Toremifene and tamoxifen are equally effective for early-stage breast cancer: first results of International Breast Cancer Study Group Trials 12-93 and 14-93

International Breast Cancer Study Group1,*,{dagger}

1 See Appendix for the names and affiliations of the participants and authors of the International Breast Cancer Study Group Trials 12-93 and 14-93

* Correspondence to: Dr O. Pagani, Instituto Oncologico Svizzera Italiana IOSI, Ospedale Beata Vergine, 6850 Mendrisio, Switzerland. Tel: +41-91-811-3467; Fax: +41-91-811-3038;opagani{at}siak.ch


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix International Breast...
 References
 
Background: Toremifene is a chlorinated derivative of tamoxifen, developed to improve its risk–benefit profile. The International Breast Cancer Study Group (IBCSG) conducted two complementary randomized trials for peri- and postmenopausal patients with node-positive breast cancer to compare toremifene versus tamoxifen as the endocrine agent and simultaneously investigate a chemotherapy-oriented question. This is the first report of the endocrine comparison after a median follow-up of 5.5 years.

Patients and methods: 1035 patients were available for analysis: 75% had estrogen receptor (ER)-positive primary tumors, the median number of involved axillary lymph nodes was three and 81% received prior adjuvant chemotherapy.

Results: Toremifene and tamoxifen yielded similar disease-free (DFS) and overall survival (OS): 5-year DFS rates of 72% and 69%, respectively [risk ratio (RR)=0.95; 95% confidence interval (CI)=0.76–1.18]; 5-year OS rates of 85% and 81%, respectively (RR = 1.03; 95% CI = 0.78–1.36). Similar outcomes were observed in the ER-positive cohort. Toxicities were similar in the two treatment groups with very few women (<1%) experiencing severe thromboembolic or cerebrovascular complications. Quality of life results were also similar. Nine patients developed early stage endometrial cancer (toremifene, six; tamoxifen, three).

Conclusions: Toremifene is a valid and safe alternative to tamoxifen in postmenopausal women with endocrine-responsive breast cancer.

Key words: adjuvant therapy, early-stage breast cancer, tamoxifen, toremifene


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix International Breast...
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Several studies have reported the value of adjuvant chemo-endocrine treatment in the management of postmenopausal patients with node-positive early breast cancer [1Go–7Go]. Endocrine responsiveness is currently recognized as the most useful prognostic and predictive tool to design tailored treatment options in different patient subpopulations [8Go]. Tamoxifen is still the antiestrogen of choice [9Go], but several endocrine options are under investigation and will become available in the near future [10Go, 11Go]. Concern about the side-effects of tamoxifen, in particular thromboembolic events, endometrial cancers and ocular toxicity, has led to the development of several analogs including toremifene, a chlorinated derivative with similar site-specific activity. In preclinical studies it has been shown to have equivalent estrogen receptor (ER) binding and anti-tumor efficacy [12Go, 13Go], with less estrogenic activity and DNA adduct formation in the endometrium [14Go–18Go]. Tamoxifen and toremifene induce similar estrogenic effects on the endometrium in postmenopausal women [19Go, 20Go], but conclusive data on the uterine carcinogenic effect of toremifene are not yet available due to the limited number of long-term users in prospective clinical trials [21Go]. No excess risk of endometrial cancer has been reported in the marketed use of toremifene so far [22Go, 23Go]. In contrast to tamoxifen [24Go], and despite its pharmacological similarity and the high dose administered in some trials, toremifene has not been associated with severe ocular toxicity [25Go].

Both tamoxifen and toremifene reduce serum total cholesterol and low density lipoprotein (LDL) levels. In contrast to tamoxifen, toremifene may increase serum high-density lipoprotein but not triglyceride levels, a finding that could translate into a better anti-atherogenic effect [26Go–28Go]. The impact of these changes on coronary artery disease risk is controversial, with some studies in women treated with adjuvant or preventive tamoxifen showing a reduction in the incidence of myocardial infarction and cardiac deaths [29Go–32Go]. In the meta-analysis of the Early Breast Cancer Trialists' Collaborative Group, adjuvant tamoxifen was not found to be associated with reduced cardiac risk, possibly due to limited available data [33Go].

Phase III trials have demonstrated that toremifene, at either 60 or 40 mg daily doses, is similar to tamoxifen as first-line treatment for metastatic breast cancer in postmenopausal patients, with a similar side-effect profile [21Go, 34Go–37Go]. In the adjuvant setting, the Finnish multicenter trial also showed no difference in recurrence rates between groups of postmenopausal node-positive patients (n=1480) receiving 40 mg/day toremifene and 20 mg/day tamoxifen for 3 years [38Go, 39Go].

In 1993 the International Breast Cancer Study Group (IBCSG) initiated two complementary randomized trials for peri- and postmenopausal patients with node-positive breast cancer. IBCSG Trial 12-93 was designed for patients who were considered to be suitable for endocrine therapy alone (tumors had to be ER positive) and for whom chemotherapy was considered an ‘experimental’ option, while IBCSG Trial 14-93 was designed for patients whose tumor characteristics required chemotherapy prior to endocrine treatment, based upon the judgment of the investigator. Both trials used factorial designs to investigate simultaneously a chemotherapy-oriented question and to compare toremifene versus tamoxifen as the endocrine agent. This paper is the first report of the toremifene versus tamoxifen comparison after a median follow-up of 5.5 years.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix International Breast...
 References
 
The combined analysis of toremifene versus tamoxifen in IBCSG Trials 12-93 and 14-93 was prospectively defined in the protocol documents as the primary evaluation of the comparison of the two endocrine agents. Because toremifene was not available in all IBCSG countries, some participating centers randomized patients only to the tamoxifen arms of the studies (thus addressing only the chemotherapy-related questions).

Study designs
IBCSG Trial 12-93 was originally designed in 1993 as a randomized three by two factorial phase III clinical trial to compare simultaneously three adjuvant systemic regimens (chemotherapy with endocrine therapy starting concurrently versus chemotherapy with endocrine therapy starting sequentially versus endocrine therapy alone) and to compare toremifene versus tamoxifen as the endocrine agent. The patient population was post- and perimenopausal women with node-positive, ER-positive breast cancer who were considered suitable for endocrine therapy alone. The chemotherapy regimen consisted of four courses of AC [anthracycline (doxorubicin or epirubicin) plus cyclophosphamide]. Because the accrual rate was low, in 1997 the protocol was modified to discontinue the three-arm randomization for the chemotherapy-oriented question and continue exclusively with randomization to toremifene versus tamoxifen; the use and type of chemotherapy prior to initiation of toremifene or tamoxifen was left to the discretion of the investigators.

IBCSG Trial 14-93, also begun in 1993, was designed as a randomized two by two factorial phase III clinical trial to compare simultaneously two ways of delivering adjuvant chemotherapy [with a 16-week gap between AC and CMF (cyclophosphamide, methotrexate and fluorouracil) versus without the 16-week gap] and to compare toremifene versus tamoxifen as the endocrine agent to follow the completion of chemotherapy. The patient population was post- and perimenopausal women with node-positive disease who were considered not suitable for endocrine therapy alone. All patients received four courses of AC followed, with or without a 16-week treatment-free interval, by three courses of classical CMF [40Go] before starting endocrine therapy.

The two trials were conducted simultaneously with common forms, procedures, protocol requirements and schedules. Informed consent was required according to the criteria established within the individual countries. Both protocols were reviewed and approved by institutional review boards. Randomization was performed centrally after stratification according to ER status (negative, positive), primary surgery (mastectomy versus breast conservation with radiation therapy planned versus breast conservation without radiotherapy) and by participating institution (see Appendix).

Eligibility criteria included: post- and perimenopausal patients (≤70 years old), T1–T3 [41Go] histologically proven unilateral breast cancer with positive lymph nodes (at least one positive out of a minimum of eight examined), primary surgery within 6 weeks prior to randomization (either a total mastectomy or a conservative procedure with axillary lymph node dissection), tumor confined to the breast and adequate hematological, renal and hepatic function. Patients were excluded if they had had prior breast cancer treatments or prior malignancies.

Post- and perimenopausal status were defined by one of the following characteristics: (i) neither hormone replacement therapy (HRT) nor hysterectomy and at least 6 months of amenorrhea; (ii) no HRT nor hysterectomy, and either greater than 55 years of age or 55 years and younger, but with postmenopausal luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol (E2) levels; (iii) currently receiving HRT and 50 years or older, or currently receiving HRT and 6 months or more of amenorrhea prior to start of HRT.

Steroid hormone receptor concentrations in the primary tumors were determined by immunohistochemistry (IHC) for 53% of the patients and by ligand-binding assay (LBA) for 47% [42Go, 43Go]. Tumors were classified as: ER-negative if IHC expression equalled none, borderline or negative, or if the LBA equalled 0–9 fmol/mg cytosol protein; and ER-positive otherwise. Grade determination was based on the local Bloom–Richardson (BR) scoring [44Go], if available. If the local BR scoring was not available, then grade was based on the local three-point differentiation scale. If neither the local BR, nor the local differentiation scale was available then grade was based on the central review BR scoring. Local BR score determined the grade in 59% of the patients, local differentiation score in 35%, central BR in 3% and grade was missing in 3%.

Staging before randomization included chest X-ray, contralateral mammogram, bone scintigram and liver imaging (ultrasound or CT scan), if clinically indicated. Clinical, hematological and biochemical assessments were required every 3 months for the first year, every 6 months for the second year and yearly thereafter. Modified World Health Organization (WHO) toxicity-grading criteria were used for reporting side-effects [45Go]. Mammography was performed yearly during follow-up.

Systemic adjuvant therapy was to begin within 6 weeks of surgery, and endocrine therapy following chemotherapy on day 15 of the final course of CMF chemotherapy. Toremifene 60 mg/day or tamoxifen 20 mg/day was continued until relapse or the end of the fifth year after randomization. For patients undergoing breast conserving surgery, radiotherapy to the conserved breast was optional, to be carried out according to the prospectively defined guidelines of each participating institution; either after all chemotherapy or integrated into CMF as agreed per institution.

The data management and medical staff reviewed all study records (eligibility, treatment, toxicity and recurrence) and conducted regular site visit audits. In particular, the study chairs (see Appendix) reviewed the records for all grade 3 or worse toxicities and clarified attribution.

Endpoints and statistical considerations
Disease-free survival (DFS) was defined as the length of time from the date of randomization to any relapse (including ipsilateral breast cancer recurrence), the appearance of a second primary cancer (including contralateral breast cancer) 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 sizes were 760 patients for Trial 14-93 and 1140 for Trial 12-93, which provided a 90% power to detect a 25% increased risk of failure with toremifene compared with tamoxifen using a one-sided {alpha}=0.05 statistical test. Because toremifene was not available in all IBCSG countries and recruitment to Trial 12-93 was lower than expected, a total of 1035 patients were actually recruited for the toremifene versus tamoxifen comparison in both trials (Figure 1). With the consequent decrease in statistical power, 95% confidence intervals (CIs) for the risk ratios (RRs) (toremifene versus tamoxifen) rather than P-values were used to provide interpretation of the results.



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Figure 1. Flow chart of patients accrued for the toremifene versus tamoxifen comparison in International Breast Cancer Study Group Trials 12-93 and 14-93.

 
DFS and OS percentages, standard errors, and treatment effect comparisons were obtained from the Kaplan–Meier method [46Go], Greenwood's formula [47Go] and log-rank tests [48Go], respectively. Cox proportional hazards regression models [49Go] were used to estimate RRs for the toremifene versus tamoxifen treatment effect and their 95% CIs both for unadjusted analyses and for analyses adjusted for other covariates. All probability values were obtained from two-sided tests. The randomization was stratified according to ER status and the intention to perform separate analyses according to ER status was specified in both of the original protocols.

The Data Safety Monitoring Committee reviewed accrual and safety data for both trials twice a year. They also reviewed two predetermined interim efficacy analyses of Trial 14-93 (in January 1999 and November 2000), and study continuation was recommended on both occasions. The predetermined number of events required for the final analysis for Trial 14-93 was reached in 2001. Because of slow accrual, Trial 12-93 was closed before the target number of events for the interim efficacy review was reached.

Quality of life
Patient self-assessments of quality of life (QoL) using the IBCSG approach [50Go, 51Go] were obtained at the beginning of treatment; at months 3, 6, 9, 12, 18 and 24, and yearly thereafter for 6 years. Single-item LASA (linear analog self-assessment) scales scored between 0 and 100 were used; higher values represent better QoL or less severe symptoms. Ten scales were used to measure physical well-being, mood, appetite, perceived adjustment/coping, tiredness, hot flushes, nausea/vomiting, perceived social support, arm restriction and a patient-rated measure of utility. Scores were transformed to reduce skewing and the statistical significance was assessed with analysis of variance adjusting for country/language group. Three hundred and thirty-eight patients were excluded from the QoL analysis for one or more of the following reasons: relapsed or died within the first 5 years, completed no QoL assessments, did not have 5 complete years of follow up, completed QoL assessments in multiple languages/undefined culture.

Patient eligibility and characteristics
Between 1993 and 1999, a total of 1421 patients enrolled in Trials 12-93 and 14-93, of whom 384 were not randomized for the toremifene versus tamoxifen comparison, and two were excluded from all analyses due to withdrawal of patient consent (Figure 1). Of the remaining 1035 patients, 26 (2.5%) did not meet protocol eligibility criteria for the following reasons: pre-menopausal status (12 patients), incorrect stage (five patients), inadequate surgery (two patients), previous cancers (three patients), ER-negative status in the ER-positive trial (one patient), medically unsuitable (one patient), too long between surgery and randomization (one patient), older than 70 years (one patient). All 26 ineligible patients were included in the intent-to-treat analyses.

The characteristics of the 1035 patients included in the toremifene versus tamoxifen analyses are shown in Table 1. The median age was 59 years, ranging from 37 to 83 years. Seventy-five percent of the patients had primary tumors classified as ER-positive and 25% as ER-negative. The median number of involved axillary lymph nodes was three (range 1–35). Eighty-one percent of the patients received adjuvant chemotherapy prior to beginning toremifene or tamoxifen, 5% received AC started at the same time as endocrine therapy per randomization, and 14% received endocrine therapy alone.


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Table 1. Patient characteristics according to treatment

 

    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix International Breast...
 References
 
Disease-free survival and overall survival
The outcomes in terms of DFS and OS were similar for toremifene and tamoxifen (Table 2, Figure 2). Overall, the 5-year DFS figures were 72% for toremifene and 69% for tamoxifen, and the 5-year OS figures were 85% for toremifene and 81% for tamoxifen.


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Table 2. Disease-free survival (A) and overall survival (B) comparing toremifene versus tamoxifen at 5.5 years' median follow-up

 


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Figure 2. Disease-free (A) and overall survival (B) comparing toremifene versus tamoxifen for the 1035 patients who were randomized between these two endocrine therapies in International Breast Cancer Study Group Trials 12-93 and 14-93 combined. Median follow-up was 5.5 years.

 
Analyses according to ER status of the primary tumor also revealed equivalent outcomes for toremifene and tamoxifen (Table 2, Figure 3). In particular, for patients with ER-positive tumors, the 5-year DFS figures were 76% for toremifene and 72% for tamoxifen. The 5-year OS figures for the ER-positive cohort were 90% for toremifene and 86% for tamoxifen.



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Figure 3. Disease-free survival comparing toremifene versus tamoxifen for patients who were randomized between these two endocrine therapies in Trials 12-93 and 14-93 combined for the 261 patients with estrogen receptor (ER)-negative tumors (A) and for 773 patients with ER-positive tumors (B). Median follow-up was 5.5 years.

 
The RRs and 95% CIs for the toremifene versus tamoxifen comparison are shown in Table 2, both for unadjusted analyses and for analyses adjusted for prognostic factors. RRs less than one indicate fewer events in the toremifene group compared with the tamoxifen group. A comparison for which the upper limit of the 95% CI is <1.25 satisfies the generally accepted criterion to declare equivalence of outcome. Based on this criterion in unadjusted and adjusted analyses, toremifene is equivalent to tamoxifen with respect to DFS, both overall and within the ER-positive cohort. Although the RRs for OS for the ER-positive cohort are less than one, the CIs are too wide to declare equivalence, possibly due to the small number of deaths in this group.

Sites of first failure
Of the 1035 patients, 330 (32%) experienced a breast cancer relapse, second primary or deaths without recurrence (DFS event) and 206 (20%) died (Table 3). A second primary endometrial cancer was observed in six patients in the toremifene group (four patients had an endometrial cancer event during toremifene administration at 11, 34, 36 and 46 months, in two patients occurrence was more than 2 years after completion of 5 years of treatment), and three patients in the tamoxifen group (two cases during tamoxifen administration at 13 and 47 months, one patient more than 2 years after completion of 5 years of treatment, subsequent to contralateral breast cancer at 30 months). All nine patients were alive and free of endometrial cancer after adequate treatment.


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Table 3. Sites of first failure at 5.5 years' median follow-up

 
Toremifene and tamoxifen treatment compliance and toxicity
Forty-eight patients (5%) did not receive any randomized treatment due to early relapse (2%), refusal or other reason (1%) or decision to treat with another drug (2%) (Table 4). At the time of this analysis, 29% were still receiving treatment, 34% stopped treatment before 5 years, primarily due to treatment failure, and 32% completed adjuvant therapy to 5 years after randomization. Compliance was similar between the two treatment groups (Table 4).


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Table 4. Overall compliance with administration of toremifene and tamoxifen

 
Of the patients who received at least some of their assigned treatment, 7% and 6% experienced grade 3 or higher toxicities during toremifene or tamoxifen therapy, respectively. The frequencies of the most clinically relevant grade 3 or higher toxicity types are reported according to treatment in Table 5. Differences between treatment groups are small. Possible treatment-related toxic deaths occurred in four patients, two in the toremifene group (one pulmonary embolism and one cerebrovascular accident) and two in the tamoxifen group (one congestive heart failure and one cerebrovascular accident).


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Table 5. Grade 3 and higher toxicities reported during toremifene or tamoxifen administration

 
Second primaries and deaths without recurrence
Table 6 shows the types of second primary for the 29 patients whose site of first treatment failure was a non-breast event. Table 7 shows the causes of death for the 17 patients who died without having a breast cancer recurrence or a second primary. Neither showed evidence of a difference between the two agents.


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Table 6. Second (non-breast) primaries as sites of first failure

 

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Table 7. Causes of death without recurrences

 
Quality of life
QoL was assessed for 697 patients who had not relapsed and had completed at least one questionnaire up to month 60. No significant difference between toremifene and tamoxifen emerged on any of the 10 items assessed at the different time points, for example physical well-being (Figure 4A) and hot flushes (Figure 4B). Physical well-being scores declined initially, possibly due to chemotherapy, but then recovered. LASA scores for hot flushes also declined initially, indicating decreased QoL associated with hot flushes, but began to recover with increasing follow-up after month 12.



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Figure 4. Median linear analogue self assessment (LASA) scores for physical well-being (A) and for hot flushes (B). Lower scores indicate a reduced quality of life (QoL) with respect to each domain. This analysis includes 697 assessable patients with at least one questionnaire in the 60-month period.

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix International Breast...
 References
 
These results confirm the similar efficacy of adjuvant toremifene and tamoxifen in terms of DFS, OS, local, regional and distant recurrence and second primaries in a population of 1035 post- and perimenopausal patients with node-positive breast cancer. Toxicities were also similar.

In our study, endometrial cancers were observed with both agents, but in the Finnish trial, with a mean follow-up time of 4.4 years, only two endometrial cancers were discovered, and both were in the tamoxifen-treated group [38Go]. In the present IBCSG trials, women were given slightly higher doses of toremifene (60 mg/day) compared with the Finnish trial (40 mg/day) and for a longer period of time (5 versus 3 years). These two dosages of toremifene have been shown to induce similar changes in the sex hormone profile, as assessed by FSH, LH and sex hormone binding globulin (SHBG) serum levels, in postmenopausal patients with advanced breast cancer [52Go]. The reported lower genotoxicity of toremifene [18Go] may be a potential favorable characteristic of the drug compared with tamoxifen [14Go], but the real clinical relevance of these findings still needs to be determined. In the earlier clinical trials conducted worldwide since 1982, a total of seven early stage endometrial cancers have been reported among women receiving toremifene [23Go]. The doses of toremifene ranged from 40 mg/day (two patients) to 60 mg/day (three patients) to >200 mg/day (two patients); most of the patients (71%) had received the drug for less than 1 year before the diagnosis of uterine cancer. The reported low cumulative incidence of endometrial cancer (about 0.07 cases per 1000 patient years) and the observation of an early onset (the majority of cases arising within 1 year of treatment), had suggested that toremifene possibly tends to unveil latent tumors [53Go]. By contrast, five of the six endometrial cancers among women receiving toremifene in the present study occurred after more than 1 year of treatment. Recent data [54Go] show an increased risk of malignant mixed Mullerian tumors among long-term breast cancer survivors treated with tamoxifen and call for careful long-term follow-up.

In our series no significant difference, either in severe thromboembolic and cerebrovascular complications or in the occurrence of possibly treatment-related deaths, was apparent in the two treatment groups. In the Finnish adjuvant trial the incidence of thromboembolic events was slightly higher in the tamoxifen-treated group (5.9%) than in the toremifene group (3.5%) but the difference was not statistically significant (P=0.11). A recent update of the available data in 1270 patients treated with adjuvant toremifene (40–60 mg/day) and in 1239 treated with adjuvant tamoxifen, with a median treatment duration of 3.1 years, showed no difference in the incidence of transitory ischemic attack (TIA), pulmonary embolism and deep vein thrombosis (DVT) in the two treatment groups, with a significant difference in favor of toremifene in the incidence of strokes (0.16% versus 0.97%, P <0.01) [55Go].

Retinopathy, formation of crystals and cataracts, have all been associated with tamoxifen at doses used in these trials [24Go]. Despite the fact that they were not designed to specifically address this topic, severe ocular toxicity was very rare in both treatment groups and comparable to previous evidence [25Go]: one patient treated with tamoxifen developed double cataracts, two patients receiving toremifene showed a retinal detachment and glaucoma associated with cataract, respectively.

In the two IBCSG trials drug compliance was good; <10% of patients in both treatment groups stopped treatment early, due to refusal or toxicity. Information on QoL during treatment was available in 67% of patients overall and no significant differences between toremifene and tamoxifen emerged for any of the items assessed at the various time points. Hayes et al. [35Go] assessed QoL in a randomized trial of tamoxifen 20 mg/day versus toremifene 60 mg/day versus toremifene 200 mg/day for 648 patients with metastatic breast cancer using three visual analog scales (pain, mood and enjoyment of life). With these assessment methods, which are very similar to those used in the current study, no statistically significant differences were found for the three treatment groups.

We conclude that toremifene is a valid and safe alternative to tamoxifen in endocrine-responsive breast cancer. Relative efficacy among specific estrogen receptor modulators such as tamoxifen and toremifene may be of lesser importance as the research agenda moves to assessing the place and timing of aromatase inhibitors in adjuvant therapy. Clinical research in patient populations with expected 5-year OS exceeding 80%, should focus not only on the search for new endocrine regimens that improve upon the results already achieved with 5 years of tamoxifen treatment, but also on the best and acceptable balance between disease control and potentially serious therapy-related side-effects.


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Table A1. Names and affiliations of the participants and authors of the International Breast Cancer Study Group Trials 12-93 and 14-93

 

    Appendix International Breast Cancer Study GroupGo
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix International Breast...
 References
 


    Acknowledgements
 
We thank the patients, physicians, nurses and data managers who participate in the IBCSG trials. We thank Orion Farmos for providing a grant and medication for this trial. We acknowledge Joie Celano for data management. We further acknowledge the initial support provided by the Ludwig Institute for Cancer Research and the Cancer League of Ticino, and the continuing support for central coordination, data management and statistics provided by the Swedish Cancer Society, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group (NHMRC grant numbers 890028, 920876, 950328, 980379, 141711), the Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research (SAKK), the Swiss Cancer League, the American Cancer Society (RPG-90-013-08-PBP) and the United States National Cancer Institute (CA-75362). 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.


    Notes
 
{dagger} Writing Committee: O. Pagani, S. Gelber, E. Simoncini, M. Castiglione-Gertsch, K. Price, D. Zahrieh, R. Gelber, A. Coates, A. Goldhirsch Back

Received for publication February 11, 2004. Revision received July 2, 2004. Accepted for publication July 5, 2004.


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 Introduction
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 Discussion
 Appendix International Breast...
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