Annals of Oncology Advance Access originally published online on April 11, 2007
Annals of Oncology 2007 18(7):1177-1184; doi:10.1093/annonc/mdm091
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© 2007 European Society for Medical Oncology
breast cancer |
Effects of a treatment gap during adjuvant chemotherapy in node-positive breast cancer: results of International Breast Cancer Study Group (IBCSG) Trials 13-93 and 14-93
* Correspondence to: Dr Marco Colleoni, Division of Medical Oncology, European Institute of Oncology, 20141 Milan, Italy. Tel: +39-2-57489439; Fax: +39-2-57489412; E-mail: marco.colleoni{at}ieo.it
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Abstract |
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Background: The International Breast Cancer Study Group (IBCSG) conducted two complementary randomized trials to assess whether a treatment-free gap during adjuvant chemotherapy influenced outcome.
Patients and methods: From 1993 to 1999, IBCSG Trials 13-93 and 14-93 enrolled 2215 premenopausal and postmenopausal women with axillary node-positive, operable breast cancer. All patients received cyclophosphamide (Cytoxan, C) plus either doxorubicin (Adriamycin, A) or epirubicin (E) for four courses followed immediately (No Gap) or after a 16-week delay (Gap) by classical cyclophosphamide, methotrexate, and fluorouracil (CMF) for three courses. The median follow-up was 7.7 years.
Results: The Gap and No-Gap groups had similar disease-free survival (DFS) and overall survival (OS). No identified subgroup showed a statistically significant difference, but exploratory subgroup analysis noted a trend towards decreased DFS for Gap compared with No Gap for women with estrogen receptor (ER)-negative tumors not receiving tamoxifen, especially evident during the first 2 years.
Conclusions: A 16-week gap between adjuvant AC/EC and CMF provided no benefit and may have increased early recurrence rates in patients with ER-negative tumors.
Key words: adjuvant therapy, chemotherapy, early-stage breast cancer, estrogen receptor, hormonal therapy, lymph node positive
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introduction |
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Adjuvant cytotoxic therapy is of established value in the management of women with early breast cancer [1]. Nevertheless, the optimal timing and duration of chemotherapy following primary surgery for early breast cancer are still uncertain.
Based on early biological models that attempted to describe effective adjuvant chemotherapy [2, 3], clinical trials in the past were designed to eradicate every viable micrometastatasis through high-dose, short-duration treatment (single drug or combination) followed by sequential non-cross-resistant treatment for a duration not exceeding 6 months. The interaction between drugs and human tumor is, however, complex [4] due to the heterogeneity of epithelial tumors and the variety of biological mechanisms that protect cells against cytotoxic substances. Interactions involve not only drugs and tumor cells but also stroma and (in the case of endocrine-responsive tumors) hormones [5–7]. Response to chemotherapy is significantly influenced by the endocrine responsiveness of the tumors [8]. Moreover, the action of common chemotherapeutic agents on stromal components, mainly vasculature, has been recently demonstrated [9]. These concepts and clinical observations questioned the simple Gompertzian model of tumor growth and led to the hypothesis that the growth of a primary breast tumor does not follow a continuous function, but may be interrupted by periods of dormancy [2]. If this were the case, reexposure to cytotoxic therapy after a treatment-free interval might permit tumor cells to move from dormant to active phase and thus become more susceptible to the additional chemotherapy. Since there were no data to indicate any particular duration of the gap, we arbitrarily chose a period of 16 weeks, a little longer than the duration of either of the separate chemotherapy courses.
Thus, in 1993 the International Breast Cancer Study Group (IBCSG) initiated two complementary randomized trials for patients with node-positive breast cancer: IBCSG Trial 13-93 for premenopausal women and IBCSG Trial 14-93 for peri/postmenopausal women. Each trial used a factorial design to simultaneously investigate the value of the gap and an endocrine therapy-oriented question, with the explicit intention of conducting a pooled analysis of the gap question across the two trials. The results of the endocrine therapy-oriented questions have been previously published [10, 11]. This paper is our first report of the analysis of the treatment-free gap.
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patients and methods |
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study designs
The patient populations in the IBCSG Trials 13-93 and 14-93 consisted of women with node-positive breast cancer considered not suitable for endocrine therapy alone. In addition to the gap question, Trial 13-93 evaluated the role of tamoxifen for premenopausal women, comparing a 5-year course and no endocrine therapy [10], while in Trial 14-93 for postmenopausal patients, the alternative selective estrogen receptor modulator toremifene was compared with tamoxifen [11]. Chemotherapy consisted of four 21-day courses of AC [doxorubicin (Adriamycin) 60 mg/m2 and cyclophosphamide (Cytoxan) 600 mg/m2 intravenously (i.v.) on day 1] or EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 i.v. on day 1) followed (according to randomization) either immediately or after a 16-week gap by three 28-day courses of ‘classical’ CMF [cyclophosphamide at 100 mg/m2 orally on days 1–14, methotrexate at 40 mg/m2 i.v. on days 1 and 8, and 5-fluorouracil at 600 mg/m2 i.v. on days 1 and 8]. The duration of the gap was arbitrary, designed to be sufficiently different from continuous therapy, yet not so long as to raise concerns about denial of therapy or later patient compliance with treatment reintroduction.
Informed consent was required according to the criteria established within the individual countries. Both protocols were reviewed and approved by institutional review boards. Investigators remained unaware of outcome data during the conduct of the studies. Data management and medical staff reviewed all study records (eligibility, treatment, toxicity, and recurrence) and conducted regular site visit audits. The IBCSG Data and Safety Monitoring Committee reviewed accrual and safety data for both trials twice a year. They also reviewed two predetermined interim efficacy analyses (in January 1999 and November 2000) and recommended study continuation on both occasions. The predetermined number of events (434) required for the final analysis for Trial 13-93 was reached in 2004 and the 263 events for Trial 14-93 in 2003.
end points and statistical considerations
Disease-free survival (DFS) was defined as the length of time from the date of randomization to any relapse (including invasive ipsilateral breast cancer recurrence), the appearance of a second primary cancer (including contralateral breast cancer and non-breast primaries), or death, whichever occurred first. Overall survival (OS) was defined as the length of time from the date of randomization to death from any cause.
The original target sample size was 900 patients for Trial 13-93 and 760 patients for Trial 14-93. In 1997 the two protocols were amended to increase the accrual goals to provide sufficient power to conduct analyses in subpopulations defined by estrogen receptor (ER) status. Trial 13-93 was increased to 1225 patients and Trial 14-93 to 884. The median follow-up was 7.7 years.
DFS and OS percentages, standard errors, and treatment effect comparisons were obtained from the Kaplan–Meier method [12], Greenwood's formula [13], and log-rank tests [14] respectively. Cox proportional hazards regression models [15] were used to estimate risk ratios for the Gap versus No-Gap treatment effect and their 95% confidence intervals both for unadjusted analyses and for analyses adjusted for other covariates. All P values were obtained from two-sided tests. The randomization was stratified according to ER status and the intention to carry out separate analyses according to ER status was prospectively specified in the protocols. To further explore the gap question unconfounded by endocrine therapy assignment inconsistent with current practice guidelines, we present our results both overall and specifically focused on patient groups treated according to current recommendations: the ER-positive cohort who were assigned hormonal therapy and in the ER-negative cohort those randomized to receive no hormonal therapy.
patient eligibility and characteristics
From 1993 to 1999, a total of 2263 women were enrolled in Trials 13-93 and 14-93. In Trial 13-93 one patient was excluded from all analyses due to withdrawal of patient consent and we decided to exclude all 47 patients from a single institution because of multiple protocol violations at that institution. No patients in Trial 14-93 were excluded from the current analyses. One patient had undetermined ER status and was therefore excluded from subgroup analyses (Figure 1). The remaining study cohort of 2215 women included 41 (2%) patients who were found not to meet protocol eligibility criteria, but who were included in these intent-to-treat analyses.
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The characteristics of the 2215 patients included in the Gap versus No-Gap analyses are shown in Table 1. The median age was 49 years, ranging from 23 to 72 years. Sixty percentage of the patients had primary tumors classified as ER positive and 40% as ER negative. Fifty-five percentage of patients had one to three positive nodes and 58% had tumors >2 cm. Most tumors were classified as grade 2 (42%) or grade 3 (48%) [16]. Fifty-eight percent were assigned tamoxifen, 14% toremifene, and 28% no hormonal treatment.
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Among the patients who received some AC/EC, 31 did not start CMF following the Gap compared with 19 in the No-Gap group (six versus one for the cohort of patients with ER-negative tumors not randomized to receive tamoxifen).
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results |
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Of the 2215 patients, 914 (41%) experienced a breast cancer relapse, second primary, or death without recurrence (DFS event) and 586 (26%) died. We carried out tests for heterogeneity of outcome according to gap between trials, separately in the predefined ER-positive and ER-negative strata: no evidence of heterogeneity was observed, so we conducted the analyses across both trials. This number of events provided 80% power for the evaluation of the gap at predefined levels. There were no differences in sites of first failure between the Gap and No-Gap groups.
In accordance with the prespecified stratification, we examined the results separately by ER status. The outcomes in terms of DFS and OS were similar for Gap and No Gap for the patients on the combined trials with ER-positive tumors [DFS HR (Gap/No Gap) = 1.01; 95% CI = 0.85, 1.19, P value = 0.94 (Table 2, Figure 2); and OS HR (Gap/No Gap) = 0.95; 95% CI = 0.75, 1.19, P value = 0.63). Patients with ER-positive tumors in both the Gap and the No-Gap groups had identical 5-year DFS percents of 70%. Similarly, gap also did not improve outcome for patients with ER-negative disease [DFS HR (Gap/No Gap) = 1.09; 95% CI = 0.89, 1.33, P value = 0.39; and OS HR (Gap/No Gap) = 1.19; 95% CI = 0.94, 1.49, P value = 0.14). Patients with ER-negative tumors had 5-year DFS percents of 61% for Gap and 65% for No Gap (Table 2, Figure 2). Cox proportional hazard analyses confirmed the absence of an advantage for gap when controlling for nodal status, tumor size, grade, and age (<40 years versus 
40), even when examined separately by ER status (data not shown).
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In an unplanned, hypothesis-generating exploratory analysis, the subgroup of premenopausal patients with ER-negative tumors who were not assigned tamoxifen (i.e. treated according to the current standard of care: all postmenopausal patients in Trial 14-93 received endocrine therapy), showed a nonsignificant trend to a worse outcome with Gap compared with No Gap. The 5-year DFS percent for these patients in the Gap group was 60% compared with 67% for the No-Gap group [DFS HR (Gap/No Gap) = 1.36; 95% CI = 0.92, 2.02, P value = 0.12) (Table 2, Figures 2 and 3B)]. This effect was apparent mainly as a difference in hazard rates during the first 2 years, and in particular, the second year after randomization [DFS hazard ratio (HR) (Gap/No Gap) = 1.79; 95% CI = 1.00, 3.19, unadjusted P value = 0.05) (Table 2, Figures 2 and 4B)]. By contrast, the HRs for Gap and No Gap were similar during the third year and beyond [DFS HR (Gap/No Gap) = 1.07; 95% CI = 0.63, 1.84, P = 0.80) (Table 2, Figures 2 and 4B)]. No significant differences were observed at any point in time for patients with ER-positive disease, whether assigned hormonal therapy or not (Table 2, Figures 2, 3A, 4A).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionappendixAcknowledgementsReferences |
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IBCSG Trials 13-93 and 14-93 were designed to prospectively evaluate whether the introduction of a 16-week gap would be beneficial for patients with node-positive breast cancer. It was hypothesized that the gap would permit tumor cells to move from dormant to active phase and thus become more susceptible to additional chemotherapy cycles on the basis of a modified Gompertzian model of tumor development with a stochastic growth rate [17, 18]. Overall, the results indicate that treatment with and without a gap yielded similar DFS and OS. The duration of the single gap chosen was arbitrary, and we cannot exclude the possibility that other gap durations or repetitions may have yielded different results. The negative result observed may have reflected an imbalance in unrecorded prognostic factors, but major imbalance is unlikely in large randomized trials. More modern chemotherapies have not to date been used in trials of any similar design, so the possibility of benefit from a gap between such therapies remains untested. Although the primary hypothesis was not confirmed, the results of these two trials offer an opportunity to explore the relationship between disease history and outcome for breast cancer patients with node-positive disease, considering endocrine responsiveness and timing and duration of adjuvant chemotherapy.
Recently published data from retrospective analyses of trial data from the Cancer and Leukemia Group B and the USA Breast Cancer Intergroup on 6644 node-positive breast cancer patients who received adjuvant chemotherapy support the value of extensive adjuvant chemotherapy in patients with endocrine nonresponsive disease [19]. Differences in outcome by treatment were observed in each of the three studies. Patients with ER-negative disease derived much greater benefit from modern improvements in chemotherapy regimens when compared with those with ER-positive disease. The observation that any trend in adverse outcome in our ER-negative patients reflected early events is in keeping with the reported higher hazard of relapse during the early years after surgery in patients with ER-negative disease [20].
Only one other prospective randomized study focused on the value of chemotherapy reintroduction after a gap. The National Surgical Adjuvant Breast and Bowel Project B-15 trial evaluated the role of three courses of i.v. CMF 6 months after completion of AC administered for four courses versus AC alone or classical CMF for six courses [21]. The group of patients who received CMF reinduction therapy 6 months after treatment with AC had a slight but non-statistically significant better 3-year DFS than after AC or classical CMF alone (68% versus 62% versus 63%; P = not significant). Information on outcome according to endocrine responsiveness is not available.
The efficacy of adjuvant systemic therapy for early breast cancer depends on features of the tumor, the patient, and the treatment. Among treatment-related factors, we have previously drawn attention to schedule [22, 23], dose–response effect [24, 25], and timing of initiation of chemotherapy [26]. The present study raises the hypothesis that, for patients whose tumors are not endocrine responsive, chemotherapy should be delivered without a no-treatment gap in order to maximize its effects. In light of the poor outcome for this population, new chemotherapy regimens, schedules, or combinations should be explored.
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Writing Committee: Marco Colleoni, Shari Gelber, Edda Simoncini, Olivia Pagani, Richard D. Gelber, Karen N. Price, Monica Castiglione-Gertsch, Alan S. Coates, and Aron Goldhirsch; Scientific Committee: A. Goldhirsch and A. S. Coates; Foundation Council: B. Thürlimann, M. Castiglione, A. S. Coates, J. P. Collins, H. Cortés Funes, 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, and A. Veronesi; Coordinating Center, Bern, Switzerland: M. Castiglione-Gertsch, A. Hiltbrunner, G. Egli, M. Rabaglio, R. Studer, B. Ruepp, R. Maibach, E. Marbot, and M. Strausak; Statistical Center, Harvard School of Public Health and Dana-Farber Cancer Institute, Boston, MA: R. Gelber, K. Price, S. Gelber, B. Cole, M. Regan, D. Zahrieh, and Z. Sun; Quality of Life Office, Bern, Switzerland: J. Bernhard, G. Egli, and Ch. Hürny; Pathology Office: B. Gusterson and G. Viale; Data Management Center, Frontier Science and Technology Research Foundation, Amherst, NY: L. Blacher, J. Celano, M. Isley, R. Hinkle, S. Lippert, and K. Scott; Centro di Riferimento Oncologico, Aviano, Italy: A. Veronesi, D. Crivellari, S. Monfardini, E. Galligioni, M. D. Magri, A. Buonadonna, S. Massarut, C. Rossi, E. Candiani, A. Carbone, R. Volpe, M. Roncadin, M. Arcicasa, F. Coran, and S. Morassut; Spedali Civili & Fondazione Beretta, Brescia, Italy: E. Simoncini, G. Marini, P. Marpicati, M. Braga, P. Grigolato, and L. Lucini; Istituto Europeo di Oncologia, Milano, Italy: A. Goldhirsch, M. Colleoni, G. Martinelli, G. Viale, L. Orlando, F. Nolè, R. Torrisi, T. De Pas, F. de Braud, S. Cinieri, F. Peccatori, A. Luini, R. Orecchia, G. Renne, F. de Braud, A. Costa, S. Zurrida, P. Veronesi, V. Sacchini, V. Galimberti, M. Intra, and U. Veronesi; Ospedale Infermi, Rimini, Italy: A. Ravaioli, D. Tassinari, G. Oliverio, F. Barbanti, P. Rinaldi, E. Pini, and G. Drudi; Ospedale S. Eugenio, Roma, Italy: M. Antimi, M. Minelli, V. Bellini, R. Porzio, E. Pernazza, G. Santeusanio, and L. G. Spagnoli; General Hospital, Gorizia, Italy: S. Foladore, L. Foghin, G. Pamich, C. Bianchi, B. Marino, A. Murgia, and V. Milan; West Swedish Breast Cancer Study Group, Göteborg, Sweden: C.-M. Rudenstam, A. Wallgren, S. Ottosson-Lönn, R. Hultborn, G. Colldahl-Jädeström, E. Cahlin, J. Mattsson, S. B. Holmberg, O. Ruusvik, L. G. Niklasson, S. Dahlin, G. Karlsson, B. Lindberg, A. Sundbäck, S. BergegÂrdh, O. Groot, L. O. Dahlbäck, H. Salander, C. Andersson, M. Heideman, A. Nissborg, A. Wallin, G. Claes, T. Ramhult, J. H. Svensson, P. Liedberg, A. Nilsson, G. Havel, G. Oestberg, S. Persson, M. Suurküla, and J. Matusik; The Institute of Oncology, Ljubljana, Slovenia: J. Lindtner, D. Erzen, T. Cufer, J. Cervek, O. Cerar, B. Zakotnik, E. Majdic, R. Golouh, J. Lamovec, J. Jancar, I. Vrhovec, and M. Kramberger; Groote Schuur Hospital, Cape Town, Republic of South Africa: E. Murray, I. D. Werner, D. M. Dent, A. Gudgeon, E. Panieri, E. McEvoy, J. Toop, and R. Bowen; Sandton Oncology Center, Johannesburg, Republic of South Africa: D. Vorobiof, M. Chasen, G. Fotheringham, G. de Muelenaere, B. Skudowitz, C. Mohammed, and A. Rosengarten; Madrid Breast Cancer Group, Madrid, Spain: H. Cortès-Funes, C. Mendiola, C. Gravalos, Colomer, M. Mendez, F. Cruz Vigo, P. Miranda, A. Sierra, F. Martinez-Tello, A. Garzon, S. Alonso, A. Ferrero, and C. Vargas; Swiss Group for Clinical Cancer Research, Inselspital, Bern: M. F. Fey, M. Castiglione-Gertsch, E. Dreher, H. Schneider, S. Aebi, K. Buser, J. Ludin, G. Beck, A. Haenel, J. M. Lüthi, H. J. Altermatt, and M. Nandedkar; Kantonsspital, St Gallen: H.-J. Senn, B. Thürlimann, Ch. Oehlschlegel, G. Ries, M. Töpfer, U. Lorenz, A. Ehrsam, B. Späti, and E. Vogel; Ospedale San Giovanni, Bellinzona: F. Cavalli, O. Pagani, H. Neuenschwander, L. Bronz, C. Sessa, M. Ghielmini, T. Rusca, P. Rey, J. Bernier, E. Pedrinis, T. Gyr, L. Leidi, G. Pastorelli, and A. Goldhirsch; Kantonsspital, Basel: R. Herrmann, C. F. Rochlitz, J. F. Harder, O. Köchli, U. Eppenberger, and J. Torhorst; Hôpital des Cadolles, Neuchâtel: D. Piguet, P. Siegenthaler, V. Barrelet, and R. P. Baumann; Kantonsspital, Zürich: B. Pestalozzi, C. Sauter, V. Engeler, U. Haller, U. Metzger, P. Huguenin, and R. Caduff; Centre Hôpitalier Universitaire, Lausanne: L. Perey, S. Leyvraz, P. Anani, C. Genton, F. Gomez, P. De Grandi, P. Reymond, R. Mirimanoff, M. Gillet, and J. F. Delaloye; Hôpital Cantonal, Geneva: P. Alberto, H. Bonnefoi, P. Schäfer, F. Krauer, M. Forni, M. Aapro, R. Egeli, R. Megevand, E. Jacot-des-Combes, A. Schindler, B. Borisch, and S. Diebold; Kantonsspital Graubünden, Chur: F. Egli, P. Forrer, A. Willi, R. Steiner. J. Allemann, T. Rüedi, A. Leutenegger, and U. Dalla Torre; Kantonsspital Aarau: A. Schönenberger, M. Wernli, M. Bargetzi, W. Mingrone, P. Schmid, E. Bärtschi, and K. Beretta; Australian New Zealand Breast Cancer Trials Group: J. F. Forbes, D. Lindsay, A. Wilson, and D. Preece; Statistical Center, NHMRC CTC, University of Sydney: R. J. Simes and H. Dhillon; The Cancer Council Victoria, Melbourne, VIC: J. Collins, R. Snyder, E. Abdi, R. Abraham, R. Basser, P. Briggs, W. I. Burns, M. Chipman, J. Chirgwin, V. Ganju, G. Goss, M. Green, I. Haines, S. Hart, R. Holmes, G. Lindeman, J. McKendrick, S. McLachlan, R. McLennan, P. Mitchell, G. Richardson, M. Schwarz, and C. Underhill; The Canberra Hospital, Canberra, ACT: R. Stuart-Harris; Flinders Medical Centre, Bedford Park, SA: T. Malden; Newcastle Mater Misericordiae Hospital, Waratah, NSW: J.F. Forbes, J. Stewart, S. Ackland, A. Bonaventura, and D. Jackson; Mount Hospital, Perth, WA: G. van Hazel; Prince of Wales Hospital, Randwick, NSW: M. Friedlander, B. Brigham, and C. Lewis; Royal Perth Hospital, Perth, WA: E. Bayliss, A. Chan, D. Ransom, and J. Trotter; Sir Charles Gairdner Hospital, Nedlands, WA: M. Byrne, G. van Hazel, A. Davidson, J. Dewar, and M. Buck; Royal Prince Alfred Hospital and Dubbo Base Hospital Sydney, NSW: J. Beith, M. Boyer, A. S. Coates, R. J. Simes, A. Sullivan, and M. H. N. Tattersall; St George Hospital Kogarah, NSW: P. de Souza; Auckland Hospital, Auckland, New Zealand: V. J. Harvey, P. Thompson, and D. Porter.
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We thank the patients, physicians, nurses, and data managers who participated in the International Breast Cancer Study Group trials. We acknowledge Joie Celano for data management. We further acknowledge support for central coordination, data management, and statistics provided by the Swiss Group for Clinical Cancer Research, the Frontier Science and Technology Research Foundation, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group (National Health Medical Research Council grant numbers 890028, 920876, 950328, 980379, 141711), the American Cancer Society (RPG-90-013-08-PBP), and the USA National Cancer Institute (CA-75362), Swedish Cancer Society. We also acknowledge support for the Cape Town participants from the Cancer Association of South Africa, and for the St Gallen participants from the Foundation for Clinical Cancer Research of Eastern Switzerland, and Orion-Farmos (for medication for Trial 14-93).
Received for publication December 26, 2006. Revision received February 12, 2007. Revision received February 13, 2007. Accepted for publication February 13, 2007.
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