CORRESPONDENCE

RESPONSE: Re: Combined Treatment With Buserelin and Tamoxifen in Premenopausal Metastatic Breast Cancer: a Randomized Study

Jan G. M. Klijn, Luc Duchateau

Affiliation of authors: Department of Medical Oncology, Rotterdam Cancer Institute (Dr. Daniel den Hoed Kliniek), University Hospital Rotterdam, The Netherlands.

Correspondence to: Jan G. M. Klijn, M.D., Ph.D., Department of Medical Oncology, Rotterdam Cancer Institute, University Hospital Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.

In his correspondence, Powles wonders why an increased rate of response during combined endocrine therapy in both of our trials was followed by statistically significantly improved survival in our European Organization for Research on Treatment of Cancer study (1), but not in his study (2), when compared with single tamoxifen treatment. Indeed, both trials are "similar" with respect to one of the main objectives of the studies (i.e., testing the hypothesis that combining estrogen deprivation with estrogen receptor [ER] blockade is clinically superior to ER blockade by tamoxifen alone). However, there are many differences between the two trials, such as menopausal and associated endocrine status, duration of follow-up, distribution of steroid receptor subgroups, pretreatment, doses of tamoxifen, and pharmacologic interaction between the different agents combined.

In our study, tamoxifen strongly increased plasma estradiol levels in premenopausal patients in contrast to what happens in postmenopausal women, as shown in the study by Powles et al. (2). In this respect, we disagree with the statement of Dr. Davidson in her excellent editorial (3) that our study suggests that the divergent effects of tamoxifen and the luteinizing hormone-releasing hormone (LHRH) agonist buserelin on the level of serum 17{beta}-estradiol are not clinically significant because there was no major difference in clinical outcomes for the tamoxifen or buserelin groups. We think that the strongly increased estradiol levels induced by tamoxifen indeed had a deleterious effect by competition with tamoxifen for the binding to ER and that, consequently, estrogen suppression by adding buserelin to tamoxifen treatment (resulting in postmenopausal estrogen levels) statistically significantly increased the antitumor efficacy of tamoxifen as shown by our data.

Furthermore, the median follow-up in the study by Powles et al., performed from September 1979 through June 1983, is, according to our estimation, around 2 years in contrast to 7.3 years in our study. Therefore, the number of events with respect to death rate (not reported in their publication) might be too low to test with adequate power for a difference in overall survival.

In our study, all of the patients had steroid receptor-positive tumors (72%) or receptor-unknown tumors, with a disease-free interval of 2 years or longer (28%). In contrast, in the study by Powles et al., 142 patients (64%) had an unknown ER status, and 22 (28%) of the 80 patients with a known receptor status were ER negative. Therefore, a large proportion of patients with ER-negative tumors may have "diluted" their study with hormone-resistant breast cancers affecting survival.

Finally, it is reported that aminoglutethimide plus hydrocortisone (AG + H) used by Powles et al. in their combination treatment decreases serum concentrations of tamoxifen (3.7 times) and its hydroxylated metabolites that have high ER affinity (two to 15 times), and the dose used in the study by Powles et al. (20 mg) was already half of that (40 mg) in our study. In addition, these alterations in tamoxifen metabolism induced by aminoglutethimide may increase the amount of estrogen agonists at the expense of estrogen antagonists (4). This pharmacologic interaction may be one of the explanations for the reported lack of an additive effect of tamoxifen and AG + H (46). In view of the fact that the modern selective aromatase inhibitors do not affect plasma tamoxifen concentrations (6), it will be very interesting to see the results of the ongoing ATAC trial comparing the efficacy of the combination of anastrozole plus tamoxifen versus that of each drug alone.

The problem of crossover was already discussed in our article (1). In the study by Powles et al. there were many patients (i.e., 43 [47%] of the 92 patients who stopped receiving tamoxifen) also unsuitable for crossover or for further endocrine therapy. Finally, we stress that the recent meta-analysis (7) of four randomized trials on combined tamoxifen and LHRH–agonist treatment based on 506 premenopausal patients with advanced breast cancer showed that combined treatment was indeed statistically significantly superior to single LHRH–agonist treatment with respect to all three efficacy parameters (i.e., response rate—progression free, survival, and overall survival).

REFERENCES

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

2 Powles TJ, Ashley S, Ford HT, Gazet JC, Nash AG, Neville AM, et al. Treatment of disseminated breast cancer with tamoxifen, aminoglutethimide, hydrocortisone, and danazol, used in combination or sequentially. Lancet 1984;1:1369–73.[Medline]

3 Davidson NE. Combined endocrine therapy for breast cancer—new life for an old idea? [editorial]. J Natl Cancer Inst 2000;92:859– 60.[Free Full Text]

4 Lien EA, Anker G, Lonning PE, Solheim E, Ueland PM. Decreased serum concentrations of tamoxifen and its metabolites induced by aminoglutethimide. Cancer Res 1990;50:5851–7.[Abstract]

5 Rose C, Kamby C, Mouridsen HT, Andersson M, Bastholt L Moller KA, et al. Combined endocrine treatment of elderly postmenopausal patients with metastatic breast cancer. A randomized trial of tamoxifen vs. tamoxifen + aminoglutethimide and hydrocortisone and tamoxifen + fluoxymesterone in women above 65 years of age. Breast Cancer Res Treat 2000;61:103–10.[Medline]

6 Dowsett M, Tobias JS, Howell A, Blackman GM, Welch H, King N, et al. The effect of anastrozole on the pharmacokinetics of tamoxifen in post-menopausal women with early breast cancer. Br J Cancer 1999;79:311–5.[Medline]

7 Klijn JG, Blamey RW, Boccardo F, Tominaga T, Duchateau L, Sylvester R. The Combined Hormone Agents Trialists' Group (CHAT) and EORTC. Combined tamoxifen and LHRH-agonist versus LHRH-agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol. In press 2000.



             
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