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Abstract

The introduction of taxanes in the armamentarium against breast cancer in the 1990s has been one of the landmarks in the treatment of this disease. Docetaxel in particular is considered one of the most active cytotoxic agents in metastatic breast cancer and has also been tested as adjuvant postsurgical therapy in earlier stages. A regimen including docetaxel, doxorubicin and cyclophosphamide (the TAC regimen) was the first combination that demonstrated the efficacy of docetaxel in the adjuvant setting. This combination has been approved by regulatory agencies for adjuvant therapy of node-positive breast cancer and is presently used worldwide. TAC is more toxic than the traditional anthracycline-containing combinations, but many of its side effects can be ameliorated with colony-stimulating growth factor support.

Keywords

adjuvant chemotherapy breast cancer docetaxel taxanes

Breast cancer is one of the leading causes of cancer mortality in women in western countries. Two-thirds of cases are diagnosed as local stage (no axillary involvement), while nearly a quarter of cases present axillary spread and the remaining patients have either locally advanced or metastatic disease at diagnosis. More than 50% of operable patients had tumor recurrence after isolated local therapy, due to the presence of occult micrometastatic disease. Once breast cancer has metastasized, it is generally incurable, and median survival is in the range of 2–4 years.

Several randomized clinical trials and a comprehensive meta-analysis have demonstrated that both chemotherapy and hormonal treatment administered after curative surgery significantly decrease the risk of recurrence and death of node-positive and -negative operable breast cancer patients [1,2]. The benefits of adjuvant hormonal therapy are limited to patients with hormone-sensitive tumors, while chemotherapy seems to be effective in both hormone-sensitive and -resistant tumors. The history of adjuvant chemotherapy for early breast cancer began in the 1970s, when prospective, randomized trials were initiated to study the potential benefit of polychemotherapy combinations including cyclophosphamide, methotrexate and 5-fluorouracil (the CMF regimen) [3]. CMF-like regimens were able to reduce the annual odds of recurrence and death of operable breast cancer patients by 24% (± 3%) and 14% (± 4%), respectively [1]. In the late 1970s and 1980s, anthracycline-containing combinations were tested in prospective, randomized adjuvant trials. Overall, the anthracycline regimens (5-fluorouracil, doxorubicin and cyclophosphamide [FAC], 5-fluorouracil, epirubicin and cyclophosphamide [FEC], doxorubicin and cyclophosphamide [AC], and others) resulted in an additional reduction in annual odds of relapse and death of 12% (± 4%) and 11% (± 5%), respectively, compared with CMF [1]. One study by the National Surgical Adjuvant Breast and Bowel Project (NSABP) group demonstrated that four cycles of AC were similar to six cycles of CMF [4], while other randomized studies and a meta-analysis clearly indicated that six cycles of an anthracycline-containing combination (e.g., FAC, FEC, cyclophosphamide, doxorubicin and 5-fluorouracil [CAF], cyclophosphamide, epirubicin and 5-fluorouracil [CEF]) were superior to six cycles of CMF [5]. A French study also demonstrated that six cycles of adjuvant FEC were superior to three cycles of the same regimen in patients with operable breast cancer [6]. Based on the results of these trials, most investigators in the 1990s considered that six cycles of a three-drug anthracycline-containing combination was the standard adjuvant chemotherapy for operable breast cancer, although the use of four cycles of AC and six cycles of CMF was still very common on both sides of the Atlantic, particularly in node-negative patients. At that time, the taxanes, docetaxel and paclitaxel, were incorporated into the standard armamentarium for metastatic breast cancer and were soon tested in the adjuvant setting. The incorporation of paclitaxel and docetaxel into the classic anthracycline-containing combination was carried out in two main ways: sequential and concurrent administration. Due to the concerns of increased cardiac toxicity [7,8] and other overlapping toxicities, the initial paclitaxel studies incorporated this drug sequentially, after four cycles of conventional AC [9,10]. Docetaxel was incorporated either in combination with anthracyclines (i.e., the docetaxel, doxorubicin and cyclophosphamide [TAC] regimen) or sequentially (i.e., four cycles of AC followed by four cycles of docetaxel). Data on the utility of anthracycline plus taxane-based adjuvant regimens are maturing and continue to show a survival advantage for high-risk (i.e., node-positive) breast cancer patients, while the results in node-negative patients are still to be announced.

This article reviews the current status of knowledge of the use of TAC as adjuvant (postsurgical) treatment for operable breast cancer and puts its efficacy and toxicity in the context of other taxane adjuvant regimens.

TAC regimen

Background

The TAC regimen was developed based on the important antitumor activity of both doxorubicin and docetaxel in metastatic breast cancer. In addition, these two drugs are not completely cross-resistant and have nonoverlapping dose-limiting toxicities. Cyclophosphamide posseses moderate activity as single agent in this disease, but is synergistic with both docetaxel and doxorubicin in laboratory breast cancer models and is often used in adjuvant breast cancer regimens. A prior Phase I trial of the combination of doxorubicin and docetaxel established the doses of 50 and 75 mg/m² as recommended doses for further studies [11]. Cyclophosphamide (500 mg/m²) was added to this combination in order to have an appropriated three-drug docetaxel–doxorubicin-containing regimen to be compared in the adjuvant setting with the standard FAC regimen (5-fluorouracil 500 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m²), one of the standard chemotherapy regimens used in the 1990s. Thus, the TAC regimen included docetaxel (75 mg/m²), doxorubicin (500 mg/m²) and cyclophosphamide (500 mg/m²) administered on day 1 every 3 weeks.

TAC in metastatic breast cancer

The TAC regimen was first tested in a Phase II study by Nabholtz and colleagues in breast cancer patients with metastatic disease [12]. The response rate among the 47 patients assessable for tumor response was 77% (81% in patients without prior adjuvant chemotherapy). The median duration of response was 59 weeks and the median time to progression was 42 weeks. All 54 patients were eligible for toxicity assessment. A total of 34% of patients had febrile neutropenia, usually during the first three cycles (78% of febrile neutropenic episodes). Despite this, only one patient (2%) had a severe infection. Grade 3 anemia was reported in 19% of patients. Severe asthenia was observed in 13% of patients. Grade 3 mucositis (6%) and diarrhea (4%) were also relevant side effects of TAC. Two patients (4%) had congestive heart failure (CHF), after eight and nine cycles of TAC, respectively. One toxic death due to CHF was reported.

The NSABP group conducted a multicenter Phase II trial of TAC as first-line chemotherapy in 89 patients with metastatic (66%) or locally advanced (33%) breast cancer [13]. The response rate among the 77 evaluable patients was 72.7% (16.9% complete responders). Febrile neutropenia occurred in 38% of patients. Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was not permitted, but the patients had secondary prophylaxis after the first episode of febrile neutropenia. No septic deaths were observed. Other grade 3 or greater side effects were stomatitis (6%), diarrhea (4%), arthralgia/myalgia (3%) and neurotoxicity (1%). Clincal CHF was observed in three patients (3.4%).

The encouraging antitumor activity of the TAC regimen observed in the Phase II trials prompted a Phase III study in which TAC was compared with standard FAC in metastatic breast cancer patients [14]. A total of 484 patients were enrolled in this multicenter, international trial. Febrile neutropenia was observed in 29% of patients in the TAC arm versus only 5% in the FAC arm, but grade 3 and 4 infection was not different (5 vs 4% of patients). Other grade 3–4 toxicities more frequently observed with the TAC regimen were stomatitis (8 vs 3%), diarrhea (5 vs 1%), clinical CHF (2.4 vs 0.4%) and left ventricular ejection fraction (LVEF) decrease of more than 30 points (4 vs 3%). Toxic deaths occurred in 2% of TAC-treated patients (1% septic) and 1% of FAC-treated patients (all septic). The antitumor activity was significantly higher with TAC than with FAC (objective response rate of 55 vs 44%; p = 0.02). The percentage of complete responses was also superior with TAC (7 vs 3%). However, the median time to progression (31 vs 29 weeks) and the median overall survival (OS) (21 vs 22 months) were not significantly different.

These studies demonstrated the relevant antitumor activity of the TAC regimen in metastatic breast cancer (Table 1) and prompted the use of this regimen in earlier stages of the disease.

Table 1.

Activity of TAC in advanced breast cancer.

Patient characteristics	Study design	RR (%)	TTP (weeks)	Ref.
54 Stage IV	Phase II	77	42	[12]
89 (two-thirds Stage IV, one-third Stage III)	Phase II	73	100	[13]
484 Stage IV	Phase III TAC vs FAC	TAC 5 5 FAC 44 (p = 0.02)	31 vs 29 (p = NS)	[14]

FAC: 5-fluorouracil, doxorubicin and cyclophosphamide; NS: Not statistically significant; RR: Response rate; TAC: Docetaxel, doxorubicin and cyclophosphamide; TTP: Median time to tumor progression.

TAC as primary (neoadjuvant) chemotherapy for breast cancer

O'Regan and colleagues administered four cycles of preoperative TAC chemotherapy to 40 patients with Stage III breast cancer [15]. A total of 83% of patients showed an objective clinical response (with 25% clinical complete response rate). Four of the patients (10%) had pathological complete responses (pCR) at surgery. Febrile neutropenia was observed in 12 patients (30%) and grade 2–3 anemia in 23 (58%). Eight patients (20%) had grade 3–4 infections in this trial, in which G-CSF was not used as primary prophylaxis.

Von Minckwitz and colleagues conducted an interesting neoadjuvant trial in which 286 patients with Stage I–III breast cancer were included [16]. Patients received two courses of neoadjuvant TAC and clinical response was evaluated. Those patients with objective response received four additional cycles of TAC before surgery, while patients with stable disease (no changes in tumor size) were randomized to receive either four cycles of TAC or four cycles of a noncross-resistant chemotherapy regimen (navelbine plus capecitabine [NX]) before surgery. The authors hypothesized that patients with suboptimal response to TAC would benefit from a noncross-resistant regimen. A total of 208 of the 286 enrolled patients had objective responses after two cycles of TAC and were administered four additional cycles of the same regimen. A total of 72 patients with less than partial response were randomized to receive either four NX cycles or four additional cycles of TAC. The hypothesis of the study was not confirmed by the results, since clinical response and pCR rates in patients not responding to two cycles of TAC were similar with additional TAC or NX (21.9 vs 22.5% and 3.1 vs 7.3%, respectively). In all enrolled patients, the clinical response rate before surgery was 88.4%, with 17.9% pCRs (excluding in situ residual carcinoma).

The most relevant side effects of TAC in this study were febrile neutropenia and grade 3–4 asthenia in 13.5 and 17.1% of patients, respectively. Table 2 shows the antitumor activity of TAC as neoadjuvant chemotherapy for breast cancer.

Table 2.

Activity of TAC as neoadjuvant chemotherapy.

Patient characteristics	Treatment	RR (%)	pCR (%)	Ref.
40 Stage III	TAC × 4	83	10	[15]
286 Stage I–III	TAC × 6	88.4	17.9	[16]

pCR: Pathological complete response; RR: Response rate (clinical) TAC: Docetaxel, doxorubicin and cyclophosphamide.

TAC as adjuvant treatment of breast cancer

Published trials

The international cooperative group Breast Cancer International Research Group (BCIRG) initiated its first study in 1997 [17]. The BCIRG 001 was an adjuvant, randomized Phase III trial comparing TAC with FAC, a common adjuvant standard at that time in the USA and many European countries. The study had a symmetrical design (Figure 1): six cycles of TAC were compared with six cycles of FAC, with docetaxel versus 5-fluorouracil as the only difference between regimens. All hormone receptor-positive patients received 5 years of tamoxifen treatment after chemotherapy, regardless of menopausal status. Radiotherapy was mandatory after breast-conserving surgery and was administered according to the institution's guidelines after mastectomy. Women aged 18–70 years, with a Karnofsky performance status of 80% or more and who had undergone primary surgery (mastectomy or tumorectomy/lumpectomy) with axillary node dissection (sentinel node biopsy was not routine practice) within 60 days of randomization for unilateral operable breast carcinoma (T1–3, N1, M0), were eligible. After stratification according to institution and number of involved axillary lymph nodes (1–3 vs ≥4), eligible patients received either TAC or FAC on day 1 every 21 days for six cycles. Therefore, the only relevant difference between arms was the substitution of 5-fluorouracil with docetaxel in the TAC arm.

Figure 1.

Design of BCIRG 001 trial.

Primary prophylaxis with G-CSF was not permitted. However, G-CSF was mandatory in subsequent cycles in patients who experienced one episode of febrile neutropenia or infection (lenograstim 150 μg/m²/day or filgrastim 5 μg/kg/day, days 4–11). Quality of life (QoL) was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQC30; version 2.0) and the breast cancer-specific QLQBR23 (version 1.0). Between June 1997 and June 1999, 1491 women from 20 countries were enrolled. After a median follow-up of 55 months, 399 disease-free survival (DFS) events (172 TAC, 227 FAC) were recorded. The estimated 5-year DFS for TAC and FAC was 75 and 68%, respectively (p = 0.001). This difference was mainly due to the greater number of patients in the FAC group with distant relapses. Treatment with TAC was associated with a 28% reduction in the risk of relapse as compared with FAC (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.59–0.88).

The superiority of TAC over FAC was also observed in all planned subgroup analyses, which included the number of involved axillary lymph nodes, hormone-receptor status and human epidermal growth factor receptor (HER)2/neu status, and was also independent of menopausal status ( Figure 2 ).

Figure 2.

BCIRG 001: Forest plot showing the risk reduction of recurrence in the main subgroups.

With 221 deaths (91 TAC, 130 FAC), TAC was associated with a 30% lower risk of death as compared with FAC (HR: 0.70; 95% CI: 0.53–0.91; p = 0.008). Estimated 5-year OS rates for TAC and FAC were 87 and 81%, respectively (p = 0.008).

Overall, the incidence of grade 3–4 or severe nonhematological adverse events, regardless of causality, was 36.3% for TAC and 26.6% for FAC (p < 0.0001, Table 3). Febrile neutropenia was observed in 24.7 and 2.5% of patients (p < 0.0001), respectively. Neutropenic infections occurred in 12.1 and 6.3% of TAC and FAC recipients (p < 0.001), respectively; no deaths occurred as a result of infection. The overall incidence of CHF was 1.6% for TAC and 0.7% for FAC (p = 0.0920). As of the cut-off date for this analysis, the only secondary hematological malignancy was acute myeloid leukemia, which developed in two TAC patients and one FAC patient.

Table 3.

BCIRG 001 study: relevant toxicities.

Toxic effect	TAC (%)	FAC (%)
Anemia
Grade 1–2	87.2	70.1
Grade 3–4	4.3	1.6
Need for blood transfusions	4.6	1.5
Febrile neutropenia
Protocol definition	24.7	2.5
NCI-CTC definition 2.0	28.8	4.4
Infection
Grade 1–2	35.5	34.1
Grade 3–4	3.9	2.2
Alopecia	97.8	97.1
Asthenia
Grade 1–2	69.6	65.6
Grade 3–4	11.2	5.6
Nausea	80.5	88
Vomiting	44.5	59.2
Stomatitis
Grade 1–2	62.3	50.9
Grade 3–4	7.1	2
Amenorrhea (premenopausal patients)	61.7	52.4
Diarrhea
Grade 1–2	31.4	26.1
Grade 3–4	3.8	1.8
Peripheral edema	33.7	12.6
Myalgia	26.7	9.9
Arthralgia	19.4	9
Skin toxicity	26.5	17.7
Anorexia	21.6	17.7
Nail disorders	18.5	14.4
Allergy	13.4	3.7
Congestive heart failure
Mild	1.5	0.6
Severe	0.1	0.1

Maximum grade per patient, in percentages.

FAC: 5-fluorouracil, doxorubicin and cyclophosphamide; NCI-CTC: National Cancer Institute Common Toxicity Criteria; TAC: Docetaxel, doxorubicin and cyclophosphamide.

Modified from [17].

A Canadian study has analyzed the overall quality-adjusted survival and cost–effectiveness of adjuvant TAC versus FAC in node-positive breast cancer patients [18]. Using a Markov model developed to project outcomes over a 5-year time horizon, and considering the perspective of the Canadian healthcare government payer, the authors concluded that TAC is, by commonly accepted standards, a cost-effective adjuvant chemotherapy for these women.

These data clearly establish that TAC is an efficacious and cost-effective adjuvant regimen for node-positive breast cancer patients aged 70 years or younger. However, the toxicity of TAC is important and should be addressed in further studies.

Ongoing adjuvant trials

A second adjuvant study with the TAC regimen was conducted by the Spanish Group for Breast Cancer Research (Grupo Español de Investigación de Cáncer de Mama [GEICAM]) [19,20]. This study (GEICAM 9805/TARGET 0), of a design very similar to that of BCIRG 001, compared six cycles of TAC with six cycles of FAC as postsurgical adjuvant therapy for patients with high-risk, node-negative breast cancer. Between July 1999 and December 2001, 1047 patients were enrolled in the trial. The preliminary efficacy results are expected by the first quarter of 2007.

In 1999, the NSABP group initiated the B-30 trial [21]. This study randomized node-positive breast cancer patients (n = 5300) to three different adjuvant arms: four cycles of AC (doxorubicin 50 mg/m² plus cyclophosphamide 600 mg/m²) followed by four cycles of docetaxel (100 mg/m²), four cycles of doxorubicin plus docetaxel (AT) (doxorubicin 50 mg/m² plus docetaxel 75 mg/m²) or four cycles of the standard TAC regimen.

The BCIRG 005 trial compared six cycles of TAC with four cycles of AC followed by four cycles of docetaxel (100 mg/m² every 3 weeks). At a median follow-up of 30 months, 392 DFS events have occurred, but the Independent Data Monitoring Committee (IDMC) has chosen not to release efficacy data at this time [22].

Control of TAC-induced toxicity

As previously mentioned, TAC induces significant toxicities both in the hematological and extrahematological spheres. Several attempts have been made to reduce the toxicity associated with TAC, in particular the hematological side effects, which can lead to life-threatening infectious complications [23]. Vogel and colleagues, from the BCIRG, have reported that more than half of the episodes of neutropenic fever occur in the first cycle of TAC [24]. In the BCIRG 001 trial, 250 of the 744 patients treated with TAC (33.6%) required secondary prophylaxis with G-CSF after a first episode of neutropenic fever or infection.

Nabholtz and colleagues compared the value of G-CSF and two schedules of leridistim (a chimeric dual agonist that binds both G-CSF and interleukin 3 receptors) as primary prophylactic therapy (starting from the first cycle) in 413 patients treated with TAC [25]. The incidence of febrile neutropenia was 7% in the G-CSF arm and 19–22% in the leridistim arms (p = 0.003). The authors concluded that up-front prophylactic use of G-CSF is a reasonable strategy for patients treated with TAC.

The Spanish group GEICAM initiated its 9805 trial in 1999 [19,20]. The study compared TAC with FAC as adjuvant therapy for high-risk, node-negative breast cancer; the initial design and G-CSF policy were similar to those of BCIRG 001 (only secondary prophylaxis with G-CSF was allowed). However, the high incidence of neutropenic fever in the TAC arm prompted a protocol amendment after the entry of the first 237 patients. Subsequent patients allocated to TAC received primary prophylaxis with G-CSF (PPG) from the first cycle onwards (days 4–10) in addition to ciprophloxacin. Therefore, 114 patients received TAC prior to amendment (without PPG, TAC-pre group), 414 patients received TAC after protocol amendment (with PPG, TAC-post group) and 519 patients received FAC in this trial. A comparative analysis of toxicities in these three groups is shown in Table 4 . The percentage of patients who had febrile neutropenia according to protocol definition (fever ≥ 38.1°C with grade 4 neutropenia requiring intravenous antibiotics and/or hospitalization in the same cycle) in one or more cycles was 24.6 and 6.5% in TAC-pre and -post groups, respectively (p = 0.0001).

Table 4.

Toxicity of TAC without and with primary prophylaxis with G-CSF and FAC in the GEICAM 9805 study.

Toxicity	TAC-pre (%)	TAC- post (%)	FAC (%)	p value (TAC-pre vs TAC-post)	p value (TAC-post vs FAC)
Febrile neutropenia	24.6	6.5	2.3	0.0001	0.0014
Grade 2–4 anemia	47.4	27.5	7.5	<0.0001	<0.0001
Grade 2–4 asthenia	64	48.1	33.3	0.0025	<0.0001
Grade 2–4 myalgia	14.9	7.7	1.2	0.0193	<0.0001
Grade 2–4 nail disorders	7.9	1.4	1.3	0.0012	NS
Grade 2–4 stomatitis	35.1	23.2	24.5	0.0101	NS

p > 0.05.

FAC: 5-fluorouracil, doxorubicin and cyclophosphamide; GEICAM: Grupo Español de Investigación de Cáncer de Mama; G-CSF: Granulocyte colony-stimulating factor; NS: Not significant; TAC: Docetaxel, doxorubicin and cyclophosphamide; TAC-post: Without G-CSF prophylaxis; TAC-pre: With G-CSF prophylaxis.

Modified from [20].

The percentage of patients with grade 2–4 anemia was also higher in the TAC-pre group than in the TAC-post group (47.4 vs 27.5%; p < 0.0001). Similarly, the percentage of patients with grade 2–4 anemia was higher in the TAC-post group than in the FAC group (27.5 vs 7.5%; p < 0.0001). Since G-CSF does not stimulate the erythroid progenitors, an indirect mechanism (i.e., reduction of infections and cytokine release, a well-known cause of anemia) could be the reason behind this finding. In support of this hypothesis, the author's group found a clear correlation between anemia and neutropenic fever in all three arms. For instance, the odds ratios for anemia grade 2 or greater in patients with no neutropenic fever were 3.072 (p = 0.0124, TAC-pre) and 6.06 (p < 0.0001, TAC-post). Thus, reducing neutropenic fever events and infections with PPG may be an indirect method of preventing anemia in TAC-treated patients.

Surprisingly, PPG also reduced some nonhematological toxicities, such as asthenia, anorexia, myalgia, nail disorders and stomatitis. The mechanism underlying this protective effect is unknown. The author speculates that the protection against clinical and subclinical infections associated with PPG could explain the reduction in the incidence of nail changes and stomatitis, disorders in which an infectious component is often involved. In spite of this improvement, TAC-post patients still had more asthenia, myalgia, diarrhea and arthralgia (but not anorexia, dysgeusia, nail disorders and stomatitis) than patients treated with FAC.

Further improvements in toxicity control in patients treated with TAC are therefore necessary. A recent report by von Minckwitz and colleagues has demonstrated that pegfilgrastim (administered on day 2 of each cycle) is superior to filgrastim or lenogastrim (administered on days 5–10 of each cycle) in the prevention of TAC-induced neutropenic fever [26]. Interestingly, in this study pegfilgrastim also reduced the incidence of grade 3–4 stomatitis and diarrhea compared with daily conventional G-CSF.

In spite of primary prophylaxis with filgrastim or pegfilgrastim, nearly a quarter of TAC-treated patients still have grade 2 or greater anemia. Reducing this toxicity by means of early erythropoietin administration could translate into an additional improvement in QoL. A prospective study of QoL in patients treated with adjuvant TAC, pegfilgrastim and dabepoietin is currently ongoing in Spain.

Regulatory affairs

Based on the data from the BCIRG 001 study, the TAC regimen has been approved by the US FDA, the European Agency for the Evaluation of Medicinal Products (EMEA) and other regulatory agencies for the indication of adjuvant therapy of early breast cancer. These agencies based their positive recommendations on the significant reduction of recurrence and death with the TAC regimen compared with standard FAC, and also the good DFS and OS curves of patients treated with FAC.

Role of the TAC regimen in the era of adjuvant taxanes

The results of several adjuvant studies comparing a conventional anthracycline-containing regimen with a taxane regimen have been reported over the past 15 years. These trials are usually referred to as first-generation taxane trials (Table 5) [9,10,27 –30]. All but one of these trials (the Eastern Cooperative Oncology Group [ECOG] 2197 trial) showed a DFS improvement in the taxane-containing arm. Overall, these trials provide level-1 evidence that the inclusion of taxanes in adjuvant treatment regimens (either in combination or in sequence) improves the outcome of node-positive breast cancer patients. Thus, the taxane regimens should now be considered as the new standard adjuvant chemotherapy for node-positive breast cancer patients.

Table 5.

First-generation taxane trials.

Study	N	Design	DFS	Absolute DFS improvement with taxane (%)	Ref.
CALGB 9344	3121	AC × 4 vs AC × 4 → P × 4	65 vs 70% (5-year)	5	[9]
NSABP B-28	3060	AC × 4 vs AC × 4 → P × 4	72 vs 76% (5-year)	4	[10]
GEICAM 9906	1248	FEC × 6 vs FEC × 4 → P x8	79 vs 86% (4-year)	7	[27]
BCIRG 001	1491	FAC × 6 vs TAC × 6	68 vs 75% (5-year)	7	[17]
ECOG 2197	2952	AC × 4 vs AT × 4	87 vs 87% (4-year) (NS)	0	[28]
PACS 01	1999	FEC × 6 vs FEC × 3 → T × 3	73 vs 78% (5-year)	5	[29]
USO 9735	1016	AC × 4 vs TC × 4	81 vs 86% (5-year)	5	[30]

All differences are statistically significant except otherwise specified (NS).

AC: Doxorubicin plus cyclophosphamide; AT: Doxorubicin plus docetaxel; BCIRG: Breast Cancer International Research Group; CALGB: Cancer and Leukemia Group B; DFS: Disease-free survival; ECOG: Eastern Cooperative Oncology Group; FEC: 5-fluorouracil, epirubicin and cyclophosphamide; GEICAM: Grupo Español de Investigación de Cáncer de Mama; NS: Not significant; NSABP: National Surgical Adjuvant Breast and Bowel Project; P: Paclitaxel; T: Docetaxel; TC: Docetaxel plus cyclophosphamide.

Trials comparing two different anthracycline–taxane-containing regimens were later initiated (second-generation taxane trials) [31 –33]. Reports of two of these trials are available. The first trial (Cancer And Leukemia Group B [CALGB] C9741) demonstrated that a dose-dense administration of doxorubicin, paclitaxel and cyclophosphamide (every 2 weeks with G-CSF support) is superior to conventional administration every 3 weeks. The second trial (ECOG 1199) demonstrated that the administration of paclitaxel every week or docetaxel every 3 weeks are the best options when the taxanes are given sequentially after four cycles of AC.

Breast cancer patients whose tumors have the HER2 gene alteration are at particularly high risk of relapse with conventional chemotherapy, although some trials have suggested that these patients get the maximum benefit with full-dose anthracyclines. In addition, a subgroup analysis of the BCIRG 001 has found that the addition of docetaxel to anthracyclines is of particular benefit to this subgroup of patients. The armamentarium against HER2-positive breast tumors has recently experienced an extraordinary improvement with the introduction of the monoclonal antibody trastuzumab. Five randomized Phase III trials involving the administration of trastuzumab plus chemotherapy in the adjuvant setting have been conducted and recently reported (NSABP B-31, North Central Cancer Treatment Group [NCCTG] 9831, HERceptin Adjuvant [HERA], BCIRG 06 and FINland HER2 [FINHER]) [34 –37]. These trials were unanimous in showing that the addition of trastuzumab to chemotherapy (concomitantly or sequentially) produces a dramatic reduction in the risk of relapse (~50% risk reduction).

According to these data, all breast cancer patients with the HER2 alteration who are at risk of relapse should receive trastuzumab in addition to chemotherapy. AC followed by docetaxel or weekly paclitaxel concomitantly with trastuzumab is an appropriate option for these patients. If the sequence of chemotherapy and trastuzumab is the choice, the chemotherapy regimen should preferably contain a taxane and an anthracycline.

In patients whose tumors do not overexpress HER2/neu (80% of the total), the selection of the best taxane-containing adjuvant regimen is a difficult task, considering that there are no formal randomized comparisons between the different taxane-containing options.

A recent retrospective analysis suggesting the lack of efficacy of paclitaxel-containing chemotherapy in hormone receptor-positive tumors [38] makes the choice even more difficult. Other taxane trials have not supported this observation [10,17,27,29,30], although in all of them the efficacy of the taxane-containing arm is greater in patients with hormone receptor-negative tumors.

Indirect comparisons suggest that TAC, FEC followed by weekly paclitaxel, FEC followed by docetaxel every 3 weeks and dose-dense doxorubicin–cyclophosphamide–paclitaxel are the best choices for node-positive breast cancer patients in general, although these studies were carried out in a mixed population of HER2-positive and -negative patients. Only the BCIRG 001 study has provided detailed data according to HER2/neu status. In this trial, TAC was found to be significantly superior to FAC in both HER2-positive and -negative patients.

Conclusions

TAC is an effective regimen for the adjuvant treatment of node-positive breast cancer. The results of the BCIRG 001 trial clearly demonstrate that this regimen is superior to traditional anthracycline-containing combinations in terms of both DFS and OS. The results of trials of TAC as adjuvant therapy for node-positive breast cancer patients compares favorably with other taxane regimens. The utility of TAC as adjuvant treatment of high-risk, node-negative breast cancer is pending the results of ongoing trials. On the other hand, TAC is considerably more toxic than the traditional anthracycline-containing combinations, particularly in terms of febrile neutropenia, asthenia, mucositis, diarrhea and nail disorders. Many of these side effects can be ameliorated with the use of colony-stimulating growth factors.

Future perspective

The TAC regimen is one of the best adjuvant options for node-positive breast cancer patients. However, the percentage of patients who received a benefit with the regimen is rather small. According to BCIRG 001 study data, nearly 60% of breast cancer patients will be disease-free in the long term with FAC and would not need to be treated with TAC. Conversely, nearly 30% of patients will experience a disease recurrence in spite of TAC. Therefore, the percentage of patients who actually benefit from TAC can be estimated to be 6–10%. The identification of prognostic and predictive factors that can identify this subpopulation of patients is crucial. Unfortunately, none of the conventional prognostic or predictive factors (e.g., hormone receptor and HER2 status, menopausal status, number of axillary lymph nodes) is good enough to distinguish between those patients who benefit from TAC from those who do not.

The efficacy of the TAC regimen in high-risk, node-negative breast cancer patients is presently unknown. The matter is relevant since this subgroup of patients is the majority in western countries. A single study (GEICAM 9805) has addressed this issue and will be reported soon.

The toxicity of TAC is an important concern for cancer doctors and patients. Neutropenic fever, anemia, asthenia, mucositis, diarrhea and nail disorders are important side effects of TAC that impair the QoL of the patients. Support with G-CSF can ameliorate many of these symptoms and should be used as primary prophylaxis in all patients treated with TAC. The efficacy of erythropoietin in improving residual anemia, asthenia and QoL is presently under investigation.

Executive summary

Docetaxel, doxorubicin and cyclophosphamide (TAC) regimen

The TAC regimen possesses significant antitumor activity in breast cancer, with response rates in Phase II studies of 73–77#x0025; (metastatic disease) and 83-88.4% (presurgical neoadjuvant treatment).

Efficacy

In a Phase III study in metastatic disease, the antitumor activity of TAC was superior to that of 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) (55 vs 44%; p = 0.02).

TAC was also significantly superior to FAC as adjuvant treatment of node-positive breast cancer, reducing the risk of recurrence and death by 28 and 30%, respectively, compared with FAC.

TAC was superior to FAC regardless of menopausal status, hormonal receptor status, human epidermal growth factor receptor (HER)2 status and number of axillary lymph nodes.

The determination of the efficacy of TAC as adjuvant therapy in node-negative breast cancer is pending the results of a single ongoing trial.

Adverse effects

The toxicity of TAC is relevant, particularly in terms of hematological (e.g., neutropenic fever and anemia) and extrahematological side effects (e.g., asthenia, mucositis, diarrhea and nail disorders).

A primary prophylaxis with granulocyte colony-stimulating factor (filgrastim, lenograstim or pegfilgrastim) significantly reduces the severity of hematological and extrahematological side effects of TAC and should be routine in all patients treated with this regimen.

References

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Docetaxel,Doxorubicin and Cyclophosphamide (the TAC regimen): An Effective Adjuvant Treatment for Operable Breast Cancer

Abstract

Keywords

TAC regimen

Background

TAC in metastatic breast cancer

TAC as primary (neoadjuvant) chemotherapy for breast cancer

TAC as adjuvant treatment of breast cancer

Published trials

Ongoing adjuvant trials

Control of TAC-induced toxicity

Regulatory affairs

Role of the TAC regimen in the era of adjuvant taxanes

Conclusions

Future perspective

References