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Microtubule Stabilization in the Treatment of Solid Tumors: Role of the Taxanes

Cancer Research UK West of Scotland Clinical Trials Unit, Beatson Oncology Centre, Western Infirmary, Glasgow, Scotland, United Kingdom

Correspondence: Paul A. Vasey, M.B.Ch.B., M.Sc., M.D., F.R.C.P., Cancer Research UK West of Scotland Clinical Trials Unit, Beatson Oncology Centre, Western Infirmary, Glasgow, Scotland, United Kingdom. Telephone: 0141-211-2318; Fax: 0141-211-6356; e-mail: p.vasey{at}beatson.gla.ac.uk

Key Words. Taxanes • Docetaxel • Paclitaxel

	INTRODUCTION

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The origins of modern chemotherapy go back to the mid-1900s and the biological and gas weapons program of World War II. The resultant marrow and lymphoid hypoplasia noted in military seamen exposed to mustard gas was the first major indication of the potential antiproliferative effects of biologic agents used as chemical warfare [1]. Based on these observations, investigators from Yale University conducted a pivotal clinical trial of nitrogen mustard in the treatment of malignant lymphoma [2]. Transient, but impressive, antitumor responses were noted. The results, initially published in 1946, could be considered to mark the beginning of modern chemotherapy.

The combination of "experiments of nature" and observations of well-trained researchers has generated a number of other important leads in the search for effective cancer treatments. In 1947, research on folic acid led to the discovery of the antitumor activity of methotrexate in acute leukemia [3]. This breakthrough was a result of the observation that folic acid accelerated the production of abnormal white blood cells by the bone marrow in patients with acute leukemia. Administration of agents that inhibit the metabolic effects of folic acid proved to be cytotoxic to leukemic cells. Methotrexate, a folic acid antagonist, was identified as an active compound, and by the mid-1950s, methotrexate monotherapy produced cures in women with widely disseminated choriocarcinoma [4]. This class of compound produced perhaps the first examples of drug-induced cures of metastatic cancer, and they remain in wide clinical use today.

These early successes with chemotherapy led to a national program for drug development established in 1955 by the National Cancer Institute (NCI). This NCI program widely screens substances from many different sources, both natural and synthetic, in order to identify lead compounds with potential antitumor activities and unique mechanisms of action. It is through this mass screening program that a number of anticancer agents have been discovered. Paclitaxel, which was identified in the 1970s by the NCI screening program, was the first in its class. The discovery of docetaxel followed in the 1980s. The taxanes are unique among anticancer agents in how they target the mitotic spindle—arresting replication of rapidly dividing cells by simultaneously promoting microtubule assembly and stabilization in addition to the inhibition of tubulin disassembly [5].

This supplement to The Oncologist has been developed from the proceedings of a satellite symposium held in conjunction with the 12th European Cancer Conference (ECCO 12) in Copenhagen, Denmark on September 23, 2003. Presentations at the symposium focused on the role of microtubule stabilization in the treatment of solid tumors. In the first article of this supplement, Dr. Joseph Gligorov (Hôpital Tenon, Paris, France) reviews the pharmacokinetic, pharmacodynamic, and preclinical differences between the taxanes, docetaxel and paclitaxel. Dr. Eric Van Cutsem (University Hospital Gasthuisberg, Leuven, Belgium) summarizes the activity of the taxanes in the treatment of advanced gastric cancer. Gastric cancer, which is the fourth most common type of cancer worldwide, confers a poor prognosis, with the majority of patients presenting with advanced disease. Strides, albeit small, have been made in the treatment of patients with advanced disease. Recent interim results of a phase III trial suggest an improvement in outcome with the incorporation of docetaxel into a standard regimen used to treat advanced gastric cancer [6].

The treatment approach for advanced non-small cell lung cancer (NSCLC) has changed in the past decade. Combinations of third-generation cytotoxic drugs, such as the taxanes, with platinum analogues have emerged as a new standard, producing high response rates and prolonged survival. Dr. James R. Rigas (Dartmouth Medical School, Hanover, NH) reviews the significant advance that taxane doublets, specifically docetaxel-platinum, offer in the first-line treatment of advanced NSCLC, highlighting the clinically relevant differences among the third-generation doublets. Finally, the extensive clinical development of the taxanes in the treatment of breast cancer is examined by Dr. John Crown (St. Vincent’s University Hospital, Dublin, Ireland). As the role of the taxanes has been consistently confirmed in the metastatic setting, numerous clinical trials have been undertaken to evaluate their role in the treatment of early-stage disease. The taxanes, in particular docetaxel, have made a major impact on the treatment of metastatic disease as well as on the adjuvant and neoadjuvant settings.

The question of whether the preclinical differences in the taxanes will translate into a difference clinically is under study. Emerging data from clinical trials in a number of solid tumors suggest a clinical benefit favoring docetaxel. Data in breast and ovarian cancer support the use of docetaxel in paclitaxel-resistant disease. This has spurred interest in studying the taxanes in head-to-head comparisons. In the Scottish Randomized Trial in Ovarian Cancer, a docetaxel-carboplatin combination was compared with a paclitaxel-carboplatin combination as the first-line treatment for 1,077 patients with advanced (International Federation of Gynecology and Obstetrics stage IC-IV) epithelial ovarian cancer [7, 8]. To date, the results demonstrate comparable antitumor efficacy (progression-free and overall survival) between the two groups, indicating that docetaxel is a viable alternative to paclitaxel in the treatment of advanced ovarian cancer. However, toxicity data in conjunction with quality-of-life assessments suggest docetaxel may be considered the taxane of choice. This underscores the importance of continued research to seek to define the optimal use of the taxanes in the treatment of cancer.

	ACKNOWLEDGMENT

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P.V. receives research support from Aventis, Eli Lilly, Roche, and Schering-Plough and has received honoraria from Aventis and Eli Lilly for advisory board work.

	REFERENCES

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1. Infield GB. Disaster at Bari. New York: Macmillan, 1971.
2. Gilman A, Philips FS. The biological actions and therapeutic applications of b-chloroethyl amines and sulfides. Science 1946;103:409.[Free Full Text]
3. Farber S, Diamond LK, Mercer RD et al. Temporary remissions in acute leukemia in children produced by the folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med 1948;238:787.
4. Hertz R, Lewis J, Lippsett M. Five years experience with chemotherapy of metastatic choriocarcinoma and related trophoblastic tumors in women. Am J Obstet Gynecol 1961;82:631–640.
5. Ringel I, Horwitz SB. Studies with RP 56976 (taxotere): a semisynthetic analogue of taxol. J Natl Cancer Inst 1991;83:288–291.[Abstract/Free Full Text]
6. Ajani JA, Van Cutsem E, Moiseyenko S et al. Docetaxel (D), cisplatin, 5-fluorouracil compare to cisplatin (C) and 5-fluorouracil (F) for chemotherapy-naïve patients with metastatic or locally recurrent, unresectable gastric carcinoma (MGC): interim results of a randomized phase III trial (V325). Proc Am Soc Clin Oncol 2003;22:249.
7. Vasey PA. Preliminary results of the SCOTROC trial: a phase III comparison of paclitaxel-carboplatin and docetaxel-carboplatin as first-line chemotherapy for stage IC-IV epithelial ovarian cancer. The Scottish Gynecologic Cancer Trials Group. Proc Am Soc Clin Oncol 2001;20:202a.
8. Vasey PA. Survival and longer term toxicity results of the SCOTROC study: docetaxel-carboplatin (DC) vs. paclitaxel-carboplatin (PC) in epithelial ovarian cancer (EOC). The Scottish Gynecologic Cancer Trials Group. Proc Am Soc Clin Oncol 2002;21:202a.

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