Rafael Rosell, MD

Pemetrexed (Alimta) possesses broad antitumor activity. It has beenevaluated in non–small-cell lung cancer (NSCLC) as front-line chemotherapyin a comprehensive phase II evaluation. While variousantifolates have been previously evaluated in clinical trials, drug developmentwas stopped or delayed in light of their lack of efficacy oroccurrence of life-threatening toxicities. While similar trends were observedwith pemetrexed early in development, investigators institutedfolic acid and vitamin B12 supplementation to minimize these toxicitieswithout hampering drug efficacy. This article briefly summarizes thecurrent evidence that supports the role of pemetrexed-based combinationsin clinical trials for chemonaive patients with advanced NSCLC.

Although no overall differences in survival have been observed betweenthe many chemotherapy combinations in non–small-cell lungcancer, the clinical application of mRNA expression levels of amplifiedgenes may disclose many genetic influences on cytotoxic drug sensitivityand enable clinicians to tailor chemotherapy according to eachindividual’s gene profile. Specifically, the assessment of ribonucleotidereductase subunit M1 and thymidylate synthase mRNA expression levelsmight select patients who benefit from gemcitabine (Gemzar) orpemetrexed (Alimta) combinations. Until recently, clinical prognosticfactors such as performance status, weight loss, and lactate dehydrogenasewere the only parameters used to predict chemotherapy responseand survival. However, accumulated data indicate that overexpressionof genes involved in cancer glycolysis pathways plays an important role,and might be an independent mechanism of chemoresistance. Thedysregulation of glycolytic genes is affected by growth signals involvingthe PI3K/Akt pathway and downstream genes such as hypoxiainduciblefactor-1-alpha. One can thus envision that substantial improvementsin therapeutic outcome could benefit from the integrationof tailored ribonucleotide reductase-dependent chemotherapy, ribonucleotidereductase antisense therapy, and targeted therapy.

Several decades of chemotherapy trials in non–small-cell lung cancer(NSCLC) have clearly shown a survival benefit for chemotherapyover best supportive care. However, only short-lived responses are attained,with an average of four cycles of chemotherapy, before tumorprogression is observed. Second-line chemotherapy has been demonstratedto improve outcome, with docetaxel (Taxotere) as the predominantcytotoxic drug. A recent randomized trial in second-line NSCLCindicated that the novel drug pemetrexed (Alimta) attained the sameresponse, time to progression, and survival as docetaxel. This findingushers in a new age in second-line treatment that can be further invigoratedby the addition of targeted agents. Accumulated evidence indicatesthat overexpression of epidermal growth factor receptor andHER2/neu, which occurs frequently in NSCLC, leads to the deregulationof PI3K and MAPK, activating Akt and enhancing chemoresistance.Future clinical trials in NSCLC will include tailored andmultitargeted therapy and pemetrexed represents a significant step forSward in this direction.

A wealth of data indicates that certain genetic abnormalities can target specific cytotoxic drugs and intervene at an early step as a mechanism of resistance in the treatment of non-small-cell lung cancer. Therefore prescribing

Despite a response rate of only 9%, single-agent carboplatin (Paraplatin) produced the best 1-year survival rate with the lowest toxicity in a five-arm Eastern Cooperative Oncology Group study of cisplatin (Platinol)