 2 weeks with granulocyte colony-stimulating factor support . RESULTS A total of 595 patients were eligible .  Median follow-up was 61.7 months for group A and 62 months for group B. The 3-year DFS was 80 % in group A and 77 % in group B. Survival rates were 93 % and 90 % , respectively . The effect of treatment on the hazard of death was different according to hormonal receptor status . More specifically , in patients with negative receptor status the hazard of death was significantly higher for group B ( hazard ratio 2.42 ) . Both regimens were well tolerated and severe acute side-effects were infrequent . No cases of severe cardiotoxicity or acute leukemia were recorded . CONCLUSIONS The present study failed to demonstrate a significant difference in DFS or OS between the two treatment groups . However , our study has shown clearly that high-dose paclitaxel can be safely incorporated to dose-dense sequential chemotherapy BACKGROUND Taxanes are among the most active drugs for the treatment of metastatic breast cancer , and , as a consequence , they have also been studied in the adjuvant setting . METHODS After breast cancer surgery , women with lymph node-positive disease were r and omly assigned to treatment with fluorouracil , epirubicin , and cyclophosphamide ( FEC ) or with FEC followed by weekly paclitaxel ( FEC-P ) . The primary endpoint of study -5-year disease-free survival (DFS)-was assessed by Kaplan-Meier analysis . Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular ( hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization ) markers . Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates : age , menopausal status , tumor size , lymph node status , type of chemotherapy , tumor size , positive lymph nodes , HER2 status , and hormone receptor status . All statistical tests were two-sided . RESULTS Among the 1246 eligible patients , estimated rates of DFS at 5 years were 78.5 % in the FEC-P arm and 72.1 % in the FEC arm ( difference = 6.4 % , 95 % confidence interval [ CI ] = 1.6 % to 11.2 % ; P = .006 ) . FEC-P treatment was associated with a 23 % reduction in the risk of relapse compared with FEC treatment ( 146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm , hazard ratio [ HR ] = 0.77 , 95 % CI = 0.62 to 0.95 ; P = .022 ) and a 22 % reduction in the risk of death ( 73 and 95 deaths , respectively , HR = 0.78 , 95 % CI = 0.57 to 1.06 ; P = .110 ) . Among the 928 patients for whom tumor sample s were central ly analyzed , type of chemotherapy ( FEC vs FEC-P ) ( P = .017 ) , number of involved axillary lymph nodes ( P < .001 ) , tumor size ( P = .020 ) , hormone receptor status ( P = .004 ) , and HER2 status ( P = .006 ) were all associated with DFS . We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment . CONCLUSIONS Among patients with operable breast cancer , FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy Purpose : The European Cooperative Trial in Operable breast cancer ( ECTO ) r and omly tested whether efficacy of adjuvant doxorubicin followed by i.v . cyclophosphamide , methotrexate , and fluorouracil ( CMF ; doxorubicin → CMF , arm A ) could be improved by adding paclitaxel ( doxorubicin/paclitaxel → CMF ) as adjuvant ( arm B ) or primary systemic therapy ( PST , arm C ) . We report here feasibility , tolerability , locoregional antitumor activity , and breast conservation rate . Methods : A total of 1,355 women entered the study . Feasibility and safety were compared in arm A versus arms B plus C. Surgical findings were compared in arms A plus B versus arm C. Results : Grade 3 or 4 National Cancer Institute toxicities were low ( < 5 % ) in all arms . Neuropathy was more frequent in the paclitaxel-containing arms ( grade 2 , 20.5 % versus 5.0 % ; grade 3 , 1.3 % versus 0.2 % ) . At 31 months of follow-up , asymptomatic drop of left ventricular ejection fraction was similar in all arms , whereas symptomatic cardiotoxicity was recorded in three patients ( 0.5 % ) in A and in three patients ( 0.3 % ) in B plus C. PST induced clinical complete plus partial remission in 78 % , with an in-breast pathologic complete response rate of 23 % and an in-breast plus axilla pathologic complete response rate of 20 % . In the multivariate analysis , only estrogen receptor ( ER ) status was significantly associated with pathologic complete response ( odds ratio for ER negative , 5.77 ; 95 % confidence interval , 3.49 - 9.52 ; P < 0.0001 ) . PTS induced a significant axillary downstaging ( P < 0.001 ) , and breast sparing surgery was feasible in 65 % versus 34 % ( P < 0.001 ) . Conclusions : Doxorubicin/paclitaxel → CMF is feasible , safe , and well tolerated . Given as PST , it is markedly active , allowing for breast-sparing surgery in a large fraction of patients BACKGROUND We compared docetaxel plus doxorubicin and cyclophosphamide ( TAC ) with fluorouracil plus doxorubicin and cyclophosphamide ( FAC ) as adjuvant chemotherapy for operable node-positive breast cancer . METHODS We r and omly assigned 1491 women with axillary node-positive breast cancer to six cycles of treatment with either TAC or FAC as adjuvant chemotherapy after surgery . The primary end point was disease-free survival . RESULTS At a median follow-up of 55 months , the estimated rates of disease-free survival at five years were 75 percent among the 745 patients r and omly assigned to receive TAC and 68 percent among the 746 r and omly assigned to receive FAC , representing a 28 percent reduction in the risk of relapse ( P=0.001 ) in the TAC group . The estimated rates of overall survival at five years were 87 percent and 81 percent , respectively . Treatment with TAC result ed in a 30 percent reduction in the risk of death ( P=0.008 ) . The incidence of grade 3 or 4 neutropenia was 65.5 percent in the TAC group and 49.3 percent in the FAC group ( P<0.001 ) ; rates of febrile neutropenia were 24.7 percent and 2.5 percent , respectively ( P<0.001 ) . Grade 3 or 4 infections occurred in 3.9 percent of the patients who received TAC and 2.2 percent of those who received FAC ( P=0.05 ) ; no deaths occurred as a result of infection . Two patients in each group died during treatment . Congestive heart failure and acute myeloid leukemia occurred in less than 2 percent of the patients in each group . Quality -of-life scores decreased during chemotherapy but returned to baseline levels after treatment . CONCLUSIONS Adjuvant chemotherapy with TAC , as compared with FAC , significantly improves the rates of disease-free and overall survival among women with operable node-positive breast cancer 596 Background : Role of weekly T in adjuvant treatment of breast cancer is presently under evaluation in several studies like GEICAM 9906 . OBJECTIVE This study compared differences in toxicity profile between arms . METHODS Patients ( pt ) with operable APBC , age : 18 - 70 , Karnofsky ≥ 90 , adequate bone marrow , renal and hepatic function , were r and omized to receive 6 FEC cy ( Fluorouracil 600 mg/m2 [ F ] , Epirubicin 90 mg/m2 [ E ] , Cyclophosphamide 600 mg/m2 [ C ] ) day 1 every 3 weeks ( Arm A ) or 4 cy of the same schedule followed by 8 weekly doses of T 100 mg/m2 ( Arm B ) . 1.249 pt were recruited in 30 months . 633 pt in arm A and 610 pt in arm B were analyzed for toxicity . Study was conducted as per GCP/ICH with 100 % source data verification . RESULTS  Median age was 50.4 years ( Arm A ) vs 50.2 ( Arm B ) . Median number of FEC cy ( A vs B ) and T doses were 6 ( range 1 - 6 ) vs 4 ( range 1 - 4 ) and 8 ( range 1 - 8 ) , respectively . No statistical differences were found between relative dose-intensities ( RDI ) of E ( 98.8 vs 98.8 % ) and C ( 99.1 vs 99.1 % ) . Median RDI of T was 99.5 % . FEC administration : febrile neutropenia ( FN ) rate was statistically higher in arm A ( 9.3 vs 5.1 % pt ; p=0.004 ) . Statistical differences were observed in ( % pt ) : G3/4 neutropenia ( 30 vs 20.5 % ) , G3 leukopenia ( 10.6 vs 7.4 % ) and G3 mucositis ( 5.4 vs 3 % ) . No statistical differences were observed in ( % pt ) : G3 nausea ( 5.8 vs 5.4 % ) and G3 vomiting ( 9.6 vs 7.4 % ) . T administration : 0.5 % of pt had FN . G3/4 neutropenia/ leukopenia occurred in 12.1 % of pt . G2 neuropathy ( sensory ) and asthenia were present in 21.3 and 23.4 % of pt , respectively . One sudden death ( 0.2 % ) occurred in Am A and 4 ( 0.7 % ) in arm B ( 2 of them late events ) ( p=0.294 ) . CONCLUSIONS Analysis of 1243 pt suggests treatment with FEC x 4 followed by T is associated with less severe neutropenia and FN events , but induces more peripheral neuropathy and asthenia . No significant financial relationships to disclose PURPOSE The primary aim of National Surgical Adjuvant Breast and Bowel Project ( NSABP ) B-28 was to determine whether four cycles of adjuvant paclitaxel ( PTX ) after four cycles of adjuvant doxorubicin/cyclophosphamide ( AC ) will prolong disease-free survival ( DFS ) and overall survival ( OS ) compared with four cycles of AC alone in patients with resected operable breast cancer and histologically positive axillary nodes . PATIENTS AND METHODS Between August 1995 and May 1998 , 3,060 patients were r and omly assigned ( AC , 1,529 ; AC followed by PTX [ AC -- > PTX ] , 1,531 ) . Patients > or = 50 years and those younger than 50 years with estrogen receptor ( ER ) or progesterone receptor ( PR ) -positive tumors also received tamoxifen for 5 years , starting with the first dose of AC . Postlumpectomy radiotherapy was m and ated . Postmastectomy or regional radiotherapy was prohibited . Median follow-up is 64.6 months . RESULTS The addition of PTX to AC significantly reduced the hazard for DFS event by 17 % ( relative risk [ RR ] , 0.83 ; 95 % CI , 0.72 to 0.95 ; P = .006 ) . Five-year DFS was 76 % + /- 2 % for patients r and omly assigned to AC -- > PTX compared with 72 % + /- 2 % for those r and omly assigned to AC . Improvement in OS was small and not statistically significant ( RR , 0.93 ; 95 % CI , 0.78 to 1.12 ; P = .46 ) . Five-year OS was 85 % + /- 2 % for both groups . Subset analysis of the effect of paclitaxel according to hormone receptors or tamoxifen administration did not reveal statistically significant interaction ( for DFS , P = .30 and P = .44 , respectively ) . Toxicity with the AC -- > PTX regimen was acceptable for the adjuvant setting . CONCLUSION The addition of PTX to AC result ed in significant improvement in DFS but no significant improvement in OS with acceptable toxicity . No significant interaction between treatment effect and receptor status or tamoxifen administration was observed PURPOSE To assess whether the addition of epirubicin ( EPI ) therapy to prolonged treatment with tamoxifen ( TAM ) improves relapse-free and overall survival in postmenopausal women with node-positive primary breast cancer . PATIENTS AND METHODS Six hundred four patients entered onto a r and omized clinical trial were allocated to receive TAM 20 mg/d for 4 years or TAM 20 mg/d for 4 years plus EPI 50 mg/m(2 ) intravenously on days 1 and 8 every 4 weeks for six cycles . Analysis was performed according to allocated treatment , with all r and omized patients included ( intention to treat ) , irrespective of eligibility status . RESULTS After a median follow-up period of 5.7 years , an improvement in relapse-free survival ( RFS ) was observed for the TAM and EPI-treated patients , compared with those who received TAM alone . The unadjusted hazard ratio was 0.72 ( 95 % confidence interval , 0.54 to 0.96 ) , with a corresponding reduction in the odds of recurrence of 27.9 % ( SD , 12 . 3 ) , which was statistically significant ( P = .023 ) . Adjustment for prognostic and /or predictive factors did not material ly affect the hazard ratio . No difference was observed in terms of overall survival ( reduction in odds of death , 11.9 % [ SD , 16.3 ] ; P = .46 ) . Combined chemohormonal treatment was associated with a higher incidence of acute side effects but without a clear increase in long-term cardiotoxicity . Twelve nonbreast second malignancies , including five hematologic malignancies ( two of which were cases of acute myelogenous leukemia ) , were observed . CONCLUSION The data show that combined chemohormonal treatment reduces the risk of relapse in postmenopausal patients with node-positive breast cancer . No evidence was found , however , for an improvement in overall survival . The size of benefit observed for both outcomes was consistent with that reported in the Early Breast Cancer Trialists ' Collaborative Group overview . The trial presented here , however , provides the first report of an improvement in RFS associated with the provision of a single cytotoxic drug in addition to prolonged TAM BACKGROUND We compared docetaxel with vinorelbine for the adjuvant treatment of early breast cancer . Women with tumors that overexpressed HER2/neu were also assigned to receive concomitant treatment with trastuzumab or no such treatment . METHODS We r and omly assigned 1010 women with axillary-node-positive or high-risk node-negative cancer to receive three cycles of docetaxel or vinorelbine , followed by ( in both groups ) three cycles of fluorouracil , epirubicin , and cyclophosphamide . The 232 women whose tumors had an amplified HER2/neu gene were further assigned to receive or not to receive nine weekly trastuzumab infusions . The primary end point was recurrence-free survival . RESULTS Recurrence-free survival at three years was better with docetaxel than with vinorelbine ( 91 percent vs. 86 percent ; hazard ratio for recurrence or death , 0.58 ; 95 percent confidence interval , 0.40 to 0.85 ; P=0.005 ) , but overall survival did not differ between the groups ( P=0.15 ) . Within the subgroup of patients who had HER2/neu-positive cancer , those who received trastuzumab had better three-year recurrence-free survival than those who did not receive the antibody ( 89 percent vs. 78 percent ; hazard ratio for recurrence or death , 0.42 ; 95 percent confidence interval , 0.21 to 0.83 ; P=0.01 ) . Docetaxel was associated with more adverse effects than was vinorelbine . Trastuzumab was not associated with decreased left ventricular ejection fraction or cardiac failure . CONCLUSIONS Adjuvant treatment with docetaxel , as compared with vinorelbine , improves recurrence-free survival in women with early breast cancer . A short course of trastuzumab administered concomitantly with docetaxel or vinorelbine is effective in women with breast cancer who have an amplified HER2/neu gene . ( International St and ard R and omised Controlled Trial number , IS RCT N76560285 . ) 620 Background : For patients ( pts ) with node-positive BC , TAC confers signficant disease-free and overall survival benefits vs FAC ( 5-fluorouracil , doxorubicin , cyclophosphamide ) , but with a higher rate of febrile neutropenia ( Martin , SABCS 2003 ab 43 ) . In our study of TAC vs FAC for node-negative BC , we performed an interim safety analysis to assess the impact of GF support on the incidence of TAC-related adverse events . METHODS Following surgery , patients ( pts ) with operable , high-risk ( St Gallen , 1998 ) , node-negative BC , 18 - 70 yr old , KPS ≥ 80 % , and adequate hematologic and organ function were r and omized to FAC  ( F 500 mg/m2 , A 50 mg/m2 , C 500 mg/m2 ) or TAC ( T 75 mg/m2 , A 50 mg/m2 , C 500 mg/m2 ) day 1 every 3 wk for 6 cycles . After enrollment of 224 pts , the study was amended to require prophylactic G-CSF for pts subsequently treated with TAC , but not FAC . The present analysis assessed the impact of G-CSF on the incidence of febrile neutropenia ( FN ; fever ≥ grade 2 with gr 4 neutropenia ) and other gr 3/4 toxicities in pts treated with TAC . RESULTS At the cut-off date for this analysis , 448 pts had been enrolled : 124 received FAC ( 111 prior to amendment ) and 124 TAC ( 109 without m and atory G-CSF [ TAC-G ] ; 115 with G-CSF [ TAC+G ] ) . For pts receiving FAC  , the incidence of FN ( % pts ) was 1.3 % ( 0.9 % pre- , 1.7 % post-amendment ) ; other gr 3/4 adverse events were observed in 26.7 % ( 27 % pre- , 26.5 % post-amendment ) . Among pts treated with TAC , the rates of FN were 23.8 % for TAC-G ( 95 % CI : 15.9 - 31.9 % ) and 3.5 % for TAC+G ( 1.0 - 8.7 % ) ; the rates of other gr 3/4 toxicities were 50.4 % for TAC-G ( 41.1 - 59.8 % ) and 20 % for TAC+G ( 12.7 - 27.3 % ) . The relative dose intensities for TAC-G vs TAC+G , respectively , were T : 92 % vs 96 % , A : 93 % vs 97 % , C : 93 % vs 97 % . CONCLUSION Within the limitations of a non-r and omized comparison , the use of G-CSF beginning with the first cycle of TAC substantially reduces the incidence of FN and other gr 3/4 toxicities and enables maintenance of chemotherapy dose intensity for women with early stage breast cancer . The adverse event rate with TAC+G is similar to that of FAC . [ Table : see text ] PURPOSE Southwest Oncology Group (SWOG)/Intergroup study 9623 was undertaken to compare treatment with an anthracycline-based adjuvant chemotherapy regimen followed by high-dose chemotherapy ( HDC ) with autologous hematopoietic progenitor cell support ( AHPCS ) with a modern dose-dense dose-escalated ( nonst and ard ) regimen including both an anthracycline and a taxane . PATIENTS AND METHODS Participants in this phase III r and omized study had operable breast cancer involving four or more axillary lymph nodes and had completed mastectomy or breast-conserving surgery . Patients were r and omly assigned to receive four cycles of doxorubicin and cyclophosphamide followed by HDC with AHPCS or to receive sequential dose-dense and dose-escalated chemotherapy with doxorubicin , paclitaxel , and cyclophosphamide . The primary end point of this study was disease-free survival ( DFS ) . RESULTS Among 536 eligible patients , there was no significant difference between the two arms for DFS or overall survival ( OS ) . Estimated five-year DFS was 80 % ( 95 % CI , 76 % to 85 % ) for dose-dense therapy and 75 % ( 95 % CI , 69 % to 80 % ) for transplantation . Estimated 5-year OS was 88 % ( 95 % CI , 84 % to 92 % ) for dose-dense therapy and 84 % ( 95 % CI , 79 % to 88 % ) for transplantation . CONCLUSION There is no evidence that transplantation was superior to dose-dense dose-escalated therapy . Transplantation was associated with an increase in toxicity and a possibly inferior outcome , although the hazard ratios were not significantly different from 1 BACKGROUND Docetaxel is more effective than doxorubicin for patients with advanced breast cancer . The Breast International Group 02 - 98 r and omized trial tested the effect of incorporating docetaxel into anthracycline-based adjuvant chemotherapy and compared sequential vs concurrent administration of doxorubicin and docetaxel . METHODS Patients with lymph node-positive breast cancer ( n = 2887 ) were r and omly assigned to one of four treatments : 1 ) sequential control ( four cycles of doxorubicin at 75 mg/m2 , followed by three cycles of cyclophosphamide , methotrexate , and 5-fluorouracil [ CMF ] ) ; 2 ) concurrent control ( four cycles of doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/m2 , followed by three cycles of CMF ) ; 3 ) sequential docetaxel ( three cycles of doxorubicin at 75 mg/m2 , followed by three cycles of docetaxel at 100 mg/m2 , followed by three cycles of CMF ) ; 4 ) concurrent docetaxel ( four cycles of doxorubicin at 50 mg/m2 plus docetaxel at 75 mg/m2 , followed by three cycles of CMF ) . The primary comparison evaluated the efficacy of including docetaxel regardless of schedule and was planned after 1215 disease-free survival ( DFS ) events ( ie , relapse , second primary cancer , or death from any cause ) . Docetaxel and control treatment groups were compared by log-rank tests , and hazard ratios ( HR ) of DFS events were calculated by Cox modeling . All statistical tests were two-sided . RESULTS Due to a lower-than-anticipated rate of relapse , this analysis was performed after 5 years with 732 events . Patients in control arms had a 5-year DFS of 73 % ( 95 % confidence interval [ CI ] = 70 % to 75 % ) . Docetaxel treatment result ed in an improvement in DFS of borderline statistical significance compared with control treatment ( HR = 0.86 , 95 % CI = 0.74 to 1.00 ; P = .05 ) . However , DFS in the sequential docetaxel arm was better than that in the concurrent docetaxel arm ( HR = 0.83 , 95 % CI = 0.69 to 1.00 ) and in the sequential control arm ( HR = 0.79 , 95 % CI = 0.64 to 0.98 ) . CONCLUSIONS Incorporating docetaxel into anthracycline-based therapy result ed in an improvement in DFS that was of borderline statistical significance . However , important differences may be related to doxorubicin and docetaxel scheduling , with sequential but not concurrent administration , appearing to produce better DFS than anthracycline-based chemotherapy PURPOSE The combination of doxorubicin and cyclophosphamide ( AC ) is a st and ard adjuvant chemotherapy regimen . Studies of docetaxel and cyclophosphamide ( TC ) in metastatic breast cancer ( MBC ) showed promise in MBC . In 1997 , we initiated a r and omized adjuvant trial of TC compared with st and ard-dose AC with a primary end point of disease-free survival ( DFS ) . PATIENTS AND METHODS Patients were eligible if they had stage I to III operable invasive breast cancer with complete surgical excision of the primary tumor . Between June 1997 and December 1999 , 1,016 patients were r and omly assigned to four cycles of either st and ard-dose AC ( 60 and 600 mg/m2 , respectively ; n = 510 ) or TC ( 75 and 600 mg/m2 , respectively ; n = 506 ) , administered intravenously every 3 weeks as adjuvant chemotherapy . Radiation therapy ( as indicated ) and tamoxifen , for patients with hormone receptor-positive disease , were administered after completion of chemotherapy . RESULTS Both treatment groups ( TC and AC ) were well balanced with respect to major prognostic factors . Patients were observed through 2005 for a median of 5.5 years . At 5 years , DFS rate was significantly superior for TC compared with AC ( 86 % v 80 % , respectively ; hazard ratio [ HR ] = 0.67 ; 95 % CI , 0.50 to 0.94 ; P = .015 ) . Overall survival rates for TC and AC were 90 % and 87 % , respectively ( HR = 0.76 ; 95 % CI , 0.52 to 1.1 ; P = .13 ) . More myalgia , arthralgia , edema , and febrile neutropenia occurred on the TC arm ; more nausea and vomiting occurred on the AC arm as well as one incident of congestive heart failure . CONCLUSION At 5 years , TC was associated with a superior DFS and a different toxicity profile compared with AC CONTEXT Adjuvant chemotherapy with new cytotoxic agents for breast cancer must be properly assessed for toxicity . OBJECTIVE To describe adverse events associated with adjuvant chemotherapy for breast cancer , which led to premature termination of a clinical trial . DESIGN , SETTING , AND PATIENTS We conducted a prospect i ve r and omized multicenter study ( Reposant sur des Arguments Pronostiques et Predictifs [RAPP]-01 ) to compare the effectiveness of 2 chemotherapy regimens . Patients ( women aged 18 - 70 years ) had primary unilateral breast cancer and either a moderate number of positive axillary lymph nodes ( < or =3 ) or no positive axillary lymph nodes ( N0 ) , but were at a high risk of relapse . Patients were treated at 11 French cancer referral centers from June 1999 through January 2003 . Primary prophylaxis for febrile neutropenia was not recommended in the study protocol . INTERVENTIONS Doxorubicin , 50 mg/m2 , plus docetaxel , 75 mg/m2 , or doxorubicin , 60 mg/m2 , plus cyclophosphamide , 600 mg/m2 , given postoperatively for 4 courses . MAIN OUTCOME MEASURES The main end point was the disease-free survival rate at 5 years , as estimated using the Kaplan-Meier product limit method . Secondary end points included safety , which is the focus of this article , and overall survival . RESULTS A total of 627 women were enrolled . Median follow-up is currently too short ( 24 months ) to analyze the primary end point . The trial was terminated prematurely when 2 deaths related to drug toxicity and 1 case of perforative peritonitis occurred among patients with febrile neutropenia , all in the doxorubicin-docetaxel group . The incidence of febrile neutropenia was significantly higher with the doxorubicin-docetaxel regimen ( 40.8 % ) than with the doxorubicin-cyclophosphamide regimen ( 7.1 % ) ( P<.001 ) . CONCLUSIONS A high risk of life-threatening complications associated with the doxorubicin-docetaxel regimen was found in this open-label controlled trial . The doxorubicin-docetaxel combination should not be considered as an alternative to the doxorubicin-cyclophosphamide regimen outside carefully design ed studies that include primary prophylaxis for febrile neutropenia PURPOSE The PACS 01 trial compared six cycles of fluorouracil , epirubicin , and cyclophosphamide ( FEC ) with a sequential regimen of three cycles of FEC followed by three cycles of docetaxel ( FEC-D ) as adjuvant treatment for women with node-positive early breast cancer . PATIENTS AND METHODS Between June 1997 and March 2000 , 1,999 patients with operable node-positive breast cancer were r and omly assigned to either FEC every 21 days for six cycles , or three cycles of FEC followed by three cycles of docetaxel , both given every 21 days . Hormone-receptor-positive patients received tamoxifen for 5 years after chemotherapy . The primary end point was 5-year disease-free survival ( DFS ) . RESULTS Median follow-up was 60 months . Five-year DFS rates were 73.2 % with FEC and 78.4 % with FEC-D ( unadjusted P = .011 ; adjusted P = .012 ) . Multivariate analysis adjusted for prognostic factors showed an 18 % reduction in the relative risk of relapse with FEC-D.  Five-year overall survival rates were 86.7 % with FEC and 90.7 % with FEC-D , demonstrating a 27 % reduction in the relative risk of death ( unadjusted P = .014 ; adjusted P = .017 ) . The incidence of grade 3 to 4 neutropenia , the need for hematopoietic growth factor , and incidence of nausea/vomiting were higher with FEC . Docetaxel was associated with more febrile neutropenia in the fourth cycle , stomatitis , edema , and nail disorders . Though rare overall , there were fewer cardiac events after FEC-D ( P = .03 ) , attributable mainly to the lower anthracycline cumulative dose . CONCLUSION Sequential adjuvant chemotherapy with FEC followed by docetaxel significantly improves disease-free and overall survival in node-positive breast cancer patients and has a favorable safety profile PURPOSE The combination of doxorubicin and cyclophosphamide ( AC ) is a st and ard adjuvant regimen . Doxorubicin and docetaxel ( AT ) is one of the most active cytotoxic regimens for metastatic breast cancer . The purpose of this trial was to determine whether adjuvant AT improved disease-free survival compared with AC in operable breast cancer . PATIENTS AND METHODS Women with invasive breast cancer were eligible if there were one to three positive lymph nodes or if the node-negative tumor was greater than 1 cm . Patients were r and omly assigned after surgery to receive doxorubicin ( 60 mg/m(2 ) ) plus either cyclophosphamide ( 600 mg/m(2 ) ; AC ) or docetaxel ( 60 mg/m(2 ) ; AT ) given every 3 weeks for four cycles , followed by hormone therapy for patients with estrogen receptor ( ER ) and /or progesterone receptor (PR)-positive tumors . RESULTS There were 2,882 eligible patients enrolled . After a median follow-up of 79.5 months , there was no significant difference in disease-free survival ( DFS ; 85 % in both arms ) or overall survival ( 91 % v 92 % ) at 5 years . The hazard ratio for AC versus AT was 1.02 ( 95 % CI for DFS , 0.86 to 1.22 ; P = .78 ) . In an exploratory analysis of prespecified stratification factors by ER and PR expression there were trends toward improved DFS for AT in ER/PR-negative disease . Grade 3 neutropenia associated with fever or infection occurred more often with AT ( 26 % v 10 % ; P < .05 ) . CONCLUSION AT did not improve DFS or overall survival in this population , and was associated with more toxicity
BACKGROUND Adjuvant chemotherapy improves survival in pre- and post-menopausal women with early breast cancer .
Taxanes are highly active chemotherapy agents in metastatic breast cancer .
Their role in early breast cancer was examined in this review .
OBJECTIVES To review the r and omised evidence comparing taxane containing chemotherapy regimens with non-taxane containing chemotherapy regimens as adjuvant treatment of pre- or post-menopausal women with early breast cancer .