PURPOSE:To determine whether switching patients from tamoxifen to antiaromatase treatment would prevent some of the relapses or deaths that we assume would occur if tamoxifen were continued. PATIENTS AND METHODS:Three hundred eighty postmenopausal breast cancer patients receiving adjuvant tamoxifen treatment for 3 years were randomized to either continue tamoxifen for 2 more years or to switch to low-dose aminoglutethimide (250 mg daily) for 2 years. RESULTS:At a median follow-up of 61 months (range, 5 to 94 months), 59 events occurred in the tamoxifen group, and 55 occurred in the aminoglutethimide group. More treatment failures at distant sites, such as viscera (P =.02), were observed in the tamoxifen group. Although no differences in disease-free survival between the two groups have emerged so far, a significant trend favors aminoglutethimide in overall survival (P =.005) and breast cancer-specific survival (P =.06). Even if more patients in the antiaromatase group complained of drug-related side effects and more of them discontinued treatment (P =.0001), the number of cardiovascular events and, in general, of life-threatening adverse events was higher in the tamoxifen arm. CONCLUSION:Switching patients from tamoxifen to aminoglutethimide treatment resulted in comparable event-free survival, but longer overall survival was achieved in patients who were switched to aminoglutethimide as compared with those who continued to receive tamoxifen. Should these preliminary results be confirmed by larger studies with a similar design, which are now testing the effectiveness of the new, more active, and tolerable aromatase inhibitors, sequencing tamoxifen with an aromatase inhibitor could become a preferable alternative to tamoxifen alone in early breast cancer patients.

The first GROCTA trial compared 5-year tamoxifen treatment to ten chemotherapy cycles in a group of 504 pre-/post-menopausal, node-positive, ER-positive breast cancer patients. This study also included an arm combining tamoxifen with chemotherapy. Fifteen-year results showed no difference between tamoxifen and tamoxifen plus chemotherapy, while both treatments were significantly superior to chemotherapy alone. A confirmatory study (GROCTA 02) was performed in 244 pre-/perimenopausal patients by comparing 5 years of tamoxifen treatment (plus 2 years of goserelin) to six CMF cycles. No difference has emerged so far between the tamoxifen and CMF arms at a median follow-up time of 62 months. Post-menopausal women were scheduled to receive 3 years of tamoxifen treatment and then to be randomly allocated to further 2 years of tamoxifen or to 2 years of low-dose aminoglutethimide (GROCTA 04B). So far 662 patients have been entered, 375 of whom have been randomized to tamoxifen (n = 188) or aminoglutethimide (n = 187). Preliminary results (median follow-up time 32 months) show no major difference in patients' outcome. A new trial (ITA trial) with a similar design but employing anastrozole in place of aminoglutethimide has been activated in 1998. The GROCTA 03 study investigated the potential superiority of alternating adjuvant chemotherapy over standard CMF. This study, which included 107 node-positive ER-negative pre-menopausal women, was prematurely closed because more patients allocated to the triple alternated chemotherapy appeared to have relapsed and died at the first interim analysis. The use of high-dose chemotherapy (HDC) was explored by the GROCTA 06 trial which included 53 patients with ten or more involved nodes and a maximum age of 55 years. These patients were scheduled to receive three standard CEF cycles followed by one cycle of HDC (cyclophosphamide 5 g/m2; etoposide 1.5 g/m2; cisplatin 150 mg/m2) without any form of bone marrow rescue. This HDC program proved to be feasible but was not superior to CMF-based chemotherapy we had previously employed in a comparable group of patients in previous GROCTA trials. These findings prompted us to explore new HDC programmes with the use of peripheral stem cell support and in addition the possible value of new drugs such as Taxol and vinorelbine. New-generation trials will also explore the value of new prognostic indicators such as tumor proliferative activity, which are prospectively used to allocate patients to different treatment options.

A multicentric randomized trial was performed in premenopausal women with node-positive, estrogen-receptor-negative breast tumors to assess the potential superiority of alternating adjuvant chemotherapy over 'standard' CMF chemotherapy. Between January 1989 and June 1992, 107 patients were entered into the study and randomly allocated to receive either cyclophosphamide 100 mg/m2 per as on days 1-14, methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 intravenously (i.v.) on days 1, 8 (CMF), every 4 weeks for a total of 6 cycles, or the following regimens: CMF as previously; epidoxorubicin 75 mg/m2 i.v. on day 1 and vincristine 0.75 mg/m2 i.v. on days 1, 8 (EV); mitomycin-C 10 mg/m2 i.v. on day 1 and vindesine 2 mg/m2 i.v. on days 1, 8 (MVs). The three regimens were given every 4 weeks for a total of 6 cycles according to the following schedule: CMF, EV, MVs, CMF, EV, MVs. At a median follow up of 48 months (range 30-72), 40 patients have relapsed and 17 have died overall. More patients in the triple-combination arm have relapsed and more have died, the latter difference tending toward statistical significance (p = 0.06). There was no statistical difference in the site of relapse between the two groups. Total duration of adjuvant therapy was similar in the two arms (312 chemotherapy cycles in the triple arm and 308 in the CMF arm). Treatment toxicity was also comparable, although more patients in the triple-combination arm were still regularly menstruating 6 months after the completion of chemotherapy. This study failed to show any advantage ensuing from the use of alternating chemotherapy in patients with early breast cancer.

504 evaluable node positive oestrogen receptor (ER) positive breast cancer patients were randomly allocated to receive either 5 years tamoxifen treatment or chemotherapy [six courses of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) followed by 4 courses of epirubicin] or a combination of both treatments. At a median follow-up of 5 years tamoxifen appeared to be more effective than chemotherapy, the difference being highly significant in postmenopausal women. The addition of chemotherapy to tamoxifen was not able to significantly improve the results achieved by tamoxifen alone, irrespective of menopausal status. Trends were similar even after stratification for the number of involved nodes. The protective effect of tamoxifen in terms of reduction of the odds of death increased with time and no rebound phenomena on recurrence or death has occurred so far after the completion of tamoxifen treatment. Overall, the prognostic value of number of involved nodes and of progesterone receptor (PgR) status was confirmed by multivariate analysis. However, the predictive value of PgR was lost in patients receiving tamoxifen alone. Similarly, the degree of ER positivity was not predictive of the response to tamoxifen. Tamoxifen treatment should still be regarded as the gold standard for postmenopausal ER positive patients. In younger women the antioestrogen proved to be safe and at least as effective as chemotherapy. However, the analysis of the annual risks suggests that the concurrent or the sequential use of chemotherapy and tamoxifen might represent a more appropriate treatment for this patient subset, particularly for those with four or more involved nodes. Different cut-offs of ER and PgR assays from those we have arbitrarily employed in the present analysis should probably be used to select more properly the patients who can benefit from endocrine therapy.