Commentary on Abstracts #403 and #278

In abstract #403 the combination of docetaxel (Taxotere) and doxorubicin was tested in a prospective, multicenter, phase II trial, by one of the foremost breast cancer research cooperative groups-the National Surgical Adjuvant Breast and Bowel Project (NSABP). The dose and schedule used in the NSABP trial was one of the two regimens previously identified by Dieras et al (Institut Curie, Paris) as the maximally tolerated doses of the two drugs given simultaneously. Patients not previously exposed to chemotherapy for locally advanced or metastatic breast cancer were candidates for this study.

Approximately 40% of the 89 patients registered had locally advanced breast cancer. Of the remainder, one-third had received prior adjuvant chemotherapy. It is of note that the plans were to continue the combination, in the absence of progressive disease, until reaching a cumulative doxorubicin dose of 480 mg/m². Subjective tolerance was excellent, although 40% of patients developed neutropenic fever during treatment. Clinical cardiac toxicity was in the lower range of what would be expected from the cumulative dose of doxorubicin, even in the absence of other cytotoxics. Therefore, there was no hint of increased or synergistic cardiotoxicity. This is in contrast with the observations based on the paclitaxel (Taxol)/doxorubicin regimen, which is associated with a higher rate of overt cardiac toxicity when cumulative doxorubicin doses exceed 360 mg/m² (Semin Oncol 24:S1-S3, 1997).

The 53% overall response rate at this preliminary analysis, and in the context of a multicenter trial, compares favorably with the results reported for other anthracycline-containing regimens. These results fully support the inclusion of the doxorubicin/docetaxel combination in the adjuvant systemic therapy of primary breast cancer.

Abstract #278 compares the outcomes of two different strategies to combine doxorubicin with docetaxel. The first strategy is the traditional simultaneous combination administered every 3 weeks. In this approach both agents are given at slightly reduced doses to minimize overlapping toxicities. The second strategy is to administer the two drugs in a dose-intensive sequence: doxorubicin at its single-agent maximally tolerated dose, but given every 14 days with hematopoietic growth factor support for two consecutive cycles; and docetaxel, given at its maximally tolerated dose, also with G-CSF support, for three cycles.

In this well-balanced randomized trial, and despite the markedly higher dose intensity achieved in the sequential arm, the response rates obtained in the two arms were identical, thus making differences in time to progression or survival (not reported in the abstract) unlikely. The response rates confirmed the high degree of activity of this combination, as previously reported by Dieras et al, Nabholtz et al, and others. However, while both treatments were reasonably well tolerated, the sequential regimen was slightly more toxic. Until additional comparative trials are completed and evidence in support of the sequential single-agent strategy is generated, the simultaneous combination will remain the preferred treatment-it is simpler, less expensive, and less toxic, yet it produces identical results.