Adjuvant therapy for early breast cancer: a time to refine.

Abstract

Adjuvant endocrine therapy and chemotherapy are now being used extensively to treat primary breast cancer and are probably beginning to have an impact on national mortality data in the U.K. (1,2). The main difficulty at present is identifying those patients who may require such treatment. The widespread use and evaluation of adjuvant combination chemotherapy started in 1976 after Bonadonna et al. (3) reported the results of an innovative trial using cyclophosphamide, methotrexate, and fluorouracil (CMF) after mastectomy for the treatment of patients with axillary lymph node-positive primary breast cancer. Their results showed that such treatment could substantially reduce the risk of relapse. Many trials have since confirmed these initial results, and, in 1985, an overview metaanalysis of these trials (4) showed a statistically significant reduction in mortality for women under the age of 50 years who were given adjuvant combination chemotherapy. Similarly, early trials of endocrine therapy using ovarian ablation had shown reductions in the rates of relapse (5,6) and were followed in 1977 by the start of the NATO (Nolvadex Adjuvant Trial Organization) trial of adjuvant tamoxifen, which subsequently showed that tamoxifen given for 2 years after mastectomy reduced the risk of relapse and death (7). Since then, other trials have shown similar results, and the 1985 overview (4) confirmed that there was a significant reduction in mortality in women aged 50 years or older who received adjuvant tamoxifen. Following these results, a National Institutes of Health consensus conference in 1985 (8) recommended that adjuvant combination chemotherapy should become standard care for premenopausal women with positive axillary lymph nodes, whereas tamoxifen should be used as the standard treatment of choice for postmenopausal women with estrogen receptor (ER)-positive tumors. Adjuvant therapy was not recommended for any other categories of patients. Subsequently, a repeat overview metaanalysis in Oxford in 1990 (9), comprising many more clinical trials, indicated that tamoxifen could be of benefit for most patients with primary breast cancer and that there was also a significant survival benefit for patients with negative axillary lymph nodes who received adjuvant combination chemotherapy. The magnitude of this survival benefit for chemotherapy appeared to be small, with an absolute odds reduction in mortality of only about 4% at 10 years for patients with negative axillary lymph nodes. However, Slevin et al. (10) have noted that most patients with breast cancer would accept severe toxicity from treatment in order to achieve as little as a 1% improvement in survival. The toxicity from adjuvant chemotherapy is generally mild and seldom life threatening; therefore, a 4% reduction in mortality at 10 years is likely to be considered an attractive option by most patients with axillary lymph node-negative primary breast cancer. In 1982, the National Surgical Adjuvant Breast and Bowel Project (NSABP) commenced a clinical trial (B-14) in which adjuvant tamoxifen was given to patients with lymph nodenegative, ER-positive primary breast cancers. Analysis in 1989 (11) showed that there was a significant reduction in relapse rates, although the survival benefit did not reach statistical significance. The investigators concluded that, although the prognosis for these patients on tamoxifen was good, additional benefit might be achieved by the addition of combination chemotherapy. Therefore, they started a new trial, NSABP B-20, which compared tamoxifen alone with tamoxifen plus CMF (or MF) chemotherapy in patients with axillary lymph nodenegative, ER-positive primary breast cancer. The results from this trial, reported in this issue of the Journal (12), show that the addition of chemotherapy to tamoxifen caused a further improvement in disease-free survival of about 5% and an additional improvement in survival of about 3%—strikingly similar to the results from the 1990 overview (9), which indirectly compared tamoxifen alone with tamoxifen plus polychemotherapy. Furthermore, no easily discernible group (age, menopausal status, and primary tumor size) could be identified that did not gain benefit. This beneficial effect of adding chemotherapy to tamoxifen in patients with axillary lymph node-negative primary breast cancer is in keeping with the 1990 overview metaanalysis data (9), which indicated that the absolute benefit for adjuvant chemotherapy was similar for patients with lymph node-negative or lymph node-positive breast cancer. This finding is not surprising, since axillary lymph node status has never been shown to be predictive of sensitivity to adjuvant chemotherapy. There is no biologic basis to suppose that axillary lymph node involvement should indicate chemosensitivity, and there are reasons to suppose that less extensive disease might be more likely to respond to chemotherapy. The principal conclusion from the NSABP B-20 trial, together with the data from the overview meta-analysis, is that