Evidence-based use of taxanes in the adjuvant setting of breast cancer. A review of randomized phase III trials

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1 Cancer Treatment Reviews (2007) 33, available at journal homepage: ANTI-TUMOUR TREATMENT Evidence-based use of taxanes in the adjuvant setting of breast cancer. A review of randomized phase III trials Laura G. Estévez a, *, Montserrat Muñoz b, Isabel Alvarez c, Yolanda Fernández d, Jesús García-Mata e, Manuel Ruiz-Borrego f, Ignasi Tusquets g, Miguel Ángel Seguí h, Alvaro Rodríguez-Lescure i, Encarna Adrover j, Ana Lluch k a Centro Integral Oncológico, Clara Campal, Madrid, Spain b Hospital Clinic i Provincial, Barcelona, Spain c Hospital Donosita, San Sebastian, Spain d Hospital Central de Asturias, Oviedo, Spain e Complexo Hospitalario de Ourense, Ourense, Spain f Hospital Universitario Virgen del Rocío, Sevilla, Spain g Hospital del Mar-IMAS, Barcelona, Spain h Hospital de Sabadell, Barcelona, Spain i Hospital Universitario de Elche, Alicante, Spain j Hospital Universitario de Alicante, Alicante, Spain k Hospital Clínico Universitario, Valencia, Spain Received 15 January 2007; received in revised form 3 April 2007; accepted 8 April 2007 KEYWORDS Adjuvant treatment; Breast cancer; Docetaxel; Paclitaxel; Randomized trials; Taxanes Summary Six major randomized clinical trials evaluating the role of taxanes in the adjuvant setting of breast cancer have demonstrated significant improvements in terms of efficacy in favour of the taxane treatment arm. In all cases, different anthracycline-based regimens were used as the control arm. Nevertheless, many clinicians are still not sufficiently convinced to incorporate the routine use of taxanes in the adjuvant treatment of breast cancer. There are two main objections, first the possible lack of effectiveness of chemotherapy in hormone-receptor positive tumors and second, some of the anthracycline-based control arms used in these trials were not the optimal ones. In this review, we have searched and analyzed all randomized studies that evaluated the role of taxanes in the adjuvant setting of breast cancer patients and have reported results in terms of * Corresponding author. Address: CIOCC. C/Oña 10, 28050, Madrid, Spain. Tel.: fax: address: borabora@pol2.jazztel.es (L.G. Estévez) /$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi: /j.ctrv

2 Evidence-based use of taxanes in the adjuvant setting of breast cancer. A review of randomized phase III trials 475 efficacy or tolerance. The suitability of the control arm, the prospective definition of patient s subgroups and the statistical methodology were taking into account. The objective of this review was to analyze if, at this point in time, there is sufficient evidence to support the routine use of taxanes in the adjuvant setting of breast cancer, and if it is valid for all subgroups including hormone-receptor and Her2/neu positive breast cancer patients. Other objectives of this review were to define the optimal regimen for administration of taxanes, how the tolerability of taxanes may be improved and also, to investigate any potential differences in efficacy or tolerability between docetaxel and paclitaxel. c 2007 Elsevier Ltd. All rights reserved. Introduction It was first demonstrated by Bonadonna and Valagussa 1 that the administration of cyclophosphamide, methotrexate and fluorouracil (CMF) at full doses as adjuvant chemotherapy in early breast cancer improved disease free survival (DFS) and overall survival (OS) compared with the results obtained in patients treated only with radical mastectomy. In the nineties, the Spanish Breast Cancer Research Group (GEICAM) 2 demonstrated that 6 cycles of 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) (500/50/500 mg/m 2 ) were superior to 6 cycles of CMF (600/60/600 mg/m 2 ) as adjuvant chemotherapy for operable breast cancer, particularly in node-negative patients. Similar results were founded by the latest meta-analyses of the Early Breast Trialist s Collaborative Group (EBTCG), 3 where the directly comparisons between CMF and anthracycline-based regimens given in different doses and schedules again favoured anthracyclines. All anthracycline-based schedules included doxorubicin or epirubicin and were usually given for about 6 months with other cytotoxic drugs (FAC or FEC). CMF, as control arm, was mostly given for about 6 months. Better outcome was observed with anthracycline treatment compared with CMF, reducing both recurrence rate (11%, p = 0.001) and breast cancer death rate (16%, p = <0.0001). In fact, the absolute difference of recurrence and breast cancer mortality between anthracycline-based and CMF chemotherapy was about 3% at 5 years and 4% at 10 years, and the benefit produced by any chemotherapy at 5 years appeared to be about twice as great in estrogen receptor (ER) poor as in tamoxifen-treated ER-positive disease. 3 Taking into account that the EBTCG analysis was restricted to randomized clinical trials of adjuvant chemotherapy started by 1995, 6 months of anthracycline-based chemotherapy was considered as the new gold standard of adjuvant chemotherapy at that stage, at least for women younger than 70 years. Moreover, future advances on adjuvant chemotherapy should be compared to this new standard. Taxanes have been widely investigated in the treatment of advanced breast cancer. The first series of trials demonstrated that both paclitaxel 4,5 and docetaxel 6 9 were active in anthracycline-resistant disease. A second series of phase III trials showed that taxanes as single agents were at least as effective as doxorubicin in patients with metastatic breast cancer. 10,11 Finally, the combination of docetaxel 12,13 or paclitaxel with anthracyclines led to an improvement of the results obtained in advanced disease, and supported the development of these drugs in the adjuvant and the neoadjuvant setting. To date, six major prospective randomized clinical trials with at least 1000 patients randomized have demonstrated significant improvements in terms of efficacy when taxanes were administered post-operatively to patients with early breast cancer As control arms, anthracycline-based regimens were used in all cases. Five of these trials included only node-positive patients and one included node-positive as well as high-risk node-negative patients. 23 The primary objective of this review was to evaluate if there is sufficient evidence to date to support the routine use of taxanes in the adjuvant setting of breast cancer, and if it is valid for all subgroups of breast cancer patients independently of nodal status, endocrine responsiveness and other tumor characteristics. Other objectives of this review were to define the optimal schedule to administrate taxanes, whether their tolerance could be improved and also to investigate any potential differences between the taxanes docetaxel and paclitaxel. To perform this revision, we searched PubMed for all randomized trials available to date assessing the role of taxanes in the adjuvant treatment of breast cancer that have reported results on efficacy and/or tolerance. Randomized trials currently available in abstract form were also included, but were clearly identified as preliminary results. The suitability of the control arm, the prospective definition of patients subgroups, the trial design and the statistical methodology were taken into account. Our search revealed 12 randomized clinical trials reported before January Seven of them evaluated the addition of a taxane to an anthracycline-based schedule. One randomized trial compared a taxane-based schedule with an anthracycline-based schedule. Another three trials contained taxanes in both treatment arms and investigated the optimal way to administer them. The last one evaluated both, the addition of a taxane to an anthracycline-based schedule and best way to administer the taxane. At the time of writing, ten of them have results on efficacy and tolerance (Table 1), and two trials have only reported results on tolerance. To facilitate their analysis, all of them were classified according to their protocol design. Anthracyclines versus anthracyclines plus taxanes According to what it was observed in the metastatic setting, where the best results in terms of efficacy were obtained when taxanes and anthracyclines were combined, the first generation of trials that evaluated the role of taxanes in

3 Table 1 Efficacy results of randomized trials assessing the role of taxanes in adjuvant breast cancer Study Patients Treatment Cycles/weeks HT Follow-up/% DFS events 1. Anthracyclines versus anthracyclines plus taxanes 1.1. Concomitant administration BGIRG TAC (75/50/500) q3w C: 6 versus 6 HR+ 55 months DFS: 75% versus 68% OS: 87% versus 81% Docetaxel N+ 6 FAC (500/50/500) q3w W: 18 versus 18 After CT 27% of events HR: 0.72, p = HR: 0.70, p = ECOG AT (60/60) q3w C: 4 versus 4 HR+ 53 months DFS: 87% versus 87% OS: NR Docetaxel N+/HR N 4 AC (60/600) q3w W: 12 versus 12 After CT 14% of events HR: 1.08, p = 0.43 HR: 1.09, p= Sequential administration with equal or similar duration of chemotherapy PACS FEC (500/100/500) q3w C: 6 versus 6 HR+ 60 months DFS: 78% versus 73% OS: 91% versus 87% Docetaxel N+ 3 FEC fi 3 T (100) q3w W: 18 versus 18 After CT 24% of events HR: 0.82, p = HR: 0.73, p = GEICAM FEC (600/90/600) q3w C: 6 versus 12 HR+ 46 months DFS: 85% versus 79% OS: 95% versus 92% Paclitaxel N+ 4 FEC q3w fi 8 P (100) q1w W: 18 versus 20 After CT 17% of events HR: 0.63, p = HR: 0.74, p = Sequential administration with different duration of chemotherapy CALGB AC (60, 75 or 90/600) q3w C: 4 versus 8 HR+ 69 months DFS: 70% versus 65% OS: 80% versus 77% Paclitaxel N+ 4 AC fi 4 P (175) q3w W: 12 versus 24 After CT 34% of events HR: 0.83, p = HR: 0.82, p = NSABP B AC (60/600) q3w C: 4 versus 8 P50, <50 HR+ 65 months DFS: 76% versus 72% OS: 85% versus 85% Paclitaxel N+ 4 AC fi 4 P (225) q3w W: 12 versus 24 During CT 28% of events HR: 0.83, p = HR: 0.93, p = Anthracyclines versus taxanes USO AC (60/600) q3w C: 4 versus 4 HR+ 66 months DFS: 86% versus 80% OS: 90% versus 87% Docetaxel N+/HR N 4 TC (75/600) q3w W: 12 versus 12 After CT 28% of events HR: 0.67, p = HR: 0.76, p = Optimizing the administration of taxanes 3.1. Docetaxel versus paclitaxel/triweekly versus weekly ECOG AC fi 4 P (175) q3w C: 8; W: 24 HR+ 47 months HR P versus P3: 89% T: Docetaxel N+/HR N 4 AC fi 12 P (80) q1w C: 16; W: 24 After CT 17% of events P = 0.83 P1: 92% Paclitaxel 4 AC fi 4 T (100) q3w C: 8; W: 24 HR q3w versus T3: 89% q1w: AC fi 12 T (35) q1w C: 16; W: 24 P = 0.54 T1: 89% 3.2. Dose-dense versus conventional/sequential versus concurrent CALGB AC (60/600) fi 4 P (175) q3w C: 8; W: 24 All POSTM and 36 months HR q2w versus q3w: 0.74 DFS OS HR q2w versus q3w: L.G. Estévez et al.

4 Evidence-based use of taxanes in the adjuvant setting of breast cancer. A review of randomized phase III trials 477 Paclitaxel N+ 4 A fi 4 P fi 4 C q3w C: 12; W: 36 PREM HR+ 16% of events P = p = AC fi 4 P q2w + G-CSF C: 8; W: 16 After CT HR CC versus SQ: HR CC versus SQ: C: 12; W: 24 p = 0.58 p = A fi 4 P fi 4 C q2w + G-CSF Not reported BIG Ia: 4 A (75) q3w fi CMF C: 7; W: 24 HR+ 62 months HR II + III versus Ia + Ib: 0.86, C: 7; W: 24 After CT 25% of events P = Docetaxel N+ Ib: 4 AC (60/600) q3w fi CMF C: 9; W: 30 HR II versus Ia: 0.79, P = II: 3 A (75) q3w fi 3 T (100) fi CMF C: 7; W: 24 HR III versus Ib: 0.93, P = 0.48 III: 4 AT (50/75) q3w fi CMF CMF: 3 (100 D1 14/40 D1 + 8/600) q28d * N+: node-positive; N : node-negative; HR: high-risk; T: docetaxel; A: doxorubicin; C: cyclophosphamide; F: 5-fluorouracil; P: paclitaxel; M: mitoxantrone; q3w: every three weeks; q2w: every two weeks; q1w: every one week; q28d: every 28 days; G-CSF: granocyte colony-stimulating factor; C: cycle; W: week; HR+: hormone-receptor positive; CT: chemotherapy; POSTM: postmenopausal; PREM: premenopausal; DFS: disease-free survival; HR: hazard ratio; CC: concurrent; SQ: sequential. the adjuvant setting did so in combination with anthracyclines. We have differentiated between trials in which taxanes and anthracyclines were administered concomitantly and sequentially and, in the latter case, whether both treatment arms were of the same duration or not. Concomitant administration of anthracyclines and taxanes Three clinical trials have been reported to date which compared the concomitant administration of anthracyclines versus anthracyclines plus taxanes, 18,24,25 but only one has been fully reported. The BCIRG 001 trial 18 randomized 1491 patients with node-positive breast cancer to receive 6 cycles of either FAC (500/50/500 mg/m 2 ) or TAC (docetaxel/doxorubicin/ cyclophosphamide: 75/50/500 mg/m 2 ) as adjuvant chemotherapy after surgery. Previous studies had shown that FAC, at this dose and schedule, did already appear to be superior to CMF in early-stage breast cancer. 2,3,26 Hormonal treatment was given to patients with positive hormonereceptor (ER+/PR+) tumors after finishing chemotherapy. The number of positive axillary lymph nodes was the only stratification variable in the analysis. Other analyses of subgroups were prospectively defined (such as hormonal-receptor and HER2/neu status), but were not sufficiently powered to detect differences. The trial was designed to detect a 27% reduction in the risk of relapse among patients receiving TAC versus FAC, with an overall power of 97%. The estimated rates of DFS at 5 years were 75% with TAC and 68% with FAC (p = 0.001). After adjustment for nodal status, TAC was associated with a 28% reduction in the risk of relapse when compared to FAC. The estimated OS rates at 5 years were 87% in the TAC group and 81% in the FAC group (p = 0.008). TAC was associated with a 30% lower risk of death than was FAC. The superiority of TAC over FAC was observed in all planned subgroups, including involved axillary lymph nodes, hormone-receptor status and HER2/ neu, and was independent of menopausal status. TAC reduced the risk of relapse in both, 1 3 (39%, p < 0.001) and four or more (17%, p = 0.17) positive lymph nodes, however the difference in the latter did not achieved statistical significance. We should wait until the final analysis with 590 events is done to see whether results obtained in four or more positive lymph nodes achieve statistical significance. The absolute reduction in mortality reported by TAC was the largest seen to date (6%). The conclusion of the study was that adjuvant chemotherapy with TAC, as compared with FAC, significantly improves the rates of DFS and OS among women with operable node-positive breast cancer. Regarding the toxicity profile, the incidence of severe adverse events was higher in the TAC arm (36% versus 27%, p < 0.001). The most important differences between the TAC and FAC arms were the incidence of grade 3 4 neutropenia (66% versus 49%, respectively, p < 0.001) and febrile neutropenia (25% versus 2.5%, respectively, p < 0.001). There were no septic deaths and the incidence of congestive heart failure was similar between both groups. With regard to neutropenia, the authors recommended the use of growth factors prophylaxis with the TAC regimen.

5 478 L.G. Estévez et al. Using the same trial design and dosing schedules, the GEI- CAM 9805 trial investigated the efficacy of TAC over FAC in 1059 high-risk node-negative breast cancer patients. 24 Due to the high incidence of febrile neutropenia in the TAC arm, the study was amended after the first 237 patients included to allow administration of primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) in this treatment arm. To date, only safety data has been reported. Taking into account that the inclusion period of GEICAM 9805 ended in 2003, DFS at 5 years could not be available until 2008, and at that time, there is still likely to be insufficient events to find statistical differences between the groups since node-negative breast cancer patients relapse later than node-positive breast cancer patients. One interesting finding from this trial, however, was that the addition of primary prophylaxis with G-CSF to TAC reduced the incidence of febrile neutropenia from 24% to 3.5%, which was close to the level found in the FAC arm (1%). Other TAC-induced side effects such as grade 2 4 anemia, asthenia, anorexia, nail disorders, stomatitis, myalgia and dysgeusia were also reduced when primary prophylaxis with G-CSF was administered. The most recent trial to compare the concomitant administration of anthracyclines versus anthracyclines plus taxanes was the Intergroup phase III trial ECOG In this trial, four cycles of doxorubicin and cyclophosphamide (AC: 60/600 mg/m 2 ) were compared with four cycles of doxorubicin and docetaxel (AT: 60/60 mg/m 2 ) in 2952 patients with node-positive or high-risk node-negative breast cancer. The selection of AC as the control arm was justified based on its equivalence with 6 cycles of CMF. 27 Hormonal therapy was administered to all ER+ and/or PR+ tumor patients after chemotherapy. Patients were stratified by nodal, hormone-receptor and menopausal status. The study was powered to detect a 25% reduction in DFS rate using AT. After a median follow-up of 53 months, outcomes were better than expected in both groups and similar in both treatment arms. DFS at 4 years was 87% for both AT and AC. AT was slightly better in ER-patients (82% versus 79%), but the difference did not achieve statistical significance. Febrile neutropenia occurred in 19% of patients with AT and 6% of patients with AC. One possible explanation for the results found in this trial and those in the BCIRG 001 trial is that the dose of docetaxel administered in the ECOG 2197 trial was much lower (60 mg/m 2 ) than that administered in the BCIRG 001 trial (75 mg/m 2 ). In fact, both dosage and the number of cycles administered in study ECOG 2197 may be suboptimal. Another important conclusion that may be drawn after analyzing BCIRG 001 and GEICAM 9805 data is that the concomitant administration of doxorubicin and docetaxel should include primary prophylaxis with G-CSF. This conclusion is also supported by the RAPP 01 trial, 28 which was prematurely closed due to a high incidence of febrile neutropenia (41%) in the AT arm with doses of 50/75 mg/m 2. Sequential administration of anthracyclines and taxanes In an attempt to reduce the incidence and severity of toxicity, which occurs during the concomitant administration of anthracyclines and taxanes, some investigators tested the sequential administration of both drugs. In a randomized phase II study of patients with advanced disease, Alba et al. 29 observed a reduction in febrile neutropenia with the sequential administration of doxorubicin and docetaxel (A fi T) compared with the concomitant schedule (AT), maintaining a similar efficacy profile in both arms. This and other trials showed a new safe, manageable and viable alternative to administer anthracyclines and taxanes in breast cancer. However, in analyzing these trials it must be taken into account whether or not the taxane and the non-taxane arms are of the same treatment duration, as longer treatment schedules of adjuvant chemotherapy are recognized to affect both DFS and OS. 30 Both treatment arms with equal or similar duration of chemotherapy To date, only two trials have been reported which compare an anthracycline-based schedule with the sequential administration of anthracyclines and taxanes, where both treatments arms are of the same or similar duration. 19,22 The PACS 01 trial randomized 1999 patients with operable node-positive breast cancer to either 6 cycles of adjuvant FEC (5-fluorouracil, epirubicin and cyclophosphamide: 500/100/500 mg/m 2 ), which was considered to be one of the gold standards in the adjuvant treatment of node-positive breast cancer patients according to FASG 05 trial, 31 or 3 cycles of FEC (500/100/500 mg/m 2 ) followed by 3 cycles of docetaxel (T: 100 mg/m 2 ). Patients were stratified by age (<50 or P50) and nodal status (1 3 and P4). In the protocol, it was stated that hormonal treatment should be administered to all hormone-receptor positive patients following completion of chemotherapy. In the overall analysis, FEC fi T was associated with a 18% reduction in the risk of relapse (adjusted p = 0.012) and a 27% reduction in the risk of death (adjusted p = 0.017). The estimated rates of DFS and OS at 5 years for FEC fi T versus FEC were 78% versus 73% and 91% versus 87%, respectively. However in the analysis of subgroups, FEC fi T did not offer any advantage compared to FEC in younger patients (<50 years old). Probably, the fact that many ER+ premenopausal patients did not finally receive tamoxifen could influence these results. The conclusion of the study was that the substitution of 3 cycles of FEC by 3 cycles of docetaxel significantly improved DFS and OS in node-positive breast cancer patients, and that this benefit was significant for patients older than 50 years. In addition to improved efficacy results with the FEC fi T schedule, patients experienced fewer cardiac events and a lower incidence of grade 3 4 neutropenia at day 21, and a reduction in nausea and vomiting. Also, secondary prophylaxis with G-CSF was used less frequently in the taxane arm. On the other hand, severe edema and nail disorders were more frequently observed in the sequential arm along with a higher incidence of grade 3 4 stomatitis on cycles 4 6. There is another sequential trial recently reported in which the duration of both treatment arms was very similar (18 versus 20 weeks). 22 The GEICAM 9906 trial randomized 1248 node-positive breast cancer patients to receive 6 cycles of FEC (600/90/600 mg/m 2 ) versus four cycles of FEC followed by 8 weekly administrations of paclitaxel (P: 100 mg/m 2 ). Tamoxifen was administered to all patients

6 Evidence-based use of taxanes in the adjuvant setting of breast cancer. A review of randomized phase III trials 479 with ER+ and/or PR+ tumors. The control arm was, at the time of the trial, one of the gold standards in the treatment of node-positive breast cancer patients. 31 After 46 months of follow-up, DFS was better in the paclitaxel arm (85% versus 79%, p = ) with a reduction of 37% in the risk of recurrence. The effect was independent of nodal, hormone-receptor, menopausal and HER2 status. At that point, there was an improvement in OS (95% versus 92%) with a reduction in the risk of death of 26%, but these differences did not achieve statistical significance (p = 0.137). In terms of toxicity, both arms were well tolerated. Myalgia and peripheral neuropathy were more frequently observed in the paclitaxel arm, but the incidence of febrile neutropenia and mucositis was higher in the control arm. Both treatment arms with a different duration of chemotherapy The first of these trials was the Cancer and Leukemia Group B 9344 (CALGB 9344) 20 which included 3121 patients with node-positive breast cancer. During the study, patients were randomized twice. First, patients were randomized to receive three different doses of doxorubicin (60, 75 or 90 mg/m 2 ) plus 600 mg/m 2 of cyclophosphamide. Subsequently, patients were randomized to receive four additional cycles of paclitaxel (P: 175 mg/m 2 infused over 3 h) to AC or nothing. The selection of the control arm of this trial (AC: 60/600 mg/m 2 ) was made after Fisher et al. 27 demonstrated that four cycles of AC were equivalent to 6 cycles of CMF in node-negative patients. The objective of this trial was to see if the effectiveness of four cycles of standard AC could be improved either by increasing the dose of doxorubicin to 75 or 90 mg/m 2 or by adding four cycles of paclitaxel. Hormonal treatment was given after chemotherapy to patients with ER+ and/or PR+ tumors. Results of this trial demonstrated that increasing doses of doxorubicin did not reduce disease recurrence or death; however, the addition of paclitaxel to AC decreased the hazard of recurrence by 17% (p = ) and the hazard of death by 18% (p = ) after 69 months of follow-up. Although this study was not powered to assess outcomes in patient subsets, the addition of paclitaxel was consistently beneficial for all subgroups although the effect of paclitaxel seems to be greater among hormone-receptor negative tumors. Also, in a retrospective analysis of this study, 32 it was observed that the delay of radiotherapy until additional paclitaxel was administered did not adversely affect local control of the disease, delivery of radiotherapy or ability to tolerate it. With regard to the incidence of adverse events, the additional toxicity from adding paclitaxel was generally modest. The design of the second trial was similar to that of CALGB 9344, but with some important differences. The NSABP B28 trial 21 randomized 3060 patients to four cycles of AC or four cycles of AC followed by four cycles of paclitaxel. The differences were the fixed dose of doxorubicin (60 mg/m 2 ), the higher dose of paclitaxel (P: 225 mg/m 2 ) and more importantly, the concomitant administration of hormonal treatment with chemotherapy to all patients P50 years and those younger than 50 years with ER+ and/ or PR+ tumors. The selection of four cycles of AC (60/ 600 mg/m 2 ) as control arm was based on its equivalence to 6 months of conventional CMF 27 as mentioned previously, and the failure to improve outcomes with different doses and schedules. 20,27,33 Although the study demonstrated that the addition of paclitaxel improved DFS by 17% (p = 0.006), the improvement in OS was smaller than in CALGB 9344 and did not achieve statistical significance (7%, p = 0.46) after 64 months of median follow-up. Data analysis did not reveal any significant interaction between the effect of paclitaxel in ER+ and/or PR+ patients compared with ER- and/or PRpatients, however paclitaxel seems to have again a greater effect among hormone-receptor negative tumors. Toxicity for study treatment was acceptable. Most common grade 3 or greater toxicity during paclitaxel included neurosensory toxicity (15%), neuromotor toxicity (7%), arthralgia and/or myalgia (12%). Febrile neutropenia was observed in 3% of patients. It is likely that a longer follow-up will be needed to observe a significant improvement in OS due to the introduction of new effective drugs in the treatment of advanced disease and the better prognosis for the cohort of patients included in the NSABP B28 compared with CALGB 9344 (70% versus 46% of patients with 1 3 positive nodes, respectively). Also, concurrent use of tamoxifen may have limited the impact of adding four cycles of paclitaxel, as it has been stated previously. 34,35 It would appear that a higher dose of paclitaxel (225 mg/m 2 ) was not more effective than the lower dose used in CALGB 9344, possibly because the cumulative neurotoxicity produced by paclitaxel at 225 mg/m 2 led to a higher percentage of patients who did not complete all four cycles of paclitaxel. A repeated criticism of the last two trials is that two variables were evaluated at the same time: 3 versus 6 months of chemotherapy (4 versus 8 cycles) and the addition of paclitaxel. According to the EBCTCG meta-analyses, 3 longer treatments reduce the rate of recurrence compared to shorter ones, but without an effect on overall survival. However, Fumoleau et al. 30 demonstrated that the duration of chemotherapy could affect both DFS and OS. Unfortunately, at this point it is not possible to determine the individual contribution of each of the variables (longer duration of chemotherapy and the addition of paclitaxel) to the improvements obtained in the CALGB 9344 and NSABP B28 trials. Taxanes versus anthracyclines In an attempt to avoid the cardiac toxicity observed when anthracyclines are administered, the US Oncology group designed a randomized trial where for the first time the taxane-based treatment arm did not include an anthracycline. 23 In this way, the USO 9735 randomized 1016 nodepositive and high-risk node-negative breast cancer patients to receive four cycles of AC (60/600 mg/m 2 ) or docetaxel and cyclophosphamide (TC: 75/600 mg/m 2 ). The rationale in selecting TC as study arm was based on the promising activity shown in metastatic disease by this schedule in previous phase II trials 36 and the greater antitumor activity of docetaxel compared with doxorubicin in phase III trials. 10 AC was previously used as control arm in several

7 480 L.G. Estévez et al. adjuvant studies. 20,21,25 Hormonal treatment was administered to all patients with ER+ and/or PR+ tumors after chemotherapy. After 66 months of median follow-up, TC compared with AC was associated with a superior DFS (86% versus 80%, HR = 0.67, p = 0.015). There was also an improvement in OS, although this difference did not achieve statistical significance (90% versus 87%, HR = 0.76, p = 0.131). There was a different toxicity profile in each treatment arm. The incidence of febrile neutropenia was higher in TC arm (6% versus 3%, p = 0.03), but AC provoked more severe nausea and vomiting. Four cycles of TC produced a longer DFS than standard AC and should be considered as a new standard of non-anthracycline adjuvant regimen for early breast cancer. Unfortunately, the sample size was insufficient to perform additional subgroups analysis. Optimizing the administration of taxanes The second generation of phase III taxane adjuvant trials contained docetaxel or paclitaxel in all treatment arms. The objective of these trials was to optimize the administration regimen of taxanes, either by determining which is the better taxane or by refining the best treatment schedule. Docetaxel versus paclitaxel/triweekly versus weekly schedules In the last few years, indirect comparisons between phase II and phase III trials suggested that docetaxel given every three weeks may be more effective than paclitaxel in patients with metastatic breast cancer. 10,11 In a phase III trial, Jones et al. 37 directly compared docetaxel (100 mg/ m 2 ) with paclitaxel (175 mg/m 2 ) every three weeks in patients with advanced breast cancer and obtained significantly longer time to progression (5.7 versus 3.6 months, p < ) and OS (15.4 versus 12.7 months, p = 0.03) with docetaxel treatment. However, these results should be taken with caution because the main objective of this trial was response rate and not time to progression or OS, and because the schedule of paclitaxel (175 mg/m 2 every 3 weeks) could not be the optimal one. Conversely, it has been observed in several phase III trials that weekly paclitaxel may be superior to triweekly paclitaxel in the metastatic and neoadjuvant setting of breast cancer. 38,39 To resolve these issues, several North American cooperative groups designed and performed the ECOG 1199 trial. 40 The study randomized 4988 node-positive breast cancer patients to receive four cycles of AC (60/600 mg/m 2 ) followed by either four cycles of paclitaxel (P: 175 mg/m 2, P3) or docetaxel (T: 100 mg/m 2, D3) every three weeks, or 12 cycles of paclitaxel (P: 80 mg/m 2, P1) or docetaxel (T: 35 mg/ m 2, D1) every week. The primary comparisons were between both taxanes (paclitaxel versus docetaxel) and both schedules (triweekly versus weekly). Secondary exploratory comparisons compared the standard P3 versus the other three experimental arms (P1, D1 and D3). P3 was selected as the control arm for this study based on the findings of both CALGB and NSABP B In the D1 treatment arm, a higher percentage of patients received fewer than 50% of doses (10%), followed by patients in the D3 treatment arm (9%). In both paclitaxel arms, the percentage of patients who received fewer than 50% of doses was only around 4%. After a median follow-up of 47 months, there were no significant differences in the hazard ratios of DFS that compared the two taxanes (HR: 0.985, p = 0.83) and the two schedules (HR: 1.043, p = 0.54). Secondary exploratory comparisons found no significant differences between the control arm (P3) and the experimental arms P1 (HR: 1.20, p = 0.06), D1 (HR: 1.03, p = 0.78) and D3 (1.13, p = 0.20). Both, P1 and D3 were the schedules with less relapses at the time of the analysis (P1: 14%, D3: 14%, P3: 16%, D1: 15%), but differences did not achieve statistical significance. Regarding the safety profile, D3 was associated with more neutropenia and febrile neutropenia. The rate of DFS events in this interim analysis was lower than expected (17%). In fact, analysis for primary DFS comparisons (the two taxanes and the two schedules) was projected after 21% of events for primary comparisons and 28% for secondary comparisons (P3 versus P1, D1 and D3). Further follow-up will be needed to confirm these results. Dose-dense versus conventional/sequential versus concurrent The INT C9741 study coordinated by the CALGB tested two hypotheses to optimize the administration of taxanes in the adjuvant setting, 41 which were based on the theoretical concepts of cell kill and log-kill in human breast cancer growth. 42 The first hypothesis was whether dose-dense taxane schedules improved efficacy over conventional drug administration. The second was whether sequential schedules allowed a better delivery of taxanes, and therefore better outcomes. With these two objectives in mind, a total of 2005 nodepositive breast cancer patients were randomized to receive: (1) four cycles of doxorubicin (A) followed by four cycles of paclitaxel (P) followed by four cycles of cyclophosphamide (C), all cycles administered every three weeks (A fi P fi C q3w); (2) the same schedule administered every two weeks with G-CSF support (A fi P fi C q2w); (3) four cycles of AC followed by four cycles of P, both every three weeks (AC fi P q3w); and (4) the same schedule administered every two weeks with G-CSF support (AC fi P q2w). The dosages of the drugs were the same for each schedule (A: 60 mg/m 2, P: 175 mg/m 2 and C: 600 mg/m 2 ). Hormonal treatment was recommended to be given to ER+ and/or PR+ premenopausal women and all postmenopausal patients irrespective of their hormonal-receptor status. The study used a 2 2 factorial design to assess both dose density (two versus three weeks) and treatment sequence (sequential versus concurrent), along with any possible interaction between them. After 36 months of median follow-up, dose-dense regimens (A fi P fi C q2w and AC fi P q2w) significantly prolonged DFS (HR: 0.74, p = 0.010) and OS (HR: 0.69, p = 0.013) compared with triweekly schedules (A fi P fi C

8 Evidence-based use of taxanes in the adjuvant setting of breast cancer. A review of randomized phase III trials 481 q3w and AC fi P q3w). However, sequential and concurrent administration showed similar outcomes. In the same way, interactions between dose density and treatment sequence were not observed. The improvement observed with dosedense regimens seems to be greater for ER than ER+ tumors, although those differences did not achieve statistical significance (32% versus 19%). The improvements observed with the dose-dense schedules were not accompanied by an increase in toxicity, highlighting the importance of the use of primary prophylaxis with G-CSF with more aggressive schedules. However, in a subsequent unplanned analysis after 69 months of follow-up, the difference in OS between dose-dense regimens and triweekly schedules was no longer significant (HR: 0.85, p = 0.12), although a trend persisted in the ER-negative subgroup. 43 Sequential versus concurrent Based on the importance of the sequential administration of anthracyclines and taxanes, the BCIRG 005 trial 44 also tried to answer the question of whether it is better to administer taxanes and anthracyclines in combination or sequentially. A total of 3298 node-positive breast cancer patients were randomized to receive 6 cycles of TAC (75/50/500 mg/m 2 ) every 3 weeks or four cycles of AC (60/600 mg/m 2 ) every 3 weeks followed by four cycles of docetaxel (T: 100 mg/ m 2 ). Primary prophylaxis with G-CSF was allowed at the discretion of the investigator for either treatment arm. Hormonal treatment was administered after chemotherapy to all ER+ and/or ER tumor patients. Only safety data has been reported to date. TAC produced a higher incidence of febrile neutropenia (18% versus 9%), in spite of the fact that more patients in the TAC arm received primary prophylaxis with G-CSF. On the other hand, a higher incidence of neurotoxicity and myalgia in the AC fi T arm was reported. Recently, another trial has just reported its first results. 45 The design of BIG 2-98 was very complex and included four treatment arms in a 1:1:2:2 randomization ratio. Patients included in Arm Ia received four cycles of A (75 mg/m 2 ) every 3 weeks followed by 3 cycles of CMF (100 D1-14/40 D1+8/600) every 28 days. In Arm Ib, patients received AC (60/600 mg/m 2 ) instead of A. In Arm II, patients received 3 cycles of docetaxel (T: 100 mg/m 2 ) every 3 weeks after 3 cycles of A (75 mg/m 2 ); and in Arm III, docetaxel and doxorubicin were administered concomitantly (AT: 50/75 mg/m 2 ) for four cycles every 3 weeks. In all cases, the same dose and schedule of CMF was given after A or after A plus T. The main hypothesis was to determine if there was a significant difference of relapse between Arm I (A fi CMF + AC fi CMF) and Arm II (A fi T fi CMF) plus Arm III (AT fi CMF). Secondary comparisons were performed between Ia and II, or between Ib and III. To test this hypothesis, 2887 node-positive patients were included. The primary objective, which was to demonstrate the benefit of adding a taxane to A fi CMF or AC fi CMF concomitantly or sequentially, was not achieved (HR: 0.86, p = 0.051), although it was of borderline significance. The only significant result observed at this point was in the comparison performed between Arm Ia and Arm II (A fi CMF versus A fi T fi CMF) in favour of the taxane arm (HR: 0.79, p = 0.035). Additional follow-up will be required to obtain the survival analysis. Discussion To date, 12 randomized clinical trials have assessed the role of taxanes in the adjuvant treatment of breast cancer and reported results, ten of them in terms of efficacy and tolerance, and two only in terms of tolerance (GEICAM 9805 and BCIRG 005). Of these, six studies directly evaluated the benefit of adding a taxane (docetaxel or paclitaxel) to an anthracycline-based chemotherapy regimen, either concomitantly or sequentially, and in five of them the taxane treatment arm did have significantly better efficacy outcomes either in terms of DFS 21,22 or in terms of DFS and OS These five clinical trials included only node-positive breast cancer patients. The superiority of the taxane arm was observed in all subgroups analysis, which included the number of involved axillary lymph nodes, hormonereceptor status and Her2/neu status, and was independent of menopausal status. One trial failed to show better efficacy results for the taxane arm (ECOG 2197), 25 but in this trial, investigators used lower taxane doses in the study arm and included both node-positive and node-negative high-risk breast cancer patients. Apart from these five positive clinical trials which evaluated the addition of a taxane to an anthracycline-based chemotherapy regimen, the USO 9735 trial evaluated the substitution of the anthracycline by a taxane, 23 and DFS again improved in the taxane arm. In fact, in this trial both node-positive and high-risk node-negative patients were included and an exploratory analysis did not find major differences between patient subgroups. So to date, six positive clinical trials support the addition of taxanes to the adjuvant treatment of node-positive breast cancer patients. At this point, it is interesting to analyze the type and duration of the anthracycline-based schedule used as control arm in these six studies. In 3 of them (two with paclitaxel and one with docetaxel), the control arm was four cycles of AC (60/600 mg/m 2 ), 20,21,23 which was already demonstrated to be at least as effective as 6 cycles of CMF. 27 In the remaining three trials (two with docetaxel and one with paclitaxel), the control arm was either 6 cycles of FAC (500/50/500 mg/m 2 ) 18 or 6 cycles of FEC (500/100/500 or 600/90/600 mg/ m 2 ), 19,22 which have been already demonstrated to be superior to 6 cycles of CMF. 2,3,26 Also, in two of the three paclitaxel trials, the control arm was of shorter duration than the study arm Conversely, in the three docetaxel trials, control and study arm were of the same duration. 18,19,23 Based on that, we considered that there are three schedules (6 TAC, 3 FEC fi 3 T and 4 FEC fi 8 P weekly) that have demonstrated to be superior in terms of DFS 22 or DFS and OS 18,19 to 6 cycles of FEC or FAC, which had already demonstrated their superiority over 6 cycles of CMF, and should be considered new options in the treatment of node-positive breast cancer patients. Also, there are another two schedules (4 AC fi 4 P and 4 TC) that at least have demonstrated to be superior in terms of DFS to four cycles of AC, 20,21,23 which had already demonstrated to be equivalent to 6 cycles of CMF, and should be

9 482 L.G. Estévez et al. considered as other options in the treatment of node-positive breast cancer patients. Also, the selection of one schedule over the rest will be based on the toxicity profile and patient convenience. In this way, some schedules need double hospital visits than others (GEICAM 9906 versus BCIRG 001). 18,22 With regard to the toxicity profile, we will need to keep in mind the general status of the patient trying to foresee how she is going to hold up chemotherapy. In this way, it is important to remember the results obtained by GEICAM 9805, 24 in which the addition of primary prophylaxis with G-CSF dramatically reduced not only the incidence of febrile neutropenia, but also other chemotherapy side effects including anaemia, asthenia, anorexia, nail disorders, stomatitis, myalgia and dysgeusia. In an effort to optimize the administration of taxanes to breast cancer patients, three important trials have been reported to date 40,41,44 but only two have efficacy and toxicity data available. 40,41 Based on the CALGB 9741 study, 41 preliminary results suggest that dose-dense schedules (every 2 weeks with primary prophylaxis with G-CSF) may be more effective than current conventional schedules (every three weeks without G-CSF) and that the sequential administration of anthracyclines and taxanes results in similar outcomes to concurrent administration. Taking into account the results obtained in the ECOG 1199 trial, 40 there do not appear to be significant differences in the efficacy outcomes obtained either with the two taxanes (docetaxel and paclitaxel) or the two schedules (weekly versus every three weeks). The later findings will need to be confirmed as they come from single trials, and in the latter case, with a low percentage of events. In summary, we conclude that there is sufficient evidence to support the routine use of taxanes to the adjuvant treatment of node-positive breast cancer patients. Patients that may be excluded from this recommendation are defined by the exclusion criteria of these clinical trials. Based on the findings of USO 9735, 23 we also believe that taxanes should be included in the adjuvant treatment of breast cancer patients even when administration of anthracyclines is contraindicated. With regard to high-risk node-negative breast cancer patients, at this point there is not sufficient evidence to justify the routine use of taxanes in the adjuvant treatment of this group of patients. Additional data from other clinical trials, such as GEICAM 9805, 24 should be awaited and considered along with the positive results already obtained in the USO Acknowledgements The authors acknowledge the support of Sanofi Aventis Spain, which has allowed maintaining the necessary meetings to evaluate and discuss all the data presented in this review, and Dr. Beatriz Gil-Alberdi from HealthCo SL for her assistance in the preparation of this manuscript. References 1. Bonadonna G, Valagussa P. Dose response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 1981;304(1): Martin M, Villar A, Sole-Calvo A, et al. Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. 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