Second-Line Chemotherapy for Non-Small-Cell Lung Cancer

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1 Chapter Second-Line Chemotherapy for Non-Small-Cell Lung Cancer 24 Eleni Karapanagiotou and Konstantinos N. Syrigos Contents 24.1 Background Docetaxel Pemetrexed Other Agents on Trial Vinorelbine Gemcitabine Inhibitors of Topoisomerase I Irinotecan Topotecan Taxanes Targeted Therapy EGFR Inhibitors Gefitinib Erlotinib Cetuximab Neoangiogenesis Inhibitors ± Bevacizumab Conclusions Background Chemotherapy for non-small-cell lung cancer (NSCLC) patients with stage IIIB or IV has only a palliation role, since their disease is incurable and the 5-year survival is less than 2% [1, 2]. Best supportive care (BSC) offers to this group of patients only 3.6 months (range 2.4± 4.9 months), while platinum-based chemotherapy offers an improvement in the median overall survival time of 6±8 weeks. It has also doubled the 1-year survival rate and demonstrated important gains in secondary end points of clinical trials, such as the time to disease progression and the quality of life [3±5]. Based on the results of several randomized clinical trials and meta-analyses, the American College of Chest Physician Lung Cancer Guidelines Committee approved the administration of chemotherapy to fit patients with advanced-unresectable or metastatic disease, with grade of recommendation A. Currently, the platinum-based regimens comprise the gold standard as first-line treatment for advanced and metastatic. Despite the undoubted gains from chemotherapy for stage IIIB or IV NSCLC patients, a proportion of approximately 50% of those who have received first-line platinum-based regimens will relapse during treatment or soon after completing it. These patients might be young, with good performance status, and their disease is expressed with only minor symptoms. In addition, clinical oncologists often come across patients with refractory disease who are willing to accept considerable toxicity in order to achieve a small prolongation in survival. Once the disease progresses the median survival time is approximately 3months. It is clear that there is strong motivation for these patients to receive secondline chemotherapy [3, 6±10] Docetaxel Until recently the role of second-line chemotherapy was undefined. Fossella and colleagues tried to review the data surrounding this field of chemotherapy, with disappointing results. The majority of studies were small single-institute studies in which drug dosages and schedules were totally different and response rates were not reported. Moreover, no phase III clinical trials had been conducted. However, the agent demonstrating the most consistent responses in the second-line setting was docetaxel, which was evaluated in refractory platinum-based patients in seven phase-ii clinical trials. A total of 312 participants received 100 mg/m 2 docetaxel every 3weeks, resulting in response rates ranging from 14 to 24%, median overall survival time greater than 7 months, and 1-year survival rates ranging from 25 to 44% [11]. Docetaxel is a second-generation taxane that is derived from the needles of the European yew tree. It has a large spectrum of antitumor activity that is expressed basically by inhibiting microtubule dynamics. The principal mechanism of action for both taxanes (docetaxel and paclitaxel) is to promote microtubulin assembly

2 306 V. Management of Advanced Non-Small-Cell Lung Cancer and stabilize the polymers against depolymerization. Docetaxel has exhibited documented cytotoxicity in murine tumor models and human tumor xenografts, and this preclinical promise has successfully translated into clinical practice. Several clinical trials have proved the efficacy of docetaxel in NSCLC patients in front-line treatment as combination therapy or monotherapy. A large randomized phase-iii clinical trial (TAX317) has been conducted to determine whether docetaxel as a single agent is effective in the second-line treatment of NSCLC patients. The primary outcome measure was survival and secondary end points were response rate, time to progression, toxicity, and quality of life. Eligible participants were those who had documented progressive disease after receiving a platinum-containing (cisplatin or carboplatin) regimen, but not a taxane. Fortynine patients received 100 mg/m 2 docetaxel and 55 received 75 mg/m 2 docetaxel once every 21 days, while the control group of 100 patients received only BSC. The docetaxel dosage changed from 100 mg/m 2 to 75 mg/m 2 during the study due to an unacceptably high toxic death rate in the experimental arm. The results of this trial were really encouraging. The median overall survival was 7.0 months for the chemotherapy arm and 4.6 months for the BSC arm, while the 1-year survival rates for the chemotherapy and BSC arm were 29 and 19%, respectively, and the overall response rate was 7%. The key point of this clinical trial was the docetaxel dosage. Prolongation of median overall survival was seen with both doses of docetaxel, but the most marked improvement was associated with the lower dose, for which the 1-year survival rate was significantly higher, at 37%. Moreover, the prolongation of patients' life was in line with the improvement of patient quality of life (well-being). The quality-of-life analysis demonstrated less worsening of performance status and less common use of tumor-related medications for docetaxel patients. Only 32% of docetaxel patients versus 49% of the BSC arm required morphine-equivalent medication for the pain, and 39% versus 55% patients, respectively, required nonmorphine analgesics. Palliation radiotherapy was required for fewer docetaxel patients (26%) than BSC patients (37%). The safety profile of docetaxel administration was satisfactory. Grade 3or 4 neutropenia occurred in 67% of those patients administered 75 mg/ m 2 docetaxel, and only one patient (1.8%) developed febrile neutropenia. Grade 3or 4 anemia occurred in three (5.5%) patients at the lower dose. Severe thrombocytopenia was observed in less than 1% of the patients, without any reported bleeding episodes. Nonhematological toxicities were similar, although sometimes worse for the BSC patients in terms of more asthenia and neurotoxicity. This trial concluded that goodperformance NSCLC patients who have progressed after receiving a platinum-based regimen should be offered the chance of a second-line docetaxel-based chemotherapy with the aim of prolongation of survival as well as a significant improvement in disease-related symptoms [11, 12]. In another phase III trial (TAX320) that examined the efficacy of docetaxel as second-line chemotherapy in NSCLC patients, 373 patients who had received 1 or more platinum-based regimens with no exclusion of prior exposure to paclitaxel were randomized to 3arms: the first received 100 mg/m 2 docetaxel, the second 75 mg/m 2 docetaxel (both arms in a cycle of 21 days), and the control arm was represented by 123patients who received either vinorelbine (n = 89) or ifosfamide (n = 34). The 1-year survival rate was significantly greater in docetaxel-treated patients (32% at 75 mg/m 2 and 21% at 100 mg/m 2 ) compared to the vinorelbine/ifosfamide-treated patients (19%). There was only a trend toward improved overall survival for the docetaxel group, although 26-week progression-free survival was significantly favored for the docetaxel-treated patients. Both docetaxel arms presented a slight increased hematological toxicity, the incidence of febrile neutropenia being 8% for those receiving the lower docetaxel dose, compared to 1% for the control arm. The nonhematological side effects were similar across treatment groups [13]. A finding from this trial that was of important clinical significance was that prior paclitaxel therapy did not predict the likelihood of a patient's response to docetaxel. This was proved by the partial response rates between patients with prior paclitaxel therapy (n = 91) and those without paclitaxel exposure (n = 157), which were rather equivalent at 10.5% and 8.5%, respectively [13]. In an attempt to minimize docetaxel toxicity, three clinical trials were conducted whereby the standard dose of 75 mg/m 2 every 3weeks was compared to one dose of 33 mg/m 2. In a landmark analysis of a total of 524 patients, no significant differences were found for either response rates or toxicity. The median time to progression and the overall survival were rather similar between arms, while the administration of docetaxel was associated with less hematological toxicity, the rate of severe neutropenia being particularly lower. In conclusion, docetaxel represents another option for patients at risk for severe neutropenia and its consequences [14±16]. Although the recent advances in chemotherapy are welcome, the outcome expectations from chemotherapy administration remain slim. In economical terms, is it cost-effective to administer docetaxel as palliation therapy? A retrospective economic evaluation of docetaxel clinical trial (TAX 317) was undertaken using data from the 63patients using the Canadian health-care system in This analysis concluded that the cost per lifeyear gained by using docetaxel at the recommended dose of 75 mg/m 2 was approximately US$20,000, which is similar to the care expenditures for palliative chemotherapy of other solid tumors [17]. There is an increasing body of evidence suggesting that the administration of second-line treatment in fit

3 E. Karapanagiotou and K. N. Syrigos Chapter 24 Second-Line Chemotherapy for Non-Small-Cell Lung Cancer 307 patients who are experiencing progressive disease after receiving platinum-containing regimens is recommended. In this context, the USA Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medical Products approved Docetaxel as standard treatment in the second-line setting Pemetrexed Patients who are candidates for second-line chemotherapy expect only a modest prolongation of life and a better quality of life with minimal disease symptoms. They are eager to receive chemotherapy, but at the same time are reluctant to spend a considerable part of their limited life in hospital due to treatment-related complications. Due to its toxicity profile, docetaxel is still greeted with a degree of unease and there have been attempts to identify new compounds with the same efficacy but reduced toxicity. One such compound, a novel chemotherapeutic agent, is pemetrexed (Alimta). It is the first multitargeted antifolate with minimal pyrimidine nucleus differences from the common antifolates. Pemetrexed inhibits more than one enzyme in the cell cycle, including thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyl transferase, aminoimidazole carboxamide ribonucleotide formyltransferase, and is implicated in the inhibition of pyrimidine and purine synthesis. The fact that a tumor is composed of a heterogeneous group of cells with varying predominant enzymes may provide an explanation regarding the multitargeted cytotoxid mechanisms of action of pemetrexed [18]. Several trials on the efficacy and toxicity of pemetrexed in malignant mesothelioma and NSCLC patients have been conducted; these have found an increase in the response rates of accrued patients, but also increased side effects of the treatment. A retrospective analysis of serious adverse events was performed consecutively. Plasma levels of homocysteine, which represent a surrogate for folate nutritional status, and plasma levels of methylmelonic acid, which is an indicator of B12 vitamin status, were markedly elevated in patients with neutropenia, thrombocytopenia, and nonhematologic toxicities such as infection, mucositis, and diarrhea. There was also an increased death rate related to this new agent. After treatment with pemetrexed, patients were prescribed a daily dose of 350±1,000 lg acid folic and 1,000 lg vitamin B12, given intramuscularly every 9 weeks, resulting in a considerable improvement in drug toxicity [19±21]. Based on the results of several phase II clinical trials, Hanna and coworkers conducted a large phase III clinical trial in an attempt to examine the superiority of pemetrexed compared to docetaxel, the standard second-line chemotherapy. In the largest phase III clinical Table Phase III clinical trial: Pemetrexed vs. Taxotere. G-CSF Granulocyte colony-stimulating factor Toxicity Docetaxel Pemetrexed Grade 3/4 neutropenia 40.2% 5.3% Febrile neutropenia 12.7% 1.9% Infections with grade 3/4 3.3% 0% neutropenia Requirements for G-CSF a 19.2% 2.6% Hospitalizations related to drug 13.4% 1.5% Alopecia 37.7% 6.4% a Requirements for G-CSF: % of cycles trial of second-line therapy, 571 NSCLC patients were accrued who had documented disease progression after receiving only 1 front-line regimen. Of these, 283patients received 500 mg/m 2 of pemetrexed once every 21 days with acid folic and vitamin B12 supplementation, and 288 patients received 75 mg/m 2 docetaxel in the same cycle. Both arms received dexamethasone premedication. From the randomized patients, 90% had previously been treated with platinum regimens and 28% with taxanes regimens. This study met the primary and secondary endpoints. The overall response rates were 9.1% for the pemetrexed-treated group and 8.8% for docetaxel-treated group; both groups had the same 1-year survival rate. With regard to toxicity, pemetrexed presented a more safety profile with less episodes of hospitalization related to drug administration and febrile neutropenia (Table 24.1). The requirements for granulocyte colony-stimulating factor were increased in the docetaxel arm. Notably, due to vitamin B12 and acid folic supplementation, pemetrexed-related myelotoxicity, diarrhea, and mucositis were limited. The prophylactic use of dexamethasone lessened the occurrences and intensity of skin rash [22]. Based on data obtained from this clinical trial, in the summer of 2004 the USA FDA approved pemetrexed as a single-agent chemotherapy agent as an alternative to docetaxel in the second-line setting for NSCLC patients Other Agents on Trial New agents have been tested in several clinical trials in the treatment of NSCLC patients, as monotherapy or in combination regimens. They can be divided into the following classes: mitotic spindle inhibitors (vinorelbine), antimetabolites (gemcitabine), inhibitors of topoisomerase I (irinotecan and topotecan), and taxanes (paclitaxel and docetaxel). If we exclude docetaxel and pemetrexed, which have been approved for use by the FDA as second-line chemotherapy agents, the new agents represent some options as salvage therapy in different combinations.

4 308 V. Management of Advanced Non-Small-Cell Lung Cancer Vinorelbine Vinorelbine is a semisynthetic derivative of vinca rosea, the Madagascar periwinkle, which is used as an antimitotic agent through its property of affecting the dynamics of spindle microtubules. Vinca alkaloids interact with tubulin subunits to prevent microtubule assembly, and consecutively induce chromosome segregation in dividing cells and cause aneuploidy. Vinorelbine has shown interesting results with respect to response rates, time to progression, and median overall survival when was tested as single, first-line treatment; its basic treatment-related toxicity is neutropenia. It has been involved in few clinical trials as second-line treatment, and with moderate results. There were no responses in two studies of patients who had previously failed to respond to platinum-based regimens, and in a third study a response rate of 20% was reported but with no other information [23±25]. Patient preference and the need for fewer visits in hospital, as well as concerns and difficulties with intravenous access have driven the development of oral vinorelbine. Several clinical trials have tried to evaluate the feasibility and safety profile of oral vinorelbine in treatment of recurrent NSCLC patients [26]. The feasibility of vinorelbine as an active agent in the salvage therapy of NSCLC patients has been explored in clinical trials in combination with other active agents such as platinol, carboplatin, docetaxel, and irinotecan. Ongoing studies are evaluating the tolerability and activity of these combinations. Those studies evaluating the efficacy of vinorelbine in combination with either platinol or carboplatin are based on small numbers (range 17±44) of pretreated patients and use different regimens and schedules, although encouraging results regarding to objective responses and 1-year survival rate with acceptable toxicity have been presented [27±30] Gemcitabine Gemcitabine is a novel deoxycytidine analogue that has been implicated in the inhibition of DNA and cellular apoptosis. It is a prodrug that, once transported into the cell, is phosphorylated by deoxycytidine kinase into an active form. This active form can be incorporated into the terminal part of elongating DNA strands, inhibiting the activity of DNA polymerases. Gemcitabine is indicated in combination with cisplatin in the front-line treatment of inoperable NSCLC patients. Response rates of 20% have been demonstrated in several phase II trials, and so gemcitabine has been evaluated in previously treated NSCLC patients at a dosage of 1,000 mg every 3±4 weeks. The published response rates range from 0 to 21% and the median overall survival was between 5.5 and 9 months. The 1-year survival was scarcely reported. In conclusion, these results are not encouraging for the use of gemcitabine as monotherapy in salvage therapy [31±35]. However, better responses were obtained when gemcitabine and vinorelbine were combined in several phase II clinical trials. The number of patients enrolled in these was small and larger studies should therefore be performed. Excluding the Camps study, which enrolled 16 patients and presented disappointing results with only 1 complete responder, no partial responders, and a median survival of 25 weeks [36], the following studies present a hint of success, which translates into a median survival ranging from 6.5 to 8.5 months and a 1-year survival rate reaching 35%. Further evaluation of this combination is needed and may represent another option for relapsing patients after receiving a platinum± taxane combination in the front-line setting (Table 24.2) [37±42]. Table Clinical trials phase II of combination gemcitabine plus navelbine in second-line setting Dose and schedule V 20 mg/m 2 G 1,000 mg/m 2 days 1, 8, 15, q28d Hainsworth [37] Kosmas [38] Pectasides [39] Herbst [40] Chen [41] Park [42] V 25 mg/m 2 G 1,000 mg/m 2 days 1, 8, q21d V 25 mg/m 2 G 800 mg/m 2 days 1, 8, q21d V 25 mg/m 2 G 900 mg/m 2 days 1, 8, 15, q21d V 20mg/m 2 G 800 mg/m 2 days 1, 8, 15, q28d Pts (n) (36) Prior CHT (%) PR (%) SD (%) N/R 55 TTP (months) N/R Median survival (months) One-year survival (%) N/R Grade 3±4 neutropenia (%) Grade 3±4 thrombocytopenia (%) N/R V 30 mg/m 2 G 1,000 mg/m 2 days 1, 8, q21d V Vinolrebine, G gemcitabine, Pts patients, CHT chemotherapy, PR partial response, SD stable disease, TTP time to progression, q28d every 28 days, q21d every 21 days, N/R not reported

5 E. Karapanagiotou and K. N. Syrigos Chapter 24 Second-Line Chemotherapy for Non-Small-Cell Lung Cancer Inhibitors of Topoisomerase I The topoisomerases (I and II) are nuclear enzymes that play a role in DNA synthesis and transcription. The role of both enzymes in the cell cycle is to relieve DNA torsional strain by forming a reversible complex with it and by introducing transient enzyme-bridged strand breaks. When the transcription is finished, the enzymes reseal the break and dissociate from the DNA. Topoisomerase inhibitors play a role in the stabilization of topoisomerase in a complex with DNA, resulting in double- stranded DNA break and subsequent programmed cell death. Examples of topoisomerase I inhibitors are irinotecan and topotecan, and these represent an interesting class of agents for the treatment of NSCLC Irinotecan Preclinical studies suggest that irinotecan has a substantial activity either alone or in combination with other agents in palliation therapy of NSCLC. There are several small studies exploring the efficacy of irinotecan in the second-line setting, reporting response rates between 0 and 29% [43±45]. Unfortunately, when this novel agent was added to docetaxel in a combination regimen and compared to standard second-line chemotherapy docetaxel at 75 mg/m 2 in a 3- schedule in two large phase II clinical studies, not only was there no improvement in response rates and 1-year survival rates, there was also increased gastrointestinal toxicity [46, 47]. Moreover, irinotecan has been studied in phase II clinical trials as a second-line treatment, in more than one combination with docetaxel, vinorelbine, cisplatin, capecitabine, or gemcitabine. The reported results showed response rates ranging between 29 and 48% and median survival ranging between 25 and 32 weeks, while the reported hematologic and nonhematologic toxicities were acceptable (Table 24.3) [48±52]. In a phase II study, Georgoulias and coworkers compared the combination of irinotecan and gemcitabine versus irinotecan in docetaxel- and cisplatin-pretreated patients (n=147). The response rates were 18.4% and 4.2%, respectively in the two arms. The combined schedule resulted in a higher response rate but without any improvement in the overall survival [53] Topotecan Topotecan is a semisynthetic derivative of camptothecin, which has been approved for the second-line treatment of small-cell lung cancer and ovarian cancer. In several phase II clinical trials in previously untreated patients with advanced NSCLC, the intravenous administration of topotecan at a dose of 1.5±2 mg/m 2 /day for 5 consecutively days resulted in moderate response rates of 15± 16%, and another study reported stable disease in half of the enrolled patients [54±56]. In the second-line setting, topotecan was evaluated in combination with gemcitabine in a small trial. Thirty-five previously treated patients received 0.75 mg/ m 2 topotecan and gemcitabine 400 mg/m 2 for 5 days in a 3-week cycle. A partial response was experienced by 11% of the participants, and another 23% experienced stable disease. The median survival time was 7 months and the 1-year survival rate was 20%. Modest hematologic toxicity was observed [57]. An oral formulation of topotecan has been tested in a large, 800-patient study as second-line treatment in NSCLC patients. Topotecan at a dose of 2.3mg/m 2 (given orally) for 5 consecutive days in a 21-day cycle has been compared to standard-therapy docetaxel 75 mg/ m 2 ; the trial results are pending Taxanes Paclitaxel, like docetaxel, is a microtubule stabilizer that results in cell cycle arrest and impairment of mitotic progression. Paclitaxel has been investigated extensively in several solid tumors including NSCLC. It has gained a position in the front-line treatment of NSCLC patients Table Irinotecan in several combinations as second-line treatment Schedule I 70 D 25 mg/m 2 days 1, 8, 15, q28 d Font [48] Gonzalez [49] Kakolyris [50] Nakanishi [51] Han [52] I 300 mg/m 2 day 1 V 30 mg/m 2 days 1, 14, q28d I 100 mg/m 2 days 1, 8 P 80 mg/m 2 day 8, q21d I 60 mg/m 2 P 30 mg/m 2 days 1, 8, 15, q28d I 90±100 mg/m 2 days 1, 8 C 2,000 mg/m 2 days 1±14 q21d Pts (n) RR% Median survival 8 months 25 weeks 8 months 32 weeks 7.4 months (6- month follow up) One-year survival 30 N/A N/A 43 N/A (%) Toxicity Mild Mild Increased Increased Acceptable I Irinotecan, D docetaxel, P cisplatin, C capecitabine, RR response rate, N/A not assessed

6 310 V. Management of Advanced Non-Small-Cell Lung Cancer in combination with other active agents. Paclitaxel has also been investigated as a single agent in the secondline setting of this target group. The results from several clinical trials using paclitaxel at very different doses and schedules show a clinical benefit rate ranging from 0 to 42% and median overall survival ranging from 16 to 52 weeks with acceptable toxicities. In summary, paclitaxel represents a favorable chemotherapeutic approach in this setting (Table 24.4) [58±70]. In an effort to maximize the efficacy of paclitaxel, it was combined with other active agents such as gemcitabine, cisplatin, and irinotecan in small phase II studies. These combinations resulted in active schemes with acceptable levels of toxicity, but future trials will clarify the role of paclitaxel-based combinations in the salvage therapy of NSCLC patients. In a randomized study including 71 patients, administration of docetaxel at a dose of 36 mg/m 2 was compared to administration of paclitaxel at a dose of 80 mg/m 2 for 6 weeks followed by a 2-week rest. Partial response was experienced by one and five patients, median time to progression was 74 and 68 days, and the median overall survival was 184 and 105 days with docetaxel and paclitaxel, respectively. Both taxanes showed a discrete efficacy in this population [71]. An oral formulation of taxane under the code name BMS has been approved for participation in combination with pemetrexed in a clinical phase I±II study in patients with recurrent pretreated NSCLC [72] Targeted Therapy Even with the introduction of new antineoplastic agents and more effective chemotherapeutic combinations, the prognosis for refractory NSCLC patients receiving second-line chemotherapy remains dismal. Recently, our knowledge of molecular oncology has significantly increased, endorsing recognition of the main signaling pathways that promotes malignant cell transformation. This in turn has raised hopes for the development of a novel therapeutic strategy that would target neoplastic cells, whilst minimizing both damage to noncancerous cells and any side effect resulting from the given therapy. Two main representatives of targeted therapy have been explored in this subpopulation of patients, the epidermal growth factor receptor (EGFR) pathway inhibitors and the neoangiogenesis inhibitors EGFR Inhibitors The EGFR family autocrine pathway plays a critical role in the malignant and metastatic development potential of NSCLC. Ligands binding to their extracellular domain initiate a molecular cascade that promotes cellular proliferation and differentiation. EGFR targeting can be achieved through two principal mechanisms: (1) through monoclonal antibodies that prevent ligand binding, or (2) by means of small-molecule tyrosinekinase inhibitors (TKIs) that inhibit the adenosine triphosphate binding site of the growth factor receptor. Table Paclitaxel as a single agent in phase II clinical trials in the second-line setting Tan [58] Murphy [59] Ruchdeschel [60] Hainsworth [61] Nauman [62] Socinski [63] Chang [64] Juan [65] Socinski [66] Sculier [67] Buccheri [68] Ceresoli [69] Yasuda [70] Schedule 135± h 175 mg/ m 2,3-h 175± h h 200 mg/m mg/ m 2, 1-h 130±175 1-h h 50± h Pts (n) Clinical /0 N/R 31 N/R benefit (%) Median survival N/R N/R 4 months N/R 10 months N/R N/R 9.7 months 5.2 months 4.5 months 58 weeks N/R 43 weeks Oneyear N/R N/R N/R N/R 45 N/R N/R N/R N/R N/R N/R survival (%) Toxicity N/R Mild Mild N/R N/R Mild N/R Mild Mild Acceptable Mild Mild Acceptable -h Hourly

7 E. Karapanagiotou and K. N. Syrigos Chapter 24 Second-Line Chemotherapy for Non-Small-Cell Lung Cancer 311 Gefitinib and erlotinib act as TKIs, while cetuximab is a monoclonal antibody that targets the extracellular domain of the human EGFR Gefitinib Gefitinib has been approved for NSCLC patients as third-line treatment after receiving platinum- and docetaxel-based regimens. Its approval by the FDA was based on the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL 2) study, which showed a response rate of 10.6% and a symptom improvement rate of 40% without the existence of any randomized trial demonstrating superior survival rates for patients treating with this drug [73]. The data obtained in two clinical studies suggesting the administration of gefitinib as monotherapy and not in combination with chemotherapy is of great clinical importance [74]. Gefitinib treatment appears to be more efficacious in nonsmoking women with bronchoalveolar carcinoma. Preliminary results of the SWONG 0126 trial showed a response rate of 12% in previously treated patients [75]. Gefitinib toxicity is limited to diarrhea and skin rash and is generally well-tolerated. A large phase III clinical trial involving gefitinib is ongoing, with the purpose of comparing a dose of 250 mg/day (taken orally) to the standard second-line chemotherapy of docetaxel at 75 mg/m 2 every 3weeks. The results are pending [76] Erlotinib Erlotinib, the other orally available EGFR TKI that demonstrated a response rate of 26% in a trial involving patients with bronchoalveolar carcinoma, was evaluated in a large phase III clinical trial compared to placebo. All 731 of the participants, had received 1 or 2 chemotherapeutic regimens and they were randomized in two arms. The results were encouraging. The median survival was 6.7 and 4.7 months, the 1-year survival rate was 31% and 22%, and the time to progression was 2.23and 1.84 months for the erlotinib- and placebotreated arms, respectively. Moreover, disease-related symptoms were better controlled in the erlotinib-treated group. Toxicity was limited to rash and diarrhea [77] Cetuximab Cetuximab is a recombinant human/mouse chimeric IgG1 monoclonal antibody that targets the extracellular domain of the human EGFR. Its efficacy has been demonstrated in solid tumors. A multicenter, open-label, randomized, phase III clinical trial is currently open to recruitment for patients with relapsed NSCLC after failure of initial platinum-based chemotherapy. Four experimental arms are presented: cetuximab plus docetaxel, cetuximab plus pemetrexed, docetaxel alone, or pemetrexed alone [78] Neoangiogenesis Inhibitors ± Bevacizumab Bevacizumab is a humanized anti-vascular endothelial growth factor antibody that is currently under investigation in a variety of solid tumors. Several ongoing studies are under way in NSCLC in front-line treatment as well as in salvage therapy. Phase II studies explore the efficacy of bevacizumab combinations with erlotinib and/or cetuximab in previously treated NSCLC patients Conclusions The role of second-line chemotherapy is the subject of a longstanding debate. In 1997, the American Society of Clinical Oncology (ASCO) guidelines stated that it could be neither confirmed nor refuted that second-line chemotherapy improves survival in patients with advanced NSCLC [79]. One year later, the ASCO guidelines stated that second-line treatment may be appropriate for good-performance-status patients for whom an investigational protocol is not available or desired, or for patients who respond to initial chemotherapy and then experienced a long progression-free interval off treatment [80]. Some years later, two large randomized phase III clinical trials with realistic and appropriate objectives were conducted. These trials showed a superiority for docetaxel regarding survival prolongation and quality of life when it was compared either to BSC or chemotherapy. In addition, these studies presented an acceptable toxicity profile. As a result, some questions have been answered. Chemotherapy in the second-line setting is of value in fit patients, offering a survival and clinical benefit. The American College of Chest Physicians Lung Cancer Guidelines Committee approved the administration of second-line chemotherapy in platinum-refractory NSCLC patients with grade of recommendation B [3]. An alternative to docetaxel chemotherapy is presented by pemetrexed, which achieves the same goals in treatment targets with minor toxicities. Moreover, several drug combinations are under investigation in an attempt to be determine the best regimen with the least toxic profile. Although current data offer a hint of victory in this war, the research efforts have been driven to molecular oncology. Targeted therapies gain new ground in the second- line treatment of NSCLC patients. New anti- EGFR and antiangiogenesis agents are being widely investigated in phase II and III clinical trials in combination with chemotherapeutic agents or alone. Research advances are orientated toward the adoption of drugs tailored to the tumor's molecular profile, with the aim of greater efficacy and less toxicity.

8 312 V. Management of Advanced Non-Small-Cell Lung Cancer Key Points l Second-line treatment of non-small-cell lung cancer patients offers a survival and clinical benefit. l It is appropriate for good-performance-status patients for whom an investigational protocol is not available or desired, or for patients who respond to initial chemotherapy and then experience a long progression-free interval off treatment. l Several drug combinations are currently under investigation in an attempt to obtained the best regimen with the least toxic profile. References 1. Parker SL, Tong T, Bolden S, et al. Cancer statistics, CA Cancer J Clin 1997; 47:5. 2. Ginsberg JK, Kris MG, Armstrong JG. Cancer of the lung: non-small cell lung cancer. In: De Vita VT, Hellman S, Rosenberg SA (eds.) Cancer: Principles and Practice of Oncology, 4th edn. Lippincott, Philadelphia, 1993; p Socinski MA, Morris DE, Masters GA, et al. Chemotherapeutic management of stage IV non-small cell lung cancer. 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