- © 2007 by American Society of Clinical Oncology
Cardiovascular Adverse Events During Adjuvant Endocrine Therapy for Early Breast Cancer Using Letrozole or Tamoxifen: Safety Analysis of BIG 1-98 Trial
- Henning Mouridsen,
- Aparna Keshaviah,
- Alan S. Coates,
- Manuela Rabaglio,
- Monica Castiglione-Gertsch,
- Zhuoxin Sun,
- Beat Thürlimann,
- Louis Mauriac,
- John F. Forbes,
- Robert Paridaens,
- Richard D. Gelber,
- Marco Colleoni,
- Ian Smith,
- Karen N. Price and
- Aron Goldhirsch
- From the Danish Breast Cancer Cooperative Group, Rigshospitalet, Copenhagen, Denmark; International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Harvard School of Public Health; Frontier Science and Technology Research Foundation, Boston, MA; IBCSG Coordinating Center and Inselspital; Swiss Group for Clinical Cancer Research, Bern; Senology Center of Eastern Switzerland, Kantonsspital, St Gallen; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; School of Public Health, University of Sydney, Sydney; Australian New Zealand Breast Cancer Trials Group, University of Newcastle, Calgary Mater Newcastle, Newcastle, New South Wales, Australia; French Breast Cancer Group, Institut Bergonié, Bordeaux, France; Department of Medical Oncology, University Hospital Gasthuisberg, Catholic University of Leuven, Belgium; European Institute of Oncology, Milan, Italy; and The Royal Marsden Hospital, London, United Kingdom
- Address reprint requests to Henning Mouridsen, MD, Department 2501, Righospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark; email: henning.mouridsen{at}rh.hosp.dk
Abstract
Purpose Previous analyses of adjuvant studies of aromatase inhibitors versus tamoxifen, including the Breast International Group (BIG) 1-98 study, have suggested a small numerical excess of cardiac adverse events (AEs) on aromatase inhibitors, a reduction in the incidence of hypercholesterolemia on tamoxifen, and significantly higher incidence of thromboembolic AEs on tamoxifen. The purpose of the present study is to provide detailed updated information on these AEs in BIG 1-98.
Patients and Methods Eight thousand twenty-eight postmenopausal women with receptor-positive early breast cancer were randomly assigned (double-blind) between March 1998 and May 2003 to receive 5 years of adjuvant endocrine therapy with letrozole, tamoxifen, or a sequence of these agents. Seven thousand nine hundred sixty-three patients who actually received therapy are included in this safety analysis, which focuses on cardiovascular events. AE recording ceased 30 days after therapy completion (or after switch on the sequential arms).
Results Baseline comorbidities were balanced. At a median follow-up time of 30.1 months, we observed similar overall incidence of cardiac AEs (letrozole, 4.8%; tamoxifen, 4.7%), more grade 3 to 5 cardiac AEs on letrozole (letrozole, 2.4%; tamoxifen, 1.4%; P = .001)—an excess only partially attributable to prior hypercholesterolemia—and more overall (tamoxifen, 3.9%; letrozole, 1.7%; P < .001) and grade 3 to 5 thromboembolic AEs on tamoxifen (tamoxifen, 2.3%; letrozole, 0.9%; P < .001). There was no significant difference between tamoxifen and letrozole in incidence of hypertension or cerebrovascular events.
Conclusion The present safety analysis, limited to cardiovascular AEs in BIG 1-98, documents a low overall incidence of cardiovascular AEs, which differed between treatment arms.
INTRODUCTION
Several third-generation aromatase inhibitors have become accepted as standard care in the adjuvant systemic therapy of postmenopausal women with endocrine-responsive early breast cancer1,2 based on superior disease-free survival in several large clinical trials of anastrozole,3-6 exemestane,7 and letrozole.8,9 The Breast International Group (BIG) study 1-98 is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole versus sequences of 2 years of one of these agents followed by 3 years of the other. In the initial report of BIG 1-98, we noted an increased number of thromboembolic adverse events (AEs) in patients receiving tamoxifen and a small increase in some types and grades of cardiac events in patients receiving letrozole. Serum cholesterol decreased on average after initiation of tamoxifen therapy, whereas it remained relatively unchanged on letrozole. Elevations of serum cholesterol, mainly low grade, were reported more frequently among patients receiving letrozole. The present report analyzes these AEs in more detail based on further follow-up and medical review of grade 3 to 5 AEs and examines the relationship between serum cholesterol elevation and cardiac AEs.
PATIENTS AND METHODS
The primary core analysis (PCA) of BIG 1-989 was based on 8,010 patients (after excluding 18 patients who withdrew consent and did not start treatment). The present safety analysis excluded 47 further patients who never received trial treatment and is based on data received as of April 15, 2005, from the 7,963 patients included in the safety portion of the PCA. As in the PCA, AEs and follow-up were included up to 30 days after therapy completion or after switch on the sequential arms.
The trial included two random assignment options. From March 1998 to March 2000, patients were randomly assigned to the two-arm option of monotherapy with letrozole (2.5 mg daily) or tamoxifen (20 mg daily); from April 1999 to May 2003, patients were randomly assigned to the four-arm option, which involved monotherapy with letrozole or tamoxifen or the sequential administration of tamoxifen followed by letrozole or letrozole followed by tamoxifen. The trial was stratified according to the participating center and according to whether chemotherapy was neither administered nor planned, was completed before random assignment, or was planned to be administered concurrently with endocrine therapy. The latter two strata have been combined into one group for this report (chemotherapy, yes).
Cardiovascular AEs
Specifically requested cardiovascular AEs were listed with check boxes on the case report forms. These included cardiac-ischemia/infarction, cerebrovascular accident (CVA)/transient ischemic event or attack (TIA), angina requiring percutaneous transluminal coronary angioplasty or requiring coronary bypass graft, thrombosis/embolism, hypercholesterolemia, and other cardiovascular event. Other cardiovascular AEs were also requested but were listed with a comment field for specification by the investigator. These other cardiovascular AEs were coded according to MedDRA, and MedDRA preferred term10 codes were further grouped by International Breast Cancer Study Group oncologists into the categories presented in the PCA safety analyses. All grade 3, 4, and 5 cardiovascular AEs were medically reviewed by senior oncologists (M.R. and M.C.-G.) at the International Breast Cancer Study Group Coordinating Center. All pre-existing cardiovascular morbidities reported at baseline (and specified via a comment field) were also medically reviewed and grouped into the categories presented in the PCA safety analyses. All reviewers were blinded to randomized treatment.
Three types of analyses were conducted to look in-depth at cardiovascular safety; the first analysis focused on cardiovascular AEs, the second one looked at lipid levels, and the third one investigated the association between cardiac AEs and presence of hypercholesterolemia at baseline or at any time before the outcome AE. In the analysis of cardiovascular AEs, the following eight end points were examined: any cardiac AE, ischemic heart disease, cardiac failure, hypertension, CVA/TIA, thromboembolic AE (including deep vein thrombosis and phlebitis), peripheral atherosclerosis (including aneurysm, aortic aneurysm rupture, aortic dilation, arteriosclerosis, atherosclerosis obliterans, femoral arterial stenosis, hypertensive angiopathy, iliac artery stenosis, and intermittent claudication), and other cardiovascular AE (including any not otherwise specified cardiovascular disorder, aortic stenosis, varicose veins, venous insufficiency, ischemic colitis, vasodilation, and venous stenosis).
To compare the incidence of cardiovascular end points between treatments, two-sided Fisher's exact tests11 were used. Time from random assignment to the first report of cardiovascular end points was compared via a log-rank test12 stratified by random assignment option (two-arm or four-arm option) and chemotherapy (yes or no, based on chemotherapy stratum), and Kaplan-Meier13 plots were generated. These analyses were not generated for peripheral atherosclerotic or other cardiovascular AEs because the data were sparse.
hypercholesterolemia
In all analyses, hypercholesterolemia was considered present if either the total cholesterol levels (mg/dL) were greater than the upper limit of normal reported in the case report form or the investigator had indicated hypercholesterolemia as a pre-existing morbidity at baseline or it was reported anytime as an AE. Box plots14 of the percent change from baseline in total cholesterol level included only patients who had baseline measurements taken and at least one follow-up measurement. Analyses of cholesterol combined fasting and nonfasting levels, although 90.9% of all recorded values were nonfasting.
Association Between Cardiac AEs and hypercholesterolemia
To examine the association between cardiac AEs and total cholesterol levels, Cox proportional hazards models15 were generated for time to first cardiac AE using randomized treatment assignment as a single covariate. Cox models were further adjusted for whether or not the patient had hypercholesterolemia before the outcome AE (as a time-varying covariate counted if hypercholesterolemia was present at at least one follow-up visit before the AE) and clinically relevant baseline covariates (full model), which were age at random assignment (≥ 55 v < 55 years), smoking status (ever v never smoker), body mass index (BMI; ≥ 30 v < 30 kg/m2), presence of hypertension (defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 90 mmHg) at baseline, presence of diabetes at baseline, and presence of cardiac morbidity at baseline. If more than 1% of patients had a missing value for a particular covariate, an indicator for whether or not the covariate was missing was included in the Cox models. Cox models were also generated for the other cardiovascular end points (excluding peripheral atherosclerotic or other cardiovascular AEs) to control for clinically relevant baseline covariates (full model). Models for time to hypertension, CVA/TIA, and thromboembolic AE were not adjusted for presence of prior hypercholesterolemia. All Cox models were stratified by random assignment option and chemotherapy.
Analyses of AEs were conducted for any grade AEs (ie, grades 1 to 5) and also restricted to AEs of grade 3 or higher. Grading of AEs was based on National Cancer Institute Common Toxicity Criteria, version 2.0.16 The ethics committees and required health authorities of each participating institution approved the study protocol, and all patients gave written informed consent.
RESULTS
The median follow-up time for this analysis was 30.1 months. As expected from this large randomized trial, baseline patient and disease characteristics, including medical history of morbidities, were well balanced (≤ 1% difference) between treatments (Table 1).
Baseline Patient and Disease Characteristics
Cardiovascular AEs
Table 2 lists the incidence of AEs by type separately for AEs of any grade and for grades 3 to 5 only. Overall, the incidence of cardiovascular events was low in both treatment arms. Tamoxifen was associated with significantly more thromboembolic AEs, whereas letrozole was associated with significantly more peripheral atherosclerotic AEs and other cardiovascular AEs of any grade. An unplanned analysis of grade 3 to 5 AEs (severe, life threatening, or fatal) noted that tamoxifen resulted in significantly more grade 3 to 5 thromboembolic AEs and letrozole resulted in significantly more grade 3 to 5 cardiac AEs of any type and, specifically, in more such events classified as cardiac failure.
Worst Grade of Cardiovascular Adverse Events
hypercholesterolemia
A total of 7,544 patients had at least one cholesterol measurement reported, and 6,446 patients had cholesterol measurements reported at baseline and at at least one follow-up visit. Most measurements (90.9%) were reported as nonfasting. Figure 1A shows box plots for total cholesterol by follow-up visit, and Figure 1B shows box plots for the percent change in total cholesterol from baseline by follow-up visit. Figure 1 is descriptive in nature, and its validity is to be verified by other data. Median total cholesterol decreased over time under both treatments. The decrease was greater for patients receiving tamoxifen, for whom the lowering was immediately apparent; the decrease for patients receiving letrozole began approximately 30 months after random assignment. In a sensitivity analysis restricted to the subset of 1,773 patients with available cholesterol measurements at baseline and at each follow-up visit through 3 years after random assignment, the box plot patterns of percent change in cholesterol were strikingly similar to that seen in Figure 1B.
Total cholesterol over time: (A) raw levels and (B) percent change from baseline. Boxes are drawn from the 25% to 75% quartiles, the horizontal line represents the median, and the whiskers are drawn out to 1.5 × interquartile range. Circles represent outliers.
Although both letrozole and tamoxifen lowered median cholesterol levels, at each follow-up visit, a greater proportion of patients receiving letrozole had an increase in total cholesterol compared with baseline (at each follow-up visit, the box for the letrozole group crosses 0, whereas the box for the tamoxifen group is almost entirely at or below 0). This pattern explains the relatively higher proportion of patients on letrozole for whom low-grade hypercholesterolemia was reported in the PCA.9 The relationship between total cholesterol grade at baseline and grade during follow-up is shown in Appendix Table A1 (online only).
Time to AE Analyses
Table 3 lists the results for treatment using univariate (treatment alone) and multivariate (full model) Cox models generated for time to AEs of any grade. The results were consistent with those found in univariate analyses of incidence. Even after controlling for clinically relevant covariates, tamoxifen resulted in significantly more thromboembolic AEs than letrozole.
Time to First Cardiovascular Adverse Event of Any Grade
Table 4 lists the results for treatment using univariate (treatment alone) and multivariate (full model) Cox models generated for time to grade 3 to 5 AEs. Again, the results were consistent with the univariate analyses of incidence, with significantly more grade 3 to 5 cardiac events and, specifically, grade 3 to 5 cardiac failure on letrozole and significantly more grade 3 to 5 thromboembolic events on tamoxifen.
Time to First Cardiovascular Adverse Event of Grades 3 to 5
Age ≥ 55 years at random assignment was a significant predictor of risk in all models, as was having a prior history of the AE being modeled. Whether or not a patient ever smoked did not significantly alter risk in any of the multivariate models. History of hypertension was a significant predictor of ischemic heart disease, CVA/TIA, hypertension, and thromboembolism. BMI was a significant predictor of hypertension only. History of diabetes was a significant predictor of any cardiac AE, particularly ischemic heart disease, and also of CVA/TIA. Presence of hypercholesterolemia before the outcome AE was a significant predictive factor for any cardiac AE and particularly for ischemic heart disease. Results for the Cox models with grade 3 to 5 AEs only were similar, with the following differences: age was not a significant predictor of ischemic heart disease; BMI was a significant predictor of cardiac failure and thromboembolism in addition to hypertension; history of diabetes was a significant predictor of cardiac failure and CVA/TIA only; and history of hypertension was a significant predictor of any grade 3 to 5 cardiac AEs, particularly ischemic heart disease, and of CVA/TIA but not of grade 3 to 5 hypertension. The direction of the effect of the covariates on risk of the AEs modeled was generally as expected, with the exception of the association of history of hypertension with decreased hypertension AE (any grade) and BMI ≥ 30 kg/m2 with decreased risk of a thromboembolic AE (grades 3 to 5). Additional results are shown in Appendix Tables A2 and A3, and Figures A1 and A2 (online only).
Association Between Cardiac AEs and hypercholesterolemia
As noted earlier, incidence of prior hypercholesterolemia was a significant predictor of any grade and of grade 3 to 5 cardiac AEs, including ischemic heart disease, but was associated with a nonsignificant decrease in risk of grade 3 to 5 cardiac failure. Even after controlling for incidence of prior hypercholesterolemia, letrozole was associated with a significantly increased residual risk of grade 3 to 5 cardiac AE, as seen in Table 4.
As shown in Figure 2, the incidence patterns for any grade cardiac AEs were quite similar between the two treatments up to 3 years after random assignment. When restricted to patients with a grade 3 to 5 AE at all time points, a greater proportion of patients receiving letrozole had an event and prior hypercholesterolemia compared with patients receiving tamoxifen. Up to 3 years after random assignment, a similar proportion of patients on the two treatments had a cardiac AE but no prior hypercholesterolemia; after 3 years, more patients on letrozole had a cardiac AE without prior hypercholesterolemia. The results shown in Figure 2 are descriptive in nature. Letrozole was associated with slightly greater incidence of grades 1 to 5 vascular AEs classified as peripheral atherosclerotic disease and with the residue of unclassified cardiovascular AEs, but in neither case did the association extend to grade 3 to 5 AEs (Table 2).
Percentage of patients with a cardiac adverse event (AE) of (A, C) any grade or (B, D) grades 3 to 5 during treatment with (A, B) letrozole or (C, D) tamoxifen according to year from random assignment, separated by whether or not the patient had hypercholesterolemia before the first cardiac AE reported.
DISCUSSION
The higher incidence of thromboembolic disease observed on tamoxifen in BIG 1-98 is consistent with the pattern of toxicity seen in other trials comparing tamoxifen with a third-generation aromatase inhibitor.3,7 Although the overall incidence was low, patients at risk for thromboembolic disease, such as those with an antecedent history of such episodes, might consider avoiding adjuvant tamoxifen therapy.
We agree with Howell and Cuzick17 that because most women now presenting with early breast cancer can expect long-term survival and vascular disease is the major cause of death in women, assessment of vascular adverse effects of highly effective adjuvant therapies such as aromatase inhibitors is important. Each of the major trials comparing a third-generation aromatase inhibitor with tamoxifen has reported a small numeric excess of cardiovascular events on the aromatase inhibitor arm, although this was not statistically significant in any of the studies. BIG 1-98 and the Arimidex (anastrozole), Tamoxifen, Alone or in Combination (ATAC) trial3 are the largest reported randomized trials comparing initial use of an aromatase inhibitor with tamoxifen. As distinct from the ATAC trial in which prespecified checklists were not used18 and from which grades of cardiac toxicity have not been reported, in the BIG 1-98 study, cardiovascular AEs and serum cholesterol were explicitly collected on data forms and graded according to National Cancer Institute Common Toxicity Criteria.16 Therefore, detailed comparison between the two studies is not possible. The large ongoing phase III trial comparing anastrozole with letrozole will provide detailed head-to-head safety evaluations of those two compounds. Despite our rigorous approach, the overall reported incidence of cardiac AEs in BIG 1-98 was low on both arms and did not differ between treatments. However, in a nonplanned secondary analysis, significantly more grades 3 to 5 cardiac AEs were seen with letrozole than with tamoxifen in BIG 1-98 (Table 2). No corresponding analysis has been published from the ATAC trial.
In BIG 1-98, median total cholesterol decreased over time on both treatments. Descriptive analyses suggested that the decrease was greater and earlier for patients receiving tamoxifen. The decrease for patients receiving letrozole began approximately 30 months after random assignment. This finding is consistent with the effect of anastrozole in the ATAC trial.18 Prior elevation of cholesterol was associated with the subsequent recording of a grade 3 to 5 cardiac AE, but this association did not completely explain the higher incidence of cardiac AEs on letrozole. The reason for the residual effect is not clear. A possible mechanism may relate to a direct effect of profoundly lowered circulating estrogen levels on vascular endothelium,17,19-21 although no similar effect was observed in the placebo-controlled MA.17 trial,8 suggesting that the difference could also reflect some protective effect of tamoxifen in BIG 1-98.
Taken together, cardiovascular AEs were relatively rare in our study, and any excess of cardiac events on letrozole seems to be outweighed by the superior control of locoregional and distant recurrence afforded by letrozole compared with tamoxifen. Nevertheless, an understanding of the nature, frequency, and mechanism of such AEs is important to optimize the therapeutic ratio in adjuvant endocrine therapy with aromatase inhibitors for postmenopausal patients with endocrine-responsive early breast cancer.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
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: Henning Mouridsen, Novartis (C); Louis Mauriac, Novartis (C); John F. Forbes, Novartis (C); Robert Paridaens, Novartis (C); Ian Smith, Novartis (C); Aron Goldhirsch, Novartis (C) Stock Ownership: Beat Thürlimann, Novartis Honoraria: Henning Mouridsen, Novartis; Louis Mauriac, Novartis; John F. Forbes, Novartis; Robert Paridaens, Novartis; Ian Smith, Novartis; Aron Goldhirsch, Novartis Research Funding: Louis Mauriac, Novartis; Robert Paridaens, Novartis; Aron Goldhirsch, Novartis Expert Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Henning Mouridsen, Aparna Keshaviah, Alan S. Coates, Richard D. Gelber
Administrative support: Monica Castiglione-Gertsch, Karen N. Price
Provision of study materials or patients: Henning Mouridsen, Alan S. Coates, Monica Castiglione-Gertsch, Beat Thürlimann, Louis Mauriac, John F. Forbes, Robert Paridaens, Marco Colleoni, Ian Smith, Aron Goldhirsch
Collection and assembly of data: Henning Mouridsen, Aparna Keshaviah, Manuela Rabaglio, Monica Castiglione-Gertsch, Beat Thürlimann, Louis Mauriac, John F. Forbes, Robert Paridaens, Richard D. Gelber, Marco Colleoni, Ian Smith, Karen N. Price, Aron Goldhirsch
Data analysis and interpretation: Henning Mouridsen, Aparna Keshaviah, Alan S. Coates, Zhuoxin Sun, Richard D. Gelber
Manuscript writing: Henning Mouridsen, Aparna Keshaviah, Alan S. Coates, Beat Thürlimann, Robert Paridaens, Richard D. Gelber, Karen N. Price
Final approval of manuscript: Henning Mouridsen, Aparna Keshaviah, Alan S. Coates, Manuela Rabaglio, Monica Castiglione-Gertsch, Zhuoxin Sun, Beat Thürlimann, Louis Mauriac, John F. Forbes, Robert Paridaens, Richard D. Gelber, Marco Colleoni, Ian Smith, Karen N. Price, Aron Goldhirsch
Appendix
Kaplan-Meier curve and stratified P value for time to any grade (A) cardiovascular, (B) thromboembolic, or (C) other cardiovascular adverse events (AE).
(A) Kaplan-Meier curve and stratified log-rank P value for time to grade 3 to 5 (A) cardiac, (B) cardiac failure, or (C) thromboembolic adverse events (AE).
Total Cholesterol: Baseline CTC Grade Versus Worst CTC Grade During Follow-Up
Significance of Covariates in Multivariate Cox Model for AEs of Any Grade
Significance of Covariates in Multivariate Cox Model for Grade 3 to 5 AEs
Trial Registration: clinicaltrials.gov ID NCT00004205.
Sources of funding and support: The coordinating group for the BIG 1-98 trial is the International Breast Cancer Study Group (IBCSG). The IBCSG received funds from Novartis to coordinate the trial as outlined in the next section. The IBCSG also receives grant support from the Swedish Cancer Society, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group (ANZ BCTG), Frontier Science and Technology Research Foundation (FSTRF), the Swiss Group for Clinical Cancer Research (SAKK), Oncosuisse/Cancer Research Switzerland, US National Cancer Institute (CA-75362), and the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK).
Role of sponsor: The IBCSG received financial support for the conduct of the study. The trial was sponsored by a pharmaceutical company, Novartis. Novartis provided drug distribution and financial support and imposed no restrictions on the investigators with respect to trial data. The IBCSG Statistical Center (unblinded) and Data Management Center (blinded) had access to the database. After the release of the results by the Data and Safety Monitoring Committee, the unblinded database was transferred to Novartis for preparation of the Clinical Study Report for health authorities.
The manuscript was prepared by the authors, who made final decisions on content, whereas the Steering Committee (including employees of Novartis) reviewed the paper and offered changes. No medical writer or editor was involved in the preparation of this manuscript.
Contract for Trial Management: Novartis provided funding for central activities as summarized below.
Novartis contracted with the IBCSG for provision of services related to the conduct and management of the trial. The following not-for-profit organizations received funds as part of the contract.
IBCSG Coordinating Center: The Coordinating Center provided trial management, medical case review, severe adverse event (SAE) review, budget management, and regulatory support.
Frontier Science Technology and Research Foundation (FSTRF): IBCSG subcontracted to FSTRF for the data management, random assignment system, and statistical design and analysis.
Dana-Farber Cancer Institute: FSTRF subcontracted to Dana-Farber Cancer Institute for statistical design and analysis.
Salary Support: The following members of the writing committee received salary support from their employers (as listed below) for their work on BIG 1-98.
IBCSG Coordinating Center: Monica Castiglione-Gertsch, Manuela Rabaglio.
FSTRF: Richard Gelber, Karen Price.
Dana-Farber Cancer Institute: Aparna Keshaviah, Richard Gelber, Zhuoxin Sun.
BIG 1-98 Collaborative Group Participants: Steering Committee: B. Thürlimann (Chair), L. Blacher, M. Castiglione, A.S. Coates, T. Cufer, J.F. Forbes, R.D. Gelber, A. Goldhirsch, A. Hiltbrunner, S.B. Holmberg, A. Keshaviah, R. Maibach, A. Martoni, L. Mauriac, H.T. Mouridsen, K.N. Price, M. Rabaglio, A. Santoro, I.E. Smith, C. Straehle, G. Viale.
Novartis: H.A. Chaudri-Ross, A. Covelli, D.B. Evans, W. Hackl, E. Raman, M.G. Porro.
IBCSG Scientific Committee: A. Goldhirsch, A.S. Coates (Co-Chairs), L. Blacher, M. Castiglione, J.F. Forbes, R.D. Gelber, B.A. Gusterson, A. Hiltbrunner, C. Hürny, E. Murray, K.N. Price, M. Rabaglio, R. Studer, G. Viale, A. Wallgren.
IBCSG Foundation Council: B. Thürlimann (President), M. Castiglione, A.S. Coates, J.P. Collins, H. Cortés Funes, M. de Stoppani, R.D. Gelber, A. Goldhirsch, M. Green, A. Hiltbrunner, S.B. Holmberg, D.K. Hossfeld, I. Láng, J. Lindtner, F. Paganetti, C.-M. Rudenstam, R. Stahel, H.-J. Senn, A. Veronesi.
Coordinating Center (Berne, Switzerland): M. Castiglione (CEO), A. Hiltbrunner (Director), M. Rabaglio, G. Egli, B. Cliffe, S. Ribeli-Hofmann, F. Munarini, R. Kammler, R. Studer, B. Ruepp, R. Maibach, N. Munarini, E. Marbot.
Statistical Center (Dana-Farber Cancer Institute, Boston, MA): R.D. Gelber (Group Statistician), K.N. Price (Director of Scientific Administration), A. Keshaviah (Trial Statistician), Z. Sun, H. Litman, H. Huang, L.J. Somos, B. Timmers, L. Nickerson.
Data Management Center (Frontier Science and Technology Research Foundation, Amherst, NY): L. Blacher (Director of Data Management), T. Heckman Scolese (Coordinating Data Manager), M. Belisle, M. Caporale, J. Celano, L. Dalfonso, L. Dooley, S. Fischer, K. Galloway, J. Gould, R. Hinkle, M. Holody, G. Jones, R. Krall, S. Lippert, J. Meshulam, L. Mundy, A. Pavlov-Shapiro, K. Scott, M. Scott, S. Shepard, J. Swick, L. Uhteg, D. Weinbaum, C. Westby, T. Zielinski.
Central Pathology Review Office (University of Glasgow, Glasgow, United Kingdom): B.A. Gusterson, E. Mallon; (European Institute of Oncology, Division of Pathology, Milano, Italy): G. Viale, P. Dell'Orto, M. Mastropasqua, B. Del Curto.
Data and Safety Monitoring Committee: D.F. Hayes, J.E. Garber, S.W. Lagakos, I. Lindgren.
Study Support (Novartis Corp, Basel, Switzerland): E. Waldie, I. van Hoomissen, M. De Smet, W. Schmidt, A. Bolton, W. Hackl.
Breast International Group (BIG)
International Breast Cancer Study Group (IBCSG)
Australian New Zealand Breast Cancer Trials Group (ANZ BCTG): Board Chair: R.D. Snyder, Group Co-ordinator: J.F. Forbes, Chair Scientific Advisory Committee: A.S. Coates; ANZ BCTG Operations Office (Newcastle, Australia): D. Lindsay (Head Data Management), D. Preece (Senior Study Coordinator), J. Cowell, D. Talbot, A. Whipp.
Australia: The Cancer Council Victoria, Melbourne, Victoria: F. Abell, R. Basser, R. Bell, B. Brady, D. Blakey, P. Briggs, I. Burns, P. Campbell, M. Chao, J. Chirgwin, B. Chua, K. Clarke, J. Collins, R. De Boer, J.C. Din, R. Doig, A. Dowling, R. Drummond, N. Efe, S.T. Fan, M. Francis, P. Francis, V. Ganju, P. Gibbs, G. Goss, M. Green, P. Gregory, J. Griffiths, I. Haines, M. Henderson, R. Holmes, P. James, J. Kiffler, M. Lehman, M. Leyden, L. Lim, G. Lindeman, R. Lynch, B. Mann, J. McKendrick, S. McLachlan, R. McLennan, G. Mitchell, S. Mitra, C. Murphy, I. Parker, K. Phillips, I. Porter, G. Richardson, J. Scarlet, S. Sewak, J. Shapiro, R. Snyder, R. Stanley, C. Steer, D. Stoney, A. Strickland, G. Toner, C. Underhill, K. White, M. White, A. Wirth, S. Wong; WP Holman Clinic, Launceston General Hospital, Launceston, Tasmania: D. Byram, I. Byard; Liverpool Hospital, Sydney, New South Wales: S. Della-Fiorentina, A. Goldrick, E. Hovey, E. Moylan, E. Segelov; Mount Hospital, Perth, Western Australia: A. Chan, M. Buck, D. Hastrich, D. Ingram, G. Van Hazel, P. Willsher; Nepean Cancer Care Centre, Sydney, New South Wales: N. Wilcken, C. Crombie; Newcastle Mater Hospital, Newcastle, New South Wales: J.F. Forbes, F. Abell, S. Ackland, A. Bonaventura, S. Cox, J. Denham, R. Gourlay, D. Jackson, R. Sillar, J. Stewart; Prince of Wales Hospital, Sydney, New South Wales: C. Lewis, B. Brigham, D. Goldstein, M. Friedlander; Princess Alexandra Hospital, Woollongabba, Queensland: E. Walpole, D. Thompson; Royal Adelaide Hospital, Adelaide, South Australia: P.G. Gill, M. Bochner, J. Coventry, J. Kollias, P. Malycha, I. Olver; Royal Brisbane and Women's Hospital, Brisbane, Queensland: M. Colosimo, R. Cheuk, L. Kenny, N. McCarthy, D. Wyld; Royal Hobart Hospital, Hobart, Tasmania: R. Young, R. Harrup, R. Kimber, R. Lowenthal; Royal Perth Hospital, Perth, Western Australia: J. Trotter, E. Bayliss, A. Chan, D. Ransom; Sir Charles Gairdner Hospital, Perth, Western Australia: M. Byrne, M. Buck, J. Dewar, A. Nowak, A. Powell, G. Van Hazel; Toowoomba Hospital, Toowoomba, Queensland: E.A. Abdi, R. Brodribb, Z. Volobueva; Westmead Hospital, Sydney, New South Wales: P. Harnett, V. Ahern, H. Gurney, N. Wilcken.
New Zealand: Auckland Hospital, Auckland: V.J. Harvey, B. Evans, W. Jones, M. McCrystal, D. Porter, P. Thompson, M. Vaughan; Christchurch Hospital, Christchurch: D. Gibbs, C. Atkinson, R. Burcombe, B. Fitzharris, B. Hickey, M. Jeffery, B. Robinson; Dunedin Hospital, Dunedin: B. McLaren, S. Costello, J. North, D. Perez; Waikato Hospital, Hamilton: I.D. Campbell, L. Gilbert, R. Gannaway, M. Jameson, I. Kennedy, J. Long, G. Round, L. Spellman, D. Whittle, D. Woolerton.
Brazil: Hospital de Clinicas de Porto Alegre, Porto Alegre: C. Menke, J. Biazús, R. Cericatto, J. Cavalheiro, N. Xavier, A. Bittelbrunn, E. Rabin.
Chile: Chilean Cooperative Group for Oncologic Research, GOCCHI: J. Gutiérrez (Chairman), R. Arriagada (Scientific Adviser), L. Bronfman (Principal Investigator), M. Zuñiga (Data Manager); Clinica Las Condes, Santiago: J. Gutiérrez, J.C. Acevedo, S. Torres, A. León, E. Salazar; Hospital DIPRECA, Las Condes, Santiago: L. Soto Diaz, R. Duval, N. Oddeshede, M.C. Venti; Hospital San Juan de Dios, Santiago: K. Peña, L. Puente, V. Maidana; IRAM/Instituto de Radiomedicina, Vitacura, Santiago: R. Baeza, R. Arriagada, P. Olfos, J. Solé, E. Vinés, C. Mariani.
Hungary: National Institute of Oncology, Budapest: I. Láng, E. Hitre, E. Szabó, Z. Horváth, E. Ganofszky, E. Juhos.
Italy: Centro di Riferimento Oncologico, Aviano: A. Veronesi, D. Crivellari, M.D. Magri, A. Buonadonna, F. Coran, E. Borsatti, E. Candiani, S. Massarut, M. Roncadin, M. Arcicasa, A. Carbone, T. Perin, A. Gloghini; Ospedali Riuniti di Bergamo, Bergamo: C. Tondini, R. Labianca, P. Poletti, A. Bettini; Ospedale degli Infermi, Biella: M. Clerico, M. Vincenti, A. Malossi, E. Seles, E. Perfetti, B. Sartorello; Spedali Civili, Brescia: E. Simoncini, G. Marini, P. Marpicati, R. Farfaglia, A.M. Bianchi, P. Grigolato, L. Lucini, P. Frata, A. Huscher, E. Micheletti, C. Fogazzi; U.O. Medicina Oncologica, Ospedale Capri, Ospedale Mirandola: F. Artioli, K. Cagossi, L. Scaltriti, E. Bandieri, L. Botticelli, G. Giovanardi; Ospedale di Cattolica “Cervesi,” Cattolica: A. Ravaioli, E. Pasquini, B. Rudnas; Ospedale Civile, Gorizia: L. Foghin; Ospedale “A. Manzoni” Lecco, Lecco: M. Visini, L. Zavallone, G. Ucci; Istituto Europeo di Oncologia, Milano: M. Colleoni, G. Viale, P. Veronesi, G. Peruzzotti, L. Corsetto, R. Ghisini, G. Renne, A. Luini, L. Orlando, R. Torrisi, A. Rocca, T. De Pas, E. Munzone, V. Galimberti, S. Zurrida, M. Intra, F. Nolé, R. Orecchia, G. Martinelli, F. de Braud, A. Goldhirsch; Ospedale Infermi, Rimini: A. Ravaioli, L. Gianni.
Peru: Instituto de Enfermedades Neoplásicas, Lima: H. Gome.
Slovenia: Institute of Oncology, Ljubljana: T. Cufer, B. Pajk, J. Cervek.
South Africa: Groote Schuur Hospital and University of Cape Town, Cape Town: I.D. Werner, E. Murray, D. Govender, S. Dalvie, T. Erasmus, B. Robertson, B. Read, E. Nel, J. Toop, N. Nedeva, E. Panieri; Sandton Oncology Centre, Johannesburg: D. Vorobiof, M. Chasen, G. McMichael, C. Mohammed. Local funding provided by the Cancer Association of South Africa.
Sweden: West Swedish Breast Cancer Study Group: S.B. Holmberg; Sahlgrenska U Hospital, Moelndal: S.B. Holmberg, J. Mattsson; Boras Hospital, Boras; Karlstads Hospital, Karlstads: H. Sellström; Kungalvs Hospital, Kungalvs: B. Lindberg.
Switzerland: Swiss Group for Clinical Cancer Research (SAKK): A. Goldhirsch (up to January 2004), R. Herrmann (from June 2004): Kantonsspital Aarau, Zentrum f. Onkologie, Aarau: A. Schönenberger, W. Mingrone, Ch. Honegger, E. Bärtschi, M. Neter, M. Rederer, G. Schär; University Hospital Basel, Basel: C. Rochlitz, R. Herrmann, D. Oertli, E. Wight, H. Moch; Institute of Oncology of Southern Switzerland: Ospedale San Giovanni, Bellinzona: J. Bernier, L. Bronz, F. Cavalli, E. Gallerani, A. Richetti, A. Franzetti; Ospedale Regionale di Lugano (Civico & Italiano), Lugano: M. Conti-Beltraminelli, M. Ghielmini, T. Gyr, S. Mauri, P.C. Saletti; Ospedale Regionale Beata Vergine, Mendrisio: A. Goldhirsch, O. Pagani, R. Graffeo, M. Locatelli, S. Longhi, P.C. Rey, M. Ruggeri; Ospedale Regionale La Carità, Locarno: E. Zucca, D. Wyss; Istituto Cantonale di Patologia, Locarno: L. Mazzucchelli, E. Pedrinis, T. Rusca; Inselspital, Berne: S. Aebi, M.F. Fey, M. Castiglione, M. Rabaglio; Kantonsspital Olten, Olten: S. Aebi, M.F. Fey, M. Zuber, G. Beck; Bürgerspital, Solothurn: S. Aebi, M.F. Fey, R. Schönenberger; Spital Thun-Simmental AG Thun: J.M. Lüthi, D. Rauch; Hôpital Cantonal Universitaire HCUG, Geneva: H. Bonnefoi; Rätisches Kantons- und Regionalspital, Chur: F. Egli, R. Steiner, P. Fehr; Centre Pluridisciplinaire d'Oncologie, Lausanne: L. Perey, P. de Grandi, W. Jeanneret, S. Leyvraz, J.-F. Delaloye; Kantonsspital St. Gallen, St. Gallen: B. Thürlimann, D. Köberle, F. Weisser, S., Mattmann, A. Müller, T. Cerny, B. Späti, M. Höfliger, G. Fürstenberger, B. Bolliger, C. Öhlschlegel, U. Lorenz, M. Bamert, J. Kehl-Blank, E. Vogel; Kantonales Spital Herisau, Herisau: B. Thürlimann, D. Hess, I. Senn, D. Köberle, A. Ehrsam, C. Nauer, C. Öhlschlegel, J. Kehl-Blank, E. Vogel; Stadtspital Triemli, Zürich: L. Widmer, M. Häfner; Universitätsspital Zürich, Zürich: B.C. Pestalozzi, M. Fehr, R. Caduff, Z. Varga, R. Trüb, D. Fink.
Swiss Private MDs: Private Praxis, Zürich: B.A. Bättig; Sonnenhof-Klinik Engeried, Berne: K. Buser; Frauenklinik Limmattalspital, Schlieren: N. Bürki; Private Praxis, Birsfelden: A. Dieterle; Private Praxis, Biel: L. Hasler; Private Praxis, Baar: M. Mannhart-Harms; Brust-Zentrum, Zürich: C. Rageth; Private Praxis, Berne: J. Richner; Private Praxis, Bellinzona: V. Spataro; Private Praxis, Winterthur: M. Umbricht.
United Kingdom: King's College Hospital/Breast Unit, London: P. Ellis, S. Harris, N. Akbar, H. McVicars, C. Lees, R. Raman, G. Crane.
Danish Breast Cancer Collaborative Group (DBCG): H.T. Mouridsen; Rigshospitalet, Copenhagen: H.T. Mouridsen; Vejle Hospital, Vejle: E. Jakobsen; Odense University Hospital, Odense: S. Cold; KAS Herlev/Herlev University Hospital, Herlev: C. Kamby; Aalborg Sygehus Syd, Aalborg: M. Ewertz; Hilleroed Hospital, Hilleroed: P.M. Vestlev; Aarhus University Hospital, Aarhus: J. Andersen; Roskilde County Hospital, Roskilde: P. Grundtvig; Esbjerg Central Hospital, Esbjerg: E. Sandberg; Naestved Central Hospital, Naestved: P. Philip; Soenderborg Sygehus, Soenderborg: E. L. Madsen; Herning Central Hospital, Herning: K.A. Moeller; Viborg Sygehus, Viborg: V. Haahr; Landspitali University Hospital, Reykjavik, Iceland: J. Johansson.
Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC): Institut Bergonié, Bordeaux: L. Mauriac, M. Debled, P. Campo; Centre Hospitalier de la Côte Basque, Bayonne D. Larregain-Fournier, S. Remy, Centre Jean Perrin, Clermont-Ferrand: H. Auvray; Centre Georges François Leclerc, Dijon: C. De Gislain, F. Delille, M.-C. Porteret; Centre Oscar Lambret, Lille: V. Servent, M. Chapoutier; CHRU, Limoges: N. Tubiana-Mathieu, S. Lavau-Denes, P. Bosc; Centre Léon Bérard, Lyon: J.P. Guastalla, Th. Bachelot, C. Arbault; Centre Hospitalier Meaux, Meaux: G. Netter-Pinon; C.H.G. André Boulloche, Montbéliard: V. Perrin, A. Monnier, Y. Hammoud; Centre Paul Lamarque, Montpellier: G. Romieu, L. Culine, V. Pinosa; Clinique Francheville, Périgueux: L. Cany, C. Maguire; Hôpital de la Milétrie, Poitiers: A. Daban, M. Le Saux, C. Grandon; Centre Eugène Marquis, Rennes: P. Kerbrat, C. Catheline; Centre Henri Becquerel, Rouen: C. Veyret, E. Jugieau, V. Talon; Centre René Gauducheau, Saint-Herblain: A. Le Mevel, S. Maury; Centre Claudius Régaud, Toulouse: L. Gladieff, N. Lignon.
North Yorkshire Group: D. Dodwell; Harrogate District Hospital, Harrogate, North Yorkshire: D. Dodwell; Huddersfield Royal Infirmary, Huddersfield: J. Joffe; Castlehill Hospital, Hull: P. Drew; Airedale General Hospital, Keighley, W. Yorkshire: A. Nejim; Leeds General Infirmary, Leeds: D. Dodwell, K. Horgan; St. James's University Hospital, Leeds: M. Lansdown, T. Perren; Weston Park Hospital, Sheffield: R. E. Coleman.
Independent Centers/Groups: Argentina: Centro Oncológico Confidence, Buenos Aires: D. Campos; Hospital Allemán, Buenos Aires: F. Cóppola; Hospital Británico, Buenos Aires: J. Martinez; Hospital Evita, Buenos Aires: M. Freue; Hospital Posadas, Buenos Aires: C. Wainstein; Hospital Zubizarreta, Buenos Aires: A. Zori Comba; Instituto Dr. Estevez, Buenos Aires: E. Cazap; Instituto Oncológico Dr. Angel H. Roffo, Buenos Aires: E. Mickiewicz; Sanatorio Municipal Julio A. Mendez, Buenos Aires: L. Balbiani; Centro Privado de Ginecología, Córdoba: A. Osuna; Hospital Privado de Córdoba, Córdoba: E. Palazzo; Instituto Modelo de Ginecología y Obstetricia, Córdoba: M. de Romedis; Fundación Mainetti-Centro Oncológico de Excelencia, La Pllata: S. Cagnolati; Hospital Privado de la Comunidad, Mar del Plata: C.A. Delfino, G. Caccia; Escuela de Medicina Nuclear (COIR), Mendoza: R.L. de Angelis; Centro Oncológico de Rosario, Rosario: L. Fein, R. Sala; Hospital Provincial de Rosario, Rosario: C. Nassurdi, A. Colombo Berra; Clínica Especializada ISIS, Santa Fe: R. Viroglio, C. Blajman; Hospital Regional de Concepción, Tucumán: H. Requejo; Instituto de Maternidad y Ginecología Nuestra Señoras de las Mercedes, Tucumán: L. Silberman.
Australia: Flinders Medical Centre, Adelaide, South Australia: S. Birrell, M. Eaton, C. Hoffman; Queen Elizabeth Hospital, Adelaide, South Australia: V. Humeniuk; The Canberra Hospital, Canberra, Commonwealth of Australia; P. Craft, R. Stuart-Harris, D. Yip; The Geelong Hospital, Geelong, Victoria: R. Bell, F. Abell, M. Francis, J. Kiffer, R. Lynch, R. McLennan, K. White; Royal Melbourne Hospital, Melbourne, Victoria: M. Green, R. Basser, J. Collins, R. De Boer, J.C. Din, N. Efe, S.T. Fan, G. Lindeman, S. Wong; Western General Hospital, Melbourne, Victoria: M. Green, R. Basser, J. Collins, R. De Boer, J.C. Din, N. Efe, S.T. Fan, G. Lindeman, S. Wong; Newcastle Mater Hospital, Newcastle, New South Wales: J. Stewart, F. Abell, S. Ackland, A. Bonaventura; Royal Perth Hospital, Perth, Western Australia: J. Trotter, E. Bayliss, A. Chan, D. Ransom, A. Redfern; St. George Hospital, Sydney, New South Wales: P. de Souza, M. Links; St. Vincent's Hospital, Sydney, New South Wales: D. Dalley, J. Grygiel, R. Ward; Murray Valley Private Hospital, Wodonga, Victoria: C. Underhill, K. Clarke, C. Steer; Princess Alexandra Hospital, Woolloongabba, Queensland: E. Walpole, D. Thompson.
Belgium: Institut Jules Bordet, Bruxelles: J.M. Nogaret; University Hospitals Leuven, Leuven: M.R. Christiaens, P. Neven, R. Paridaens, A. Smeets, I. Vergote, C. Weltens, H. Wildiers; Les Cliniques Saint-Joseph ASBL, Liège: C. Focan; Clinique du Parc Léopold, Bruxelles: L. Marcelis; C.H. Etterbeek - Ixelles, Bruxelles: J.P. Kains; Service d'Oncologie Clinique Notre-Dame, Charleroi: J.-L. Canon; CHU André Vèsale, Montigny-Le Tilleul: D. Brohèe.
Canada: Cambridge Memorial Hospital, Cambridge: J. Gowing; CHUM Campus Notre Dame, Montreal: L. Yelle; Hôpital Maisonneuve-Rosemont, Montreal: P. Dubé.
Chile: Fundacion Lopez Perez, Santiago: C. Vogel; Hospital Carlos Van Buren, Valparaiso: M. León Prieto.
Czech Republic: Institute of Oncology, Brno: K. Petrakova, M. Palacova, R. Demlova; Department of Clinical and Radiation Oncology, Ceske Budejovice: H. Siffnerova, J. Fischer, I. Bustova; Centre of Breast Diseases, Prague: H. Kankova, M. Pintova; Institute of Radiation Oncology, Prague: P. Vitek; University Hospital, Prague: J. Abrahamova, D. Kordikova; University Hospital Prague: L. Petruzelka, E. Sedlackova, H. Honova.
Germany: Onkologische Gemeinschaftspraxis, Augsburg: B. Heinrich; Zentralklinikum/Frauenklinik, Augsburg: A. Wischnik; Universitätsklinikum Essen, Essen: C. Oberhoff, A.E. Schindler; Universitäts-Frauenklinik d. JLU Giessen, Giessen: K. Münstedt; Onkologische Gemeinschaftspraxis, Göttingen: D. Meyer; Martin-Luther-Universität Halle-Wittenberg, Halle: R. Grosse, H. Kölbl; Universitätskliniken des Saarlandes, Homburg: W. Schmidt, D. Mink; Universitäts-Frauenklinik und Poliklinik Universitätskrankenhaus Eppendorf, Hamburg: F. Jänicke; Kliniken d. Med. Hochschule, Frauenklinik, Hannover: H.J. Lück; Krankenanstalt Mutterhaus der Borromäerinnen, Trier: W. Dornoff; Gynäkologische Abteilung des St. Josefshospital, Wiesbaden: G. Hoffmann; Gynäkologische Abteilung d. Marienhospitals, Universität Witten-Herdecke, Witten: J. Hackmann, W. Bader.
Hungary: SZOTE Onkoterápiás Klinika, Szeged: Z. Kahan; BM Központi Kórház, Budapest: G. Pajkos, K. Kristo; SOTE Radiológiai és Onkoterápiás Klinika, Budapest: M. Dank; Uzsoki Utcai Kórház, Budapest: T. Nagykalnai, L. Landherr; Almási Balogh Pál Kórház, Ózd: E. Kner; Területi Kórház Onkologia, Szentes: M. Kispál; Szent Borbála Kórház, Megyei Onkológiai Gondozó, Tatabánya: Á. Dani.
Italy: Policlinico S. Orsola-Malpighi, Bologna: A. Martoni, C. Zamagni, S. Giaquinta, E. Piana; Ospedale S. Croce, Fano: R. Mattioli, L. Imperatori; Istituto Clinica Humanitas, Milan/Rozzano: A. Santoro, C. Carnaghi, L. Rimassa; Azienda Ospedaliera San Filippo Neri, Rome: G. Gasparini, G. Sciarretta, A. Morabito; Az. Ospedaliera Treviglio-Caravaggio, Treviglio: S. Barni, M. Cazzaniga, M. Cabiddu; Policlinico Universitario (PUDG), Udine: F. Puglisi; Ospedale di Torrette, Ancona: R. Cellerino, S. Antognoli, F. Freddari; Universitiy of Cagliari, Policlinico Universitario, Cagliari: G. Mantovani, E. Massa, G. Astara; Ospedale Civile Feltre, Feltre: R. Segati; Istituto Nazionali Ricerca Cancro, Genova: R. Rosso, L. Del Mastro, M. Venturini, C. Bighin; Istituto Nazionale dei Tumori, Milano: E. Bajetta, N. Zilembo, D. Paleari, G. Procopio; Azienda Ospedaliera di Parma, Parma: S. Salvagni, M.A. Perrone, V. Franciosi; Azienda Ospedaliera “S. Salvatore,” Pesaro: G. Catalano, S. Luzi Fedeli; Azienda Ospedaliera “Ospedale di Circolo e Fondazione Macchi” Varese: G. Pinotti, G. Giardina, I. Vallini; Universitiy of Cagliari, Policlinico Universitario, Cagliari: B. Massidda, M.T. Ionta, M.C. Deidda; Ospedale Maggiore, Lodi: G. Nalli, G. Sita; Policlinico Universitario, Palermo: I. Carreca, S. Cucciarré, D. Burgio; Ospedale Civile dello Spirito Santo, Pescara: M. Lombardo, G. Pandoli, P. Di Stefano; Azienda Ospedaliera Santa Maria Nuova, Reggio Emilia: C. Boni, G. Bisagni, M.C. Banzi, P. Linarello; Azienda Ospedaliera Desenzano del Garda, Manerbio: G. Colosini, A. Spasiano, A. Caldonazzo; Ospedale Civile ASL 20, Tortona: M.G. Pacquola.
Netherlands: Ziekenhuis Leyenburg, Den Haag: H.P. Sleeboom; Catharina Ziekenhuis, Eindhoven: H.J.T. Rutten; St. Anna Ziekenhuis, Geldrop: E.J.T. Luiten; Tweesteden Ziekenhuis, Tilburg: H.Th.J. Roerdink; Maxima Medisch Centrum, Veldhoven: R.H.M. Roumen.
New Zealand: Dunedin Hospital, Dunedin: B. McLaren, S. Costello, J. North, D. Perez, K., Bayston, M. Pfieffer; Waikato Hospital, Hamilton: I. Kennedy, I.D. Campbell, L. Gilbert, R. Gannaway, M. Jameson, J. Long, G. Round, L. Spellman, D. Whittle, D. Woolerton.
Poland: Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk: J. Jassem, M. Welnicka-Jaskiewicz, E. Senkus-Konefka, K. Matuszewska; Rydygier's Memorial Hospital, Krakow-Nova Huta: P. Koralewski, J. Pernal; Klinika Nowotworów Piersi i, Chirurgii Rekonstrukcyjnej-Warszawa, Warszawa: T. Pienkowski, E. Brewczynska, B. Bauer-Kosinska, R. Sienkiewicz-Kozlowska, A. Jagiello-Gruszfeld, K. Sudol; Centrum Onkologii w Bydgoszczy, Oddzial Onkologii Klinicznej, Bydgoszcz: J. Tujakowski, B. Zurawski; Collegium Medicum Jagiellonian University, Krakow: J. Pawlega, E. Jablonska, A. Zygulska; Oddzial Kliniczny Onkologiczny, Centralnego Szpitala Klinicznego Wojskowej, Akademii Medycznej-Warszawa, Warszawa: M. Górnasiowa; Dolnoslaskie Centrum Onkologii, Wroclaw: E. Filypczyk-Cisarz, K. Pajak.
Portugal: Hospital de S. João, Porto: M. Damasceno; Instituto Português de Oncologia de Coimbra, Coimbra: J.Q. Albano; Hospital de Santa Maria, Lisboa: B. da Costa, L. Costa; Instituto Português de Oncologia de Lisboa, Lisboa: A. Henriques, H. Amaral; Hospital Geral de Santo António, Porto: F. Marques.
Russia: Cancer Research Centre, Moscow: D.V. Komov, S.B. Polikarpova; Moscow Municipal Hospital No. 62, Moscow: A.N. Makhson, N.V. Zabaznyi; Moscow Research Institute of Diagnostics and Surgery, Moscow: E.K. Vozny, N.Y. Dobrovolskaya, S. Bolshakova, O.V. Yurgina; N.M. Emmanuel Institute of Biochemical Physics, Moscow: D.B. Korman, I.A. Maslova; N.N. Petrov Research Institute of Oncology, St. Petersburg: V. Semiglazov, V. Ivanov; Saint-Petersburg City Oncological Dispensary, St. Petersburg: G. Manikhas, G. Dolmatov.
South Africa: Mamma Clinic, Tygerberg Hospital, Cape Town: J. Apffelstaedt; Southern Cross Hospital, Cape Town: D. Eedes; Pretoria Academic Hospital, Pretoria: C. Slabber; Pretoria East Hospital, Pretoria: M.A. Coccia-Portugal; Eastern Cape Oncology Centre, Port Elizabeth: K. Maart.
Spain: Hospital Ruber Internacional, Madrid: J.E. Alés Martinez, P. Aramburo, R. Sánchez; Hospital Son Dureta, Palma del Mallorca: J. Rifa, J. Martin; Centro Oncológico Integral de Madrid (CONIM), Madrid: R. Pérez-Carrión, J.L. González Larriba, A. Cubillo; Hospital Universitario San Carlos, Madrid: M.M. Jiménez, A. Casado; Hospital Central de Asturias, Oviedo: J. Fra, J.M. Vieitez, E. Esteban, A.J. Lacave.
Switzerland: Universitätsfrauenklinik, Basel: E. Wight, S. Bartens, R. Decio, U. Güth; Klinik am Park, Zürich: U. Breitenstein.
Turkey: Ankara University Ibni Sina Hospital, Ankara: F. Icli, D. Dincol; Hacettepe University Oncology Institute, Ankara: E. Baltali, Y. Ozisik; Istanbul University Oncology Institute, Istanbul: E. Topuz, M. Basaran, A. Aydiner; Ege University Medical School, Izmir: E. Ozdedeli; 9 Eylul University Medical School, Izmir: O. Harmancioglu, A.U. Yilmaz.
United Kingdom: The Royal Marsden Hospital, London, Royal Marsden NHS Trust, Surrey: I.E. Smith; University of Dundee, Dundee: A.M. Thompson; Christie Hospital NHS Trust, South Manchester University Hospital Trust, Manchester: A. Wardley; Royal Bournemouth Hospital, Bournemouth: T. Hickish; North Middlesex Hospital, London: F. Neave.
Uruguay: Hospital de Clinicas Dr. Manuel Quintela, Montevideo, Uruguay: G. Sabini.
Acknowledgments
We thank the patients, physicians, nurses, monitors, and data managers who participate in the BIG 1-98 trial.
Footnotes
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published online ahead of print at www.jco.org on November 12, 2007.
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The coordinating group for the BIG 1-98 trial is the International Breast Cancer Study Group (IBCSG). The IBCSG receives funds from Novartis to coordinate the trial and also receives grant support from the Swedish Cancer Society, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group, Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research, US National Cancer Institute (Grant No. CA-75362), Oncosuisse/Cancer Research Switzerland, and the Foundation for Clinical Cancer Research of Eastern Switzerland.
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Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
- Received April 18, 2007.
- Accepted September 18, 2007.
