Doxorubicin plus paclitaxel in advanced breast cancer.

The combination of bolus doxorubicin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) as a 3-hour infusion is highly active in patients with metastatic breast cancer, but it has considerable cardiotoxicity. In this ongoing study, the potential effect of increasing the interval between administration of a short infusion of doxorubicin followed by a 3-hour infusion of paclitaxel was evaluated. Included were patients with metastatic breast cancer, who received doxorubicin 50 mg/m2 followed by paclitaxel 200 mg/m2 at intervals of 30 minutes, 4 hours, and 24 hours every 3 weeks. As of February 1997, 34 patients have been enrolled, two patients are too early to evaluate, and 13 are continuing treatment. The preliminary response rate is 69% (95% confidence interval, 50% to 84%), ranging from 60% to 80% within the three schedules. The main toxicities consisted of grade 3/4 neutropenia in 65% of all courses, with febrile neutropenia in 2%. Stomatitis and paresthesia were rare. To date, eight of 32 patients have developed abnormal left ventricular ejection fraction values and one patient has developed congestive heart failure. Our preliminary conclusions are that bolus doxorubicin followed by a 3-hour infusion of paclitaxel is highly active against metastatic breast cancer. The potential for cardiotoxicity with the regimen is reduced considerably if the maximum recommended cumulative dose of doxorubicin is reduced to 360 mg/m2 with a maximum single dose of 50 mg/m2.

Paclitaxel and doxorubicin in metastatic breast cancer.

For the past decades the anthracyclines have been regarded as among the most active drugs for the treatment of metastatic breast cancer. However, the 5-year survival rate in patients with stage IV breast cancer continues to be below 20%, and new active drugs and drug combinations clearly must be explored. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been demonstrated to be highly effective in treating patients with advanced breast cancer, including those with anthracycline-resistant breast cancer, a fact that has led to efforts to combine paclitaxel and anthracyclines. Several studies aiming to define the optimal dose and schedule of combination paclitaxel/doxorubicin have now been completed or are ongoing. Phase I/II studies have yielded encouraging preliminary response rates but quite variable toxicity profiles depending on the schedule used. These clinical trials involving combination paclitaxel/doxorubicin are reviewed, with special emphasis on the short-infusion trials.

Doxorubicin and paclitaxel, a highly active combination in the treatment of metastatic breast cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is active against advanced breast cancer and anthracycline-resistant breast cancer. We assessed the efficacy and toxicity of doxorubicin followed by a 3-hour infusion of paclitaxel in women with advanced breast cancer. Participants could have received at most one prior adjuvant chemotherapy regimen, but no previous exposure to anthracyclines or taxanes was permitted. The patients were treated every 3 weeks with doxorubicin (50 or 60 mg/m2) followed 30 minutes later by paclitaxel (155, 175, or 200 mg/m2). After reaching the maximum cumulative doxorubicin dose, treatment could be continued with paclitaxel alone. Thirty women were included, of whom 29 were evaluable for response. The overall response rate was 83% (95% confidence interval, 64% to 94%), with 24% of patients attaining complete remission. Median response duration for complete responders was 8+ months (range, 4 to 13 months) and median time to progression was 9 months (range, 2 to 18 months). Main toxicities were neutropenia, paresthesia, nausea/vomiting, alopecia, myalgia, and cardiotoxicity. In 15 patients (50%), the left ventricular ejection fraction decreased to below normal levels; six patients (20%) developed congestive heart failure. In conclusion, the combination of doxorubicin and paclitaxel is highly active; dose-limiting toxicities are neutropenia, neuropathy, and cumulative cardiotoxicity.

Combined doxorubicin and paclitaxel in advanced breast cancer: effective and cardiotoxic.

BACKGROUND: Paclitaxel has shown activity in metastatic breast cancer, including anthracycline-resistant breast cancer. The efficacy, toxicity and optimal scheduling of the combination of the two drugs needs to be defined. PATIENTS AND METHODS: Thirty women with advanced breast cancer who had undergone at most one prior adjuvant chemotherapy regimen, were treated at three different dose levels with doxorubicin (50, 60 and 60 mg/m2) followed 30 minutes later by paclitaxel (155, 175 and 200 mg/m2, respectively) every 3 weeks. RESULTS: The overall response rate was 83% (95% CI: 64-94), with 24% of patients achieving CR. The median response duration for complete responders was 11 months (range 4-14+) and median survival 18 months (range 3-28+). Two hundred sixty-five treatment courses were given (median 9, range 3-13) and the median cumulative dose of doxorubicin was 369 mg/m2 (range 114-550). The main toxicities were neutropenia, parestesia, nausea/vomiting, alopecia, myalgia and cardiotoxicity. Fifteen patients (50%) had reductions of left ventricular ejection fraction of below normal levels and 6 of these patients (20%) developed congestive heart failure. CONCLUSION: The combination of doxorubicin and paclitaxel is highly active, but is accompanied by the dose-limiting toxic effects of neutropenia, neuropathy and cardiotoxicity.

Paclitaxel and doxorubicin, a highly active combination in the treatment of metastatic breast cancer.

The activity of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been documented in untreated and previously treated metastatic breast cancer, including both patients with anthracycline-resistant disease and those with extensive pretreatment. Such activity has prompted investigations of the optimal doses and schedules of paclitaxel/doxorubicin combinations. With one exception, paclitaxel has been administered as either a 24- or a 3-hour infusion, while the administration times for doxorubicin vary from bolus injection to 72-hour infusion. Results of these completed phase I and II trials are reviewed. Also reported are two European trials that have achieved promising results. In Milan, a phase I/II trial has shown a preliminary response rate exceeding 90% in 32 chemotherapy-naive patients treated with an alternating schedule of paclitaxel given over 3 hours and intravenous bolus doxorubicin. At doses of paclitaxel 200 mg/m2 and doxorubicin 60 mg/m2, the dose-limiting toxicities were neutropenia, oral mucositis, myalgias, and peripheral neuropathy. Congestive heart failure occurred in six patients. A phase I/II study of a 30-minute doxorubicin infusion preceding a 3-hour paclitaxel infusion every 3 weeks in minimally pretreated patients also is reported. Of 29 patients evaluable for response, 17 have achieved partial responses and seven complete responses, for an overall response rate of 83% (95% confidence interval, 79% to 99%). Toxicities observed were grades 3 to 4 neutropenia and moderate paresthesias, nausea/vomiting, alopecia, myalgia, and mucositis. Cardiotoxicity also occurred, as 15 patients had a significant decrease in left ventricular ejection fraction measured by isotope cardiography. Six of these developed congestive heart failure. This effect has been observed only in studies using short infusions of both drugs, and it is now being investigated whether lowering the peak doxorubicin concentration will preclude it.

Treatment of metastatic breast cancer with paclitaxel and doxorubicin.

The activity of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) against untreated and previously treated metastatic breast cancer (documented in anthracycline-resistant disease and in extensively pretreated patients as well) has prompted investigations of the optimal doses and schedules of paclitaxel/doxorubicin combinations. With one exception, paclitaxel has been administered in either a 24- or a 3-hour infusion, while the administration times for doxorubicin vary from bolus injection to a 72-hour infusion. Results of these completed phase I and II trials are reviewed. Also reported are two ongoing European trials that have achieved promising preliminary results. In Milan, a phase I trial has achieved a preliminary response rate exceeding 90% in 30 chemotherapy-naive patients treated with an alternating schedule of paclitaxel over 3 hours and intravenous bolus doxorubicin. At doses of paclitaxel 200 mg/m2 and doxorubicin 60 mg/m2, the dose-limiting toxicity is leukopenia and mucositis. Furthermore, congestive heart failure has occurred in six patients. We are conducting a phase I/II study in minimally pretreated patients, with a 30-minute doxorubicin infusion preceding a 3-hour paclitaxel infusion every 3 weeks. Of 24 patients evaluable for response, five have achieved partial responses and three complete responses. (Another five partial and two complete responses need confirmation.) Of the two dose levels now given, all responses occurred at the higher paclitaxel/doxorubicin level, 175 and 60 mg/m2, respectively. Despite grades 3 and 4 neutropenia in 31% and 60% of courses, respectively, only six patients have been hospitalized for febrile neutropenia. Of concern, the left ventricular ejection fraction has decreased to below normal in six patients and two have developed symptomatic congestive heart failure. Whether lowering the peak doxorubicin concentration will preclude this effect, which has been observed only in the studies using short infusions of both drugs, is under investigation.

Ondansetron plus metopimazine compared with ondansetron alone in patients receiving moderately emetogenic chemotherapy.

BACKGROUND AND METHODS: The serotonin (5-hydroxytryptamine3) antagonists have improved the treatment of acute chemotherapy-induced nausea and vomiting, but their ability to prevent delayed nausea and vomiting seems less pronounced. The results of a preliminary open trial suggested that the addition of a selective dopamine D2 antagonist could improve the antiemetic efficacy of the serotonin antagonists. In a randomized, double-blind, crossover trial, we compared oral treatment with ondansetron (8 mg twice a day) and the dopamine D2 antagonist metopimazine (30 mg four times a day) with treatment with ondansetron alone for three days in 30 patients who had vomited during the previous cycle of chemotherapy. All the patients received moderately emetogenic chemotherapy. RESULTS: Combination treatment with ondansetron and metopimazine significantly reduced the incidence of acute (P = 0.006) and delayed (P = 0.02) nausea and acute (P = 0.02) and delayed (P = 0.006) vomiting, as compared with treatment with ondansetron alone. Patients had significantly fewer days of nausea (P = 0.03) and vomiting (P = 0.003) if they received combination therapy. Sixty-seven percent of the patients preferred ondansetron and metopimazine, and 33 percent favored ondansetron alone (P = 0.10). Adverse reactions were mild with both regimens. With the exception of constipation, which was reported more frequently with combination therapy (P = 0.03), there were no significant differences in adverse reactions. CONCLUSIONS: Ondansetron plus metopimazine is a highly effective and safe antiemetic regimen that is markedly superior to treatment with ondansetron alone in patients receiving moderately emetogenic chemotherapy.