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Journal of Clinical Oncology, Vol 26, No 1 (January 1), 2008: pp. 44-53 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.3787 Taxane-Based Combinations As Adjuvant Chemotherapy of Early Breast Cancer: A Meta-Analysis of Randomized Trials
From the Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università di Napoli "Federico II"; Dipartimento di Chirurgia Generale, Oncologica e Videoassistita, Università di Napoli "Federico II", Napoli, Italy Corresponding author: Michele De Laurentiis, MD, PhD, Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università "Federico II", via Sergio Pansini, 5, 80131, Napoli, Italy; e-mail: delauren{at}unina.it; e-mail: michele.delaurentiis{at}unina.it
Purpose We conducted a meta-analysis of randomized trials that evaluated the efficacy of incorporating taxanes into anthracycline-based regimens for early breast cancer (EBC). We aimed to determine whether this approach improves disease-free survival (DFS) and overall survival (OS) and whether benefits are maintained across relevant patient subgroups. Methods Studies were retrieved by searching the PubMed database and the proceedings of major conferences. We extracted hazard ratios (HR) and 95% CIs for DFS and OS from each trial and obtained pooled estimates using an inverse-variance model. Results Thirteen studies were included in the meta-analysis (N = 22,903 patients). The pooled HR estimate was 0.83 (95% CI, 0.79 to 0.87; P < .00001) for DFS and 0.85 (95% CI, 0.79 to 0.91; P < .00001) for OS. Risk reduction was not influenced by the type of taxane, by estrogen receptor (ER) expression, by the number of axillary metastases (N1 to 3 v N4+), or by the patient's age/menopausal status. Sensitivity analysis showed that taxanes given in combination with anthracyclines, unlike sequential administration, did not significantly improve OS. However, the test for interaction showed that HR did not differ between the two schedules (P = .54). Taxane administration resulted in an absolute 5-year risk reduction of 5% for DFS and 3% for OS. Conclusion The addition of a taxane to an anthracycline-based regimen improves the DFS and OS of high-risk EBC patients. The DFS benefit was independent of ER expression, degree of nodal involvement, type of taxane, age/menopausal status of patient, and administration schedule.
Adjuvant chemotherapy based on combinations of cytotoxic drugs reduces the risk of recurrence of radically resected early breast cancer (EBC). Anthracycline-based combinations are generally more effective than earlier combinations like cyclophosphamide-methotrexate-fluorouracil (CMF) and have become the standard adjuvant chemotherapy for most patients with breast cancer.1,2 Taxanes have recently emerged as the most active cytotoxic agents for breast cancer. In the metastatic setting, these compounds were active in anthracycline-resistant disease, and in phase III trials, single-agent taxanes were at least as active as, and sometimes more active than, single-agent anthracyclines.3-5 Furthermore, the combination of anthracyclines and taxanes resulted in a better response rate and, in some cases, a longer time-to-progression than standard anthracycline-based regimens.6 Consequently, taxane-anthracycline combinations are now widely used as standard first-line treatment for advanced breast cancer. The results of the phase III trials prompted randomized trials designed to evaluate the effect of taxanes, combined with or in sequence with anthracycline-based regimens, in the adjuvant treatment of EBC patients. Most, but not all, of the efficacy data published to date show a significant improvement in disease-free survival (DFS) for the taxane-based treatment versus the control anthracycline-based treatment.7-20 Nonetheless, the role of taxane-based chemotherapy as adjuvant treatment of EBC remains controversial. For instance, a benefit in overall survival (OS) has been found only in a few trials.8,10,14,17 In addition, it remains unclear whether taxane-based regimens yield worthwhile benefits in patients with four or more axillary metastases (N4+), because some trials have shown, at subgroup analysis, a lower or no benefit for such patients.14,17 However, one of the major issues is whether endocrine-responsive tumors benefit from adjuvant taxane-based therapy. Most trials carried out so far did not find a significant benefit in this subgroup of patients7,8,10,16,20; hence, a panel of international breast cancer experts proscribed taxane-based therapy for endocrine-responsive breast cancers.1 Nonetheless, this apparent lack of benefit in single trials may well be due to chance or to the low statistical power of subgroup analyses. In this scenario, we carried out a meta-analysis of randomized trials to address questions about the efficacy of adjuvant taxane-based therapy, particularly in relevant subgroups of EBC patients.
The review was conducted according to a predefined written protocol developed by M.D.L. who also coordinated a discussion among all authors to reach a consensus about each specific methodologic issue.
Study Identification
Selection Criteria
Outcomes for Analysis
Data Extraction The following information was extracted from each report: study design, regimen details, allocated patients, nodal status, median follow-up, HRs for the whole study populations and for major patient subgroups (if available), and year of reporting. Data were independently extracted from each report by A.G. and M.G., who were blinded to each other, using a standardized data recording form. After extraction, data were reviewed and compared by M.D.L. and G.C. Instances of disagreement between the two data extractors were resolved by consultation. Author-reported HRs with 95% CIs were used when possible. If 95% CIs were not directly reported, they were estimated by the P value of the log-rank statistics.21 For two studies,10,16 reported HRs referred to the standard arm rather than the taxane-based arm (ie, HR > 1 favoring taxanes) and were, therefore, recalculated by taking the exponential of negative ln(HR) to keep consistency with other trials. When HRs were not directly reported in the original study, they were estimated indirectly using either the reported number of events and the corresponding P value for the log-rank statistics, or by reading off survival curves as suggested by Parmar et al.21 To reduce reading errors, original survival curves were digitalized and enlarged, and data extraction was based on reading off electronic coordinates for each point of interest.
Data Synthesis We carried out a sensitivity analysis by recalculating the pooled HR estimate for different subsets of studies based on relevant clinical features. This analysis serves to determine whether the pooled estimates are stable or whether they depend on some features of the studies included in the meta-analysis. Consequently, it shows whether or not the overall result would be affected by a change in the meta-analysis selection criteria. A subgroup analysis was performed by pooling estimates for similar subsets of patients across trials where available. An interaction test between treatment effect and subgroup factors was calculated according to Deeks et al.28 To estimate the absolute gains in DFS and OS, we calculated meta-analytic survival curves as suggested by Parmar et al.21 All statistical calculations were done by computer routines developed in-house.
Results of Literature Search Fourteen studies were identified.7-20 Of these, the US Oncology study by Jones et al18 was excluded because it investigated the role of a taxane in substitution of (and not in addition to) an anthracycline. Therefore, 13 studies were used in the main pooled analysis (22,903 patients). Table 1 presents the studies identified and their main characteristics.
Overall Effect of Taxanes on Risk of Recurrence
Overall Effect of Taxanes on the Risk of Death One study7 did not report OS data, and thus the meta-analysis of the effect of taxanes on the risk of death is limited to 12 studies and 22,379 patients, accounting for 3,329 deaths. Single-study HRs ranged from 0.41 to 1.03 and were statistically significant in four studies. The estimated pooled HR for all the studies shows a highly significant reduction of the risk of death for patients receiving a taxane-based therapy (P < .0001; Fig 2). There was no statistical heterogeneity among studies (P = .10; I2 = 36.2%) or evidence of publication bias (Begg-Mazumdar test, P = .27; Egger test, P = .19). The improvement in OS was similar for the paclitaxel group and for the docetaxel group (test for interaction, P = .55). The sensitivity analysis (Table 2) shows that OS was not significantly improved when the meta-analysis was restricted to studies of combination regimens, and there was significant heterogeneity among trials (P = .02). However, the test for interaction (P = .54) indicates that the risk reduction observed for this subset of studies was not significantly different from that observed for studies of sequential regimens.
Effect of Taxanes in Specific Subgroups of Patients Because of lack of information in most trials, subgroup analysis according to estrogen receptor (ER) status (ER positive v ER negative), nodal status (N1 to 3 v N4+), age (  50 v > 50), menopausal status (premenopausal v postmenopausal) and HER-2 status (HER-2 positive v HER-2 negative) was possible only for subsets of trials and only for DFS. Treatment effect according to ER status was available, either directly reported or indirectly derived, for 10 studies and a total of 17,324 patients. Pooled HR estimates indicate that taxanes significantly reduced the risk of recurrence for both ER-positive and ER-negative patients (Fig 3). There was indeed no statistically significant difference between the HRs in the two patient subgroups (test for interaction, P = .31). This was independent of whether paclitaxel or docetaxel was administered (data not shown). HR estimates by nodal status were available for four trials and 6,179 patients. The pooled HR for DFS was similar for patients with one to three positive lymph nodes and for patients with four or more positive lymph nodes (test for interaction, P = .63; Fig 4).
Treatment effect according to age/menopausal status is reported in Figure 5. Only three trials reported DFS information based on age grouping ( 50 v > 50 years), and two other trials reported data based on menopausal status. Because postmenopausal status usually arises around the age of 50 years, these two groupings are partially interchangeable, and we analyzed them together to obtain a more precise estimate. Taxanes resulted in a significant risk reduction for both age 50 years/premenopausal and older than 50 years/postmenopausal patients. The large benefit observed in the older group in the Spanish Breast Cancer Research Group (GEICAM) trial resulted in statistical heterogeneity. However, there is no statistically significant difference between the HRs for the two subgroups of patients (test for interaction, P = .13). Results were similar when the analysis was restricted to age grouping (data not shown). Only two studies reported DFS data according to HER-2 expression, and, therefore, HR estimates are less reliable (Fig 6). However, there was no interaction between HER-2 expression and taxane administration in terms of reduction of risk of recurrence (test for interaction, P = .28).
Absolute Benefits of Taxane Therapy Figure 7 depicts metacurves of DFS and OS derived from stratified pooling of the data of the trials. Cumulative estimates of probability of DFS and OS are drawn up to 5 years. Estimates became unreliable beyond this time because follow-up is still immature. Based on these curves, the estimated absolute risk reduction at 5 years, gained by adding a taxane to an anthracycline-based adjuvant regimen, is approximately 5% for DFS and 3% for OS.
We identified 13 studies that assessed the addition of a taxane to an anthracycline-based regimen. These studies accounted for a total of 22,452 randomly assigned women, 5,829 recurrences, and 3,329 deaths. These data are sufficient to provide reliable evidence to endorse or to confute the use of these drugs as adjuvant treatment for EBC. However, interpretation of such a large quantity of data is a challenging task for the average oncologist because single trials may report conflicting results. This is particularly true when we attempt to derive efficacy estimates in clinically relevant subgroups of patients. Indeed, this exercise can probably produce spurious results (either false-negative or false-positive) for each single trial just because of chance. In such a situation, meta-analyses may help resolve controversial issues because they give more accurate (ie, with narrower CIs) estimates of the average effect of a treatment, and also because they help identify causes of statistical heterogeneity among data (ie, single trials or specific subgroups of patients in which the observed treatment effect does not appear to be compatible with the average overall treatment effect). In the attempt to evaluate the efficacy of the taxane-anthracycline combination in EBC cancer treatment, we extracted HRs from relevant trials and performed a meta-analysis of all available data. Specifically, we aimed to: (1) give the best estimate of the relative reduction of risk of recurrence and death; (2) give the best estimate of the magnitude of benefit in terms of absolute reduction of the risk of recurrence and death; and (3) verify whether or not such benefits remain consistent across some relevant subgroups of patients. We used data from trials published in extenso and from trials reported at meetings to minimize publication bias. The results of the Begg-Mazumdar test and of its regression equivalent indicate the absence of publication bias in our analysis. Our meta-analysis shows that the addition of a taxane to an anthracycline-based regimen results in a statistically significant reduction of the risk of relapse (approximately 17% relative reduction) and death (approximately 15% relative reduction) for high-risk EBC patients. These benefits are also clinically relevant since they correspond to an absolute risk reduction at 5 years of approximately 5% for recurrence and 3% for death. To put these data in context, anthracyclines became the gold standard adjuvant treatment for EBC when, in the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), meta-analysis showed an absolute risk reduction at 5 years of approximately 3% both for DFS and OS.2 A crucial issue is whether taxanes should be combined with anthracyclines or whether they should be administered after an anthracycline-based regimen. Both options have theoretical advantages and drawbacks: combination regimens require dose-reduction for both compounds, but may, in theory, exploit drug synergism. On the other hand, in sequential regimens, both compounds can be administered at optimal doses. Comparing these two approaches was not an aim of this meta-analysis, making the conclusions about this point speculative. However, due to the importance of the findings, it merits some discussion. Our sensitivity analysis shows that only sequential regimens yielded a statistically significant improvement of both DFS and OS. Conversely, with combination regimens, the trend to OS improvement was not significant, and there was statistical heterogeneity among trials. However, this result should be interpreted with caution because the test for interaction indicates that the difference between the pooled HRs of the two regimens may well be ascribed to chance. In this situation, the best HR estimate for both schedules remains that which was observed in the overall meta-analysis (Figs 1 and 2). Yet, because such results pertain to indirect comparisons, we cannot exclude that there could still be moderate but worthwhile differences in efficacy between these types of regimens, which can only be identified in a direct randomized comparison.
There is some controversy about whether taxanes produce consistent benefit across specific subgroups of patients. Single trial figures suggest that the benefits of taxanes may be lower, if not negligible, for N4+14,17 and for ER-positive patients.7,8,10,16,20 Other trials suggest that benefit differs between younger and older patients.13,14,17 We were able to derive pooled estimates for these subgroups, although relevant data were available only for a subset of trials. We show that taxanes significantly reduce the risk of recurrence irrespective of ER status (ER positive v ER negative), nodal status (N1 to 3 v N4+), and age/menopausal status ( Like all studies based on aggregated data, our meta-analysis, does not reach the level of evidence obtainable with a meta-analysis based on individual patient data (IPD) because: (1) it is impossible to determine the appropriateness of random assignment procedures; (2) trial heterogeneity can only be statistically tested, but never verified; and (3) it is not possible to do an intention-to-treat analysis because data from excluded patients cannot be retrieved. However, in our case, all authors declared their data were based on the intention-to-treat principle. In this respect, the EBCTCG is currently obtaining IPD from trials exploring the role of adjuvant taxane-based treatment. This will result in a more unbiased pooled analysis and in a finer and more comprehensive subgroup analysis. Nonetheless, provided a rigorous methodology is used, pooling aggregated data, as in our case, yields information that is far superior to the simple tally of positive and negative trials. As opposed to IPD meta-analysis, the simpler method we used has the advantage of speed, which is especially important when relevant clinical questions are pending. While awaiting the definitive results of the EBCTCG overview, our meta-analysis offers the most comprehensive insight into taxane-based adjuvant regimens and may help physicians and their patients worldwide to make a better informed decision regarding the most appropriate adjuvant therapy.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Michele De Laurentiis, Sanofi-aventis; Angelo Raffaele Bianco, Sanofi-aventis; Sabino De Placido, Sanofi-aventis Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: Michele De Laurentiis, Giuseppe Cancello, Angelo Raffaele Bianco, Sabino De Placido Provision of study materials or patients: Michele De Laurentiis, Emilia Montagna, Rossella Lauria, Valeria Forestieri, Angela Esposito, Lucrezia Silvestro, Roberta Pennacchio, Carmen Criscitiello, Agnese Montanino, Gennaro Limite Collection and assembly of data: Michele De Laurentiis, Giuseppe Cancello, Diego D'Agostino, Mario Giuliano, Antonio Giordano, Emilia Montagna, Rossella Lauria, Valeria Forestieri, Angela Esposito, Lucrezia Silvestro, Roberta Pennacchio, Carmen Criscitiello, Agnese Montanino, Gennaro Limite Data analysis and interpretation: Michele De Laurentiis, Giuseppe Cancello, Diego D'Agostino, Mario Giuliano, Antonio Giordano, Emilia Montagna, Rossella Lauria, Valeria Forestieri, Angela Esposito, Lucrezia Silvestro, Roberta Pennacchio, Carmen Criscitiello, Agnese Montanino, Gennaro Limite, Angelo Raffaele Bianco, Sabino De Placido Manuscript writing: Michele De Laurentiis, Giuseppe Cancello, Diego D'Agostino, Mario Giuliano, Antonio Giordano Final approval of manuscript: Michele De Laurentiis, Giuseppe Cancello, Diego D'Agostino, Mario Giuliano, Antonio Giordano, Emilia Montagna, Rossella Lauria, Valeria Forestieri, Angela Esposito, Lucrezia Silvestro, Roberta Pennacchio, Carmen Criscitiello, Agnese Montanino, Gennaro Limite, Angelo Raffaele Bianco, Sabino De Placido
Supported by Grant No. 1044: AIRC (Associazione Italiana Ricerca sul Cancro) regional grant. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
