Breast cancer is the most common malignancy diagnosed in women in industrialized countries. In the United States, an estimated 203,500 women will develop breast cancer in 2002 and 39,600 women are expected to die from the disease the same year. Effective chemotherapy prolongs survival and provides important palliation for patients with metastatic breast cancer. Historically, anthracycline-based regimens were considered superior to non-anthracycline-containing regimens. The development of the taxanes in the 1990s opened new avenues for the treatment of patients with metastatic breast cancer.
Docetaxel (Taxotere) is among the most active agents for metastatic breast cancer. Initial phase II studies of docetaxel(Drug information on docetaxel) administered at 100 mg/m² showed response rates of 53% to 68% in patients previously treated with chemotherapy.[2-6] A multicenter phase II study of docetaxel at 75 mg/m² showed a response rate of 52%. Docetaxel is particularly active in patients with anthracycline-resistant breast cancer. In two studies published simultaneously, the objective response rates to docetaxel at 100 mg/m² in patients with breast cancer resistant to anthracyclines were 53% and 57%, respectively.[2,3] Ando et al reported that docetaxel given at a dose of 60 mg/m² produces a response rate of 49% in patients previously exposed to anthracyclines. The high response rates observed with docetaxel in this patient population were confirmed in randomized phase III trials.
In one study, docetaxel at 100 mg/m² was compared with mitomycin (Mutamycin) plus vinblastine(Drug information on vinblastine) in patients with anthracycline-resistant metastatic breast cancer. Patients treated with docetaxel had significantly better response rates (30% vs 11.6%, P < .0001), time to progression (19 vs 11 weeks, P = .01) ), and overall survival (11.4 vs 8.7 months, P = .01). Another sudy compared docetaxel at 100 mg/m² with sequential methotrexate(Drug information on methotrexate) at 200 mg/m² and fluorouracil(Drug information on fluorouracil) (5-FU) at 600mg/m², on days 1, 8, administered to patients with advanced anthracycline-resistant breast cancer. The results from this phase III trial indicate that docetaxel is more active than the sequential two-drug combination. Response rates (42% vs 21%, P < .001) and median time to progression (6.3 months vs 3 months, P < .001) were significantly better in the docetaxel arm in comparison with methotrexate/5-FU.
Another phase III study showed a higher response rate for docetaxel compared with 5-FU plus vinorelbine (Navelbine) as second-line therapy. Taken together, these studies demonstrate that docetaxel is effective therapy against anthracycline-resistant breast cancer, and, to date, docetaxel is the first and only chemotherapeutic drug to demonstrate a survival benefit in this patient population.
Historically, regimens that contained doxorubicin(Drug information on doxorubicin) or epirubicin(Drug information on epirubicin) (Ellence) were considered the first-line treatment of choice for patients with metastatic breast cancer. This paradigm is being challenged by novel nonanthracycline regimens. A randomized trial compared docetaxel at 100mg/m² with doxorubicin at 75 mg/m² in patients with metastatic breast cancer who had failed an alkylating-containing regimen. Docetaxel demonstrated significantly better response rates compared with doxorubicin in this patient population (48% vs 33%, P = .008), with a trend toward improved time to progression. Of the 326 evaluable patients, 49% were classified as having resistant disease (progression on prior chemotherapy), 70% of patients received docetaxel or doxorubicin as second-line therapy for metastatic breast cancer, and 30% received this regimen as first-line therapy for metastatic disease after having relapsed for 12 months or more after adjuvant therapy. These phase III results are the only time that a single agent (ie, docetaxel) has outperformed the previous standard drug (doxorubicin).[13,14]
The dose-limiting toxicity of docetaxel administered on an every 3-week schedule is neutropenia. Other reported toxicities include skin reactions, nail changes, neurosensory toxicity, and hypersensitivity reactions. Fluid retention was a major concern in the initial phase I and II clinical trials of docetaxel, in which patients had not received any premedication. A randomized study conducted by the European Organization for Research and Treatment of Cancer (EORTC) showed that the docetaxel-induced fluid retention could be reduced using a premedication regimen of corticosteroids.
Currently, docetaxel is approved by the Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. The approved outpatient regimen is 60 to 100 mg/m², administered intravenously for 1 hour every 3 weeks. All patients should be premedicated with oral corticosteroids, such as dexamethasone(Drug information on dexamethasone) 16 mg/d (eg, 8 mg bid), for 3 days starting 1 day prior to administration of docetaxel in order to reduce the incidence and severity of fluid retention, as well as the severity of hypersensitivity reactions. Of interest, a randomized clinical trial exploring the efficacy of three doses of docetaxel (60 mg/m², 75 mg/m², and 100 mg/m²) has been closed to accrual. The results of this study will provide additional details on the safety and efficacy of docetaxel in various doses.
Docetaxel can be administered safely and effectively at lower doses when given on a weekly schedule. Additionally, weekly docetaxel administration allows for the possibility of combined use with alternative agents, including those normally administered on a weekly basis (eg, trastuzumab(Drug information on trastuzumab) [Herceptin], vinorelbine), or those that become feasible in combination because of the change in the hematologic toxicity profile of docetaxel.
In a phase II trial conducted by Loeffler et al, docetaxel 40 mg/m² was administered once a week for 6 weeks, followed by a 2-week rest. An overall response rate of 47% was reported in 41 metastatic breast cancer patients who had been previously exposed to chemotherapy, including prior paclitaxel(Drug information on paclitaxel). In this study, no cases of grade 2 or greater neutropenia were seen with doses of less than 43 mg/m² per week and grade 2 or higher thrombocytopenia was not observed. In addition to causing minimal hematologic toxicity, the data showed that weekly docetaxel was likely to be associated with a very low incidence of other acute toxicities.
Another phase II study by Burstein et al, showed a response rate of 41% in a population of 29 metastatic breast cancer patients treated with weekly docetaxel, 40 mg/m² IV administered over 1 hour. Treatment was administered weekly for 6 weeks, followed by a 2-week rest. Hematological toxicity in this study was minimal. Grade 3 neutropenia occurred in 14% of patients, and grade 4 neutropenia in none. There were no cases of grade 3 or 4 anemia or thrombocytopenia of any grade. The incidence of nonhematologic toxicity was low, in particular the rate of grade 3/4 neurologic toxicity was very low, with 3% of patients experiencing neuropathy. Fatigue and asthenia occur with prolonged therapyas may fluid retentionalthough at a higher cumulative dose than is seen with every-3-week schedules. A newly reported toxicity of frequent tearing and visual problems, which is generally mild and manageable, may also occur after substantial total exposure to weekly docetaxel, but was not reported at the grade 3/4 level in this trial.
Hainsworth and colleagues reported on the use of docetaxel at 36 mg/m² per week for 6 consecutive weeks, followed by 2 weeks without treatment. A total of 41 women with advanced breast cancer who were elderly (65 years or older) or who were considered poor candidates for combination chemotherapy were enrolled on the study. When assessed after 8 weeks of treatment, 12 of 36 assessable patients had an objective response. An additional 14 patients had either a minor response or stable disease and continued treatment with weekly docetaxel. One of these patients subsequently achieved a partial response. Therefore, an overall response rate of 36% was achieved with 72% of patients achieving either a partial response or stable disease. Therapy was well tolerated, with infrequent grade 3/4 leukopenia (4%). Nonhematologic toxicities included grade 3/4 fatigue and asthenia (20%), which was difficult to distinguish as treatment- or cancer-related.
A large study of weekly docetaxel for the treatment of first- and second-line metastatic breast cancer patients is being conducted by Stemmler et al in Germany. In the first cycle, patients receive 35 mg/m² per week for 6 consecutive weeks and 2 weeks of rest, followed by treatment for 3 consecutive weeks and 2 weeks of rest. Preliminary results in 33 evaluable patients demonstrate an overall response rate of 36%, with stable disease in an additional 40%. Toxicity data for 40 patients included grade 3 neutropenia (3%), fluid retention (5%), nail toxicity (5%), and lacrimation (5%).
Comandone and colleagues treated 40 heavily pretreated metastatic breast cancer patients, all of whom had received prior anthracyclines, with weekly docetaxel. Treatment consisted of three cycles of docetaxel at 40 mg/m² for 6 weeks, with 1 week of rest (one cycle). An overall response rate of 19% was reported after two cycles of therapy with stable disease in 47.5% of patients. Toxicity data after one cycle included grade 3 neutropenia (2.5%) and grade 3 fatigue (2.5%).
The University of Texas M. D. Anderson Cancer Center is conducting a phase III study comparing weekly and every-3-week docetaxel in patients with metastatic breast cancer. In this study, patients are randomized to docetaxel at 100 mg/m² every 3 weeks or docetaxel at 35 mg/m² per week for 6 weeks, followed by 2 weeks of rest.