VIEWS &: REVIEWS

Tamoxifen still hormonal gold standard in metastatic breast cancer

-Roben Carlson-

Thmoxifen ['Nolvadex'] was the first nonsteroidal synthetic antiestrogen agent to establish a place in the treatment of patients with breast cancer. Toremifene ['Fareston'], a relative new kid on the block, is a novel antiestrogen agent with a simllar antitumour effect to tamoxifen in the treatment of advanced breast cancer. However, limited information is available about the use of toremifene as adjuvant therapy for patients with breast cancer. The European and American perspectives on the challenge posed by toremifene to tamoxifen's role as the gold standard therapy for the treatment of patients with breast cancer were outlined at the 20th Annual San Antonio Breast Cancer Symposium [Texas, US; December 1997].

Tamoxifen is still the first-line treatment for metastatic breast cancer in Europe, said Dr Kaija Holli from Tampere University Hospital, Tampere, Finland. Although toremifene is now being used more extensively in patients with breast cancer it is primarily used in tamoxifen-refractory cases. The currently approved aromatase inhibitors, such as anastrozole ['Arimidex'] and letrozole ['Femara'], are also used in patients with refractory disease.

Challenging the status quo Dr Holli is chairperson of the Finnish Breast

Cancer Group, which in 1992 began a trial comparing tamoxifen and toremifene. All 9 Finnish oncology centres are involved in the trial and 1100 women with postmenopausal node-positive breast cancer have been enrolled to date, she said. Participants are randomised to receive oral adjuvant treatment with toremifene 40 mglday or tamoxifen 20 mglday.

The goal of the study is to compare the efficacy and tolerability of the 2 agents after 3 years of treatment in 1460 women. The trial organisers expect to complete patient accrual in late 1998.

An interim data analysis of the first 500 patients, with a mean follow-up period of 18 months, shows no significant differences in efficacy or adverse effects between the 2 hormonal therapies, said Dr Holli.

Additional benefits? Two additional considerations arise when

considering possible alternatives to tamoxifen, said Dr Holli. As well as being an antiestrogen, tamoxifen also has partial estrogen agonist effects on bone and serum lipoproteins. Consequently, tamoxifen therapy helps to maintain bone mineral density and lowers serum LDL-cholesterollevels. The effects on serum LDL-cholesterol may lead to an antiathero­genic action.

Toremifene increases bone density to the same extent as tamoxifen, and perhaps even more, said Dr Holli. It also reduces the serum LDL-cholesterol level to a similar extent as tamoxifen, but has the additional benefit of increasing the serum concen­tration of HDL-cholesterol to a greater extent than tamoxifen, according to results from Finnish adjuvant therapy trials. I

Some cancer concerns On the other hand, tamoxifen's estrogen agonist

effects give it the potential to induce endometrial cancer. This is also a factor to take into account when considering future therapies, added Dr Holli. At the moment, there is no information about any link

between toremifene and endometrial cancer since it has been used for a far shorter time than tamoxifen, she said.

A US perspective In the US, tamoxifen is still the gold standard as

first-line therapy for patients with metastatic breast cancer, according to Professor Charles Vogel from the University of Miami Comprehensive Cancer Center, US, in an interview with Inpharma. The current thrust of research with other anti estrogen agents, including the aromatase inhibitors, is to try and see if any of these are superior to tamoxifen. -

According to Professor Vogel, if toremifene is going to make a major clinical impact, then it would probably have to be at least equivalent to tamoxifen in the adjuvant setting. If this is proved then toremifene could possibly replace tamoxifen in the adjuvant and chemopreventive settings. But, definitive evidence for this will not be available until the ongoing controlled, randomised trials, are completed and the data is analysed, he added.

Low endometrial cancer risk While tamoxifen produces at least some

genotoxicity in animal tumour systems, this has essentially no impact in the metastatic disease setting, because of tamoxifen's tremendous clinical benefits and the very low risk of inducing other tumors, said Professor Vogel. However, these potential adverse effects could be more important when the agent is used in the adjuvant and chemopreventive setting.

Tamoxifen's estrogen agonist effects and consequently it's potential for inducing endometrial cancer are what concern clinicians. But the actual incidence of endometrial cancer in women taking tamoxifen is really quite low, approximately 0.3% over a 10-year period, explained Professor Vogel. This means that the risk to an individual woman receiving tamoxifen is so low that the general recom­mendation is that there should be no preemptive testing other than routine gynaecological examinations and prompt attention to any abnormal uterine bleeding. The routine use of endometrial biopsy sampling or transvaginal ultrasound should be discouraged in tamoxifen recipients, he opined.

Other front runners Two newer challengers for tamoxifen's crown are

the aromatase inhibitors anastrozole and letrozole. Both these drugs inhibit aromatase leading to a selective suppression of estrogen synthesis. In addition, both are devoid of estrogen agonist

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4 VIEWS & REVIEWS

effects. Because of this, they will be vying to replace tamoxifen in the long run, or at least will be competing to be used in those patients who fail to respond to tamoxifen therapy, said Professor Vogel. Both these agents are more potent and specific aromatase inhibitors than amino glutethimide , with a superior tolerability profile, and should probably render this older agent obsolete, he commented.

While anastrozole and letrozole do not appear to share tamoxifen's benefits of preserving bone mineral density and lowering LDL-cholesterollevels, other strategies exist for protecting bones and lowering lipids, commented Dr Lewis Smith, Director of the Medical Research Council Toxicology Laboratory, UK. 'Clinical trials, I believe, will show that one of the new drugs will provide the beneficial effects of tamoxifen without incurring some of the toxico­logical effects, but so far the trials have not had sufficient numbers of subjects to prove this', said Dr Smith. 1. Saarto T, et al. Antiatherogenic effects of adjuvant antiesttogens: a randomized triaJ comparing the effects of tamoxifen and toremifene on plasma lipid levels in postmenopausal women with node-positive breast cancer. Journal of Clinical Oncology 14: 429-433, Feb 1996 800631862

.. Editorial comment: Toremifene has been available in Europe since 1996 and was launched in the US in 1997. It was the first antiestrogen therapy for breast cancer to become available in the US in 19 years [see 1npharma 1117: 22, 13 Dec 1997; 800653422J.

Inpharmae 28 Feb 1998 No. 1126 1173-832419811126-OOO4I$01.0rP Adls International Limited 1998. All rights reserved