Second-Line Treatment Options in Non Small Cell Lung Cancer: A Comparison of Cytotoxic Agents and Targeted Therapies

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1 Second-Line Treatment Options in Non Small Cell Lung Cancer: A Comparison of Cytotoxic Agents and Targeted Therapies Filippo de Marinis, a Stefano De Santis, a and Luigi De Petris b Current options for the second-line treatment of non small cell lung cancer (NSCLC) include cytotoxic drugs, such as docetaxel and pemetrexed, and targeted therapies. Docetaxel was approved in the United States and Europe in 2000 after two phase III trials showed drug superiority versus best supportive care alone and versus alternative singleagent chemotherapy. Pemetrexed was approved in the United States and Europe in 2004 after a phase III trial showed that, compared with docetaxel, it had comparable activity (median survival time of approximately 8 months in both arms) and a more favorable toxicity profile: grade 3-4 neutropenia was observed in 5.3% versus 40.2% of patients in the pemetrexed and docetaxel arms, respectively, while febrile neutropenia was observed in 1.9% versus 12.7% of patients, respectively. In the United States, gefitinib and erlotinib have also been approved for the treatment of recurrent NSCLC (in 2003 and 2004, respectively), while in Europe the registration of these agents is currently under evaluation. This review focuses on the use of docetaxel and pemetrexed for the second-line treatment of NSCLC and compares these drugs with targeted therapies, highlighting the latest developments in pharmacogenomics that might lead to a more tailored approach to treatment. Semin Oncol 33(suppl 1):S17-S Elsevier Inc. All rights reserved. Second-line chemotherapy for non small cell lung cancer (NSCLC) can be considered a standard treatment for patients resistant to first-line treatment who still have a good performance status (PS). 1 This is based on several considerations: the survival advantage of platinum-based first-line chemotherapy for NSCLC established by a metaanalysis published in ; the fact that third-generation drugs (gemcitabine, vinorelbine, taxanes), as single agents or in combination with platinum derivates, have been shown to be more active than second-generation drugs, and with their lower toxicity profile have opened new treatment possibilities; the development of imaging technologies, which allow earlier diagnosis of lung cancer than previously possible; the increase in disease-free survival, also because of the use of combined treatment at early stages of disease; the fact that at time of recurrence the PS a 5th Pneumo-oncology Unit, Department of Oncology, S. Camillo-Forlanini Hospitals, Rome, Italy. b Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden. Address reprint requests to Filippo de Marinis, MD, 5th Pneumo-oncology Unit, Department of Oncology, S. Camillo-Forlanini Hospitals, Via Portuense Rome, Italy; demarinis.filippo@virgilio.it of patients is often good (0-1), and this, together with the improvement in supportive care, allows patients to better tolerate a second-line treatment, especially if administered with single agents; finally, the patient requests to receive further treatment at disease progression have substantially increased. Although several cytotoxic drugs have been tested in the second-line setting, docetaxel has evolved as standard treatment for advanced NSCLC. However, pemetrexed has shown similar efficacy as docetaxel (with a more favorable toxicity profile), which makes it a promising alternative. 3 This article reviews the use of docetaxel and pemetrexed in the secondline treatment of NSCLC and compares their efficacy and safety with that of targeted therapies such as gefitinib and erlotinib. Docetaxel in the Second-line Treatment of NSCLC Trials describing the use of docetaxel for treating NSCLC have used regimens in which docetaxel is administered either /06/$-see front matter 2006 Elsevier Inc. All rights reserved. doi: /j.seminoncol S17

2 S18 de Marinis, De Santis, and De Petris Table 1 Randomized Trials Testing Efficacy and Safety of Docetaxel in Second-Line Non Small Cell Lung Cancer Study Arm Patients (N) RR Median Survival (mos) 1-Year Survival Grade 3-4 Neutropenia Febrile Neutropenia Most Frequent Grade 3-4 Non-Hematologic Toxicity TAX D Pulmonary events (36.7) D Pulmonary events (20) BSC Pulmonary events (30) TAX D Fatigue (17) D Fatigue (12) V/I Fatigue (11) Quoix et al 7 D Asthenia (19.1) Diarrhea (4.5) D Asthenia (8.6) Diarrhea (1.1) Gervais et al 8 D Asthenia (4.8) D Asthenia (11) Camps et al 9 D Asthenia (12.1) D Asthenia (11.4) Schuette et al 10 D Alopecia (22.5) D > Alopecia (11.4) Gridelli et al 11 D Fatigue (7) D Fatigue (6) Abbreviations: BSC, best supportive care; D100, 3-week docetaxel 100 mg/m 2 ; D75, 3-week docetaxel 75 mg/m 2 ; D40, 1-week docetaxel 40 mg/m 2 ; D36, 1-week docetaxel 36 mg/m 2 ; D35, 1-week docetaxel 35 mg/m 2 ; D33.3, 1-week docetaxel 33.3 mg/m 2 ; RR, response rate; V/I, vinorelbine or ifosfamide. every 3 weeks or once weekly. In an attempt to improve drug efficacy, some studies have investigated the use of combinations of docetaxel plus other single agents, such as other third-generation drugs, for second-line treatment. Single-Agent Docetaxel Administered Every 3 Weeks Phase III trials have shown that docetaxel, administered intravenously at 75 mg/m 2 every 3 weeks, can improve overall survival and quality of life compared with docetaxel 100 mg/m 2 every 3 weeks, best supportive care (BSC) alone, 4 or alternative single-agent treatment with vinorelbine (30 mg/m 2 ) or ifosfamide (2 mg/m 2 /day) 5 (Table 1). These results led to the US and European registration of docetaxel (75 mg/m 2 every 3 weeks) in 2000 as the first cytotoxic agent approved for the second-line treatment of NSCLC. However, docetaxel-related toxicity was substantial despite a significant improvement in quality of life scores concerning pain control, weight loss, and PS compared with the control groups, 6 and this toxicity was found to be more pronounced with docetaxel 100 mg/m 2 (Table 1). A recent phase II randomized trial 7 comparing the two doses of docetaxel confirmed the earlier observations that docetaxel 75 mg/m 2 has a more favorable toxicity profile and similar efficacy as the 100 mg/m 2 dosage; however, hematologic toxicity remains the main problem (Table 1). Doselimiting toxicity was observed in the registration trials for docetaxel 75 mg/m 2 every 3 weeks, with neutropenia occurring in 54% to 67% of patients and febrile neutropenia in 1.8% to 8% of patients. Single-Agent Docetaxel Administered Weekly Several clinical trials have explored the weekly administration of docetaxel in an attempt to develop less toxic and more tolerable regimens. In these trials, the standard regimen of docetaxel 75 mg/m 2 every 3 weeks was compared with docetaxel 33 to 40 mg/m 2 weekly There was a trend toward better disease control in the 3-week schedule, but several studies report that grade 3-4 toxicity levels were often significantly higher than in the weekly schedule (Table 1). This has led the authors to recommend the 3-week schedule as the standard treatment in the second-line setting, and they have proposed the weekly schedule as an alternative for patients who are at high risk of febrile neutropenia. 8 Until enough data are available for a meta-analysis of randomized trials with weekly docetaxel, the weekly docetaxel schedule cannot be considered as a standard second-line treatment in NSCLC, despite the fact that the 3-week schedule has a high toxicity burden. Combination Chemotherapy With Docetaxel In the context of second-line doublets, a recent trial has compared docetaxel with the combination of docetaxel plus irinotecan. 12 There was a nonsignificant increase in objective response rate (P.36) and time to progression (P.065) in favor of the combination, but no observed advantage in median survival time (P.49) or 1-year survival rate (P.72). Similar results were obtained in another randomized phase II study that compared single-agent irinotecan with the combination of irinotecan plus gemcitabine. 13 Combination therapy was associated with an advantage in terms of objective

3 Cytotoxic chemotherapy in second-line NSCLC S19 Table 2 Phase III Studies Comparing Pemetrexed and Docetaxel in Second-Line Non Small Cell Lung Cancer Study Variable Pemetrexed Docetaxel P Value Hanna et al 3 Overall response NS Progression-free survival, median (mos) NS Time to progression, median (mos) NS Duration of response, median (mos) NS Survival time, median (mos) NS 1-year survival rate NS Neutropenia grade <.001 Febrile neutropenia <.001 >1 hospitalization for febrile neutropenia <.001 G-CSF <.001 >1 hospitalization for any drug-related AE Pujol et al 17 Median grade 3-4 TFS (mos) < year grade 3-4 TFS Bhalla et al 16 Mean time with grade 3 hematologic toxicity* (days) <.001 Mean time with grade 4 hematologic toxicity* (days) <.001 Abbreviations: NS, non-significant; AE, adverse event; G-CSF, granulocyte-colony stimulating factor; TFS, toxicity-free survival (the time from the date of randomization to the first date of any grade 3/4 toxicity or death due to any cause). *Amount of time spent with each grade 3 or 4 hematologic toxicity. response rate (P.009), but did not show any gain in time to progression (P.346) or overall survival rate (P.589). Pemetrexed in Second-Line NSCLC Several novel cytotoxic drugs (platinum derivatives, taxanes, epothilones, and alkaloid derivatives) have been tested for efficacy and safety in the treatment of NSCLC. Pemetrexed, a multi-targeted antifolate that strongly inhibits three enzymes involved in the synthesis of purines and pyrimidines (thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase), has been found to be active in NSCLC as well as in a variety of other tumor types including malignant pleural mesothelioma, an indication for which it has been approved in the United States and Europe. Single-Agent Pemetrexed In a recent phase II trial, pemetrexed (500 mg/m 2 every 3 weeks) showed good efficacy and low toxicity when administered to NSCLC patients who had a poor prognosis because of progression during or within 3 months of completion of first-line treatment, but who still had a good Eastern Cooperative Oncology Group PS (0-1). 14 The discovery that the plasma level homocysteine is a good surrogate marker predictor of pemetrexed-induced myelosuppression in patients 15 led to the use of vitamin supplementation (oral folic acid and intramuscular B 12 ) as a part of the pemetrexed dosing regimen to reduce homocysteine plasma levels and the hematologic toxicity of pemetrexed. Subsequently, a phase III registration trial was undertaken to show the non-inferiority of pemetrexed as second-line treatment when compared with the standard 3-week docetaxel regimen. 3 In a 1-year period, 571 patients who were resistant to first-line chemotherapy were randomized: 28% were female, median age was 58 years (range, 22 to 87 years), approximately 12% of patients had PS2, and 75% of patients had stage IV disease. More than 90% of patients had previously received platinumbased chemotherapy, while 35% had received first-line paclitaxel. Approximately one third of patients responded to first-line chemotherapy, with a time since last chemotherapy of less than 3 months in almost half the patients. Finally, 50% of patients had an adenocarcinoma histology, and more than 40% of patients had previously received radiotherapy. Pemetrexed administered at 500 mg/m 2 every 3 weeks with a median of four treatment cycles plus vitamin supplementation was found to be similar to docetaxel in terms of efficacy. The median survival times, response rates, and 1-year survival rates in both arms were approximately 8 months, 9%, and 30%, respectively (Table 2). At multiple regression analysis, prognostic factors associated with longer survival, in both arms, were PS (0 or 1 v 2), stage of disease (III v IV), and time since last chemotherapy ( 3 months v 3 months). Single-Agent Pemetrexed: Role of Third-Line Treatment. However, it is worth considering the possible role that thirdline treatment could have had on survival, and whether docetaxel administered at disease progression after pemetrexed could have influenced survival results. Forty-two percent of patients received further treatment outside of the study, and in the pemetrexed arm 67% of patients received docetaxel, with a median survival time for treated patients (N 126) of 9.8 months. Because the off-study administration of pemetrexed was not possible, almost 70% (N 107) of patients in the docetaxel arm received gemcitabine, vinorelbine, or gefitinib as third-line treatment, with a median survival time of 10.8 months. These data suggest that docetaxel had no additive effect on survival in the pemetrexed arm. Safety Profile of Single-Agent Pemetrexed The most interesting data from the phase III trial described above are the toxicity results. The safety profile of pemetrexed was significantly better than that of docetaxel (Ta-

4 S20 ble 2). Patients treated with docetaxel were more likely to experience grade 3-4 neutropenia (P.001), febrile neutropenia (P.001), and infections associated with neutropenia (3.3% v 0%; P.004) than patients treated with pemetrexed. Consequently, fewer patients in the pemetrexed arm required hospitalization because of neutropenic fever and there was less need to administer white blood cell growth factors than there was to patients who received docetaxel. Furthermore, when palliation is the main endpoint of treatment and life expectancy is short, the impact of drug-related toxicity is an important concern. Toxicity data from this phase III trial have been analyzed separately, not only from the point of view of the percentage of patients experiencing a certain adverse event but also with respect to how long patients could expect to spend with or without adverse events while receiving chemotherapy (Table 2). 16 In comparison with patients who received docetaxel, patients treated with pemetrexed had a shorter mean time with drug-related toxicity (2.1 days v 10 days and 0.9 days v 14.9 days for grades 3 and 4 hematologic toxicity, respectively, and 4.6 days v 10.3 days and 0.3 days v 1.2 days for grade 3 and 4 nonhematologic toxicity, respectively). Another interesting evaluation by Pujol et al 17 calculated the toxicity-free survival time (ie, the time between randomization and the date of assessment of any grade 3-4 toxicity or death due to any cause). As Table 2 shows, patients in the pemetrexed arm had a longer toxicity-free survival time compared with patients in the docetaxel arm, not only for overall grade 3-4 toxicity but also for grade 4 adverse events when considered alone (7.5 months and 28.4% in the pemetrexed arm v 2.3 months and 16% in the docetaxel arm for median and 1-year toxicity-free survival, respectively). Independent of toxicity, the same scores were achieved in terms of symptom palliation and quality of life in both arms. A further analysis showed that the average symptom burden index, regarding fatigue, anorexia, pain, cough, dyspnea, and hemoptysis, was directly related to tumor response to second-line chemotherapy. Without differences between the two study arms, patients who responded to treatment had an improvement in average symptom burden index score of 9.9 points from baseline, significantly higher (P.05) than the improvement achieved by patients with stable disease (4.3 points), while patients with progressive disease worsened ( 3.7 points). 18 The overall results obtained from this registration trial, from the similar efficacy compared with docetaxel to the definite gain in tolerability and lower toxicity, make second-line treatment with pemetrexed a new therapeutic option for recurrent NSCLC, and superior to what has been available in the past. In 2004, the US Food and Drug Administration (FDA) and the European Medicines Agency approved pemetrexed for advanced NSCLC in the second-line setting, as well as for the first-line therapy of unresectable malignant pleural mesothelioma. This has led to the recent revision of guidelines from the European Society of Medical Oncology on the treatment of NSCLC, which state that docetaxel or pemetrexed, administered as second-line treatment, improve survival and disease-related symptoms in selected patients. 19 de Marinis, De Santis, and De Petris Combination Chemotherapy With Pemetrexed The excellent safety profile demonstrated by pemetrexed has opened the possibility of improving its activity in the secondline setting either by increasing the dose or by combining it with other agents. While a phase III study that tests pemetrexed 900 mg/m 2 every 3 weeks versus the standard schedule of 500 mg/m 2 is ongoing, several phase II randomized trials that include pemetrexed as the reference arm versus pemetrexed plus a targeted agent are being planned. Indirect Comparison Between Chemotherapy and Targeted Treatment Options The possibility of targeting a pathway specifically involved in the tumor phenotype has prompted researchers and the pharmaceutical industry to develop new drugs such as targeted therapies. Table 3 shows selected trials that have tested the activity of some of these drugs, alone or in combination, in the treatment of recurrent NSCLC ,32,35 41 Efficacy of Targeted Therapies In addition to docetaxel and pemetrexed, the FDA has also approved two small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, for the treatment of recurrent NSCLC. Gefitinib 250 mg/day was fast-track registered by the FDA following the positive results of two randomized phase II trials (Table 3). 20,21 In these studies, the response rate ranged from 12% to 20%, and the median survival time was 7 to 8 months. Unfortunately, these results have not been confirmed by a recent phase III multicenter, randomized trial, in which gefitinib was compared with placebo. 22 Thus, subsequent label changes required by the FDA now limit the administration of gefitinib to patients who have shown benefit from the drug, or to patients enrolled in non-investigational new drug clinical trials. On the other hand, in another trial of similar design, erlotinib 150 mg/day showed a survival advantage versus BSC alone (median survival times of 6.7 and 4.7 months, respectively). 23 Post-hoc analyses from these registration trials have identified some main differences in activity of targeted therapies compared with conventional cytostatic agents. In fact, while there does not seem to be any established clinical predictive factor of response to second-line chemotherapy, but a trend toward sensitivity to first-line treatment, 4 EGFR inhibitors seem to be more active in specific subsets of patients, such as women with adenocarcinoma who have never smoked (never-smoker) and Asian ethnicity. Moreover, the activity of targeted agents, in terms of response rate and survival benefit, seems to be independent of the number of previous chemotherapy lines received by patients. 23 In addition to clinical factors, appropriate patient selection based on molecular markers is the ultimate goal of clinical research in the new era of high-throughput technologies. By identifying molecular characteristics that confer changes in

5 Cytotoxic chemotherapy in second-line NSCLC S21 Table 3 Selected Trials With Targeted Therapies in the Treatment of Recurrent/Progressive Non Small Cell Lung Cancer Study Phase Treatment Patients (N) RR SD Median Survival (mos) Most Relevant Grade 3-4 Toxicities IDEAL 2 20 II R Gefitinib Pulmonary events 5% IDEAL 1 21 II R Gefitinib ALT increase 1.9% ISEL 22 III Gefitinib NR 5.6 NR BSC NR 5.1 NR BR III Erlotinib Fatigue 19% Skin rash 9% BSC Fatigue 23% Lilenbaum et al 35 II Cetuximab Dyspnea 15.2% Asthenia 13.6% Infection 9.1% Kim et al 36 II Cetuximab Doc Fatigue 21% Infection 21% Rash 20% Herbst et al 32 I/II Erlotinib bevacizumab Infection 9% Rash 6% Cufer and Vrdoljak 37 II R Gefitinib Dyspnea 8.8% Doc Neutropenia 46% Heymach et al 38 II R ZD mg Doc NR NR ZD mg Doc NR Rash 18.2% Diarrhea 12% Doc NR NR Natale et al 39 II R ZD mg NR Diarrhea 7.2% Gefitinib NR NR Fanucchi et al 40 II R Bortezomib Fatigue 19% Bortezomib Doc Neutropenia 65% Lilenbaum et al 41 II R Irinotecan Doc or Gem Diarrhea 19% Celecoxib Irinotecan Doc or Gem Diarrhea 24% Abbreviations: ALT, serum alanine aminotransferase; BSC, best supportive care; Doc, docetaxel; Gem, gemcitabine; RR, response rate; SD, stable disease; II R, randomized phase II study; NR, not reported. Doses and schedules: Ref , 37, 39 gefitinib 250 mg/day; Ref. 23, 32 erlotinib 150 mg/day; Ref. 35, 36 cetuximab 400 mg/m 2 loading dose, followed by 250 mg/m 2 /week; Ref docetaxel 75 mg/m 2 every 3 weeks; Ref. 32 bevacizumab 15 mg/kg every 3 weeks; Ref. 38 ZD mg/day or 300 mg/day; Ref. 39 ZD mg/day; Ref. 40 single agent bortezomib 1.5 mg/m 2 d 1,4,8,11 every 3 weeks; bortezomib 1.3 mg/m 2 d 1,4,8,11 every 3 weeks docetaxel 75 mg/m 2 every 3 weeks; Ref. 41 celecoxib 400 mg twice daily, irinotecan 60 mg/m 2 docetaxel 35 mg/m 2 dd 1,8 every 3 weeks; irinotecan 100 mg/m 2 gemcitabine 1,000 mg/m 2 d 1,8 every 3 weeks. the ability to metabolize or activate cancer agents, as well as changes in target sensitivity, a personalized approach can be taken to patient treatment. Pharmacogenomics (ie, the detection of genetic or somatic mutations that could sensitize the tumor to a specific agent) is a possible tool that could be used to identify predictive markers of response. With this in mind, targeted therapies may be a step forward compared with chemotherapy. For example, the high mrna levels of thymidylate synthase in the tumor, or the presence of a certain gene polymorphism, might provide useful markers to predict resistance to pemetrexed, although the inhibition of other enzymes by this agent might overcome a resistance linked to the expression of a single target. 24,25 Aberrant expression of class III -tubulin might be associated with resistance to paclitaxel, but little is known about a possible link with docetaxel activity. On the other hand, markers for response to targeted therapies have been more widely studied, probably because of the possibility of studying a single molecule and consequent pathway targeted by the specific agent. For example, the correlation between response to EGFR tyrosine kinase inhibitors and EGFR overexpression, EGFR gene amplification, and phosphorylation of downstream EGFR effector proteins such as Akt has been extensively studied. 26,27 Furthermore, extensive work has been conducted worldwide to identify possible somatic mutations in the EGFR gene that could be linked to EGFRinhibitor sensitivity or resistance, as well as specific genotype variations harbored in different ethnicities. 28,29 Interestingly, the gene mutations that confer sensitivity to gefitinib or erlotinib are also associated with the specific patient phenotypes described above. With a lack of comparative studies, the proper selection of patients for treatment with chemotherapy or a targeted therapy in the second-line setting of NSCLC, based on the analysis of a molecular marker, should be validated through prospective randomized trials. In our opinion, then, chemotherapy, because of its broader action and less selectivity, should be proposed as the standard second-line treatment, while EGFR inhibitors should be considered for patients with phenotypes suggesting a benefit from this

6 S22 treatment, or in the presence of factors that, in the opinion of the treating physician, exclude the administration of chemotherapy. Toxicity of Targeted Therapies In an indirect comparison with chemotherapy, the different toxicity profiles of targeted therapies and the possibility of successful combination with the aim of increasing their activity can immediately be noted. While the main adverse event of chemotherapy is myelosuppression and consequent infections, the toxicity of biologic agents is more strictly linked to the inhibited target and ranges from skin rash and diarrhea for EGFR tyrosine kinase inhibitors, 20,23 to bleeding for vascular-endothelial growth factor receptor inhibitors 30 or diarrhea and sensory neuropathy for proteasome inhibitors. 31 Thus, if combination chemotherapy in the second-line setting is far from providing good results, with data showing an increase in toxicity and no gain in activity, then combining targeted therapies might provide the breakthrough necessary (Table 3). The combination of erlotinib plus bevacizumab is an interesting example that has shown good efficacy with an acceptable toxicity profile. In a phase I/II study, 32 this combination obtained a response rate of 20% and a median survival time of 12.6 months, at the cost of very mild toxicity, mainly non-hematologic. However, it should be noted that this combination was administered in a very select population of patients with non-squamous NSCLC to avoid the risk of bleeding associated with patients who have squamous carcinomas and are administered bevacizumab. While awaiting results from ongoing trials, a general comparison can be made of the toxicity of drugs currently approved for the treatment of recurrent NSCLC (ie, docetaxel, pemetrexed, and erlotinib). Hematologic toxicity of docetaxel was shown to be higher than that of pemetrexed (grade 3-4 neutropenia in 40% v 5% of patients, respectively), 3 and both were higher than hematologic toxicity of erlotinib (no cases of grade 3-4 neutropenia). 23 Inversely, nonhematologic toxicity of docetaxel and pemetrexed are low and statistically comparable (grade 3-4 fatigue registered in 5% of patients), 3 and indirectly much lower than erlotinib. In the phase III trial that compared erlotinib to BSC, in fact, although fatigue was the most common grade 3-4 toxicity (19% of patients), severe skin rash and diarrhea were the most common causes of treatment interruption (in 14% and 6% of patients, respectively). 23 More interestingly, it seems that occurrence and severity of skin rash might be a surrogate marker of erlotinib efficacy, being directly associated with patients survival. 33 Cost-Effectiveness Studies in Second-Line Treatment of NSCLC Pemetrexed and Docetaxel Drug toxicity has a direct effect in terms of costs. To explore this issue, resource utilization data (hospital admissions, concomitant medications, and transfusions) were collected from patients treated with docetaxel and pemetrexed for at least one cycle (541 patients) in a trial by Hanna et al. 3 Different evaluations have been reported from the health care centers participating worldwide in the trial. Among others, an Italian study has calculated costs for the overall population enrolled in the study from the perspective of its national health care system. The lower toxicity experienced by patients treated with pemetrexed translated directly into cost savings, with 367 Euros/patient being the mean cost for toxicity management in the pemetrexed arm compared with 1,385 Euros/ patient in the docetaxel arm. This striking difference was primarily because of the increase in hospitalization and concomitant medications used in an outpatient setting during docetaxel treatment. 34 Targeted Therapies A cost analysis of targeted therapies in second-line treatment of NSCLC is, to our knowledge, not yet available. Moreover, the major costs of treatment are based on the expenses related to the treatment of drug-related adverse events, and for this reason the proper evaluation of cost-effectiveness of targeted agents should be performed in trials that challenge these drugs versus an active treatment, and not versus BSC alone. Conclusion de Marinis, De Santis, and De Petris In conclusion, certain considerations must be accounted for regarding chemotherapy or targeted therapy as possible treatment options in the second-line setting of NSCLC. These considerations rely on the evidence available and on different approaches to treatment between the United States and Europe. As outlined earlier, the updated European Society for Medical Oncology guidelines only indicate docetaxel and pemetrexed as treatment options on the basis of drug availability and current evidence. For instance, pemetrexed is the only drug for which efficacy has been directly challenged with an active cytotoxic agent, ie, docetaxel, in the context of second-line setting alone, and not versus BSC, as is the case for erlotinib or gefitinib. Moreover, the demonstrated superiority of targeted therapies versus BSC in the third-line setting opens up the debate, in our opinion, of whether secondand third-line treatment options should be evaluated separately. While awaiting results of a phase III trial currently randomizing patients to receive docetaxel or gefitinib (Iressa NSCLC Trial Evaluating Response and Survival Against Taxotere), the demonstrated comparable activity of pemetrexed, together with its more favorable toxicity profile versus docetaxel, suggests pemetrexed is the best candidate at present for second-line treatment of recurrent NSCLC. References 1. 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