Originally published as JCO Early Release 10.1200/JCO.2006.09.3849 on July 2 2007

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Efficacy and Safety of Ixabepilone (BMS-247550) in a Phase II Study of Patients With Advanced Breast Cancer Resistant to an Anthracycline, a Taxane, and Capecitabine

Edith A. Perez, Guillermo Lerzo, Xavier Pivot, Eva Thomas, Linda Vahdat, Linda Bosserman, Patrice Viens, Can Cai, Brian Mullaney, Ronald Peck, Gabriel N. Hortobagyi

From the Department of Hematology and Oncology, Mayo Clinic, Jacksonville, FL; Division of Oncology, Hospital de Oncologia Maria Curie, Ciudad de Buenos Aires, Argentina; Division of Oncology, Centre Hospitalier Universitaire de Besançon, Besançon, France; Departments of Medicine and Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Medicine, Weill Cornell Breast Center, New York, NY; Department of Medical Oncology and Hematology, Wilshire Oncology Medical Group Inc, La Verne, CA; Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France; and Oncology Research, Bristol-Myers Squibb, Wallingford, CT

Address reprint requests to Edith A. Perez, MD, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; e-mail: Perez.edith{at}mayo.edu

	ABSTRACT

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Purpose To evaluate the efficacy and safety of ixabepilone in patients with metastatic breast cancer (MBC) resistant to anthracycline, taxane, and capecitabine, in this multicenter, phase II study.

Patients and Methods Patients with measurable disease who had tumor progression while receiving prior anthracycline, taxane, and capecitabine were enrolled. Ixabepilone 40 mg/m² monotherapy was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle. The primary end point was objective response rate (ORR), assessed by an independent radiology facility (IRF).

Results A total of 126 patients were treated and 113 were assessable for response. Patients were heavily pretreated: 88% had received at least two lines of prior chemotherapy in the metastatic setting. IRF-assessed ORR was 11.5% (95% CI, 6.3% to 18.9%) for response-assessable patients. Investigator-assessed ORR for all treated patients was 18.3% (95% CI, 11.9% to 26.1%). Fifty percent of patients achieved stable disease (SD); 14.3% achieved SD 6 months. Median duration of response and progression-free survival were 5.7 and 3.1 months, respectively. Median overall survival was 8.6 months. Patients received a median of 4.0 treatment cycles (range, one to 16 cycles), and 25% of patients received eight cycles. Grade 3/4 treatment-related events included peripheral sensory neuropathy (14%), fatigue/asthenia (13%), myalgia (8%), and stomatitis/mucositis (6%). Resolution of grade 3/4 peripheral sensory neuropathy occurred after a median period of 5.4 weeks.

Conclusion Ixabepilone demonstrated clear activity and a manageable safety profile in patients with MBC resistant to anthracycline, taxane, and capecitabine. Responses were durable and notable in patients who had not previously responded to multiple prior therapies.

	INTRODUCTION

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More than one million women worldwide are diagnosed with breast cancer every year,¹ 30% to 80% of whom develop metastatic disease. Anthracyclines and taxanes are two of the most active chemotherapeutic agents in breast cancer, but key limitations remain. For metastatic breast cancer (MBC), for example, a proportion of tumors fail to respond to these agents, whereas those that do initially respond will eventually progress.² With increasing use of anthracycline/taxane-containing regimens as the standard of care for adjuvant therapy in early breast cancer (EBC), it is anticipated that growing numbers of patients will have pretreated MBC that has developed resistance to anthracyclines and taxanes. The only approved treatment currently available for patients with tumors resistant to anthracyclines/taxanes is capecitabine.

Minimal information has been published on patients with MBC resistant to capecitabine in this setting and there are no proven treatment options available, highlighting the need for novel therapies that are effective in patients with heavily pretreated MBC that is resistant to multiple prior agents.

The epothilones and their analogs are a new class of antineoplastic agent, derived from the myxobacterium Sorangium cellulosum.³ These compounds have some similarities to taxanes in targeting and stabilizing microtubules⁴ but also have important differences; the class is structurally unrelated to taxanes, and unlike taxanes and anthracyclines, has low susceptibility to multiple mechanisms of drug resistance.^5-7

Ixabepilone (BMS-247550), the first semisynthetic epothilone analog, has been designed to optimize the pharmacologic profile of the natural epothilone B compound. Ixabepilone demonstrated consistent preclinical activity in chemotherapy-resistant cell lines and xenograft models.^6,7 Phase II clinical studies have demonstrated activity in patients with taxane-resistant and anthracycline-pretreated MBC^8,9 and other chemoresistant tumor types.^10-12 The preclinical profile and available clinical data provide the rationale for ixabepilone to be evaluated in patients with MBC resistant to anthracyclines, taxanes, and capecitabine.

	PATIENTS AND METHODS

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Study Design and Treatment
This phase II, multicenter, single-arm study was designed to assess the objective response rate (ORR) of ixabepilone 40 mg/m² monotherapy administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle. Treatment continued for 18 cycles or until disease progression or unacceptable toxicity. The ixabepilone dose could be reduced to 32 or 25 mg/m² based on tolerability during the previous cycle.

This study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice, the Declaration of Helsinki, and the institutional review board/independent ethics committee at each study site.

Eligibility
Women age 18 years with MBC or locally advanced breast cancer resistant to anthracyclines (doxorubicin or epirubicin), taxanes (paclitaxel or docetaxel), and capecitabine were eligible for inclusion. Patients had to have at least one radiographically measurable target lesion as assessed by the investigator. Resistance to each drug class was defined as disease progression while receiving therapy in the metastatic setting (within 8 weeks of last treatment) or recurrence within 6 months of adjuvant or neoadjuvant anthracycline or taxane chemotherapy. Alternatively, patients could have demonstrated resistance to both taxane and capecitabine and could have received a minimum cumulative anthracycline dose of 240 mg/m² (doxorubicin) or 360 mg/m² (epirubicin). Patients could have received agents from these classes in any order, and were required to receive at least two cycles of each regimen. No more than five prior chemotherapy regimens were permitted in total, with no more than three prior regimens in the metastatic setting. Patients with estrogen receptor (ER) –positive tumors should have demonstrated tumor progression after prior hormonal therapy and no longer be considered candidates for hormonal treatment. Patients with human epidermal growth factor receptor 2 (HER-2) –positive tumors (immunohistochemistry 3+ and/or fluorescent in situ hybridization positive status) must have received prior trastuzumab and demonstrated tumor progression during treatment or after discontinuation of treatment. Patients were required to have a Karnofsky performance score of 70 to 100.

Exclusion criteria included prior treatment with an epothilone, concurrent chemotherapy, current or previous brain metastases, or grade 2 neuropathy (National Cancer Institute Common Toxicity Criteria) at study entry. Patients suitable and eligible for trastuzumab or hormonal therapy based on HER-2 or ER positivity were excluded.

Efficacy Assessment and Response Criteria
Tumor evaluation (by physical examination and/or imaging studies when appropriate) was performed every two cycles. Response was defined according to Response Evaluation Criteria in Solid Tumors and was assessed both by investigators at the site and by an independent radiology facility (IRF). Selection of target and nontarget disease by the IRF occurred without knowledge of the investigator target or response assessment. IRF response was based on integrating the IRF radiologist and oncologist assessments. Target lesions assessed by physical examination only (eg, chest wall lesions and skin nodules) were not included in the IRF assessment of target disease, but are included in the investigator-reported ORRs. Missing scans at any time point led to an IRF assessment of inassessable.

Tolerability Assessment
At baseline and before each cycle, a physical examination including neurologic assessment, vital signs, and performance status was performed. Adverse events (AEs) were evaluated continuously and graded according to National Cancer Institute Common Toxicity Criteria version 3.0. Hematology was evaluated weekly, and serum chemistry and hematology were evaluated before each cycle.

Statistical Design and Methodology
The primary end point of this study was ORR as assessed by IRF. ORR was calculated for all patients who received any dose of ixabepilone and also the prospectively defined subset of response-assessable patients. Response-assessable patients were defined as patients with measurable disease, as determined by IRF, who met the resistance criteria for anthracyclines, taxanes, and capecitabine.

Secondary efficacy end points included duration of response, time to response, progression-free survival (PFS), and overall survival (OS), and with the exception of OS, analyses were based on IRF data.

This study used a modified Gehan two-stage design¹³ where at least one response was required in the initial 29 patients to proceed to the second stage. Two-sided 95% CIs were computed for ORR. The median duration of survival, duration of response, and PFS were calculated for each cohort using Kaplan-Meier methodology. Univariate statistics were used to summarize time to response.

	RESULTS

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Patients
Between February 24, 2004, and December 21, 2005, 128 patients were enrolled across 36 study centers in 10 countries. Of these, 126 were treated and 113 were designated as assessable for response by the IRF. Of the 13 inassessable patients, 11 did not have IRF-measurable disease, and two had disease that did not meet the taxane-resistance criteria (with disease in both patients progressing 8 weeks and 5 days after their last dose of taxane chemotherapy in the metastatic setting).

Patient demographic characteristics and baseline disease characteristics were representative of a population with MBC resistant to anthracyclines, taxanes and capecitabine (Tables 1 and 2); efficacy and safety results therefore can be extrapolated directly to this difficult-to-treat population. Patients had significant baseline disease: 77% had visceral disease in the liver and/or lung and 43% presented with at least three target lesions. Most patients (88%) had received at least two lines of chemotherapy in the metastatic setting, whereas 48% had received at least three lines of chemotherapy, with 15% and 30% of patients receiving more than one line of anthracycline and taxane, respectively. Of the 126 patients, 38% had anthracycline-resistant tumors; the remainder met the criteria for minimum cumulative dose. All but two of the 126 patients had MBC that met the criteria for taxane resistance (both patients were excluded from the assessable-for-response population), whereas all patients had disease that met the criteria for resistance to capecitabine. In addition to meeting the strict resistance criteria for anthracyclines, taxanes, and capecitabine, the MBC of many patients had also failed to respond to other agents commonly administered in MBC (eg, 26% had experienced treatment failure with vinorelbine and 13% gemcitabine, in addition to hormonal therapies). Most patients were postmenopausal (87%), white (79%), and had Karnofsky performance score 80 (96%). All HER-2–positive tumors had failed prior treatment with trastuzumab, although the limited number of patients with tumors that overexpressed HER-2 precluded additional meaningful conclusions from being drawn for this subpopulation.

Figure 1 illustrates the degree of tumor shrinkage/growth across all patients, with many responders demonstrating marked tumor regression. Responses were seen across the prospectively defined subpopulations based on age, hormone-receptor status, and presence or absence of liver metastases. Ixabepilone demonstrated activity in five of 42 IRF response-assessable patients (ORR, 12%) with triple-negative tumors (tumors that did not express ER, progesterone receptor, or HER-2).

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Maximum percentage change by target lesion per patient.

Agreement between IRF and investigator assessments of best tumor response was evident for 71% of patients, including 10 with confirmed objective tumor responses assessed by both IRF and investigator. A review of those patient cases for which investigator-assessed responses were not confirmed by the IRF identified patient-specific reasons for the difference and highlighted a number of additional patients for which the investigator assessment was particularly relevant. In a number of additional patient cases, responses could not be confirmed by independent review simply due to technical difficulties.

Dosing
Overall, patients received a median of 4.0 cycles (range, one to 16 cycles) of ixabepilone therapy; 25% of patients received at least eight cycles. Eighty percent of cycles were administered at the planned dose of 40 mg/m² and 70% of patients (n = 88) achieved more than 90% of their planned dose-intensity. Median dose intensity was 12.8 mg/m²/wk (range, 0.2 to 14.2 mg/m²/wk). A total of 101 treatment cycles (21%) administered after cycle 1 were delayed; administrative reasons were the most common cause of such delays.

Tolerability
Ixabepilone demonstrated an acceptable safety profile, consistent with that observed in two previous monotherapy studies in MBC. One treatment-related death was reported, in a patient with baseline grade 4 cardiac failure (a protocol deviation) from prior doxorubicin therapy, who developed septic shock in association with grade 4 neutropenia.

Treatment-related AEs generally were manageable and primarily grade 1/2 (55%) in intensity (Table 4). In total, 118 treated patients (94%) had at least one treatment-related event.

View this table: [in this window] [in a new window]   Table 4. Overall Treatment-Related Nonhematologic Adverse Events Occurring in 5% Patients and Hematology (worst on-study CTC grade; n = 126)

Peripheral neuropathy was the most common nonhematologic AE. This was primarily sensory, mild to moderate (grade 1/2) in intensity, generally reversible, and often manageable with dose reduction. At baseline, peripheral neuropathy was already evident (grade 1 or 2) in 34 patients (27%) of this heavily pretreated population (grade 2 in two of the patients). Forty-nine percent of patients developed grade 1/2 neuropathy during the study. Grade 3/4 neuropathy was reported in 17 patients (13%), with only a single grade 4 occurrence; the number of occurrences was similar for those with (12 of 92 patients; 13%) or without (five of 34 patients; 15%) baseline neuropathy. Severe peripheral neuropathy generally was characterized by paresthesiae of the hands and feet, and developed after a median of four treatment cycles (range, one to 11 cycles; Fig 2).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Incidence of peripheral neuropathy by cycle.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. (A) Kaplan-Meier analysis of time to resolution of grade 3 or higher peripheral neuropathy. (B) Kaplan-Meier analysis of time to improvement of worst (grade 3 or higher) peripheral neuropathy.

	DISCUSSION

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Despite recent advances in the management of MBC, drug resistance remains a major clinical challenge limiting the effectiveness of various therapies.² Anthracyclines and taxanes initially established themselves as treatment for metastatic disease but anthracycline/taxane regimens are increasingly being used in EBC. The majority of patients with metastatic disease will experience relapse after such regimens; in many patients, tumors will develop resistance, whereas in others, patients can no longer be considered candidates for additional treatment with these agents.¹⁴ Currently, capecitabine is the only approved treatment option for these patients. Treatment of patients with disease resistant to capecitabine has not been well studied in this setting. Given that the management of MBC continues to evolve and improve toward a chronic disease model with the sequential use of lines of therapy, a clear need remains for novel therapies for heavily pretreated patients with MBC resistant to multiple drugs.

This multicenter, international, phase II study was designed to provide robust evidence of the activity of ixabepilone in such patients. The study incorporated stringent definitions for resistance to each drug and used an IRF for response and progression. The patient population was heavily pretreated and had significant baseline disease.

The activity of ixabepilone in this population (IRF ORR, 12%; investigator ORR, 18%; plus an additional 13% with SD 6 months) can be put into context with one of the few other studies in an anthracycline-, taxane-, and capecitabine-pretreated population, which reported an investigator-only assessed ORR of 8% with pemetrexed, despite the lack of specific criteria for resistance to prior therapy.¹⁵ Two phase III studies of capecitabine in anthracycline/taxane-pretreated patients used IRFs. One reported ORRs of 9.1% and 19.1% for IRF and investigator assessments, respectively,¹⁶ whereas the other reported an IRF-assessed ORR of 14.3% for a trastuzumab-resistant population.¹⁷ In an additional phase III study (with no IRF), an ORR of 19% was reported for paclitaxel in taxane-naïve patients, where 80% of patients had no more than one line of prior chemotherapy in the metastatic setting.¹⁸

In this study of ixabepilone, identification of target lesions and determination of response and progression were conducted independently by investigators and an IRF. As in other studies using multiple independent assessments of response, differences were reported between IRF and investigator assessments.^19,20

The majority of patients who responded to ixabepilone in this study failed to respond to their prior chemotherapy. Of particular note, nine of these patients had not responded to multiple sequential lines of prior chemotherapy (including combination chemotherapy).

Ixabepilone demonstrated a manageable and acceptable safety profile. Myelosuppression was manageable even in this heavily pretreated population; febrile neutropenia was reported in 3% of patients and was managed effectively by dose reduction. Grade 3/4 peripheral neuropathy was reported in 13% of patients; approximately one fourth of patients had baseline grade 1 neuropathy, consistent with that previously reported in ixabepilone studies and similar to that reported with taxane usage in less heavily pretreated patients. Neuropathy was primarily sensory, and largely reversible within an acceptable timeframe. With dose reduction, most patients remained on therapy without any worsening of their neuropathy.

The activity of ixabepilone in this study is consistent with its preclinical profile, in which activity is evident in various chemotherapy-resistant models with overexpression of efflux pump proteins, tubulin mutations, and in taxane-resistant models with overexpression of ßIII-tubulin isotype.^6,7 Other phase II clinical studies have demonstrated that ixabepilone is active in taxane-resistant MBC; non–small-cell lung cancer; taxane-resistant, hormone-refractory prostate cancer; renal and pancreatic carcinomas; and drug-resistant non-Hodgkin's lymphoma.^10,11,21-23 In taxane-naïve settings, ixabepilone has demonstrated encouraging activity in first-line MBC, as neoadjuvant therapy in EBC, and in hormone refractory prostate cancer.^9,24,25

In conclusion, ixabepilone demonstrated promising activity in MBC resistant to an anthracycline, a taxane, and capecitabine, and had an acceptable and manageable safety profile. These results warrant additional evaluation of ixabepilone in other disease settings.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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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: Can Cai, Bristol-Myers Squibb; Brian Mullaney, Bristol-Myers Squibb; Ronald Peck, Bristol-Myers Squibb Leadership: N/A Consultant: Xavier Pivot, Roche, GlaxoSmithKline Stock: Brian Mullaney, Bristol-Myers Squibb; Ronald Peck, Bristol-Myers Squibb Honoraria: Xavier Pivot, Roche, GlaxoSmithKline; Patrice Viens, Roche, GlaxoSmithKline Research Funds: Edith A. Perez, Bristol-Myers Squibb; Guillermo Lerzo, Bristol-Myers Squibb; Eva Thomas, Bristol-Myers Squibb; Linda Bosserman, Bristol-Myers Squibb; Patrice Viens, Funds, Bristol-Myers Squibb; Gabriel N. Hortobagyi, Novartis Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Edith A. Perez, Linda Bosserman, Ronald Peck, Gabriel N. Hortobagyi

Financial support: Ronald Peck

Administrative support: Gabriel N. Hortobagyi

Provision of study materials or patients: Edith A. Perez, Guillermo Lerzo, Xavier Pivot, Linda Vadhat, Linda Bosserman, Patrice Viens, Brian Mullaney, Gabriel N. Hortobagyi

Collection and assembly of data: Brian Mullaney

Data analysis and interpretation: Edith A. Perez, Eva Thomas, Linda Vadhat, Linda Bosserman, Can Cai, Brian Mullaney, Gabriel N. Hortobagyi

Manuscript writing: Edith A. Perez, Eva Thomas, Linda Vadhat, Linda Bosserman, Brian Mullaney, Gabriel N. Hortobagyi

Final approval of manuscript: Edith A. Perez, Xavier Pivot, Eva Thomas, Linda Vadhat, Linda Bosserman, Patrice Viens, Brian Mullaney, Gabriel N. Hortobagyi

	Appendix

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The following investigators and institutions participated in this trial (primary investigators are listed first for each institution): Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115-6013 (Craig A Bunnell, Karen Anderson, Harold Burstein, Susana Campos, Wendy Chen, Steven Come, Reed Drews, Judy Garber, Michael Goldstein, Lyndsay Harris, Anne-Renee Hartman, Mark Huberman, Ian Krop, Roger Lange, Jennifer Ligibel, Ursula Matulonis, Leroy Parker, Ann Partridge, Rochelle Scheib, Lowell Schnipper, Susan Schumer, Lawrence Shulman, Daniel Silver, Nadine Tung, Eric Winer, Gerburg Wulf); Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 (Monica Fornier, Jacqueline Bromberg, Violante Currie, Gabriella D'Andrea, Chau Dang, Maura Dickler, Theresa Gilewski, Clifford Hudis, Arti Hurria, Diana Lake, Mark Moasser, Mary Ellen Moynahan, Larry Norton, Mark Robson, Andrew Seidman, Nancy Sklarin, Maria Theodoulou, Catherine VanPoznak); Carolinas Hematology-Oncology Associates, 1100 S Tryon Street, Suite 400 Charlotte, NC 28203 (Steven Limentani, Gary Frenette, Michael Livingston, John Mahoney, David Miller, Warden Woodard); New York Presbyterian Hospital, Weill Medical College of Cornell University, 425 East 61st St, 8th Floor, New York, NY 10021 (Linda Vahdat, Ellen Chuang, Diana Donovan, Ellen Gold); Mayo Clinic Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224 (Edith A. Perez, Gerardo Colon-Otero, Elizabeth A Johnson, George P. Kim, Susan Lanier, William Maples, Alvaro Moreno-Aspitia, Vicki Parks, Candido E. Rivera, Vivek Roy, Lawrence A. Solberg, Winston W. Tan, Han W. Tun, Mona B. Wirk); Magee-Womens Hospital, 300 Halket Street, Women's Cancer Center - Room 4628, Pittsburgh, PA 15213 (Adam M. Brufsky, Joseph Baar, Theodore Crandall, Virginia Dinger, Martin Earle, Carol Evans, Terry Evans, Ronald Fierro, David Friedland, Robert Gluckman, Samuel Jacobs, Andrew Laman, Barry Lembersky, Stanley Marks, Dennis Meisner, Kiran Rajasaman, Priya Rastogi, Jeffrey E.Shogan, Shannon Smith, Ronald Stoller, Matthew Sulecki, Franklin Viverette, Victor Vogel); The University of Texas M.D. Anderson Cancer Center, Department of Breast Medical Oncology-1354, 1515 Holcombe Blvd, Unit 1354, Houston, TX 77030 (Eva Thomas, Banu Arun, Robert Bast Jr, Daniel Booser, Abenaa Brewster, Joan Bull, Aman Buzdar, Massimo Cristofanilli, Cesar De Las Casas, Francisco Esteva, Sharon Giordano, Ana Maria Gonzalez-Angulo, Marjorie Green, Karin Hahn, Gabriel Hortobagyi, Nuhad Ibrahim, Stacy Molder, James Murray, Lajos Pusztai, Edgardo Rivera, Marguerite Rosales, Richard Theriault, Vicente Valero, Ronald Walters); University Oncology Associates, 979 East Third St, Suite A0540, Chattanooga, TN 37403 (Larry Schlabach, John McCravey, Lawrence Nagle); Wilshire Oncology Medical Group Inc, 1502 Arrow Highway, La Verne, CA 91750 (Linda D. Bosserman, Ben Ebrahimi, Richard C.Horns, Jr., Wendy Hu, Cynthia Martel, Gargi H.Upadhyaya, Mayank J.Vakil, Christina H.Yeon, Janice York, Traci Young); Hopital du Sacre-Coeur de Montreal, 5400 Gouin Blvd West, Montreal, Quebec H4J 1C5, Canada (Josee-Anne Roy, Guylaine Gaudet, Caroline Girouard, Bernard Lesperance, Jean-Pierre Moquin, Roxanne Pichette, Julie Rousseau, Renaud Whittom); Hopital Jean Minjoz, Service d'Oncologie, 3 Boulevard Fleming, Besancon Cedex 25,030, France (Xavier Pivot, Armelle Dufresne); Hopital Avicenne, Service d'Oncologie, 125, Rue de Stalingrad, Bobigny Cedex 93009, France (Jean-Francois Morere, Abdel-Kader Chouahnia, Pierre Saintigny); Centre Anticancereux Alexis Vautrin, Avenue de Bourgogne, Vandoeuvre Les Nancy Cedex 54511, France (Dominique Spaeth, Elisabeth Luporsi, Maria Rios, Celia Roemer-Becuwe, Lionel Uwer, Beatrice Weber, Ivan Krakowski); East Valley Hematology Oncology Medical, Group, 2601 W Alameda Ave, Suite 210, Burbank, CA 91505 (Raul R. Mena, Richy Agajanian, Karo K. Arzoo, Boris Bagdasarian, Mercedes Brenneisen, Francesco Federico, Ira Felman, Jack Freimann Jr, Cary Hajime Gota, Sheldon Herman, Valerie Israel, Edwin L. Jacobs, Peter S. Kennedy, Brian Le Berthon, Eduardo Lim, Gregg Arden Olsen, Cary Presant, Jerry Kiyoharu Wada); Karolinska Hospital, Radiumhemmet, Stockholm 171 76, Sweden (Birgitta Wallberg, Sven Nyrén, Sven Tornberg, Henrik Ullen); Ulleval University Hospital, Onkologisk Avd, Oslo 0407, Norway (Erik Wist, Bjorn Oestenstad, Ragnhild Undseth); Hospital Clinica Del Parque, Calle Dr. Pedro Leal Rodriguez No. 1802, Zona Centro, Chihuahua, Chih. CP 31,000, Mexico (Roberto Lugo Quintana, Juan Cruz Baca); Institut Paoli Calmettes, Centre Regional de Lutte Contre ie, Cancer, 232 Bd Sainte Marguerite, Marseille Cedex 09 13,273, France (Patrice Viens, Sophie Bagattini, Jacques Camerlo, Anthony Goncalves, Anne Madroszyk-Flandin, Frederic Viret); Klinikum Der Johann Wolfgang Goethe-Universitaet, Theodor-Stern-Kai 7, Frankfurt 60,596, Germany (Gunter Von Minckwitz, Uwe Berner, Joachim Kohl, Sibylle Loibl, Nicole Saenger); Hospital Regional de Merida ISSSTE, 7 Av. Barrera Vazquez y 36, Col. Pensiones, Merida, Yucatan 94500, Mexico (Tirzo Suarez Sahui, Edwin Franco, Jorge Mendoza); Instituto Medico Especializado Alexander, Fleming, Cramer 1180, Capital Federal, Buenos Aires 1426, Argentina (Jorge Nadal, Rosmarie Gidekel, Juan Manuel O'Connor); Breast Clinic, Calle 7 No. 432, La Plata, Buenos Aires 1900, Argentina (Nora Giacomi, Fabiana Marmissolle, Paola Price, Claudia Saiz, Silvina Vigo); Hospital de Oncologia Marie Curie, Patricias Argentinas 750, Capital Federal, Buenos Aires 1405, Argentina (Guillermo Lerzo, Jorge Lescano, Guillermo Mendez); Instituto Brasileiro de Controle do Cancer, Avenida Alcantara Machado, 2576, Centro de Estudos-Mooca, Sao Paulo 03102-002, Brazil (Celia Tosello de Oliveira, Mariana T. Laloni, Fernando M. Silva); Hospital Sao Lucas da PUCRS, Av. Ipiranga, 6690, Pesquisa, Sala 228/03, Jd. Botanico, Porto Alegre 90610-000, Brazil (Carlos Barrios, Alan Azambuja, Fabiana Viola, Fernanda Costa, Mauricio Marques); Centro de Atencao Integral a Saude da Mulher-CAISM, Alexander Flemming, 101, Campinas, Sao Paulo 13,081 to 970, Brazil (Luiz Carlos Teixeira, Lucia Kraft, Yara Teixeira); Clinica de Oncologia do Vale, Rua Major Antonio Domingues, 494, Sao Jose dos Campos 12245 to 750, Brazil (Carlos Frederico Pinto, Adriano Mendes); Hospital Perola Byington-Quimioterapia, Brigadeiro Luis Antonio, 683, Sao Paulo 05426-100, Brazil (Elias Abdo, Andre Dias, Adriana Ferreira); Universitetssjukhuset I Lund, Getingevagen 4, Lund 221 85, Sweden (Per Malmstrom, Christina Haapaniemi Ohlsson, Vilberg Johannesson, Sara Kinhult, Niklas Loman, Lotta Lundgren); Department of Clinical Oncology, LUMC, PO Box 9600, Leiden 2300 RC, the Netherlands (J.W.R. Nortier, Marianne Nooij, Andre Johan Gelderblom); Antoni Van Leeuwenhoek Ziekenhuis, Department of Internal Medicine, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands (Jan Herman Schornagel); CHUM-Hopital Notre-Dame, 1560 Sherbrooke St East, Montreal, Quebec H2L-4M1, Canada (Louise Yelle, Jean-Pierre Ayoub, Joseph Ayoub, Karl Belanger, Guy Biron, Danielle Charpentier, Bernard Lemieux, Anne-Marie Nutini, Harold J. Olney, Denis Soulieres); Clinica de Oncologia Medica do Hospital, Brigadeiro, Av. Nove de Julho, 4634, Sao Paulo 01406-100, Brazil (Artur Malzyner, Daniele Vieira, Ricardo Caponero, Renata Santos, Patricia Maeda, Rubem Almeida Jr); Hospital Privado Sudamericano, Calle 2 #432, La Plata, Buenos Aires 1900, Argentina (Hebe Fasce, Miriam Cimini, Luis Flores Acosta, Cecilia Harsanyi, Eduardo Moritan); Hospital Militar Central, Luis Maria Campos 726 7Mo, Capital Federal, Buenos Aires 1426, Argentina (Ricardo Santos, Emilio Batagelj, Oscar Lehmann); Hospital Central Sur de Alta Especialidad PEMEX, Periferico Sur 4091, Colonia Fuentes del Pedregal, Distrito Federal 14140, Mexico (Jorge Robles Avina, Mario Perez Martinez).

	ACKNOWLEDGMENTS

 
We thank Laura Whitaker, Bristol-Myers Squibb, for operational management of the study, and Michelle Utton, Medicus International, for editorial assistance.

	NOTES

 
published online ahead of print at www.jco.org on July 2, 2007.

Supported by Bristol-Myers Squibb Co (study and editorial).

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted September 29, 2006; accepted April 26, 2007.

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