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Randomized Trial of 2 Versus 5 Years of Adjuvant Tamoxifen for Women Aged 50 Years or Older With Early Breast Cancer: Italian Interdisciplinary Group for Cancer Evaluation Study of Adjuvant Treatment in Breast Cancer 01

M. Sacco, M. Valentini, M. Belfiglio, F. Pellegrini, G. De Berardis, M. Franciosi, A. Nicolucci

From the Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, S. Maria Imbaro, Italy.

Address reprint requests to A. Nicolucci, MD, Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, Via Nazionale, 66030 S. Maria Imbaro, Italy; email: nicolucc{at}negrisud.it.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Purpose: To compare 2 with 5 years of adjuvant tamoxifen therapy in the treatment of early breast cancer.

Patients and Methods: Women with breast carcinoma T1–3, N0–3, M0, who were between 50 and 70 years of age, were eligible irrespective of menopausal status, tumor grade, or estrogen receptor (ER) status. Patients who were event-free after 2 years of tamoxifen therapy were randomly assigned to stop or continue tamoxifen therapy for an additional 3 years. The primary end point was length of disease-free survival (DFS). Secondary end points included overall survival (OS) and toxicity.

Results: From 1989 through 1996, 1,901 patients were randomly assigned either to stop treatment (n = 958) or to receive tamoxifen for 3 additional years (n = 943). The median duration of postrandomization follow-up was 52 months. We found no statistically significant differences between the 5-year arm and the 2-year arm in terms of DFS (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.76 to 1.08) and OS (HR, 1.16; 95% CI, 0.92 to 1.46). In ER-positive patients, a statistically significant prolongation of DFS related to longer treatment duration was observed (HR, 0.74; 95% CI, 0.59 to 0.93), whereas no difference in OS could be detected (HR, 0.98; 95% CI, 0.72 to 1.32). No differences in terms of endometrial cancers, cardiac or cerebrovascular events, or fractures were detected, whereas a doubling in the risk of thromboembolic events was found in the 5-year arm.

Conclusion: Our results confirm previous research that shows that 5 years of tamoxifen decreases recurrence compared to 2 years in patients with ER-positive tumors.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
HORMONAL ADJUVANT therapy with tamoxifen in early breast cancer is widely accepted as a standard treatment because of its documented efficacy in improving disease-free survival (DFS) and overall survival (OS).^1–4 Nevertheless, the optimal treatment duration has not yet been well established. The first overview on hormonal therapy, published in 1990,¹ did not answer this question because most of the trials compared only 1 or 2 years of treatment versus no therapy. In the next overview, published in 1992,^2,3 indirect comparisons indicated that a longer treatment duration (> 2 years) might produce better outcomes. The last overview, in 1998,⁴ which compared different treatment durations versus no hormonal therapy, confirmed the previous results. The indirect comparison of different lengths of tamoxifen therapy showed that a 5-year period of treatment significantly reduces the risk of relapse and death. Nevertheless, no data deriving from trials with patients randomly assigned to receive different tamoxifen durations were available.

In 1996, preliminary results of two randomized clinical trials comparing 2 versus 5 years of tamoxifen treatment were published.^5,6 Both trials demonstrated that the incidence of relapse was significantly reduced in the longer treatment arm; only the Swedish trial also showed a significant difference in terms of OS. More recently, a third trial confirmed the positive effect of longer tamoxifen duration in terms of DFS but not OS.⁷

In 1989, the Italian Interdisciplinary Group for Cancer Care Evaluation (GIVIO) launched the Italian Study of Adjuvant Treatment in Breast Cancer 01 (SITAM-01), a multicenter, randomized, unblinded clinical trial comparing 2 versus 5 years of tamoxifen treatment in women between 50 and 70 years of age with early stage invasive breast cancer. The study design was pragmatic in entry criteria and conduct. This approach was adopted to ensure wide participation and high patient accrual.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The trial flow chart is shown in Fig 1. All women with operable invasive breast carcinoma T1–3, N0–3, M0 (according the tumor-node-metastasis staging system⁸) between 50 and 70 years of age were eligible, irrespective of menopausal status, tumor grade, or estrogen receptor (ER) status. Patients were not eligible if they had in situ breast carcinoma, bilateral tumor, previous malignancy (other than squamous or basal cell carcinoma of the skin or carcinoma-in-situ of the cervix), if they were unlikely to comply with trial requirements, or if they suffered from psychiatric disorders. Ethical aspects of the protocol were approved by the Italian Ministry of Health, and the study was conducted according to the national law regulating clinical research.

View larger version (23K): [in this window] [in a new window]   Fig 1. Trial flow chart.

Primary surgical treatment was performed according to the local practice and patient preference. It consisted of either modified radical mastectomy or breast-conserving surgery in combination with axillary lymph node dissection. ER levels were determined according to routine procedures in every center, usually by the method of dextran-coated charcoal assay or immunohistochemistry, with no central pathology review. ER positivity was defined as an ER level ≥ 10 fmol/mg cytosol protein or ≥ 10% positive staining tumor cells. Radiotherapy to the breast was offered to all patients treated with conserving surgery.

Patients were registered at any time up to 2 years after surgery. Tamoxifen treatment had to be started within 1 month of surgery at a dose of 20 mg orally once a day for 2 years. In patients receiving chemotherapy, hormonal treatment was postponed after systemic therapy, and in any case no more than 6 months from surgery. After 2 years of treatment with tamoxifen, those patients who were alive and event-free were randomly assigned to stop or continue receiving tamoxifen for an additional 3 years. Random assignment of patients was accomplished through telephone calls by the trialists to the trial office. Treatment allocation was stratified by center, prior chemotherapy (yes or no), and axillary nodal status (negative, one to three positive nodes, more than three positive nodes). Those patients who accepted random assignment were reviewed regularly at the outpatient clinic (every 6 months for up to 3 years after random assignment and then annually) and reports on them were submitted to the trial office on each occasion. After an event (local or distant recurrence, second breast cancer, or new primary tumor) the follow-up visits were performed every 6 months for the next 5 years. Information on treatment toxicity, including new cancers, fractures, and cardiovascular events, was collected at each visit on ad hoc forms.

When the trial was started, two randomized trials aimed at assessing the optimal modalities for the follow-up of breast cancer patients were ongoing in Italy.^9,10 Therefore, each center was left free to adopt the preferred follow-up strategy in terms of clinical and diagnostic procedures, provided that all patients included in the trial were followed with the same modalities, which had to be communicated to the coordinating center before the study initiation. An annual gynecologic visit was requested for all patients because of the increased risk of endometrial cancer.

Death reports were received from the participating clinicians. For patients lost to follow-up, information about vital status was requested from the registry offices. For patients whose cause of death was unknown, information was requested from the health districts.

The primary end point was length of DFS, defined as the time to the earliest occurrence of any of the following events: locoregional recurrence or distant metastasis, second breast cancer, new primary other than squamous or basal cell carcinoma of the skin, or death irrespective of the underlying cause. Locoregional recurrence was defined as any recurrence in the ipsilateral breast, chest wall, or axillary lymph nodes. In these analyses, patients who had not experienced an event at the end date for follow-up were treated as censored observations. Secondary end points included OS and toxicity of hormonal treatment.

Statistical Analysis
At the time the trial was initiated, little, if anything, was known about the benefit of prolonging adjuvant tamoxifen in terms of the relative reduction of treatment failures. Sample size estimation was thus based on the hypothesis that prolonging tamoxifen treatment to 5 years could decrease the risk of any first event by 25%. With this assumption, it was estimated that a number of events between 384 (1 - ß = 0.80) and 514 (1 - ß = 0.90) was needed to detect a significant difference (log-rank test, P < .05) between the two treatment arms. As reported below, the current analysis was based on a total of 491 first events among 1,901 patients who were alive and event-free at 2 years.

All analyses were performed on an intention-to-treat basis. Probabilities of DFS and OS were calculated using the Kaplan-Meier method,¹¹ and comparisons were carried out using the log-rank test. An additional subgroup analysis for ER-positive patients was performed. All reported P values are two-sided.

Adjusted hazard ratios (HRs) with their associated 95% confidence intervals (95% CIs) were also estimated using the Cox proportional hazards model.¹² The following covariates were included in the model (reference category [RC] is also listed): age (continuous variable), pathologic tumor size (T1 [RC], T2, T3), number of positive axillary nodes (N0 [RC], N1–3, N > 3), estrogen receptor status (ER-positive [RC], ER-negative, ER unknown), and previous chemotherapy (yes [RC], no).

Rates of contralateral breast cancers, endometrial cancers, and thromboembolic events have also been expressed as incidence rates (events/1,000 woman-years at risk).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patients
From July 1989 through December 1996, 2,551 eligible patients were identified; among them, 1,901 were randomly assigned either to stop treatment (n = 958) or to receive 20 mg of tamoxifen per day for 3 additional years (n = 943). The remaining 650 patients were not randomly assigned for the following reasons (Fig 1): 35 patients died and 222 had a disease recurrence before the random assignment; 164 patients were lost to follow-up; 45 patients interrupted the hormonal therapy for events not related to breast cancer; 44 patients refused random assignment; 83 patients were lost because of the withdrawal of four centers; and 57 patients were not randomly assigned for other reasons. The closing date for this analysis was December 2000. The clinical and pathologic characteristics of the randomized patients are shown in Table 1. Regarding nodal status, only two patients (one per arm) were classified as N3.

Overall Findings
The number of postrandomization first events was 258 in the 2-year treatment group and 234 in the 5-year group. Table 2 shows the different types of events according to the treatment arms for the whole population and ER-positive patients.

View larger version (11K): [in this window] [in a new window]   Fig 2. Disease-free survival, all patients.

View larger version (11K): [in this window] [in a new window]   Fig 3. Overall survival, all patients.

View larger version (11K): [in this window] [in a new window]   Fig 4. Disease-free survival, estrogen receptor-positive patients.

View larger version (10K): [in this window] [in a new window]   Fig 5. Overall survival, estrogen receptor-positive patients.

Contralateral Breast Cancer and Second Cancers
Overall, 107 second cancers, including contralateral breast cancer, were detected during follow-up; 58 occurred in the 2-year arm and 49 occurred in the 5-year arm. Three and five patients with endometrial cancer were detected in the short- and long-term groups, respectively, corresponding to incidence rates of 0.86/1,000 woman-years for the 2-year arm and 1.46/1,000 woman-years in the 5-year arm. Thirty-seven patients developed contralateral breast cancer (22 in the 2-year and 15 in the 5-year arm, corresponding to incidence rates of 5.4/1,000 woman-years and 3.8/1,000 woman-years, respectively). This translated into a nonsignificant benefit for patients allocated to longer treatment (unadjusted HR, 0.69; 95% CI, 0.36 to 1.34; P = .27). The analysis restricted to ER-positive patients showed similar results (unadjusted HR, 0.61; 95% CI, 0.27 to 1.40; P = .25).

Other Events
Table 4 shows other events detected during the follow-up and possibly related to hormonal treatment. There were no statistically significant differences in terms of cardiovascular and cerebrovascular events or fractures, whereas a significant increase in thromboembolic events was detected in the 5-year arm. Incidence rates for thromboembolic events were 2.43/1,000 woman-years in the 2-year arm and 5.52/1,000 woman-years in the 5-year arm.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

After a median follow-up of 52 months after random assignment to treatment (78 months after surgery), our study showed that 5 years of treatment with tamoxifen significantly improved EFS only among ER-positive patients. In this subgroup, a relative reduction of 26% in first events was documented, confirming the previous results of the Swedish and French trials.^5,7

In our study the benefit in DFS in ER-positive patients did not translate into prolonged survival. These findings are in agreement with the results of the French trial.⁷ A lack of benefit on overall survival was also documented in the Cancer Research Campaign (CRC) trial, even though no data on receptor status were reported in this study.^6,7 It should be noted that the median duration of observation after randomization was substantially lower for the CRC trial (median follow-up of 24 months), but similar for the French trial (median follow-up of 48 to 49 months). Conversely, in the Swedish trial a significant improvement in survival associated with longer tamoxifen duration was documented, but survival curves started to diverge only after 6 years from surgery.⁵ Therefore, the lack of adequate statistical power to detect significant differences in terms of overall survival is the most likely explanation for our findings. Nevertheless, the interpretation of mortality data can also be made difficult by the possible carry-over effect. In fact, it has been suggested that the benefits of tamoxifen therapy can extend well beyond the end of therapy.⁴ Hence, even if 5 years of adjuvant tamoxifen is better than 2 years of adjuvant tamoxifen, this advantage may not become substantial until well after 5 years. Furthermore, among women who relapsed in the 2-year arm, a high percentage (ie, 41%) of patients were treated again with hormone therapy, represented by tamoxifen in 50% of the patients. As a consequence, the benefits in terms of OS deriving from prolonging tamoxifen may have been lessened and the difference documented in terms of DFS can take several years to translate into different mortality rates.

For these reasons, a much longer follow-up would be needed before definite conclusions could be drawn about the effects of long-term tamoxifen on mortality. We have already planned a second analysis on mortality after 10 years from randomization.

Continuation of tamoxifen therapy beyond 2 years was also associated with a nonsignificant reduction in the risk of contralateral breast cancer of about 30%, in agreement with the Swedish and French trials,^5,7 whereas no difference in contralateral breast cancer incidence could be detected in the CRC trial.⁶ Tamoxifen prolongation was also associated with a doubled risk of thromboembolic events. Nevertheless, the excess risk of thromboembolic events was almost entirely counterbalanced by the benefit derived from the protection against contralateral breast cancer. The risk-benefit profile of prolonged tamoxifen therapy could be further improved by avoiding administration of the drug in women at particularly high risk of thromboembolic events. Recent data have shown that anastrozole in the adjuvant setting is associated with a significantly lower incidence of thromboembolic events as compared with tamoxifen given for 5 years.¹³ Anastrozole could thus represent the first-choice treatment in women with high thromboembolic risk.

In our study no statistically significant differences in endometrial cancer incidence could be detected, probably as a consequence of the small number of events. Nevertheless, the ratio of incidence rates in the 5- and 2-year arms was 1.70, thus indicating a higher probability of developing endometrial cancer associated with the prolongation of tamoxifen treatment.

Our data are consistent with the last world overview, indicating that tamoxifen treatment for 5 years is associated with a doubling in the risk of endometrial cancer as compared with 2 years of treatment.⁴

Some potential limitations of our study should be discussed. First, the population enrolled showed, in general, a favorable risk profile, also determined by the exclusion of those patients who experienced an early relapse. In fact, more than half of the population had T1 tumors and negative axillary lymph nodes, whereas about 80% had ER-positive tumors. Furthermore, only 10% of the patients were treated with chemotherapy. Therefore, it is not clear to what extent our findings can be generalized to patients with different risk profiles.

Second, about one third of the patients were lost to follow-up. This could have led to an underestimation in the number of events and side effects. Nevertheless, it should be noted that the median follow-up of patients lost to follow-up was more than 30 months, and about one third of them were followed for 4 years or more. Therefore, even patients lost to follow-up gave a substantial contribution to the estimation of DFS. That the estimates of DFS at 5 years after randomization (73% for the 5-year arm and 71% for the 2-year arm) were not significantly underestimated in our study is further confirmed by the similar proportion of patients free from disease found in the CRC (75% v 70%), French (approximately 80%), and Swedish (approximately 76%) trials. The incidence rates of contralateral breast cancer and endometrial cancer are also similar to those reported in the literature,⁴ further supporting the reliability of our data. Furthermore, overall survival estimates were not affected by the loss of patients to follow-up; the information on vital status was available for more than 98% of the patients enrolled.

In summary, our results confirm previous research that shows that 5 years of tamoxifen decreases recurrence compared to 2 years of treatment in patients with ER-positive tumors, and stress the importance of ER status measurement as a fundamental factor in prescribing hormone treatment.^4,14–16 The ongoing combined analysis of the existing trials comparing different treatment durations will allow more reliable estimates of treatment benefit in different patients subgroups.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following investigators participated in this study: Giampaolo Sacchetto, Loredana De Filippi, Alba (CN); Francesco Di Vito, Mariella Cucchi, Aosta; Giuseppe Di Biagio, Assisi (PG); Franco Testore, Asti; Luciano Isa, Gorgonzola (MI); Tonino Pedicini, Claudia Corbo, Antonio Febbraro, Benevento; Patrizia Marpicati, Giovanni Marini, Edda Simoncini, Brescia; Mario Costanzo, Catania; Ettore Cianchetti, Simona Grossi, Paolo Noccioli, Ortona (CH); Donata Tabiadon, Riccardo Valsecchi, Gino Luporini, Milano; Giordano Beretta, Cinisello Balsamo (MI); Fulvio Peradotto, Cuorgnè (TO); Angelo Gambi, M. Cristina Cappelli, Flavia Foglietta, Faenza (RA); Monica Indelli, Caterina Modonesi, Ferrara; M. Antonietta De Meo, Giuseppe Cardi, Formia (LT); Giorgio Baratelli, Gravedona (CO); Liberato Di Lullo, Isernia; Giampaolo De Rubeis, L’Aquila; Stefano Graziani, Lanciano (CH); Michele Antonello, Giambeppi Pizzi, Mestre (VE); Elisa Locatelli, Milano; Vito Schena, Sergio Peonetto, Patrizia Grace Bianchi, Milano; Francesco Arceri, Novara; Paola Viola, Rho (MI); Mauro Antimi, Mauro Minelli, Vincenzo Bellini, Giuseppe Marinuzzi, Riccardo Samaritani, Roma; Nina Olmeo, Antonio Contu, Sassari; Luciano Galletto, Marcella Sussio, Savigliano (CN); Fabrizio Fracchia, Raffaella Fiorella, Giorgio Giardina, Torino; Maria Grazia Pacquola, Anna Tava, Tortona (AL); Antonella Richetti, Marinella Molteni, Varese; Attilio D’Arrigo, Ivrea (TO); Enrico Ansaldi, Ciriè (TO); Sano Pasqualucci, Carlo Floris, Maria Cristina Cherchi, Enrichetta Valle, Cagliari; Italo Rasciale, Antonello Conte, Lorena Biasizzo, Udine; Antonio Tedde, Alberto Desogus, Marco Pintus, Cagliari; Giovanni Ambrosini, Orazio Caffo, Trento; Aurora Ferrari, Vittorio Corsetti, Ileana Capatà, Calcinato (BS); Pietro Masullo, Francesco D’Episcopo, Vallo della Lucania (SA); Giorgio Mustacchi, Michela Muggia, Trieste; Maria Concetta Chetrì, Brindisi; Giuseppe Serravezza, Antonella Elia, Giuseppe Quarta, Casarano (LE); Stefano Bravi, Franco Biagioni, Città di Castello (PG); Antonio Rulli, Annarita Vento, Paola Naninato, Perugia; Virginia Liguori, Candida Mastroianni, Salvatore Palazzo, Cosenza; and Enza Defabiani, Mario Campogrande, Torino, Italy.

	NOTES

 
Supported by AstraZeneca Italia, Busiglio, Italy.

Parts of this study were presented in abstract form at the ASCO 2000 Annual Meeting, New Orleans, LA, May 20–23, 2000, and at the ECCO 11 (European Cancer Conference) Lisbon, Portugal, October 21–25, 2001.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
1. Early Breast Cancer Trialists’ Collaborative Group: Treatment of early breast cancer. Vol 1: Worldwide evidence 1985–1990. Oxford: Oxford University Press, 1990

2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 339:1–15, 1992[Medline]

3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 339: 71–85, 1992 (review)[Medline]

4. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Tamoxifen for early breast cancer: An overview of the randomized trials. Lancet 351:1451–1467, 1998[CrossRef][Medline]

5. Swedish Breast Cancer Cooperative Group: Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer. J Natl Cancer Inst 88:1543–1549, 1996[Abstract/Free Full Text]

6. Current Trials Working Party of the Cancer Research Campaign Breast Cancer Trials Group: Preliminary results from the Cancer Research Campaign Trial evaluating tamoxifen duration in women aged fifty years or older with breast cancer. J Natl Cancer Inst 88:1834–1839, 1996[Abstract/Free Full Text]

7. Delozier T, Spielmann M, Mace-Lesec’h J, et al: Tamoxifen adjuvant treatment duration in early breast cancer: Initial results of a randomized study comparing short-term treatment with long-term treatment. J Clin Oncol 18:3507–3512, 2000[Abstract/Free Full Text]

8. International Union Against Cancer: TNM classification of malignant tumours. Berlin; New York, Springer-Verlag, 1987

9. The GIVIO Investigators: Impact of follow-up testing on survival and health-related quality of life in breast cancer patients: A multicenter randomized controlled trial. JAMA 271:1587–1592, 1994[Abstract/Free Full Text]

10. Rosselli Del Turco M, Palli D, Cariddi A, et al: Intensive diagnostic follow-up after treatment of primary breast cancer: A randomized trial—National Research Council Project on Breast Cancer follow-up. JAMA 271:1593–1597, 1994[Abstract/Free Full Text]

11. Kaplan EL, Meier P: Nonparametric estimation from incomplete observation. J Am Stat Assoc 53:457–481, 1958[CrossRef]

12. Cox DR: Regression models and life tables (with discussion). J R Stat Soc Series B 34:187–220, 1972

13. The ATAC Trialists’ Group: Arimidex, tamoxifen alone or in combination: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer—First results of the ATAC randomised trial. Lancet 359:2131–2139, 2002[CrossRef][Medline]

14. Rutqvist LE, Cedermark B, Fornander T, et al: The relationship between hormone receptor content and the effect of adjuvant tamoxifen in operable breast cancer. J Clin Oncol 7:1474–1484, 1989[Abstract]

15. Rose C, Thorpe SM, Andersen KW, et al: Beneficial effect of adjuvant tamoxifen therapy in primary breast cancer patients with high estrogen receptor values. Lancet 1:16–19, 1985[CrossRef][Medline]

16. Fisher B, Redmond C, Brown A, et al: Influence of tumor estrogen and progesterone receptor levels on the response to tamoxifen and chemotherapy in primary breast cancer. J Clin Oncol 1:227–241, 1983[Abstract]

Submitted June 19, 2002; accepted April 1, 2003.

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