Accrual to this trial is complete at 208 patients, but preliminary analysis is only available for the first 100 patients (55 treated with paclitaxel(Drug information on paclitaxel) and 45 with CMFP). No formal comparative analysis will be performed on the first 100 patients. Objective responses were attained by 31% (95% confidence interval [CI], 19% to 45%) of patients in the paclitaxel-treatment group and 36% (95% CI, 22% to 51%) of those given CMFP. An additional 33% of patients on the paclitaxel arm and 29% of those on the CMFP arm had stable disease. By the time of this report, disease progression had occurred in 89% of paclitaxel-treated patients and 91% of CMFP-treated patients. The median progression-free survival was 5.5 months (95% CI, 4.1 to 5.7 months) in the paclitaxel arm and 6.4 months (95% CI, 4.1 to 7.6 months) in the CMFP arm. At the time of the preliminary report, the median survival was 17.3 months (95% CI, 13.2 to 24.7 months) for paclitaxel-treated patients and 11.3 months (95% CI, 9.2 to 15.3 months) for CMFP-treated patients. Of those first 100 cases, 65% of the paclitaxel group and 47% of the CMFP group were alive at 12 months.
Toxicity comparisons revealed that WHO grade 3 and 4 neutropenia developed in 64% of patients treated with paclitaxel and 63% with CMFP (Table 2). There were 2% WHO grade 2 to 4 infections with paclitaxel and 14% with CMFP. Hospital admissions were required for febrile neutropenia in two of 332 (1%) courses of paclitaxel and 15 of 184 (8%) courses of CMFP. There were 13% of paclitaxel patients with WHO grade 2 to 3 mucositis and 27% with CMFP. WHO grade 3 peripheral neuropathy was seen in 5% of paclitaxel patients with grade 2 in 35% compared to no grade 2 or 3 peripheral neuropathy on CMFP. Although 36% of paclitaxel patients experienced mild hypersensitivity reactions, none had severe reactions, and there were no reactions with CMFP. In 58% of paclitaxel patients WHO grade 2 to 3 myalgia or arthralgia developed, compared to 7% of CMFP patients.
Quality of life was assessed by the patient using a linear analogue scale and by the physician. The change in quality of life with treatment compared to baseline values suggested that paclitaxel-treated patients, overall, maintained or improved their quality of life, while CMFP-treated patients experienced a deterioration in their quality of life (Table 3).
Further follow-up of all 208 patients accrued to this study is required before the final results are known and can be reported. However, the investigators concluded that these preliminary results suggest that single-agent paclitaxel, used as initial chemotherapy in an outpatient setting, was well tolerated and effected comparable control of metastatic cancer in comparison to standard CMFP therapy. Preliminary quality-of-life assessment in the first 100 patients studied revealed that quality of life may have improved with paclitaxel but appeared to decline with the CMFP regimen.
Paclitaxel is clearly an active drug for treatment of metastatic breast cancer and represents an important addition to other chemotherapy agents. Its place as a single agent in the first-line treatment of metastatic breast cancer will be determined by randomized studies such as this one and others comparing paclitaxel to anthracycline-containing regimens. Preliminary results are encouraging and suggest that front-line paclitaxel may produce similar antitumor control with improved quality of life compared to CMFP.
Ultimately, however, paclitaxel is likely to be used in combination with other chemotherapy drugs. Particularly exciting phase II studies of combination paclitaxel/doxorubicin have reported responses from 58% to 94%. These studies suggest that an important future role for paclitaxel will be in combination with anthracyclines.[39,40] In the study by Gianni and colleagues, a maximum tolerated dose of paclitaxel 200 mg/m² was established, with doxorubicin(Drug information on doxorubicin) given at fixed dose of 60 mg/m². In that study, dose-limiting toxicities were neutropenia and mucositis. Six women had reversible congestive heart failure after a median total doxorubicin dose of 480 mg/m². Complete responses were seen in 41% of patients, for a total objective response of 94%. This response rate compares with a complete response rate of 15% reported in most studies of combination chemotherapy for metastatic breast cancer.[12,17,23] The median response duration in the study by Gianni and colleagues was 8 months for complete responders and 11 months for partial responders. Caution may be needed in patient selection, scheduling, and monitoring to avoid cardiac or other side effects with this combination. Subsequent studies by Gianni and colleagues[41,42] showed that six courses of the same combination resulted in similar efficacy but a major reduction in cardiotoxicity.
Combination paclitaxel/doxorubicin is now the subject of a large, randomized Intergroup study in the United States comparing single-agent doxorubicin (60 mg/m²), single-agent paclitaxel (175 mg/m²), and doxorubicin (50 mg/m²) plus paclitaxel (150 mg/m²); it is also the subject of other studies. The Southwest Oncology Group (SWOG) is randomizing patients to doxorubicin 60 mg/m2 and paclitaxel 200 mg/m² compared with AC. The European Organization for the Research and Treatment of Cancer is studying doxorubicin 60 mg/m² and paclitaxel 175 mg/m² compared with AC. If the high response rates previously reported are confirmed in these trials and translate into a meaningful survival advantage in a large cooperative-group setting, paclitaxel will have made another important contribution to the treatment of breast cancer.