Efficacy and safety of ixabepilone plus capecitabine in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer

J O U RN A L OF GE RI A TR I C O NC O LOG Y 4 ( 20 1 3 ) 3 4 6–3 5 2

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Efficacy and safety of ixabepilone plus capecitabine in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer☆ Linda T. Vahdat a,⁎, Eduard Vrdoljak b , Henry Gómez c , Rubi Khaw Li d , Linda Bosserman e , Joseph A. Sparano f , Jose Baselga g , Pralay Mukhopadhyay h , Vicente Valero i a

Weill Cornell Medical College, New York, NY, USA Klinicka Bolnica Split, Split, Croatia c Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru d St. Luke's Medical Center, Quezon City, Philippines e Wilshire Oncology, Pomona, CA, USA f Montefiore Medical Center, Bronx, NY, USA g MGH Cancer Center, Massachusetts General Hospital, Boston, MA, USA h Bristol-Myers Squibb, Wallingford, CT, USA i The University of Texas MD Anderson Cancer Center, Houston, TX, USA b

AR TIC LE I N FO

ABS TR ACT

Article history:

Objectives: Data on chemotherapy regimens in elderly patients with metastatic breast cancer

Received 13 December 2012

(MBC) are limited. The aim of this retrospective pooled analysis was to determine efficacy

Received in revised form

and safety of ixabepilone plus capecitabine versus capecitabine alone in patients with MBC

14 May 2013

aged ≥65 years.

Accepted 23 July 2013

Materials and Methods: A total of 1973 patients with MBC previously treated with or resistant

Available online 23 August 2013

to anthracyclines and taxanes were randomized in two open-label, multinational, phase 3 studies (study 046 and study 048). Patients received ixabepilone (40 mg/m2 as a 3-hour

Keywords:

intravenous infusion every 3 weeks) plus oral capecitabine (1000 mg/m2 administered twice

Ixabepilone

each day), or capecitabine alone (1250 mg/m2 twice each day).

Capecitabine

Results: In total, 251 randomized patients were aged ≥65 years (ixabepilone plus capecitabine,

Elderly patients

n = 116; capecitabine monotherapy, n = 135). Efficacy results were consistent in patients aged

Metastatic breast cancer

<65 and ≥65 years with respect to the observed improvement in progression-free survival and objective response rate with ixabepilone plus capecitabine compared with capecitabine alone. No significant differences in overall survival between arms were observed for either subgroup. In the ixabepilone plus capecitabine arm, grade 3/4 hematologic adverse events (AEs) were similar in both subgroups except leukopenia and febrile neutropenia, which had a higher incidence in patients aged ≥65 years. The majority of grade 3/4 nonhematologic AEs were similar in the two subgroups, including fatigue, peripheral sensory neuropathy, and hand–foot syndrome. Conclusion: The combination of ixabepilone plus capecitabine maintains its efficacy in elderly patients with anthracycline and taxane pretreated MBC, with a similar safety profile to patients aged <65 years. © 2013 Published by Elsevier Ltd.

☆ ClinicalTrials.gov: NCT00080301/NCT00082433. ⁎ Corresponding author at: Iris Cantor Breast Center, Weill Cornell Medical College, New York, NY, USA. Tel.: +1 212 821 0644; fax: +1 212 821 0758. E-mail address: [email protected] (L.T. Vahdat). 1879-4068/$ – see front matter © 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.jgo.2013.07.006

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1.

Introduction

The estimated risk of developing breast cancer increases with age. From 2003 to 2007, the median age of breast cancer diagnosis in the US was 61 years [1], while approximately 48% of women with metastatic breast cancer (MBC) at presentation are aged 65 years or older [2]. Despite advances in breast cancer therapy, patients with MBC continue to have a poor prognosis, with an overall 5-year survival rate of 23% in the US [3]. As well as stabilizing the disease and prolonging survival, the aims of systemic therapy for MBC are to alleviate symptoms and to prevent disease complications [4]. Improving patient quality of life is also a key aspect of palliative therapy for late-stage disease, so potential drug-related side effects should be minimized. Currently, there is no gold standard regimen for treatment of MBC although numerous therapeutic options exist. Treatment options for patients with MBC have begun to improve over the last two decades. Several chemotherapy agents – ixabepilone, capecitabine, and eribulin – have received Food and Drug Administration (FDA) approval for anthracycline and/or taxane pretreated breast cancer (including inoperable locally advanced or metastatic disease), whereas gemcitabine in combination with paclitaxel, capecitabine and docetaxel, and nanoparticle albumin-bound (nab)-paclitaxel are approved for use following progression on anthracyclines in the MBC or adjuvant settings [5]. The efficacy of subsequent cytotoxic therapy is usually reduced, with a progressive decline in tumor response over subsequent lines of treatment [6]. Therapeutic choice for MBC is influenced by many factors, including extent and efficacy of prior chemotherapeutic exposure, patient age, menopausal status, location and burden of disease, and hormone receptor or human epidermal growth factor receptor 2 (HER2) expression within the tumor [4]. In addition to challenges common to all patients with MBC [7], elderly patients experience an increased rate of co-morbidities and a greater risk of adverse reactions [8]. Few studies have evaluated efficacy and safety of chemotherapy regimens in elderly patients with refractory MBC. A recently reported retrospective analysis of results from the phase 3 EMBRACE trial of eribulin in MBC showed similar overall survival (OS), progression-free survival (PFS), and the rate of grade 3/4 adverse events (AEs) among 508 intention-to-treat (ITT) patients in four age-groups (<50, n = 161; 50–59, n = 174; 60–69, n = 129; >70, n = 42) indicating that efficacy and toxicity of eribulin is independent of patient age [9]. In an exploratory pooled analysis of three phase 2 and two phase 3 registration trials of capecitabine monotherapy or combination therapy in patients with MBC, no statistically significant association was demonstrated between age and OS, clinical benefit, or objective response [10]. Frequency of AEs and serious AEs was not related to age at treatment, although women ≥65 years were more likely to withdraw from treatment because of an AE [10]. In a pivotal phase 3 study of ixabepilone in patients with MBC resistant to taxanes and pretreated with or resistant to anthracyclines (study 046; n = 752), ixabepilone combined with capecitabine prolonged PFS (5.8 vs 4.2 months) and reduced the estimated risk of disease progression by 25% compared with capecitabine monotherapy (p = 0.0003). Objective response rate (ORR) was increased with ixabepilone plus capecitabine,

compared with capecitabine alone (35% vs 14%; p < 0.0001) [11], although OS was not significantly different between combination therapy and capecitabine monotherapy [12]. These results were supported by a confirmatory phase 3 trial of 1221 patients with MBC previously treated with but not necessarily resistant to an anthracycline and a taxane (study 048) [13]. Ixabepilone was subsequently approved by the FDA on October 16, 2007, in combination with capecitabine, for the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline and a taxane. Here we report the results of a retrospective pooled analysis of these two studies to determine efficacy and safety of ixabepilone plus capecitabine versus capecitabine alone in patients aged ≥65 years.

2.

Patients and Methods

2.1.

Study Design and Patient Population

A total of 1973 patients with MBC previously treated with or resistant to anthracyclines and taxanes were randomized in two open-label, multinational, randomized phase 3 studies (Fig. 1). The trials were designed, implemented, and reported in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice; applicable local regulations were observed along with the ethical principles laid down in the Declaration of Helsinki. The trials received Institutional Review Board or Independent Ethics Committee approval prior to initiation at study sites. Detailed inclusion and exclusion criteria for the trials have been reported previously [11,13]. Briefly, eligible women were ≥18 years of age and had measurable or nonmeasurable, metastatic or locally advanced disease, a Karnofsky performance status (KPS) score between 70% and 100%, and life expectancy ≥ 12 weeks. Patients were pretreated with both an anthracycline-containing (doxorubicin or epirubicin) and a taxane-containing (paclitaxel or docetaxel) regimen [11,13]. Some patients were resistant to anthracyclines or taxanes (defined as tumor progression during treatment or within 3 months of last

Randomized to study 046a (n=752)

Randomized to study 048 (n=1221)

Ixabepilone + capecitabine or capecitabine alone (n=1973)b

Patients aged ≥65 years (n=251)

Ixabepilone + capecitabine (n=116) aAge

Capecitabine alone (n=135)

Patients aged <65 years (n=1721)

Ixabepilone + capecitabine (n=868)

Capecitabine alone (n=853)

was unknown for 1 patient in study 046 analysis from both treatment groups

b Pooled

Fig. 1 – CONSORT diagram of the phase 3 trials of ixabepilone/ capecitabine.

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dose in the metastatic setting, or recurrence within 6 months in the neoadjuvant or adjuvant setting) [11]. In the pivotal phase 3 trial, patients were permitted up to three prior chemotherapy regimens, including those administered in the neoadjuvant/ adjuvant setting [11]; in the confirmatory trial, patients had received two or fewer regimens [13]. Selected exclusion criteria included brain metastases; motor or sensory neuropathy grade ≥ 2 based on National Cancer Institute Common Terminology Criteria for Adverse Events version 3 (CTCAE v3.0); reduced hematologic or renal function, and prior epothilone or capecitabine therapy.

subgroup, patient characteristics were broadly comparable between the two treatment arms (Table 1). The median age was 68 years in the elderly patient subgroup, compared with 51 years in the subgroup < 65 years of age. The percentage of patients with a KPS score of ≤ 80 was numerically higher in the subgroup of elderly patients than those aged ≤ 65 (37% vs 30%). The proportions of patients with HER2-positive or triple-negative breast cancer (TNBC) were slightly lower in the elderly patient group (15.9% vs 9.2% of HER2-positive breast cancer, respectively; and 23.2% vs 17.5% of TNBC, respectively).

2.2. Treatment Schedule, Response Assessment, and Safety/Tolerability

3.2.

Patients were randomly assigned in a 1:1 ratio to receive ixabepilone plus capecitabine or capecitabine alone. Patients received ixabepilone 40 mg/m2 as a 3-hour intravenous infusion on day 1 of a 21-day cycle, plus oral capecitabine 1000 mg/m2, administered twice each day on days 1 through 14 of a 21day cycle, or capecitabine alone, 1250 mg/m2 twice each day on days 1 through 14 of a 21-day cycle. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of the pivotal phase 3 trial was an ITT analysis of PFS (defined as the time from random assignment to disease progression or death). For the confirmatory trial, the primary endpoint was an ITT analysis of OS. Secondary endpoints included OS (pivotal study) and PFS (confirmatory trial); both trials also assessed ORR by Response Evaluation Criteria in Solid Tumors [14], time to response and duration of response, safety measures, and patient-reported outcomes (symptoms). The incidence, nature, severity, and relationship to treatment of AEs were recorded and graded according to CTCAE v3.0.

2.3.

Statistical Analysis

Due to the similarity of the study populations from the two phase 3 trials, individual patient data from both studies were pooled for statistical analysis. Selected outcomes (PFS, OS, ORRs and AEs) for the subgroup of patients aged ≥65 years were summarized using descriptive statistics, alongside those for the subgroup of patients aged <65 years. Kaplan–Meier methodology was used to estimate OS and PFS, and a stratified Cox proportional hazards model for group comparisons was used to estimate the hazard ratio (HR; two-sided 95% confidence interval [CI]). ORR and 95% CI were presented for response rates in both arms. Analyses of PFS and ORR were restricted to stratum of patients with measurable disease using two-sided 0.05 level of significance tests.

3.

Results

3.1.

Patient Population

In total, 251 randomized patients were aged ≥ 65 years (ixabepilone plus capecitabine, n = 116; capecitabine monotherapy, n = 135), and 1721 patients were aged < 65 years (n = 868 and n = 853, respectively) (Fig. 1). Within each

Efficacy

The number of patients evaluable for analysis of PFS and ORR was 1491 in the subgroup aged <65 years and 220 in the subgroup aged ≥65 years (Table 2). Efficacy results were consistent across subgroups with respect to the observed improvement in PFS and ORR with ixabepilone plus capecitabine compared with capecitabine alone (Table 2, Fig. 2). Patients aged <65 years treated with ixabepilone plus capecitabine achieved a median PFS of 5.6 months, versus 4.2 months with capecitabine alone (HR [95% CI]: 0.81 [0.73–0.90]). Patients aged ≥65 years treated with ixabepilone plus capecitabine achieved a median PFS of 5.5 months, versus 3.9 months with capecitabine alone (HR [95% CI]: 0.77 [0.59–1.02]). The ORR with ixabepilone plus capecitabine was 42% in patients aged < 65 years, and 37% in patients aged ≥ 65 years; the ORR with capecitabine alone was 26% and 19%, respectively. A total of 1972 patients were evaluable for OS; 1721 in the subgroup aged <65 years and 251 in the subgroup aged ≥65 years. No significant differences in OS between arms were observed for either subgroup (Table 2). In patients aged < 65 years, OS was 14.7 months with ixabepilone and capecitabine versus 13.9 months with capecitabine alone (HR [95% CI]: 0.90 [0.81–1.01]). In patients aged ≥ 65 years, OS was 13.9 months with ixabepilone and capecitabine versus 12.2 months with capecitabine alone (HR [95% CI]: 1.07 [0.81–1.40]).

3.3.

Exposure and Safety

Patients aged ≥ 65 years received a median of 5.0 cycles of treatment with ixabepilone combined with capecitabine, and a median of 4.0 cycles of capecitabine alone (compared with 6.0 and 5.0 cycles, respectively, for patients aged < 65 years). Grade 3 or 4 hematologic AEs occurring in >5% of patients receiving ixabepilone plus capecitabine were similar in patients aged <65 and ≥65 years except leukopenia and febrile neutropenia, which had a higher incidence in the elderly subgroup (8% vs. 18%, and 5% vs. 10%, respectively) (Table 3). The majority of grade 3 or 4 nonhematologic AEs occurring in >5% of patients receiving ixabepilone plus capecitabine were similar in the two subgroups, including fatigue (10% vs 12%), peripheral sensory neuropathy (14% vs. 17%), and hand–foot syndrome (20% vs 19%) (Table 4). The elderly group reported higher rates of some AEs compared with the group aged <65 years: asthenia (6% vs. 14%), stomatitis (1% vs. 5%), and anorexia (1% vs. 5%). Based on the known safety profiles of single-agent ixabepilone and capecitabine, the pattern of AEs was as expected. Allgrade peripheral sensory neuropathy was reported in a

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Table 1 – Patient demographics and disease characteristics. Aged ≥ 65 years

Aged < 65 years Ixabepilone + capecitabine

Capecitabine

Ixabepilone + capecitabine

Capecitabine

Patients, n

868

853

116

135

Median age, years

51.0

51.0

68.0

68.0

KPS, n (%) 100 90 80 70 <70 Not reported

292 299 204 63 2 8

(33.6) (34.4) (23.5) (7.3) (0.2) (0.9)

324 276 192 56 2 3

(38.0) (32.4) (22.5) (6.6) (0.2) (0.4)

35 (30.2) 33 (28.4) 33 (28.4) 14 (12.1) 0 1 (0.9)

46 (34.1) 44 (32.6) 40 (29.6) 4 (3.0) 1 (0.7) 0

Hormone receptor status, n (%) ER+, PRER-, PR+ ER+, PR+ ER-, PRNot reported

107 31 322 305 103

(12.3) (3.6) (37.1) (35.1) (11.9)

109 55 294 302 93

(12.8) (6.4) (34.5) (35.4) (10.9)

15 5 43 33 20

(12.9) (4.3) (37.1) (28.4) (17.2)

17 6 61 38 13

(12.6) (4.4) (45.2) (28.1) (9.6)

HER2 status, n (%) a Positive Negative Unknown Not reported

134 552 13 169

(15.4) (63.6) (1.5) (19.5)

140 547 14 152

(16.4) (64.1) (1.6) (17.8)

10 64 4 38

(8.6) (55.2) (3.4) (32.8)

13 87 2 33

(9.6) (64.4) (1.5) (24.4)

Triple negative, n (%) Yes No

194 (22.4) 674 (77.6)

205 (24.0) 648 (76.0)

19 (16.4) 97 (83.6)

25 (18.5) 110 (81.5)

Note: ER = estrogen receptor; FISH = fluorescence in situ hybridization; HER2 = human epidermal growth factor 2; KPS = Karnofsky performance status; PR = progesterone receptor. a HER2 positive: tumor is either FISH positive or immunohistochemistry 3+.

higher proportion of patients receiving ixabepilone plus capecitabine, compared with patients receiving capecitabine alone, irrespective of age (< 65 years, 41% vs. 7%; ≥ 65 years, 40% vs. 13%).

4.

Discussion

Currently, there are no guideline recommendations specifically related to the treatment of elderly patients with advanced breast cancer or MBC, although typical therapy

for this patient population often includes sequential monotherapy with capecitabine. In the absence of robust data supporting combination chemotherapy regimens, elderly patients may be more likely to receive lower doses of single-agent chemotherapies [7] with the aim of minimizing the potential for treatment-related side effects. However, it is not known whether sequential single agent therapy or combined modality therapy is better in achieving the best possible clinical outcome for patients with metastatic disease previously treated with an anthracycline and a taxane.

Table 2 – Efficacy. Aged ≥65 years

Aged < 65 years Ixabepilone + capecitabine Patients, n ORR a, n (%) Median PFS a, months HR (95% CI) Patients, n Median OS, months HR (95% CI)

751 317 (42) 5.6 0.81 (0.73–0.90) 868 14.7 0.90 (0.81–1.01)

Capecitabine 740 194 (26) 4.2 853 13.9

Ixabepilone + capecitabine 104 38 (37) 5.5 0.77 (0.59–1.02) 116 13.9 1.07 (0.81–1.40)

Capecitabine 116 22 (19) 3.9 135 12.2

Note: CI = confidence interval; HR = hazard ratio; ORR = objective response rate; OS = overall survival; PFS = progression-free survival. a ORR and PFS were computed on all randomized patients with measurable disease.

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Proportion not progressed

1.0 0.9 0.8 0.7 0.6

Ixa+Cape Censored

0.5

Cape Censored

0.4 0.3 0.2 0.1 0.0 0

2

4

6

8

10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Months Patients at risk Ixa+Cape 104 85

74

40

29

20

15

11

8

5

4

3

3

2

1

1

1

1

1

1

0

Cape

57

40

27

19

13

8

5

2

2

1

0

0

0

0

0

0

0

0

0

116 81

Group

# Progressed/# Randomized

Ixa+Cape Cape Ixa+Cape OVER Cape

Median (95% CI)

HR (95% CI)

5.5 (4.5–6.8) 3.9 (2.9–5.3)

96/104 113/116

0.77 (0.59–1.02)

Fig. 2 – Kaplan–Meier plot of PFS in patients aged ≥ 65 years. Note: PFS = progression-free survival.

Our pooled analysis of two phase 3 trials revealed that the combination of ixabepilone plus capecitabine maintains its efficacy in elderly patients with anthracycline and taxane pretreated MBC. The safety profile of ixabepilone plus capecitabine was also similar between patients aged < 65 and ≥ 65 years. Given the increasing number of elderly women presenting with MBC and the lack of available data for these patients, this retrospective analysis of a large data set may provide some guidance to the use of ixabepilone plus capecitabine in patients over the age of 65 years. Although many elderly patients may be diagnosed with MBC rather than early-stage breast cancer (and therefore, do not receive adjuvant therapy), they are usually treated at some juncture with anthracyclines and taxanes. Hence, many will develop resistance to these agents during the course of treatment [15,16], creating a management challenge over subsequent lines of therapy [6]. The improved ORR and PFS originally reported for ixabepilone in combination with capecitabine in two phase 3 trials [11,13] were maintained in elderly patients with MBC, indicating that the efficacy of ixabepilone plus capecitabine is independent of age. This is consistent with recent results reported for capecitabine [10]

and eribulin [9] in MBC. Unfortunately, OS was not significantly different between the combination arm and the capecitabine monotherapy arm in either age subgroup. Drug safety and tolerability is of great concern in elderly patients [8]. Age did not impact the incidence of the majority of severe hematological or non-hematological AEs with ixabepilone and capecitabine in this pooled analysis. Only a minority of patients experienced grade 3/4 AEs and the pattern of events was as expected, based on the known safety profiles of single-agent ixabepilone and capecitabine in breast cancer [17,18]. Effective management of AEs allowed a sufficient number of treatment cycles to be administered in patients in the elderly subgroup (median of 5.0 cycles of ixabepilone and capecitabine, and 4.0 cycles of capecitabine alone). While the number of cycles was slightly fewer compared with the younger subgroup (6.0 and 5.0 cycles, respectively), most patients received a reasonable course of treatment leading to comparable levels of efficacy. In conclusion, ixabepilone in combination with capecitabine showed generally consistent efficacy and toxicity profile in patients aged ≥65 years as in those aged <65 years. This combination offers a viable therapeutic alternative to elderly

Table 3 – Grade 3 or 4 hematologic AEs occurring in >5% of patients in any group. Aged ≥ 65 years

Aged < 65 years Grade 3/4 AEs

Ixabepilone + capecitabine

Capecitabine

Neutropenia, n (%) Neutrophil count decreased, n (%) Leukopenia, n (%) White blood cell count decreased, n (%) Febrile neutropenia, n (%)

175 (21) 63 (7) 70 (8) 41 (5) 46 (5)

19 (2) 3 (< 1) 5 (< 1) 2 (< 1) 5 (< 1)

Note: AEs = adverse events.

Ixabepilone + capecitabine 30 9 20 7 11

(26) (8) (18) (6) (10)

Capecitabine 0 1 (<1) 1 (<1) – 1 (<1)

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Table 4 – Grade 3 or 4 non-hematologic AEs occurring in >5% of patients in any group. Aged ≥ 65 years

Aged < 65 years Grade 3/4 AEs

Ixabepilone + capecitabine

Diarrhea, n (%) Nausea, n (%) Vomiting, n (%) Stomatitis, n (%) Fatigue, n (%) Asthenia, n (%) Myalgia, n (%) Peripheral sensory neuropathy, n (%) Palmar-plantar erythrodysesthesia syndrome, n (%) Anorexia, n (%) Dehydration, n (%)

53 32 40 12 88 48 51 116 171

(6) (4) (5) (1) (10) (6) (6) (14) (20)

11 (1) 7 (< 1)

Capecitabine 65 9 12 7 21 8 1 3 150

Ixabepilone + capecitabine

(8) (1) (1) (< 1) (3) (< 1) (< 1) (< 1) (18)

5 (< 1) 3 (< 1)

10 9 9 6 14 16 5 19 22

(9) (8) (8) (5) (12) (14) (4) (17) (19)

6 (5) 1 (< 1)

Capecitabine 23 (17) 8 (6) 7 (5) 3 (2) 9 (7) 3 (2) 0 1 (< 1) 33 (25) 2 (2) 7 (5)

Note: AEs = adverse events.

patients with MBC pretreated with an anthracycline and a taxane, a difficult-to-treat group with limited therapeutic options. Further prospective studies are required to confirm these observations, to determine if the ultimate goal of improving OS in this difficult-to-treat patient population can be met, and to understand if the added cost of multiple chemotherapies and their toxicities, after progression following previous anthracycline and taxane therapy, are warranted compared with sequential, single-agent therapy.

Previous Presentation of Data

Disclosures and Conflict of Interest Statements

Poster presented at the ASCO Annual Meeting, June 3–7, 2011, Chicago, IL, USA.

Linda T. Vahdat has received consulting payments and honoraria.

Acknowledgments

Eduard Vrdoljak has received funding for clinical trials from Roche, and consulting payments or honoraria from Pfizer, Roche, GlaxoSmithKline, Novartis and Bayer. Linda Bosserman has received consulting payments from Roche/Genentech. Joseph A. Sparano has received consulting payments and honoraria from Bristol-Myers Squibb. Pralay Mukhopadhyay is an employee and a stock owner of Bristol-Myers Squibb.

Author Contributions Study Concepts: Linda T. Vahdat, Joseph A. Sparano, Jose Baselga, Vicente Valero. Study Design: Linda T. Vahdat, Linda Bosserman, Joseph A. Sparano, Jose Baselga, Pralay Mukhopadhyay, Vicente Valero. Data Acquisition: Eduard Vrdoljak, Henry Gómez, Rubi Khaw Li, Linda Bosserman, Vicente Valero. Data Analysis and Interpretation: Linda T. Vahdat, Eduard Vrdoljak, Henry Gómez, Linda Bosserman, Joseph A. Sparano, Pralay Mukhopadhyay, Vicente Valero. Statistical Analysis: Pralay Mukhopadhyay. Manuscript Preparation: Linda T. Vahdat, Eduard Vrdoljak, Pralay Mukhopadhyay, Vicente Valero.

Manuscript Editing: Linda T. Vahdat, Eduard Vrdoljak, Henry Gómez, Linda Bosserman, Joseph A. Sparano, Pralay Mukhopadhyay, Vicente Valero. Manuscript Review: Linda T. Vahdat, Eduard Vrdoljak, Henry Gómez, Rubi Khaw Li, Linda Bosserman, Joseph A. Sparano, Jose Baselga, Pralay Mukhopadhyay, Vicente Valero.

The authors wish to acknowledge StemScientific, funded by Bristol-Myers Squibb, for providing writing and editorial support. Neither Bristol-Myers Squibb nor StemScientific influenced content of the manuscript, nor did the authors receive financial compensation for authoring the manuscript.

REFERENCES

1. Altekruse SF, Kosary CL, Ruhl J, Neyman N, Aminou R, Waldron W, et al. SEER cancer statistics review, 1975–2007. Bethesda, MD: National Cancer Institute; 2010 (, http://seer.cancer.gov/csr/ 1975_2007/. Based on November 2009 SEER data submission; posted to the SEER web site, 2010). 2. Holmes CE, Muss HB. Diagnosis and treatment of breast cancer in the elderly. CA Cancer J Clin 2003;53:227–244. 3. Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Altekruse SF, et al, editors. SEER Cancer Statistics Review, 1975–2008. Bethesda, MD: National Cancer Institute; 2011. (, http://seer.cancer.gov/csr/1975_2008/. Based on November 2010 SEER data submission, posted to the SEER web site, 2011). 4. National Comprehensive Cancer Network. Practice guideline in oncology — v. 2.2011: breast cancer, http://www.nccn.org/ professionals/physician_gls/PDF/breast.pdf (Accessed November 2011).

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J O U RN A L OF GE RI A TR I C O NC O LOG Y 4 ( 20 1 3 ) 3 4 6–3 5 2

5. Cortazar P, Justice R, Johnson J, Sridhara R, Keegan P, Pazdur R. US Food and Drug Administration approval overview in metastatic breast cancer. J Clin Oncol 2012;30: 1705–1711. 6. Greenberg P, Hortobagyi GN, Smith TL, Ziegler LD, Frye DK, Buzdar AU. Long-term follow up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 1996;14:2197–2205. 7. Crivellari D, Aapro M, Leonard R, von Minckwitz G, Brain E, Goldhirsch A, et al. Breast cancer in the elderly. J Clin Oncol 2007;25:1882–1890. 8. Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol 2011;29: 3457–3465. 9. Twelves C, Vahdat LT, Cortes J, Wanders J, Dutcus CE, Seegobin S, et al. The relationship between age and survival outcomes for eribulin in metastatic breast cancer. J Clin Oncol 2011;29 (Suppl., abstract 1060). 10. Blum JL, Kohles J, McKenna E, Scotto N, Hu S, Odom D, et al. Association of age and overall survival in capecitabine-treated patients with metastatic breast cancer in clinical trials. Breast Cancer Res Treat 2011;125:431–439. 11. Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 2007;25:5210–5217.

12. Hortobagyi GN, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, et al. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracycline and taxanes. Breast Cancer Res Treat 2010;122:409–418. 13. Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2010;28:3256–3263. 14. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–216. 15. Moreno-Aspitia A, Perez EA. Anthracycline- and/or taxane-resistant breast cancer: results of a literature review to determine the clinical challenges and current treatment trends. Clin Ther 2009;31:1619–1640. 16. Rivera E. Management of metastatic breast cancer: monotherapy options for patients resistant to anthracyclines and taxanes. Am J Clin Oncol 2010;33:176–185. 17. IXEMPRA® PI. , http://packageinserts.bms.com/pi/pi_ixempra. pdf (Accessed November 2011). 18. Xeloda® PI. , http://www.gene.com/gene/products/information/ xeloda/pdf/pi.pdf (Accessed November 2011).