Pemetrexed combination therapy in the treatment of non-small cell lung cancer

Until recently, the treatment of non-small cell lung cancer (NSCLC) was limited to the cisplatin combinations, including a small number of cytotoxic drugs. More recently, combinations with taxanes and gemcitabine have slightly improved outcome. However, when the literature is revisited, it can be realized that older drugs such as nitrogen mustard have some degree of activity in NSCLC, traditionally considered a chemoresistant tumor. However, drugs that are mostly ineffective when used as single agents, such as 5-fluorouracil (5-FU), have significant activity when combined with cisplatin in the treatment of patients with NSCLC. 5-FU constitutes the backbone of chemotherapy for colorectal cancer patients. 5-FU is equally interesting because it permits investigation of thymidylate synthase (TS) levels as a genetic target for predicting response and survival. The assessment of TS levels and ERCC1 as a marker of cisplatin resistance is leading to customized chemotherapy. The possibility of discriminating cisplatin resistance is particularly attractive in choosing between cisplatin and non-cisplatin combinations in the treatment of NSCLC. We have reviewed phase I and II studies of pemetrexed in NSCLC. The response rate is approximately 20% with single-agent pemetrexed and approximately 40% in combination with cisplatin. This combination has mild to moderate toxicity. Other synergistic combinations that should be explored include pemetrexed with gemcitabine, CPT-11, docetaxel, carboplatin, or oxaliplatin. In the future, pharmacogenomically oriented chemotherapy trials should be undertaken based on the accumulated evidence that several genetic markers, such as ERCC1, beta-tubulin mutations, and loss of heterozygosity in the region of the enzyme ribonucleotide reductase, can predict resistance to cisplatin, taxanes, or gemcitabine, respectively. Mechanisms of resistance to pemetrexed need to be investigated, including the potential role of TS messenger RNA. In summary, pemetrexed has emerged as a promising new cytotoxic drug in the arsenal of chemotherapy treatments for NSCLC.