It is nearly 30 years since the start of clinical trials of adjuvant chemotherapy in patients with operable breast cancer. The rationale for using adjuvant chemotherapy at that time was that surgery and radiotherapy could only control local disease and cure patients who did not already have metastases. Chemotherapy could be used in patients with a poor prognosis to treat undetected micrometastatic disease and thereby reduce the risk of metastatic relapse and death from breast cancer.
The initial improvement in relapse-free and overall survival reported by Bonadonna in 1974 with the use of the CMF regimen (cyclophosphamide [Cytoxan, Neosar], methotrexate(Drug information on methotrexate), fluorouracil(Drug information on fluorouracil) [5-FU]) has now been confirmed in many subsequent trials using different types of chemotherapy. Most of the early trials were limited to patients with a relatively poor prognosis, usually those with positive axillary nodes. Subsequently, patients who were node-negative were also included in trials of adjuvant therapy and they seemed to gain a similar absolute reduction in relapse and mortality as poorer-prognosis patients.
Adjuvant Therapy Reduces Mortality
The results of the 1995 Oxford meta-analysis of all adjuvant trials in breast cancer indicated, rather surprisingly, that most prognostic groups of patients up to the age of 65 or 70 years gained a clinically worthwhile absolute reduction in mortality. More importantly, there were apparently no subgroups of patients who did not gain some benefit, apart from perhaps those with very small node-negative well-differentiated cancers. It seems that these patients have such a good prognosis that chemotherapy adds little extra benefit. The meta-analysis also indicated that anthracycline-containing combinations were more beneficial than the standard CMF regimens, with an optimal four to six courses of treatment.
However, despite 30 years of research via many hundreds of clinical trials, the overall absolute reduction in mortality remains about 10%. This means that about 90% of patients gain no benefit, either because they have chemoresistant micrometastases or because they are already cured. How can this be improved? How can we select patients who need treatment, and how can we optimize their treatment? How can we more rapidly evaluate new drugs for use as adjuvant therapy? How can we more accurately identify patients who do not need treatment? These questions need to be answered in the next generation of clinical trials.
Neoadjuvant Therapy Guides Therapy
One approach depends on accepting the fact that most patients at this time are likely to be offered chemotherapy, and if the chemotherapy is administered prior to surgery (neoadjuvantly), the reaction at the primary tumor site may be a marker of micrometastatic response. If micrometastatic response is indeed indicated, treatment can be continued or intensified, or further non-cross-resistant chemotherapy can be added to maximize the response. If the primary tumor fails to respond to neoadjuvant chemotherapy, further treatment can be stopped with less associated toxicity, or a non-cross-resistant therapy can be initiated to achieve a response.