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Tamoxifen with or without Breast Irradiation in Women 50 Years of Age or Older with Early Breast Cancer

Background: Breast-conserving surgery together with local radiotherapy reduces the risk of relapse of breast cancer. Adjuvant tamoxifen therapy further reduces the risk of relapse. Because of advances in detection and salvage therapy, there is interest in identifying patients at low risk who could avoid radiotherapy.

Objective: To determine if radiotherapy has a significant role when combined with tamoxifen in the treatment of early breast cancer in women 50 and over and if radiotherapy may not be necessary in some women.

Methods: This was a randomly assigned, controlled trial. The inclusion criteria were: age > 50 at the time of diagnosis of invasive adenocarcinoma 5 cm or less in diameter and in the T1 or T2 pathological stage, previous breast-conserving surgery for this tumor, pathologically negative resection margins at the time of initial or repeated resection, and pathologically negative axillary lymph nodes except in patients older than 65 who were eligible if they were node-negative on the basis of either clinical or pathological criteria. The exclusion criteria were: previous cancer with a disease-free survival of less than 5 years, previous breast cancer with a disease-free survival less than 10 years, bilateral breast cancer or multifocal primary breast tumors, unable to undergo radiation therapy, unable to use tamoxifen, metastatic disease at initial assessment, and planned adjuvant chemotherapy or tamoxifen preventative therapy. 769 women were enrolled with 386 women randomly assigned to receive tamoxifen plus breast irradiation and 383 women randomly assigned to receive tamoxifen alone. A 20 mg dose of tamoxifen was given orally for 5 years to both groups. The group that received the combination also was given radiotherapy within 12 weeks of the most recent surgery. Patients were seen every 3 months for the first 3 years, every 6 months for the next 2 years, and yearly thereafter. The primary outcome measure was disease-free survival, which is the time from randomization to the first treatment failure in the ipsilateral breast, in the auxillary nodes, or at a distant site, or death. The secondary outcome measures were the incidence of relapse in the breast and axillae and overall survival. Adverse events were documented at an interview that was conducted at each follow-up visit. The power of the study was 90% with a one-sided alpha of 0.05. An intent-to-treat analysis was used in this study.

Results: 271 women who took the combination and 291 women who received tamoxifen alone completed the study. The disease free survival rate at 5 years was 84% in the tamoxifen group and 91% in the combination group with a hazard ratio of 1.7 (95% CI: 1.2-2.5) p=0.004. The overall survival rate at 5 years was 93.2% in the tamoxifen group and 92.8% in the combination group p=0.83. 54 women in the tamoxifen group and 27 women in the combination group experienced relapse. The rate of relapse in the ipsilateral breast at 5 years was 7.7% in the tamoxifen group and 0.6% in the tamoxifen plus radiotherapy group with a hazard ratio of 8.3 (95% CI: 3.3-21.2) p<0.001. At eight years the rate of local relapse was 17.6% in the tamoxifen group and 3.5% in the group receiving combination treatment. The rate of relapse in the ipsilateral axilla at 5 years was 0.5% in the group receiving the combination and 2.5% in the tamoxifen group, p=0.049. The rate of distant relapse was 4.5% in patients receiving the combination and 4% in patients receiving tamoxifen p=0.69. No significant difference existed in the number of deaths overall. 10 women in each group died as a result of breast cancer.

Strengths: The treatment groups were similar as a result of stratification. The authors were not associated with drug companies, which decreased the amount of bias present. Also an intent-to-treat analysis was used so even though some patients discontinued therapy they were still included in the analysis. A modified intent to treat analysis may have been an even better option. Since the population chosen for the study had a good prognosis, women may be identified that do not need to be treated with radiation therapy.

Weaknesses: Lots of patients were excluded from the study. Some patients did not complete the entire study. The study only looked at older women with less severe cancer. The great majority in the trial were older than 60, had a tumor size < 2, and had a positive hormone receptor status. Using this patient group does not afford the reader the opportunity to see how effective the treatment regimens are in more severe cases of cancer. Also, no compliance measure was used.

Conclusion: Tamoxifen plus radiation is the preferred treatment for women who are 50 and over who have early breast cancer because of its effectiveness and minimal toxicity. Adding radiation therapy to tamoxifen significantly decreases the rate of local relapse in women 50 and over who had T1 or T2 negative breast cancer. Many opportunities exist for future trials with tamoxifen and radiation. A trial could be done to examine women 40 to 50 years of age with a larger tumor size to see if tamoxifen plus radiation is beneficial in this group. Also a future study could include only women 60 years of age or older who have tumors 1 cm or less in size and positive hormone-receptor breast cancer to determine if these low risk patients could avoid radiation therapy.

Fyles AW, McCready DR, Manchul LA, et. al. Tamoxifen with or without Breast Irradiation in Women 50 Years of Age or Older with Early Breast Cancer. The New England Journal of Medicine 2004 Sep;351(10):963-970.

William S. Kehayes, Pharm D Candidate