adjuvant chemotherapy substantially reduces the risk of recurrence and death among women with breast cancer [ 1 , 2 ] . anthracyclines and taxanes are mainstays in treating women with axillary node - positive breast cancer , and anthracycline - containing regimens have been shown to confer higher response rates and longer overall survival . large adjuvant taxane trials were designed to test whether there was a benefit to taxanes after , or combined with , anthracycline - containing regimens [ 46 ] . taxanes given sequentially or concurrently with anthracyclines have resulted in a significant improvement in disease - free and overall survival particularly in node - positive disease [ 47 ] . the semisynthetic taxoid docetaxel ( taxotere ) is probably the most active single agent in breast cancer , and results in advanced disease supported the development of trials including both paclitaxel and docetaxel , in combination or in sequence with anthracyclines , in the adjuvant setting . another study demonstrated that concurrent administration of docetaxel with doxorubicin and cyclophosphamide was more effective than fluorouracil , doxorubicin , and cyclophosphamide which led to regulatory approval of docetaxel for node - positive breast cancer . despite growing evidence [ 1114 ] that adding a taxane to conventional anthracycline - based regimens is one of the best therapeutic options for patients with node - positive disease   and taxanes are already approved in this indication , the optimal dose and schedule of taxane remain undetermined . hryniuk and levine , 1986 , first suggested that dose - dense adjuvant chemotherapy was correlated to disease - free survival in breast cancer . dose - intensity refers to administration of drugs with a shortened treatment interval . based on mathematical modeling of tumor growth [ 16 , 17 ] , shortening the interval between treatment cycles from every 3 weeks to 2 weeks , or using a dose - dense schedule , improved the outcome for patients with breast cancer with axillary node - positive disease . a randomized trial has demonstrated a significant survival for women , with positive lymph node breast cancer , whom are treated with dose - dense ( 2-week intervals ) chemotherapy accompanied by granulocyte colony stimulating factor ( g - csf ) support compared to conventional 3-week schedules . epirubicin is an anthracycline that may be less cardiotoxic and less myelosuppressive than doxorubicin , with no less of antitumor efficacy . the major adverse effects of epirubicin are acute dose - limiting haematological toxicity and cumulative dose - related cardiac toxicity . . the equimolar dose ratios of doxorubicin to epirubicin for myelosuppression and cardiotoxicity are 1  :  1.2 and 1  :  1.72.0 , respectively [ 20 , 21 ] . based on these findings and because of limited such studies in our country , we evaluated the safety and feasibility of dose - dense epirubicin and cyclophosphamide ( ec ) followed by docetaxel ( t ) with g - csf support in women with node - positive breast cancer . women eligible for the study were between 18 and 70 years of age and had undergone primary surgery ( i.e. , mastectomy , tumorectomy , or lumpectomy ) , with histologically proven invasive breast cancer and at least one histologically resected positive auxiliary lymph node ( size of tumor was assessed during surgery by pathological examination ) . eastern cooperative oncology group performance 0 - 1 , adequate biological functions ( hemoglobin > 10  g / dl ; absolute neutrophil count > 1.5  10/l ; platelets > 100  10/l ; serum creatinine clearance > 60  ml / min ; bilirubin < upper normal limit ( unl ) ; alkaline phosphatase ( alp ) < 5  unl and aminotransferases < 2.5  unl ) , and normal cardiac function were confirmed by clinical examination and left ventricular ejection fraction ( lvef > 50% ) . the hormone receptor assays were performed by immunohistochemistry ( ihc ) in all cases and a positive test defined by 1% . patients were excluded if they had even one of the following : t4 stage ( clinical and pathological ) , inflammatory breast cancer , ductal carcinoma in situ ( dcis ) , basal skin carcinoma , in situ cervical caner or anticancer therapy , other serious illness or medical conditions ( most notably cardiac and/or neurologic disorders ) , sensory or motor neuropathy of severity greater than who grade 1 , pregnant or breast - feeding patient or inadequate contraception , or any other condition that was considered to make the patient ineligible for this study by the investigators . the study was performed in accordance with the declaration of helsinki , and written informed consent was obtained prior to participation in the study . the study protocol was reviewed and approved by institutional review board of the shohadaye - tajrish hospital . eligible patients who had given a consent were invited to attend the assessment to provide baseline data as follows : full medical history and physical examination , hematology and biochemistry assessment ( such as renal and liver function tests ) , hormone receptor status , chest radiography and/or computed tomography ( ct ) scan , electrocardiogram and echocardiography , abdominal and pelvic ultrasound or computed tomography ( ct ) scan , bone scan , and other evaluation based on symptoms of patients . all patients received epirubicin ( 100  mg per square meter of body - surface area , given by slow intravenous push during a period of 5 to 15 minutes ) and cyclophosphamide ( 600  mg per square meter by intravenous infusion for 30 to 60 minutes ) every 2 weeks for four cycles followed by docetaxel ( 100  mg per square meter by intravenous infusion for 60 minutes ) every 2 weeks for four cycles ; granulocyte - colony - stimulating factor ( g - csf ) 300 microgram daily was administered in all patients on days 310 of each course of epirubicin and cyclophosphamide . premedication for ec consisted of a 5-ht3 serotonin receptor antagonist ( e.g. , granisetron 3  mg or ondansetron 1  mg ) and dexamethasone 16  mg intravenously . standard premedication with glucocorticoids , h1 and h2 receptor blockers ( e.g. , promethazine , clemastine , and ranitidine ) , was given before docetaxel administration . actual body weight was used for body surface area calculations . a complete blood count with leukocyte differential patients were seen every two weeks during treatment for history and physical examination and assessment of performance status and toxicity . treatment was given on day 1 of every cycle if absolute neutrophils count ( ans ) and platelet were 1.5  10/l and 100  10/l , respectively , or grade 4 nonhematologic toxicities ( excluding nausea , vomiting , and alopesia ) day 1 doses in the subsequent cycle were reduced , but doses in the current cycle were administered according to protocol . a maximum of two - dose reduction was allowed . when platelet count , absolute neutrophil count , or failure of nonhematologic toxicities to recover to  grade 1 were noted , either singly or in combination , on the scheduled start day of the subsequent cycle , treatment was delayed by up to one week , and complete blood count and toxicity grading were repeated weekly . patients requiring a treatment delay of more than three weeks were removed from the study . after chemotherapy completed , radiation therapy in patients treated with conservation was conducted following the last cycle of chemotherapy and after recovery from any toxicity according to standard institutional dosing guidelines and techniques . patients whose tumors expressed either ( or both ) the estrogen or progesterone receptor positive were offered a 5-year course of tamoxifen 20  mg / day . toxicity for each cycle was assessed before the commencement of the following cycle and was graded using the national cancer institute common toxicity criteria ( nci - ctc version 3 ) . patients were followed closely by history and physical examination within 15 days and one month after last infusion , and this followup was processed every 2-month intervals for the first year of chemotherapy completion then every six - month interval for years 4 - 5 . each visit included a complete blood count , along with hematologic studies and chemistries ( liver and renal function tests ) , chest x - ray , and ecg . computed tomography scan of the chest , abdomen , and pelvic and a bone scan ( or both ) were considered if clinically indicated by symptomatology or abnormal laboratory values at the discretion of the physician . the objective of the study was to evaluate the toxicity of epirubicin and cyclophosphamide plus docetaxel in node - positive breast cancer . statistical analyses were carried out using spss software version 16 , and p < 0.05 was considered significant . the study was designed as a one - stage three - outcome phase ii study , in which h0 was : r > 50% and ha : r < 25% . under these assumptions and with  and  errors rate of 5% each , 58 patients were assigned to reject a toxic treatment ( with > 50% grade 4 ) and accept a nontoxic treatment ( with < 25% grade 4 ) with a probability > 90% . if < 14 grade 4 toxic events occurred , the treatment was to be considered tolerable . if > 29 grade 4 toxic events occurred , the treatment was to be considered intolerable . fifty - eight eligible patients were enrolled into the study from april 2007 to march 2009 in shohadaye - tajrish hospital . patients ' characteristics at the time of entering the study are listed in table 1 . the mean sd age of the patients was 44.52  9.65 year , and 68.9% of the patients were < 50 years old . the median number of examined lymph nodes was 12 ( range 524 ) , and mean number of involved lymph nodes was 4 . the tumor was positive for estrogen receptor in 63.8% of patients , positive for progesterone receptor in 65.5% , positive for both estrogen and progesterone receptors in 60% , and positive for her2 in 39.7% . the chemotherapy cycle was completed in all patients except in sixteen patients ( 27.6% ) . thirty - two patients ( 55% ) have undergone any grade 4 adverse events that fifteen of them went off the study after the second or third infusion of docetaxel cycle due to grade 4 skin - nail disorders concomitant with myalgia , arthralgia , and neuropathy which was not tolerable by patients and did not further receive docetaxel . the cause of delay was nausea , vomiting , diarrhea , skin - nail disorders , and neuropathy . two patients died due to toxicity , one patient because of grade 4 febrile neutropenia after the third infusion of docetaxel cycle and another patient due to congestive heart failure after the last infusion of docetaxel . seventeen patients ( 29.3% ) were hospitalized due to adverse events : one patient because of grade 4 febrile neutropenia , thirteen patients due to grade 4 adverse events such as skin - nail disorders , arthralgia , dehydration , nausea , vomiting , and diarrhea , and three patients due to reduction of lvef and signs of congestive heart failure in which one of them developed to heart failure and in others subsequently recovered . initial echocardiography in all patients was normal , but at the end of study , two patients ( 3.4% ) had abnormal echocardiography , and they experienced congestive heart failure which was reversible . also , 50 patients ( 86.2% ) experienced total alopecia .   as a consequence of the assessment of blood counts , there was a nearly high rate of grade 1/2 neutropenia and febrile neutropenia , but it was asymptomatic and almost did not modify the treatment plan ; however , grade 3/4 of these adverse events was uncommon . however , it was the reason for the use of g - csf in all patients . albeit none of the patients suffered grade 3/4 thrombocytopenia , grade 3 anemia was 6.9% , and grade 1/2 anemia was common ( 58.6% ) . incidences of hematological and nonhematological toxicities are shown in table 2 . at the time of the analysis , the median follow - up period was 20 months ; four systemic relapses were observed , and two patients died during follow - up period due to brain metastasis . as a therapeutic option for patients with node - positive breast cancer , the combination of taxane with an anthracycline has been recently investigated in several studies [ 12 , 13 , 22 , 23 ] . some studies included that dose - dense regimens ( 2-week intervals ) not only prolong both disease - free survival and overall survival but also are as safe and as tolerated as giving the 3-week intervals conventional regimens [ 18 , 24 ] . this study evaluated the toxicity of dose - dense epirubicin and cyclophosphamide followed by docetaxel with g - csf support in node - positive breast cancer . it was found that this chemotherapy regimen was not tolerable , with a high incidence of grade 3/4 toxicities . although in our trial there was one death due to grade 4 febrile neutropenia , frequency of grade 4 hematologic toxicity was low , and it is likely that this low incidence was due to jones et al .   compared accelerated epirubicin or doxorubicin with cyclophosphamide given at 2-week interval with g - csf support with 3-week intervals in early breast cancer and observed fewer grade 3/4 neutropenia . citron et al .   compared standard 3 weekly and accelerated 2 weekly schedules of concurrent doxorubicin and cyclophosphamide followed by paclitaxel , or sequential doxorubicin , paclitaxel , and cyclophosphamide . they found that grade 4 neutropenia was more frequent in the standard 3 weekly schedules than in the accelerated regimens ( 33% versus 6% , p < 0.0001 ) .   in our study , three patients ( 5/2% ) experienced signs of congestive heart failure and one developed to heart failure and death . piedbois et al .   compared docetaxel , epirubicin , and cyclophosphamide every 3 weeks with dose - dense 2-weekly schedules of epirubicin and cyclophosphamide followed by docetaxel or the reverse sequence . as in our study , they found that the most frequent hematologic toxicity was neutropenia ; also it was more frequent in group receiving epirubicin and cyclophosphamide followed by docetaxel , and frequency of grade 3 - 4 cardiac toxicity was 3% in group receiving dose - dense regimen of epirubicin and cyclophosphamide followed by docetaxel in comparison with no cases of this toxicity in another schedules . they concluded that no significant difference was between nonhematological toxicity and between the standard and dose - dense schedules of doxorubicin or epirubicin with cyclophosphamide .   in another phase ii trial of docetaxel plus epirubicin , grade 3 - 4 cardiac disorders occurred in two patients . whereas in other trials of epirubicin and docetaxel , very low level of cardiotoxicity ( reversible congestive heart failure in one of sixty patients only ) or no grade 3 - 4 cardiac toxicity was observed [ 18 , 2426 ] . recently , sparano reported a randomized trial of four cycles of ac every 3 weeks postoperatively and followed by one of four taxane - based treatments , namely , paclitaxel administered weekly or every three weeks , or docetaxel administered weekly or every three weeks . results showed that in comparison with the group receiving standard therapy , the group receiving weekly paclitaxel had significantly more moderate - to - severe neuropathy , and the group receiving docetaxel every 3 weeks had significantly more severe neutropenia and its associated complications . besides , it was more frequent with docetaxel than paclitaxel . the arms that received weekly paclitaxel and 3-weekly docetaxel were associated with improved disease - free survival compared with 3-weekly paclitaxel , and the disease - free survival of the weekly docetaxel arm was similar to 3-weekly paclitaxel . the weekly paclitaxel arm was also associated with improved survival compared with 3-weekly paclitaxel , and 5-year overall survival was higher with weekly paclitaxel . we found that a significant fraction of patients had grade 3 or higher of skin disorders and peripheral neuropathy during treatment , and also nearly a high percentage of patients experienced moderate - to - severe arthralgia that were treated symptomatically . our trial was consistent with a study that demonstrated more patients given dose - dense regimens reported nail disorders , hand - foot syndrome , peripheral neuropathy and fluid retention of any grade , and more grade 3 or 4 events , compared with standard group [ 18 , 2327 ] . another phase ii of epirubicin plus docetaxel versus 5-fluorouracil plus epirubicin and cyclophosphamide concluded that skin infection and peripheral neuropathy were more frequent in docetaxel group . these toxic effects , albeit manageable , notably impaired patients ' quality of life , and the benefit / risk ratio of dose - dense regimens in the adjuvant setting should be cautiously evaluated . various studies demonstrated that docetaxel with doxorubicin and cyclophosphamide ( ac ) or with epirubicin and cyclophosphamide ( ec ) have had more favorable chemotherapy results , and epirubicin is an anthracycline that may be less cardiotoxic than doxorubicin . albeit , a randomized pilot phase ii study of ac and ec signified no significant difference between ac and ec cardiac toxicities , unless some toxicities , such as sepsis neutropenia , stomatitis , nausea , and vomiting , were more frequent in ac regimen in comparison with ec , but ec regimen was more tolerable than ac . followup of patients in this study will demonstrate results for the efficacy of this treatment , which is a secondary endpoint of disease - free and overall survival . the end point was the incidence of grade 4 toxic events . according to the statistical design of the trial , 32 patients ( 55% ) experienced grade 4 toxicity with this chemotherapy regimen . furthermore , two toxic deaths and sixteen related adverse events which led to treatment discontinuation , leading to assume that dose - dense epirubicin and cyclophosphamide plus docetaxel with g - csf support is not feasible and a tolerable regimen , and this regimen might not be selected for further assessment in other trials . in addition , this result is in agreement with several previous publications that have reported nonfeasibility of dose - dense docetaxel mainly due to hand - foot - skin toxicity but also severe problems with nail disorders and peripheral neuropathy [ 22 , 28 , 29 ] . in conclusion , our results indicate that the dose - dense epirubicin and cyclophosphamide followed by docetaxel with g - csf support was not tolerable and feasible and also might not be selected for further assessment in phase iii trials according to the protocol hypothesis .
background . adding taxanes to anthracycline - based adjuvant chemotherapy has shown significant improvement particularly in node - positive patients , but optimal dose and schedule remain undetermined . 
 objectives . 
 this study aimed to assess the feasibility of dose - dense epirubicin and cyclophosphamide followed by docetaxel in node - positive breast cancer . 
 methods . all patients first received 4 cycles of epirubicin ( 100  mg / m2 ) and cyclophosphamide ( 600  mg / m2 ) at 2-week interval then followed by docetaxel ( 100  mg / m2 ) at 2-week interval for 4 cycles , with daily pegfilgrastim ( g - csf ) that was administered in all patients on days 310 after each cycle of epirubicin and cyclophosphamide infusion . results . 
 fifty - eight patients with axillary lymph node - positive breast cancer were enrolled in the study , of whom 42 ( 72.4% ) completed the regimen . 
 there were two toxicity - related deaths , one patient due to grade 4 febrile neutropenia and the other due to congestive heart failure . 
 grade 3/4 neutropenia and febrile neutropenia were 13.8% and 5.1% . 
 the most common grade 3/4 nonhematological complications were as follows : skin - nail disorders ( 48.3% ) , hand - foot syndrome ( 34.4% ) , paresthesia ( 38% ) , arthralgia ( 27.5% ) , and paresis ( 24.1% ) . 
 conclusions . 
 dose - dense epirubicin and cyclophosphamide followed by docetaxel with g - csf support are not feasible , and it is not recommended for further investigation .