Second-line chemotherapy in non-small-cell lung cancer (NSCLC) is a relatively new approach. For a long time, it was not recognized that cisplatin(Drug information on cisplatin)-based chemotherapy improved survival in the metastatic setting. A Canadian study[1] showed a median survival of 4 months with best supportive care and 8 months (P = .01) with vindesine(Drug information on vindesine) (Eldesine) at 3 mg/m² weekly * 4 and then every 2 weeks plus cisplatin at 120 mg/m², days 1 and 21 and then every 6 weeks. One-year survival rates were 10% and 22%, respectively. The cisplatin-based chemotherapy meta-analysis[2] of cisplatin combined with vinca alkaloids or etoposide showed a chemotherapy benefit with a hazard ratio of 0.73 and an increase in median survival of 1.5 months. The response rate with gemcitabine(Drug information on gemcitabine) (Gemzar)/cisplatin was higher than with etoposide(Drug information on etoposide)/cisplatin (41% vs 22%; P = .02) and time to progression was also longer in the gemcitabine arm (6.9 vs 4.3 months; P = .01).[3] In the British study, median survival was 6.7 months with mitomycin(Drug information on mitomycin) (Mutamycin)/ifosfamide (Ifex)/ cisplatin (MIC) as compared to 4.8 months with best supportive care (P = .03).[4] In the Southwest Oncology Group study,[5] cisplatin-based chemotherapy was a strong significant prognostic factor for survival. Furthermore, in cisplatin-treated patients, three different prognostic subsets were observed based on performance status, age, hemoglobin, and lactate dehydrogenase (LDH), with 1-year survival of 27%, 16%, and 6% (P < .0001). These parameters could be useful to distinguish patients expected to respond to second-line chemotherapy. More recently, overexpression of genes involved in the nucleotide excision repair pathway has been related to cisplatin response and survival. In gemcitabine/cisplatin-treated patients, overexpression of excision repair cross-complementing 1 (ERCC1) mRNA was associated with a median survival of 5 months, in contrast with 15 months in patients with normal ERCC1 mRNA levels (P = .009).[6] In spite of the statistically demonstrated benefit of cisplatin chemotherapy, patients often perceive a relatively small benefit, and hence are reluctant to receive chemotherapy. In scripted interviews, when patients were asked to indicate the benefit required to accept the toxicity associated with chemotherapy, only 22% chose chemotherapy over best supportive care for a survival benefit of 3 months.[7] Moreover, in a British study, patients were randomized to receive three or six cycles of mitomycin/ vinblastine(Drug information on vinblastine)/cisplatin (MVP); no differences were observed in time to progression (5 months in both arms) or in median survival (6 vs 7 months).[8] No single chemotherapy combination has demonstrated an overall superiority to any other in survival benefit[9,10] or in quality of life[10] in metastatic NSCLC. The average time to progression ranged from 3.4 to 5.5 months, median survival from 7.4 to 9.9 months, 1-year survival from 31% to 43%, and 2-year survival from 10% to 13%.[9,10] In these studies, a fraction of patients received poststudy therapy, mainly with crossover doublet combinations.[10] However, no consistent second-line treatment had been undertaken until recently. The British randomized study[8] highlighted the point that time to progression occurred early on, after three to five cycles of chemotherapy. Customized chemotherapy can help to improve outcome by selecting patients[11] and planning second-line treatment in all clinical trials. There are only a few drugs that have demonstrated activity in the second-line approach, and there is some evidence of activity for cisplatin-based chemotherapy in patients receiving frontline noncisplatin combinations.[12] Phase II Second-Line Trials in NSCLC Multiple phase II studies have been performed with almost all available cytotoxic drugs. The majority of these studies included vinorelbine (Navelbine), gemcitabine, paclitaxel(Drug information on paclitaxel), and docetaxel(Drug information on docetaxel) (Taxotere). A complete review[ 13] found that with the exception of docetaxel, the response in some of these studies was null. Median survival from the time of starting second- line treatment ranged from 3 to 11 months (Table 1). Many of these early phase II studies included a small number of patients. Moreover, from the inclusion criteria, it is difficult to discern whether the patients were cisplatin- refractory (no response was observed) or cisplatin-resistant (a prior response was attained), as there was no common agreement on the concept of cisplatin-resistant and -refractory tumors.[13] The largest gemcitabine study, including 83 patients, attained a partial response of 19%, including patients who had previously responded to gemcitabine/cisplatin chemotherapy.[14] Pemetrexed(Drug information on pemetrexed) (Alimta) has been tested in patients with progressive disease within 3 months after first-line chemotherapy or progression while being treated with first-line chemotherapy.[ 15] Patients were stratified according to whether the first-line treatment included a platinum regimen. Pemetrexed was administered at 500 mg/m² every 21 days. The response rate was 4.5% in the platinumpretreated group and 14% in the non-platinum-pretreated group. Median survival was 6.4 and 4 months, respectively. Time to progression was 2.3 and 1.6 months, respectively (Table 1). In this trial, no folic acid(Drug information on folic acid) or vitamin B₁₂ was administered. Vitamin supplementation with daily folic acid (350 μg) and vitamin B₁₂ (1,000 μg) every 9 weeks significantly lowered homocysteine levels and reduced severe myelosuppression and gastrointestinal toxicity.[16] Randomized Second-Line Trials in NSCLC To date, the only drug approved for second-line treatment of NSCLC is docetaxel, based on the results of two phase III randomized studies (Table 2).[17,18] Among the many intriguing questions surrounding this point, perhaps the most salient is why paclitaxel has not been identified as a potential second-line treatment. Several lines of evidence indicate that HER2/neu overexpression is related to paclitaxel resistance. Pérez-Soler et al reported that in NSCLC heterotransplants in nude mice, lack of HER2/neu expression was linked to better response to paclitaxel (0% of responding tumors and 48% of nonresponders expressed HER2/neu).[19] Furthermore, paclitaxel yielded a significantly lower growth inhibition than docetaxel in HER2/neu-overexpressing MCF/18 cells (a MCF-7 human breast cancer cell line transfected with HER2/ neu).[20] Growth factor receptor-mediated signal transduction has been involved in chemoresistance. The HER2/neu/phosphatidylinositol-3 kinase (PI3K)/Akt pathway mediates resistance to chemotherapy and EGFR inhibitors. Overexpression of Akt confers chemoresistance in NSCLC.[21] Akt regulates cell survival by phosphorylating downstream apoptotic targets (BAD, procaspase 9, Forkhead family of transcription factors, NFkappaB regulator IKK) (Figure 1).[22] The loss of phosphatase PTEN leads to activation of Akt.[23] In breast cancer cell lines, expression of both HER2/neu and HER3 caused a PI3Kdependent activation of Akt that was linked to increased resistance to paclitaxel, doxorubicin(Drug information on doxorubicin), fluorouracil(Drug information on fluorouracil) (5- FU), etoposide, and camptothecin.[24] These preclinical lines of evidence have led some investigators to design second-line studies of gefitinib(Drug information on gefitinib) (Iressa, an EGFR inhibitor) plus trastuzumab(Drug information on trastuzumab) (Herceptin, a HER2/neu inhibitor). HER2/neu has been studied by immunohistochemistry in resected NSCLC tumors, and 2+ or 3+ overexpression was found in 17%.[25] However, with real-time quantitative polymerase chain reaction (RTQPCR), HER2/neu mRNA expression was detected in 100% of specimens analyzed. HER2/neu expression level segregated patients into poor and good prognostic subgroups. The segregation method used a tumor-normal tissue ratio of 1.8 as a cutoff value.[26] Almost 35% of patients had high HER2/neu expression, and nearly 38% had high epidermal growth factor receptor (EGFR) expression. High HER2/neu expression was associated with inferior survival in this group of resected NSCLC patients. The Shepherd et al study[17] demonstrated that docetaxel at 75 mg/m² every 3 weeks yielded a 6% response. When compared with best supportive care, time to progression was 3 vs 1.7 months, median survival was 7.5 vs 4.6 months, and 1-year survival was 37% vs 12%. These differences were all statistically significant. Better outcome was observed in patients with a performance status of 1, those who had responded to prior cisplatin treatment, those who had received only one prior chemotherapy regimen, those who had no weight loss, or those with normal LDH (Table 2). The Fossella et al [18] study showed as well that docetaxel at 75 mg/m² every 3 weeks achieved a 7% response rate, with a median survival of 5.7 months and a 1-year survival of 30%, while vinorelbine or ifosfamide(Drug information on ifosfamide) yielded a 1% response rate, with a median survival of 5.6 months and a 1-year survival of 20%. The differences at 1 year were significant. In this study, prior paclitaxel treatment did not influence the responses attained with docetaxel (Table 2). The Camps et al[27] phase III study compared two different docetaxel dose schedules (75 mg/m² every 3 weeks vs 36 mg/m² weekly for 6 weeks, every 8 weeks). Preliminary observations in 179 patients show response rates of 11% and 7%, time to progression of 3.4 and 3.5 months, and median survival of 6.3 and 6.1 months, respectively. Eighteen percent of patients had received prior paclitaxel-based treatment. No substantial differences in toxicity were observed (Table 2). Hanna et al conducted the largest phase III randomized trial in secondline treatment,[28] comparing docetaxel at 75 mg/m² every 3 weeks with pemetrexed at 500 mg/m² every 3 weeks. In the pemetrexed arm, folic acid (350-1,000 μg daily) and vitamin B₁₂ (1,000 μg every 9 weeks) were administered. Patients were stratified according to performance status,best response to prior chemotherapy, number of prior chemotherapy regimens, time since last chemotherapy, prior platinum- and taxane-based chemotherapy, and baseline homocysteine serum levels. Ninety percent of patients had received prior cisplatin treatment and 26% had received prior taxanes. The median number of cycles administered was 4 in both arms. Response rates were 8.8% in the docetaxel arm and 9.1% in the pemetrexed arm, respectively. Time to progression was 2.9 months in both arms. Median survival was 7.9 and 8.3 months, respectively. One-year survival was 29.7% in both arms (Table 2). While response, time to progression, and survival were similar in the two arms, in the pemetrexed arm less severe neutropenia, fewer hospitalizations, and less need for ancillary measures were observed. This study opens the gates for new second-line chemotherapy combinations (Figure 2). A phase II second-line randomized trial of irinotecan(Drug information on irinotecan)/cisplatin vs cisplatin alone was carried out in patients pretreated with taxanes/gemcitabine.[ 29] Response rates were 24% and 8.3%, respectively. Time to progression was 2.5 and 2 months, respectively. Median survival was identical in both arms (9 months). One-year survival was 40.5% and 31.2%, respectively (Table 2). Although the number of patients included in the trial was small, the results were promising for the use of the novel combination. EGFR inhibitors have also been used as targeted therapies, attaining meaningful response rates ranging from 11% to 18.4%, with median survival times of 6.5 to 8.4 months, and 1-year survival rates of 29% to 40%.[30,31] These outcomes are relevant, especially considering that most of these patients had received more than two prior chemotherapy regimens. Skin toxicity was linked to better survival in some of these trials (Table 2). The combination of cetuximab(Drug information on cetuximab) (Erbitux), the monoclonal antibody against the extracellular ligand-binding domain of EGFR, plus docetaxel yielded a 25% response rate with a 7.5-month median survival.[32]