Trastuzumab Plus Chemotherapy: Convincing Survival Benefit or Not?

Abstract

Trastuzumab has altered the lives of many women with Her-2/neu–amplified metastatic breast cancer (MBC). Within our clinical practice, we have several women who continue receiving trastuzumab 5 to 9 years after the initiation of therapy. Long survival durations in MBC are not uncommon for patients with hormonally sensitive tumors, but for Her-2/neu–amplified tumors the prognosis was dismal before the use of this agent. Improvements in survival from first relapse with MBC have occurred during the last decades secondary to the development of new hormonal and cytotoxic agents. Despite these gradual improvements in survival from first relapse, there are few trials demonstrating convincing benefits in overall survival for a novel regimen compared with a more standard comparator. The article by Marty et al in this issue of the Journal of Clinical Oncology confirms an overall survival benefit produced by a trastuzumab plus chemotherapy combination over chemotherapy alone. The survival benefit for a combination of trastuzumab plus chemotherapy was originally described by Slamon et al in one of the pivotal clinical trials of trastuzumab. In the trial by Marty et al, weekly trastuzumab plus docetaxel 100 mg/m every 3 weeks proved superior to the same dose of single-agent docetaxel in all end points including response rate, response duration, time to progression, treatment failure, and most importantly, overall survival (31.2 v 22.7 months; P .0062). In the pivotal trial, there was also a statistically significant survival benefit when patients treated with chemotherapy plus trastuzumab (n 235) were compared with those treated with chemotherapy alone (n 234; 25.1 v 20.3 months; P .046). In that trial, women with no prior anthracycline adjuvant therapy received an anthracycline plus cyclophosphamide (AC) alone or in combination with trastuzumab. Women with prior anthracycline adjuvant therapy were randomly assigned to paclitaxel 175 mg/m every 3 weeks alone or with trastuzumab. The overall survival advantage for AC trastuzumab over AC alone was 26.8% v 21.4% (P .16). An unexpected high cardiotoxicity rate led to the recommendation to avoid concomitant anthracycline use with trastuzumab outside of clinical trials. These recommendations are being challenged by provocative trials, such as the neoadjuvant trial by Buzdar, in which paclitaxel followed by an epirubicin-containing regimen was administered with concurrent trastuzumab, resulting in a 65% pathologic complete response rate with no cardiotoxicity. Other trials are re-exploring anthracyclines plus trastuzumab, also with encouraging efficacy results and a relative lack of cardiotoxicity. Examples include the liposomal doxorubicins and epirubicin. However, such combinations should still be limited to clinical trials. Although the anthracycline plus trastuzumab clinical trials cited above are of interest for future development, data by Marty et al are more relevant to current practice, given that taxane plus trastuzumab combinations are commonly used worldwide for the treatment of MBC. This practice is based on the results from the paclitaxel plus trastuzumab subset of the pivotal trial, which reported an overall survival benefit compared with paclitaxel alone (22.1 v 18.4 months), although this result was not statistically significant (P .17). We believe that paclitaxel administered on a 3-week schedule is unlikely to be the most effective combination for Her-2/neu–amplified MBC for three reasons. First, efficacy seems less for administration of paclitaxel on a 3-week schedule than on a weekly schedule. Second, a recent phase III trial of paclitaxel compared with docetaxel every 3 weeks showed superiority for docetaxel in all end points, including overall survival (15.4 v 12.7 months; P .03). Third, the trial by Marty et al showed a statistically significant survival benefit, whereas the pivotal trial using paclitaxel plus trastuzumab did not. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 19 JULY 1 2005