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]
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 and as first-line treatment of metastatic breast cancer, and high response rates with the gemcitabine/ doxorubicin combination in advanced breast cancer.
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 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.
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.
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 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.
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.
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.
1. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 13:2688-2699, 1995.
2. Sledge GW, Neuberg D, Ingle J, et al: Phase III trial of doxorubicin vs. paclitaxel vs. doxorubicin + paclitaxel as first-line therapy for metastatic breast cancer: An Intergroup trial (abstract 2). Proc Am Soc Clin Oncol 16:1a, 1997.
3. Noble S, Goa KL: Gemcitabine: A review of its pharmacology and clinical potential in non- small-cell lung cancer and pancreatic cancer. Drugs 54:447-472, 1997.
4. Stadler WM, Kuzel T, Roth B, et al: Phase II study of single agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol 15:3394-3398, 1997.
5. Carmichael J, Possinger K, Philip P, et al: Gemcitabine: A phase II study in patients with advanced breast cancer (abstract 57). Proc Am Soc Clin Oncol 12:64, 1993.
6. Possinger K, Kaufmann M, Helsing M, et al: Advanced breast cancer: A phase II trial with gemcitabine (abstract 369). Eur J Cancer 31 (suppl 5): 80, 1995.
7. Spielmann M, Pouillart P, Espie M, et al: Activity of gemcitabine in metastatic breast cancer patients previously treated with anthracycline containing regimens (abstract 99). Ann Oncol 7(5):23, 1996.
8. Rothenberg ML, Sharma A, Weiss GR, et al: Phase I trial of paclitaxel and gemcitabine administered every two weeks in patients with refractory solid tumors. Ann Oncol 9:733-738, 1998.
9. Colomer R, Llombart A, Lluch A, et al: Biweekly paclitaxel and gemcitabine in advanced breast cancer. Phase II trial and predictive value of HER2 extracellular domain. Proc Am Soc Clin Oncol 19:373, 2000.
10. Pérez Manga G, Lluch A, Alba E, et al: Gemcitabine in combination with doxorubicin in advanced breast cancer: Final results of a phase II pharmacokinetic trial. J Clin Oncol 13:2545-2552, 2000.
11. Lozano A, Sánchez-Rovira P, Medina B, et al: Phase II biweekly paclitaxel, doxorubicin and gemcitabine as first-line chemotherapy for metastatic breast cancer: Preliminary results (abstract 84P). Ann Oncol 9 (suppl 4): 16, 1998.
12. Sánchez-Rovira P, Mohedano N, Moreno MA, et al: Preliminary results from a early phase II trial of combination gemcitabine and paclitaxel in metastatic breast cancer. Eur J Cancer 33 (suppl 8):S154, 1997.
13. Dombernowsky P, Gehl J, Boesgard M, et al. Doxorubicin and paclitaxel: A highly active combination in the treatment of metastatic breast cancer. Semin Oncol 23(suppl 11):23-27, 1996.
14. Cazap E, Ventriglia M, Rubio G, et al: Taxol plus doxorubicin in the treatment of metastatic breast cancer (abstract 248). Proc Am Soc Clin Oncol 15:146, 1996.
15. Gennari A, Donati S, Danesi R, et al: The gemcitabine/epirubicin/paclitaxel combination in advanced breast cancer. Semin Oncol 27(suppl 2):14-19, 2000.
16. Kroep JR, Tolis C, Voorn DA, et al: Paclitaxel and gemcitabine cell cycle interactions in non-small-cell lung cancer cell lines. Proc Am Assoc Cancer Res 40:678, 1999.
17. Amadori D, Frassineti GL, Zoli W, et al: A phase I/II study of sequential doxorubicin and paclitaxel in the treatment of advanced breast cancer. Semin Oncol 23(suppl 11):23-27, 1996.
18. Amadori D, Frassineti G, Zoli W, et al: A phase I/II study of doxorubicin and paclitaxel (sequential combination) in the treatment of advanced breast cancer. Oncology 11(4 suppl 3):30-33, 1997.