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Originally published as JCO Early Release 10.1200/JCO.2005.04.5393 on December 11 2006 © 2007 American Society of Clinical Oncology. Adjuvant Chemotherapy Followed By Goserelin Compared With Either Modality Alone: The Impact on Amenorrhea, Hot Flashes, and Quality of Life in Premenopausal Patients—The International Breast Cancer Study Group Trial VIII
From the International Breast Cancer Study Group (IBCSG); IBCSG Coordinating Center, Swiss Group for Clinical Cancer Research (SAKK), Department of Medical Oncology, Bern; Bürgerspital and Kantonsspital, St Gallen; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; IBCSG Statistical Center, Dana-Farber Cancer Institute, Frontier Science and Technology Research Foundation, Harvard School of Public Health, Boston, MA; Australian New Zealand Breast Cancer Trials Group and Newcastle Mater Misericordiae Hospital, Newcastle; Department of Surgery, The Royal Melbourne Hospital, Melbourne; the University of Sydney, Sydney, Australia; Groote Schuur Hospital and University of Cape Town, South Africa; and the European Institute of Oncology, Milan, Italy. Address reprint requests to Jürg Bernhard, PhD, International Breast Cancer Study Group Coordinating Center, Effingerstr 40, 3008 Bern, Switzerland; e-mail: juerg.bernhard{at}ibcsg.org
PURPOSE: The purpose of this article is to compare quality of life (QOL) and menopausal symptoms among premenopausal patients with lymph node-negative breast cancer receiving chemotherapy, goserelin, or their sequential combination, and to investigate differential effects by age. PATIENTS AND METHODS: We evaluated QOL data from 874 pre- and perimenopausal women with lymph node-negative breast cancer who were randomly assigned to receive six courses of classical cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy, ovarian suppression with goserelin for 24 months, or six courses of classical CMF followed by 18 months of goserelin. We report QOL data collected during 3 years after random assignment in patients without disease recurrence. RESULTS: Overall, patients receiving goserelin alone showed a marked improvement or less deterioration in QOL measures over the first 6 months than those patients treated with CMF. There were no differences at 3 years after random assignment according to treatment except for hot flashes. As reflected in the hot flashes scores, patients in all three treatment groups experienced induced amenorrhea, but the onset of ovarian function suppression was slightly delayed for patients receiving chemotherapy. Younger patients (< 40 years) who received goserelin alone returned to their premenopausal status at 6 months after the cessation of therapy, while those who received CMF showed marginal changes from their baseline hot flashes scores. CONCLUSION: Age-adjusted risk profiles that consider patient-reported outcomes enable patients to adapt to their disease and treatment, such as considering the trade-offs between delayed endocrine symptoms, but higher risk of permanent menopause with chemotherapy, and immediate but reversible endocrine symptoms with goserelin, in younger premenopausal patients.
The International Breast Cancer Study Group (IBCSG) trial VIII for pre- and perimenopausal women with lymph node-negative breast cancer compared sequential chemotherapy followed by the gonadotropin-releasing hormone agonist goserelin with either modality alone. Disease-related outcomes have been reported.1 Patients with estrogen receptor (ER) -negative tumors achieved better disease-free survival (DFS) if they received treatments that included cyclophosphamide, methotrexate, and fluorouracil (CMF) than if they received goserelin alone. In contrast, for patients with ER–positive disease, chemotherapy alone and goserelin alone provided similar outcomes, whereas sequential therapy provided a statistically nonsignificant benefit compared with either modality alone, due largely to the results for the younger patients. In this report, we compare the impact of the randomized treatments on quality of life (QOL). Similar adjuvant trials have been reported.2,3 The trade-offs between early (first 6 months), intermediate (months 6 to 24), and late (month 36) QOL effects require patients and physicians to balance different impacts of treatment at different time points, making individual decision making more challenging.4 However, minor differences in the toxicity profiles may be important for a patient’s choice.3,4 Age may influence a patient’s perception of fertility, body image, and sexuality. Younger women are especially vulnerable for physical and emotional sequelae of breast cancer, with an early menopause as a main concern.5-10 We expanded the QOL analysis by investigating the time course of amenorrhea and patient-rated hot flashes, a key symptom of estrogen deprivation, between treatments and by patient age.
Trial From March 1990 through October 1999, 1,111 pre- and perimenopausal patients were randomly assigned to receive either no adjuvant systemic treatment, six 28-day courses of classical CMF chemotherapy (in which one course, every 28 days, consisted of cyclophosphamide at 100 mg/m2 on days 1 through 14, orally; methotrexate at 40 mg/m2 on days 1 and 8, intravenously; and fluorouracil at 600 mg/m2 on days 1 and 8, intravenously), 24 monthly subcutaneous implants of a gonadotropin-releasing hormone analog (goserelin at 3.6 mg every 28 days), or six 28-day courses of classical CMF followed by 18 implants of goserelin. Systemic adjuvant therapy was to begin within 6 weeks of primary surgery. For the sequential treatment arm, the first goserelin implant was scheduled to be given on day 28 of the sixth course of CMF. Informed consent was required according to the criteria established within the individual countries. The protocol was approved by institutional review boards as required by national and local law. The details of the trial protocol and conduct are described elsewhere.1 In April 1992, after accrual of 205 patients, random assignment to the no-adjuvant treatment control arm (46 patients) was discontinued because of results from other trials. This report concerns QOL comparisons among the three active treatment arms. For the first 36 months of treatment, patients received a calendar to record their menses. These data were checked by the medical staff at visits and transmitted to the menstrual status form with 1 = normal; 2 = scanty; 3 = no menses.
QOL Analysis The protocol required that all patients participate in the QOL study. As a primary hypothesis, based on experience in patients with node-positive disease11 we predicted worse QOL during chemotherapy (months 3 and 6) as compared with goserelin but no residual effects in treatment groups after completion of chemotherapy, using coping effort as primary end point. As a secondary hypothesis, we expected a smaller adverse effect of CMF on mood at baseline for patients with ER-negative tumors than for those with ER-positive tumors.17 We considered a change of 8 points or more on a scale of 0 to 100 as clinically significant.18 Of the 1,065 patients randomly assigned to one of the three adjuvant-treatment arms, 1,043 were deemed eligible and assessable. Of these, 874 patients were included in the QOL analysis (Table 1). We expected the QOL assessment at month 36 from all patients randomly assigned at a time point less than 3 years before June 1, 1995, resulting in a total of 746 (85%) of the 874 patients for this assessment. To identify reasons for the lower submission rate at month 36, we investigated the association between missing data and baseline characteristics, treatment assignment, participating center, and toxicity, and fit a logistic regression model to examine the relative importance of these factors. For a sensitivity analysis, two imputation techniques were used. Missing values at month 36 were replaced by the previous assessment score, and the lower quartile from the compliant cases at month 36 was applied to the noncompliant cases.
The indicators were scored between 0 and 100 and analyzed separately; higher values represented better QOL or less severe symptoms/adverse effects. QOL scores were transformed to reduce skewing. The statistical significance of treatment differences at each time point was assessed with analysis of variance, adjusting for country/language group.11 The figures show the results in the original scores from 0 to 100. We also tested for differences in QOL scores between baseline and month 3 of the within patient changes in an analysis of variance model that included assigned treatment and country/language group. Similarly, we analyzed changes from baseline to month 6 and month 36. Differential treatment effects by age were analyzed post hoc using the hot flashes indicator with the anchors of none and a lot, with age categorized as 39 years or younger and 40 years or older. Treatment-covariate interactions were studied by use of the nonparametric Subpopulation Treatment Effect Pattern Plot (STEPP) methodology.19,20 STEPP involves defining overlapping subgroups of patients on the basis of a covariate of interest and studying the resulting pattern of the treatment effects estimated within each subgroup. Patient age at study entry was the covariate of interest. The treatment effects estimated within each subgroup were calculated as mean of the square root of the hot flashes scores, then transformed back for visual display.
Probability values are two sided. P
The submission rates of the QOL forms were similar across treatment groups and decreased as follow-up went on, from 90% at baseline, to 77% at month 12, to 74% at month 24, and to 62% at month 36. Participants and nonparticipants at month 36 were similar regarding age, tumor size, tumor grade, and ER status at random assignment. The toxicity profile of participants and nonparticipants at month 36 within the goserelin (submission rate, 65%) and CMF (60%) arms was similar. Participating center was most strongly associated with missing data at month 36 (P = .02; data not shown). Table 2 presents characteristics of the 874 patients. Nineteen percent of the patients were age 39 years or younger. The median age within this cohort was 36 years (range, 22 to 39). The median age within the cohort of patients age 40 or older was 46 years (range, 40 to 58). Sixty-eight percent of patients had primary tumors classified as ER–positive, 29% of patients had primary tumors classified ER–negative, and 3% of patients had primary tumors classified ER–unknown.
During the first 3, 6, and 36 months, we compared the change (mean, SE) in QOL scores from baseline between patients receiving goserelin alone with patients receiving CMF (Table 3). Significant benefits were found for goserelin, with less impairment by nausea/vomiting and an improvement in coping and subject health estimation. For the first 3 months, patients receiving goserelin reported a bigger increase in hot flashes and a worse mood. There were no differences at 36 months according to treatment in any of the indicators, except for hot flashes (Fig 1). The coping scores indicated a rapid, clinically significant improvement after completing chemotherapy (Fig 2).
At baseline, patients receiving CMF reported more coping effort, although this difference was not statistically significant (P = .12). Of the patients who submitted a baseline QOL form, 43% completed the form before random assignment (45% goserelin; 42% CMF); thus up to 57% did so after knowing treatment assignment. When we excluded those patients who filled out their baseline assessment after random assignment, the results were similar but slightly more pronounced on average for each indicator. At month 36, the results of both imputation techniques were consistent with our main findings (data not shown). We tested for QOL differences among treatment groups at each time point separately for both the ER–negative and ER–positive cohorts. Results were similar within both cohorts (data not shown). Patients in all three treatment arms experienced induced amenorrhea, but the onset was delayed slightly for those patients who received chemotherapy relative to those patients who received initial goserelin—a pattern also reflected in the hot flashes scores (Fig 1). After cessation of goserelin treatment, patients who received goserelin alone indicated fewer hot flashes than those patients who had received CMF (P < .01 at months 24 and 36).
The percentage of patients who reported no menses during each month after random assignment according to treatment group is shown separately for younger (age
The pattern of incidence of amenorrhea over time was different for patients age  40 (Fig 3B). Chemotherapy-induced amenorrhea was observed sooner and in a larger proportion of patients than was observed in the younger cohort. More than 90% of these patients who received six courses of CMF reported amenorrhea by the end of chemotherapy. Although menses resumed in a few patients who did not receive goserelin after chemotherapy, nearly all cases had amenorrhea during the entire 36-month follow-up period, regardless of whether goserelin was used. We analyzed the hot flashes scores according to the same age groups (Figs 4A and 4B). The same pattern seen for all patients across time was observed within the cohort of older patients. However, within the cohort of younger patients, patients on all three arms eventually returned to their initial status after completing treatment by CMF and/or goserelin, respectively. The patterns of changes were similar: goserelin was associated with greater early deterioration, which later recovered, whereas the effect of CMF, though slower in onset, was persistent, especially among older patients (data not shown).
We performed a STEPP analysis at months 3, 6, and 36 for the hot flashes indicator to evaluate the differences in treatment effects according to age (Fig 5), limited to the 323 patients with complete data for hot flashes at months 3, 6, and 36. For this sliding window analysis, each subpopulation contained approximately 70 patients, and each subsequent subpopulation was formed moving from left to right by dropping approximately 45 patients with the lowest age and adding approximately 45 patients with the next higher age. At month 3 (Fig 5A), significantly more hot flashes were observed at all ages for patients randomly assigned to goserelin alone compared with CMF (P < .01) and CMF followed by goserelin (P < .01). Patients in older cohorts who were assigned CMF and CMF followed by goserelin reported hot flashes scores similar to those for goserelin alone. By month 6 (Fig 5B), the youngest cohort receiving CMF reported fewer hot flashes than for patients assigned to goserelin alone, however, as age increased there was no clear pattern of treatment differences as all patients reported similar hot flashes scores. By month 36 (Fig 5C), when all patients were no longer receiving treatment, the youngest patients returned to the low or absent hot flashes scores reported at baseline. This return to initial status was most striking in the goserelin alone group. As the median age increased, fewer patients randomly assigned to goserelin alone experienced hot flashes compared with those randomly assigned to CMF (P = .03) or to CMF followed by goserelin (P = .03).
We compared the impact of the goserelin, CMF, and CMF followed by goserelin on various QOL indicators measured during 3 years after beginning of adjuvant therapy according to age, specifically examining patient-rated hot flashes, a very common complaint of peri- and postmenopausal women.21 The patterns of amenorrhea and patient-reported hot flashes were strikingly similar over time. This correspondence supports the clinical validity of patient-reported data by this type of simple single-item indicator. Baseline assessment was required before adjuvant treatment but allowed before or after random assignment. A substantial proportion of patients, similar between those with versus without chemotherapy, completed the QOL form after random assignment. To eliminate any differential anticipatory effects on baseline scores in future studies, we have since introduced a completed QOL form as an eligibility criterion. Firm conclusions at month 36 are hampered by incomplete participation of patients. Those who did participate, however, were representative of each treatment arm, and baseline characteristics were balanced according to participants and nonparticipants. Participating center, a stratification factor at random assignment, was the most important predictor of forms submission at 36 months. Because we recognize that missing data cannot be ignored in QOL studies, the IBCSG has introduced a missing QOL form to collect reasons for missing data. Overall, patients treated with goserelin alone showed a more pronounced improvement or less decline in various QOL indicators during the first 6 months than those with CMF. A similar early benefit in favor of goserelin was shown in the Zoladex Early Breast Cancer Research Association (ZEBRA) and the Zoladex in Premenopausal Patients (ZIPP) trials.2,3 In the ZEBRA trial, the same indicator for coping was used and showed the same pattern: patients with goserelin alone required less effort to cope reflecting less burden by adverse effects. In agreement with both trials, in our trial there was no difference in mood and in physical domains at 3 years. Peri- or postmenopausal status per se is not an independent predictor of lower QOL.22 The improvement of these QOL domains over time, in particular coping, confirms the pattern of adaptation described in our previous trials,11,23,24 pointing to the major importance of a patient’s psychological adaptation for her QOL. Patients can be supported in their adaptation by psycho-oncologic interventions. This is particularly relevant to the age group of our trial, given that younger women are more vulnerable for physical and emotional sequelae of a breast cancer diagnosis. Contrary to our hypothesis, patients’ QOL under chemotherapy was not affected by the ER-status of their tumor. Both CMF and goserelin induce amenorrhea. However, while it is reversible in the majority of patients after cessation of goserelin, it is often permanent after CMF. Patients in whom treatment results in permanent amenorrhea have the short and long-term effects of an early menopause. In the ZEBRA and the ZIPP trials, the hormonal symptoms were worse in the goserelin group during the 2-year goserelin treatment period compared with the CMF group. One year after the cessation of goserelin therapy, this trend was reversed.
The same pattern was seen for patient-rated hot flashes. Patients randomly assigned to receive goserelin alone returned to baseline values at 3 years, while patients who received CMF underwent early menopause. However, there were substantial age-related differences among patients who received CMF. Younger patients ( For patients with ER-positive disease, CMF alone and goserelin alone provided similar DFS outcomes.1 Hence, QOL considerations become even more relevant to treatment choice. They have to be balanced from patient’s individual perspective. In the younger patients, this includes trade-offs between the early and a lower risk of immediate symptoms but higher risk of permanent menopause by chemotherapy, and initially greater but reversible endocrine symptoms with 2 years of goserelin. In the ZIPP trial, the effects on sexuality of CMF were comparable with those of goserelin.25 After age 40, when fertility becomes less important for many women, the perspective of going once (chemotherapy) or twice (goserelin) through menopause is an additional issue to consider. Sequential therapy provided a statistically nonsignificant trend to benefit in DFS compared with either modality alone, due largely to the results among younger patients.1 CMF followed by goserelin showed the same effect on all QOL indicators as CMF alone. The effects of chemotherapy appear to mask those of endocrine therapy. This finding confirms those of the ZIPP trial, where no difference was found regarding physical symptoms or sexual dysfunction between corresponding groups.3,25 Endocrine therapy had differential effects on symptoms only in patients not treated with CMF. Those receiving tamoxifen indicated milder menopausal symptoms than those with goserelin, with the exception of vaginal discharge. Vasomotor symptoms and vaginal dryness were most troublesome. Differences in endocrine adverse effect profiles may assist in supportive care needs but do not necessarily impact overall QOL.26,27 Thus, our trial shows patterns of QOL effects caused by adjuvant chemotherapy, goserelin, or their sequential combination similar with those described in previous trials in premenopausal patients. However, patterns of symptoms differed substantially by age. The risk of menopause induced by chemotherapy was low in younger patients and increased with age. Age-adjusted adverse effect risk profiles offer an opportunity to support patients’ in their adaptation to disease and treatment.
The authors indicated no potential conflicts of interest.
Conception and design: Jürg Bernhard, Christoph Hürny, Richard D. Gelber, Alan S. Coates Provision of study materials or patients: Elizabeth Murray, John Collins, Stefan Aebi Data analysis and interpretation: Jürg Bernhard, David Zahrieh, Richard D. Gelber Manuscript writing: Jürg Bernhard, David Zahrieh, Monica Castiglione-Gertsch, Christoph Hürny, Richard D. Gelber, John F. Forbes, Elizabeth Murray, John Collins, Stefan Aebi, Beat Thürlimann, Karen N. Price, Aron Goldhirsch, Alan S. Coates Final approval of manuscript: Jürg Bernhard, David Zahrieh, Monica Castiglione-Gertsch, Christoph Hürny, Richard D. Gelber, John F. Forbes, Elizabeth Murray, John Collins, Stefan Aebi, Beat Thürlimann, Karen N. Price, Aron Goldhirsch, Alan S. Coates
Scientific Committee. A. Goldhirsch, A.S. Coates (co-chairs); Foundation Council: J. Collins (Pres), B. Thürlimann (VP), H-J Senn (Treasurer), S. Holmberg, J. Lindtner, A. Veronesi, H. Cortés-Funes; Coordinating Center, Bern, Switzerland: M. Castiglione-Gertsch (CEO and study chair), M.L. Nasi (studies coordinator), C. Jenatsch, G. Egli, M. Rabaglio, A. Saurer, R. Maibach, M. Iannino Gerber, A. Hiltbrunner; Statistical Center, Harvard School of Public Health and Dana-Farber Cancer Institute, Boston, MA: R. Gelber (group statistician), A. O’Neill, K. Price (scientific director), M. Bonetti, H. Peterson, D. Zahrieh, M. Zelen, S. Gelber, A. Keshaviah, S. Li; Data Management Center, Frontier Science & Tech. Res. Found., Amherst, NY: R. Hinkle, M. Isley, L. Blacher (Director), S. Lippert, J. Celano; Pathology Office: B. Gusterson, R. Bettelheim, R. Reed, G. Viale, E. Mallon; Quality of Life Office: J. Bernhard, Ch. Hürny, H. Gusset, N. Mathys, B. Cliffe; The Ontario Cancer Treatment and Research Foundation, Toronto Sunnybrook Regional Cancer Centre, Toronto, Canada: K. Pritchard, D. Sutherland, C. Sawka, G. Taylor, R. Choo, C. Catzavelos, K. Roche; National Institute of Oncology, Budapest, Hungary: I. Láng, E. Hitre, E. Juhos, I. Szamel; Centro di Riferimento Oncologico, Aviano, Italy: D. Crivellari, S. Monfardini, E. Galligioni, M.D. Magri, A. Veronesi, A. Buonadonna. S. Massarut, C. Rossi, E. Candiani, A. Carbone, R. Volpe, M. Roncadin, M. Arcicasa, F. Coran, S. Morassut; Spedali Civili & Fondazione Beretta, Brescia, Italy: E. Simoncini, G. Marini, P. Marpicati, M. Braga, P. Grigolato, L. Lucini; General Hospital, Gorizia, Italy: S. Foladore, L. Foghin, G. Pamich, C. Bianchi, B. Marino, A. Murgia, V. Milan; European Institute of Oncology, Milano, Italy: A. Goldhirsch, M. Colleoni, G. Martinelli, L. Orlando, F. Nolé, A. Luini, R. Orecchia, G. Viale, F. Peccatori, F. de Braud, A. Costa, S. Zurrida, P. Veronesi, V. Sacchini, V. Galimberti, M. Intra, U. Veronesi; Ospedale Infermi, Rimini, Italy: A. Ravaioli, D. Tassinari, G. Oliverio, F. Barbanti, P. Rinaldi, L. Gianni, G. Drudi; Ospedale S. Eugenio, Roma, Italy: M. Antimi, M. Minelli, V. Bellini, R. Porzio, E. Pernazza, G. Santeusanio, L.G. Spagnoli; Ospedale S. Bortolo, Vicenza, Italy: M. Magazu, V. Fosser, P. Morandi, G. Scalco, M. Balli, M. Gion, S. Meli, G. Torsello; The Institute of Oncology, Ljubljana, Slovenia: J. Lindtner, D. Erzen, E. Majdic, B. Stabuc, A. Plesnicar, R. Golouh, J. Lamovec, J. Jancar, I. Vrhoved, M. Kramberger; Groote Schuur Hospital and University of Cape Town, Cape Town, Rep. of South Africa: D.M. Dent, A. Gudgeon, E. Murray, I.D. Werner, P. Steynor, J. Toop, E. McEvoy; E. Panieri, Sandton Oncology Center, Johannesburg, Rep. of South Africa: D. Vorobiof, M. Chasen, G. Fotheringham, G. de Muelenaere, B. Skudowitz, C. Mohammed, A. Rosengarten; Madrid Breast Cancer Group, Madrid, Spain: H. Cortés-Funes, C. Mendiola, J. Hornedo, R. Colomer, F. Cruz Vigo, P. Miranda, A. Sierra, F. Martinez-Tello, A. Garzon, S. Alonso, A. Ferrero; West Swedish Breast Cancer Study Group, Göteborg, Sweden: C.M. Rudenstam, A. Wallgren, S. Ottosson-Lönn, R. Hultborn, G. Colldahl-Jäderström, E. Cahlin, J. Mattsson, S.B. Holmberg, L. Ivarsson, O. Ruusvik, L.G. Niklasson, S. Dahlin, G. Karlsson, B. Lindberg, A. Sundbäck, S. Bergegårdh, H. Salander, C. Andersson, M. Heideman, Y. Hessman, O. Nelzén, G. Claes, T. Ramhult, J.H. Svensson, P. Liedberg, M Suurküla, S. Persson; Swiss Group for Clinical Cancer Research (SAKK) member institutions - Inselspital, Bern, Switzerland: M.F. Fey, M. Castiglione-Gertsch, E. Dreher, H. Schneider, S. Aebi, J. Ludin, G. Beck, A. Haenel, J.M. Lüthi, H.J. Altermatt, M. Nandedkar, K. Buser; Kantonsspital, St. Gallen, Switzerland: H.J. Senn, B. Thürlimann, Ch. Oehlschlegel, G. Ries, M. Töpfer, U. Lorenz, O. Schiltknecht, B. Späti, A. Ehrsam, M. Bamert, W.F. Jungi; Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland: 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, G. Caccia, A. Goldhirsch; Kantonsspital, Basel, Switzerland: R. Herrmann, C.F. Rochlitz, J.F. Harder, S. Bartens, U. Eppenberger, J. Torhorst; Hôpital des Cadolles, Neuchâtel, Switzerland: D. Piguet, P. Siegenthaler, V. Barrelet, R.P. Baumann; University Hospital, Zürich, Switzerland: B. Pestalozzi, C. Sauter, D. Fink, M. Fehr, U. Haller, U. Metzger, P. Huguenin, R. Caduff; Centre Hospitalier Universitaire Vandois, Lausanne, Switzerland: L. Perey, S. Leyvraz, P. Anani, F. Gomez, D. Wellman, G. Chapuis, P. De Grandi, P. Reymond, M. Gillet, J.F. Delaloye; Hôpital Cantonal, Geneva, Switzerland: P. Alberto, H. Bonnefoi, P. Schäfer, F. Krauer, M. Forni, S. Diebold; Kantonsspital Graubünden, Chur, Switzerland: F. Egli, P. Forrer, A. Willi, R. Steiner. J. Allemann, T. Rüedi, A. Leutenegger, U. Dalla Torre; Australian New Zealand Breast Cancer Trials Group (ANZ BCTG) member institutions - Operations Office, University of Newcastle: J.F. Forbes, D. Lindsay, A. Wilson; Statistical Center, Australian National Health and Medical Research Council Clinical Trials Center, University of Sydney: R. J. Simes, H. Dhillon; The Cancer Council Victoria (previously Anti-Cancer Council of Victoria), Clinical Trials Office, Melbourne: J. Collins, R. Snyder, E. Abdi, A. Barling, R. Basser, W.I. Burns, M. Chipman, J. Chirgwin, I. Davis, R. Holmes, M. Green, D. Hastrich, P. Gregory, R. McLennan, L. Mileshkin, P. Mitchell, G. Richardson, M. Schwarz, I. Russell, C. Underhill, D. Reading, A. Zimet; Auckland Breast Cancer Study Group, Auckland, New Zealand: V.J. Harvey, P. Thompson, D. Porter; Flinders Medical Centre, Bedford Park, South Australia: T. Malden; Newcastle Mater Misericordiae Hospital Waratah, Newcastle, Australia: J.F. Forbes, J. Stewart, D. Jackson, R. Gourlay, J. Bishop, S. Cox, S. Ackland, A. Bonaventura, C. Hamilton, J. Denham, P. O’Brien, M. Back, S. Braye, R. Muragasu; Prince of Wales, Randwick, Australia: M. Friedlander, B. Brigham, C. Lewis; Royal Adelaide Hospital, Adelaide, Australia: I.N. Olver, P.G. Gill, A. Taylor, D. Keefe; University of Sydney, Dubbo Base Hospital and Royal Prince Alfred Hospital, Sydney, Australia: J. Beith, M. Boyer, A.S. Coates, R. J. Simes, A. Sullivan, M.H.N. Tattersall; W.P. Holman Clinic, Launceston: D. Boadle, I.Byard, D. Byram.
We thank the patients, physicians, nurses, and data managers who participate in the International Breast Cancer Study Group trials and Rita Hinkle for data management.
published online ahead of print at www.jco.org on December 11, 2006. Supported by Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group, Australian National Health and Medical Research Council (project 920876), National Cancer Institute Grant No. CA-75362; Bethesda, MD, Swedish Cancer Society, Cancer Association of South Africa, and Foundation for Clinical Research of Eastern Switzerland (OSKK). Astra-Zeneca provided the Zoladex free of charge. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Psychooncology 13:769-778, 2004[CrossRef][Medline] Submitted October 8, 2005; accepted October 17, 2006.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
.05 was deemed statistically significant. No adjustment was made for multiple testing. 
