Exemestane

Switching to exemestane therapy after 2-3 years of tamoxifen treatment improves disease-free survival in postmenopausal women with breast cancer, according to Dr. R. Charles Coombes and his associates in the Intergroup Exemestane Study, a large randomized trial.

The standard approach of giving tamoxifen alone for 5 years after resection of estrogen-receptor-positive breast cancer now appears to be "suboptimal." Physicians should consider offering tamoxifen for 2-3 years and the aromatase inhibitor exemestane for the balance of the 5-year period of adjuvant endocrine therapy, said Dr. Coombes of the department of cancer medicine at Imperial College, London, and his associates.

The researchers don't yet know the molecular mechanism that makes this sequential regimen more effective. It is possible that, over time, tamoxifen's antagonist properties decline and sensitivity to estradiol increases. Aromatase inhibitors and inactivators are known to decrease estradiol levels.

In theory, switching to exemestane should counter the resistance that often develops to tamoxifen, sometimes as early as 12-18 months after starting treatment. It should also avert the serious side effects, including thromboembolism and uterine cancer, that can develop with prolonged tamoxifen therapy, they said.

The study, which involved 4,742 women treated in 37 countries, was halted in December and its results announced early after an interim analysis of the data revealed that switching to exemestane yielded an absolute disease-free survival benefit of nearly 5%, compared with continuing tamoxifen. Whether such a switch yields a benefit in overall survival cannot be determined yet because "the observed number of deaths over the relatively short follow-up period precludes the detection of a statistically significant difference in overall survival," the researchers noted (New Engl. J. Med. 350[11]:1081-92, 2004).

The study subjects had undergone resection of primary unilateral breast carcinoma, as well as postoperative radiotherapy or chemotherapy as indicated. All had received adjuvant tamoxifen for 2-3 years. A total of 2,380 were randomly assigned to continue on oral tamoxifen (20 mg or 30 mg), and 2,362 were assigned to switch to oral exemestane (25 mg).

After a median follow-up of 30 months, there were 449 cases of local or metastatic recurrence, contralateral breast cancer, or death: 183 cases occurred in the exemestane group and 266 in the tamoxifen group.

Disease-free survival was 91.5% for patients who switched to exemestane, compared with 86.8% for those who continued on tamoxifen.

Exemestane significantly reduced the risk of developing contralateral breast cancer, local recurrence, and metastases. It was equally effective in all subgroups of patients regardless of the number of positive lymph nodes, type of previous chemotherapy, progesterone-receptor status, or the use at any time of hormone therapy.

Exemestane users reported a higher incidence of arthralgia and diarrhea. Tamoxifen users reported more gynecologic symptoms, vaginal bleeding, and muscle cramps. Thromboembolic events occurred more frequently in the tamoxifen group (55 patients, or 2.4%) than in the exemestane group (30 patients, or 1.3%).

There was a trend toward more cases of osteoporosis in the exemestane group, and fractures were reported more often. However, the difference between the two patient groups was not statistically significant. "Recent studies have shown that all third-generation aromatase inhibitors or inactivators increase bone resorption," the investigators said, adding that they are conducting a substudy to determine the degree of bone mineral loss in patients who switched to exemestane.

Endometrial cancer, lung cancer, and melanoma developed more often in patients who continued on tamoxifen, but at this stage of follow-up the differences between the two patients groups did not reach statistical significance. It is not clear whether the rise in new primary cancers could be due to higher risk with prolonged tamoxifen treatment, an undiscovered protective effect of aromatase inhibition, or chance findings, said Dr. Coombes and his associates.

The results of several substudies comparing these two agents will be reported soon. Their effects on quality of life, uterine thickness, and bone metabolism currently are being assessed.

The Intergroup Exemestane Study was supported by Pfizer Pharmaceuticals.

BY MARY ANN MOON

Contributing Writer

COPYRIGHT 2004 International Medical News Group
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