EDITORIAL

Tamoxifen: Five Versus Ten Years—Is the End in Sight?

Jeffrey S. Abrams

Affiliation of author: Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.

Correspondence to: Jeffrey S. Abrams, M.D., National Institutes of Health, 6130 Executive Blvd., EPN 7040, Bethesda, MD 20892 (e-mail: abramsj{at}ctep.nci.nih.gov).

This issue of the Journal updates a truly seminal study, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 (1). For students of history, few clinical trials provide as many valuable lessons as B-14 does with regard to both hormone-responsive breast cancer treatment and clinical trials methodology. Initiated in 1981, it was the first placebo-controlled trial performed by the NSABP. A total of 2892 women with lymph node-negative, estrogen receptor (ER)-positive tumors were enrolled. By 1988, initial results indicated a disease-free survival (DFS) benefit for tamoxifen in this subset of women (2). More important, premenopausal and postmenopausal women benefited equally from tamoxifen in B-14, contrary to the predominant belief at the time that only postmenopausal women should receive adjuvant tamoxifen (3). The findings led to the issuance by the National Cancer Institute (NCI) (Bethesda, MD) of a clinical alert (4), with the result that tamoxifen rapidly increased in use in the United States in the large subset of women with lymph node-negative breast cancer (5).

Tamoxifen's success in patients with invasive cancer at low risk of recurrence permitted investigators to stretch the boundaries of hormonal intervention. The observation, in B-14 and in other randomized trials (6), that tamoxifen decreased the incidence of contralateral breast cancers by almost half was quickly seized on by enthusiasts of chemoprevention. Before large prevention trials could be reasonably undertaken, long-term toxicity information on tamoxifen was required. B-14 provided the requisite vanguard toxicity data, allowing investigators to dare to explore the role of tamoxifen in women at even less risk, such as those with very small invasive tumors, those with noninvasive in situ carcinomas, and, ultimately, those with multiple risk factors but without breast cancer.

As the indications for tamoxifen increased, the optimal duration of administration became a pressing question. Successive adjuvant trials indicated that 2 years of tamoxifen treatment was better than 1 year (7), and the B-14 results were consistent with 5 years being better still. Recent results (6) from randomized comparisons of 2 versus 5 years of tamoxifen have indeed confirmed this observation. By performing a second randomization in B-14 limited to the subset of patients (n = 1166) who were disease free after completing 5 years of tamoxifen, NSABP investigators attempted to answer whether 10 years of therapy was better than 5 years.

However, in 1993, before results from the second randomization became available, 25 patients on B-14 were found to have endometrial cancer. In six of these patients, endometrial cancer was presumed to be the cause of death. Fisher et al. (8) published evidence that tamoxifen resulted in a twofold to threefold increase in endometrial cancer. This increase translated to one or two cases annually per 1000 patients treated with tamoxifen. Although this serious side effect had been noted several years earlier, B-14's large sample size, the precise estimates of risk obtainable from its placebo-controlled design, and the initiation by the NSABP of a prevention trial using tamoxifen (BCPT-1) in 1992 all coincided to heighten concern (9). Congressional hearings were held, and press coverage was extensive. Appropriately, the U.S. Food and Drug Administration (Rockville, MD) added the possibility of death from endometrial cancer to the tamoxifen drug label, and the NCI modified consent forms for all patients receiving the drug in its trials. The different roles for tamoxifen in treatment and prevention exacerbated the confusion at the time. However, as recently reiterated at the National Institutes of Health (NIH) Consensus Development Conference on Adjuvant Therapy for Breast Cancer (10), the improvement in survival obtained with tamoxifen in invasive breast cancer far outweighs the risks from endometrial cancer and other toxic effects. Additionally, contrary to some fears at the time, studies [reviewed in (11)] have now shown that tamoxifen-associated endometrial cancer is not more aggressive than de novo disease and is often curable by surgery alone.

The B-14 trial was back in the news again in 1995. The independent Data and Safety Monitoring Committee (DSMC) decided to release the results from the second randomization earlier than projected. The DSMC alone is entrusted with viewing unblinded data and making recommendations to the study leadership in all NCI-sponsored phase III trials. As detailed by the NSABP (12,13), the DSMC decision to unblind the study relied primarily on two factors: 1) There was a high statistical likelihood that prolonged tamoxifen would not be beneficial, even if the study was continued to the time of the planned, final analysis, and 2) patients on the prolonged tamoxifen arm had more breast cancer recurrences and endometrial cancers. The only other trial with available results in 1995 regarding this issue was the Scottish Adjuvant Tamoxifen Trial (14). Although similar in design to that of B-14, this trial was smaller (only 342 patients were randomly assigned to stop tamoxifen or to continue until relapse), and patients with lymph node-positive as well as lymph node-negative tumors were included. It too showed a small disadvantage for the prolonged tamoxifen arm at the time. The sum of these data convinced the NCI to release a clinical announcement in November 1995 (15) that recommended limiting adjuvant treatment with tamoxifen to 5 years in routine practice. This recommendation was not without its detractors, who argued that the number of recurrences at the time was too small (56 versus 32 events) to draw definitive conclusions (16).

Additional information on tamoxifen duration soon became available. The Eastern Cooperative Oncology Group (17) published results from a small randomized trial (194 patients) in which patients with lymph node-positive tumors were randomly assigned either to stop tamoxifen after 5 years or to continue tamoxifen until relapse. Fifty-three patients had ER-negative tumors, making the relevant study sample even smaller. No survival advantage was noted for the prolonged therapy, although a subset analysis in those with ER-positive disease for time to relapse did favor prolonged therapy. A French trial (18) compared 2–3 years with 10 years of tamoxifen. The longer therapy demonstrated an improved disease-free survival. However, the median duration of prolonged treatment, thus far, in this trial is only 6 years. An updated analysis of the Scottish trial (19), through 15 years of follow-up, was published recently. No advantage was seen for the group who continued to receive tamoxifen (median duration, 163 months) compared with the group who stopped at 5 years.

In view of the relative paucity of randomized data comparing 5 years of tamoxifen with more prolonged durations, B-14 results updated through 7 years of follow-up, as presented by Fisher et al. (1) in this issue of the Journal, take on increasing importance. The new results continue to indicate that stopping treatment at 5 years, as opposed to continuing (for about 8 years), results in a small but statistically significant benefit in DFS and in a trend favoring overall survival. Overall, more local and distant recurrences have occurred in those who continued tamoxifen. In addition, the incidence of endometrial cancer, albeit small, is double in the group continuing tamoxifen compared with those stopping: 12 women (2.1%) versus six women (1.1%).

At the recent NIH Consensus Development Conference, representatives from the Early Breast Cancer Trialists' Collaborative Group argued that the survival benefit from 5 years of tamoxifen therapy, rather than remaining constant, continues to increase during the next 5 years (carryover effect), despite the drug being stopped. The carryover effect would be expected to minimize differences between the two arms of B-14 during the first 5 years of follow-up. An advantage for prolonged therapy, they reasoned, might be expected to emerge after 10–15 years of follow-up. Supporting this viewpoint, more recurrences did occur in the placebo group (n = 16) than in the tamoxifen group (n = 11) in B-14 when only recurrences diagnosed more than 6 years after randomization were examined. However, as Fisher et al. (1) contend, the carryover effect does not explain the benefit observed for those who stopped tamoxifen during the initial 5 years of follow-up. A hormone withdrawal (rebound effect) is more consistent with the low recurrence rate observed in the placebo arm during the first 5 years of follow-up.

Another interesting finding in B-14 concerns the incidence of contralateral breast cancers. No difference in incidence occurred between the two groups after the second randomization. Given the striking reduction in contralateral breast cancers seen with tamoxifen during the first 5 years of treatment in this study, a continued preventive effect with prolonged therapy was anticipated. Might it be that tamoxifen only protects against the development of pre-existing, occult tumors likely to appear in the first 5 years, rather than preventing the actual carcinogenic process itself? Alternatively, a rebound effect from tamoxifen withdrawal or a carryover effect might minimize differences during years 5–10 after randomization, whereas differences could possibly emerge with more prolonged follow-up.

The debate over the optimal duration of tamoxifen will undoubtedly persist until and unless additional data can clarify this issue. Results of two ongoing European-led trials are not anticipated for several years (20). Further follow-up of B-14 has shown, however, that the DSMC decision in 1995 was not premature. It remains improbable that B-14 will ever show a statistically significant advantage for continuing tamoxifen beyond 5 years. This view doesn't preclude the possibility that larger trials, especially in women at higher risk (lymph node-positive patients), could show a benefit for longer durations. However, the evidence to date from trials testing duration suggests that, for routine practice, tamoxifen treatment should be limited to 5 years. Perhaps the more relevant question for future research is the optimal choice of hormone therapy in premenopausal and postmenopausal women. Third-generation aromatase inhibitors (anastrozole, exemestane, and letrozole) are challenging tamoxifen's supremacy in postmenopausal women (21). Two large studies, NSABP B-33 and MA-17 (a Canadian-led multinational trial), are testing the advantage of adding exemestane or letrozole, respectively, after 5 years of adjuvant tamoxifen in postmenopausal women. For premenopausal women, ovarian ablation may become a critical component of therapy (22). These new approaches may some day render the tamoxifen duration issue moot, but the role of tamoxifen in improving survival of women worldwide with breast cancer is undisputed.

REFERENCES

1 Fisher B, Dignam J, Bryant J, Wolmark N. 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 2001;93:684–90.[Abstract/Free Full Text]

2 Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 1989;320:479–84.[Abstract]

3 Consensus conference. Adjuvant chemotherapy for breast cancer. JAMA 1985;254:3461–3.[Abstract]

4 Clinical Alert from the National Cancer Institute, May 18, 1988; reprinted in Breast Cancer Res Treat 1988;12:3–5.

5 Johnson TP, Ford L, Warnecke RB, Nayfield SG, Kaluzny G, Cutter G, et al. Effect of a National Cancer Institute Clinical Alert on breast cancer practice patterns. J Clin Oncol 1994;12:1783–8.[Abstract]

6 Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998;351:1451–67.[Medline]

7 Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992;339:71–85.[Medline]

8 Fisher B, Costantino J, Redmond CK, Fisher ER, Wickerham DL, Cronin WM. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994;86:527–37.[Abstract]

9 Friedman MA, Trimble EL, Abrams JS. Tamoxifen: trials, tribulations, and trade-offs [editorial]. J Natl Cancer Inst 1994;86:478–9.[Medline]

10 National Institutes of Health Consensus Development Conference Statement: Adjuvant therapy for breast cancer. November 1–3, 2000. http://consensus.nih.gov/.

11 Carlson RW. Scientific review of tamoxifen. Overview from a medical oncologist. Semin Oncol 1997;24(1 Suppl 1):S1–151–S1–57.[Medline]

12 Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, 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 1996;88:1529–42.[Abstract/Free Full Text]

13 Dignam JJ, Bryant J, Wieand HS, Fisher B, Wolmark N. Early stopping of a clinical trial when there is evidence of no treatment benefit: protocol B-14 of the National Surgical Adjuvant Breast and Bowel Project. Control Clin Trials 1998;19:575–88.[Medline]

14 Stewart HJ, Forrest AP, Everington D, McDonald CC, Dewar JA, Hawkins RA, 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 1996;74:297–9.[Medline]

15 National Cancer Institute Clinical Announcement: Adjuvant therapy of breast cancer—tamoxifen update. Bethesda (MD): National Institutes of Health, November 30, 1995.

16 Peto R. Five years of tamoxifen—or more? [editorial]. J Natl Cancer Inst 1996;88:1791–3.[Free Full Text]

17 Tormey DC, Gray R, Falkson HC. Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst 1996;88:1828–33.[Abstract/Free Full Text]

18 Delozier T, Spielmann M, Mace-Lesec'h J, Janvier M, Hill C, Asselain B, et al. Tamoxifen adjuvant treatment duration in early breast cancer: initial results of a randomized study comparing short-term treatment with long-term treatment. Federation Nationale des Centres de Lutte Contre le Cancer Breast Group. J Clin Oncol 2000;18:3507–12.[Abstract/Free Full Text]

19 Stewart HJ, Prescott RJ, Forrest PM. Scottish Adjuvant Tamoxifen Trial: a randomized study updated to 15 years. J Natl Cancer Inst 2001;93:456–62.[Abstract/Free Full Text]

20 Earl H, Gray R, Kerr D, Lee M. The optimal duration of adjuvant tamoxifen treatment for breast cancer remains uncertain: randomize into aTTom. Clin Oncol (R Coll Radiol) 1997;9:141–3.

21 Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, et al. Anastrozole is superior to tamoxifen in first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 2000;18:3758–67.[Abstract/Free Full Text]

22 Klijn JG, Beex LV, Mauriac L, van Zijl JA, Veyret C, Wildiers J, et al. Combined treatment with buserelin and tamoxifen in premenopausal meta-static breast cancer: a randomized study. J Natl Cancer Inst 2000;92:903–11.[Abstract/Free Full Text]


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