ABSTRACT: In a phase II trial, 29 patients with anthracycline-pretreated or anthracycline-resistant metastatic breast cancer in whom anthracycline-containing first- or second-line chemotherapy failed received combination paclitaxel (Taxol)/gemcitabine (Gemzar). The initial regimen of paclitaxel at 175 mg/m2 on day 1 and gemcitabine at 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle was given to five patients for a total of 27 cycles. The regimen resulted in excessive thrombocytopenia and was subsequently changed to gemcitabine at the same dose on days 1 and 8 of a 21-day cycle, with study treatment being given for a maximum of eight cycles. This regimen was well tolerated. Further evaluation of this regimen in minimally and heavily pretreated patients with advanced breast cancer is warranted. [ONCOLOGY 15(Suppl 3):25-27, 2001]
The combination of paclitaxel (Taxol) and gemcitabine (Gemzar) is associated with manageable toxicity and significant activity as salvage therapy in metastatic breast cancer. Second-line treatment of refractory metastatic breast cancer remains primarily palliative. Responses may be achieved in 20% to 40% of patients with drug combinations; however, rapid tumor progression is typical in this setting and no significant impact on survival has been observed.[1-4]
Treatments that could improve outcome in patients failing initial chemotherapy would be of great value. Therefore, further evaluation of this regimen in minimally and heavily pretreated patients with advanced breast cancer is warranted.
Paclitaxel has shown single-agent activity comparable to that of anthracyclines when used at doses of 175 to 250 mg/m2 in pretreated patients with metastatic breast cancer.[5-8] Gemcitabine has also shown significant activity as single-agent first- or second-line therapy in metastatic breast cancer at doses of 725 to 1,200 mg/m2[9-13] and has been associated with generally mild myelosuppression and minimal nonhematologic toxicity. Given the single-agent activity of both paclitaxel and gemcitabine in metastatic breast cancer, their different mechanisms of action, and their nonoverlapping nonhematologic toxicity profiles, combining the agents appears to be a promising strategy. Thus, we performed a phase II study of salvage treatment with the paclitaxel/gemcitabine combination in patients with metastatic breast cancer.
It is important to note that we anticipated that there might be an additive or synergistic effect of combining paclitaxel and gemcitabine given the single-agent activity of both and their differing cellular mechanisms of action. Antagonistic effects of the combination in vitro have recently been reported in a study assessing concurrent and sequential use of the agents in a number of cell lines. Our study was not designed to assess potential cross resistance or in vivo synergy or antagonism of the two agents. This issue needs to be addressed in further studies.
Eligible patients were less than 70 years old with histologically confirmed metastatic breast cancer who had received first- or second-line therapy with anthracycline-containing regimens. Each had bidimensionally measurable lesions, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, absolute neutrophil count ³ 2 × 109/L, platelet count ³ 130 × 109/L, and adequate renal and hepatic function. Patients with central nervous system involvement or carcinomatous meningitis, significant cardiac disease, or history of current peripheral neuropathy were excluded from the study. Patients were permitted to have prior radiation therapy if it was completed ³ 4 weeks prior to the study and it encompassed < 30% of the total marrow-bearing skeleton. Prior hormonal therapy was permitted if it was discontinued ³ 3 weeks prior to the study.
Patients received paclitaxel at 175 mg/m2 via 3-hour intravenous (IV) infusion on day 1 and gemcitabine at 1,000 mg/m2 via 40-minute IV infusion on day 1 (after paclitaxel) and day 8 in 21-day cycles for a maximum of eight cycles. The first five patients received gemcitabine at 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Due to an unacceptable level of thrombocytopenia in these patients, the treatment schedule was subsequently modified to the 21-day cycle with gemcitabine administration on days 1 and 8 only. Scheduled therapy was delayed for 1 week for neutrophil counts ≤ 1 × 109/L and platelet counts £ 120 × 109/L; patients were withdrawn from the study if values did not exceed these levels after 2 weeks.
Paclitaxel and gemcitabine doses were reduced by 50% if febrile neutropenia occurred or if a neutrophil count nadir < 0.5 × 109/L or platelet count nadir < 50 × 109/L was observed. Patients were withdrawn from the study if progressive disease was observed after the second cycle of chemotherapy or if stable or progressive disease was observed after the fourth cycle.
Treatment responses were defined as follows:
Complete response: the resolution of all identified disease without development of new disease as determined by two measurements at least 4 weeks apart.
Partial response: a decrease of ³ 50% in the sum of the products of the two perpendicular diameters of all measured lesions and development of no new lesions on two measurements at least 4 weeks apart.
No change: a decrease of < 50% or increase of < 25% in size of lesions.
Progressive disease: an increase of ³ 25% in size of at least one lesion or appearance of a new lesion. Pleural effusion or ascites with positive cytology also constituted progressive disease.
Survival and response durations were calculated using the Kaplan-Meier method. The 95% confidence intervals (CIs) for response rates were calculated using the binomial theorem.
Each of the 29 patients enrolled was considered evaluable for safety and response. Patients had a median age of 46 years (range: 32 to 68 years). ECOG performance status was 1 in 5 patients and 2 in 24. The predominant sites of metastatic disease were liver (11 patients), lung (7), bone (6), and soft tissue/skin (5). Prior adjuvant chemotherapy consisted of CMF (cyclophosphamide [Cytoxan, Neosar]/methotrexate/fluorouracil) in 12 patients and FAC (fluorouracil/doxorubicin [Adriamycin]/cyclophosphamide) in 6. Prior treatment for metastatic disease consisted of FAC in 18 patients, CMF plus mitoxantrone (Novantrone) in 4, fluorouracil/epirubicin (Ellence)/cyclophosphamide in 4, and cisplatin (Platinol)/vinblastine/mitomycin in 3.
Hormonal therapy had been received as part of adjuvant treatment by 5 patients and in treatment of metastatic disease by 8 patients; 17 had received radiotherapy for metastatic disease. Prior chemotherapy for metastatic disease had resulted in tumor response in 25 of 29 patients.
A total of 137 cycles of paclitaxel/gemcitabine were administered, with a median of 4 cycles per patient. The first 27 cycles were 28-day cycles with gemcitabine administered on days 1, 8, and 15. Toxicities according to grade and proportions of treatment cycles affected are shown in Table 1.
Grade 3 neutropenia occurred in 8 patients (27.6%); grade 4 neutropenia with fever occurred in 2 patients (6.9%) in 4 cycles among the first 27 cycles. Grade 3 or 4 thrombocytopenia was observed in 5 (18.5%) of the first 27 cycles and in 6 (5.4%) of the remaining 110 cycles using the 21-day schedule (P = .04 for comparison between the two periods by Fisher’s exact test). Most patients experienced grade 1 nausea/vomiting, grade 2/3 alopecia, and grade 1 neutropenia; five patients had grade 1 neuropathy and two had grade 3 neuropathy.
In the 137 cycles, treatment delays occurred in 13 (9.4%); delays were due to thrombocytopenia in 8 cycles (5.8%) and neutropenia in 4 cycles (2.9%). Dose reductions occurred in 17 cycles (12.4%), including reductions due to myelotoxicity in 9 cycles (6.5%). Three patients received blood transfusion for treatment of anemia. One patient developed reversible bradycardia during paclitaxel infusion.
Objective responses were observed in 16 (55%) of the 29 patients (95% CI: 36% to 73%), consisting of complete response in 5 patients (17.2%; 95% CI: 3% to 30%) and partial response in 11 patients (37.9%; 95% CI: 19% to 56%). Stable disease was observed in six patients (20.5%). Median duration of response was 8 months, with a range of 4 to 26 months. Median overall survival was 12 months, with a range of 4 to > 28 months (Figure 1); the 1-year survival rate was 45% and the 2-year survival rate was 30%.
In this study, the combination of paclitaxel and gemcitabine exerted significant activity as second- or third-line treatment in metastatic breast cancer, with objective response achieved in more than half the patients and complete response achieved in 5 of the 29. The median survival duration (12 months) and the 1- and 2-year survival rates (45% and 30%, respectively) are quite impressive in this setting. Toxicity of the regimen was acceptable and manageable.
Hematologic toxicity consisted primarily of mild neutropenia, with grade 3 neutropenia being observed in 8 patients (27.6%). The 4 cycles in which grade 4 neutropenia with fever was observed and 5 of the 11 cycles in which grade 3 or 4 thrombocytopenia was observed occurred during the first 27 cycles, in which gemcitabine was administered on days 1, 8, and 15 of a 28-day cycle. The decrease in more serious hematologic toxicity with the schedule of gemcitabine on days 1 and 8 of a 21-day cycle suggests that the latter may be the optimal schedule for combination with paclitaxel. Nonhematologic toxicities were generally mild, and the regimen was well tolerated. Overall, treatment delays occurred in only 8.7% of cycles and dose reductions occurred in only 6.5% of cycles.
In summary, we found that the combination of paclitaxel and gemcitabine was associated with manageable toxicity, a high response rate, and remarkably prolonged survival durations when used as salvage therapy in metastatic breast cancer. The schedule of paclitaxel on day 1 and gemcitabine on days 1 and 8 of a 21-day cycle was associated with a marked reduction in hematologic toxicity compared with a schedule of gemcitabine on days 1, 8, and 15 of a 28-day cycle. Thus, the former schedule appears to be optimal for use in subsequent studies. This combination regimen warrants further evaluation in minimally and heavily pretreated patients with advanced disease.
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