Both gemcitabine(Drug information on gemcitabine) (Gemzar) and paclitaxel(Drug information on paclitaxel) exhbit good singleagent activity in advanced breast cancer.[1-5] In phase II trials reported to date, the combination has produced good objective response rates as both first-line chemotherapy and in heavily pretreated patients with advanced disease.[6-9] We report on a phase II trial of gemcitabine/paclitaxel as first-line treatment in patients with advanced breast cancer. Patients and Methods To be eligible for study entry, patients had to be at least 21 years of age with Zubrod performance status of 0 to 2: they had to have histologically or cytologically confirmed met-astatic disease, or metastatic plus locally advanced breast cancer with bidimensionally measurable disease. Prior adjuvant chemotherapy-excluding gemcitabine and taxanes, hormonal therapy, and radiotherapy- was permitted. Patients had to have adequate bone marrow, hepatic, and renal function, as indicated by absolute neutrophil count > 1,500/μL, platelet count >100,000/μL, serum total bilirubin < 2.0 mg/dL, alanine/aspartate aminotransferase level < 3 times the upper limit of normal, and serum creatinine < 1.5 mg/dL. Study treatment consisted of gemcitabine at 1,200 mg/m2 given as a 30-minute intravenous (IV) infusion on days 1 and 8 plus paclitaxel at 175 mg/m2 given as a continuous 3-hour IV infusion on day 1 every 21 days for a maximum of 8 cycles. Patients received routine antiemetic treatment 1 hour before the study treatment infusions. Treatment was discontinued in the event of unacceptable toxicity, treatment delay longer than 3 weeks, disease progression, or patient refusal. Dose adjustments were made as follows. On day 8, the gemcitabine dose was reduced by 25% if granulocyte count was between 2.0 and 2.49 * 106/L or platelet count was between 75 and 99 * 106/L, or reduced by 50% if granulocyte count was between 1.0 and 1.99 or platelet count was between 50 and 74 * 106/L. For the cycle following any cycle in which hematologic toxicity occurred, doses were adjusted by reducing gemcitabine and paclitaxel doses by 25% for granulocyte counts between 1.0 and 1.49 * 106/L or platelet counts between 75 and 99 * 106/L, or by 50% for granulocyte counts between 0.5 and 0.99 × 106/L or platelet counts between 50 and 74 * 106/L. Depending on clinical judgment, treatment was withheld for granulocyte counts less than 1.0 * 106/L and/or platelet counts less than 50 * 106/L. For World Health Organization (WHO) grade 3 nonhematologic toxicity, with the exception of nausea/ vomiting and alopecia, doses of both gemcitabine and paclitaxel were reduced by 50% or withheld, depending on clinical judgment. Patients with WHO grade 4 nonhematologic toxicity had their doses withheld at the discretion of the investigator. Results A total of 45 patients entered the study and were evaluable for efficacy and safety. Patient baseline characteristics are shown in Table 1. Patients had a median age of 53.5 years. None of the patients had previously received chemotherapy for metastatic disease. A total of 60% of patients had received prior adjuvant therapy, with 12 patients (26.7%) receiving prior anthracycline adjuvant therapy. All patients had stage IV disease; 35 (77.8%) of patients had visceral disease, with the most common metastatic sites being soft tissue and lung and most patients having one or two metastatic sites. Objective response was observed in 30 of 45 patients, yielding a response rate of 66.7% (95% confidence interval [CI] = 52%-71%). Complete response was observed in 10 patients (22.2%) and partial response was observed in 20 (44.4%). Seven patients (15.6 %) had stable disease. Eight patients (17.8 %) had progressive disease. Objective response rates according to disease site were as follows: soft tissue, 72%; bone, 50%; lung, 54%; liver, 34%; and other visceral sites, 50%. No significant differences in response rates were seen between patients who were estrogen receptor positive vs estrogen receptor negative or between those who had previous adjuvant chemotherapy (with or without anthracyclines) vs no previous adjuvant chemotherapy. The median duration of follow-up was 29 months. The median duration of response was 18 months (95% CI = 11.0-26.7 months). Median time to tumor progression for the entire population was 11 months (95% CI =7.1- 18.7 months). Median overall survival was 19 months (95% CI = 17.3-21.7 months), and the 1-year survival rate was 69%. Both tumor progression and survival are illustrated in Figure 1. Treatment was well tolerated, with infrequent grade 3/4 toxicities (Table 2). Grade 3/4 leukopenia, neutropenia, and thrombocytopenia were each observed in six patients (13.3%); none of the study patients developed grade 3/4 anemia and none received platelet transfusions. Among nonhematologic toxicities, severe alopecia, mucositis, and diarrhea were infrequently observed and grade 3 neuropathy was observed in 1 patient. No patient was discontinued from the study due to toxicity. No treatment-related deaths occurred. A total of 260 treatment cycles were administered, with patients receiving a median of 5.7 cycles (range: 2-8). Dose reductions of 25% and 50% for both drugs were required in 19 (7.3%) and 10 cycles (3.8%), respectively, due to neutropenia. Twenty-three cycles (8.8%) were delayed due to toxicity, and dose adjustments were made in 29 (11.2%). The planned weekly dose intensities were paclitaxel 60 mg/m2 and gemcitabine 800 mg/m2. The mean delivered doses were paclitaxel 48 mg/m2 and gemcitabine 680 mg/m2 per week. Conclusion This trial showed the gemcitabine/ paclitaxel combination to be highly active and well tolerated as first-line treatment in advanced breast cancer. The results achieved are consistent with those reported by other investigators in both chemotherapy-naive and heavily pretreated patients. For example, in a study assessing an every- 2-week regimen of gemcitabine at 2,500 mg/m2 on day 1 and paclitaxel at 150 mg/m2 on day 1 as first-line therapy in 42 patients, 72% of whom had received adjuvant therapy, Colomer and colleagues found objective responses in 29 patients (69%), including complete response in 10 (24%) and partial response in 19 (45%); median duration of response was 9 months. Using an every 3- week regimen of gemcitabine at 1,200 mg/m2 on days 1 and 8 and paclitaxel at 175 mg/m2 as first-line chemotherapy, Genot and colleagues reported an objective response in 15 (42%) of 36 patients, including complete response in 2 (6%) and partial response in 13 (36%); median duration of response was 344 days and median time to progression was 224 days. In a study in heavily pretreated patients by Sànchez-Rovira et al, gemcitabine at 2,500 mg/m2 on days 1 and 15 and paclitaxel at 135 mg/m2 on days 1 and 15 every 28 days produced response in 20 (45%) of 44 patients, with 7 (16%) having complete response and 13 (30%) having partial response; median response duration was 8 months and median survival was 12 months. In another study in heavily pretreated patients, Murad and colleagues reduced the regimen dose from gemcitabine at 1,000 mg/m2 on days 1, 8, and 15 and paclitaxel at 175 mg/m2 on day 1 every 28 days to a 21-day schedule with gemcitabine given on days 1 and 8 and paclitaxel on day 1 after unacceptable toxicity in the first 5 patients treated with the former regimen. Objective response was observed in 16 (55%) of 29 patients, including complete response in 5 (17%) and partial response in 11 (38%); median response duration was 8 months, median survival was 12 months, and 1- and 2-year survival rates were 45% and 30%, respectively. When given at the doses described above on 21- or 14-day schedules, the combination has been very well tolerated. Most recently, O'Shaughnessy and colleagues have reported interim findings in a phase III trial showing superiority of gemcitabine/paclitaxel over paclitaxel alone in anthracycline-pretreated patients with advanced breast cancer using the 21-day schedule. In this trial, patients with metastatic breast cancer who had prior anthracycline treatment and no prior chemotherapy for metastatic disease were randomized to receive gemcitabine 1,250 mg/m2 by 30-minute infusion on days 1 and 8 plus paclitaxel at 175 mg/m2 by 3-hour infusion on day 1 every 21 days (n = 267) or paclitaxel alone at 175 mg/m2 on day 1 every 21 days (n = 262). Median patient age was 53 years; more than 70% of patients had visceral metastases, 75% had at least two sites of metastatic disease, and one-third had receptorpositive disease. The objective response rate in the gemcitabine/paclitaxel group was 39.3% (95% CI = 33.5%-45.2%) compared with 25.6% (95% CI = 20.3%-30.9%) in the paclitaxel group (P = .0007).On interim analysis, median time to disease progression was 5.4 months (95% CI = 4.6-6.1 months) with gemcitabine/paclitaxel, compared with 3.5 months (95% CI = 2.9-4.0 months) for paclitaxel (P = .0013). The hazard ratio for progression with gemcitabine/paclitaxel was significantly reduced (0.734; 95% CI = 0.607-0.889; P = .0015); the probability of being progression-free at 6 months was increased by approximately 50% with combined treatment. Progression-free survival was significantly increased with gemcitabine/ paclitaxel (P = .0021). Effects of the study treatments on overall survival will be provided in the final report from this trial. Grade 4 hematologic toxicity was more common in the gemcitabine/paclitaxel group than in the paclitaxel, with neutropenia occurring in 17.2% vs 6.6%, anemia in 1.1% vs 0.4%, thrombocytopenia in 0.4% vs 0%, and febrile neutropenia in 0.4% vs 0%. Nonhematologic toxicity was predictable and manageable in both groups. In conclusion, our findings indicate that the combination of gemcitabine and paclitaxel is associated with impressive activity and a good safety profile when used as first-line chemotherapy on a 21-day schedule in patients with advanced breast cancer. Similar results have been reported in other phase II studies of this combination in advanced disease, and interim results of a phase III trial using the 21-day regimen indicate significantly improved response rate, time to disease progression, and progression-free survival with the combination vs paclitaxel alone in first-line chemotherapy. This promising combination should be assessed in additional comparative trials- eg, vs standard anthracyclinebased chemotherapy or vs sequential combination treatment with doxorubicin(Drug information on doxorubicin), paclitaxel, and gemcitabine.