This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Delozier, T. Articles by Namer, M. Search for Related Content PubMed PubMed Citation Articles by Delozier, T. Articles by Namer, M.

Tamoxifen Adjuvant Treatment Duration in Early Breast Cancer: Initial Results of a Randomized Study Comparing Short-Term Treatment With Long-Term Treatment

From the Fédération Nationale des Centres de Lutte Contre le Cancer, Paris, France.

Address reprint requests to Thierry Delozier, MD, Centre François Baclesse, Route de Lion Sur Mer, 14076 Caen Cedex, France; email t.delozier{at}baclesse.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: In 1986, The Fédération Nationale des Centres de Lutte Contre le Cancer Breast Group initiated a multicenter randomized trial to assess the usefulness of long-term adjuvant tamoxifen treatment. Short-term adjuvant tamoxifen treatment was to be compared with lifelong adjuvant tamoxifen treatment.

PATIENTS AND METHODS: Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen treatment were eligible for the trial. From September 1986 to May 1995, 3,793 patients were randomized from France, Belgium, and Argentina. A total of 1,882 patients stopped tamoxifen (short-term group), and 1,911 patients were to continue tamoxifen for life (long-term group) at the same dose as previously prescribed. The protocol was modified in February 1997, limiting tamoxifen treatment to 10 years after randomization, thus giving a comparison between a 2- to 3-year treatment and a 12- to 13-year treatment. To date, the median duration of tamoxifen treatment is 30 months in the short-term group, and 70 months in the long-term group.

RESULTS: Overall, longer tamoxifen treatment induced a 23% reduction in relapse rates, leading to a 7-year disease-free survival rate of 78%, compared with 72% in the shorter-treatment group. In contrast, overall survival did not differ between the two groups, with a 79% overall survival rate in both groups. This improvement in disease-free survival could be observed in node-positive patients (P = .001); however, it was not found in node-negative patients. Prolonged tamoxifen treatment corresponded to a significant increase in disease-free survival in estrogen receptor–positive patients (P = .03) as well as in estrogen receptor–negative patients (P = .05). Furthermore, longer treatment reduced contralateral breast cancers and did not increase the number of endometrial cancers.

CONCLUSION: : Although no survival advantage was noted, patients did benefit from longer tamoxifen treatment over 3 years and had significantly better disease-free survival compared with patients who stopped hormonal treatment. Long-term follow-up is needed to assess these results. Most patients in the long-term group are still receiving treatment. Comparison of results as time passes will enable conclusions to be made on the value of long-term treatment over 5 years compared with 2 to 3 years.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE NEED FOR adjuvant treatment in early breast cancer is now well established. Although tamoxifen has become the reference hormone treatment in this indication, some questions concerning its use remain: should its use be restricted to positive hormone receptor tumors? Should it be prescribed in node-negative tumors? From what age should it be administered? How important are the long-term toxicity and, in particular, the risk of second cancer? Finally, the question of optimal adjuvant treatment duration remains unanswered.

In 1990, the first Early Breast Cancer Trialists’ Collaborative Groups worldwide overview was published.¹ It combined the quasitotality of a breast cancer adjuvant trial and confirmed the efficacy of tamoxifen, indicating a (mean ± SD) 30% ± 2% reduction in recurrences and a 16% ± 3% reduction in mortality. Indirect comparisons suggested that 2 or more years of tamoxifen might be more effective than treatment of 1 year or less. The last overview, based on 1995 collected data, gives similar findings²: a highly significant increase in treatment effect was noted in trials with longer-term tamoxifen treatment. In all cases, the treatment never exceeded 5 years. These results were also based on indirect comparisons among different clinical trials.

In 1986, Fédération Nationale des Centres de Lutte Contre le Cancer Breast Group decided to launch a multicenter study on adjuvant treatment duration. The study’s primary objective was to assess the effects of treatment duration on relapse and mortality in early breast cancer. Secondary objectives were to research the prognostic factors linked to possible long-term treatment benefits and to assess long-term treatment toxicity.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The study compared two tamoxifen duration regimens in early breast cancer.

Patients
Early breast cancer patients up to 75 years old undergoing tamoxifen adjuvant treatment for at least 2 and up to 3 years were eligible for the study, on the condition that no evidence of local-regional or distant recurrence was present at the time of inclusion. Various primary therapies (surgery, radiotherapy, and chemotherapy) were allowed, as long as the patient no longer presented evolving cancer at treatment’s end. The indication and the tamoxifen dose could vary from institution to institution. Estrogen receptor (ER) status was determined in 2,791 patients. Most laboratories underwent quality-control checks (European Organization for Research and Treatment of Cancer quality control). ER positivity was defined as an ER level 10 fmol/mg cytosol protein; 2,435 patients were found to be ER-positive. All tumors with ER levels less than 10 fmol/mg cytosol protein were defined as ER-negative. The 356 patients classified as ER- included those with ER- tumors and those with ER- poor tumors.

Randomization
Patients were randomized by telephone during patient status visits. Patients were stratified according to center. The population was thus divided into two treatment groups. In the first group, tamoxifen was immediately stopped (3-year treatment group); in the second group, patients were advised to continue tamoxifen at the same dose, for life. In February 1997, after publication of several reports on the toxicity of this therapy, the protocol was amended. Consequently, long-term tamoxifen treatment was limited to 10 years after randomization. The present study, therefore, involved the comparison of two groups, a short-term group, ie, patients who had undergone treatment for 2 to 3 years, and a long-term group, ie, patients continued tamoxifen for a further 10 years. The protocol was approved by the Caen Committee for the Protection of Persons in Biomedical Research.

Statistical Analysis
The disease-free interval was defined as the time elapsed between inclusion and relapse. Considered as proof of relapse were local or regional recurrence, metastases, and death preceding one of the former events. Second primary cancers, including contralateral breast cancers, were not considered as proof of relapse. Survival was defined as the time elapsed between inclusion and death, regardless of its cause. In April 1997, all existing data were updated. An intent-to-treat analysis was carried out. Probabilities of overall survival and disease-free survival were calculated using the Kaplan-Meier method, and comparisons were carried out using the log-rank test.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Between September 1986 and May 1995, 3,793 patients were randomized by 18 French, one European, and one American comprehensive cancer center; 1,882 patients were randomized to the short-term group, and 1,911 were randomized to the long-term group. Due to the presence of metastases detected before inclusion, 19 patients in the short-term group and 17 in the long-term group were excluded.

Population
Population characteristics, such as age, tumor features (node invasion, ERs), and primary treatment (type of surgery, adjuvant chemotherapy), were well balanced between the two arms (Table 1). Daily doses of tamoxifen ranged from 20 to 40 mg, except in three cases in which two patients received 10 mg and one patient received 70 mg (Table 2). The median short- and long-term group follow-up, from randomization, was 49 and 48 months, respectively. In April 1997, the median duration of tamoxifen treatment was 30 months in the short-term group and 70 months in the long-term group.

View larger version (11K): [in this window] [in a new window]   Fig 1. Survival and disease-free survival through 8 years after randomization, according to treatment group.

View larger version (11K): [in this window] [in a new window]   Fig 2. Disease-free survival through 8 years after randomization, according to treatment group, in node-negative (N- and node-positive (N+) patients.

View larger version (11K): [in this window] [in a new window]   Fig 3. Disease-free survival through 8 years after randomization, according to treatment group, in ER-negative (ER-) and ER-positive (ER+) patients.

Dose Effect
Of the 1,718 patients who received 20 mg of tamoxifen daily at randomization, 234 patients relapsed: 123 in the short-term group and 111 in the long-term group. Of the 1,339 patients who received 30 mg of tamoxifen daily at randomization, 271 relapsed: 151 and 120, respectively. Finally, of the 616 patients who received 40 mg of tamoxifen daily, 107 experienced recurrence: 62 and 45, respectively. Respective 7-year disease-free survival probabilities were as follows for the short- and long-term groups: 74% and 77% at 20 mg/d (P = .35), 70% and 78% at 30 mg/d (P = .004), and 73% and 80% at 40 mg/d (P = .16).

Second Cancers
Overall, 211 second cancers were detected during follow-up: 104 in the short-term group and 97 in the long-term group. There was no increase in the number of endometrial cancers in the prolonged-treatment group (13 and 12 cancers were recorded in both groups). Twenty-seven contralateral breast cancers were detected in the long-term group compared with 44 in the short-term group. This difference was statistically significant (P < .02).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Discussion of our results should take into consideration results from prior studies that directly compared different durations of tamoxifen treatment. In five studies, the shorter treatment duration was more than 1 year. Two of them compared 5-year tamoxifen treatment with 2-year treatment. The design of these studies was very close to the present statement of our trial. Three trials assessed the efficacy of maintaining tamoxifen treatment beyond 5 years.

The Swedish study³ compared 2 and 5 years of adjuvant tamoxifen for postmenopausal women. The population (3,545 patients) included 51% node-positive patients. The ER status was known in 77% of cases and was positive in 81% of these cases. The median follow-up time was 3.5 years. At the current stage in our study, in which median duration of treatment is 30 and 70 months in the two groups, the similarity with the Swedish study is notable.

In the Cancer Research Campaign trial,⁴ 2,937 patients who had completed an initial 2-year course of tamoxifen after primary surgery were allocated to stop or to continue for an additional 3-year period of tamoxifen treatment. This pragmatic trial allowed flexibility in primary treatment and adjuvant therapy other than tamoxifen (radiotherapy and chemotherapy). The median follow-up after randomization was 2 years.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) study⁵ compared 5 years of treatment with more than 5 years of treatment in node-negative and ER+ patients. This study is in fact a second randomization of disease-free patients who had been treated with tamoxifen for 5 years in an earlier study, the B-14 trial. In the longer-treatment arm, the intended duration was to be 10 years; however, after interim analyses that failed to show superiority of longer treatment, the trial was stopped on November 30, 1995. Interim analysis and additional computations indicated that the rate of failure in patients from whom tamoxifen was withdrawn after 5 years was markedly lower than that in patients who continued tamoxifen. Local, regional, or distant recurrences were observed in 12 patients in the placebo group and 26 in the tamoxifen group. The median duration of treatment in the over-5-years arm was not specified. The mean follow-up period was 48 months after the second randomization.

In the Scottish tamoxifen trial,⁵ 1,323 women were randomly allocated to receive adjuvant tamoxifen for 5 years or to a control group without adjuvant tamoxifen. After 1984, consenting disease-free women in the study arm were offered further randomization at 5 years to continue or to stop tamoxifen. Thus, 169 patients were selected to stop tamoxifen and 173 to continue. The median duration of tamoxifen therapy was 60 and 128 months in the two groups.

The Eastern Cooperative Oncology Group performed a randomized trial to assess the efficacy of maintaining tamoxifen therapy beyond 5 years in women with node-positive breast cancer.⁷ All of the 194 randomized patients had been treated with surgery followed by 1 year of chemotherapy. Median follow-up was 5.6 years after randomization.

With regard to overall population, our study showed a significant increase in disease-free survival with prolonged adjuvant tamoxifen over 30 months (P = .0023): it indicates a 23% reduction in the odds of relapse. This improvement in disease-free survival was not associated with a significant improvement in overall survival.

The Swedish study³ indicated an 18% relative reduction of first event with the longer treatment, with a corresponding relative reduction in deaths. The Cancer Research Campaign trial⁴ demonstrated a difference in event-free survival in favor of the 5-year group, which is of borderline significance (P = .03), and no significant difference in overall survival. Both of these large trials included node-positive and node-negative patients. In each trial, adjuvant chemotherapy was given in some cases.

Conversely, no trial that assessed prolongation of therapy after 5 years showed any benefit in disease-free or overall survival. Furthermore, the NSABP trial,⁵ in a large node-negative population, pointed out a significant advantage in disease-free survival for patients who discontinued tamoxifen treatment, and the Scottish trial⁶ showed a nonsignificantly greater number of relapses in patients who continued tamoxifen. In the Eastern Cooperative Oncology Group trial,⁷ no significant differences were observed in relapse-free or overall survival.

In the Swedish trial,³ there were no statistically significant differences in the relative hazards between the nodal subgroups for any of the study end points. In our trial, the increase in disease-free survival was statistically significant in patients with nodal involvement (relative risk, 0.79; 95% confidence interval, 0.65 to 0.96). This increase in disease-free survival was not significant in node-negative patients (relative risk, 0.84; 95% confidence interval, 0.54 to 1.30); however, no interaction was found between treatment group and nodal status (P = .23). Nevertheless, no firm conclusion can be made from these results because of the small number of events in the node-negative group. In this population, further follow-up is needed to evaluate the impact of longer adjuvant tamoxifen treatment.

ERs represent an important factor for assessing the efficacy of hormonal treatment. Several studies have shown that a relationship exists between the benefits of tamoxifen adjuvant treatment and ERs.^8-11 Others have shown benefits related to treatment in patients with ER-negative tumors.^12,13 The Swedish study did not find a reduction in recurrence with longer treatment in ER-negative patients. In our study, prolonged tamoxifen treatment corresponded to a significant increase in disease-free survival in ER+ patients (relative risk, 0.79; 95% confidence interval, 0.64 to 0.98) as well as in ER- patients. In fact, the so-called ER-negative population could include tumors with low but detectable ER (3 to 10 fmol/mg cytosol protein), which can be sensitive to tamoxifen. The high cutoff level could partially explain our results. Do those patients with less sensitive tumors need longer treatment, or are our results just a play of chance?

Currently, the median duration of treatment in our long-term group is 70 months, which does not yet permit evaluation of tamoxifen effects beyond 5 years. The NSABP trial examines, in particular, the results of treatment lasting more than 5 years. These results show that of 583 ER+ and node-negative long-term treatment patients, 66 had recurrence in the following 4 years. In those who had stopped tamoxifen, only 36 presented with recurrence (P = .003). The data included only node-negative patient results. Combined data from both node-negative and node-positive groups will be needed before optimal treatment duration can be determined.

In conclusion, our initial results confirm the need to pursue tamoxifen treatment beyond 3 years, at least in node-positive patients. The interest in pursuing longer treatment is warranted for ER+ tumors. Continuing tamoxifen beyond 3 years does not increase the risk of endometrial cancer and does significantly reduce the risk of contralateral breast cancer. Currently available data do not allow us to predict future results. The majority of patients in the long-term group are still receiving treatment, and tamoxifen effects may become stronger or weaker over time. Comparison of results in the future will enable conclusions to be made on the value of long-term treatment (more than 5 years). Comparison with the Swedish study, in which tamoxifen treatment is of fixed duration of 2 and 5 years, may prove to be particularly interesting.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

2. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351: 1451-1467, 1998[Medline]

3. 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]

4. 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]

5. Fisher B, Dignam J, Bryant J, et al: Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 88: 1529-1542, 1996[Abstract/Free Full Text]

6. Stewart HJ, Forrest AP, Everington D, et al: Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer: The Scottish Cancer Trials Breast Group. Br J Cancer 74: 297-299, 1996[Medline]

7. Tormey D, Gray R, Falkson H: Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. J Natl Cancer Inst 88: 1828-1833, 1996[Abstract/Free Full Text]

8. 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]

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

10. 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]

11. Delozier T, Julien JP, Juret P, et al: Adjuvant tamoxifen in postmenopausal breast cancer: Preliminary results of a randomized trial. Breast Cancer Res Treat 7: 105-109, 1986[Medline]

12. "Nolvadex" Adjuvant Trial Organisation: Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. Br J Cancer 57: 608-611, 1988[Medline]

13. Adjuvant tamoxifen in the management of operable breast cancer: The Scottish Trial—Report from the Breast Cancer Trials Committee, Scottish Cancer Trials Office (MRC). Edinburgh, Lancet 2: 171-175, 1987

Submitted October 13, 1998; accepted September 19, 2000.

This article has been cited by other articles:

				K. L. Kahn Moving Research From Bench to Bedside to Community: There Is Still More to Do J. Clin. Oncol., February 1, 2008; 26(4): 523 - 526. [Full Text] [PDF]

				C. Alliot Weekly Epirubicin Plus Tamoxifen Versus Tamoxifen Alone As Adjuvant Treatment of Operable, Node-Positive, Elderly Breast Cancer Patients J. Clin. Oncol., June 20, 2005; 23(18): 4237 - 4238. [Full Text] [PDF]

				M. Sacco, M. Valentini, M. Belfiglio, F. Pellegrini, G. De Berardis, M. Franciosi, and A. Nicolucci 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 J. Clin. Oncol., June 15, 2003; 21(12): 2276 - 2281. [Abstract] [Full Text] [PDF]

				R. Arriagada, M. Spielmann, S. Koscielny, T. Le Chevalier, T. Delozier, M. Ducourtieux, T. Tursz, and C. Hill Patterns of failure in a randomized trial of adjuvant chemotherapy in postmenopausal patients with early breast cancer treated with tamoxifen Ann. Onc., September 1, 2002; 13(9): 1378 - 1386. [Abstract] [Full Text] [PDF]

				J. Bryant, B. Fisher, and J. Dignam Duration of Adjuvant Tamoxifen Therapy J Natl Cancer Inst Monographs, December 1, 2001; 2001(30): 56 - 61. [Abstract] [Full Text] [PDF]

				J. S. Abrams Tamoxifen: Five Versus Ten Years--Is the End in Sight? J Natl Cancer Inst, May 2, 2001; 93(9): 662 - 664. [Full Text] [PDF]

				B. Fisher, J. Dignam, J. Bryant, and N. Wolmark Five Versus More Than Five Years of Tamoxifen for Lymph Node-Negative Breast Cancer: Updated Findings From the National Surgical Adjuvant Breast and Bowel Project B-14 Randomized Trial J Natl Cancer Inst, May 2, 2001; 93(9): 684 - 690. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Delozier, T. Articles by Namer, M. Search for Related Content PubMed PubMed Citation Articles by Delozier, T. Articles by Namer, M.