Phase III trial comparing granulocyte colony-stimulating factor to leridistim in the prevention of neutropenic complications in breast cancer patients treated with docetaxel/doxorubicin/cyclophosphamide: results of the BCIRG 004 trial

This randomized, double-blind, phase III trial compared granulocyte colony-stimulating factor (G-CSF; filgrastim) and leridistim (formerly myelopoietin), a chimeric dual agonist that binds both G-CSF and interleukin-3 receptors, for the prevention of neutropenic complications in patients with breast cancer receiving TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy. Patients with metastatic (44%) or localized breast cancer (56%) were randomized to G-CSF 5 microg/kg subcutaneously (s.c.) daily (n = 135), leridistim 5 microg/kg s.c. daily (n = 139), or leridistim 10 microg/kg s.c. every other day alternating with placebo (n = 139). Following administration of TAC (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2) on day 1, patients received growth factor beginning on day 2 until the postnadir absolute neutrophil count exceeded 1500 cells/ microL. Chemotherapy cycles were repeated every 21 days. The incidence of febrile neutropenia was 7% in the G-CSF arm, 19% in the daily leridistim arm (P = 0.003 for comparison with G-CSF) and 22% in the alternate-day leridistim arm (P < 0.001 for comparison with G-CSF). There was no significant difference between treatment arms in the cumulative percentage of patients experiencing grade 4 neutropenia at some point during therapy (85%-88%). However, grade 4 neutropenia occurred in 53% of cycles in the G-CSF cohort, 61% of cycles in the daily leridistim group (P = 0.063 for comparison with G-CSF), and 63% of cycles in the alternate-day leridistim group (P = 0.015 for comparison with G-CSF). We conclude that G-CSF is superior to leridistim in the prevention of febrile neutropenia in patients with advanced breast cancer receiving TAC chemotherapy. The up-front prophylactic use of G-CSF is a reasonable supportive therapy for patients treated with docetaxel/anthracycline-based combination chemotherapy.     

Phase II study of docetaxel, doxorubicin, and cyclophosphamide as first-line chemotherapy for metastatic breast cancer.

PURPOSE: This pilot phase II study investigated the efficacy and toxicity of docetaxel with doxorubicin and cyclophosphamide (TAC) as first-line chemotherapy for anthracycline-naive patients with metastatic breast cancer. PATIENTS AND METHODS: Fifty-four patients received a total of 359 courses consisting of docetaxel 75 mg/m2 given intravenously (IV) over 1 hour, preceded by IV doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 for a maximum of eight 3-week cycles. RESULTS: After an independent panel review, the overall objective response rate was 77% (complete response, 6%). Overall objective response rates in patients with visceral, bone, and liver involvement were 82%, 82%, and 80%, respectively. Median duration of response was 52 weeks, and median time to progression was 42 weeks. With a median follow-up of 32 months, the median survival had not yet been reached, whereas the 2-year survival was 57%. The main toxicities were hematologic (neutropenia grade 3/4 in 100% of patients and 95% of cycles; febrile neutropenia in 34% of patients and 9% of cycles). Documented grade 3 infection was seen in one patient (2%) in one cycle, and no toxic death was reported. Severe acute or chronic nonhematologic adverse events were infrequent, and docetaxel-specific toxicities (such as fluid retention and nail changes) were mild, with only one patient being discontinued for fluid retention. Congestive heart failure was seen in two patients (4%). CONCLUSION: TAC is an active and manageable regimen that has been chosen as the basis of five randomized phase III trials, including two pivotal studies comparing TAC to fluorouracil plus doxorubicin and cyclophosphamide in the metastatic and adjuvant treatment of breast cancer.     

Taxane/anthracycline combinations: setting a new standard in breast cancer?

Among the novel chemotherapeutic drugs introduced in the 1990s, the taxanes have emerged as the most powerful compounds in breast cancer. Both compounds, paclitaxel and docetaxel, have been evaluated in metastatic settings before adjuvant trials proceeded. Docetaxel was shown in several phase III trials to be superior, particularly in terms of survival, for salvaging polychemotherapies after failure of prior chemotherapy, including that with anthracyclines. A benefit of docetaxel was also reported when compared with doxorubicin after failure of alkylating agents. In phase III trials paclitaxel was reported to be as efficacious over 24 hours as doxorubicin 60 mg/m(2), while paclitaxel was significantly inferior to doxorubicin 75 mg/m(2) over 3 hours and was close to CMF in another trial. The role of taxanes in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging. Following several phase II studies, a phase III trial showed the significant superiority of docetaxel/doxorubicin (AT) versus doxorubicin/cyclophosphamide (AC) in terms of response and time to progression. In several phase II studies with paclitaxel (3 hours), anthracyclines in the metastatic setting showed high efficacy but produced cardiac toxicity related to a pharmacokinetic interaction between the two agents. This finding led to the implementation of metastatic strategies (phase III trials) aimed at avoiding the pharmacokinetic interaction, while the adjuvant strategies with paclitaxel focused primarily on the sequential approach (AC followed by paclitaxel). In contrast, adjuvant strategies with docetaxel/anthracycline-based programs were implemented following both sequential and combination approaches.     

Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial

BackgroundThe optimal regimen for adjuvant breast cancer chemotherapy is undefined. We compared sequential to concurrent combination of doxorubicin and cyclophosphamide with docetaxel chemotherapy in women with node-positive non-metastatic breast cancer. We report the final, 10-year analysis of disease-free survival (DFS), overall survival (OS), and long-term safety.Patients and methodsA total of 3298 women with HER2 nonamplified breast cancer were randomized to doxorubicin and cyclophosphamide every 3 weeks for four cycles followed by docetaxel (AC → T) every 3 weeks for four cycles or docetaxel, doxorubicin, and cyclophosphamide (TAC) every 3 weeks for six cycles. The patients received standard radiotherapy and endocrine therapy and were followed up for 10 years with annual clinical evaluation and mammography.ResultsThe 10-year DFS rates were 66.5% in the AC → T arm and 66.3% in the TAC arm (P = 0.749). OS was 79.9% in the AC → T arm and 78.9% in the TAC arm (P = 0.506). TAC was associated with higher rates of febrile neutropenia, although G-CSF primary prophylaxis greatly reduced this risk. AC → T was associated with a higher rate of myalgia, hand-foot syndrome, fluid retention, and sensory neuropathy.ConclusionThis 10-year analysis of the BCIRG-005 trial confirmed that the efficacy of TAC was not superior to AC → T in women with node-positive early breast cancer. The toxicity profiles differ between arms and were consistent with previous reports. The TAC regimen with G-CSF support provides shorter adjuvant treatment duration with less toxicity.Trial RegistrationClinicalTrials.gov Identifier NCT00312208.     

The choice of adjuvant combination therapies with taxanes: rationale and issues addressed in ongoing studies

The taxanes are emerging as the most powerful compounds in breast cancer. Both compounds, paclitaxel and docetaxel, have been evaluated in the metastatic setting before proceeding with adjuvant trials. Docetaxel was shown in phase III trials to be superior, in particular, in terms of time to progression and survival, to salvage polychemotherapies after failure of prior chemotherapy including anthracyclines. Also, after failure of alkylating agents, a benefit in favor of docetaxel was reported when compared to doxorubicin, whereas paclitaxel was reported to be either as efficacious or inferior to doxorubicin, while being comparable to cyclophosphamide/methotrexate/5-fluorouracil. The role of taxanes in combination with anthracyclines in first-line therapy of advanced breast cancer is still unclear although emerging. One phase III trial showed the significant superiority of doxorubicin/docetaxel (AT) versus doxorubicin/cyclophosphamide (AC) in terms of response and time to progression. Several phase II studies with paclitaxel (over 3 hours) and anthracyclines in the metastatic setting showed high efficacy, but they also showed cardiac toxicity related to a pharmacokinetic interaction between the 2 agents. This fact led to the implementation of metastatic strategies (several phase III trials) aimed at avoiding the pharmacokinetic interaction or specifically limiting the cardiac toxicity that resulted in contradictory results. Consequently, adjuvant strategies with paclitaxel focused mostly on the sequential approach (AC followed by paclitaxel). In contrast, adjuvant strategies with docetaxel/anthracycline-based programs were implemented following both sequential and combination approaches. Results of all of these trials in the adjuvant setting are eagerly awaited in order to establish the role of taxanes in adjuvant breast cancer.     

Docetaxel

? Docetaxel is an antimicrotubule agent established as a first- and/or second-line intravenous therapy in a variety of cancers, including locally advanced or metastatic breast cancer. It also is approved in the US as adjuvant therapy in early breast cancer, and continues to be investigated in this setting in combination with other agents and in various dosing schedules. ? The efficacy of docetaxel-containing adjuvant therapy has been evaluated in two large (n >1000 per trial), randomized clinical trials. One trial compared intravenous docetaxel plus doxorubicin and cyclophosphamide (TAC) every 3 weeks with standard fluorouracil plus doxorubicin and cyclophosphamide (FAC) chemotherapy. Another trial compared intravenous docetaxel plus cyclophosphamide (TC) every 3 weeks with doxorubicin plus cyclophosphamide (AC). ? Treatment with TAC improved disease-free survival (75% vs 68%; p = 0.001) and overall survival (87% vs 81%; p = 0.008) at 55 months to a greater extent than FAC. ? There were no significant differences in disease-free survival and overall survival between TC and AC. Nevertheless, a nonsignificant trend in disease-free survival favors TC and follow-up data were for a period of only 43 months. ? Tolerability in docetaxel-containing adjuvant chemotherapy regimens was manageable. The most frequently reported severe adverse events with TAC were predominantly hematologic, including neutropenia, febrile neutropenia, and neutropenic infection.      

Rationale and use of epirubicin-based therapy in the adjuvant setting

The taxanes paclitaxel and docetaxel have an important role in the treatment of breast cancer, and numerous randomized trials have evaluated their efficacy for this indication. A systematic, evidence-based review was performed, which included all randomized, controlled trials evaluating taxanes for the treatment of early- or advanced-stage breast cancer that were identified in CANCERLIT and MEDLINE searches. The primary objectives of this review were to determine the dose and schedule for each taxane that was associated with the most favorable therapeutic index, and to determine whether (and under what circumstances) the taxanes improved survival. The search revealed 18 randomized phase II (n=1) or phase III (n=17) trials. For metastatic breast cancer, the dose and schedule associated with the most favorable therapeutic index for paclitaxel was 175 mg/m2 given as a 3-hour infusion every 3 weeks, and docetaxel was 60-100 mg/m2 given as a 1-hour infusion every 3 weeks. Survival was improved under the following circumstances: (1) when 4 cycles of paclitaxel (175 mg/m2 every 3 weeks) was given following 4 cycles of conventional doxorubicin- cyclophosphamide for axillary node-positive operable breast cancer, (2) when trastuzumab was added to paclitaxel as first-line therapy for metastatic breast cancer that overexpressed HER2/neu, and (3) when docetaxel was given as second-line therapy for anthracycline-resistant disease. Although a survival benefit was found for taxanes as a component of first-line therapy in two of six trials, the interpretation of both positive trials was confounded by a lack of crossover to taxane therapy in those who were initially randomized to receive standard therapy. The taxanes improve survival in patients with early-stage breast cancer and selected patients with metastatic breast cancer. Further research is necessary in order to identify the efficacy of docetaxel relative to paclitaxel, the optimal dose of docetaxel, the role of weekly taxane therapy, the role of trastuzumab plus taxanes in early-stage disease, and whether taxanes are more effective when given concomitantly or sequentially in patients with early-stage disease     

多西他赛联合表柔比星、环磷酰胺治疗转移性乳腺癌的临床观察

目的：观察多西他赛联合表柔比星、环磷酰胺治疗转移性乳腺癌的临床疗效及不良反应。方法：回顾性分析40例转移性乳腺癌患者的化疗资料,采用国产多西他赛75mg/m2,表柔比星70-90mg/m2静脉滴注,环磷酰胺500mg/m2每3周1次。观察每次化疗后的不良反应,完成4个疗程后观察疗效。结果：全部病例均按计划完成4个周期的化疗。完全缓解（CR）3例,部分缓解（PR）20例,稳定（SD）12例,进展（PD）5例。总有效率（CR＋PR）为57.5%,控制率（CR＋PR＋SD）87.5%。主要不良反应为中性粒细胞减少、恶心、呕吐、腹泻等。结论：多西他赛联合表柔比星、环磷酰胺治疗转移性乳腺癌临床疗效较好,不良反应患者可以耐受。     

A phase II feasibility trial of dose-dense docetaxel followed by doxorubicin/cyclophosphamide as adjuvant or neoadjuvant treatment for women with node-positive or high-risk node-negative breast cancer

PURPOSE: Dose-dense adjuvant chemotherapy with doxorubicin/cyclophosphamide (AC) followed by paclitaxel has improved results compared with standard dosing at 3-week intervals. Because docetaxel might be more active than paclitaxel in the treatment of metastatic breast cancer, we explored the feasibility of substituting docetaxel for paclitaxel in dose-dense adjuvant therapy. PATIENTS AND METHODS: Seventy-six patients with node-positive breast cancer received treatment with 4 cycles of docetaxel followed by 4 cycles of AC administered with pegfilgrastim at 2-week intervals. When treatment proved difficult for the first 33 patients, 2 additional cohorts were treated: first, with a reduction of pegfilgrastim and dexamethasone prophylaxis doses (cohort 2) and then with a reduction of docetaxel from 100 mg/m2 to 75 mg/m2 (cohort 3). RESULTS: Treatment with dose-dense docetaxel at 100 mg/m2 resulted in unacceptable toxicity (24% of patients required hospitalization) and compromised subsequent dosing of AC as a result of neutropenia on the day of scheduled treatment. Only 21 patients (40%) who received docetaxel 100 mg/m2 were able to receive all 8 doses at full dose and on schedule. Reduction of docetaxel to 75 mg/m2 allowed 74% of patients to receive all 8 doses as scheduled. Delivery of AC as scheduled occurred in 82% of patients who received docetaxel 75 mg/m2 versus 40% when docetaxel 100 mg/m2 was administered. CONCLUSION: Full-dose docetaxel is difficult to administer as part of this dose-dense treatment regimen. Docetaxel 75 mg/m2 can be administered with improved subsequent delivery of 4 courses of dose-dense AC. Until comparative clinical studies are available, docetaxel should not be substituted for paclitaxel in dose-dense adjuvant chemotherapy for patients with high-risk breast cancer.     

Clinical effect of irinotecan in advanced and metastatic breast cancer patients previously treated with doxorubicin- and docetaxel-containing regimens

BACKGROUND: Previous phase II trials in Japan suggested that irinotecan was a promising agent for advanced or metastatic breast cancer pretreated with anthracycline. However, irinotecan has not yet been evaluated in the salvage setting for breast cancer pretreated with both anthracycline and taxane, which are two active agents for breast cancer. METHODS: The efficacy and safety of irinotecan were retrospectively evaluated in patients with breast cancer who had previously been treated with both doxorubicin and docetaxel. From 1996 to 1999, irinotecan was administered to 20 patients, all with a performance status of <2. Irinotecan treatment was repeated in approximately 6 week cycles consisting of the administration of irinotecan once weekly for 4 weeks followed by a 2 week rest. The median dose of irinotecan administered was 100 mg/m(2) weekly. The median number of irinotecan cycles given was 1 (range: 1-8 cycles). The median total dose was 388 mg/m(2) (range: 50-2400 mg/m(2)). RESULTS: Performance status declined to >3 after treatment with irinotecan in four patients. Two patients had grade 3 leukopenia; three had grade 3 anemia and one had a creatinine elevation of grade 4. The objective response rate for all patients was 5.0% (95% CI: 0-15.5%). The median time to progression and overall survival were 35 days (range: 17-285 days) and 124 days (range: 17-667 days), respectively, since the start of the administration of irinotecan. CONCLUSIONS: Salvage chemotherapy with irinotecan may be inactive against advanced and metastatic breast cancer pretreated with doxorubicin and docetaxel. We will evaluate irinotecan for advanced and metastatic breast cancer patients as first- or second-line chemotherapy combined with anthracycline or taxane.     

A case of effective combination therapy with docetaxel, cyclophosphamide and trastuzumab as primary systemic therapy for locally advanced HER2-positive breast cancer

We experienced a case of locally advanced breast cancer achieving a significant improvement by using a combination of docetaxel(DOC), cyclophosphamide(CPA)and trastuzumab as a primary systemic therapy.The patient was a 54-year-old woman suffering from a right breast mass, who was referred to our hospital and diagnosed with HER2-positive breast cancer with subclavicular lymph nodes metastases.The combination therapy of DOC(75 mg/m / 2), CPA(600 mg/m2)and trastuzumab(loading dose 8 mg/kg, then 6 mg/kg)for 6 courses at q3 week intervals, was started as the primary systemic therapy. After 6 courses of treatment, a right modified radical mastectomy was performed.There were a little breast cancer cells in the breast, and no axillary lymph node metastases.The combination chemotherapeutic regime with DOC, CPA and trastuzumab seems to be useful for treatment of HER2-positive breast cancer.     

环磷酰胺联合多西紫杉醇治疗转移性乳腺癌临床观察

目的 观察环磷酰胺联合多西紫杉醇治疗既往接受过多程化疗的转移性乳腺癌患者的近期疗效和毒副反应.方法 26例接受过多程化疗的转移性乳腺癌患者接受环磷酰胺联合多西紫杉醇方案化疗,环磷酰胺:600 mg/m2,d1;多西紫杉醇37.5 mg/m2,d1.8,21 d为1个周期,3个周期后评价疗效和毒副反应.结果 26例患者总...     

Adjuvant therapy of breast cancer with docetaxel-containing combination (TAC) — A Hungarian experience in the BCIRG 001 trial

The adjuvant chemotherapy of breast cancer changed in the past two decades. Docetaxel containing regimens are highly active in metastatic breast cancer. A logical approach was their incorporation into trials of early breast cancer adjuvant therapy. The authors present the Hungarian interim analysis and experience with the BCIRG 001 randomized, multicentric, phase III clinical trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) and FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer patients. The results are presented compared to the international data. Three Hungarian centers — Szt. Margit Hospital, Budapest, National Institute of Oncology, Budapest, Petz Aladár Hospital, Gyôr — participated in the international trial. Between June 1997 and June 1999, 61 patients with node positive breast cancer were enrolled in the study after the surgery. Thirty-four patients were randomized to TAC (75/50/500 mg/m² 6xq3wk) and 27 patients were randomized to FAC (500/50/500 mg/m² 6x q3wk) chemotherapy, with prospective stratification by node (1–3, 4+). Patients with hormone receptor positive tumors received tamoxifen for 5 years after the chemotherapy. Radiotherapy was performed after the 6^th cycle of chemotherapy. 33 months of follow up was performed. In both arms the hematological toxicity was more frequent. The TAC group showed a higher incidence of neutropenia (76%) compared to the FAC (22%), as well as a higher incidence of febrile neutropenia (26 % versus none), without grade 3–4 infection and there was no cases of septic death. More grade 3–4 nausea and vomiting was observed in the FAC group. At three years follow up, results indicated improvement in disease-free survival (88% vs. 76%) in favour of TAC, and similar tendency was observed in the case of overall survival (97% vs. 88%). Based on the international data analysis TAC was superior to FAC chemotherapy, the results show statistically significant differences between the two arms. This benefit with TAC was seen regardless of hormone receptor status. Additional follow up data will evaluate the role of TAC in the adjuvant setting of early breast cancer treatment.     

A Phase I study of docetaxel plus cyclophosphamide in solid tumors followed by a Phase II study as first-line therapy in metastatic breast cancer.

PURPOSE: In Phase I, the purpose was to determine the maximum tolerated dose and pharmacokinetics of docetaxel plus cyclophosphamide (DC) with and without granulocyte colony-stimulating factor in the treatment of patients with solid tumors. For Phase II, the purpose was to determine the safety and efficacy of this combination as first-line treatment in patients with metastatic breast cancer (MBC). EXPERIMENTAL DESIGN: In Phase I (45 patients), docetaxel was escalated from 60 mg/m(2) to 85 mg/m(2), and cyclophosphamide from 600 mg/m(2) to 800 mg/m(2). Pharmacokinetic evaluation of docetaxel was performed in 19 patients with MBC. In Phase II (34 patients), patients received cyclophosphamide (600 mg/m(2)) followed by docetaxel (75 mg/m(2)), i.v. RESULTS: In Phase I, the dose-limiting toxicity was neutropenia-related events. The maximum tolerated dose for DC was 75 mg/m(2)/700 mg/m(2) in solid tumor patients treated previously and 75 mg/m(2)/800 mg/m(2) for patients not treated previously for MBC. Dose escalation of docetaxel >75 mg/m(2) was not tolerated, despite prophylactic granulocyte colony-stimulating factor treatment. In Phase II, 71% of patients received prior anthracycline therapy. Neutropenic fever requiring i.v. antibiotics occurred in 6 patients (19%). One patient had grade 3 neuropathy. There was no cardiotoxicity. The overall Phase II intent-to-treat objective response rate was 65% (complete responses, 12%). The median overall survival was 22 months, and the median time to progression was 6 months. CONCLUSIONS: DC combination therapy is an active regimen with acceptable toxicity and is appropriate regardless of prior anthracycline therapy. In view of the high activity and lack of cardiotoxicity, this combination warrants additional investigation in early stage breast cancer and in combination with trastuzumab.     

多西他赛联合表柔比星、环磷酰胺治疗转移性乳腺癌的临床观察

目的:观察多西他赛联合表柔比星、环磷酰胺治疗转移性乳腺癌的临床疗效及不良反应。方法:回顾性分析40例转移性乳腺癌患者的化疗资料,采用国产多西他赛75mg/m2,表柔比星70-90mg/m2静脉滴注,环磷酰胺500mg/m2每3周1次。观察每次化疗后的不良反应,完成4个疗程后观察疗效。结果:全部病例均按计划完成4个周期的化疗。完全缓解(CR)3例,部分缓解(PR)20例,稳定(SD)12例,进展(PD)5例。总有效率(CR+PR)为57.5%,控制率(CR+PR+SD)87.5%。主要不良反应为中性粒细胞减少、恶心、呕吐、腹泻等。结论:多西他赛联合表柔比星、环磷酰胺治疗转移性乳腺癌临床疗效较好,不良反应患者可以耐受。     

A randomised feasibility/phase II study (SBG 2004-1) with dose-dense/tailored epirubicin, cyclophoshamide (EC) followed by docetaxel (T) or fixed dosed dose-dense EC/T versus T, doxorubicin and C (TAC) in node-positive breast cancer

The aim of the study was to evaluate the feasibility of tailored and dose-dense epirubicin and cyclophosphamide followed by docetaxel as adjuvant breast cancer therapy. Material and methods. Patients with node-positive breast cancer received either four cycles of biweekly and tailored EC (epirubicin 38-60-75-90-105-120 mg/m(2), cyclophosphamide 450-600-900-1200 mg/m(2)) followed by four cycles of docetaxel (60-75-85-100 mg/m(2)) (arm A) or the same regimen with fixed doses (E(90)C(600) + 4 → T(75) + 4) (arm B) or docetaxel, doxorubicin and cyclophosphamide (T(75)A(50)C(500)) every three weeks for six cycles (arm C). All patients received G-CSF support and prophylactic ciprofloxacin. Results. One-hundred and twenty-four patients were randomised in the study. In the A, B and C arm, 17% 19% and 3% of the patients had one or more cycles delayed due to side-effects whereas 24%, 5% and 15% experienced a grade 3 infection or febrile neutropenia. After the introduction of an extra week between the EC and T parts in the A and B arms, grade 3 hand-foot-skin reactions were reduced from 5 to 0.2%. Twenty-nine percent (A and B) and 20% (C) of the patients were hospitalised due to side-effects. Discussion. Dose-dense and tailored EC/T can be given with manageable toxicity and is after adjustment presently studied in the phase III Panther trial.     

Phase III randomized trial of doxorubicin and docetaxel versus doxorubicin and cyclophosphamide as primary medical therapy in women with breast cancer: an anglo-celtic cooperative oncology group study.

PURPOSE To compare the clinical and pathologic response rates of doxorubicin and cyclophosphamide (AC) with doxorubicin and docetaxel (AD) as primary chemotherapy in women with primary or locally advanced breast cancer. PATIENTS AND METHODS Eligible patients with histologically proven breast cancer with primary tumors >/= 3 cm, inflammatory or locally advanced disease, and no evidence of metastases were randomly assigned to receive a maximum of six cycles of either doxorubicin (60 mg/m(2)) plus cyclophosphamide (600 mg/m(2)) administered intravenously (IV) every 3 weeks or doxorubicin (60 mg/m(2)) plus docetaxel (75 mg/m(2)) IV every 3 weeks, followed by surgery on completion of chemotherapy. Results A total of 363 patients were randomly assigned to AC (n = 180) or AD (n = 183). A complete clinical response was observed in 17% and 20% of patients treated with AC and AD, respectively (P = .42). Overall (complete and partial) clinical response rates for AC and AD were 61% and 70%, respectively (P = .06). There was no significant difference in either the pathologic complete response rates in the breast with AC (24%) and AD (21%; P = .61) or in the number of patients with positive axillary nodes at surgery with AC (61%) and AD (66%; P = .28). At a median follow-up of 32 months, there is no significant difference between the two groups for the number of relapses. CONCLUSION In contrast to the positive results reported for sequential docetaxel after AC as primary chemotherapy of breast cancer, our data do not suggest a benefit for simultaneous AD over AC.     

Adjuvant sequential dose-dense doxorubicin, paclitaxel, and cyclophosphamide (ATC) for high-risk breast cancer is feasible in the community setting.

PURPOSE: This study evaluated the feasibility, when given in the community, of dose-dense, sequential ATC (doxorubicin, paclitaxel, cyclophosphamide) as adjuvant therapy for breast cancer with four or more metastatic axillary lymph nodes. PATIENTS AND METHODS: Patients were recruited after definitive breast cancer surgery if four or more axillary nodes were involved by metastatic cancer and if distant metastases were not present on computed tomographic scan or bone scan. Forty patients received doxorubicin, 90 mg/m2 every 14 days for three cycles; paclitaxel, 250 mg/m2 every 14 days for three cycles; and cyclophosphamide, 3 g/m2 every 14 days for three cycles with filgrastim support. Chemotherapy was administered by the referring physician. RESULTS: Mean dose intensity was 99% for doxorubicin, 96% for paclitaxel, and 99% for cyclophosphamide. Grade 3 toxicities included mucositis (13%), nausea/vomiting (10%), neuropathy (13%), and myalgia/arthralgia (10%). Thirteen patients had neutropenic fever. One patient developed acute leukemia. Three relapses have occurred. Ninety percent of patients are alive and disease-free at a median follow-up of 24 months. DISCUSSION: ATC can be administered in the community at full doses with acceptable toxicity. Preliminary efficacy data suggest that this high-dose, intensively scheduled regimen warrants comparison with standard therapy for high-risk patients.     

Advances in the use of taxanes in the adjuvant therapy of breast cancer

Among the novel chemotherapeutic drugs introduced in the 1990s, the taxanes have emerged as the most powerful compounds in breast cancer. Paclitaxel and docetaxel have been evaluated in the metastatic setting before proceeding with adjuvant trials. The adjuvant strategies of development of both taxanes have been different, mostly as a result of pharmacokinetic differences and dose-schedule issues. As a consequence, paclitaxel was studied nearly exclusively in sequential programs such as AC (doxorubicin/cyclophosphamide) followed by paclitaxel or doxorubicin, followed by paclitaxel, followed by cyclophosphamide. In contrast, docetaxel has been investigated in sequence (AC followed by docetaxel) and in combination chemotherapy (doxorubicin/docetaxel and docetaxel/doxorubicin/cyclophosphamide). Available results of large-scale phase III trials confirm that the taxanes have the potential to change the natural history of early-stage breast cancer. It is becoming clear that sequential chemotherapy and polychemotherapy approaches with taxanes are to be considered in the treatment of patients with node-positive breast cancer. Further results are eagerly awaited to fully understand the role of taxanes and to optimize their impact on early-stage breast cancer. It is our opinion that the real pending issue is no longer whether taxanes will make a difference in the adjuvant setting (the answer is most likely yes), but the definition of their optimal strategic use for maximum patient benefit.     

Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer

Purpose: To determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose of docetaxel in combination with doxorubicin, and to evaluate the activity in patients with advanced breast cancer.Patients and methods: Forty-two women with untreated metastatic breast cancer (79% with visceral metastases; 52% with prior adjuvant anthracycline therapy) were treated with doxorubicin (40–60 mg/m2) i.v. bolus followed one hour later by docetaxel (50–85 mg/m2) one-hour i.v. infusion every three weeks, without G-CSF support.Results: The MTD occurred at the dose level combining 85 mg/m2 of docetaxel and 50 mg/m2 of doxorubicin, with the DLT being neutropenic sepsis. Neutropenia and/or its complications were manageable and no grade 3–4 or severe non-hematological toxicities were observed. Fluid retention was frequent but never severe. With a median cumulative dose of doxorubicin of 392 mg/m2 (240–559 mg/m2) and a median follow-up time of 29 months (9+–41), no congestive heart failure was observed. High activity was observed at all dose levels, particularly the last four, with a response rate of 81% (95% confidence interval (95% CI): 62.5–92.5). Median time to progression was 46 weeks (6+–62). Two-year survival was 66%, and median survival has not yet been reached.Conclusions: Docetaxel–doxorubicin is feasible, safe and highly active. The incidence of febrile neutropenia without G-CSF requires careful monitoring but is acceptable in this setting. There does not appear to be an increase in the cardiac toxicity of doxorubicin. The recommended dose is either docetaxel 75 mg/m2 and doxorubicin 50 mg/m2 or docetaxel 60 mg/m2 and doxorubicin 60 mg/m2, administered every three weeks.