Chemotherapy in metastatic disease: an overview

Many different cytotoxic agents are currently available for the treatment of metastatic breast cancer (MBC), and multiple factors determine the choice of treatment. These include previous adjuvant therapy, tumour characteristics (for example, molecular receptors, sites of relapse), patient characteristics (for example, performance status, age) and patient preference.

The aims of treatment with chemotherapy for MBC are: to prolong survival; to relieve symptoms; to improve and maintain quality of life; and to delay disease progression.

Only a small minority of MBC chemotherapy trials has shown a significant survival benefit, and to some extent this is explained by the multiple lines of potential further therapy following completion of the trial. Survival is therefore an uncertain endpoint in MBC trials.

Symptom improvement has been shown to correlate with response rate in one trial but this important endpoint is not used often enough. Quality-of-life endpoints are appropriate in principle, but in reality many trials have shown a poor correlation with outcome, suggesting that this tool may be relatively insensitive in this context. Time to disease progression is a much used and important endpoint because it takes into account the fact that symptom relief and prolonged survival relate not just to patients achieving objective response, but also to those with minor response or stable disease.

Specific issues relating to chemotherapy for MBC include the following. There is evidence from older trials supporting the principle that endocrine therapy should be used before chemotherapy in patients with nonlife-threatening hormone-receptor-positive disease. Patients whose primary is HER2-unknown should have this checked at the time of relapse to determine whether trastuzumab should be given in addition to chemotherapy. Ideally, patients with primary HER2-negative disease should have metastatic disease rechecked since there is evidence of HER2-positive conversion in up to 25% of such patients. The choice of combination versus single-agent sequential chemotherapy is a complex one. The weight of current evidence suggests no significant survival difference with the combination, and this may be associated with more toxicity. There is no absolute answer here; choice depends on the nature of the drugs being used.

Multiple lines of chemotherapy are now available for MBC. Current evidence suggests that it is only worth proceeding to third-line treatment if there has been a response to first-line and/or second-line therapy. New drug trials are appropriate for fit patients who have failed two lines of conventional therapy, and sometimes earlier than this in patients with nonlife-threatening disease.