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. 2010 Dec 18;137(6):1005–1013. doi: 10.1007/s00432-010-0967-8

A literature-based meta-analysis taxane-based doublet versus single-agent taxane chemotherapy in patients with advanced breast cancer

Hong-Bin Xu 1,✉, Qing Xu 2, Ling Li 1
PMCID: PMC11942608  PMID: 21170550

Abstract

Purpose

Clinical trials have reported conflicting results as to whether taxane-based doublet improves outcome over single-agent taxane in patients with advanced breast cancer.

Methods

We performed a meta-analysis comparing primary and secondary end points of taxane-based doublet with single-agent taxane chemotherapy in patients with advanced breast cancer and prior anthracycline treatment. The event-based relative risk ratio (RR) with 95% confidence intervals (95% CI) was derived, and a test of heterogeneity was applied.

Results

Four eligible trials (2,343 patients) were selected from 488 studies that initially were identified. A significant difference in favoring taxane-based doublet over single-agent taxane was observed in progression-free survival (PFS) (RR, 1.33; 95% CI, 1.02–1.75; P = 0.039) and partial response (PR) (RR, 1.43; 95% CI, 1.10–1.86; P = 0.008). The ORR was higher for patients receiving taxane-based doublet, although not statistically significant (RR, 1.17; 95% CI, 0.91–1.50; P = 0.220). Whereas there was no difference in 1-year survival rate (1-year SR) (RR, 1.05; 95% CI, 0.94–1.17; P = 0.422), clinical benefit (CB) (RR, 1.02; 95% CI, 0.95–1.09; P = 0.642), and complete response (CR) (RR, 0.75; 95% CI, 0.31–1.79; P = 0.512). Toxicities did not differ significantly except stomatitis and diarrhea.

Conclusion

Taxane-based doublet appeared to improve PFS and PR compared with single-agent taxane in the treatment of patients with advanced breast cancer. Further prospective, randomized, controlled trials will be necessary.

Keywords: Meta-analysis, Taxane, Breast cancer, Doublet regimen, Advanced

Introduction

To date, breast cancer still represents the second leading cause of cancer-related death in women in western countries. Despite significant improvements in the early diagnosis and adjuvant treatment of the disease, a significant number of women will relapse (Bontenbal et al. 2005; Bergh et al. 2001). Indeed, about 25–30% of patients with negative axillary lymph nodes and more than two-thirds of those with axillary node involvement will have recurrent and/or metastatic disease and eventually die. Metastatic breast cancer (MBC) is unlikely to be cured by currently available treatment; however, systemic therapy can provide symptomatic relief and prolong survival (Gennari et al. 2005). Cytotoxic chemotherapy is generally the treatment option of choice in patients with hormone receptor-negative disease, patients whose disease has become resistant to hormonal therapy, and patients in whom impending organ failure necessitates rapid tumor shrinkage. Anthracycline monotherapy or combination therapy has been used as first-line treatment of MBC for over 30 years (Bria et al. 2005; Verma et al. 2008). Although anthracycline-based chemotherapy remains the standard treatment, several toxic effects can limit its usefulness in a palliative setting (Verma et al. 2008; Jensen 2006; Von Hoff et al. 1979).

During the past decade, other cytotoxic drugs with activity in advanced breast cancer were identified, including the taxanes (paclitaxel and docetaxel). For example, paclitaxel produced response rates in the range of 22–53% in pretreated patients, with a median TTP of 5–6 months (Seidman et al. 1998; Wist et al. 2004; Lombardi et al. 2004; Sato et al. 2003; Baltali et al. 2004; Gori et al. 2002; Perez et al. 2001). Docetaxel is also approved for patients who have had prior therapy and is one of the most active single cytotoxic agents for metastatic disease (Trudeau et al. 1996; Chan et al. 1999). Docetaxel yielded responses in 30–40% of pretreated MBC patients, with a median TTP of around 7 months (Jackisch et al. 2000; Ramos et al. 2003; Mey et al. 2003; Maisano et al. 2003; Kuroi et al. 2003; Burstein et al. 2000; Aihara et al. 2002; Hainsworth et al. 2001; D’Hondt et al. 2004).

The efficacy of taxanes in MBC seems to correlate with prior exposure to anthracyclines. Single-agent docetaxel has been compared with combination regimens in anthracycline-pretreated patients and was found to be superior to mitomycin/vinblastine (MV) and methotrexate/5-FU (M/5FU) but equivalent to continuous infusion of 5-FU with vinorelbine (Nabholtz et al. 1999; Sjostrom et al. 1999; Bonneterre et al. 2002). On the other hand, single-agent paclitaxel was compared with a salvage regimen of cisplatin–etoposide and was found inferior in response rate and TTP (Icli et al. 2002).

Several randomized phase 3 trials have also compared taxane-based doublet with single-agent taxane chemotherapy in anthracycline-pretreated patients with MBC. However, individually, these trials found that response rates, survival rate, and toxicities were statistically inconsistent. The purpose of this study was to perform a meta-analysis to examine whether taxane-based doublet chemotherapy is effective compared with single-agent taxane in patients with advanced breast cancer and prior anthracycline treatment.

Methods

The meta-analysis was performed according to a prospectively written protocol and analysis plan.

Objective of the current study

The current literature-based meta-analysis was performed to evaluate the efficacy (progression-free survival (PFS), response rate, 1-year survival rate (SR), and clinical benefit (CB)) and the toxicity profile of taxane-based doublet compared with single-agent taxane chemotherapy for the treatment of patients with advanced breast cancer and prior anthracycline treatment.

Definition of outcome

Efficacy was assessed using PFS, overall response rate (ORR), and 1-year SR as the primary outcome. The secondary endpoints were CB, the rate of clinical complete and partial response (CR and PR), and the rate of grade 3 and 4 toxicities. PFS is defined as the time (in months) between randomization and either disease progression or death from any cause; ORR is the percentage of patients who have a complete or partial tumor response; 1-year SR is defined as the percentage of patients who remain alive 1 year after randomization, and CB defined as the proportion of patients in each arm with a complete response, a partial response, or a stable disease according to World Health Organization criteria. Regarding toxicity, we considered both hematologic (neutropenia) and nonhematologic (nausea/vomiting, fatigue, alopecia, stomatitis, and diarrhea) grade 3 and 4 side effects of treatment.

Selection of trials

Only published, randomized, phase 3 trials that compare taxane-based doublet with single-agent taxane chemotherapy in patients with advanced or metastatic breast cancer were selected for evaluation.

Search stratery

A literature search was carried out in May 2010 to identify all published randomized trials. The search was performed using MEDLINE (from 1966 to December 2009) and the Cochrane Central Register of Controlled Trials, with the following search terms in all the possible combinations, “randomized”, “phase III”, “paclitaxel”, “docetaxel”, “taxanes”, and “breast cancer”. The search was limited to trials that were randomized, controlled, and published in the English language. When two or more articles reported the same data, the most recently updated data were included. References of the identified articles were also checked and principal investigators were asked if they were aware of other trials.

Data collection

Data abstraction was performed by two independent observers who extracted the data from the respective trials and verified the results by comparison. The following data were collected from the identified trials: first author’s name, journal, year of publication, treatment schedule, number of patients, age of patients, number of progression, ORR, 1-year SR, CB, CR, PR, and percentage of patients who experienced grade 3 and 4 toxicities.

Statistical methods

The doublet was considered an investigational treatment, and the single agent was used as control treatment. When a trial compared >2 different chemotherapy regimens, the investigational or control arm was counted twice or more in the analysis so that the number of comparisons was greater than the number of included trials. The outcomes were represented by dichotomous variables: The PFS, response rate, CB, and 1-year SR analysis were calculated by applying an intent-to-treat analysis, respectively. Grade 3 and 4 toxicity analysis was performed by considering the number of patients evaluable for toxicity. The event-based risk ratio (RR) was estimated for each considered endpoint, and 95% confidence interval (CI) was derived (Case et al. 2002). By this method, it was possible to apply a fixed effect model as well as a random effect model according to the inverse variance and the Mantel–Haenszel method. To test for heterogeneity between trials, the Q statistic was used. The significance of the heterogeneity test suggests a preference for the random effect estimation for a more appropriate evaluation of the results. The results are depicted in all figures as conventional meta-analysis forest plots. The meta-analysis calculations were accomplished using the Comprehensive Meta-Analysis Software (version 1.0.23; CMA, Biostat, Englewood, NJ).

Results

Selected trials

Nine potential eligible trials were identified from a total of 488 randomized trials (Fig. 1) (Nabholtz et al. 1997, 1999; Sjostrom et al. 1999; Sparano et al. 2009; Albain et al. 2008; Fountzilas et al. 2009; Verma et al. 2005; Icli et al. 2005; O’Shaughnessy et al. 2002). Of these, 4 trials were excluded (1,268 patients) because of the absence of taxanes in the experimental arm (Nabholtz et al. 1997, 1999; Sjostrom et al. 1999; Icli et al. 2005). Of the 5 remaining trials from a more detailed evaluation (2,718 patients), 1 study (511 patients) was excluded because of repeated publication (Verma et al. 2005). Finally, 4 RCTs that included 2,207 patients (1,179 in the investigational arms and 1,028 in the control arms) were gathered for the meta-analysis. The trial characteristics were listed in Table 1. The number of enrolled patients for each trial ranged from 272 to 751. Two trials compared the taxane-based doublet with single-agent docetaxel, whereas two used the paclitaxel as the single-agent arm (Sparano et al. 2009; Albain et al. 2008; Fountzilas et al. 2009; O’Shaughnessy et al. 2002). One trial modified the dose according to toxicities during treatment (O’Shaughnessy et al. 2002). Because one trial had >2 eligible arms, the number of comparisons was 5 (2,343 patients) (Fountzilas et al. 2009).

Fig. 1.

Fig. 1

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The flowchart of selected trials

Table 1.

Characteristics of the 4 randomized phase 3 trials included in the meta-analysis

Characteristic O’Shaughnessy 2002 Albain 2008 Fountzilas 2009 Sparano 2009
Chemotherapic regimen arm A D 100 mg/m2 d 1; 21-d cycle T 175 mg/m2 d 1; 21-d cycle T 80 mg/m2; 7-d cycle D 75 mg/m2; 21-d cycle
arm B C 2,500 mg/m2 d 1 and 14 + D75 mg/m2 d 1; 21-d cycle# T175 mg/m2 d 1 + G1250 mg/m2 d 1 and 8; 21-d cycle T 175 mg/m2 + Cbp; 21-d cycle* G 1,000 mg/m2 d 1 and 8 + D75 mg/m2 d 8; 21-d cycle PLD 30 mg/m2 + D 60 mg/m2; 21-d cycle
Sample size 511 (256/255) 529 (263/266) 272 (136/136) 280 (136/144) 751 (373/378)
Age (years) 25–79 26–83 27–84 27–80 26–87
Median OS (months) arm A 11.5 15.8 41 41 20.6
arm B 14.5 18.6 29.9 26.9 20.5
Median TTP (months) arm A 4.2 3.98 11.4 11.4 7
arm B 6.1 6.14 11.5 10.4 9.8
CR (%) arm A 4 5 18 18 NP
arm B 5 8 11 5 NP
PR (%) arm A NP 22 31 31 NP
arm B NP 34 27 41 NP
Overall response rates (%) arm A 30 26 49 49 26
arm B 42 41 38 46 35
Clinical benefit (%) arm A 74 NP 76 76 NP
arm B 80 NP 72 72 NP
One year overall survival (%) arm A 47 57 79 79 66
arm B 57 67 74 71 71
Grade 3 and 4 toxicity (%)
 Neutropenia arm A 15 59 12 11 11
arm B 16 57 48 13 30
 Nausea arm A 2 1 1.5 2 2
arm B 6 1 1.1 0 3
 Fatigue arm A 11 3 1.1 6 6
arm B 8 3 7 3 5
 Alopecia arm A 7 0 22 44 44
arm B 6 0 17 67 43
 Stomatitis arm A 5 1 1 0 0
arm B 17 12 2 0 2
 Diarrhea arm A 5 1 2 0 0
arm B 14 2 3 1 3
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* The dose of carboplatin did not mentioned in the trial

#Capecitabine was given by oral administration

D docetaxel, C capecitabine, T paclitaxel, G gemcitabine, PLD Pegylated liposomal doxorubicin, Cb Carboplatin, OS overall survival, TTP time to progression, CR complete response, PR partial response, ORR overall response rate, CB clinical benefit, SR survival rate, NP not reported

Combined analysis

All obtained results are displayed in Table 2 (primary endpoints) and Table 3 (secondary endpoints); primary endpoint plots are depicted in Figs. 2, 3, and 4.

Table 2.

Primary endpoints analysis

Outcome RCTs Patients RR 95% CI P Heterogeneity (p)
PFS 4 2,207 1.33 1.02, 1.75 0.039 <0.001
ORR 4 2,207 1.17 0.91, 150 0.220 <0.001
1-year SR 2 927 1.05 0.94, 1.17 0.422 0.007
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PFS progression-free survival, ORR overall response rate, SR survival rate, RCTs randomized clinical trials, RR relative risk ratio, CI confidence intervals

Table 3.

Secondary endpoints analysis

Outcome RCTs Patients RR 95% CI P Heterogeneity (p)
CB 2 1,063 1.02 0.95, 1.09 0.642 0.163
CR 3 1,592 0.75 0.31, 1.79 0.512 0.002
PR 2 1,081 1.43 1.10, 1.86 0.008 0.061
Grade 3 and 4 toxicity
 Neutropenia 4 2,308 1.67 0.88, 3.17 0.118 <0.001
 Nausea 4 2,308 1.52 0.79, 2.90 0.207 0.253
 Fatigue 4 2,308 1.08 0.54, 2.16 0.837 0.028
 Alopecia 4 2,308 1.15 0.65, 2.05 0.624 0.002
 Stomatitis 4 2,308 5.42 3.21, 9.14 <0.001 0.317
 Diarrhea 4 2,308 2.51 1.53, 4.12 <0.001 0.796
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CB clinical benefit, CR complete response, PR partial response, SR survival rate, RCTs randomized clinical trials, RR relative risk ratio, CI confidence intervals

Fig. 2.

Fig. 2

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Progression-free survival (PFS) of all randomized controlled trials (RCTs)

Fig. 3.

Fig. 3

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Overall response rate (ORR) of all randomized controlled trials (RCTs)

Fig. 4.

Fig. 4

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1-year survival rate (1-year SR) of all randomized controlled trials (RCTs)

Primary endpoints

Trials were consistent in the way they defined PFS (Sparano et al. 2009; Albain et al. 2008; Fountzilas et al. 2009; O’Shaughnessy et al. 2002). In the overall population (including 2,343 patients) reporting PFS, there was a statistically significant benefit in favor of taxane-based doublet over single-agent taxane (RR, 1.33; 95% CI, 1.02–1.75; P = 0.039), with significant heterogeneity (P < 0.001) (Table 2 and Fig. 2).

All the trials reported ORR representing a total of 2,343 patients (Sparano et al. 2009; Albain et al. 2008; Fountzilas et al. 2009; O’Shaughnessy et al. 2002). The ORR was increased for taxane-based doublet (467/1,180 = 40%) compared with taxane single-agent (377/1,164 = 32%). The Q-statistics showed the presence of heterogeneity (P < 0.001). The pooled RR was 1.17 (95% CI, 0.91–1.50; P = 0.220) by random effect model which suggested that there was no difference between taxane-based doublet and single-agent taxane (Table 2 and Fig. 3).

The numbers of patients achieving 1-year survival were available in all eligible trials (2,343 patients) (Sparano et al. 2009; Albain et al. 2008; Fountzilas et al. 2009; O’Shaughnessy et al. 2002). In the overall population, the 1-year SR was found to be not significant high for patients receiving taxane-based doublet (RR, 1.05; 95% CI, 0.94–1.17; P = 0.422), with significant heterogeneity (P = 0.007) (Table 2 and Fig. 4).

Secondary endpoints

Two trials reported CB representing a total of 1,063 patients (Fountzilas et al. 2009; O’Shaughnessy et al. 2002). The CB was 76% (405/535) and 75% (395/528) for taxane-based doublet and single-agent taxane. The Q-statistics for heterogeneity was not statistically significant (P = 0.163). The pooled results by fixed effect model demonstrated no difference in the clinical benefit rate between patients who had taxane-based doublet treatment and those who had taxane single-agent treatment (RR, 1.02; 95% CI, 0.95–1.09; P = 0.642) (Table 3).

The numbers of patients who achieved a CR were available in 3 of 4 trials (1,592 patients) (Albain et al. 2008; Fountzilas et al. 2009; O’Shaughnessy et al. 2002). In the overall population, the chance to achieve a CR was not different for patients receiving taxane-based doublet or single-agent taxane (RR, 0.75; 95% CI, 0.31–1.79; P = 0.512), with significant heterogeneity (P = 0.002) (Table 3).

The chance to achieve PR was available in 2 of 4 trials (1,081 patients) (Albain et al. 2008; Fountzilas et al. 2009) and found to be significantly higher in taxane-based doublet (RR, 1.43; 95% CI, 1.10–1.86; P = 0.008), without significant heterogeneity (P = 0.061) (Table 3).

Although toxicity including both hematologic and nonhematologic grade 3 and 4 side effects of treatment differed among all trials, taxane-based doublet had relatively high incidence of toxicity compared with single-agent taxane except fatigue. In the evaluable population, no significant difference between taxane-based doublet and single-agent taxane was found for grade 3 and 4 neutropenia (RR, 1.67; 95% CI 0.88–3.17; P = 0.118), nausea (RR, 1.52; 95% CI 0.79–2.90; P = 0.207), fatigue (RR, 1.08; 95% CI 0.54–2.16; P = 0.837), and alopecia (RR, 1.15; 95% CI 0.65–2.05; P = 0.624). The analysis for grade 3–4 stomatitis (RR, 5.42; 95% CI 3.21–9.14; P < 0.001) and diarrhea (RR, 2.51; 95% CI 1.53–4.12; P < 0.001) was found significantly higher in taxane-based doublet (Table 3).

Discussion

Since the introduction of taxane as first-line treatment for advanced breast cancer in the 1990 s, many attempts have been made to improve on the results obtained with single-agent chemotherapy (Fumoleau et al. 1997). A number of randomized studies combining taxane with other chemotherapeutic agents, most in doublets, have been conducted with conflicting results. So, we planned the current meta-analysis to evaluate whether taxane-based doublet could provide better results than single-agent taxane chemotherapy without the increased occurrence of severe toxicities in patients with advance breast cancer.

Even if contradictory results were reported from prospective trials that compared taxane-based doublet with taxane single-agent, our meta-analysis indicated a significantly increased PFS and PR with taxane-based doublet over single-agent taxane and a clear trend toward an improved ORR, although the latter improvement missed statistical significance. One possible explanation for the lack of significance in ORR may rely on the use in the largest study of 25% lower dose of docetaxel compared with the dose administered in the another study. It is possible that with more homogeneous dosage and larger samples, a significant result may have been achieved. Additionally, we noticed 3 trials in our meta-analysis using taxane combination with antimetabolites as doublet regimen (Albain et al. 2008; Fountzilas et al. 2009; O’Shaughnessy et al. 2002). Antimetabolites such as capecitabine and gemcitabine are attractive drugs to combine with taxane, given distinct mechanism of action, additive or synergistic activity in preclinical studies, nonoverlapping toxicity, and lack of cardiotoxicity (Sawada et al. 1998). However, the pooled results showed that there was no significant difference of efficacy between taxane combination with antimetabolites doublet and single-agent taxane in the present meta-analysis (data not shown). This may also partly interpret the lack of significance in ORR, survival rate between taxane-based doublet, and single-agent taxane.

With regard to tolerability, only data on hematologic (neutropenia) and nonhematologic (nausea/vomiting, fatigue, alopecia, stomatitis, and diarrhea) were available in all trials, so that no definitive conclusion could be drawn. The rate of severe hematologic (neutropenia) toxicities, as expected, increased when a second drug was added to taxanes, but the difference was not significant with single-agent regimen.

The heterogeneity in data regarding therapeutic regimens among the meta-analysis may reflect the selection bias of the available randomized phase 3 trials. In 2 of the selected studies (Sparano et al. 2009; O’Shaughnessy et al. 2002), patients treated with 3 weekly single-agent docetaxel were included. In the other 2 trials, patients treated with one weekly or 3 weekly single-agent paclitaxel were included (Albain et al. 2008; Fountzilas et al. 2009). The taxane-based doublet regimens in the selected 4 trials were also different. Docetaxel plus other cytotoxic agent including capecitabine, doxorubicin, and gemcitabine was used in three trials, and paclitaxel plus other cytotoxic agent including carboplatin and gemcitabine was used in two trials. The different therapeutic regimens may partly lead to selection bias.

There are some limitations to our approach. First, our meta-analysis was potentially limited due to the small number of trials. Second, our meta-analysis was limited to trials that were randomized, controlled, and published in the English language, not based on individual patient data. Meta-analysis based on published data tends to overestimate treatment effects compared with individual data analysis. An individual data-based meta-analysis would give a more robust estimation for the association; therefore, we should interpret the results with care, especially for a positive result. Although the risk of publication bias exists in any meta-analysis, whether based on individual patient data or not, we feel this was not an important aspect of our study. Last, the meta-analysis was focused on taxane-based chemotherapy combination and excluded combinations with target agents.

Although considering all drawbacks and controversies related to literature-based meta-analysis (Di Leo et al. 2008), the results of the current meta-analysis do not indicate a significant impact of taxane-based doublet chemotherapy on the ORR and 1-year SR of patients with advanced breast cancer and do not support their routine use in clinical practice despite the observed advantage in terms of PFS and PR. With regard to combine taxane with new drugs such as molecularly targeted agents, the available data from retrospective analyses of large randomized trials do not support their ordinary use. Randomized trial comparing paclitaxel plus vascular endothelial growth factor (VEGF) antibody bevacizumab versus paclitaxel did not show a significant survival benefit. Although the combination demonstrated higher ORR, did not appear to be particularly suitable for patients with MBC, because it was too toxic. More disappearing results were obtained from inhibition of the epidermal growth factor receptor (EGFR) by the oral tyrosine kinase inhibitor lapatinib. The combination of paclitaxel with lapatinib induced a significant improvement of ORR and CBR when compared to paclitaxel alone. However, preliminary data from the trial did not show a significant survival benefit for the combination (Miller et al. 2007; DerSimonian and Laird 1986). Trastuzumab, the first agent approved for use in patients with human epidermal growth factor receptor-2 (HER2) overexpression breast cancer, combination with paclitaxel was well tolerated and effective for patients with HER2-positive breast cancer. However, overall survival was not improved compared with HER2-negative MBC patients receiving single-agent paclitaxel (Horiguchi et al. 2009; Bullock and Blackwell 2008).

The analysis of available literature performed for this meta-analysis confirmed the absolute urgency of prospective randomized clinical trials dedicated to patients with MBC to guide therapeutic decisions. Further trials comparing taxane-based doublet with single-agent regimen in anthracycline-pretreated patients with advanced breast cancer should be considered using adapted doses and schedules to obtain an effective and well-tolerated treatment.

Conflict of interest

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work; there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled, “A literature-based meta-analysis of taxane-based doublet versus single-agent taxane chemotherapy in patients with advanced breast cancer”.

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