Benefit from exemestane (EXE) as extended adjuvant therapy after 5 years of tamoxifen (TAM): intent-to-treat analysis of NSABP B-33
Reviewer: John P. Plastaras, MD, PhD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 16, 2006
Presenter: E. Mamounas Affiliation: NSABP Operations & Biostatistical Centers, Pittsburgh, PA
For hormone receptor positive breast cancers, 5 years of adjuvant tamoxifen had been the standard. Aromatase inhibitors (AIs) were tested in three different settings:
AI x 5 yr vs. Tamoxifen x 5 yr
Sequential Tam/AI (2-3 yr each) x 5 yr vs. Tam x 5 yr
Extended AI vs. placebo after Tam for 5 yr.
The NSABP intended to test the 3 rd approach with a trial that was started in May 2001. It was designed to test the benefit of adding exemestane (EXE) therapy sequentially after 5 year of tamoxifen.
The ATAC trial reported results in December 2001 showing that the AI was superior to Tam in terms of disease free survival. In 10/03, the NCIC MA.17 trial reported that extended adjuvant letrozole after 5 years of tamoxifen was superior to placebo. At that time, accrual in this NSABP B-33 trial was halted, unblinded and patients were allowed to crossover to EXE.
The intention to treat analysis is presented here.
1598 post-menopausal women with hormone receptor positive breast cancer, clinical stage T1-3 N0-1 who were disease free after 5 years of tamoxifen
Randomized, double-blind, multicenter, phase III, two-arms:
Tam x 5 yr, followed by placebo x 5 yr
Tam x 5 yr, followed by EXE (25 mg po daily) x 5 yr
The original design was for 2 years of EXE, but the protocol was amended in 2002 to extend the duration to 5 years
The trial was originally powered to detect a 21% reduction in the hazard rate with a power of 80% with an accrual goal of 3000 patients. After the NCIC MA.17 trial was reported, only 1598 patients had been randomized.
Primary: disease free survival
Secondary: overall survival, relapse free survival, bone mineral density, blood lipid profile, and quality of life
Patients: Arms were well-balanced. 80% were ER+/PR+, 12% were ER+/PR-, and 3% were ER-/PR+
After accrual was closed and unblended, women on both arms were offered EXE, free of charge
560 of 783 (72%) on EXE continued on EXE
344 of 779 (44%) on placebo started taking EXE
Most switched between 6-12 months
It is unknown whether the remaining women started taking an alternate AI, such as anastrazole.
Disease free survival was better in EXE arm, but did not reach significance:
EXE 91% vs. Placebo 89%, p=0.07 (RR 0.68)
Distant disease free survival favored but EXE, but did not reach significance:
EXE 94% vs. Placebo 93% (RR 0.69, p=0.13)
Relapse free survival favored EXE:
EXE 96% vs. Placebo 94% (RR 0.50, p=0.03)
Overall survival favored Placebo, but was not significant
16 deaths on EXE vs. 13 deaths on Placebo (RR 1.2, p=0.63)
Toxicity favored placebo:
There was 1% grade 4 toxicity in each arm
Grade 3: EXE 9% vs. 6%, p=0.03
The most common were arthralgia, fatigue, and bone pain
Fractures were not significantly different: EXE 28 vs. Placebo 20, p=0.33
Quality of Life: 454 participants. There were no differences between the arms.
Despite early closure and crossover, there was a borderline significant benefit in disease free survival and a significant benefit in relapse free survival with the addition of 5 years of EXE after 5 years of tamoxifen
The toxicity of EXE was acceptable.
The optimal choice of AI and sequence with tamoxifen is not known, but AI's are currently standard treatment in hormone positive, post menopausal breast cancer
Unfortunately, after cross over, use of other AIs was not recorded, which would allow an analysis based on treatment received in addition to this intention to treat analysis.
Thus conclusions cannot be definitively drawn from this study
Dec 6, 2012 - For women with estrogen receptor-positive early breast cancer, continuing tamoxifen to 10 years correlates with reduced risk of recurrence and lower breast cancer-specific and overall mortality, according to a study published online Dec. 5 in The Lancet to coincide with presentation at the annual San Antonio Breast Cancer Symposium, held from Dec. 4 to 8.