Clinical Update - Breast Cancer
Radiotherapy with tamoxifen after lumpectomy for early breast cancer - does it make a difference for women in different age groups?
Commentary by Dr Liz Kenny
The articles:
- Fyles A et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 2004;351:963–970.
- Huges K et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 2004;351:971–977.
The reviewer:
Dr Liz Kenny is a senior radiation oncologist with the Division of Oncology, Royal Brisbane Hospital, with a special interest in breast cancer. Dr Kenny has held eminent positions including president of the Clinical Oncological Society of Australia (2002–2003) and Dean of the Faculty of Radiation Oncology, The Royal Australian and New Zealand College of Radiologists (1998–2002).
In this issue...
- Summary
- What do these articles add to existing clinical evidence in this area?
- How adequate was the methodology used in addressing the aims of the studies?
- What are the implications of these studies for clinical practice in Australia?
Summary
Two randomised trials were published in the September 2, 2004 issue of the New England Journal of Medicine comparing tamoxifen (TAM) with or without breast radiotherapy (RT) in older women.
The article by Fyles et al compared TAM, with or without breast RT, in women 50 years of age or older with early breast cancer. The authors concluded that compared to TAM alone, RT plus TAM significantly reduced the risk of breast and axillary recurrence in women with small, node-negative hormone receptor-positive breast cancers.
The article by Hughes et al compared lumpectomy plus TAM, with or without RT, in women 70 years of age or older with early breast cancer. The trial showed a highly significant reduction in locoregional recurrence at 5 years in the combined therapy group, but the authors concluded that the clinical benefit was small, suggesting that lumpectomy plus TAM is a realistic choice for women 70 years or older who have early oestrogen-receptor (ER) positive breast cancer.
What do these articles add to existing clinical evidence in this area?
Both papers add significantly to the body of literature on older women with early breast cancer, both reporting a statistically significant benefit in terms of disease-free survival (DFS), yet each drawing different conclusions.
How adequate was the methodology used in addressing the aims of the studies?
In the paper by Fyles et al, a total of 769 women with cancers 5 cm or less were randomised after complete resection to receive TAM alone (n=383) or TAM and RT (n=386). A shortened radiotherapy fractionation schedule was used. The median follow-up was 5.6 years. A planned subgroup analysis of 611 women with T1 cancers was also performed. The median age of the women was 68 years. The majority of women (over 80%) had known positive hormone receptor status.
Overall the rate of local relapse at 5 years was 7.7% in the TAM alone group and 0.6% in the combined group (p<0.001). By 8 years the rate had increased to 17.6% and 3.5% respectively. In the planned subgroup analysis of women with T1 cancers, the 5-year local relapse rate was 5.9% in the TAM alone arm and 0.4% in the combined arm (p<0.001). By 8 years in this T1 group, the recurrence rate was 15.2% and 3.6% respectively. Axillary recurrence was also decreased in the combined group (it should be noted that not all women had undergone axillary dissection). An unplanned subgroup analysis of women 60 years or older with 1cm cancers and ER-positive status suggested a low risk of recurrence at 5 years (1.2% and 0% respectively). The small number of women and the likelihood of further relapse with longer follow-up means this should be interpreted with caution.
This was a non-inferiority trial designed to have 90% power to rule out a 7% or greater difference in locoregional recurrence rates. It was not designed to show differences in overall survival.
A multivariate analysis demonstrated that not having RT, having negative hormone receptors, and large tumour size were independent predictors of local recurrence.
In the paper by Hughes et al, 636 women 70 years or older with T1 ER-positive breast cancer were randomised to receive TAM alone or TAM plus RT after complete resection. The rates of locoregional recurrence were 4% and 1% respectively (p<0.001). The 5-year mastectomy rate for local recurrence was not significantly different between the two groups; however the number of events was small. There was no significant difference in overall survival. At 2 years, cosmesis was rated as worse in the women who had received RT, but this difference had resolved by 4 years.
The planned sample size of 572 women gave 90% power to show a difference in locoregional recurrence at 3 years of 16% versus 9%. However, the trial’s power was reduced by rates of local recurrence that were much lower than expected. The study was not powered to show a difference in survival. Median follow-up was 5 years.
Rates of local or regional recurrence were significantly lower with radiation than without it (4% versus 1% at 5 years, respectively (p<0.001), and as anticipated, the recurrence rates continued to diverge beyond 5 years.
The trials tested similar questions in overlapping but distinct populations. Both trials showed a marked and statistically significant difference in local and regional recurrence of breast cancer by the addition of RT to TAM. Rates of recurrence in the two trials were similar for similar groups of women. Differences in local and regional recurrence continued to diverge in both trials beyond the median follow-up of 5 years, but longer follow-up is needed to estimate differences accurately beyond 5 years.
What are the implications of these studies for clinical practice in Australia?
Currently in Australia , the Australian Bureau of Statistics estimates that the average additional years of life for a woman aged 70 years is 16.8 years, and for a woman aged 75 is 13 years. This means that many Australian women aged 70 years or older will live well beyond the 5-year and 8-year follow-up periods reported in both of these trials. Thus, even women with small receptor-positive breast cancers treated by TAM alone are likely to experience local recurrence rates in excess of 15% in their lifetimes. The findings reported here indicate that this recurrence rate can be markedly reduced by breast RT. However, for clinicians and women with breast cancer assessing the benefit of a reduction in local recurrence, the impact of recurrence on the woman must be weighed against the side effects and inconvenience of treatment.
Editor: Dr Karen Luxford, Deputy Director NBCC.
Editorial Committee: Mr Max Coleman, Mr John Collins, Dr Sue-Anne McLachlan, Dr Sue Pendlebury, Dr Martin Stockler.
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