Commentary on Abstracts #254 and #330

Before the introduction of the taxanes into the management of breast cancer, the anthracyclines (and doxorubicin and epirubicin [Ellence] in particular) were considered the most active agents against this malignancy. The marked activity of single-agent taxanes suggested that their antitumor efficacy might match and perhaps exceed that of the anthracyclines. Several prospective randomized trials have confirmed these initial impressions. At intermediate doses (60 mg/m²), the activity of doxorubicin and paclitaxel (Taxol) was similar; at higher doses (75 mg/m²), doxorubicin appeared more effective. Conversely, docetaxel (Taxotere) was reported to be more active than doxorubicin in one trial.

With these data in hand, it was logical to develop taxane/anthracycline combinations. The first few attempts utilized longer infusions of both taxanes and anthracyclines. Dose-limiting toxicity was mucositis, myelosuppression, and febrile neutropenia. Response rates were reported in the 50% to 65% range.

The second generation of taxane/anthracycline combinations used short infusions of taxane and anthracyclines given as a bolus. The initial reports by Gianni and collaborators (J Clin Oncol 13:2688-2699, 1995) and Dombernowsky and coworkers (Ann Oncol 7:687-693, 1996) were very encouraging, with response rates exceeding 80% and complete remission rates approaching 35% to 40%. Unfortunately, this degree of antitumor activity was not confirmed by subsequent trials utilizing the same doses and schedules of these drugs. Furthermore, cardiotoxicity emerged as a serious toxicity at cumulative doses of doxorubicin below the “usual” cardiotoxic threshold.

Subsequent clinical studies showed that cardiotoxicity could be decreased by limiting the cumulative doxorubicin dose to 360 mg/m² or less, or by incorporating a lag period of at least 4 hours between the administration of doxorubicin and paclitaxel. Other authors, including Conte et al (Semin Oncol 23:28-31, 1996; 23:39-42, 1996) substituted epirubicin for doxorubicin in this combination. The epirubicin/paclitaxel combination was reported to be safe and effective, and without problems related to cardiac toxicity. It was only natural to develop docetaxel/doxorubicin combinations.

The results of several phase II trials (including the one reported by Marcus and collaborators [abstract #254]) demonstrated the good tolerance, cardiac safety, and marked antitumor efficacy of the docetaxel/doxorubicin combination.

Nabholtz et al (abstract #330) present the preliminary data of an important comparative trial. In this study, the doxorubicin/docetaxel (ATaxotere) regimen produced a higher response rate and a longer time to progression than AC. Additional information about survival effects will determine whether the anthracycline/taxane combinations represent a new standard for the management of metastatic and locally advanced breast cancer. There are similar comparative trials ongoing in groups of patients with operable primary breast cancer.

Additional taxane/anthracycline combinations, substituting infusional doxorubicin, or a liposomal anthracycline, or adding a cardioprotector (such as dexrazoxane [Zinecard]) are currently under development. However, with the information at hand, both paclitaxel/doxorubicin (epirubicin) and docetaxel/doxorubicin are suitable alternatives to more standard anthracycline-containing regimens for the treatment of metastatic breast cancer. The role of these combinations in the adjuvant setting is currently under investigation.