In early breast cancer, letrozole and tamoxifen alone or sequentially give similar five year outcome
Final results from a major trial comparing tamoxifen and letrozole in patients with early hormone-responsive breast cancer found no significant difference in disease-free survival between the two drugs, whether given alone or sequentially in either order.
A number of controlled trials suggest that aromatase inhibitors give somewhat better outcomes than tamoxifen in women with early hormone-responsive breast cancer, and there is some evidence suggesting that sequential use (tamoxifen first) also improved outcomes. One of the major trials contributing to this data was the Breast International Group (BIG) 1-98 study, in which initial results of the tamoxifen vs. letrozole comparison at just over two years showed some additional benefit for letrozole. The current paper reports the final outcomes from the full study including a pre-specified analysis of monotherapy at ten years from its start.
BIG 1-98 involved postmenopausal women with hormone-receptor–positive breast cancer. They were randomised to one of four treatment arms: letrozole or tamoxifen alone for five years, or one drug for two years followed by the alternate drug for three. After publication of the original results, patients who were disease-free were allowed to crossover to the letrozole arm on request. Primary outcome was disease-free survival from randomisation. Outcome events were defined as occurrence of one of the following: disease recurrence at a local, regional, or distant site; a new invasive cancer in the contralateral breast; any second (non-breast) cancer; or death without a previous cancer event. Analyses were carried out for letrozole vs. tamoxifen followed by letrozole, or letrozole followed by tamoxifen, and tamoxifen alone vs. letrozole alone.
There were 6,182 women in the sequential therapy comparison groups, and 4,922 in the monotherapy comparison. Overall, after a median follow-up of 71 months, there were no significant differences in the primary outcome between the two sequential groups and letrozole monotherapy. In the comparisons of sequential therapy vs. letrozole alone, hazard ratios (HR) for the primary outcomes were: tamoxifen followed by letrozole, HR 1.05 (99% CI, 0.84 to 1.32) letrozole followed by tamoxifen, HR 0.96 (99% CI, 0.76 to 1.21).
In the monotherapy comparison, after a median follow-up of 76 months, the primary outcome was similar for tamoxifen and letrozole with no significant difference in overall survival between the groups (HR for letrozole, 0.87; 95% CI, 0.75 to 1.02; P=0.08). Some secondary outcomes favoured letrozole, but see note below.
The authors conclude that in this study group, sequential treatment with letrozole and tamoxifen, whichever was used first, had no significant benefits compared to letrozole alone. In an updated analysis of monotherapy, there was no significant difference in disease-free survival between letrozole and tamoxifen after nearly six years follow-up. Adverse effects were as expected.
[Editor’s note: it is a general rule that the statistical validity of secondary outcome evaluations is not robust when the primary outcome shows no significant difference. Such results should be interpreted with caution and considered hypothesis-generating rather than a basis for changes in practice.]
New Engl J Med 2009; 361: 766-76 (link to abstract)
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