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a Department of Medicine, Seatle Cancer Care Alliance, Seattle, Washington; b The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Correspondence: Robert B. Livingston, M.D., Professor of Medicine, Department of Medicine, Seattle Cancer Care Alliance, 825 Eastlake Avenue, East, Box 358081- Mailstop 4-830, Seattle, Washington 98109, USA. Phone: 206-288-1085; Fax: 206-288-2054. accepted for publication August 2, 2001.
An important but often underappreciated goal when treating metastatic breast cancer is the selection of a regimen that extends and improves patient quality of life in addition to providing high tumor response rates. The currently available single-agent or combination chemotherapy regimens often have negative effects on patient quality of life. Targeted therapies such as trastuzumab (Herceptin®, Genentech, Inc.; South San Francisco, CA), a humanized monoclonal antibody specific for p185HER-2/neu, are well tolerated compared with conventional chemotherapy but often do not result in high response rates when used as single agents. Consequently, there has been a great deal of interest in combining targeted therapeutics with chemotherapy for the treatment of metastatic breast cancer. Preclinical and clinical data suggest that trastuzumab may potentiate the activity of chemotherapeutic agents and improve patient quality of life relative to chemotherapy alone [1-3]. Clinical trials of trastuzumab in combination with taxanes, vinca alkaloids, platinum agents, hormone therapy, and anthracyclines have been completed or are ongoing. In our experience, two agents that have demonstrated favorable efficacy when combined with trastuzumab include vinorelbine (Navelbine®, GlaxoSmithKline; Philadelphia, PA) and paclitaxel (Taxol®, Bristol-Myers Squibb; Princeton, NJ)
In a recent report published in the Journal of Clinical Oncology, Burstein et al. [4] presented the results of weekly trastuzumab (4 mg/kg at week 1; with 2 mg/kg at subsequent weeks) and vinorelbine (25 mg/m2/week) combination treatment for HER-2-positive metastatic breast cancer. The overall response rate for this combination was 75% in the 40 patients evaluated. The response rate was 80% among patients overexpressing HER-2 (3+ by immunohistochemistry) and 84% of patients responded to trastuzumab and vinorelbine as first-line therapy. Interestingly, 50% of patients previously treated with taxanes responded to weekly trastuzumab and vinorelbine. These response rates were comparable with those reported by Seidman et al. [5] in a trial of weekly trastuzumab (4 mg/kg at week 1; with 2 mg/kg at subsequent weeks) and paclitaxel (90 mg/m2/week) performed in a similar patient population of which 57% expressed HER-2+ or 3+ by immunohistochemistry. The overall response rate reported in the Seidman trial was 61.4% (4.5% complete responses) and ranged from 67% to 81% in patients with HER-2-overexpressing tumors, depending on the method of HER-2 detection. Because no randomized comparisons of the two treatment regimens have been performed and because the methods used to determine HER-2 expression were different for each trial, the response rates cannot be directly compared. Nevertheless, both combination therapies are promising, and both should be considered viable treatment options for patients with HER-2-overexpressing metastatic breast cancer.
Although trastuzumab plus vinorelbine provides antitumor activity comparable with that of trastuzumab plus paclitaxel, the two regimens demonstrate important differences in the pattern and severity of adverse events. Both regimens were generally well tolerated, but vinorelbine in combination with trastuzumab appears to be associated with less neurotoxicity and alopecia, two adverse effects that can diminish patient quality of life. In the trastuzumab plus paclitaxel study the most common toxicity was neuropathy, with significant grade 3 or 4 neuropathy in 28 of 95 (29%) patients [5]. In contrast, there were no grade 3 or 4 neuropathic adverse events associated with trastuzumab plus vinorelbine [4]. The most common toxicity in the vinorelbine trial was manageable hematologic toxicity, and neutropenia was the only grade 4 adverse event. Furthermore, many of the grade 1 and 2 neuropathic events occurred in women with pre-existing neuropathy due to previous taxane-based treatments. Finally, the trastuzumab and vinorelbine combination resulted in only mild gastrointestinal side effects, and the incidence of alopecia was modest. Overall, the toxicity profile for the combination of vinorelbine and trastuzumab was similar to that expected for each individual agent. Hematologic toxicity was managed by adjusting the dose of vinorelbine, and no dose adjustments were required for trastuzumab.
As a single agent, paclitaxel given every 3 weeks (as reported for trastuzumab) is associated with neurotoxicity and marked alopecia. Although these adverse effects can occur during vinorelbine therapy, neurotoxicity and alopecia associated with vinorelbine are usually mild (grade 1 or 2) compared with the moderate to severe (grade 3 or 4) adverse events that can occur with paclitaxel. By combining trastuzumab with a well-tolerated chemotherapeutic agent such as vinorelbine, trastuzumab response rates, which range from 15% to 23% depending on the patient population, improved approximately three- to four-fold without substantial increases in toxicity [6-7]. Furthermore, although no randomized comparisons with other treatment regimens have been performed, the response rates achieved with trastuzumab and vinorelbine are similar to the best responses achieved in HER-2-positive metastatic breast cancer with other therapeutic regimens. Because of the favorable toxicity profile of vinorelbine in combination with trastuzumab, we believe that this efficacious treatment regimen has the potential to significantly improve the quality of life of patients with HER-2-positive metastatic breast cancer. The results of this clinical trial should encourage further investigation of well-tolerated chemotherapeutics in combination with targeted cancer therapy with the goal of not only improving the duration but also the quality of a patient's life. Recently, a randomized trial to directly compare these two treatment regimens was initiated. In addition to clearly determining the relative efficacy of trastuzumab combined with either vinorelbine or paclitaxel, this trial should define the impact of these two treatment regimens on patient quality of life. A randomized comparison of vinorelbine alone with vinorelbine and trastuzumab has been undertaken in patients with metastatic breast cancer that has progressed after taxane plus trastuzumab therapy to further evaluate the clinical benefits of this combination regimen.
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