A Better Tamoxifen?

Summarized by Robert W. Griffith, MD
December 19, 2001 (Reviewed: December 5, 2003)

Introduction

Endocrine therapy is at least as successful as cytostatic drugs in the treatment of hormone-sensitive advanced breast cancer, and it's much better tolerated. Tamoxifen is the current drug of choice, being equally effective as the non-specific aromatase inhibitor aminoglutethamide, and the progestins; however, it has fewer side effects. Response rates between 30% and 45% can be expected.

Aromatase inhibitors that are even more specific have been developed. One of them, anastrozole, has been shown to produce similar response rates to tamoxifen in two comparative studies. Another, letrozole, has recently been reported to be significantly superior to tamoxifen. The results of a large comparative study, reported in the Journal of Clinical Oncology, are summarized here.

Method

This was a randomized, double-blind, study conducted at 201 centers in 29 countries. Patients were assigned to receive either letrozole 2.5 mg once daily or tamoxifen 20 mg once daily, until disease progression. After disease progression (or discontinuation for any reason) patients could be crossed-over to the alternative treatment.

Patients had to be postmenopausal with locally advanced, locoregionally recurrent, or metastatic breast carcinoma. Tumors had to be estrogen receptor- and/or progesterone receptor-positive tumors, or the status of both receptors was unknown. One prior treatment regimen of chemotherapy for advanced disease was allowed, provided there was evidence of disease progression within 3 months of enrollment. Exclusion criteria included CNS metastases, pulmonary carcinomatosis, metastases involving more than 1/3 of the liver, and inflammatory breast cancer.

The primary efficacy endpoint was time to progression (TTP) -- the interval between the date of randomization and the earliest date of disease progression, as defined by an increase of 25% in measurable lesions or assessable disease, the appearance of new lesions, discontinuation due to clinical deterioration, or death. Secondary endpoints included overall objective tumor response rate (ORR), rate/duration of clinical benefit, time to treatment failure (TTF), time to response (TTR), number of deaths, overall survival, and tolerability.

Results

A total of 939 patients were enrolled, and of these 907 were entered into the intent-to-treat population (453 letrozole, 454 tamoxifen). At entry 93% of them had metastatic disease -- soft tissues in 62%, bone in 52%, liver in 12.5%. At the cutoff date (March 2000) the median duration of the study was 18 months.

The TTP was significantly greater for letrozole patients than for those on tamoxifen; medians of 41 and 26 weeks, respectively (p=0.001). The TTF showed virtually the same results; medians of 40 and 25 weeks (p=0.001).

The ORR was significantly greater for letrozole (30%) than for tamoxifen (20%, p=0.0006), as was the rate of clinical benefit (letrozole 49% vs. 38%, p=0.001). There was no difference in the durations of overall response or clinical benefit between the letrozole and tamoxifen groups. The TTR did not differ between the two treatment groups.

Multivariate analyses of TTP and ORR, with adjustments for baseline receptor status, prior adjuvant anti-estrogen treatment, and dominant disease site, revealed no relevant differences in the results.

Most patients reported at least one adverse effect of treatment during the trial period, but they were of similar nature and frequency in both treatment groups. The commonest were hot flushes, nausea, and hair thinning. Drug discontinuations due to an adverse event, consent withdrawal, or death, were the same in each group (7%).

Comment

In this study letrozole was clearly more effective than the established first-line endocrine therapy for advanced breast cancer, tamoxifen. This was the case even in the 1/3 of patients in whom the endocrine status of the tumors was unknown. On the other hand, the safety and tolerability of the two drugs was similar, making letrozole an obvious new choice for first-line treatment. The greater efficacy of letrozole shown in this study is supported by the results of an earlier comparison of the two compounds used as primary treatment in a pre-operative setting.¹

It must be noted that the response rate for tamoxifen (20%) was lower in this study than that reported in the literature for this compound. This is possibly because of the extremely strict criteria for response that were used in this study.

Source

• Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer. H. Mouridsen, M. Gershanovich, Y. Sun,  et al., J Clin Oncology, 2001, vol. 19, pp. 2596--2606

Footnotes
1. Neo-adjuvant treatment of post-menopausal breast cancer patients with letrozole (Femara); a randomized multicenter study versus tamoxifen. Abstract. S. Paepke, J. Apffelstaedt, J. Eremin,  et al., Eur J Cancer, 2000, vol. 36(Suppl 5)

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