European Trials Show Dose-Related Efficacy of Docetaxel In Metastatic Breast Cancer, Value of Steroid Pretreatment

LISBON, Portugal--Studies from the Breast Cancer Cooperative Groupand the Clinical Screening Group of the Euro-pean Organizationfor Research and Treatment of Cancer (EORTC) have spotlighteddocetaxel (Taxotere) as a promising second- and first-line treatmentfor metastatic breast cancer. What's more, the EORTC findingsindicate that steroid premedication can delay the fluid retentionthat frequently limits therapy with this taxoid.

[See "FDA Oncology Drugs Committee Fails to Recommend Taxotere and Ethyol"for a report on the recent decision by the FDA's Oncology DrugsAdvisory Committee not to recommend docetaxel for approval.]

Dr. Martine J. Piccart, of Institut Jules Bordet, Brussels, whochairs the EORTC Breast Cancer Cooperative Group, explained thatthe Group's objective was twofold: to assess the efficacy of anew docetaxel schedule, 50 mg/m² on days 1 and 8 every 3weeks, in women who had previously undergone therapy for advancedor metastatic disease, and to compare the incidence of fluid retentionand dermatologic side effects with and without premedication.

Thus, the 70 participants were randomized to receive an antihistaminealone or in combination with methylprednisolone, 40 mg orallyfor 3 days, starting the day before each docetaxel dose.

"The interesting finding of this study," Dr. Piccartsaid, "was that corticosteroids do make a difference in theonset of the fluid retention phenomenon." Steroid pretreatmentsignificantly delayed the development of docetaxel-associatededema and pleural effusion.

Dr. Piccart also noted that premed-ication with steroids appearedto blunt the severity of pleural effusion and reduce the needfor pleural drainage. However, steroids had no impact on the incidenceof hematologic toxicity, which was not pronounced, or on the frequencyof nonhematologic side effects, including skin and nail reactions.

"The good news is the antitumor activity of the drug,"Dr. Piccart said. Intention-to-treat analysis revealed a responserate of 37.1% (95% confidence interval, 25% to 49%) in these heavilypretreated patients, with a 7½-month median duration of responseand a 5-month time-to-progression interval.

First-Line Treatment

In two consecutive studies of docetaxel (without prophylacticpremedication) as first-line treatment for progressive metastaticor locally advanced breast cancer, the EORTC Clinical ScreeningGroup found that reducing the dose from 100 mg/m2 to 75 mg/m²every 3 weeks compromised response without significantly changingthe safety profile.

Dr. Pierre Fumoleau, of Centre Rene-Gauducheau (ICERC), Nantes(France), reported that the 35 women receiving 100 mg/m2 achieveda superior 68% response rate (95% confidence interval, 49% to83%), compared with 52% (95% confidence interval, 33% to 70%)in the 40 low-dose participants.

Liver Metastases Respond

The median duration of response, he noted, was 44 weeks with thehigh dose versus 34 weeks with the low dose, and time to progressionwas 37 weeks with the high dose versus 24 weeks with the low dose.The dose-related efficacy of docetaxel was especially strikingin liver metastases, three quarters of which responded to the100 mg/m² dose.

The only advantage of dose reduction, Dr. Fumoleau said, was alesser incidence of febrile neutropenia, which developed in 11%of high-dose cycles and 3% of low-dose cycles. Nonhematologictoxicity was similar at both doses; however, fluid retention occurredin about 75% of these nonpremedicated patients, accounting for50% of withdrawals from the high-dose study and 41% from the lowdose.

"Docetaxel is a highly active drug in metastatic breast cancer,and a dose of 100 mg/m2 IV every 3 weeks is currently recommendedfor first-line chemotherapy of advanced disease," Dr. Fumoleausaid. "Furthermore, EORTC Clinical Screening Group resultsfrom ongoing studies with steroid premedication showed a clearbenefit in reducing the incidence and severity of fluid retention."