Letrozole (Page 6 of 9)

14.2 Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months

A double-blind, randomized, placebo-controlled trial (MA-17, NCT00003140) of letrozole was performed in over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who were disease free after 5 years of adjuvant treatment with tamoxifen.

The planned duration of treatment for patients in the study was 5 years, but the trial was terminated early because of an interim analysis showing a favorable letrozole effect on time without recurrence or contralateral breast cancer. At the time of unblinding, women had been followed for a median of 28 months, 30% of patients had completed 3 or more years of follow-up and less than 1% of patients had completed 5 years of follow-up.

Selected baseline characteristics for the study population are shown in Table 8.

Table 8: Selected Study Population Demographics (Modified ITT Population)
Baseline Status Letrozole Placebo
N=2582 N=2586
Hormone Receptor Status (%)
ER+ and/or PgR+ 98 98
Both Unknown 2 2
Nodal Status (%)
Node Negative 50 50
Node Positive 46 46
Nodal Status Unknown 4 4
Chemotherapy 46 46

Table 9 shows the study results. Disease-free survival was measured as the time from randomization to the earliest event of loco-regional or distant recurrence of the primary disease or development of contralateral breast cancer or death. DFS by hormone receptor status, nodal status and adjuvant chemotherapy were similar to the overall results. Data were premature for an analysis of survival.

Table 9: Extended Adjuvant Study Results
Letrozole N = 2582 Placebo N = 2586 Hazard Ratio (95% CI) P -Value
Disease Free Survival (DFS) 1 Events 122 (4.7%) 193 (7.5%) 0.62 (0.49, 0.78) 2 0.00003
Local Breast Recurrence 9 22
Local Chest Wall Recurrence 2 8
Regional Recurrence 7 4
Distant Recurrence 55 92 0.61 (0.44 to 0.84) 0.003
Contralateral Breast Cancer 19 29
Deaths Without Recurrence or Contralateral Breast Cancer 30 38
CI = confidence interval for hazard ratio. Hazard ratio of less than 1.0 indicates difference in favor of letrozole (lesser risk of recurrence); hazard ratio greater than 1.0 indicates difference in favor of placebo (higher risk of recurrence with letrozole). 1 First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause 2 Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization). P -value based on stratified log-rank test.

14.3 Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months

Table 10: Update of Extended Adjuvant Study Results
Letrozole N = 2582 (%) Placebo N = 2586 (%) Hazard Ratio 1 (95% CI) P -Value 2
Disease Free Survival (DFS) events 3 344 (13.3) 402 (15.5) 0.89 (0.77, 1.03) 0.12
Breast cancer recurrence (Protocol definition of DFS events 4) 209 286 0.75 (0.63, 0.89) 0.001
Local Breast Recurrence 15 44
Local Chest Wall Recurrence 6 14
Regional Recurrence 10 8
Distant Recurrence 140 167
Distant Recurrence (first or subsequent events) Contralateral Breast Cancer 142 37 169 53 0.88 (0.70,1.10) 0.246
Deaths Without Recurrence or Contralateral Breast Cancer 135 116
1 Adjusted by receptor status, nodal status and prior chemotherapy 2 Stratified log-rank test, stratified by receptor status, nodal status and prior chemotherapy 3 DFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or death from any cause, and ignoring switches to letrozole in 60% of the placebo arm. 4 Protocol definition does not include deaths from any cause

Updated analyses were conducted at a median follow-up of 62 months. In the letrozole arm, 71% of the patients were treated for a least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. After the unblinding of the study at a median follow-up of 28 months, approximately 60% of the selected patients in the placebo arm opted to switch to letrozole.

In this updated analysis shown in Table 10 letrozole significantly reduced the risk of breast cancer recurrence or contralateral breast cancer compared with placebo (HR 0.75; 95% CI 0.63, 0.89; P =0.001). However, in the updated DFS analysis (interval between randomization and earliest event of loco-regional recurrence, distant metastasis, contralateral breast cancer, or death from any cause) the treatment difference was heavily diluted by 60% of the patients in the placebo arm switching to letrozole and accounting for 64% of the total placebo patient- years of follow-up. Ignoring these switches, the risk of DFS event was reduced by a non-significant 11% (HR 0.89; 95% CI 0.77, 1.03). There was no significant difference in distant disease-free survival or overall survival.

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