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Anthracycline-containing chemotherapy
Source: Breast Cancer Treatment (PDQ®)–Health Professional Version, National Cancer Institute.
Source updated: April 25, 2025 · Captured 2026-09-09.
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An Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis included 11 trials that began from 1976 to 1989 in which women were randomly assigned to receive regimens containing anthracyclines (e.g., doxorubicin or epirubicin) or CMF (cyclophosphamide, methotrexate, and fluorouracil [5-FU]). The result of the overview analysis comparing CMF and anthracycline-containing regimens suggested a slight advantage for the anthracycline regimens in both premenopausal and postmenopausal women. The HER2 status of the women in these trials was unknown.[21]
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Several trials have addressed the benefit of adding a taxane (paclitaxel or docetaxel) to an anthracycline-based adjuvant chemotherapy regimen.[22-26]
A literature-based meta-analysis of 13 studies demonstrated that the inclusion of a taxane improved both DFS and OS (DFS: HR, 0.83; 95% CI, 0.79–0.87; P < .001; OS: HR, 0.85; 95% CI, 0.79–0.91; P < .001). Five-year absolute survival differences were 5% for DFS and 3% for OS, in favor of taxane-containing regimens.[22][Level of evidence A1]
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A number of studies have addressed the optimal chemotherapy schedule and taxane selection.
An Eastern Cooperative Oncology Group–led intergroup trial (E1199 [NCT00004125]) involving 4,950 patients compared, in a factorial design, two schedules (weekly and every 3 weeks) of the two drugs (docetaxel vs. paclitaxel) after standard-dose AC chemotherapy given every 3 weeks.[27][Level of evidence A1] Study findings include the following:
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There was no difference observed in the overall comparison of docetaxel to paclitaxel with regard to DFS (odds ratio [OR], 1.03; 95% CI, 0.91–1.16; P = .61) or between the 1-week and 3-week schedules (OR, 1.06; 95% CI, 0.94–1.20; P = .33).
There was a significant association between the drug administered and schedule for both DFS (0.003) and OS (0.01). Thus, compared with paclitaxel given every 3 weeks, paclitaxel given weekly improved both DFS (OR, 1.27; 95% CI, 1.01–1.57; P = .006) and OS (OR, 1.32; 95% CI, 1.02–1.72; P = .01).
Docetaxel given every 3 weeks was also superior in DFS to paclitaxel given every 3 weeks (OR, 1.23; 95% CI, 1.00–1.52; P = .02), but the difference was not statistically significant for OS (OR, 1.13; 95% CI, 0.88–1.46; P = .25).
Docetaxel given weekly was not superior to paclitaxel given every 3 weeks. There was no stated a priori basis for expecting that varying the schedule of administration would have opposite effects for the two drugs.
Several studies sought to determine whether decreasing the duration between chemotherapy cycles could improve clinical outcomes. The overall results of these studies support the use of dose-dense chemotherapy for women with HER2-negative breast cancer.
Evidence (administration of dose-dense chemotherapy in women with HER2-negative breast cancer):
A U.S. intergroup trial (CALGB-9741 [NCT00003088]) of 2,005 node-positive patients compared, in a 2 × 2 factorial design, the use of concurrent AC followed by paclitaxel with sequential doxorubicin, paclitaxel, and cyclophosphamide given every 2 weeks with filgrastim or every 3 weeks.[28][Level of evidence A1]
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A U.S. intergroup trial (CALGB-9741 [NCT00003088]) of 2,005 node-positive patients compared, in a 2 × 2 factorial design, the use of concurrent AC followed by paclitaxel with sequential doxorubicin, paclitaxel, and cyclophosphamide given every 2 weeks with filgrastim or every 3 weeks.[28][Level of evidence A1]
At a median follow-up of 68 months, dose-dense treatment improved DFS, the primary end point, in all patient populations (HR, 0.80; P = .018), but not OS (HR, 0.85; P = .12).[29][Level of evidence A1]
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A U.S. intergroup trial (CALGB-9741 [NCT00003088]) of 2,005 node-positive patients compared, in a 2 × 2 factorial design, the use of concurrent AC followed by paclitaxel with sequential doxorubicin, paclitaxel, and cyclophosphamide given every 2 weeks with filgrastim or every 3 weeks.[28][Level of evidence A1]
There was no interaction between density and sequence.
A U.S. intergroup trial (CALGB-9741 [NCT00003088]) of 2,005 node-positive patients compared, in a 2 × 2 factorial design, the use of concurrent AC followed by paclitaxel with sequential doxorubicin, paclitaxel, and cyclophosphamide given every 2 weeks with filgrastim or every 3 weeks.[28][Level of evidence A1]
Severe neutropenia was less frequent in patients who received the dose-dense regimens.[30][Level of evidence A1]
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An Italian trial (NCT00433420) compared two versus three weekly doses of epirubicin plus cyclophosphamide (with or without 5-FU) in a factorial design, with a result similar to a U.S. intergroup trial; however, this trial also demonstrated a difference in OS.[31]
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An Italian trial (NCT00433420) compared two versus three weekly doses of epirubicin plus cyclophosphamide (with or without 5-FU) in a factorial design, with a result similar to a U.S. intergroup trial; however, this trial also demonstrated a difference in OS.[31]
For the dose-density comparison, the 5-year DFS rate was 81% (95% CI, 79%–84%) in patients treated every 2 weeks and 76% (95% CI, 74%–79%) in patients treated every 3 weeks (HR, 0.77; 95% CI, 0.65–0.92; P = .004).
An Italian trial (NCT00433420) compared two versus three weekly doses of epirubicin plus cyclophosphamide (with or without 5-FU) in a factorial design, with a result similar to a U.S. intergroup trial; however, this trial also demonstrated a difference in OS.[31]
Five-year OS rates were 94% (95% CI, 93%–96%) and 89% (95% CI, 87%–91%; HR, 0.65; 0.51–0.84; P = .001).[31][Level of evidence A1]
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A meta-analysis of 26 randomized trials that included 37,298 women treated with anthracycline- and taxane-containing chemotherapy compared standard regimens (given every 3–4 weeks) with more dose-intense regimens. Regimens that increased dose intensity by shortening the interval between cycles (i.e., dose-dense therapy or administration of the same dose over a shorter time period) and regimens that increased dose intensity by administering individual drugs in sequence to allow for higher doses (i.e., sequential scheduling).[32]
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A meta-analysis of 26 randomized trials that included 37,298 women treated with anthracycline- and taxane-containing chemotherapy compared standard regimens (given every 3–4 weeks) with more dose-intense regimens. Regimens that increased dose intensity by shortening the interval between cycles (i.e., dose-dense therapy or administration of the same dose over a shorter time period) and regimens that increased dose intensity by administering individual drugs in sequence to allow for higher doses (i.e., sequential scheduling).[32]
Patients who received more dose-intense regimens had superior recurrence-free survival (RFS) (28.0% vs. 31.4%; RR, 0.86; 95% CI, 0.82–0.89; P < .0001) and OS (18.9% vs. 21.3%; RR, 0.87; 95% CI, 0.83–0.92; P < .0001) at 10 years. The difference was present and statistically significant in receptor-positive and receptor-negative subgroups.
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