Combination chemotherapy of the taxanes and antimetabolites: its use and limitations

In an effort to improve response rates of chemotherapy. taxanes have been c ombined with other cytotoxic agents such as antimetabolites. However. the u se of some of these combinations in patients has been restricted by severe toxicity. The significance of the sequence of drug administration in combin ing methotrexate (MTX) find taxanes was recognised in in vitro Studies, sho wing synergistic effects for the sequence of MTX followed by paclitaxel. an d antagonism for exposure in the revere order. A possible explanation might he an MTX-induced synchronisation of cells in the S phase of the cell cycl e. after which cells Lire more susceptible for the cytotoxic action of taxa nes. Clinical studies using this sequence were hampered by severe neutropen ia and mucositis at relatively low doses of both drugs. As no pharmacokinet ic interactions were observed, the excess of toxicity may have been due to sequence-dependent synergistic actions on bone (narrow find mucosa. In cont rast. and confusingly, in vitro studies oil 5-fluorouracil (5-FU) and taxan es indicate that 5-FU preceeding or simultaneously given to paclitaxel impa irs cytotoxicity;is compared with paclitaxel monotherapy. while the reverse sequence results in additive or synergistic cytotoxicity. While almost all clinical studies have used the sequence of a taxane followed by 5-FU, vari ous schedules appeared feasible and effective. The combination of a 5-FU an alogue, capecitabine and taxanes was supported by in vitro data. A large ph ase III trial confirmed the feasibility and Superior efficacy of this combi nation in breast cancer patients relapsing after an anthracycline. Conflict ing results exist on the benefit of combining gemcitabine and taxanes in tu mour cell lines. Although the accumulation of gemcitabine triphosphate (dFd CTP) in mononuclear cells was significantly higher with an increasing dose of paclitaxel, no pharmacokinetic interactions for both agents were noticed . A pharmacokinetic analysis of the gemcitabine-docetaxel combination thera py has not been published in detail. Despite numerous trials, so far no opt imum schedule has been established. Regarding data on actually delivered do se intensities, a 2- or 3-weekly cycle seems favourable and feasible. Howev er. possible severe pulmonary toxicity warrants cautious monitoring of pati ents treated with this combination. Different outcomes of preclinical and c linical studies reveal that combining two chemotherapeutic agents is not si mply a matter of putting antitumour activities together. Drug interaction m ay result in synergism, not only of efficacy but also of toxic side-effects . Adding two drugs may also implicate antagonism in drug efficacy due to un wanted interference in cytotoxicity or pharmacokinetics. For agents acting at a specific phase of the cell cycle, the sequence of administration may d etermine the efficacy and toxicity of a combination therapy. Because of Lin observed discrepancy between in vitro data;ind clinical studies, we would like to emphasise the need for adequate dose-finding clinical trials togeth er with pharmacokinetic data analysis before examining any new combination chemotherapy in more detail in phase II studies. (C) 2001 Published by Else vier Science Ltd. All rights reserved.