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. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. Does timing of adjuvant chemotherapy influence the prognosis after early breast cancer? Results of the Danish Breast Cancer Cooperative Group (DBCG) Does timing of adjuvant chemotherapy for early breast cancer influence survival? Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. Impact of Administration‐Related Factors on Outcome of Adjuvant Chemotherapy for Primary Breast Cancer Effect of timing of initiation of adjuvant chemotherapy on disease-free survival in breast cancer Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. Time to initiation of adjuvant chemotherapy in patients with rapidly proliferating early breast cancer.
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 To determine the influence of the epirubicin dose in operable node-positive breast cancer patients with factors of poor prognosis . PATIENTS AND METHODS Between April 1990 and July 1993 , 565 operable breast cancer patients with either more than three positive nodes or between one and three positive nodes with Scarff Bloom Richardson grade > or = 2 and hormone receptor negativity were r and omized after surgery to receive either fluorouracil 500 mg/m(2 ) , epirubicin 50 mg/m(2 ) , and cyclophosphamide 500 mg/m(2 ) every 21 days for six cycles ( FEC 50 ) or the same regimen except with epirubicin dose of 100 mg/m(2 ) ( FEC 100 ) . Postmenopausal patients received tamoxifen 30 mg/d for 3 years at the beginning of chemotherapy . Radiotherapy was delivered at the end of chemotherapy in both groups . RESULTS The median follow-up was 67 months . The 5-year disease-free survival ( DFS ) was 54.8 % with FEC 50 and 66.3 % with FEC 100 ( P = .03 ) . The 5-year overall survival ( OS ) was 65.3 % and 77.4 % , respectively ( P = .007 ) . The mean relative dose-intensity was similar in the two groups ( 90.3 % and 86.1 % , respectively ) . Neutropenia and anemia were significantly more frequent in FEC 100 ( P < 10(-3 ) ) , as were nausea-vomiting ( P = .008 ) and stomatitis and alopecia ( P < 10(-3 ) ) . Nine cases of grade 3 infection occurred only with FEC 100 , and no toxic deaths occurred . Three cases of acute cardiac toxicity were observed ( FEC50 = 1 , FEC100 = 2 ) and 10 patients ( FEC50 = 6 , FEC100 = 4 ) presented delayed cardiac dysfunctions . Two cases of secondary leukemia were observed ( acute lymphatic leukemia with FEC 50 and acute myelogenous leukemia with FEC 100 ) . CONCLUSION After 5 years of follow-up , the increased epirubicin dose led to a significant benefit in terms of DFS and OS , with a high survival rate among patients with poor-prognosis breast cancer PURPOSE To determine the relative efficacy of an intensive cyclophosphamide , epirubicin , and fluorouracil ( CEF ) adjuvant chemotherapy regimen compared with cyclophosphamide , methotrexate , and fluorouracil ( CMF ) in node-positive breast cancer . PATIENTS AND METHODS Premenopausal women with node-positive breast cancer were r and omly allocated to receive either cyclophosphamide 100 mg/m2 orally days 1 through 14 ; methotrexate 40 mg/m2 intravenously ( i.v . ) days 1 and 8 ; and fluorouracil 600 mg/m2 i.v . days 1 and 8 or cyclophosphomide 75 mg/m2 orally days 1 through 14 ; epirubicin 60 mg/m2 i.v . days 1 and 8 ; and fluorouracil 500 mg/m2 i.v . days 1 and 8 . Each cycle was administered monthly for 6 months . Patients administered CEF received antibiotic prophylaxis with cotrimoxazole two tablets twice a day for the duration of chemotherapy . RESULTS The median follow-up was 59 months . One hundred sixty-nine of the 359  CMF patients developed recurrence compared with 132 of the 351 CEF patients . The corresponding 5-year relapse-free survival rates were 53 % and 63 % , respectively ( P = .009 ) . One hundred seven CMF patients died compared with 85 CEF patients . The corresponding 5-year actuarial survival rates were 70 % and 77 % , respectively ( P = .03 ) . The rate of hospitalization for febrile neutropenia was 1.1 % in the CMF group compared with 8.5 % in the CEF group . There was one case of congestive heart failure in a patient who received CMF compared with none in the CEF group . Acute leukemia occurred in five patients in the CEF group . CONCLUSION The results of this trial show the superiority of CEF over CMF in terms of both disease-free and overall survival in premenopausal women with axillary node-positive breast cancer The purpose of this study was to examine the effect on survival of delaying the start of adjuvant chemotherapy for early breast cancer for up to 3 months after surgery . In the nation-wide clinical trials of the Danish Breast Cancer Cooperative Group , 7501 breast cancer patients received chemotherapy within 3 months of surgery between 1977 and 1999 : 352 with classical cyclofosfamide , metotrexate and 5-fluorouracil ( CMF ) ; 6065 with CMF i.v . and 1084 with cyclofosfamide , epirubicin and 5-fluorouracil . For the analysis , the time between surgery and the start of chemotherapy was divided into four strata ( 1–3 , 4 , 5 and 6–13 weeks ) . The results show that within the three groups of chemotherapy , there was an even distribution of known prognostic factors across the four strata of initiation of chemotherapy . There was no pattern indicating a benefit from early start of chemotherapy . No significant interactions were found for subgroups of patients with a poorer prognosis ( many involved lymph nodes , high- grade malignancies or hormone receptor negative disease ) . In conclusion , we have found no evidence for a survival benefit due to early initiation of adjuvant chemotherapy within the first 2–3 months after surgery PURPOSE Theoretically , patients with early breast cancer might benefit from starting adjuvant chemotherapy soon after surgery , and this would have important clinical implication s. We have addressed this question from a large , single-center data base in which the majority of patients received anthracyclines . PATIENTS AND METHODS A total of 1161 patients from a prospect ively maintained data base treated with adjuvant chemotherapy for early breast cancer at the Royal Marsden Hospital ( London , United Kingdom ) , including 686 ( 59 % ) receiving anthracyclines , were retrospectively analyzed . The disease-free survival ( DFS ) and overall survival ( OS ) of the 368 patients starting chemotherapy within 21 days of surgery ( group A ) were compared with those of the 793 patients commencing chemotherapy > or= 21 days after surgery ( group B ) . Median follow-up time was 39 months ( range , 12 to 147 months ) . RESULTS No significant difference in 5-year DFS was found between the two groups overall ( 70 % for group A v 72 % for group B ; P = .4 ) or in any subgroup . Likewise , there was no difference in 5-year OS ( 82 % for group A v 84 % for group B ; P = .2 ) or when the interval to the start of chemotherapy was considered as a continuous variable ( P = .4 ) . CONCLUSION We have been unable to identify any significant survival benefit from starting adjuvant chemotherapy early after surgery , either overall or in any subset of patients CONTEXT Breast cancer estrogen-receptor ( ER ) status is useful in predicting benefit from endocrine therapy . It may also help predict which patients benefit from advances in adjuvant chemotherapy . OBJECTIVE To compare differences in benefits from adjuvant chemotherapy achieved by patients with ER-negative vs ER-positive tumors . DESIGN , SETTING , AND PATIENTS Trial data from the Cancer and Leukemia Group B and US Breast Cancer Intergroup analyzed ; patient outcomes by ER status compared using hazards over time and multivariate models . R and omized trials comparing ( 1 ) : 3 regimens of cyclophosphamide , doxorubicin , and fluorouracil ( January 1985 to April 1991 ) ; ( 2 ) 3 doses of doxorubicin concurrent with cyclophosphamide , with or without subsequent paclitaxel ( May 1994 to April 1997 ) ; ( 3 ) sequential doxorubicin , paclitaxel , and cyclophosphamide with concurrent doxorubicin and cyclophosphamide followed by paclitaxel , and also 3-week vs 2-week cycles ( September 1997 to March 1999 ) . A total of 6644 node-positive breast cancer patients received adjuvant treatment . MAIN OUTCOME MEASURES Disease-free and overall survival . RESULTS For ER-negative tumors , chemotherapy improvements reduced the relative risk of recurrence by 21 % , 25 % , and 23 % in the 3 studies , respectively , and 55 % comparing the lowest dose in the first study with biweekly cycles in the third study . Corresponding relative risk reductions for ER-positive tumors treated with tamoxifen were 9 % , 12 % , and 8 % in the 3 studies , and 26 % overall . The overall mortality rate reductions associated with chemotherapy improvements were 55 % and 23 % among ER-negative and ER-positive patients , respectively . All individual ER-negative comparisons and no ER-positive comparisons were statistically significant . Absolute benefits due to chemotherapy were greater for patients with ER-negative compared with ER-positive tumors : 22.8 % more ER-negative patients survived to 5 years disease-free if receiving chemotherapy vs 7.0 % for ER-positive patients ; corresponding improvements for overall survival were 16.7 % vs 4.0 % . CONCLUSION Among patients with node-positive tumors , ER-negative breast cancer , biweekly doxorubicin/cyclophosphamide plus paclitaxel lowers the rate of recurrence and death by more than 50 % in comparison with low-dose cyclophosphamide , doxorubicin , and fluorouracil as used in the first study The  survival of 229 patients treated with adjuvant i.v . cyclophosphamide , methotrexate , and 5-fluorouracil ( CMF ) after surgery for primary breast cancer was analyzed according to three administration-related factors : total number of cycles received , time elapsed between surgery and start of chemotherapy , and dose intensity of treatment . All parameters were found to be significantly associated with survival of patients in a univariate analysis . Multivariate analysis confirmed the independent prognostic importance of dose intensity and time between surgery and chemotherapy .  Although prospect i ve studies are needed to confirm such results , clinicians should be aware that unnecessary treatment delays or dose reductions in adjuvant chemotherapy for breast cancer are probably detrimental to patient survival Summary Four hundred and sixty patients with stage II or III breast cancer following regional therapy  were treated with an adjuvant combination chemotherapy consisting of fluorouracil , doxorubicin , and cyclophosphamide ( FAC ) . The relationship between the length of disease-free survival and length of delays in initiation of chemotherapy after surgery was evaluated . Patients were divided into four subgroups according to the length of delay in initiation of chemotherapy  ( < 10 weeks , 10–13 , 14–17 , and ≥ 18 weeks ) . Overall four year diseasefree survival was 64 % , 68 % , 60 % , and 63 % for patient groups with delays of < 10 weeks , 10–13 , 14–17 , or ≥ 18 weeks respectively ( p = 0.39 ) . There was no trend for longer delay in treatment to be associated with shorter disease-free survival , except in poor prognosis patients BACKGROUND Adjuvant combination chemotherapy with cyclophosphamide , methotrexate , and fluorouracil was administered after radical mastectomy for primary breast cancer with histologically positive axillary lymph nodes to assess whether it would improve treatment outcome as compared with surgery alone . Here we report a 20-year follow-up of this investigation . METHODS In 1973 we began a trial involving 386 women who were r and omly assigned to receive either no further treatment after radical mastectomy ( 179 women ) or 12 monthly cycles of adjuvant combination chemotherapy ( 207 women ) . All patients were admitted to the Istituto Nazionale Tumori in Milan , Italy .  Adjuvant chemotherapy was delivered in the outpatient clinic of the Division of Medical Oncology . RESULTS After a median follow-up of 19.4 years , the patients given adjuvant combination chemotherapy had significantly better rates of relapse-free survival ( unadjusted relative risk of relapse , 0.71 ; 95 percent confidence interval , 0.56 to 0.90 ; P = 0.004 ; adjusted relative risk , 0.65 , 95 percent confidence interval , 0.51 to 0.83 ; P < 0.001 ) and total survival ( unadjusted relative risk of death , 0.78 ; 95 percent confidence interval , 0.62 to 0.99 ; P = 0.04 ; adjusted relative risk , 0.76 ; 95 percent confidence interval , 0.60 to 0.97 ; P = 0.03 ) . With the exception of postmenopausal women , a benefit from adjuvant chemotherapy was evident in all subgroups of patients . CONCLUSIONS The long-term results of this trial of adjuvant combination chemotherapy confirm our preliminary observations of the effectiveness of the treatment in women with node-positive breast cancer AIM To evaluate the optimal time interval from definitive surgery to commencing chemotherapy in early breast cancer ( EBC ) . PATIENTS AND METHODS The relationship between time to initiation of adjuvant chemotherapy ( TTC ) , calculated in weeks , and disease-free ( DFS ) or overall survival ( OS ) , was assessed in 921 EBC patients with rapidly proliferating tumours ( thymidine labelling index > 3 % or G3 or Ki67 > 20 % ) , r and omised in a phase III clinical trial ( NCT01031030 ) to receive chemotherapy with or without anthracyclines ( epirubicin→cyclophosphamide , methotrexate and fluorouracil ( CMF ) versus CMF→epirubicin versus CMF ) . DFS , OS and 95 % confidence intervals ( 95 % confidence interval ( CI ) ) were calculated by the Kaplan-Meier method . Multivariate Cox analysis was performed in relation with nodal involvement , oestrogen receptor and human epidermal growth factor receptor 2 ( HER2 ) status , Ki67 value , type of adjuvant chemotherapy , menopausal status and tumour size . RESULTS At a median follow-up of 105 months ( range 2 - 188 ) , a prolonged TTC result ed in a significant increase in the risk of relapse : hazard ratio ( HR ) 1.15 ( 95 % CI 1.02 - 1.30 , p=0.019 ) . Using a backward elimination procedure , TTC , tumour size and nodal involvement remained significantly associated with DFS . A time-dependent receiver-operating characteristic ( ROC ) curve analysis was subsequently utilised to evaluate the best cut-off for TTC , identifying 7 weeks as the best threshold for longer OS ( p=0.043 ) : 8-year OS 88 % ( 95 % CI 85 - 90 ) for patients with a TTC < 7 weeks and 78 % ( 95 % CI 68 - 87 ) for the other group . CONCLUSIONS Our results confirm that a shorter TTC may reduce relapses and possibly also improve clinical outcome in patients with highly proliferating EBC
The relationship between survival and time to the start of adjuvant chemotherapy ( AC ) among breast cancer patients is unclear .
In order to illustrate the effect of delaying the initiation of AC on survival we have undertaken a systematic review and meta- analysis .