Abstract
BackgroundThe 3-weekly combination of trastuzumab and paclitaxel has been approved for the treatment of advanced breast cancer based on a large pivotal study. However, mono and combination chemotherapy trials suggest that weekly paclitaxel has a better therapeutic index, especially in the palliative setting. The present trial examined the efficacy and safety of weekly paclitaxel over a limited duration combined with continued trastuzumab in HER2+ patients.MethodsPatients with histologically confirmed metastatic breast cancer overexpressing HER2 were eligible if pretreated with anthracycline in either the adjuvant or palliative setting. Treatment consisted of weekly trastuzumab (2 mg/kg/week for up to one year after a loading dose of 4 mg/kg in week 1) and paclitaxel (90 mg/m², administered in weeks 1–6 and 8–13).ResultsTwenty-seven German centers enrolled 121 patients. The median number of metastatic sites was two (range 1–5); 38% of patients had received chemotherapy for advanced disease. After a median 42 weeks of trastuzumab treatment, limited by disease progression in roughly half the patients, a best objective response rate (complete response + partial response) of 76% was achieved, including complete remissions in 29%. 74% of patients lived without tumor progression at six months. Median progression-free and overall survival were 9.4 (95% confidence interval [CI]: 8.1–11.3) and 22 months (95% CI: 17–46). After alopecia, Common Toxicity Criteria grade ≥2 toxicity was predominantly hematological (leukopenia [31%] and anemia [41%]); however, thrombocytopenia occurred in only 5%. Neurotoxicity was remarkably low. Two cardiac events (grades 2 and 3) were presumed treatment-related.ConclusionsWeekly paclitaxel plus trastuzumab allows an increased dose density and offers an attractive and effective alternative to the conventional schedule. Limiting the duration of cytotoxic therapy to 3 months seems to be an option to reduce neurotoxicity without impairing long-term outcome.
Highlights
The 3-weekly combination of trastuzumab and paclitaxel has been approved for the treatment of advanced breast cancer based on a large pivotal study
25% of advanced breast cancer patients overexpress human epidermal growth factor receptor type 2 (HER2) [1]. This led to the development of trastuzumab (Herceptin®), a humanized monoclonal antibody against this epitope [2] that shows considerable antitumor efficacy as a single agent even in heavily pretreated patients with advanced disease [3,4]
The pivotal randomized phase III study on combination trastuzumab in advanced breast cancer allowed for two chemotherapy backbones: either doxorubicin/cyclophosphamide or single-agent paclitaxel, both given 3-weekly [6]
Summary
The 3-weekly combination of trastuzumab and paclitaxel has been approved for the treatment of advanced breast cancer based on a large pivotal study. Recent advances in understanding cancer biology have spurred the development of a plethora of targeted agents that have revolutionized the treatment of a number of malignancies. Their mechanism of action often depends on specific molecular features allowing for individualized strategies, in contrast to the non-selective approaches of the conventional chemotherapy era. 25% of advanced breast cancer patients overexpress human epidermal growth factor receptor type 2 (HER2) [1] This led to the development of trastuzumab (Herceptin®), a humanized monoclonal antibody against this epitope [2] that shows considerable antitumor efficacy as a single agent even in heavily pretreated patients with advanced disease [3,4]. While added trastuzumab increased response and survival rates in each of these strata, combination with anthracyclines unexpectedly increased cardiotoxicity [7] ( less markedly with epirubicin [8]), impeding its widespread use and favoring taxane-oriented strategies
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