Home: Educational Supplement: Appendix

Overview: Postmastectomy Radiotherapy

Jack Cuzick, Ph.D.

The first issue in cancer treatment to be addressed by a randomized trial was the role of radiotherapy in breast cancer. Although that trial took place in 1948, the question of whether radiotherapy is an appropriate treatment for breast cancer remains controversial. There is little doubt that radiotherapy is effective in improving local control of the disease. The rate of local recurrence with radiotherapy is reduced to about one-third of the rate when surgery alone is used, although this absolute reduction is very much dependent on the extent of the surgery and the nodal status of the patient (see table 1). The relative reduction in local recurrence is substantial in all trials and appears to be unaffected by patient age, nodal status, dose, axillary or internal mammary chain irradiation, adjuvant chemotherapy or tamoxifen, or time of trial commencement. Slightly better results are seen in larger trials and also in trials employing smaller doses of radiotherapy per fraction.

What is less clear is the effect of radiotherapy on patient survival. This question has been examined in five large studies since 1987. In the first, Cuzick and colleagues observed an increase in late mortality (Cuzick, Stewart, Peto, et al., 1987). A subsequent study (Cuzick, Stewart, Rutqvist, et al., 1994) found that this increase was due to cardiovascular mortality, but it also suggested that there might be a late reduction in breast cancer deaths. Two subsequent and much larger overviews have confirmed and extended these observations (EBCTCG, 1995; EBCTCG, 2000). The most recent study of radiotherapy involved the examination of the deaths of more than 10,000 women out of a total of about 20,000 women in 40 randomized trials worldwide. No clear effect of radiotherapy on total mortality was found, but the study found highly significant differences in breast cancer deaths and non-breast-cancer deaths (see figures 1 and 2). After 20 years of followup, breast cancer deaths were reduced by 4.8 percent, but non-breast-cancer deaths were elevated by 4.3 percent. Both of these changes were highly significant (p< 0.001). The change in non-breast-cancer deaths emerged later than the change in breast cancer deaths, the differences being 1.0 percent for breast cancer mortality and 3.0 percent for non-breast-cancer mortality at 10 years. Most of the excess non-breast-cancer deaths were due to vascular disease, which increased by 30 percent. There were no significant subgroup effects on the relative death rates from breast cancer and from non-breast-cancer causes. However, an increased absolute death rate was seen in the radiotherapy arm for older and for node-negative women, due to the lower ratio of breast cancer deaths to other kinds of death in those two groups. More recent trials have reported larger overall mortality benefits from radiotherapy, but the followup from these trials is shorter, so uncertainty remains about the long-term mortality effects, especially for non-breast-cancer deaths.

Chief among these uncertainties is whether the newer kinds of radiotherapy, which allow for more accurate delivery of the dose, can achieve reduction in breast cancer mortality without increasing cardiovascular mortality. It will also be important to try to separate out the effects of radiation of the breast/chest wall versus radiation of lymph nodes. These questions are particularly relevant for women with small tumors or ductal carcinoma in situ (DCIS) who receive lumpectomy and radiotherapy, since their survival rate is very good and deleterious late effects would be most damaging.

It is clear that radiotherapy is of net benefit to patients who are at high risk of local recurrence and is inappropriate for others where the risk is low. Much uncertainty still exists about where to draw the dividing line between these groups and the extent to which improved techniques have shifted this boundary.

Preliminary data from the next overview (to be published in September 2000) will be available before the consensus development conference and should cast additional light on these uncertainties.

References

Cuzick J, Stewart H, Peto R, Baum M, Fisher B, Host H, et al. Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer. Cancer Treat Rep 1987;71:15-29. Abstract.

Cuzick J, Stewart H, Rutqvist L, Houghton J, Edwards R, Redmond C, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 1994;12:447-53. Abstract.

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and surgery in early breast cancer: an overview of the randomized trials. N Engl J Med 1995;333:1444-55. Abstract.

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000;355:1757-70. Abstract.