Lung cancer is the leading cause of cancer death worldwide, accounting for 1.1 million deaths (17.8% of all cancer deaths) in the year 2000. Non-small-cell lung cancer (NSCLC) comprises 85% of all lung cancer cases, and almost 45% of patients present with distant metastasis at diagnosis. In the first-line treatment setting, platinum-based chemotherapy prolongs survival and improves disease-related symptoms and quality of life when compared to best supportive care.[2,3] Moreover, new drug development and the investigation of novel chemotherapeutic combinations have resulted in a further improvement in progression-free survival, overall survival, and quality of life. Nevertheless, 5-year survival rates still remain extremely poor, and progressively more patients receive second-line treatment following failure in first-line setting. Docetaxel(Drug information on docetaxel) (Taxotere), an antimicrotubule agent was first approved by US Food and Drug Administration (FDA) and also recommended in the updated 2004 guidelines of the American Society of Clinical Oncology (ASCO) for second-line therapy use in patients with progressive disease following platinum-based chemotherapy.[ 5] Despite potent activity, docetaxel is associated with significant toxicity, and in clinical practice, its use remains indicated for patients with good performance status (PS). Pemetrexed(Drug information on pemetrexed) (Alimta) is a novel, multitargeted antifolate that inhibits at least three enzymes involved in DNA synthesis pathways: thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). After phase I studies assessed an optimal pemetrexed dose of 500 mg/m2 once every 3 weeks, several trials investigated its role as a single agent and in combination chemotherapy with cisplatin(Drug information on cisplatin) as first-line treatment of NSCLC.[8,9] In this article, we present a brief overview of current second-line options in the treatment of NSCLC, and we also review trials investigating the role of pemetrexed as a single agent in second- line chemotherapy for NSCLC. Second-Line Chemotherapy for NSCLC Several phase II studies investigated single-agent chemotherapy with third-generation drugs as second-line treatment for recurrent NSCLC. Response rates ranged from 3% achieved with paclitaxel(Drug information on paclitaxel) (median survival 4.5 months) to 19% with gemcitabine(Drug information on gemcitabine) (Gemzar) (median survival 8.0 months).[10,11] The approval of docetaxel by the FDA and the European Agency for the Evaluation of Medical Products (EMEA) as standard treatment in this setting was based on two phase III studies. In the Tax 317 trial of Shepherd et al, 204 patients were randomized to receive docetaxel at 100 mg/m2 every 3 weeks or best supportive care alone (Table 1). After an interim-safety analysis recorded a higher treatment- related death rate in the docetaxel arm, the dose was reduced to 75 mg/m2. The objective overall response rate was 5.8% in the docetaxel arm, with an Eastern Cooperative Oncology Group (ECOG) PS of 0 as the best predictor of response. All efficacy parameters were significantly improved for patients treated with docetaxel than the best supportive care group, with a time to progression of 2.6 vs 1.7 months (P < .001), a median overall survival of 7 vs 4.6 months (P = .047), and a 1-year survival rate of 29% vs 19%. Even better results were reported in the subset of patients who received docetaxel at 75 mg/m2 vs the corresponding best supportive care group for median survival (7.5 vs 4.6 months [P = .01]) as well as 1- year survival percentage (37% vs 12%; P = .003). Hematologic toxicity was the most relevant grade 3/4 toxicity observed, with rates of neutropenia and febrile neutropenia of 76% and 11.5%, respectively. Despite the high rate of side effects reported, at the qualityof- life evaluation performed with both the Lung Cancer Symptom Scale and the European Organization for Research and Treatment of Cancer (EORTC) instruments, docetaxeltreated patients reached higher scores in terms of pain control, weight loss, and PS. Furthermore, patients receiving docetaxel at 75 mg/m2 required significantly fewer opioid and nonopioid drugs. Similar results were obtained in the TAX 320 trial reported by Fossella et al summarized in Table 1. In this study, docetaxel at 100 mg/m2 or 75 mg/m2 was compared with an alternative single-agent chemotherapy, either vinorelbine (Navelbine) or ifosfamide(Drug information on ifosfamide) (Ifex), known as V/I. Overall, 373 patients were randomized, and 358 were evaluable for response and survival. The overall response rates were 10.8%, 6.7%, and 0.8% for the docetaxel 100 mg/m2 and 75 mg/m2 and the control groups, respectively. Time to progression and overall survival (range: 5.5 to 5.7 months) were comparable in all groups, but 1-year survival was significantly in favor of the docetaxel 75 mg/m2 group vs control (32% vs 19%; P = .025). The docetaxel 100 mg/m2 group achieved a 1- year survival rate of 21%, not significantly different from the control group. The progression-free survival at 26 weeks was significantly increased for patients receiving docetaxel compared to V/I (P = .005). The incidence of neutropenia and febrile neutropenia was significantly higher in both docetaxel groups than in the V/I group; moreover, two toxic deaths were observed in both the docetaxel 100 mg/m2 and V/I groups, but not in the docetaxel 75 mg/m2 group. On the basis of data obtained in the TAX 317 and 320 trials, docetaxel at 75 mg/m2 was considered a new control group in other forthcoming studies conducted in the second-line setting for treatment of NSCLC. To decrease docetaxel toxicity while maintaining efficacy, two phase III trials compared the 3-week 75 mg/m2 schedule with a weekly schedule. The results are summarized in Table 1. The preliminary results of the Italian multicenter study (n = 220; 215 evaluable) of Gridelli et al show that weekly docetaxel has a better impact on aspects of quality of life (eg, coginitive function, pain, cough, hair loss) with a comparable activity for the 3-week vs the standard schedule (overall response: 2.7% vs 5.5%; median survival: 7.2 vs 7.9 weeks). However, Camps and colleagues[ 14] in their Spanish study (n = 240; 179 evaluable) did not confirm the advantage previously reported for the safety profile with the weekly schedule. While the safety profiles were similar, neutropenia, leukopenia, alopecia, and hepatic toxicity were more common in the 3-week schedule, while diarrhea, mucositis, and dyspnea were more common in the standard schedule. The overall response rate, time to progression, and 1-year survival rates did not differ between groups, the every-3-week schedule achieved significantly improved median survival (7.1 vs 5.4 months; P = .004). Overall, data from such trials generated a growing interest in the developemnt and evaluation of new agents for use in the second-line treatment of NSCLC. Pemetrexed in Second-Line Chemotherapy for NSCLC Several studies exploring the activity and safety profile of pemetrexed as an anticancer compound demonstrated a good tolerability profile, with severe myelosuppression and skin rush as the dose-limiting toxicities. As second-line therapy, it has been investigated in a phase II trial, and consequently, in a phase III randomized trial vs the standard docetaxel as a comparator. In a large phase II trial conducted in Europe and Australia, Smit et al administered pemetrexed to 81 refractory patients (79 evaluable), defined as patients who progressed during first-line treatment or within 3 months after completion of first-line treatment. Accrual was carefully restricted to patients with demonstrated disease progression by computed tomographic (CT) scan or x-ray. Patients were required to have bidimensionally measurable disease and an estimated life expectancy of more than 8 weeks. Patients with an ECOG PS of 2 (considered unfit) were not accrued. Patients received pemetrexed 500 mg/m2 in 10 minutes intravenously (IV) every 3 weeks, and were stratified according to prior treatment: platinum- containing regimens (n = 45) vs no platinum-containing regimens (n = 36). Furthermore, all patients received premedication with oral dexamethasone(Drug information on dexamethasone) once every 12 hours, starting 24 hours before treatment and continuing for four doses after treatment. At the time of study initiation and completion, folic acid(Drug information on folic acid) and vitamin B12 supplementation were not yet systematically implemented, and patients did not receive that premedication. Table 2 summarizes the results of this study. The overall response rate was 8.9%, and all but one patient who responded to pemetrexed had previously responded to first-line treatment. Response rate was higher in the platinum- naive patients (14.3% vs 4.5%), but in this subgroup, the median survival time was only 4 months vs 6.4 months in patients who were pretreated with a platinum compound. Pemetrexed was well tolerated, with 35% of patients experiencing grade 3/4 neutropenia. Nevertheless, three toxic deaths associated with neutropenia- related sepsis were recorded. The use of oral prophylactic dexamethasone at any cycle reduced the incidence of grade 3 skin rash to only four patients. The favorable results obtained in this trial led to a phase III randomized registration trial for comparing pemetrexed to the standard docetaxel as second-line therapy in patients with NSCLC. Moreover, subsequent studies showed that the frequency of severe myelosuppression was directly related to the folate and vitamin B12 status of the patients. The levels of homocysteine, a measure of folate and vitamin B12 status, were directly related to neutropenia and infection-toxicities that are associated with a greater risk of death. Folic acid and vitamin B12 supplementation was shown to reduce toxicity and to lower homocysteine levels. Vitamin supplementation was thus adopted as an integral part of pemetrexed treatment. From March 2001 to February 2002, Hanna et al accrued on-study 571 NSCLC patients who had previously received only one first-line chemotherapy regimen into a randomized, multicenter phase III registration trial.[ 17] (This trial was the largest phase III trial of second-line NSCLC reported to date.) Patients received pemetrexed at 500 mg/m2 IV day 1 or docetaxel at 75 mg/m2 IV day 1, every 21 days. In the pemetrexed arm, patients were premedicated with corticosteroids, folic acid, and vitamin B12; patients in the docetaxel arm received corticosteroids. Ninety percent of patients had previously received platinum therapy, while 28% had received taxanes. The primary end point was overall survival; secondary end points included toxicity, response rate, progression-free survival, and changes in the average symptom burden index. There was no overall difference between the study arms in efficacy (summarized in Table 3). The median survival time was 8.3 months for pemetrexed vs 7.9 months for docetaxel. The overall response rates were 9.1% vs 8.8% for pemetrexed and docetaxel, respectively, and no difference between the two arms was observed for symptom relief. There was a statistically significant difference between arms in regard to toxicity in favor of pemetrexed. Patients receiving docetaxel (vs pemetrexed) were more likely to experience grade 3/4 neutropenia (40.2% vs 5.3%; P < .001), febrile neutropenia (12.7% vs 1.9%; P < .001), infections with grade 3/4 neutropenia (3.3% vs 0%; P = .004), and alopecia (37.7% vs 6.4%; P < .001) compared to patients in the pemetrexed arm. Moreover, the requirements for granulocyte colony-stimulating factor (G-CSF)/granulocyte-macrophage colony-stimulating factor (GMCSF) were increased in the docetaxel arm (19.2% vs 2.6% of cycles; P < .001). Moreover, hospitalization attributable to either febrile neutropenia or drug-related adverse events was more common among patients in the docetaxel arm vs those in the pemetrexed group (13.4% vs 1.5%, P < .001; 40.6% vs 31.7%, P = .092, respectively). The data demonstrate that pemetrexed possesses an improved safety profile when compared with docetaxel in the second-line setting, and it is an effective agent in second-line chemotherapy in NSCLC. Conclusion The new multitargeted antifolate pemetrexed is directed to cellular targets that are distinct from those commonly targeted by conventional agents currently used in the management of NSCLC. This lack of cross-resistance might take advantage of clinical synergism when pemetrexed is combined with other agents that possess high activity in the first-line setting, as well as in salvage therapy for patients who are resistant to standard treatments. The optimal administration of second- line treatment in NSCLC is currently unclear, as are the prognostic and/or predictive selection factors for response to further therapy regimen. In this regard, a phase II study conducted by Smit et al reported that pemetrexed achieved good activity in selected patients who entered on study with a common ("poor") prognostic factor (eg, resistance to first-line platinum- based therapy). The overall response rate was 9%, with a 1-year survival rate of 23% data comparable to that obtained with other agents in this setting. Recent data from a randomized phase III trial by Hanna and colleagues[ 17] demonstrated that pemetrexed and the standard triweekly docetaxel achieved comparable efficacy, but patients in the pemetrexed group reported a better safety profile for hematologic and nonhematologic toxcity, and improved quality of life. Moreover, the introduction of daily oral folate and intramuscular vitamin B12 supplementation every 9 weeks, independent of the vitamin level of the patients, allowed investigators to evaluate properly the efficacy and safety profile of the regimen in relation to dose intensity. Due to these results, in the summer of 2004 pemetrexed was approved by the FDA as single-agent chemotherapy for second-line treatment in recurrent NSCLC; thus it can be considered a standard treatment option in this setting.