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Breast Cancer

First-Line Treatment Options for Patients with HER-2–Negative Metastatic Breast Cancer: The Impact of Modern Adjuvant Chemotherapy

^aDivision of Medical Oncology, Sunnybrook and Women's College Health Sciences Centre, Toronto, Canada; ^bPrincess Margaret Hospital, Toronto, Canada

Key Words. Metastatic breast cancer • Taxane • Anthracycline • Adjuvant • Capecitabine • First-line

Correspondence: Sunil Verma, M.D., M.S.Ed., FRCP(C), Division of Medical Oncology, Sunnybrook and Women's College Health Sciences Centre, T-Wing, 2nd Floor, TSRCC, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada. Telephone: 416-480-5248; Fax: 416-480-6002; e-mail: sunil.verma{at}sunnybrook.ca

Received February 14, 2007; accepted for publication April 30, 2007.

	Learning Objectives

Top Learning Objectives Abstract Introduction Evolving Adjuvant Therapy First-Line Treatment Decisions... Search Strategy and Selection... What Is the Optimal... What Is the Optimal... What Is the Optimal... Conclusion Disclosure of Potential... Acknowledgments References

 
After completing this course, the reader will be able to:

1. Describe how changes in adjuvant treatment are having a major influence on treatment options in the first-line setting for metastatic breast cancer.
   
2. Select the most appropriate first-line treatment for a patient with metastatic breast cancer based on previous adjuvant therapy.
   
3. Discuss how as treatment options become more complex, there may no longer be a single "gold standard" therapy, and a variety of factors must be considered when selecting therapy.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Evolving Adjuvant Therapy First-Line Treatment Decisions... Search Strategy and Selection... What Is the Optimal... What Is the Optimal... What Is the Optimal... Conclusion Disclosure of Potential... Acknowledgments References

 
The management of early breast cancer has evolved rapidly in recent years. Consequently, the range of first-line treatment options for metastatic breast cancer (MBC) is becoming increasingly complicated and therapy depends on a complex interaction of tumor, patient, and physician variables. Arguably one of the most important factors determining choice of first-line chemotherapy is prior adjuvant therapy. We have reviewed data from large, randomized clinical trials to identify the most effective regimens and help clinicians to select first-line treatment based on previous adjuvant therapy. In this review we provide recommendations on the most appropriate first-line therapy according to the type of previous adjuvant therapy. With such a wide array of treatment options available, none is likely to become the gold-standard first-line treatment for MBC. Furthermore, as increasing emphasis is placed on the quality as well as the duration of survival after development of MBC, treatment decisions should take into account tumor characteristics, toxicity, convenience, potential impact on quality of life, and patient preference, in addition to robust efficacy data.

Disclosure of potential conflicts of interest is found at the end of this article.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Evolving Adjuvant Therapy First-Line Treatment Decisions... Search Strategy and Selection... What Is the Optimal... What Is the Optimal... What Is the Optimal... Conclusion Disclosure of Potential... Acknowledgments References

 
The management of early breast cancer has evolved rapidly in recent years. This pace has been driven by factors that include earlier initiation of adjuvant trials assessing agents that are effective in the metastatic setting, the introduction of new agents with superior efficacy and tolerability, and better use of established agents and molecularly targeted agents, such as trastuzumab. The paradox is that for those patients who subsequently develop metastatic breast cancer (MBC), treatment options are becoming increasingly complicated and the choice of first-line treatment depends on a complex interaction of tumor, patient, and physician variables. The main systemic treatment options for MBC are hormonal therapy, chemotherapy, or chemotherapy in combination with trastuzumab (Table 1). More recently, the addition of bevacizumab to chemotherapy has become an option. Unfortunately, despite the range of exciting therapies available, the outlook for patients with distant metastases remains quite dismal, with a 5-year survival rate of only 26% [1]. As oncologists we therefore need to continuously balance the potential benefits of a particular therapy with the potential side effects patients may suffer in this palliative setting.

	EVOLVING ADJUVANT THERAPY

Top Learning Objectives Abstract Introduction Evolving Adjuvant Therapy First-Line Treatment Decisions... Search Strategy and Selection... What Is the Optimal... What Is the Optimal... What Is the Optimal... Conclusion Disclosure of Potential... Acknowledgments References

View larger version (41K): [in this window] [in a new window]   Figure 1. Current treatments for patients with HER-2–negative MBC according to prior adjuvant therapy, in order of preference based on strength of clinical data (treatment options not supported by data from randomized trials shown in italics). Abbreviations: HER-2, human epidermal growth factor receptor; MBC, metastatic breast cancer.

	FIRST-LINE TREATMENT DECISIONS BASED ON PRIOR ADJUVANT THERAPY

Top Learning Objectives Abstract Introduction Evolving Adjuvant Therapy First-Line Treatment Decisions... Search Strategy and Selection... What Is the Optimal... What Is the Optimal... What Is the Optimal... Conclusion Disclosure of Potential... Acknowledgments References

 
In patients treated with anthracyclines and/or taxanes in the adjuvant setting, first-line treatment options include re-exposure to the same agent or introduction of a different treatment. Studies evaluating retreatment with anthracyclines and taxanes after exposure in the adjuvant setting have yielded conflicting results. In the past 5 years, data for other agents evaluated in the growing population of anthracycline- and/or taxane-pretreated patients have become available.

	SEARCH STRATEGY AND SELECTION CRITERIA

Top Learning Objectives Abstract Introduction Evolving Adjuvant Therapy First-Line Treatment Decisions... Search Strategy and Selection... What Is the Optimal... What Is the Optimal... What Is the Optimal... Conclusion Disclosure of Potential... Acknowledgments References

 
We reviewed randomized trials evaluating first-line treatment options. We included only studies that included >50 patients and in which the same type of adjuvant therapy had been used in the majority of patients, or for which efficacy results were reported by subpopulation according to the type of prior adjuvant therapy. Trials included had been published either in peer-reviewed journals or as abstracts from the San Antonio Breast Cancer Symposium, the American Society of Clinical Oncology (ASCO) Annual Meeting, the European Society of Medical Oncology conference, or the European Conference on Clinical Oncology between 2001 and 2006.

	WHAT IS THE OPTIMAL FIRST-LINE OPTION FOR PATIENTS TREATED WITH ADJUVANT ANTHRACYCLINES?

Top Learning Objectives Abstract Introduction Evolving Adjuvant Therapy First-Line Treatment Decisions... Search Strategy and Selection... What Is the Optimal... What Is the Optimal... What Is the Optimal... Conclusion Disclosure of Potential... Acknowledgments References

 
Anthracycline-Based Regimens
In patients who have received adjuvant anthracyclines, first-line anthracycline therapy may be considered, particularly in patients who have a disease-free interval (DFI) of >12 months [14] and in whom the maximal dose of anthracycline has not been reached. A different anthracycline, a different dose, or an altered schedule may be used.

The data supporting this approach are limited and often contradictory (Table 3) [15–30]. In many of the phase III trials evaluating first-line anthracycline-containing regimens, a considerable proportion of patients (14%–34%) had received anthracyclines in the adjuvant setting [31–34]. However, the efficacy of anthracycline-containing therapy in subgroups of patients previously treated with adjuvant anthracyclines is rarely reported. The only randomized study designed to prospectively evaluate retreatment with first-line anthracyclines in patients treated with anthracycline-based adjuvant therapy was stopped because of poor recruitment [15].

Several retrospective analyses have been performed in an attempt to understand whether re-exposure to an anthracycline after adjuvant anthracycline therapy is a valid approach. In most cases, these analyses were not preplanned, involved small numbers of patients, and yielded conflicting results. In a retrospective analysis of the pooled subpopulation of 68 patients who had received adjuvant doxorubicin and subsequently received first-line study treatment in two phase III trials, nonpegylated liposomal doxorubicin-containing regimens led to a significantly higher response rate than with conventional doxorubicin-containing therapy (31% versus 11%, respectively; p = .04) [36]. Time to treatment failure was also significantly longer in the experimental arm (4.2 versus 2.1 months, respectively; p = .01), presumably because of the significantly lower incidence of cardiac events. However, there was no significant difference in TTP or OS duration. In another retrospective analysis, the type of prior adjuvant therapy did not appear to influence response to cyclophosphamide, epirubicin, and 5-fluorouracil (CEF) [37]. Similarly, Gennari et al. [38] found no relationship between prior adjuvant anthracycline exposure and response rate in their retrospective study of first-line epirubicin plus paclitaxel. However, the complete response rate was significantly lower in patients who had received prior adjuvant anthracyclines than in chemotherapy-naïve patients after adjustment for age and site. As in the analysis by Venturini et al. [37], there was no significant difference in the median progression-free survival (PFS) and OS times between anthracycline-pretreated and chemotherapy-naïve patients, suggesting that prior anthracycline-based adjuvant therapy does not preclude the use of anthracyclines in the first-line setting. However, the authors noted that patients included in this study had received only a relatively low dose of adjuvant anthracyclines (<360 mg/m² epirubicin and <280 mg/m² doxorubicin) and therefore it may not be appropriate to extend these conclusions to the general population of anthracycline-pretreated patients. In addition, the limitations of a retrospective analysis must be considered.

Taxane-Based Therapy
Traditionally, re-exposure to anthracyclines up to the maximum cumulative dose was a valid option in patients with MBC. This was partly because there were no effective alternatives after anthracycline therapy. Nowadays, taxane-based therapy is considered the standard of care in MBC after anthracycline therapy. Docetaxel is significantly more active than vinorelbine plus continuous infusion 5-fluorouracil [24], and in a head-to-head trial docetaxel produced a significantly longer TTP and OS time compared with paclitaxel, but was also associated with greater toxicity [22]. Both docetaxel and paclitaxel have been used as combination partners and comparators for randomized, phase III trials of newer agents in anthracycline-pretreated patients.

One of the difficulties in comparing trials in anthracycline-pretreated patients is the use of different definitions of anthracycline resistance. All but the first and last of the trials described below have been published only in abstract form, and detailed definitions of anthracycline resistance are lacking. Therefore, potential differences in DFI and degree of exposure to anthracyclines must be taken into account when comparing data from these trials.

O'Shaughnessy et al. [23] reported a randomized, phase III trial in anthracycline-pretreated patients, defined as: progression while receiving anthracycline-based therapy without any transient improvement, no response after administration of at least four cycles of anthracycline-based therapy, relapse within 2 years of completing (neo)adjuvant anthracycline-based chemotherapy, or a brief objective response followed by progression during or within 12 months of completing anthracycline-based therapy [23]. In that trial, the combination of capecitabine (1,250 mg/m² twice daily, days 1–14 every 21 days) plus docetaxel (75 mg/m², day 1 every 21 days) produced a significantly greater response rate, TTP, and OS time than docetaxel alone. The most common toxicities were gastrointestinal effects and hand–foot syndrome, which were generally manageable with appropriate dose modification without compromising efficacy [39]. Based on retrospective analyses and toxicity data, the regimen has been refined. Preliminary results of a large, randomized trial in the adjuvant setting indicate that capecitabine (900 mg/m²) plus docetaxel (60 mg/m²) is better tolerated than single-agent docetaxel (80 mg/m²) [40].

In a randomized, phase II trial in 100 patients pretreated with adjuvant anthracyclines, first-line capecitabine plus docetaxel combination therapy was significantly more effective than sequential docetaxel followed at progression by capecitabine in terms of response rate, TTP, and OS time [27]. However, it is important to note that while all patients in the single-agent docetaxel arm were required to cross over to capecitabine, only 74% of patients in the sequential arm received capecitabine after docetaxel. In another phase III trial, anthracycline-pretreated patients (cumulative dose 550 mg/m² doxorubicin or 1,000 mg/m² epirubicin) were randomized to one of three arms: capecitabine plus docetaxel, capecitabine plus paclitaxel, or sequential capecitabine followed at progression by taxane therapy (either docetaxel or paclitaxel) [28]. Response rates were significantly higher in the combination arms than in the sequential arm, but there were no significant differences in TTP and OS time among the three groups, leading the authors to conclude that unless rapid response is the primary goal, sequential capecitabine followed by a taxane is an equally appropriate choice to capecitabine plus taxane combination therapy.

Gemcitabine has also been evaluated in combination with taxanes in anthracycline-pretreated patients. At the interim analysis of a randomized study in patients pretreated with adjuvant anthracyclines (or other chemotherapy if anthracyclines were contraindicated), a trend toward a survival benefit was observed with the addition of gemcitabine to paclitaxel as first-line treatment for MBC [25]. However, this trend was not strong enough to be confirmed until the protocol-specified analysis after 440 events, which was expected in early 2005. In a three-arm, randomized study conducted in Asia, patients were randomized to 3-weekly cycles of gemcitabine (1,250 mg/m² on days 1 and 8) plus paclitaxel (175 mg/m² on day 1), gemcitabine (1,000 mg/m² on days 1 and 8) plus paclitaxel (100 mg/m² on days 1 and 8), or gemcitabine (1,000 mg/m² on days 1 and 8) plus docetaxel (40 mg/m² on days 1 and 8) [30]. Efficacy outcomes were similar in the three treatment arms, suggesting that adjusting the schedule of gemcitabine–taxane combination regimens has little effect on activity.

At the 2005 ASCO annual meeting, Chan et al. [29] reported a phase III trial comparing capecitabine plus docetaxel with gemcitabine plus docetaxel. The study did not meet its primary objective, to demonstrate a longer PFS time with the gemcitabine–docetaxel combination. Despite the substantially shorter median follow-up in the capecitabine–docetaxel arm (78 weeks versus 88 weeks in the gemcitabine–docetaxel arm), the median PFS times were identical in the two arms. The log-rank p-value for PFS was .2886, and the p-value for the difference in response rate was .9332. OS data have not been reported. An update at the 2006 ASCO Annual Meeting demonstrated no differences between the two arms in quality of life [41].

In the randomized, phase III trial of nanoparticle albumin-bound paclitaxel versus conventional paclitaxel reported by Gradishar et al. [26], study treatment was given as first-line therapy for MBC in 41% of patients. More than three fourths of all patients had received previous anthracycline therapy (no criteria for DFI or degree of anthracycline exposure described), but in most cases, this was given in the metastatic, not the adjuvant, setting. In the overall population, the response rate and TTP were significantly greater in patients receiving nanoparticle albumin-bound paclitaxel than in those receiving conventional paclitaxel. A subpopulation analysis demonstrated response rates of 42% and 27%, respectively (p = .029), in the subpopulation of 186 patients receiving study therapy in the first-line setting, and 34% and 18%, respectively (p = .002), in the 351 anthracycline-pretreated patients. Patients who received nanoparticle albumin-bound paclitaxel also had a significantly longer median TTP (23.0 versus 16.9 weeks; p = .006) than those who received conventional paclitaxel. In the overall population there was no significant difference in OS, although a significant survival benefit was observed in the subpopulation receiving study therapy as second-line treatment.

Bevacizumab
The monoclonal antibody bevacizumab, which targets vascular endothelial growth factor, has shown high activity in combination with a taxane in the first-line setting [42]. In the Eastern Cooperative Oncology Group Breast Cancer Intergroup Trial E2100, patients were randomized to receive 4-week cycles of weekly paclitaxel (90 mg/m² on days 1, 8, and 15) plus bevacizumab (10 mg/kg on days 1 and 15) or weekly paclitaxel alone as first-line therapy for MBC or locally recurrent disease. Of the 722 patients in the trial, 65% had received adjuvant chemotherapy, including taxanes in 19% and anthracyclines in 49%. The addition of bevacizumab to paclitaxel produced a significantly longer PFS time, the primary endpoint of the trial (based on the all-randomized population: hazard ratio, 0.48; p < .0001; median, 13.3 months versus 6.7 months with paclitaxel alone) [42]. An exploratory analysis of immature survival data demonstrated a longer OS time, albeit not statistically significant, with the addition of bevacizumab; mature survival data are expected in 2007.

Vinorelbine
Apart from the trial by Bonneterre et al. [24], no randomized trials have evaluated vinorelbine alone or in combination as first-line therapy after adjuvant anthracyclines. However, in a multicenter, phase II trial, oral vinorelbine plus capecitabine produced a response in 46 (55%) of 84 patients who had previously received anthracycline-based adjuvant therapy [43]. In another study, in 50 patients pretreated with anthracyclines in the adjuvant setting, vinorelbine plus docetaxel, both administered on day 1 every 21 days, gave a 46% response rate, median PFS time of 4.8 months, and median OS time of 10.8 months [44].

	WHAT IS THE OPTIMAL FIRST-LINE OPTION FOR PATIENTS TREATED WITH ADJUVANT TAXANES AND ANTHRACYCLINES?

Top Learning Objectives Abstract Introduction Evolving Adjuvant Therapy First-Line Treatment Decisions... Search Strategy and Selection... What Is the Optimal... What Is the Optimal... What Is the Optimal... Conclusion Disclosure of Potential... Acknowledgments References

 
As described earlier, many patients now receive adjuvant anthracyclines and taxanes. However, optimal first-line treatment for this emerging population has not yet been defined. A recent Canadian survey revealed that approximately half (48%) of the patients treated with adjuvant taxanes are retreated with taxanes in the first-line metastatic setting [7]. One in five oncologists questioned said that all patients in their clinic who had received adjuvant taxanes received further taxane therapy in the first-line setting. As no data from randomized trials in patients treated with adjuvant anthracyclines and taxanes are yet available, we must extrapolate data from patients who have received anthracyclines and taxanes in either the adjuvant or the metastatic setting.

As with anthracycline retreatment, data supporting re-exposure to taxanes are sparse (Table 4) [45–53]. Seidman et al. [45] evaluated 96-hour paclitaxel infusion in patients whose disease had progressed during short-infusion taxane treatment (3-hour paclitaxel in 23 patients, 1-hour docetaxel in two patients, docetaxel then paclitaxel in one patient). Although 21 of those patients (81%) had not responded to short-infusion taxane therapy, objective responses were observed in seven patients (27%). In a large (n = 212), single-arm, phase II study of weekly paclitaxel reported by Perez et al. [46], responses were observed in seven (16%) of 45 evaluable patients previously exposed to taxanes. Weekly paclitaxel (80 mg/m²) produced a 17% response rate in patients with docetaxel-resistant MBC in a Japanese prospective study [47]. Valero et al. [48] observed some activity with 3-weekly docetaxel (100 mg/m²) in patients with paclitaxel-resistant MBC. Interestingly, all eight responding patients had received paclitaxel by 1- to 3-hour infusion, giving a 25% response rate in this subpopulation, whereas none of the 12 patients who had previously received paclitaxel by 24-hour infusion responded to docetaxel.

The reference treatment in patients with anthracycline- and taxane-pretreated MBC, against which most new therapies are now being evaluated, is capecitabine [54]. Because of the lack of a recognized standard treatment with proven activity in taxane-pretreated breast cancer at the time, regulatory approval of capecitabine was based on efficacy and tolerability demonstrated in two large, single-arm, phase II trials [55, 56]. These results were confirmed in two single-arm studies, both in more than 100 patients, conducted in Germany [54] and France [57, 58].

The only mature randomized phase III trials in anthracycline- and taxane-pretreated patients evaluated capecitabine plus bevacizumab versus capecitabine alone [50], and PLD versus weekly vinorelbine or mitomycin C plus vinblastine [51]. The addition of bevacizumab to capecitabine produced a significantly higher response rate than with capecitabine alone (20% versus 9%, respectively; p = .001) [50]. However, this did not translate into a significantly longer PFS time (the primary endpoint; hazard ratio, 0.98; 95% confidence interval [CI], 0.77–1.25; p = .857) or OS time.

In the second randomized, phase III trial, PLD was compared with weekly vinorelbine or mitomycin C plus vinblastine, neither of which is considered a standard of care in this setting, in 301 patients whose disease had progressed with first- or second-line taxane-containing therapy for MBC [51]. There was no significant difference between PLD and the comparator in PFS (hazard ratio, 1.26; 95% CI, 0.98–1.62; p = .11) or OS (hazard ratio, 1.05; 95% CI, 0.82–1.33; p = .71) times, although the PFS time was significantly longer with PLD than with the comparator in a retrospective analysis of the subgroup of anthracycline-naïve patients. The choice of a nonstandard comparator makes the significance of these results questionable.

Recently, preliminary results were reported from a randomized, phase III trial comparing capecitabine monotherapy (n = 54) with a combination of vinorelbine plus gemcitabine (n = 60) in anthracycline- and taxane-pretreated patients [52]. Although trends toward a greater response rate, TTP, and OS time with capecitabine monotherapy versus the combination were not statistically significant at an interim analysis, the duration of response was significantly longer in patients receiving capecitabine than in those treated with gemcitabine plus vinorelbine (12 versus 5 months, respectively; p = .02). The trial is ongoing and the total planned enrollment is 144 patients.

In a randomized phase II trial comparing two schedules of irinotecan, a weekly regimen appeared to be slightly better tolerated and more active than a 3-weekly regimen, although patients in the former arm were less heavily pretreated [53]. Among the subpopulation of patients pretreated with both an anthracycline and a taxane, the response rate was 27% in 30 patients receiving weekly irinotecan and 13% in 32 patients receiving 3-weekly irinotecan.

Gemcitabine and vinorelbine are commonly used in anthracycline- and taxane-pretreated patients. However, neither has consistently demonstrated high activity in this setting: 0% response rates have been reported for both agents [59, 60] and median OS durations are 6–9 months with single-agent vinorelbine and approximately 8 months with single-agent gemcitabine in heavily pretreated patients [59–65]. Taken together with results of the study by Mavroudis et al. [52], there is little evidence to support the use of either agent in this setting.

In the study of PLD by Al-Batran et al. [16] described above, 68% of patients had received prior taxanes as well as anthracyclines. Ardavanis et al. [20] reported a response rate of 31% among the subpopulation of 29 taxane-pretreated patients in their small phase II study of PLD plus vinorelbine. Therefore PLD shows promise in this setting and merits further evaluation.

The epothilone ixabepilone has demonstrated encouraging antitumor activity in several single-arm phase II studies in taxane-pretreated MBC patients. The response rate among 126 patients previously exposed to anthracyclines, taxanes, and capecitabine was 18%, the median PFS time was 3.1 months, and the median OS time was 8.6 months in a recent study [66]. In two smaller studies (n = 49 and n = 37) in taxane-pretreated patients, response rates were 12% and 22%, the median TTP were 2.2 and 2.6 months, and the median OS time was 7.9 months in one study and was not reported in the other [67, 68]. In a very small, recently reported study exploring a novel regimen (8–10 mg/m² per day, days 1–3 every 3 weeks), there were no objective responses among 12 patients, although 10 had stable disease for at least 6 weeks [69]. Another agent, pemetrexed, has shown activity in anthracycline- and taxane-pretreated patients [70] and in patients whose disease has progressed with anthracyclines, taxanes, and capecitabine [71], and may provide another treatment option in this setting.

	WHAT IS THE OPTIMAL FIRST-LINE OPTION FOR ANTHRACYCLINE- AND TAXANE-NAÏVE PATIENTS?

Top Learning Objectives Abstract Introduction Evolving Adjuvant Therapy First-Line Treatment Decisions... Search Strategy and Selection... What Is the Optimal... What Is the Optimal... What Is the Optimal... Conclusion Disclosure of Potential... Acknowledgments References

 
Historically, standard adjuvant chemotherapy was CMF. No randomized studies have evaluated CMF retreatment, although in retrospective studies, first-line CMF after adjuvant CMF yielded response rates of 52% and 55% [72, 73]. The efficacy of CMF retreatment was strongly associated with DFI in one study [72].

As chemotherapy evolved, patients presenting with MBC who had received neither anthracycline- nor taxane-containing therapy in the adjuvant setting received first-line anthracyclines and/or taxanes. A pooled analysis of seven phase III trials demonstrated a significant difference for overall response rate (relative risk, 1.21; p < .001), borderline significance for TTP (relative risk, 1.10; p = .05), and a trend toward a longer OS time, all in favor of taxane-containing therapy [74]. Not surprisingly, neutropenia and febrile neutropenia were significantly more common with anthracyclines plus taxanes as first-line therapy than with anthracycline-based therapy alone.

More recently, a randomized phase III trial by the German Arbeitsgemeinschaft Gastroenterologische Onkologie group, in which the majority of patients were anthracycline- and taxane-naïve, demonstrated that capecitabine plus paclitaxel is a viable alternative to first-line anthracycline–taxane combination therapy [75]. There were no significant differences in the PFS time (the primary endpoint), response rate, or OS time between capecitabine plus paclitaxel and epirubicin plus paclitaxel. These findings are consistent with preliminary results of another randomized phase III trial in the first-line setting, in which capecitabine–docetaxel combination therapy showed similar activity to epirubicin–docetaxel combination therapy but with less severe toxicity [34].

Emerging data suggest that non–anthracycline-containing regimens may provide a valid alternative to anthracycline plus taxane combinations in patients who have received neither of these agents in the adjuvant setting. Further data on bevacizumab in combination with other chemotherapeutic agents will expand our understanding of how use of this new agent may broaden and potentially improve treatment options for women with HER-2–negative MBC.

In patients who are not suited to intense chemotherapy or prefer oral chemotherapy in the first-line setting, capecitabine monotherapy is an appropriate treatment choice. A recent phase III trial demonstrated that oral capecitabine monotherapy produced a significantly longer OS time compared with classic oral CMF (hazard ratio, 0.72; p = .02; median, 22 months with capecitabine versus 18 months with CMF) [76].

	CONCLUSION

Top Learning Objectives Abstract Introduction Evolving Adjuvant Therapy First-Line Treatment Decisions... Search Strategy and Selection... What Is the Optimal... What Is the Optimal... What Is the Optimal... Conclusion Disclosure of Potential... Acknowledgments References

 
Rapid developments in adjuvant chemotherapy for breast cancer, and in particular the earlier use of anthracyclines and taxanes, are likely to drive changes in the first-line treatment of MBC. We have to accept that the rapid progress in newer adjuvant regimens with lower doses of both anthracyclines and taxanes will mean that the choices for patients with MBC will continue to expand. Treatment options will range from re-exposure to either anthracyclines or taxanes after adjuvant administration to the use of newer chemotherapeutic and/or biologic agents.

Results of small studies in anthracycline-pretreated breast cancer suggest that retreatment may be an option in some patients, providing the cumulative anthracycline dose does not put patients at a higher risk for cardiotoxicity. However, strong data support the use of several other regimens in this setting. Taxanes are a well-established and highly effective treatment option in anthracycline-pretreated patients and data indicate that survival can be further improved by combining taxanes with capecitabine. The response rate is improved with the addition of gemcitabine to taxane therapy, although survival data are not conclusive. There are insufficient data on vinorelbine-based combinations to recommend them. The addition of bevacizumab to chemotherapy appears to further improve outcomes, and numerous trials are evaluating chemotherapy plus bevacizumab as first-line therapy.

It is difficult to comment on the impact of the interval between adjuvant anthracycline treatment and re-exposure in the metastatic setting because some of the trials excluded patients with an anthracycline-free interval <12 months. In the study that included patients regardless of anthracycline-free interval, retrospective analysis suggested no influence of this factor on the efficacy of PLD [16]. Without data from randomized trials, the benefit of re-exposure to anthracyclines versus other treatment options cannot be determined. Because the single study designed to prospectively evaluate anthracycline retreatment had to be terminated because of recruitment difficulties, it seems unlikely that we will have a definitive answer to this issue.

In patients who have received neither anthracyclines nor taxanes in the adjuvant setting, anthracyclines are frequently used. However, data are emerging to suggest that non–anthracycline-based regimens, such as capecitabine plus a taxane, may provide valid, equally effective and well-tolerated alternatives to anthracycline–taxane combinations [34, 75]. At the opposite end of the spectrum, the only approved agent for patients with anthracycline- and taxane-pretreated disease is capecitabine, and therefore this can be considered a valid first-line treatment option in patients who have received adjuvant anthracyclines and taxanes.

By extrapolating data from the metastatic setting, we suggest that the options summarized in Figure 1 may be appropriate. Above all, treatment should be tailored to each individual patient based not only on prior adjuvant chemotherapy, but also on tumor characteristics, robust efficacy and safety data, important considerations such as convenience and potential impact on quality of life, and patient preference. Of these, tolerability will probably become one of the most important factors in the future, with increasing emphasis on the quality as well as the duration of survival after development of metastatic disease. Oncologists will have to accept that there will be many effective treatment options for patients in this setting and that none is likely to become the gold standard first-line treatment for MBC. Lastly, as the use of newer agents moves into the (neo)adjuvant setting and patients are exposed to a greater range of treatments in the early breast cancer setting, first-line treatment practice for MBC will continue to evolve. Clinical trials in the first-line metastatic setting will become increasingly difficult to interpret because of the wider range of previous treatments and differences in patient populations.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Learning Objectives Abstract Introduction Evolving Adjuvant Therapy First-Line Treatment Decisions... Search Strategy and Selection... What Is the Optimal... What Is the Optimal... What Is the Optimal... Conclusion Disclosure of Potential... Acknowledgments References

 
S.V. has received honoraria from Pfizer, Roche, Aventis, Abraxis Inc., and Bristol-Myers Squibb. M.C. has received honoraria from Roche, Aventis, Abraxis Inc., and Pfizer and a travel grant from Bristol-Myers Squibb.

S.V. has performed contract work for Abraxis, Bristol-Myers Squibb, Roche, Pfizer, and Aventis, and has a financial interest in Roche, Aventis, and Pfizer. M.C. has acted as a consultant for Roche, Aventis, Abraxis, Pfizer, and Bristol-Myers Squibb.

	ACKNOWLEDGMENTS

Top Learning Objectives Abstract Introduction Evolving Adjuvant Therapy First-Line Treatment Decisions... Search Strategy and Selection... What Is the Optimal... What Is the Optimal... What Is the Optimal... Conclusion Disclosure of Potential... Acknowledgments References

 
The authors acknowledge medical writing assistance from Jennifer Kelly, Medi-Kelsey Limited, supported by F. Hoffmann-La Roche, Basel, Switzerland.

	REFERENCES

Top Learning Objectives Abstract Introduction Evolving Adjuvant Therapy First-Line Treatment Decisions... Search Strategy and Selection... What Is the Optimal... What Is the Optimal... What Is the Optimal... Conclusion Disclosure of Potential... Acknowledgments References

 

1. National Cancer Institute. SEER Cancer Statistics Review, 1975–2003. Available at http://seer.cancer.gov/csr/1975_2003/results_merged/sect_04_breast.pdf. Accessed July 4, 2006.
2. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;365:1687–1717.[CrossRef][Medline]
3. Mamounas EP, Bryant J, Lembersky B et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. J Clin Oncol 2005;23:3686–3696.[Abstract/Free Full Text]
4. Henderson IC, Berry DA, Demetri GD et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003;21:976–983.[Abstract/Free Full Text]
5. Roché H, Fumoleau P, Spielmann M et al. Five years analysis of the PACS 01 trial: 6 cycles of FEC100 vs 3 cycles of FEC100 followed by 3 cycles of docetaxel (D) for the adjuvant treatment of node positive breast cancer. Breast Cancer Res Treat 2004;88:S16.
6. US Tandem breast cancer supplemental study MAT Q1 2006.
7. Tendler View Oncology. Xeloda: Use in 1st line BC metastatic setting, March 2006 Wave. April 2006.
8. F. Hoffmann-La Roche, Synovate European Cancer Monitor MAT Q1 2006. data on file 2006.
9. Colozza M, de Azambuja E, Cardoso F et al. Breast cancer: Achievements in adjuvant systemic therapies in the pre-genomic era. The Oncologist 2006;11:111–125.[Abstract/Free Full Text]
10. Campone M, Fumoleau P, Bourbouloux E et al. Taxanes in adjuvant breast cancer setting: Which standard in Europe? Crit Rev Oncol Hematol 2005;55:167–175.[CrossRef][Medline]
11. Fumoleau P, Bonneterre J, Luporsi E. Adjuvant chemotherapy for node-positive breast cancer patients: Which is the reference today? J Clin Oncol 2003;21:1190–1191; author reply 1191–1192.[Free Full Text]
12. Goldhirsch A, Glick JH, Gelber RD et al. Meeting highlights: International expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 2005;16:1569–1583.[Abstract/Free Full Text]
13. Poole CJ, Earl HM, Hiller L et al. NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med 2006;355:1851–1862.[Abstract/Free Full Text]
14. Beslija S, Bonneterre J, Burstein H et al. Second consensus on medical treatment of metastatic breast cancer. Ann Oncol 2007;18:215–225.[Abstract/Free Full Text]
15. Pacilio C, Morabito A, Nuzzo F et al. Is epirubicin effective in first-line chemotherapy of metastatic breast cancer (MBC) after an epirubicin-containing adjuvant treatment? A single centre phase III trial. Br J Cancer 2006;94:1233–1236.[CrossRef][Medline]
16. Al-Batran SE, Bischoff J, von Minckwitz G et al. The clinical benefit of pegylated liposomal doxorubicin in patients with metastatic breast cancer previously treated with conventional anthracyclines: A multicentre phase II trial. Br J Cancer 2006;94:1615–1620.[Medline]
17. Rivera E, Valero V, Esteva FJ et al. Lack of activity of stealth liposomal doxorubicin in the treatment of patients with anthracycline-resistant breast cancer. Cancer Chemother Pharmacol 2002;49:299–302.[CrossRef][Medline]
18. Fabi A, Ferretti G, Papaldo P et al. Pegylated liposomal doxorubicin in combination with gemcitabine: A phase II study in anthracycline-naive and anthracycline pretreated metastatic breast cancer patients. Cancer Chemother Pharmacol 2006;57:615–623.[CrossRef][Medline]
19. Rivera E, Valero V, Arun B et al. Phase II study of pegylated liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer. J Clin Oncol 2003;21:3249–3254.[Abstract/Free Full Text]
20. Ardavanis A, Mavroudis D, Kalbakis K et al. Pegylated liposomal doxorubicin in combination with vinorelbine as salvage treatment in pretreated patients with advanced breast cancer: A multicentre phase II study. Cancer Chemother Pharmacol 2006;58:742–748.[CrossRef][Medline]
21. Trudeau ME, Provencher L, Panasci L. Pegylated liposomal doxorubicin (PLD) plus cyclophosphamide as 1st-line therapy for metastatic breast cancer in patients previously treated with anthracyclines. J Clin Oncol 2005;23(suppl 16):745.
22. Jones SE, Erban J, Overmoyer B et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 2005;23:5542–5551.[Abstract/Free Full Text]
23. O'Shaughnessy J, Miles D, Vukelja S et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J Clin Oncol 2002;20:2812–2823.[Abstract/Free Full Text]
24. Bonneterre J, Roche H, Monnier A et al. Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure. Br J Cancer 2002;87:1210–1215.[CrossRef][Medline]
25. Albain KS, Nag S, Calderillo-Ruiz G et al. Global phase III study of gemcitabine plus paclitaxel (GT) vs. paclitaxel (T) as frontline therapy for metastatic breast cancer (MBC): First report of overall survival. J Clin Oncol 2004;22(suppl 14):510.
26. Gradishar WJ, Tjulandin S, Davidson N et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 2005;23:7794–7803.[Abstract/Free Full Text]
27. Beslija S, Obralic N, Basic H et al. Randomized trial of sequence vs. combination of capecitabine (X) and docetaxel (T): XT vs. T followed by X after progression as first-line therapy for patients (pts) with metastatic breast cancer (MBC). J Clin Oncol 2006;24(suppl 18):571.[Abstract/Free Full Text]
28. Soto C, Torrecillas L, Reyes S et al. Capecitabine (X) and taxanes in patients (pts) with anthracycline-pretreated metastatic breast cancer (MBC): Sequential vs. combined therapy results from a MOSG randomized phase III trial. J Clin Oncol 2006;24(suppl 18):570.
29. Chan S, Romieu G, Huober J et al. Gemcitabine plus docetaxel (GD) versus capecitabine plus docetaxel (CD) for anthracycline-pretreated metastatic breast cancer (MBC) patients (pts): Results of a European phase III study. J Clin Oncol 2005;23(suppl 16):581.
30. Khoo K-S, Zaidi M, Srimuninnimit V et al. Randomized phase II trial of three gemcitabine (GEM)-taxane combinations in metastatic breast cancer (MBC). J Clin Oncol 2004;22(suppl 14):710.
31. Langley RE, Carmichael J, Jones AL et al. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute Trial AB01. J Clin Oncol 2005;23:8322–8330.[Abstract/Free Full Text]
32. Fountzilas G, Kalofonos HP, Dafni U et al. Paclitaxel and epirubicin versus paclitaxel and carboplatin as first-line chemotherapy in patients with advanced breast cancer: A phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 2004;15:1517–1526.[Abstract/Free Full Text]
33. Fountzilas G, Papadimitriou C, Dafni U et al. Dose-dense sequential chemotherapy with epirubicin and paclitaxel versus the combination, as first-line chemotherapy, in advanced breast cancer: A randomized study conducted by the Hellenic Cooperative Oncology Group. J Clin Oncol 2001;19:2232–2239.[Abstract/Free Full Text]
34. Mavroudis D, Boukovinas I, Ardavanis A et al. A multicenter phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first line treatment in patients with locally advanced and metastatic breast cancer. Preliminary report. the 2005 San Antonio Breast Cancer Symposium; December 8–12, 2005; San Antonio, TX, Presented at.
35. O'Brien MER, Wigler N, Inbar M et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX^TM/Doxil® versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004;15:440–449.[Abstract/Free Full Text]
36. Batist G, Harris L, Azarnia N et al. Improved anti-tumor response rate with decreased cardiotoxicity of non-pegylated liposomal doxorubicin compared with conventional doxorubicin in first-line treatment of metastatic breast cancer in patients who had received prior adjuvant doxorubicin: Results of a retrospective analysis. Anticancer Drugs 2006;17:587–595.[CrossRef][Medline]
37. Venturini M, Bruzzi P, Del Mastro L et al. Effect of adjuvant chemotherapy with or without anthracyclines on the activity and efficacy of first-line cyclophosphamide, epidoxorubicin, and fluorouracil in patients with metastatic breast cancer. J Clin Oncol 1996;14:764–773.[Abstract/Free Full Text]
38. Gennari A, Bruzzi P, Orlandini C et al. Activity of first-line epirubicin and paclitaxel in metastatic breast cancer is independent of type of adjuvant therapy. Br J Cancer 2004;90:962–967.[CrossRef][Medline]
39. Leonard R, O'Shaughnessy J, Vukelja S et al. Detailed analysis of a randomized phase III trial: Can the tolerability of capecitabine plus docetaxel be improved without compromising its survival advantage? Ann Oncol 2006;17:1379–1385.[Abstract/Free Full Text]
40. Joensuu H, Hemminki A, Huovinen R et al. The FinXX trial: Safety results in 600 patients (pts) randomized to either docetaxel (T) followed by cyclophosphamide (C) + epirubicin (E) + 5-FU (F) (CEF) or T + capecitabine (X) followed by CEX as adjuvant therapy for early breast cancer (BC). J Clin Oncol 2007;25(suppl 18):11035.
41. Fumoleau P, Romieu G, Chan S et al. Impact of symptoms and toxicity on quality of life: Exploratory analysis of gemcitabine plus docetaxel vs capecitabine plus docetaxel in metastatic breast cancer. J Clin Oncol 2006;24(suppl 18):682.
42. Roche Products Limited. Avastin SPC (date of revision 13^th April 2007). electronic Medicines Compendium (eMC). Available at http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=15748#CLINICAL_PARTS. Accessed April 17, 2007.
43. Finek J, Holubec L, Elgrova L et al. The effect of oral vinorelbine and capecitabine in patients with metastatic breast cancer. J Clin Oncol 2006;24(suppl 18):10605.
44. Marti JL, Bueso P, Mayordomo JI et al. Combination chemotherapy with docetaxel plus vinorelbine in metastatic breast cancer patients with prior exposure to anthracyclines. Ann Oncol 2001;12:1061–1065.[Abstract/Free Full Text]
45. Seidman AD, Hochhauser D, Gollub M et al. Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: A phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer. J Clin Oncol 1996;14:1877–1884.[Abstract/Free Full Text]
46. Perez EA, Vogel CL, Irwin DH et al. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol 2001;19:4216–4223.[Abstract/Free Full Text]
47. Taguchi T, Aihara T, Takatsuka Y et al. Phase II study of weekly paclitaxel for docetaxel-resistant metastatic breast cancer in Japan. Breast J 2004;10:509–513.[CrossRef][Medline]
48. Valero V, Jones SE, Von Hoff DD et al. A phase II study of docetaxel in patients with paclitaxel-resistant metastatic breast cancer. J Clin Oncol 1998;16:3362–3368.[Abstract]
49. O'Shaughnessy JA, Blum JL, Sandbach JF et al. Weekly nanoparticle albumin paclitaxel (Abraxane) results in long-term disease control in patients with taxane-refractory metastatic breast cancer. the 2005 San Antonio Breast Cancer Symposium; December 8–12, 2005; San Antonio, TX, Presented at.
50. Miller KD, Chap LI, Holmes FA et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–799.[Abstract/Free Full Text]
51. Keller AM, Mennel RG, Georgoulias VA et al. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol 2004;22:3893–3901.[Abstract/Free Full Text]
52. Mavroudis D, Ardavanis A, Boukovinas I et al. A multicenter randomized study comparing vinorelbine plus gemcitabine versus capecitabine monotherapy as salvage treatment in patients with advanced breast cancer pretreated with taxane and anthracycline chemotherapy: A preliminary report. J Clin Oncol 2006;24(suppl 18):658.
53. Perez EA, Hillman DW, Mailliard JA et al. Randomized phase II study or two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J Clin Oncol 2004;22:2849–2855.[Abstract/Free Full Text]
54. Reichardt P, Von Minckwitz G, Thuss-Patience PC et al. Multicenter phase II study of oral capecitabine (Xeloda®) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol 2003;14:1227–1233.[Abstract/Free Full Text]
55. Blum JL, Jones SE, Buzdar AU et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999;17:485–493.[Abstract/Free Full Text]
56. Blum JL, Dieras V, Lo Russo PM et al. Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 2001;92:1759–1768.[CrossRef][Medline]
57. Fumoleau P, Largillier R, Clippe C et al. Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer 2004;40:536–542.[CrossRef][Medline]
58. Largillier R, Fumoleau P, Clippe C et al. Capecitabine (X) monotherapy after anthracycline and taxane failure in metastatic breast cancer (MBC): Long-term survival data. Ann Oncol 2006;17(suppl 9):ix74.
59. Fazeny B, Zifko U, Meryn S et al. Vinorelbine-induced neurotoxicity in patients with advanced breast cancer pretreated with paclitaxel – a phase II study. Cancer Chemother Pharmacol 1996;39:150–156.[CrossRef][Medline]
60. Smorenburg C, Bontenbal M, Seynaeve C et al. Phase II study of weekly gemcitabine in patients with metastatic breast cancer (MBC) relapsing or failing on both an anthracycline (A) and a taxane (T). Ann Oncol 2000;11:31.[Abstract/Free Full Text]
61. Udom DI, Vigushin DM, Linardou H et al. Two weekly vinorelbine: Administration in patients who have received at least two prior chemotherapy regimes for advanced breast cancer. Eur J Cancer 2000;36:177–182.[CrossRef][Medline]
62. Zelek L, Barthier S, Riofrio M et al. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer 2001;92:2267–2272.[CrossRef][Medline]
63. Jara-Sánchez C, Martin M, García-Sáenz JA et al. Vinorelbine as a 96-hour continuous infusion in heavily pretreated patients with metastatic breast cancer: A cooperative study by the GEICAM group. Clin Breast Cancer 2003;3:399–404.[Medline]
64. Ibrahim NK, Valero V, Rahman Z et al. Phase I-II vinorelbine (Navelbine) by continuous infusion in patients with metastatic breast cancer: Cumulative toxicities limit dose escalation. Cancer Invest 2001;19:459–466.[CrossRef][Medline]
65. Livingston RB, Ellis GK, Gralow JR et al. Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1997;15:1395–1400.[Abstract]
66. Pivot X, Thomas E, Lerzo G et al. Ixabepilone in patients (pts) with metastatic breast cancer (MBC) that is resistant to an anthracycline, a taxane and capecitabine. Ann Oncol 2006;17(suppl 9):ix70.
67. Conte P, Thomas E, Martin M et al. Phase II study of ixabepilone in patients (pts) with taxane-resistant metastatic breast cancer (MBC): Final report. J Clin Oncol 2006;24(suppl 18):10505.
68. Low JA, Wedam SB, Lee JJ et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol 2005;23:2726–2734.[Abstract/Free Full Text]
69. Denduluri N, Lee JJ, Walshe J et al. Phase II trial of ixabepilone, an epothilone B analog, given daily for three days every three weeks, in metastatic breast cancer. Invest New Drugs 2007;25:63–67.[CrossRef][Medline]
70. Martin M, Spielmann M, Namer M et al. Phase II study of pemetrexed in breast cancer patients pretreated with anthracyclines. Ann Oncol 2003;14:1246–1252.[Abstract/Free Full Text]
71. O'Shaughnessy JA, Clark RS, Blum JL et al. Phase II study of pemetrexed in patients pretreated with an anthracycline, a taxane, and capecitabine for advanced breast cancer. Clin Breast Cancer 2005;6:143–149.[Medline]
72. Valagussa P, Tancini G, Bonadonna G. Salvage treatment of patients suffering relapse after adjuvant CMF chemotherapy. Cancer 1986;58:1411–1417.[CrossRef][Medline]
73. Castiglione-Gertsch M, Tattersall M, Hacking A et al. Retreating recurrent breast cancer with the same CMF-containing regimen used as adjuvant therapy. The International Breast Cancer Study Group. Eur J Cancer 1997;33:2321–2325.[CrossRef][Medline]
74. Bria E, Giannarelli D, Felici A et al. Taxanes with anthracyclines as first-line chemotherapy for metasta