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As a result, in analyses updated since 2005, the estimated outcomes of the tamoxifen arm in the ITT analysis are likely to be better than if all patients randomly assigned to tamoxifen continued to receive the drug for 5 years.
To account for selective crossover and improve on the ITT analysis, we considered various approaches to adjust for potential bias caused by this specific nonadherence with the randomized treatment assignment.
Adverse events that occurred more than 30 days after selective crossover from tamoxifen to letrozole were collected but excluded from data summaries.
The primary trial end point was DFS, defined as the time from random assignment to the earliest occurrence of one of the following: invasive recurrence in local, regional, or distant sites; new invasive contralateral breast cancer; any second nonbreast malignancy; or death as a result of any cause.
Of 8,010 postmenopausal women with hormone receptor–positive, early breast cancer enrolled on the Breast International Group (BIG) 1-98 study, 4,922 were randomly assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen.
Of 2,459 patients enrolled in the tamoxifen treatment arm, 619 (25.2%) selectively crossed over to either adjuvant or extended letrozole after initial trial results were presented in January 2005.
Other end points included overall survival (OS), defined as the time from random assignment to death as a result of any cause, and time to distant recurrence, defined as the time from random assignment to recurrence at a distant site.
An amendment of the protocol in April 2005 allowed for the provision of letrozole to any patient assigned to tamoxifen monotherapy who was free of disease, who was still receiving or recently (within 6 months) stopped tamoxifen, and who wished to cross over to letrozole (selective crossover).Specifically, we employed inverse probability of censoring weighted (IPCW) Cox modeling.In the setting of selective crossover, IPCW modeling artificially creates a scenario of missing follow-up data by censoring the follow-up of each woman at the time she crossed over (informative censoring).To gain better estimates of relative treatment effects in the presence of selective crossover, we used inverse probability of censoring weighted (IPCW) modeling.Weighted Cox models, by using IPCW, estimated a statistically significant, 18% reduction in the hazard of an OS event with letrozole treatment (hazard ratio [HR], 0.82; 95% CI, 0.70 to 0.95).
Initial results of the BIG 1-98 primary core analysis, which showed statistically significant reductions in both distant recurrences and DFS events with letrozole compared with tamoxifen, were presented in January 2005, and led to the unblinding of patients in the tamoxifen-alone treatment arm.