Originally published as JCO Early Release 10.1200/JCO.2007.14.4659 on September 15 2008

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Phase III Study Comparing Exemestane With Tamoxifen As First-Line Hormonal Treatment of Metastatic Breast Cancer in Postmenopausal Women: The European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group

Robert J. Paridaens, Luc Y. Dirix, Louk V. Beex, Marianne Nooij, David A. Cameron, Tanja Cufer, Martine J. Piccart, Jan Bogaerts, Patrick Therasse

From the Universitair Ziekenhuis Gasthuisberg, Leuven; Algemeen Ziekenhuis Sint Augustinus, Antwerp; Institut Jules Bordet, Université Libre de Bruxelles; European Organisation for Research and Treatment of Cancer Data Centre, Brussels, Belgium; Radboud University Nijmegen Medical Centre, Nijmegen; Leiden University Medical Centre, Leiden, the Netherlands; University of Edinburgh & Western General Hospital, Edinburgh, United Kingdom; and The Institute of Oncology, Ljubljana, Slovenia

Corresponding author: Robert J. Paridaens, MD, PhD, University Hospital Gasthuisberg Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; e-mail: robert.paridaens{at}uz.kuleuven.ac.be

	ABSTRACT

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Purpose This phase III randomized open-label clinical trial was designed to evaluate the efficacy and safety of the steroidal aromatase inactivator exemestane versus the antiestrogen tamoxifen as first-line treatment for metastatic breast cancer (MBC) in postmenopausal women.

Patients and Methods The study was conducted at 81 centers and enrolled postmenopausal patients with measurable hormone-sensitive metastatic or locally advanced breast cancer. Prior adjuvant chemotherapy and/or tamoxifen were allowed. One previous chemotherapy regimen and no prior hormone therapy for advanced disease were permitted. Patients were randomly assigned to receive exemestane 25 mg or tamoxifen 20 mg orally once daily until disease progression or unacceptable toxicity occurred.

Results A total of 371 patients enrolled at 79 sites (182 exemestane, 189 tamoxifen) were included in the analysis. Both treatments were generally well tolerated without major toxicity. Overall response rate was greater for exemestane than for tamoxifen treatment (46% v 31%; odds ratio = 1.85; 95% CI, 1.21 to 2.82; P = .005). Median progression-free survival (PFS) was longer with exemestane (9.9 months; 95% CI, 8.7 to 11.8 months) than with tamoxifen (5.8 months; 95% CI, 5.3 to 8.1 months). However, these early differences (Wilcoxon P = .028) did not translate to a longer-term benefit in PFS, the primary study end point (log-rank P = .121). There was also no difference in survival between both study arms.

Conclusion Exemestane is an effective and well-tolerated first-line hormonal treatment for postmenopausal women with MBC and offers significant early improvement in time to tumor progression when compared with tamoxifen.

	INTRODUCTION

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Tamoxifen, a competitive estrogen-receptor (ER) antagonist, was until recently the standard first-line hormonal therapy for metastatic hormone-receptor–positive breast cancer (MBC) in postmenopausal women.¹ The development of resistance to tamoxifen, and long-term toxicities including thromboembolic events and endometrial cancer, has led to increasing use of alternative hormonal therapies including exemestane (Aromasin; Pfizer Inc, New York, NY), a steroidal aromatase inactivator, and other aromatase inhibitors (AIs).

AIs inhibit the conversion of androgens into estrogens, thereby significantly reducing circulating estrogens in postmenopausal women. Their efficacy in breast cancer is well established.² Currently available AIs include the steroidal compound exemestane as well as nonsteroidal compounds such as anastrozole and letrozole.^3-5 Exemestane has been extensively investigated across the spectrum of hormone-receptor-positive postmenopausal breast cancer. Phase II studies have demonstrated its effectiveness as third-line therapy for breast cancer progressing after tamoxifen and nonsteroidal AIs.^4,6,7 Exemestane was also superior to megestrol acetate in prolonging time to progression and even overall survival in patients who had progressed with tamoxifen.⁸

The European Organisation for the Research and Treatment of Cancer (EORTC) Breast Cancer Cooperative Group has investigated the efficacy and tolerability of exemestane compared with tamoxifen in first-line for hormone-responsive MBC in postmenopausal women. The phase II portion of the trial was designed to assess efficacy and safety of exemestane, with the intent to extend the trial into a randomized phase III in the event of promising results.⁹ Additional safety studies focusing on lipids and endometrium were conducted in parallel.^10,11 Of 62 patients who received exemestane, 41% (95% CI, 29% to 53%) achieved an objective complete or partial response, whereas the remission rate for 60 tamoxifen-treated patients was 17% (95% CI, 7% to 27%).⁹ A low incidence of clinically relevant toxicity was observed, and the criteria for extension into a phase III randomized trial were met.

The phase III study reported herein was specifically designed to compare the efficacy and safety of first-line therapy with exemestane versus tamoxifen in postmenopausal women with hormone-sensitive MBC, focusing on progression-free survival (PFS) as the primary study end point.

	PATIENTS AND METHODS

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Study Design
This was a multicenter, randomized open-label phase II/III study conducted at 81 centers. All phase II data were incorporated into this report. Eligible patients were randomly assigned to receive either exemestane (25 mg) or tamoxifen (20 mg) orally once daily. Central randomization was performed at the EORTC Data Center in a 1:1 ratio, using the minimization method¹² based on stratification for institution, previous adjuvant tamoxifen (yes v no), previous chemotherapy for metastatic disease (yes v no), and dominant metastatic site (visceral ± others v bone only v bone and soft tissue v soft tissue only). Patients received the designated treatment until disease progression or occurrence of unacceptable toxicity. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by all local ethics boards.

Patients
Eligibility criteria were similar to those of the phase II part of the trial.⁹ Patients had to provide written informed consent before study participation. Female patients with metastatic or locally recurrent inoperable breast cancer with at least one bidimensionally measurable lesion were eligible, provided that they were postmenopausal, either by natural installation or after surgical castration. Patients with radiotherapy- or chemotherapy-induced amenorrhea lasting at least 1 year also were eligible, but for them and for any patient younger than age 56 years, follicle-stimulating hormone, luteinizing hormone, and plasma estradiol had to be within the postmenopausal range. Target lesions had to be measurable in two perpendicular diameters, with at least one diameter of at least 2.5 cm and not preirradiated. Exceptions included liver and extra-abdominal lesions that were followed by computed axial tomography (CT) of at least 2.0 cm; lesions followed by chest x-ray of at least 1.5 cm; photographed skin lesions of at least 1 cm; and purely lytic bone lesions identified by x-ray or CT scan, surrounded by calcified bone, at least 1 cm in diameter, and not previously irradiated unless they had clearly progressed since and the irradiation had occurred at least 3 months before. Primary tumors or metastases had to be hormone-receptor positive. Patients with hormone-receptor–unknown tumors were also eligible, provided that they had a disease-free interval (DFI) of at least 2 years since completing adjuvant therapy (or after surgery without adjuvant therapy). Prior adjuvant chemotherapy and/or tamoxifen were allowed, but the recurrence-free interval after tamoxifen had to be at least 6 months. No previous hormone therapy for MBC was allowed; previous radiotherapy and at most one previous chemotherapy regimen for metastatic disease were permitted, provided that the patient had recovered completely from treatment-associated acute toxicities. Patients with rapidly progressive disease, large-volume visceral disease, or brain metastases were excluded.

Treatment Protocol and Evaluations
Patients were instructed to take either exemestane or tamoxifen orally once daily after breakfast until disease progression or unacceptable toxicity. Patients were evaluated at baseline; at weeks 8, 16, and 24; then every 12 weeks until week 96; and thereafter every 24 weeks. Baseline assessments included a detailed history of previous treatments. A complete physical examination and laboratory evaluations were performed at baseline and at each follow-up visit. Adverse events (AEs) were graded according to National Cancer Institute of Canada Common Toxicity Criteria (NCIC-CTC; December 1994 version) definitions. Tumor assessments at baseline comprised chest radiographs, bone scintigraphy, and imaging of target lesions. Tumor evaluations were made at 8-week intervals, using the same methods as at baseline. If the number of measurable lesions was too great, then up to eight representative lesions were selected. Tumor responses were classified using WHO criteria.¹³ During the phase II part of the study, an independent panel of radiologists reviewed all objective responses. During the phase III trial, which focused on PFS, all case report forms were reviewed at the EORTC Data Center and by the study coordinator (R.J.P.) or the EORTC director (P.T.).

Study End Points
The primary efficacy end point for the phase III trial was PFS, defined as the length of time between random assignment and the onset of disease progression or death. When progressive disease (PD) was established, the time to progression was the time from random assignment until the day on which progression was suspected and documented. Progressive disease was defined as an increase of at least 25% in the size of at least one bidimensionally or unidimensionally measurable lesion or as the appearance of any new lesion. Appearance of pleural effusion or ascites with positive cytology were also considered to be PD. Pathologic fractures or bone collapse were not necessarily indicative of PD. The development of brain metastases was considered as PD even if disease elsewhere responded.

Secondary end points were overall survival (number of deaths at final analysis) and safety. The major safety end point was the incidence and severity of AEs based on NCIC-CTC grades.

Statistical Considerations
A hazard ratio (HR) of 0.71 in favor of exemestane was hypothesized based on earlier phase III trial data and the assumption that the median PFS would be 7.14 months with tamoxifen and 10.0 months with exemestane.^14-16 The study was designed to detect a 0.71 HR for PFS with 80% power by a two-sided log-rank test ( = 5%). To obtain this power, 278 events were required; therefore, based on the anticipated median PFS, 342 patients were to be enrolled. Data from the phase II and phase III portions of the trial were pooled for analysis.

All statistical analyses were based on the intention-to-treat (ITT) population. The Kaplan-Meier method was used to calculate PFS from the random assignment date until documented PD or death. Statistical testing was performed by log-rank test; associated HR values smaller than 1 are in favor of exemestane. Similar statistical methods were used for overall survival. An additional comparison of PFS was performed post hoc using the Wilcoxon test. Response rates were compared by ² test and associated odds ratios. Values greater than 1 reflect better odds for response to exemestane. A Cox proportional hazards model was used as an exploratory analysis, with backward and forward selection, while stratifying for treatment, to select a prognostic model.

The 5% level was used as cutoff for statistical significance throughout the study including exploratory analyses. Patients who did not experience an event (progression and/or death) by the time of analysis were censored at the last available follow-up date. Analyses of AEs were descriptive and were summarized as the worst grade of toxicity per patient.

	RESULTS

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Patients
Between October 1996 and December 2002, 382 patients were randomly assigned to receive exemestane (n = 190) or tamoxifen (n = 192). Two sites, which enrolled 11 patients, were excluded from analysis because of inadequate documentation, leaving 79 sites with 371 assessable patients (182 exemestane, 189 tamoxifen), who were analyzed on an ITT basis. The flow of participants through the study is summarized in Figure 1.

View larger version (22K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Patient flow. ER, estrogen receptor; PgR, progesterone receptor; ITT, intention to treat; MBC, metastatic breast cancer; PP, per protocol. (*) Patients may have had more than 1 reason for discontinuation.

Efficacy Analyses
PFS. A total of 319 events (progression or death) were observed: 161 (85%) in the tamoxifen arm and 158 (87%) in the exemestane arm. The associated HR was 0.84 (95% CI, 0.67 to 1.05) in favor of exemestane. The HR for the 79% of patients without prior hormonal treatment was 0.83 in favor of exemestane. In addition, at both 6 and 12 months, the percentage of patients without disease progression was greater with exemestane (66.2% [95% CI, 59.3% to 73.1%] and 41.7% [95% CI, 34.5% to 48.9%], respectively) than with tamoxifen (49.5% [95% CI, 42.2% to 56.6%] and 31.2% [95% CI, 24.4% to 37.9%]). Although results of the log-rank test analysis were not statistically significant (P = .121), observation of the Kaplan-Meier curves (Fig 2A) indicated that the HR was not constant over time, with apparently greater differences in the earlier part of the follow-up period. Indeed, the 4.1-month difference in median PFS between treatment arms (Table 2) was statistically significant using the Wilcoxon test (P = .028), which gives greater weight to earlier events. In a follow-up analysis of key end points after a median of 46 months, the HR for PFS was similar at 0.87 (95% CI, 0.70 to 1.08).

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Progression-free and (B) overall survival. O, total number of events observed; N, total number of patients.

Finally, the results of sensitivity analyses including the 11 patients excluded because of inadequate documentation did not differ from those reported for the 371 assessable patients (data not shown).

Overall survival. As shown in Table 2 and illustrated in Figure 2B, no differences in overall survival were observed between treatment arms (log-rank P = .821). The 1-year survival rates in the tamoxifen and the exemestane groups were 82% and 86%, respectively. The HR for overall survival was 1.04 (95% CI, 0.76 to 1.41) after 29 months follow-up. At the 49-month updated analysis, 163 patients had died, 81 in the tamoxifen arm and 82 in the exemestane arm, and the HR remained essentially the same (HR = 1.13; 95% CI, 0.85 to 1.50).

Tumor Response and Prognostic Factors
As shown in Table 2, the objective response rate (complete response + partial response) was 46% for exemestane and 31% for tamoxifen. Consistent with the higher response rate in favor of exemestane (odds ratio = 1.85; 95% CI, 1.21 to 2.82; exact ² P = .005), there were fewer patients with disease progression at 29-month follow-up with exemestane (33 patients [18.1%]) than with tamoxifen (54 patients [28.6%]).

Response rates by prognostic factors and treatment arm are shown in Table 3. With the exception of patients who received previous adjuvant tamoxifen, in whom response rates were nearly identical for both study arms, response rates for exemestane-treated patients were higher than for tamoxifen-treated patients in each prognostic subgroup.

	DISCUSSION

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It is noteworthy that the improvement in medians was met as hypothesized. Corresponding to these medians, most patients had an event (progression or death) within the first year. Interpretation of the Kaplan-Meier curves should concentrate on the first 2 years after random assignment because by that time point almost all patients have either experienced progression or died.

Our results are consistent with those observed in other randomized phase III studies that compared AIs and tamoxifen as first-line therapy for MBC (Table 5).^14,15,17 In contrast to these previously reported trials, patients enrolled onto our study were required to have measurable disease. The difference in PFS found here in favor of exemestane is corroborated by a significantly better quality of response and did not emanate from any subgroup analysis. These findings in the metastatic setting support the growing body of evidence that AIs have broad utility throughout the spectrum of breast cancer and may have clinical advantages over tamoxifen. Exemestane demonstrated excellent tolerability and safety. Because it differs from nonsteroidal AIs such as anastrozole and letrozole in its irreversible inhibition of aromatase⁴ and its efficacy in MBC patients whose disease progressed during treatment with nonsteroidal AIs,⁷ this expands the options available for treating hormone-sensitive breast cancers.

The expansion of hormonally based therapeutic options for all stages of hormone-sensitive breast cancer is encouraging. Ongoing research aimed at fully characterizing the efficacy, safety, and tolerability profile of exemestane and other AIs will help elucidate which agents are most appropriate at each stage of disease, as well as the optimal sequence in which they should be administered. The results of the present study in first-line treatment of MBC extend the positive survival findings previously obtained comparing exemestane to megestrol acetate in advanced disease after tamoxifen failure.⁸ As in previous similar trials conducted with nonsteroidal AIs, however, there is no survival advantage to be expected by using first-line exemestane instead of tamoxifen in a palliative setting. For that reason, lengthening of PFS is worthwhile provided that it supports the preservation or improvement of quality of life. Quality of life is therefore an important end point to include in future comparable studies of AIs as first-line treatment of hormone-sensitive MBC.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: None Consultant or Advisory Role: David A. Cameron, Pfizer Inc (C), Novartis (C), Astra Zeneca (C) Stock Ownership: None Honoraria: Robert J. Paridaens, Pfizer Inc, Novartis; Louk V. Beex, Pfizer Inc; David A. Cameron, Pfizer Inc, Novartis, Astra Zeneca Research Funding: Robert J. Paridaens, Pfizer Inc, Novartis; David A. Cameron, Pfizer Inc, Novartis Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Robert J. Paridaens, Luc Y. Dirix, Louk V. Beex, Marianne Nooij, Patrick Therasse

Provision of study materials or patients: Robert J. Paridaens, Luc Y. Dirix, Louk V. Beex, Marianne Nooij, David A. Cameron, Tanja Cufer

Collection and assembly of data: Robert J. Paridaens, Luc Y. Dirix, Marianne Nooij, Tanja Cufer, Jan Bogaerts, Patrick Therasse

Data analysis and interpretation: Robert J. Paridaens, Luc Y. Dirix, Marianne Nooij, Jan Bogaerts, Patrick Therasse

Manuscript writing: Robert J. Paridaens, Luc Y. Dirix, David A. Cameron, Tanja Cufer, Martine J. Piccart, Jan Bogaerts, Patrick Therasse

Final approval of manuscript: Robert J. Paridaens, Luc Y. Dirix, Louk V. Beex, Marianne Nooij, David A. Cameron, Tanja Cufer, Martine J. Piccart, Jan Bogaerts, Patrick Therasse

	ACKNOWLEDGMENTS

 
We thank Complete Healthcare Communications Inc for editorial support (funded by Pfizer Inc), J.P. Lobelle (Pfizer) for his invaluable contribution to the design and conduct of the study, and the following individuals for their active contribution to the study: Argentina—L. Fein, Centro de Oncologia Rosario, Rosario; Australia—M. Chipman, Austin-Repatriation Medical Centre, Heidelberg; S. Della-Fiorentina, Liverpool Hospital, Liverpool; F. Kirsten, Bankstown-Lidcombe Hospital, Bankstown; T. Price, Queen Elizabeth Hospital, Woodville; J. Stewart, Newcastle Mater Hospital, Newcastle; E. Walpole, Princess Alexandra Hospital University of Queensland, Woolloongabba, Brisbane; Belgium—D. Becquart, Algemeen Ziekenhuis Middelheim, Antwerpen; L. Dirix, Algemeen Ziekenhuis Sint-Augustinus, Antwerpen; F. Majois, Hopital de Jolimont, Haine St Paul; R. Paridaens, Universitair Ziekenhuis, Gasthuisberg, Leuven; M. Piccart, Institut Jules Bordet, Université Libre de Bruxelles, Brussels; A. Vindevoghel, Clinque Sainte Elisabeth, Namur; Egypt—N. El-Ghamry, University of Alexandria, Alexandria; T. Hashem, Menofeya University, Menofeya; H. Kohail, Medical Research Institute University of Alexandria, Alexandria; Estonia—V. Valvere, North Estonia Regional Hospital, Tallinn; France—P. Chollet, Centre Jean Perrin, Clermont-Ferrand; M. Debled, Centre Henri Becquerel, Rouen; P. Fargeot, Centre Georges-Francois-Leclerc, Dijon; J. Guastalla, Centre Leon Berard, Lyon; L. Mauriac, Institut Bergonie, Bordeaux; M. Tubiana-Hulin, Centre Rene Huguenin, Saint-Cloud; Germany—C. Thomssen, Universitaets-Krankenhaus Eppendorf, Hamburg; Hong Kong—L. Chow, University of Hong Kong Queen Mary Hospital; India—S. Advani, Tata Memorial Hospital, Parel, Mumbai; D. Doval, Rajiv Gandhi Cancer Institute & Research Centre, New Delhi; R. Naik, Curie Centre of Oncology St John's College & Hospital, Bangalore; Israel—A. Sella, Assaf Harofeh Medical Center, Zerifin; Japan—T. Asaga, Kanagawa Cancer Center, Yokohama City, Kanagawa; H. Fujii, Tochigi Cancer Center, Tochigi; Y. Iino, Gunma University School of Medicine, Maebashi-City, Gunma; H. Inaji, Osaka Medical Center for Cancer & Cardiovascular Diseases, Higashinari-Ku, Osaka; M. Kimura, Gunma Cancer Center, Ota-City, Gunma; H. Minami, National Cancer Center Hospital East, Kashiwa-City, Chiba; S. Miura, Aichi Cancer Center, Chikusa-Ku Nagoya, Aichi; R. Nishimura, Kumamoto City Hospital, Kumamoto; S. Ohno, National Kyushu Cancer Center, Fukuoka-City, Fukuoka; T. Saeki, National Shikoku Cancer Center, Matsuyama-City, Ehime; M. Sano, Niigata Prefectural Cancer Center Hospital, Niigata-City; H. Sonoo, Kawasaki Medical School, Kurashiki-City, Okayama; T. Tabei, Saitama Cancer Center, Kitaadachi-Gun, Saitama; S. Takenoshita, Fukushima Medical University School of Medicine, Fukushima; M. Toi, Tokyo Metropolitan Komagome Hospital, Tokyo; Y. Tokuda, Tokai University School of Medicine, Isehara-City, Kanagawa; T. Watanabe, National Cancer Center Hospital, Tokyo; Malaysia—P. Gomez, Hospital Kuala Lumpur, Kuala Lumpur; Pakistan—Shaharyar, Mayo Hospital, Lahore; Y. Shakeeb, Shaukat Khanum Memorial Cancer Hospital, Lahore; Philippines—P. Caguioa, St Luke's Medical Center, Quenzon City; Poland—J. Jassem, Medical University of Gdansk, Gdansk; Serbia and Montenegro—Z. Neskovic-Konstantinovic, Institute of Oncology & Radiology, Belgrade; Slovenia—T. Cufer, The Institute of Oncology, Ljubljana; Spain—J. Gracia Marco, Hospital de Cabuenes, Gijon; J. Illarramendi-Veasco, Hospital de Navarra, Pamplona; C. Mendiola, Hospital Universitario 12 de Octubre, Madrid; Taiwan—C. Chen, Koo Foundation Sun Yat-Sen Cancer Center, Taipei; Y. Jyh-Cherng, National Defense Medical Center Tri-Service General Hospital, Neihu 114, Taipei; Thailand—C. Akewanlop, Siriraj Hospital Mahidol University, Bangkok; P. Lertsanguansinchai, Chulalongkorn Hospital, Bangkok; the Netherlands—L. Beex, Radboud University Nijmegen Medical Centre, Nijmegen; G. Creemers, Catharina Ziekenhuis, Eindhoven; H. De Graaf, Medisch Centrum Leeuwarden-Zuid, Leeuwarden; F. Erdkamp, Maaslandziekenhuis, Sittard; M. Nooij, Leiden University Medical Centre, Leiden; K. Roozendaal, Onze Lieve Vrouw Gasthuis, Amsterdam; C. Seynaeve, Erasmus University Medical Center, Rotterdam; H. Sleeboom, Leyenburg Ziekenhuis, S. Gravenhage Den Haag; D Ten Bokkel Huinink, Diakonessenhuis, Utrecht; A. Van Bochove, Ziekenhuis De Heel, Zaandam; C. Van Der Heul, St Elisabethziekenhuis, Tilburg; G. Vreugdenhil, Maxima Medisch Centrum Locatie Veldhoven, Veldhoven; Ukraine—Y. Shparyk, Lviv Cancer Center, Lviv; United Kingdom—D. Cameron, University of Edinburgh & Western General Hospital, Edinburgh; R. Coleman, Weston Park Hospital, Sheffield; A. Wardley, Christie Hospital, Manchester; United States—D. Cuevas, St Louis Cancer Care LLP, Chesterfield, MO.

	NOTES

 
published online ahead of print at www.jco.org on September 15, 2008

Supported in part by a grant from Pfizer Inc and Grant No. 2U10 CA11488-25 5U10 CA11488-34 from the National Cancer Institute (Bethesda, MD).

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

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

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Submitted September 19, 2007; accepted June 4, 2008.

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