Japanese Journal of Clinical Oncology 33:514-517 (2003)
© 2003 Foundation for Promotion of Cancer Research
Combination of Trastuzumab and Vinorelbine in Metastatic Breast Cancer
Department of Surgery, Tokai University School of Medicine, Isehara, Kanagawa, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Since the clinical introduction of trastuzumab (Herceptin®) for metastatic breast cancers that overexpress human epidermal growth factor receptor 2 (HER2), this anticancer agent has played an important role in breast cancer treatment. We examined the effects of trastuzumab and vinorelbine (Navelbine®) as a second- or third-line therapy in 24 patients whose HER2-positive tumors did not respond to or relapsed after administration of trastuzumab alone or in combination with taxane.
Methods: Trastuzumab was administered at 2 mg/kg (loading dose 4 mg/kg) once weekly and vinorelbine at 25 mg/m2 once weekly. The median treatment duration was 118.5 days (range, 22–351 days).
Results: The response rate was 42% (95% confidence interval (CI): 22%–63%). The adverse events of NCI-CTC grade 3 or above consisted of neutropenia in three patients; other adverse events, including vasculitis, generalized fatigue, anemia and thrombocytopenia, were grade 1 or 2. All adverse events were reversible after treatment withdrawal and were easily manageable.
Conclusion: A combination of trastuzumab and vinorelbine can be safely administered on an outpatient basis, and is useful in the treatment of patients with HER2-overexpressing metastatic breast cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The clinical introduction of trastuzumab (Herceptin®) for HER2-overexpressing breast cancer has changed the treatment of metastatic diseases, and trastuzumab is currently used as first-line chemotherapy in HER2-positive metastatic breast cancer. We have reported its efficacy in previous studies (1,2). Trastuzumab is recommended for use in combination with taxanes. Trastuzumab with paclitaxel proved to have an additive effect, and it has been established as the standard regimen (3). Seidman et al. (4) reported a response rate of 61% with a weekly dose of trastuzumab with paclitaxel. Esteva et al. (5) reported a response rate of 63% and a median time to progression (TTP) of 9 months with weekly doses of docetaxel and trastuzumab, although their study was not comparative. However, some patients do not respond to or relapse after these treatment regimens, and this poses a problem in the clinical setting.
Pegram et al. (6) combined trastuzumab with other cancer chemotherapeutics in vitro and reported synergistic effects with vinorelbine, cisplatin, docetaxel, thiotepa, cyclophosphamide or etoposide; additive effects with doxorubicin, paclitaxel, methotrexate or vinblastine; and antagonistic effects with 5-fluorouracil. Burstein et al. (7) reported a multicenter phase II study of trastuzumab with vinorelbine in 40 patients with HER2-overexpressing metastatic breast cancer who had received two or more chemotherapy regimens. The combination with vinorelbine at 25 mg/m2 produced a response rate of 75% in the whole study population and that of 84% in the previously untreated patients. They further conducted a multicenter phase II study of trastuzumab with vinorelbine in 54 patients with HER2-overexpressing tumors, who did not undergo prior treatment for metastatic breast cancer and reported a response rate of 68% in the whole study population and that of 63% in the patients who had received prior anthracyclines (8).
In view of this data, we administered trastuzumab with vinorelbine to 24 patients with HER2-overexpressing metastatic breast cancer as a second- or third-line therapy. We report the response rate and adverse events in this paper.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients
Twenty-four patients having a median age of 52.5 years (range, 26–79 years), with metastatic breast cancer that had not responded to or relapsed after administration of trastuzumab as a single agent or in combination with taxane, were enrolled. The Hercep Test (DAKO Japan) was used for the immunohistologic analysis of the tumors, and patients with HER2- overexpression of 2+ (n = 7) or 3+ (n = 17) were eligible (Table 1). A neutrophil count of
2000/mm3 or a leukocyte count of 4000/mm3, within 2 weeks prior to drug administration, was required because the dose-limiting toxicity (DLT) of vinorelbine is leukopenia. The patients were also required to have normal organ function.
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The sites of metastases were the liver in 10 patients (42%), lung and pleura in eight (33%), bone in eight (33%), breast and chest wall in six (25%), skin in three (13%) and lymph nodes in two (8%). The characteristics of 24 patients are shown in Table 2.
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Treatment
Trastuzumab was administered weekly at 2 mg/kg (loading dose 4 mg/kg) and vinorelbine weekly at 25 mg/m2 according to the protocol approved by the Institutional Review Board of the Tokai University School of Medicine. We settled the administration dosage of vinorelbine on the basis of the data of Burstein et al. (7). On the day of drug administration, the neutrophil count was required to be
1000/mm3 or the leukocyte count 3000/mm3; chemotherapy was withheld for 1 week if patients could not satisfy either of these requirements and resumed at the same doses when patients met these criteria in the ensuing weeks.
Evaluation of Response and Toxicity
A complete response (CR) was defined as the complete disappearance of all tumor lesions lasting at least 4 weeks, a partial response (PR) as a reduction of 50% in the sum of the products of the two longest perpendicular dimensions of all measurable tumors for a duration of at least 4 weeks, and stable disease (SD) as a reduction of <50% in the sum of measurable lesions or an increase of <25% lasting more than 4 weeks. Progressive disease (PD) was defined as an increase of 25% in the sum of the measurable lesions or the appearance of new lesions. The severity (grade) of adverse events was assessed using the NCI-CTC system (9).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Tumor Response
Ten patients had a CR (n = 2, 8%) or PR (n = 8, 33%). Three patients (13%) showed SD, and 11 (46%) had a PD. The median TTP was 92+ days (range, 36–225+ days) (Table 3).
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Toxicity
The most frequent adverse events were neutropenia, vasculitis and angialgia. The severity of neutropenia was grade 1 in two patients (9%), grade 2 in six (27%), and grade 3 in three (14%). Decreased hemoglobin was grade 1 in one patient (5%) and grade 2 in two (9%). Thrombocytopenia was grade 1 in two patients (9%) and grade 2 in one (5%). All of these adverse events were reversible after a 1-week withdrawal of chemotherapy. None of the patients required dose reduction or granulocyte colony-stimulating factor or had fever. Vasculitis and angialgia were grade 1 in three patients (14%) and grade 2 in one (5%). They were likewise reversible by withdrawal of the treatment for 1 to 2 weeks. Other adverse events, generalized fatigue and numbness in the fingers, were mild (grade 1 or 2) and could be treated on an outpatient basis (Table 4). Cardiac dysfunction with heart failure symptoms was not observed.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Since the clinical introduction of trastuzumab for metastatic breast cancer overexpressing the HER2 protein in June 2001, the treatment for this cancer has made definite progress, and chemotherapy including trastuzumab is now positioned as a first-line treatment. Vogel et al. (10) studied the efficacy and safety of trastuzumab as a single agent in 114 patients with recurrent breast cancer and reported a response rate of 26%. In approximately half the patients, tumors did not progress, and quality of life could be maintained. Trastuzumab is recommended in combination with taxanes. Trastuzumab with weekly paclitaxel proved to be have additive effects, and it has been established as the standard regimen (6). Trastuzumab with paclitaxel (4) and trastuzumab with docetaxel (5) have also produced good response rates. However, even with these treatment regimens, physicians have difficulty in treating patients with refractory or relapsing disease. Pegram et al. (6) reported a synergistic effect of trastuzumab with vinorelbine, and the combination has been reported to be clinically useful (7,8).
Vinorelbine is a semisynthetic derivative of a vinca alkaloid. It was first synthesized in France in 1979 from chatharanthine and vindoline extracted from the periwinkle plant, Catharanthus roseus (11). Its antitumor effect is attributable to inhibition of mitosis at G2M through interaction with tubulin, the major protein constituent of microtubules, and inhibition of its polymerization. Vinorelbine causes less neurotoxicity because of its higher selectivity for macrotubules than for axonal microtubules in non-nervous tissues (12).
In a phase II study reported by Fumoleau et al. (13) the response rate to vinorelbine as a single agent in advanced/recurrent breast cancer was 41% when it was administered at 30 mg/m2 to 145 patients without prior treatment. Weber et al. (14) reported a response rate of 25% to vinorelbine as a first-line therapy and that of 32% as a second-line therapy. In the treatment of HER2-overexpressing metastatic breast cancer, trastuzumab is administered alone or in combination with other chemotherapeutics, including taxanes, according to the performance status of patients and the presence or absence of metastases to other organs. However, some patients do not respond or relapse. According to the report by Pegram et al. (6), vinorelbine is the most promising candidate for combination following taxanes. In a phase II study, weekly trastuzumab with vinorelbine at 25 mg/m2 produced high response rates: 75% in the whole study population and 84% in the patients receiving the combination as a first-line therapy (7). In a multicenter phase II study of the same combination, the response rate was 68% in the whole study population and 63% in the anthracycline-pretreated patients (8).
In this study, we used a combination therapy with trastuzumab and vinorelbine in 24 patients who did not respond to or relapsed after trastuzumab alone or in combination with taxane as a second- or third-line treatment. Although this study enrolled only a small number of patients and the duration was short, trastuzumab with vinorelbine produced a response rate of 42% as a second- or third-line therapy with a median TTP of 92 days. These figures are very satisfactory, and this combination chemotherapy will play an important role in the treatment of metastatic breast cancer in the future. Adverse events were reversible by the withdrawal of chemotherapy, and patients could receive the drugs continuously. Adverse events such as vasculitis, angialgia and peripheral nerve disorders that were anticipated to arise, were mild; and no symptomatic cardiac dysfunction was observed.
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FOOTNOTES |
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+ For reprints and all correspondence: Yutaka Tokuda, Bohseidai, Isehara, Kanagawa 259-1193, Japan. E-mail: tokuda{at}is.icc.u-tokai.ac.jp
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REFERENCES |
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1 Tokuda Y, Suzuki Y, Ohta M, Saito Y, Kubota M, Tajima T, et al. Compassionate use of humanized anti-HER2/neu protein, trastuzumab for metastatic breast cancer in Japan. Breast Cancer 2001;8:310–5.[Medline]
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Received July 1, 2003; accepted September 1, 2003
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