Doxorubicin has long been recognized as one of the most effective single agents in the treatment of metastatic breast cancer, and doxorubicin(Drug information on doxorubicin) combinations are among the most active in advanced or metastatic disease. Docetaxel(Drug information on docetaxel) (Taxotere) is highly active as a first- or second-line agent in the same setting. Moreover, there is no clinical cross-resistance between the two drugs.
These observations were the rationale for a feasibility study using the two drugs in combination.[4,5] The objectives of the study were to ascertain the dose-limiting toxicity, the maximum tolerated doses of these drugs in combination, and the recommended doses for future phase II and III trials, and to establish a safety profile of this combination therapy.
To be eligible, patients had to have metastatic breast cancer with measurable and/or evaluable disease. Other criteria included no prior chemotherapy for metastatic disease and a World Health Organization performance status 2 or less. Prior chemotherapy was allowed only if it occurred at the adjuvant stage, at least 1 year before entry into the study, with a cumulative dose of less than 300 mg/m² of doxorubicin, less than 500 mg/m² of epirubicin(Drug information on epirubicin), or less than 500 of mg/m² pirarubicin(Drug information on pirarubicin). Patients were required to have normal baseline left-ventricular ejection fraction; during the trial, ejection fraction was monitored every two cycles, and then every cycle after a cumulative dose of anthracycline 400 or more mg/m² was reached.
Every 3 weeks, doxorubicin was administered to outpatients as an intravenous bolus over 15 minutes, followed after 1 hour by docetaxel as a 1-hour infusion. No prophylactic supporting granulocyte colony-stimulating factor (G-CSF, filgrastim(Drug information on filgrastim) [Neupogen]) was used.
Doxorubicin doses increased from 40 mg/m² at levels I and II, to 50 mg/m² at levels III through V, and to 60 mg/m² at level VI (Table 1). Docetaxel doses increased from 50 mg/m² at level I, to 60 mg/m² at levels II and III, 75 mg/m² at level IV, 85 mg/m² at level V, and dropped to 60 mg/m² at level VI. Cumulative doses were monitored, and doxorubicin administration was stopped at a cumulative dose of 550 mg/m².
To avoid hypersensitivity reactions, patients received prophylactic premedication consisting of dexamethasone(Drug information on dexamethasone), cetirizine (an H1-blocker), ranitidine(Drug information on ranitidine), and Tanakan (ginkgo-biloba extracts) beginning on the day of first infusion, and continuing throughout treatment until the first symptoms of fluid retention appeared.
At least three patients were included at each dose level and followed for a minimum of 3 weeks before escalation to the next dose level. If a dose-limiting toxicity was noted in a patient, three more patients were included at that level, and the average maximum tolerated dose was determined. Maximum tolerated dose was defined if a dose-limiting toxicity was observed in 2 of 3 or 3 of 6 patients.
Dose-limiting toxicity was defined as grade 4 neutropenia lasting more than 7 days, febrile neutropenia lasting more than 3 days, grade 4 thrombocytopenia, grade 3 or 4 infection, and any grade 3 or 4 adverse event except anemia. The recommended dose for the phase II study is the highest dose that can be safely administered to a patient. Usually it is chosen as the dose level below the maximum tolerated dose.
A total 42 patients were entered into the study. Patients were characterized by a high prevalence of visceral involvement (79%). The majority of the patients (60%) had had prior adjuvant chemotherapy, with 52% receiving an anthracycline-containing regimen. The prior median cumulative dose of anthracycline was 152 mg/m² (range, 82 to 287 mg/m²).
Hematologic Adverse Events
The most frequent grade 3 and 4 toxicity was neutropenia. With the exception of the lowest dose level, grade 4 neutropenia occurred in more than 70% of cycles, with a median duration of 5 days (Table 1).
Febrile neutropenia occurred in less than 10% of cycles (30/314 cycles). One patient at level IV and two patients at level V developed a grade 3 or 4 infection (sepsis; Table 2). The maximum tolerated doses were defined as doxorubicin, 50 mg/m², and docetaxel, 85 mg/m², with sepsis as the dose-limiting toxicity occurring in 3 of 42 patients. The recommended doses were defined as 50 mg/m² of doxorubicin and 75 mg/m² of docetaxel, or 60 mg/m² on both drugs on day 1 every 3 weeks, without G-CSF support.
Nonhematologic Adverse Events
Nonhematologic toxicity was mild, with no grade 3 or 4 adverse events. There were no cases of severe fluid retention, although the median cumulative dose of docetaxel was 610 mg/m² (range, 199 to 1,010 mg/m²).
Patients were carefully monitored for cardiotoxicity. At a median of 18.4 months of follow-up, only four patients had abnormal grade 1 cardiac function, but all were asymptomatic; no congestive heart failure was observed, although 23 patients needed a cumulative dose of doxorubicin more than 360 mg/m². No patient had to leave the study because of cardiac toxicity.
Although this was a phase I study, all 42 patients were evaluable for response. Responses were observed at all dose levels. Response rates were higher at dose levels III to V (80% to 90%). Response rates were also high in patients whose disease had metastasized to the liver (82%). The median follow-up of 18.4 months (range, 9.0 to 28.3 months) was not sufficient to assess median duration of response or time to progression. Median survival has not been reached, but 9 patients (21.4%) have died, and 33 patients (78.6%) survive.
The results of five phase I studies of paclitaxel(Drug information on paclitaxel) (Taxol)/doxorubicin combination therapy in a total of 122 patients with advanced breast cancer are summarized in Table 3. In the first three studies, paclitaxel was administered by a prolonged (72- or 24-hour) infusion, while doxorubicin dosing varied from a bolus to a 48- or 72-hour infusion.[1-3,6] Administering paclitaxel as a 24-hour infusion before doxorubicin resulted in sequence-dependent toxicity, consisting of an increased incidence of severe mucositis and neutropenia. Similarly, giving both drugs simultaneously in a 72-hour infusion caused a high, schedule-dependent incidence of thrombocytopenia and typhlitis.
The response rates to these regimens were high, from 42% to 94% overall. However, the complete response rate was less than 10%. Two of the studies demonstrated that using shorter administration (3-hour) periods for both drugs permitted higher dose intensity, with paclitaxel doses as high as 200 mg/m² and doxorubicin at 60 mg/m².[1,6,7] This resulted in very good response rates. The 94% overall response rate of Gianni et al included 40% complete responses in a chemotherapy-naive patient population. However, these higher dosages were accompanied by an increase in cardiomyopathy, which occurred in as many as 20% of patients.
In the current study, the maximum tolerated doses were defined as 50 mg/m² of doxorubicin and 85 mg/m² of doctaxel. The dose-limiting toxicity was sepsis, occurring in two of five patients. The only grade 3 or 4 adverse event was neutropenia. There was no congestive heart failure, significant decrease in left-ventricular ejection fraction, or discontinuation of treatment because of fluid retention.
This study did not use G-CSF; an increase in dose intensity of this combination might be possible if G-CSF were added to the regimen to control febrile neutropenia. The recommended doses were defined as 75 mg/m² of docetaxel and 50 mg/m² of doxorubicin, or 60 mg/m² of both drugs on day 1 every 3 weeks, without G-CSF support. Responses were observed at all dose levels.
The recommended doses used in this study demonstrated an acceptable safety profile; ie, an acceptable incidence and severity of febrile neutropenia, with no grade 3 or 4 toxicity or severe infection. A phase II trial is underway, and an ongoing phase III study is investigating whether the doxorubicin/docetaxel combination is more effective than doxorubicin/cyclophosphamide (Cytoxan, Neosar).