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Neoadjuvant Chemotherapy for Operable Breast Cancer

Neoadjuvant Chemotherapy for Operable Breast Cancer

It is nearly 30 years since the start of clinical
trials of adjuvant chemotherapy in patients with operable breast cancer.[1] 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, fluorouracil [5-FU]) has now been confirmed in many
subsequent trials using different types of chemotherapy.[2] 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.[2] 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.

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