Breast cancer is the most common
malignancy in women, accounting for about 18% of female
cancers, and over half a million new cases are diagnosed worldwide each year. Its incidence increases with age and is currently rising. Although the increased availability of screening programs has allowed earlier detection and treatment of primary breast
cancers, many patients relapse with
metastases after apparently successful treatment of their primary
tumor and over 15,000 women in the UK and about 50,000 in the USA die from advanced disease each year. The natural course of
breast cancer is very variable even after the development of
metastases, and depends on a variety of
tumor characteristics and prognostic factors. This is reflected in the large number of treatments currently employed. However, despite this wide choice and considerable research over the years, treatment of metastatic
breast cancer (MBC) prolongs average survival times only slightly. Current
therapy is aimed at achieving a balance between producing maximal
tumor shrinkage to produce the most effective possible palliation of symptoms, and minimizing adverse effects. Anticancer
chemotherapy is the preferred option in patients who do not respond to
hormones, those with
hormone-independent
tumors, those with aggressive
breast cancer subtypes. A variety of anticancer
chemotherapy regimens, using both single and combined agents, have been shown to be effective in achieving
tumor regression in MBC.
Anthracyclines (
doxorubicin,
epirubicin) are the most active of the established monotherapies, typically producing response rates of 50-60% during initial (first-line) treatment for metastatic disease, but being effective in fewer than 25% of patients requiring second-line
therapy. The drawbacks of
anthracyclines include dose-limiting cumulative
cardiotoxicity and the development of resistant
tumor clones after the use of
anthracyclines for adjuvant or first-line
therapy, especially if subsequent courses are required within a year. The success of these established chemotherapeutic agents depends greatly on the number and location of metastatic sites. Lymph node and soft tissue secondaries tend to respond well, while visceral
metastases (especially in the liver) carry a particularly poor prognosis despite treatment. The outlook for patients with
metastases involving more than two organ systems is also bleak. Although some patients can live for years with metastatic disease, the average survival time in patients with MBC is 18-24 months, while in those with liver
metastases, life expectancy averages only 6 months. High-dose anticancer
chemotherapy with
granulocyte-colony stimulating factor (
G-CSF) or autologous
bone marrow transplantation has allowed the dose intensity of
anthracyclines to be increased, and has improved the response rate to about 70% in selected patients with MBC. However, this approach has not been proven to improve survival, involves the risk of greater toxicity and
drug-related mortality, and patients with reduced clearance of
anthracyclines due to hepatic dysfunction from liver
metastases may not be suitable candidates. A number of new
anticancer agents have also recently been introduced in an attempt to improve on the performance and avoid the tolerability problems associated with
anthracyclines. Among these, antitubulin agents (
taxoids and
vinorelbine) have shown highly promising activity in MBC. This paper reviews the preclinical, phase I and phase II data for one
taxoid,
docetaxel.
Docetaxel (
Taxotere) belongs to the
taxoid class of
cytotoxic agents, the development of which began more than 20 years ago. In 1971,
paclitaxel (
Taxol) was identified as the active compound of the
crude extract of the bark of the Pacific Yew tree Taxus brevifolia. However, at that time the development of
paclitaxel was hampered because of the limited source of the
drug and difficulties with isolation, extraction and formulation. The second active
taxoid,
docetaxel, was isolated by Potier et al. in 1986.
Docetaxel is prepared from a non-cytotoxic precursor, extracted from the needles of the European Yew tree Taxus baccata, that is condensed with a chemically-synthesized side-chain. As the
docetaxel precursor is freely available because of the regenerating capacity of the needles the development of
docetaxel has thus been rapid.