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Both studies were restricted to premenopausal women who underwent modified radical mastectomy and received adjuvant chemotherapy. And both asked whether the addition of radiation treatment to the chest wall and regional lymph nodes increases survival. The hypotheses underlying this question are complex. The first is that chemotherapy can eliminate distant micrometastases but is less effective against local and regional disease. These persistent sites of disease, according to this hypothesis, are the source of subsequent fatal metastases. The second hypothesis is that local and regional disease is not treated as satisfactorily by chemotherapy as by radiotherapy because of a greater tumor-cell burden, decreased drug access after surgery, or altered local physiology in the residual tumor. A third, related hypothesis is that radiation therapy can eradicate these local and regional deposits.
The results of both trials are strongly positive. The Danish trial shows an overall survival of 54 percent at 10 years in the radiotherapy-plus-chemotherapy group, as compared with 45 percent in the group treated only with chemotherapy. And in the Canadian study, the relative risk of dying of breast cancer at 15 years was reduced by nearly one third when chemotherapy was compared with chemotherapy plus radiation. Both studies were restricted to patients with a high risk of residual disease -- those with involved axillary lymph nodes or very large tumors. The overall likelihood of local or regional recurrence was 32 percent in the Danish study and was reduced to 9 percent when radiotherapy was added to chemotherapy. The data in the smaller Canadian study are remarkably similar, with local or regional recurrence in one third of the patients at 15 years when chemotherapy was administered alone, as compared with 10 percent of the patients when radiation was added. In the Danish study, almost half the recurrences were in the axilla, as detailed previously in an interim report of that trial. (3) Comparing the current report with the 1988 one reveals that, whereas both show statistically significant differences in local control and distant metastases, there was no significant difference in overall survival in 1988 between patients given chemotherapy and those given chemotherapy plus radiotherapy. With continued observation, the later results with regional radiation therapy show an important survival advantage. This implies that local failure can eventually cause fatal metastases and that differences in the incidence of these two events serve as harbingers of differences in survival.
Breast-cancer management has changed since these trials began, the Canadian study in 1978 and the Danish one in 1982. Because of much more extensive use of screening mammography, patients are presenting with smaller tumors and less axillary-node involvement. (4) For example, in a survey of practice in the United States conducted by the American College of Surgeons, (5) the proportion of invasive breast cancers less than 2 cm in diameter increased from 28 percent in 1983 to 36 percent in 1990. The incidence of regional lymph-node disease at presentation decreased from 38 percent to 31 percent. Presumably, these trends have continued in the subsequent seven years. In addition to this stage migration, (6) the use of adjuvant chemotherapy has increased to the point at which it is now the usual treatment for premenopausal women in the United States with invasive breast cancers more than 1 cm in diameter. There has also been a great increase in the use of breast-preservation techniques that combine local excision with breast radiotherapy and axillary-node dissection. An important potential difference between the Danish study and current American practice may have to do with the extent of the axillary operation. In that study, the reported recurrence rate in the axilla appears to be high and the median number of nodes -- seven -- is somewhat low.
The practical questions for current American practice are these: Should radiation be given to patients in earlier stages of disease who now receive adjuvant chemotherapy? Should regional radiation treatment be given even when chemotherapy is not? And how does one apply this information to current programs of breast conservation? The premise underlying the first two questions is that even in patients with less extensive disease, treatment may fail because of persistent local or regional disease. The Danish and Canadian trials both suggest that the treatment is effective in T1 tumors (<2 cm) as well as T2 tumors (2 to 5 cm), although the data were not analyzed according to tumor size. Patients with T1 tumors are especially interesting, because a limited number of positive nodes (fewer than four) does not worsen the prognosis. (7,8) Presumably, these nodes represent oligometastases, metastases limited in number and location and still amenable to regional treatment. (9) Oligometastases must also have been present in patients with regionally restricted tumor burdens whose chemotherapy eliminated many micrometastases, leaving only residual local oligometastases.
The observation that differences in overall survival do not appear for many years suggests that we might use survival free of distant disease as a surrogate end point in making tentative early interpretations of studies. For example, the B-06 study by the National Surgical Adjuvant Breast and Bowel Project (10) shows a marked increase in local recurrence among patients receiving lumpectomy without any radiation therapy. These patients already have a statistically significant increase in the number of distant metastases. A reasonable interim conclusion would be that such treatment is not satisfactory, since local recurrence often leads to distant metastases that are likely eventually to decrease overall survival.
The two studies reported in this issue suggest that all patients with positive nodes treated by mastectomy should have radiation therapy to the chest wall and internal mammary nodes. The treatment of the supraclavicular area and upper axilla would depend on the amount of nodal disease found and the extent of the axillary surgery. I believe that similar treatment should be used in patients who undergo breast-conservation surgery. The most vexing problem is presented by the patient with a small tumor (<2 cm in diameter) and negative nodes. The proper treatment for her is unclear, but in some institutions she would receive adjuvant chemotherapy. I suggest that under those circumstances the treatment should also include local and regional irradiation. Also unanswered is the question of how to treat postmenopausal women, but similar logic suggests that if adjuvant chemotherapy is used, then radiation therapy should be added.
It is important to emphasize the positive nature of these studies. These are substantial survival advantages. They are part of a continuum of advances in the treatment of breast cancer. To the 30 percent reduction in breast-cancer deaths attributable to the use of screening mammography and the proven benefit of adjuvant chemotherapy, we can now add the further benefit from regional radiation treatment when combined with such chemotherapy.
Samuel Hellman, M.D.
University of Chicago
Chicago, IL 60637-1470
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