A Randomized Trial of Tamoxifen With or Without Breast Radiation in Women With Early Breast Cancer 50 Years of Age and Over

Reviewer: Charles Wood, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 5, 2004

Presenter: A. Fyles
Presenter's Affiliation: Princess Margaret Hospital, Toronto, ON, Canada
Type of Session: Plenary

Background

The search continues for a subset of women with favorable breast cancer characteristics in whom radiation may be avoided.
This trial was designed to determine the effects of radiation therapy plus tamoxifen versus tamoxifen alone following lumpectomy on breast relapse and disease-free survival (DFS) in women age 50 years and older with T1 and T2 node negative breast carcinoma.

Materials and Methods

769 women with a median age of 68 years were randomized between 12/92-6/00, to radiation plus tamoxifen (n=386) versus tamoxifen alone (n=383) following lumpectomy with negative pathologic margins, though there was no central pathology review
tamoxifen was given as 20 mg/day for five years in both arms
40 Gy was administered to the whole breast in 16 fractions followed by a 12.5 Gy boost in 5 fractions representing the standard fractionation scheme at Princess Margaret Hospital at that time
639 patients (83%) had pT1 tumors, 636 patients (83%) had pN0 tumors, and 133 patients over age 65 were clinically N0
hormone receptors were postitive or unknown in 723 patients (94%)
patient characteristics were well-balanced between the two arms
median follow-up was 5.6 years

Results

breast relapse at 5 years was 7.7% (n=38) in the tamoxifen alone group and 0.6% (n=5) in the radiation plus tamoxifen group (p<0.0001) with corresponding DFS at 5 years of 84% and 91% (p=NS)
breast relapse at 8 years was 18% in the tamoxifen alone group and 3.5% in the radiation plus tamoxifen group (p=sig)
significant features on multivariate analysis included treatment arm, tumor size, and hormone receptor status
age was significant only on univariate analysis
an unplanned subgroup analysis of receptor positive patients with tumors less than or equal to 1cm demonstrated a 2.6% risk of breast relapse at 5 years with tamoxifen alone (n=139) compared with 0% with radiation plus tamoxifen (n=124, p<0.025)
an unplanned subgroup analysis of receptor positive patients with tumors less than or equal to 1cm and age 60 or greater demonstrated a 1.2% risk of breast relapse at 5 years with tamoxifen alone versus 0% with radiation plus tamoxifen (p=0.16)
an unplanned subgroup analysis of receptor positive patients with tumors 1cm or less and age 60 or greater demonstrated a 2.8% risk of breast relapse at 8 years with tamoxifen alone versus 0% with radiation plus tamoxifen
an unplanned subgroup analysis of receptor positive patients with tumors 1cm or less and age 70 or greater demonstrated a 3.6% risk of breast relapse at 8 years with tamoxifen alone versus 0% with radiation plus tamoxifen (p=0.34)
an unplanned subgroup analysis of receptor positive patients with tumors greater than 1cm to 2cm and age 70 or greater demonstrated a 17.6% risk of breast relapse at 8 years with tamoxifen alone versus 0% with radiation plus tamoxifen (p=0.08)
there was a significant difference in axillary relapse at 5 years (2.5% tam vs. 0.5% tam+RT, p=0.049)
there were no significant differences in either distant relapse or overall survival

Author's Conclusions

radiation plus tamoxifen significantly decreases breast relapse versus tamoxifen alone in node negative patients age 50 and over with tumors 2cm or less
patients age 60 and over with receptor positive tumors 1cm or less may consider tamoxifen alone
late relapse is a potential problem, especially with tumors 1cm or greater
radiation decreases axillary relapse
further follow-up will determine control following salvage therapy for local and locoregional failures

Clinical/Scientific Implications

The results of this Canadian trial are similar with both NSABP B-21 and the recently published CALGB/ECOG/RTOG breast study. Though this trial was slightly larger than the other two, its unplanned subgroup analysis was inadequately powered to assess the need for radiation in the over 60, receptor positive, favorable tumor size subset. Conversely, NSABP B-21 was adequately powered to address this issue, demonstrating a 93% reduction in breast failure in the age 60-69 patient group with the addition of radiation to tamoxifen. If eradication of cancer is the primary goal, radiation plus tamoxifen remains the gold standard. The side effects of tamoxifen use over a five year period are not insignificant, as demonstrated in the ATAC trial, and perhaps radiation alone would prove preferable to tamoxifen alone in a subgroup of advanced age patients with favorable tumor characteristics. Even in the patient age group over 70, the median life expectancy includes an additional 15 years, and 5 year follow-up regarding local control in this subgroup as reported in the CALGB/ECOG/RTOG trial is inadequate.