Commentary on “Platinum Compounds in the Treatment of Advanced Breast Cancer”

Abstract

In this issue of Clinical Breast Cancer, Dr. Martin reviewed the results of studies reporting on the efficacy of platinum compounds in the treatment of advanced breast cancer.1 The clinical data reported to date indicate that both cisplatin and carboplatin have considerable activity as single agents in metastatic breast cancer when used as first-line therapy. Response rates range from 42%-54% for cisplatin and 16%-35% for carboplatin, depending on the dose and whether patients had received prior adjuvant therapy. Importantly, a number of small phase II studies in which many patients had received extensive prior chemotherapy demonstrated low response rates to cisplatin or carboplatin as single agents (8.5% and 6%, respectively), thereby prompting investigators to conclude that platinum salts had no significant activity in advanced breast cancer. The data presented, however, suggest that in appropriately selected patients without extensive chemotherapy pretreatment, platinum salts achieve levels of efficacy comparable to other therapeutic agents such as vinorelbine,2 paclitaxel, or doxorubicin3 when given as a single agent in first-line therapy for advanced breast cancer. As the current review highlights, higher activity has been reported for cisplatin as first- and second-line therapy of metastatic breast cancer, when combined with either etoposide (25%-58%), vinorelbine (25%-74%), 5-fluorouracil (29%-61%), or gemcitabine (29%-50%). Somewhat lower response rates were reported for carboplatin in combination with etoposide (22%-42%), vinorelbine (46%), or 5-fluororuracil (9%21%). Retrospective comparison of these response rates with those reported for any of the above-mentioned single agents suggests that both cisplatin and carboplatin do contribute to the overall activity of these combination regimens. As shown by Dr. Martin, high response rates have been reported in first-line therapy of metastatic breast cancer for combinations of cisplatin with paclitaxel or docetaxel, with response rates ranging between 23%90% and 34%-60%, respectively.1 Similarly, the use of carboplatin in combination with paclitaxel or docetaxel resulted in high response rates ranging between 43%-76% and 40%-60%, respectively. The combination of platinum salts with taxanes for the treatment of patients with advanced breast cancer is not only attractive because of the single-agent activity of these agents, but also because their major toxicity profiles do not overlap.4 Recently, trastuzumab, a novel humanized monoclonal antibody directed against the epithelial growth factor receptor HER2/neu, has been reported to have powerful synergistic interactions with platinum agents and docetaxel. These findings have prompted evaluation of the triplet docetaxel/platinum salt/trastuzumab in the therapy of metastatic breast cancer.5-7 Moreover, concomitant therapy of trastuzumab with doxorubicin is associated with significant cardiotoxicity. Class I-IV of cardiac dysfunction, as defined by the New York Heart Association (NYHA), occurred in 38 of 143 patients (27%) receiving trastuzumab plus doxorubicin/cyclophosphamide (AC) versus 6% receiving AC alone. The incidence of NYHA class III/IV cardiac dysfunction was highest among patients receiving trastuzumab plus AC, with a 16% versus 3% incidence in those receiving AC alone.8 Future studies will therefore require careful design to avoid the cardiotoxicity issues associated with use of trastuzumab/anthracycline administration. With recognition of the cardiotoxicity potential, nonanthracycline chemotherapy/trastuzumab regimens consisting of docetaxel/cisplatin or docetaxel/carboplatin have been proposed.7 Preliminary results of these studies demonstrate high activity of the triplet docetaxel/platinum salt/trastuzumab combination in HER2/neu-positive metastatic breast cancer. Importantly, this approach takes advantage of the observed syner