Doxorubicin-Paclitaxel Combination Active in Metastatic Breast Cancer: ECOG Phase II Trial

SAN ANTONIO—A phase II trial conducted by the Eastern Cooperative Oncology Group (ECOG) of doxorubicin plus paclitaxel (Taxol) with G-CSF (filgrastim, Neupogen) in metastatic breast cancer produced an overall response rate of approximately 50%, with a median response duration of about 4 months, said Joseph A. Sparano, MD, of Albert Einstein Cancer Center, New York City, at the 20th Annual San Antonio Breast Cancer Symposium. However, complete responses were uncommon.

“The efficacy of doxorubicin plus paclitaxel [given over 3 hours] reported in this study was roughly comparable to that of doxorubicin plus 24-hour paclitaxel employed in ECOG’s phase III trial [#1193],” Dr. Sparano noted. However, he added, the overall and complete response rates were substantially lower than those reported by Gianni (Milan) and other groups with doxorubicin and paclitaxel given as a 3-hour infusion.

“The regimen that we employed,” he said, “was identical to that employed by Gianni with one exception—we restricted the cumulative doxorubicin dose to between 240 and 360 mg/m² given in four to six cycles, compared with 480 mg/m² given in up to eight cycles by Gianni.”

Therefore, Dr. Sparano said, the lower overall and complete response rates in the ECOG study, compared with Gianni’s report, are likely due to differences in patient selection and treatment duration. “Restricting the duration of therapy, however, did reduce the incidence of congestive heart failure from 20%, reported by Gianni, to 4% in our trial,” he said.

The 52 women (median age, 51 years; range, 18 to 72 years) who participated in the phase II study had measurable and/or evaluable metastatic breast cancer and ECOG performance status 0 or 1. Over half (58%) had visceral disease, and approximately two-thirds had three or more sites of metastasis.

None of the patients had received prior chemotherapy for metastatic disease. One-quarter had received prior adjuvant therapy (although not with doxorubicin or paclitaxel).

Doxorubicin (60 mg/m² IV bolus) was given first, followed, after a 15-minute interval, by paclitaxel (200 mg/m² infused over 3 hours). G-CSF (5 µg/kg SC) was started on day 2 and continued until the postnadir absolute neutrophil count (ANC) was at least 10,000. Treatment was repeated every 3 weeks, as long as the ANC was at least 1,500 and platelet count at least 100,000.

Left ventricular ejection fraction (LVEF) was measured after four cycles of therapy. An additional two cycles were given to patients who showed responses and whose LVEF was normal and had not declined more than 10% from baseline. In addition, those whose disease responded or stabilized after four or six cycles received further treatment with single-agent paclitaxel until either disease progression or prohibitive toxicity occurred.

Of 48 evaluable patients, 25 (52%) responded to doxorubicin-paclitaxel. Two patients (4%) had a complete response. “Responses occurred at all sites with equal frequency, including soft-tissue, bone, and visceral sites,” he said.

Three (25%) of the 12 patients who had received prior adjuvant chemotherapy had a partial response to doxorubicin-paclitaxel. In contrast, 61% of those who had not received adjuvant therapy responded to the combination, 6% of whom had a complete response.

Duration of Response

The median duration of response was 3.9 months, and median time to treatment failure was 7.9 months. “Median survival has not yet been reached after a median follow-up of 10.5 months,” Dr. Sparano noted. Fourteen patients (27%) have died of progressive disease.

Ejection fraction decreased to subnormal values in approximately 20% of patients after a median of four cycles of therapy and a mean cumulative doxorubicin dose of 240 mg/m², Dr. Sparano said. LVEF declined by 10% or more in only 33% of these patients. To date, congestive heart failure has occurred in only two patients (4%).

Although severe leukopenia was observed in 80% of patients, only 20% developed severe infections. Nearly half of the patients experienced stomatitis or diarrhea, but this was mild to moderate in most cases. Severe neurotoxicity developed in fewer than 20% of patients.

Based on the data from the phase II trial, one audience member questioned whether there is any advantage of the doxorubicin plus paclitaxel combination over standard FAC (fluorouracil, Adria-mycin, cyclophosphamide).

In response, Dr. Sparano said that “there is very little evidence that any combination, including doxorubicin and a taxane, is superior to doxorubicin alone with regard to survival.”

He added that although his group’s strategy of restricting the cumulative dose of doxorubicin greatly reduced the incidence of congestive heart disease, “an unacceptably large proportion of patients developed a subclinical but substantial decline in their ejection fraction below normal.”

Sequential Use Suggested

Dr. Sparano concluded: “Doxorubicin-based therapy should still remain the standard of care for patients with metastatic breast cancer. At this time, there does not seem to be any survival advantage if doxorubicin and the taxanes are given concomitantly. Therefore, sequential use of the drugs would seem to be the most prudent strategy, reserving the taxane for progression after initial doxorubicin-based therapy.”