Aromasin (exemestane) Shows Some Advantages Over Tamoxifen As Adjuvant Therapy In Early Breast Cancer; First Results Of The TEAM Trial

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Main Category: Breast Cancer
Also Included In: Cancer / Oncology;  Clinical Trials / Drug Trials
Article Date: 17 Dec 2008 - 1:00 PDT

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Interim findings of the TEAM (Tamoxifen Exemestane Adjuvant Multicenter) trial reported on 11th December at the 2008 San Antonio Breast Cancer Symposium (SABCS) suggest women with early invasive breast cancer can expect fewer breast cancer recurrences and a longer time to the occurrence of distant metastases if they are treated with the aromatase inhibitor Aromasin (exemestane) rather than the standard adjuvant therapy tamoxifen after initial therapy (surgery plus chemotherapy and/or radiotherapy).

TEAM includes almost 10,000 postmenopausal women with invasive hormone-receptor-positive early breast cancer from nine countries. It is the largest ever prospective randomised trial comparing five years adjuvant therapy with an aromatase inhibitor (exemestane) against two to three years of tamoxifen followed by the same duration of exemestane. The open label trial was originally designed in 2001 to compare five years' adjuvant exemestane against five years tamoxifen therapy head to head. However in 2004 results of the Intergroup Exemestane Study showed a survival advantage for women who switched from tamoxifen to exemestane after two to three years. For this reason it was considered unethical to randomise women to five years tamoxifen in TEAM and the trial design was modified accordingly.

TEAM's two co-primary endpoints are disease-free survival (DFS) at 2.75 and 5 years. DFS takes account of breast cancer events and deaths from all causes so will flag up any unforeseen harm to other organ systems from a study drug. The trial's secondary endpoints are relapse-free survival (RFS) which takes account of breast cancer events only, time to distant metastases (TDM), safety and tolerability, and a censored analysis excluding data from women not adhering to allocated study drugs before the designated time for switching. Over 750 women switched from tamoxifen to exemestane before 2.75 years.

Results from a first planned analysis of 9775 patients in TEAM at 2.75 years were presented by Dr Steve Jones, Medical Director of US Oncology Research, Dallas, Texas. "Trials of aromatase inhibitors are increasingly complicated by non-compliance issues," Dr Jones commented. Women who switch over from one arm of the study to another arm 'muddy the water' making it difficult to assess how one treatment compares against the other. Some 29 per cent of women randomised initially to tamoxifen discontinued treatment as per protocol before 2.75 years when they were due to switch to exemestane, 508 more than the number who discontinued exemestane.

Results showed an 11 per cent relative risk reduction (HR 0.89) in DFS in the "intention to treat" analysis favouring the study arm where patients were originally randomised to exemestane only but which later included women who had crossed over from the other study arm (p=0.12). When the analysis excluded women who had originally been allocated tamoxifen but who switched over to exemestane, the relative reduction in risk from taking exemestane compared to the tamoxifen/exemestane sequential therapy increased to a significant 17 per cent (p=0.02).

Both tamoxifen and exemestane are very effective at preventing cancer recurrence so by 2.75 years relatively few breast cancer events had occurred despite the trial including almost 10,000 women, noted Dr Jones. On the ITT analysis RFS showed a 15 per cent relative risk reduction favouring exemestane (p=0.05) and TDM showed a 19 per cent risk reduction, again favouring exemestane (p=0.03). "TDM is increasingly used as an endpoint by breast cancer researchers," he said. "We are intrigued by it because ultimately it is reflected in overall survival".

The most common adverse symptoms experienced with tamoxifen use were hot flushes (33 vs 28.5 per cent) and with exemestane were arthralgia (18.4 vs 9.2 per cent). There was more osteoporosis reported among exemestane users (4.7 vs 2.1 per cent) but no differences in fracture rates between the two treatment arms. Other TEAM substudies presented during the meeting showed the only clinically relevant symptom attributed to exemestane that impacted adversely on quality of life was insomnia but there were no adverse cognitive effects. In fact, a TEAM substudy of 80 women taking tamoxifen, 99 taking exemestane and 120 healthy controls, found women taking exemestane performed no differently on cognitive tests than healthy controls. However, exemestane users performed significantly better than women taking tamoxifen on verbal memory and executive function tests and were significantly faster at processing information.

Exemestane was shown to reduce bone mineral density (BMD) in the first six months of a German one-year TEAM substudy but stabilised thereafter. In a two-year TEAM substudy Dutch researchers found no significant decrease in BMD at hip or spine in exemestane-users although a trend to increased bone resorption was noted.

Five-year data from the TEAM study will be presented at next year's SABCS.

Written by
Olwen Glynn Owen
Glynnowen(at)macline.co.uk


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