Biweekly Gemcitabine, Doxorubicin, and Paclitaxel as First-Line Treatment in Metastatic Breast Cancer
In a single-center, open, phase II trial, we assessed the toxicity and activity of a triple combination therapy-doxorubicin at 30 mg/m2 (day 1), paclitaxel (Taxol) at 135 mg/m2 (day 2), and gemcitabine (Gemzar) at 2,500 mg/m2
ABSTRACT: In a single-center, open, phase II trial, we assessed the toxicity and activity of a triple combination therapy-doxorubicin at 30 mg/m2 (day 1), paclitaxel (Taxol) at 135 mg/m2 (day 2), and gemcitabine (Gemzar) at 2,500 mg/m2 (day 2 after paclitaxel)-administered biweekly in a 28-day cycle for six cycles. This was given as first-line treatment in 41 patients with metastatic breast cancer. Granulocyte colony-stimulating factor was used in 27 patients to permit maintenance of dose density. Hematologic toxicity was moderate. Nonhematologic adverse events were generally mild. The objective response rate was 82.9% (34/41) with 18 patients (43.9%) achieving complete response and 16 (38%) achieving partial response; progressive disease was observed in 4 patients (9.8%). Responses were observed at all metastatic sites, including complete responses in lung, liver, bone, and soft tissue. Median duration of response was 14.1 months and median time to progression was 13.9 months. Median survival was 26.2 months. The biweekly combination of gemcitabine, doxorubicin, and paclitaxel is safe and highly active as first-line treatment in metastatic breast cancer. [ONCOLOGY 15(Suppl 3):44-47, 2001]
Introduction
The combination of paclitaxel (Taxol) and doxorubicin is one of the more active combinations in metastatic breast cancer.[1,2] Gemcitabine (Gemzar), too, exhibits activity in a range of solid tumors, including breast carcinoma.[3-7] The use of gemcitabine in combination with paclitaxel and doxorubicin is attractive because gemcitabine has a favorable toxicity profile and is at least partially non-cross resistant with the other agents. Early phase studies have shown activity of the paclitaxel/gemcitabine combination in a biweekly schedule in a variety of solid tumors[8] and as first-line treatment of metastatic breast cancer,[9] and high response rates with the gemcitabine/ doxorubicin combination in advanced breast cancer.[10]
A phase II study of the triple combination given every other week as first-line treatment in metastatic breast cancer was performed. The doxorubicin dose used in this trial was identified in a phase I study[11] of the triple combination evaluating escalating doxorubicin doses in combination with fixed doses of gemcitabine and paclitaxel derived from our prior experience with biweekly gemcitabine/paclitaxel as second-line treatment in metastatic breast cancer.[12]
Patients and Methods
Eligible patients were age 18 or older with histologically confirmed metastatic breast cancer not suitable for curative surgery or radiotherapy, bi-dimensionally measurable lesions, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Patients also had to have a granulocyte count ³ 1.5 ´ 109/L, a platelet count = 100 ´ 109/L, and adequate hepatic and renal function. Hormonal therapy and radiotherapy were permitted as part of adjuvant treatment; anthracyclines could have been received as part of previous adjuvant treatment only if cumulative doses did not exceed 360 mg/m2 for epirubicin (Ellence) or 200 mg/m2 for doxorubicin. Patients who received adjuvant anthracycline treatment were not to receive doxorubicin in the last treatment cycle in the current study, to ensure that a maximum doxorubicin dose of 480 mg/m2 was not exceeded.
Dosing
Study treatment consisted of doxorubicin at 30 mg/m2 via bolus intravenous (IV) infusion on day 1, paclitaxel at 135 mg/m2 via 3-hour IV infusion on day 2, and gemcitabine at 2,500 mg/m2 via 30- to 60-minute IV infusion following paclitaxel administration on day 2. Treatment was repeated every 2 weeks in 28-day cycles for a maximum of six cycles.
Treatment was delayed for grade 3 or 4 hematologic toxicity until recovery of granulocyte count to > 1.5 ´ 109/L and platelet count to > 75 ´ 109/L. Granulocyte colony-stimulating factor (G-CSF [Neupogen]) could be administered to permit scheduled chemotherapy doses if the absolute neutrophil count was < 1.5 ´ 109/L on the day prior to the next scheduled dose. The paclitaxel dose was reduced in the case of grade 3 neurotoxicity and discontinued in the case of grade 4 neurotoxicity.
Cardiac toxicity is a serious potential complication of combined doxorubicin and paclitaxel; all patients underwent electrocardiography, chest x-ray, and measurement of left ventricular ejection fraction at baseline after the sixth chemotherapy cycle, and at 6-month intervals thereafter.
Patient Response
Patient responses were categorized as follows:
Complete response: if all measurable lesions were resolved.
Partial response: if there was a reduction of > 50% in lesion size with no development of new lesions.
Progressive disease: if lesions increased by > 25% in size or new lesions developed.
Stable disease: in the absence of any of the three categories above.
For patients with complete or partial response, duration of response was determined as the duration from the start of treatment until disease progression. Time to progression was determined as the duration from the start of treatment until disease progression. Median values were calculated using the Kaplan-Meier method.
Results
Each of the 41 patients enrolled were analyzed for toxicity and response on an intent-to-treat basis. Patients had a mean age of 55 years (range: 33 to 68 years). ECOG performance status was 0 in 26 patients and 1 in 15. Patients with metastatic disease included 20 (48.8%) with one metastatic site, 13 (31.7%) with two sites, and 8 (19.5%) with three. Metastatic sites included lung in 19 patients (46.3%), bone in 19 (46.3%), soft tissue/skin in 18 (43.9%), and liver in 11 (26.8%). The majority had received adjuvant radiotherapy or hormonal therapy.
In total, 28 patients had received adjuvant chemotherapy, consisting of epirubicin (17) and cyclophosphamide (Cytoxan, Neosar)/methotrexate/fluorouracil (11). The median cumulative study dose of doxorubicin in patients who had previously received epirubicin was 420 mg/m2, with a range of 300 to 500 mg/m2.
Toxicity
A total of 216 chemotherapy cycles were administered, with a median of six per patient. Toxicities are shown in Table 1. Neutropenia was the most common adverse effect, with grade 3 or 4 neutropenia occurring in 18 patients (43.9%) and in 9.7% of chemotherapy courses; 1 patient had an episode of febrile neutropenia. Neutropenia was of short duration in all cases.
G-CSF treatment was administered on days 5 to 10 in 27 patients (65.8%). Grade 3 and 4 thrombocytopenia occurred in two patients (4.8%, 0.9% of cycles) and one patient (2.4%, 0.5% of cycles), respectively. Grade 3 anemia occurred in five patients (12.2%, 3.4% of cycles). In total, 10 units of packed red blood cells were transfused and one patient required platelet transfusion.
Nonhematologic toxicities were generally mild, with no grade 4 toxicities observed. Nausea/vomiting was the most common nonhematologic toxicity, with grade 3 toxicity occurring in 14.6% of patients. Of 37 patients with at least two measurements of left ventricular ejection fraction, three (8.1%) exhibited decreased ejection fractions, including two who had received adjuvant epirubicin treatment. None of these patients developed heart failure, and ejection fractions returned to normal in two of the patients during follow-up.
In total, 21.3% of chemotherapy cycles (n = 46) were delayed, primarily due to neutropenia. Median delivered dose intensities of the study drugs were doxorubicin 13.8 mg/m2/wk, paclitaxel 60.3 mg/m2/wk, and gemcitabine 1,100 mg/m2/wk. Dose reductions were required in two patients due to mucositis and in one due to grade 3 neurotoxicity.
Response
In total, objective response was achieved in 34 (82.9%) of the 41 patients (95% confidence interval [CI]: 67.9% to 92.8%), consisting of complete response in 18 (43.9%) and partial response in 16 (39%); stable disease was observed in 2 patients (4.9%). Progressive disease occurred in four patients (9.8%). One patient was withdrawn from the study after febrile neutropenia during the first treatment cycle.
Responses were observed at all metastatic sites. The response rate in soft tissue was 85%, with 72% in lung, and 50% in both liver and bone sites. Complete response was observed in the lung in eight patients, in bone and soft tissue in five patients each, and in the liver in two patients. The median duration of response was 14.1 months and the median time to disease progression was 13.9 months (95% CI: 10 to 15 months) (Figure 1). A total of five patients remain free of disease progression after a median follow-up of 25 months. The median survival time was 26.2 months (95% CI: 16.4 to 44.3 months).
Discussion
We observed a high overall response rate of 82.9%, including complete response in 43.9% of patients, with bi-weekly gemcitabine, doxorubicin, and paclitaxel as first-line treatment in metastatic breast cancer. Responses were observed at all metastatic sites, including lung, liver, bone, and soft tissue. The activity of this regimen compares favorably with the best response rates observed with doxorubicin/paclitaxel combinations[13,14] and is consistent with the high response rate reported by Gennari and colleagues in a study of gemcitabine, epirubicin, and paclitaxel in advanced breast cancer.[15]
Most of the patients in the current study had good performance status. However, the generally poor prognostic status of the group is indicated by the fact that half had multiple metastatic sites and visceral metastases.
Hematologic Toxicity
Hematologic toxicity of the regimen was moderate, with grade 4 neutropenia occurring in only 14.6% of patients and grade 4 thrombocytopenia occurring in 2.4%; G-CSF was used to permit scheduled dosing in two-thirds of patients. Nonhematologic toxicity was generally mild, consisting primarily of nausea/vomiting, myalgia, and neuropathy.
The high activity of the triple combination may be associated with the increased drug exposure resulting from reduced intervals between drug administrations. Findings suggestive of such an effect have been made in other studies of dose-dense combinations of paclitaxel with doxorubicin or gemcitabine.[ 9-11] It should also be noted that concurrent administration of paclitaxel and gemcitabine has been reported to increase levels of the gemcitabine active metabolite (difluorodeoxycytidine).[ 16]
Cardiac Toxicity
Cardiac toxicity is a major concern with anthracycline/paclitaxel combinations. Some studies have reported an incidence of symptomatic heart failure of up to 20% with the combination of doxorubicin and paclitaxel.[1,13] One of the methods that has been assessed in the attempt to reduce cardiac toxicity is adjustment of the interval between administration of these drugs.[17,18]
In our regimen, paclitaxel was administered the day after (16 hours after) doxorubicin. We observed reduced left ventricular ejection fractions in three patients (10%-20% in two patients and 20% in one). Of these, two received a cumulative doxorubicin dose of 420 mg/m2 and one received a cumulative dose of 360 mg/m2; none of these patients developed heart failure.
The minimal cardiotoxic effect is consistent with the lack of significant cardiotoxicity observed in other studies in which doxorubicin and paclitaxel were administered sequentially.[17,18] Thus, this strategy may result in reduced cardiotoxicity and permit an increase in the cumulative dose of doxorubicin to > 360 mg/m2 when used in combination with paclitaxel.
Response
The median duration of response was 14.1 months and the median time to progression was 13.9 months. The small difference between these values may be associated with the fact that many patients had not exhibited progression during the course of follow-up. The median survival of 26.2 months is impressive in a patient population such as this one. However, no conclusions regarding the potential effect of the triple combination on survival should be made in the absence of data from randomized trials.
It must be noted that a significant effect of combination therapy on prolonging survival in first-line treatment of metastatic breast cancer has yet to be demonstrated. The phase III randomized Intergroup trial[2] of paclitaxel plus doxorubicin as first-line treatment in metastatic breast cancer showed that the combination was associated with significantly greater response rate and time to progression than either component alone, but no significant differences in survival were observed.
Conclusion
In summary, we have found that the combination of gemcitabine, doxorubicin, and paclitaxel administered on a biweekly basis produces a high response rate and an extended progression-free interval, and is associated with acceptable toxicity when used as first-line treatment in metastatic breast cancer. The effect of such a regimen on survival requires study in a larger-scale randomized trial.
On the basis of the activity observed in this study, including a high complete response rate, we have initiated a phase II trial of this combination as primary therapy in locally advanced breast cancer.
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