Gemcitabine, Paclitaxel, and Trastuzumab in Metastatic Breast Cancer
Gemcitabine, Paclitaxel, and Trastuzumab in Metastatic Breast Cancer
Gemcitabine (Gemzar) and paclitaxel show good activity as single agents and combined in metastatic breast cancer, and the combination of paclitaxel/trastuzumab (Herceptin) has been shown to prolong time to disease progression and survival significantly in this setting. Preclinical data indicate additive or synergistic effects of gemcitabine and trastuzumab in HER2-positive human breast cancer cell lines. In a phase II trial, patients with HER2-overexpressing metastatic breast cancer who had received no prior chemotherapy for metastatic disease received gemcitabine at 1,200 mg/m2 on days 1 and 8 and paclitaxel at 175 mg/m2 on day 1 every 21 days for six cycles plus trastuzumab at an initial loading dose of 4 mg/kg followed by 2 mg/kg weekly; patients without progressive disease after six cycles continued to receive trastuzumab until disease progression. Overall, objective response was observed in 28 (67%) of 42 evaluable patients, including complete response in 4 (10%) and partial response in 24 (57%); stable disease was observed in 7 (17%) and progressive disease was observed in 6 (14%). Median time to treatment failure was 9+ months. Median overall survival has not yet been reached, but is estimated at approximately 27 months. Significant toxicities apart from neutropenia were uncommon. The triplet combination of gemcitabine, paclitaxel, and trastuzumab is highly active and well tolerated in patients with HER2-overexpressing metastatic breast cancer.
Compelling data exist to support the rationale for combining gemcitabine (Gemzar), paclitaxel, and trastuzumab (Herceptin) in the treatment of metastatic breast cancer. Gemcitabine and paclitaxel show good activity as single agents and when used in combination in this setting.[1-7] Phase II studies of the combination have shown objective response rates of 45%, 55%, and 69%, including relatively large numbers of complete responses. The combination of paclitaxel and the monoclonal antibody trastuzumab has been widely studied, and has been shown to improve time to disease progression and survival significantly in patients with HER2-overexpressing tumors compared with chemotherapy alone. The combination of gemcitabine and trastuzumab has been shown to have additive or synergistic effects in HER2-positive human cancer cell lines, including breast cancer cell lines SK-BR-3 and MCF-7. Preliminary results of a phase II study assessing the gemcitabine/ trastuzumab combination in heavily pretreated patients with metastatic breast cancer have been promising.[ 10] We have assessed the triple combination of gemcitabine, paclitaxel, and trastuzumab as first-line therapy in a phase II study in metastatic breast cancer patients. Patients and Methods Eligible patients included those with HER2-positive metastatic breast cancer with HER2 overexpression of 2-3+ on immunohistochemistry (IHC) or positive gene amplification on fluorescence in situ hybridization (FISH). Patients could not have received prior chemotherapy for metastatic disease, and no prior gemcitabine or trastuzumab treatment. Adjuvant taxane treatment was permitted if it had been completed at least 1 year before trial entry. Patients had to have a Karnofsky performance score of ≥ 60 with adequate organ function. Exclusion criteria included active central nervous system metastasis, congestive heart failure, and recent history of myocardial infarction. Patients received gemcitabine at 1,200 mg/m2 via 30-minute IV infusion on days 1 and 8, paclitaxel at 175 mg/m2 via 3-hour IV infusion on day 1 every 21 days, and trastuzumab given as a 4-mg/kg loading dose via 90- minute IV infusion on day 1 during the first study week and then 2 mg/kg IV over 30 minutes weekly thereafter. Study treatment was administered for a maximum of six 21-day cycles; patients with no progressive disease continued to receive weekly trastuzumab thereafter until disease progression. Responses were assessed after every two cycles of combined chemotherapy and at least every 16 weeks during single-agent trastuzumab treatment. Results A total of 45 patients have been studied to date, with 42 evaluable for treatment response. Patients had a median age of 54 years (range: 32-78 years) and a median Karnofsky performance score of 90 (range: 70-100). HER2 status was 2+ and 3+ on IHC in 8 (18%) and 11 (24%) patients, respectively, with 3 (7%) being HER2-positive on FISH. For 23 (51%) patients, pathology reports indicated IHC-positive findings without a specified HER2 grade. Sites of metastatic disease included the liver in 24 patients (53%), lung in 22 (49%), bone in 18 (40%), and lymph node/soft tissues in 9 (20%). Toxicities reported among 45 patients are shown in Table 1. Although grade 3 or 4 neutropenia was common, febrile neutropenia and significant infectious complications were rare. Significant gastrointestinal effects were infrequent. Minor fatigue was common, and primarily minor taxane-related neuropathy and myalgia were observed. Although four patients reported pulmonary adverse events (grade 3), the adverse events appeared to be related to underlying breast cancer rather than chemotherapy. Clinical congestive heart failure was observed in three patients who developed absolute left-ventricular ejection fractions < 45%. One of these patients experienced a decrease in left-ventricular ejection fraction of ≥ 15%; the other two patients entered the study with ejection fractions of approximately 50% and became symptomatic with smaller decreases in ejection fraction. All of these patients discontinued treatment and subsequently recovered. Objective responses were observed in 28 (67%) of 42 evaluable patients, consisting of complete response in 4 (10%) and partial response in 24 (57%). Seven patients (17%) had stable disease; 6 patients (14%) had progressive disease. Of the three patients who were nonevaluable for response, two were removed from the study before completing the first cycle of chemotherapy. Time to treatment failure, defined as time to disease progression, death, or discontinuation due to toxicity, and overall survival are shown in Figure 1. Median time to treatment failure was 283 days (approximately 9 months). Median survival has not yet been reached in the population, but it is estimated to be approximately 27 months. Conclusions The triplet combination of gemcitabine, paclitaxel, and trastuzumab is highly active and well tolerated in patients with HER2-positive metastatic breast cancer. The trial was community- based, and recruitment of patients with HER2 2+ IHC status without confirmation of HER2 overexpression by FISH was common practice during the period of initial enrollment in this trial (1999-2000). The absence of the grading and FISH confirmation suggests that this study population is less highly selected for HER2 overexpression than would be typical of current trials. It is likely that the response rate would have been higher than the 67% rate observed in this population if patient selection based on HER2 status had been more precise. Significant toxicities were minimal with the triplet regimen. Although pulmonary toxicity has been reported in 1.4% of all patients treated with gemcitabine, it was not a significant problem in the current study. The gemcitabine/paclitaxel/ trastuzumab triplet is a promising regimen for treatment of HER2- positive metastatic breast cancer.
The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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