Paclitaxel and carboplatin as first-line chemotherapy combined with gefitinib (IRESSA) in patients with advanced breast cancer: a phase I/II study conducted by the Hellenic Cooperative Oncology Group

Abstract

Paclitaxel (Taxol) and carboplatin are an effective combination regimen for treating advanced breast cancer. Gefitinib (IRESSA) is the first epidermal growth factor receptor tyrosine kinase inhibitor to be approved for cancer treatment. This multicenter phase II trial treated 68 patients with advanced breast cancer with paclitaxel (175 mg/m(2) over 3 h) and 3-weekly carboplatin (area under the curve of 6) for six cycles, and 250 mg/day gefitinib orally. Median age was 57 (range 35-77) years, patients had performance status 0 (69.1%), 1 (27.9%) 2 (2.9%), 82.4% of patients had visceral metastases and 63.2% had received adjuvant chemotherapy. Forty-eight (70.6%) patients completed six cycles of chemotherapy and 20 (29.4%) patients discontinued treatment (seven [10.3%] due to disease progression, seven [10.3%] due to toxicity, five [7.4%] withdrew consent and one [1.5%] died after the first cycle). Sixty-three (92.7%) patients were evaluable for response; nine (13.2%) had complete responses, 30 (44.1%) had partial responses, 21 (30.9%) had stable disease and three (4.4%) had disease progression. Grade 3/4 adverse events in > or =5% of patients except of alopecia, included neutropenia (17.7%), anemia (10.3%), diarrhea (7.4%), thrombocytopenia (5.9%) and peripheral neuropathy (5.9%). Of those tumor biopsies available for immunohistochemical analysis (n=60), 5.0% were positive and 35.0% negative for expression of all HER-family receptors. Comparable numbers of tumor biopsies were nuclear p27(kipl) positive and negative (39.7 and 42.7%, respectively), with the majority (72.1%) negative for cytoplasmic p27(kipl). The observed efficacy data in this study were similar to those reported for the combination of paclitaxel and carboplatin alone.

A phase II clinical trial of ZD1839 (Iressa™) in combination with docetaxel as first-line treatment in patients with advanced breast cancer

“…The decision by investigator and patient in these instances may have been influenced by the disappointing results of multiple negative studies involving gefitinib and erlotinib in metastatic breast cancer, reported during the accrual of this trial [23,24]. The results of this trial compare with other recently published phase II trials using EGFR TKI therapy [25][26][27][28]. Gefitinib and erlotinib have shown objective response rates of 0-1.7% as monotherapy in unselected populations of metastatic breast cancer patients.…”

Tolerability of and adherence to combination oral therapy with gefitinib and capecitabine in metastatic breast cancer

“…[27] Combination therapy with paclitaxel, carboplatin, and gefitinib in a phase I/II trial in the first-line setting produced a response rate of 57.3%. [28] Phase II studies of gefitinib and docetaxel in the first-line setting in predominantly taxane-naïve patients have demonstrated response rates of 39–54%. [29, 30] In the absence of randomized trials, it is unclear if these results indicate superior benefit over that expected with chemotherapy alone.…”

Tumor inhibitory effect of gefitinib (ZD1839, Iressa) and taxane combination therapy in EGFR‐overexpressing breast cancer cell lines (MCF7/ADR, MDA‐MB‐231)

“…5 In respect to combination therapies of gefitinib and other cytotoxic drugs, such as anthracycline drugs or platinum, a phase I/II study completed by Fountzilas et al found that a combination therapy of gefitinib, paclitaxel and carboplatin showed no acceleration of efficacy. 31 Taking these reports together, combinations of gefitinib and other drugs such as taxane are generally favorable at preclinical studies, but their efficacies have not been demonstrated in clinical trials. The efficacy of the gefitinib and taxane combination therapy reported here remains unclear; as our present results revealed, this combination is not effective for all breast cancer cell lines that overexpress EGFR.…”