Commentary on Abstracts #407 and #424

Over the past 5 years it has become evident that the administration of taxanes on a weekly schedule dramatically changes their toxicity profile, compared to the standard 3-weekly schedule. Weekly docetaxel (Taxotere) is markedly less myelosuppressive, and most other subjective toxicities are substantially reduced. It has also been noticed that the incidence of hypersensitivity reactions decreases with weekly administration. Ironically, the more frequent administration of docetaxel in association with dexamethasone premedication has been observed to produce increased steroid-related toxicity.

A number of recent reports have documented the high response rate obtained with the docetaxel/doxorubicin combination. This regimen is an ideal induction chemotherapy regimen, producing rapid objective responses; consequently, it has been introduced into the management of locally advanced and operable primary breast cancer and is also a commonly used regimen for induction of remission prior to high-dose consolidation programs. Weekly administration of this combination is an attractive option. Compared to 3-weekly docetaxel/doxorubicin, the incidence of severe neutropenia and neutropenic fevers is markedly reduced, while antitumor activity is preserved. One would also expect a reduction in the already low incidence of cardiac abnormalities, based on the decreased risk of cardiac toxicity associated with weekly anthracycline administration.

Over the past 5 years it has become evident that the administration of taxanes on a weekly schedule dramatically changes their toxicity profile, compared to the standard 3-weekly schedule. Weekly docetaxel (Taxotere) is markedly less myelosuppressive, and most other subjective toxicities are substantially reduced. It has also been noticed that the incidence of hypersensitivity reactions decreases with weekly administration. Ironically, the more frequent administration of docetaxel in association with dexamethasone premedication has been observed to produce increased steroid-related toxicity.

A number of recent reports have documented the high response rate obtained with the docetaxel/doxorubicin combination. This regimen is an ideal induction chemotherapy regimen, producing rapid objective responses; consequently, it has been introduced into the management of locally advanced and operable primary breast cancer and is also a commonly used regimen for induction of remission prior to high-dose consolidation programs. Weekly administration of this combination is an attractive option. Compared to 3-weekly docetaxel/doxorubicin, the incidence of severe neutropenia and neutropenic fevers is markedly reduced, while antitumor activity is preserved. One would also expect a reduction in the already low incidence of cardiac abnormalities, based on the decreased risk of cardiac toxicity associated with weekly anthracycline administration.

In our experience, weekly administration of docetaxel does not require the same high-dose dexamethasone premedication, as described in abstract #407. If no hypersensitivity reactions occur during the first two to three doses, dexamethasone should be reduced to one or two doses (4 mg each) with each dose of docetaxel. This results in a reduction of steroid-associated toxicity and an improvement in quality of life, with preservation of the marked antitumor activity of the combination.

Epirubicin (Ellence) was recently approved by the US Food and Drug Administration for use in the adjuvant therapy of high-risk primary breast cancer. However, epirubicin has been used for almost 20 years in Europe and other parts of the world. It has a similar activity profile to doxorubicin, but milligram per milligram, it is less toxic than the latter drug; there is less myelosuppression, mucositis, alopecia, and cardiotoxicity reported with epirubicin. Therefore, the development of epirubicin/docetaxel combinations is a logical step toward developing better tolerated regimens.

The results reported by Dominguez et al in abstract #424 show the activity of the docetaxel/epirubicin combination to be in the ballpark of docetaxel/doxorubicin combinations, with a substantially lower rate of neutropenic fevers and gastrointestinal toxicities. The absence of any reference to cardiac toxicity also suggests that this regimen will have limited cardiotoxic potential. However, the total cumulative dose of epirubicin was limited to 450 mg/m², which is well under the cardiotoxic threshold of epirubicin. Lacking the high frequency of grade 4 neutropenia, neutropenic fever, and cardiotoxicity, this combination compares favorably with other taxane/anthracycline combinations, and should be further evaluated in both metastatic and primary breast cancers.