Lung cancer is the second most common cancer and the leading cause of cancer death in both men and women in the United States.[1] It is responsible for more deaths than prostate, colon, and breast cancer combined, with an estimated 157,200 deaths from lung cancer in 2003.[1] The 5-year survival rate for patients diagnosed with lung cancer in 2003 is projected to be 15%, reflecting only a 2% increase over the last 4 years.[1,2] Of the estimated 172,000 cases of lung cancer in 2003, non-small-cell lung cancer will account for 80% to 85%.[3] Unfortunately, due to the inherent resistance of non-small-cell lung cancer to chemotherapy and radiation therapy, coupled with a limited understanding of the molecular events involved in the development and progression of lung cancer, it appears that this disease will be one of the most challenging to overcome in the 21st century. Non-small-cell lung cancer is one of the most aggressive types of cancers, with 30% to 40% of patients presenting with distant metastases. Left untreated, the median survival time for a patient with metastatic disease is approximately 4 to 5 months. In general, when surgery is not considered, patients with locally advanced or metastatic non-smal--cell lung cancer (stage III and IV) and good performance status are treated with concurrent radiation and platinum-based chemotherapy for palliation of symptoms from the primary tumor.[4,5] The time between diagnosis and treatment appears to be a critical prognostic factor for median survival. The American Society of Clinical Oncology Guidelines support treatment as soon as a diagnosis is made.[5] Findings suggest that appropriate and early delivery of chemotherapy improves patient survival. Studies that support these findings will be discussed in the following sections, including those that support the use of combination chemotherapy to provide symptom relief and enhance survival time. In addition, selected novel agents are reviewed, especially those targeted to pathways critical to oncogenesis. Platinum-Based Chemotherapy With the entry of cisplatin(Drug information on cisplatin) in the 1970s, the median survival time for patients with advanced non-small-cell lung cancer increased, especially when cisplatin was combined with chest irradiation.[ 6,7] Early clinical studies with cisplatin in patients with advanced- stage non-small-cell lung cancer demonstrated that this agent improved median survival (by approximately 3 months), relieved symptoms, and improved patient quality of life compared with best supportive care.[8] A meta-analysis of patient data from 54 randomized clinical trials (1965 through 1991) showed that cisplatin-based chemotherapy combined with radiation therapy was associated with short-term palliation of symptoms and an absolute survival benefit of 4% at 2 years.[4] Third-Generation Chemotherapeutics First-and second-generation platinum therapies (ie, cisplatin-and carboplatin(Drug information on carboplatin) [Paraplatin]-based regi- mens) appear to be equally effective when used for advanced non-smallcell lung cancer, although carboplatin has a more favorable therapeutic index than cisplatin, particularly with regard to nonhematologic toxicities.[ 9,10] These regimens, however, have resulted in a limited short-term survival benefit in patients with stage IIIB/IV non-small-cell lung cancer.[ 8,11] Since the 1990s, third-generation non-platinum-based agents, such as paclitaxel(Drug information on paclitaxel), gemcitabine(Drug information on gemcitabine) (Gemzar), vinorelbine (Navelbine), docetaxel(Drug information on docetaxel) (Taxotere), and irinotecan(Drug information on irinotecan) (CPT-11, Camptosar), have been used as first- and second-line therapies for non-small-cell lung cancer and have shown efficacy and good tolerability.[ 12-16] How Effective Are Current Combination Chemotherapies? To evaluate whether a selected combination regimen might be superior to other regimens, the Eastern Cooperative Oncology Group (ECOG) conducted a randomized study to compare four different regimens in 1,207 patients (1,155 eligible) with advanced non-small-cell lung cancer (stage IIIB/IV) and good performance status (ECOG score of 0-1 vs 2).[17] Treatment arms included (1) gemcitabine at 1,000 mg/m² on days 1, 8, and 15 plus cisplatin at 100 mg/m² on day 1 of a 4-week cycle; (2) docetaxel at 75 mg/m² plus cisplatin at 75 mg/m² on day 1 of a 3-week cycle; (3) paclitaxel at 225 mg/m² given over a 3-hour period on day 1, plus carboplatin on the same day at a dose calculated to produce an area under the concentration-time curve (AUC) of 6.0 mg/mL/min in a 3-week cycle; and (4) paclitaxel at 135 mg/m² delivered over a 24-hour period on day 1, plus cisplatin at 75 mg/m² given on day 2 for a 3-week cycle (as the reference regimen). While no significant difference in response rates and survival were observed between treatment groups, gemcitabine/cisplatin was associated with a significantly longer time to disease progression than cisplatin/ paclitaxel (4.2 vs 3.4 months, P = .001) (Table 1). Survival at 2 years was also longest for patients receiving gemcitabine/cisplatin (13%), although this difference was not statistically significant. The gemcitabine/cisplatin arm was associated with an increased likelihood of grade 3, 4, or 5 renal toxicity compared with paclitaxel/cisplatin (9% vs 3%) and a higher rate of grade 3/4 thrombocytopenia (50% vs 6%). Overall grade 4 and 5 toxicities were similar for all treatment groups with the exception of paclitaxel/carboplatin, which showed a significantly decreased incidence in grade 4 and 5 toxicities compared with paclitaxel/ cisplatin (P < .05). It was concluded that, while all treatments are effective as palliative therapy and moderately improve survival at 1 and 2 years, none of the four combination regimens were superior for treatment of advanced non-small-cell lung cancer. A recent multicenter phase III study, TAX 326, was designed to compare the safety and efficacy of platinum combinations in advanced non- small-cell lung cancer using identical doses of a third-generation chemotherapeutic agent (docetaxel) in combination with comparable doses of either cisplatin or carboplatin (Table 2).[10,18] TAX 326 was an international, multicenter, randomized trial that included 1,220 patients with advanced non-small-cell lung cancer. Patients were randomized to receive one of three regimens: (1) docetaxel at 75 mg/m² plus cisplatin at 75 mg/m² every 3 weeks; (2) docetaxel at 75 mg/m² plus carboplatin at AUC 6 every 3 weeks; or (3) vinorelbine at 25 mg/m² days 1, 8, 15, and 22 plus cisplatin at 100 mg/m² day 1 every 4 weeks (control arm). Median survival was 11.3 months in arm 1, 9.4 months in arm 2, and 10.1 months in the control arm. The 1-year survival rates were 46% in arm 1, 38% in arm 2, and 41% in the control arm. Arm 1 was equivalent to and nearly superior to arm 2 with respect to survival. The efficacy of arm 2 was not inferior to the control arm. Hematologic toxicity was similar across treatment arms. Patients treated with vinorelbine/cisplatin had the highest incidence of nausea and vomiting. Over 900 patients completed qualityof- life evaluations. Improvements in quality of life and clinical benefit, as measured by reduction in pain, improvement in performance status, and lack of major weight loss, were seen on both docetaxel arms. TAX 326, the largest trial yet conducted in advanced non-small-cell lung cancer, has demonstrated that the combination of docetaxel/cisplatin is at least equivalent to the combination of vinorelbine and cisplatin, and in this study was shown to be superior in terms of survival. In a phase III study by the Swedish Lung Cancer Study Group,[19] gemcitabine in combination with carboplatin for the treatment of advanced disease was found to significantly increase objective response rate (30% vs 12%) and median time to progression (6 vs 4 months, P = .001) compared to treatment with gem- gemcitabine alone. Median survival for both groups was 9 months. In a study conducted by the Cancer and Leukemia Group B, paclitaxel in combination with carboplatin was associated with an improvement in response rate compared with paclitaxel alone (30% vs 16%, P < .001), with a median survival of 8.5 months for the combination vs 6.5 months for paclitaxel alone (P = .023). Another study by Georgoulias and colleagues[20] compared the combination of docetaxel/cisplatin to docetaxel alone. The regimen resulted in a significantly higher objective response rate, but this did not translate into improved overall survival. Thus, it is logical to determine which doublet combinations are best tolerated and offer the greatest benefit for patients with advanced non-small-cell lung cancer. This was difficult, however, as no single comparative study had been statistically powered to address such an issue. In addition to the aforementioned studies, numerous other randomized trials have shown that there are several third-generation platinum-based combinations that may be considered in patients with metastatic non-smallcell lung cancer. Triple Combination Chemotherapy Regimens Triple combination chemotherapy has recently been evaluated to determine if this would further improve patient outcomes relative to doublet regimens. The Spanish Lung Cancer Group conducted a phase III trial comparing a cisplatin-based triple combination regimen, a nonplatinum sequential doublet regimen, and a cisplatin-based regimen (as the reference arm) in 562 patients with advanced non-small-cell lung cancer.[21] Treatment regimens consisted of arm A: cisplatin at 100 mg/m² on day 1 plus gemcitabine at 1,250 mg/m² on days 1 and 8; arm B: cisplatin at 100 mg/m² on day 1, gemcitabine at 1,000 mg/m² on days 1 and 8, and vinorelbine at 25 mg/m² on days 1 and 8, repeated every 3 weeks; and arm C: gemcitabine at 1,000 mg/m² plus vinorelbine at 30 mg/m² on days 1 and 8 for three cycles, followed by ifosfamide(Drug information on ifosfamide) (Ifex) at 3 g/m² on day 1 plus vinorelbine at 30 mg/m² on days 1 and 8. Eligibility criteria included measurable stage IV (brain metastases eligible if asymptomatic) or stage IIIB (malignant pleural effusion) non-small-cell lung cancer and a performance status of 0 to 2. Overall response rates among 410 eligible patients were best in arm A (41%) and arm B (40%) compared with arm C (24%). Median survival was similar for the three treatment groups. Toxicities observed in arms A, B, and C included grades 3/4 neutropenia in 26.3%, 30.1%, and 18.5%; neutropenic fever in 6.3%, 22.4%, and 7.4%; and grades 3/4 thrombocytopenia in 18.2%, 23.1%, and 7.4%, respectively. The overall incidence of neuropathy, nausea and vomiting, and renal toxicity was similar in all three arms. Thus, triple combination chemotherapy was associated with an increase in overall toxicity and did not have an efficacy advantage over twodrug combinations. Furthermore, alternating two-drug combinations failed to improve response or survival compared with a standard two-drug regimen. The mitomycin(Drug information on mitomycin), ifosfamide, and cisplatin (MIP) regimen, which is commonly used in Europe, was not found to be superior for survival in patients with advanced non-small-cell lung cancer compared with the doublet of gemcitabine/carboplatin.[22] In this study, 422 patients were randomized to receive gemcitabine (1,200 mg/m² on days 1 and 8) plus carboplatin at AUC 5, or mitomycin (6 mg/m² on day 1) plus ifosfamide (3 mg/m² on day 1) and cisplatin (50 mg/m² on day 1). The gemcita-bine/carboplatin combination was better tolerated than the triple combination but was associated with greater grade 3/4 thrombocytopenia (8% vs 3%). While overall response rates were similar, median survival and 1-year survival were improved with gemcitabine/carboplatin compared with the triple combination (10.0 vs 6.5 months and 38% vs 40%, respectively; P = .0043). In summary, data do not suggest that three-drug combinations or alternating two-drug combinations are superior to two-drug combinations in the treatment of non-mall-ell lung cancer. Chemotherapy in the Elderly The incidence of lung cancer is highest in patients between the ages of 70 and 80. Due to a reluctance to administer chemotherapy to elderly patients because of lack of a perceived benefit and/or possible increased toxicity, presence of comorbidities, and/or poor performance status, elderly patients have often not received chemotherapy. However, a retrospective analysis of a randomized phase III trial of platinum-based chemotherapy regimens (ECOG 5592) was recently reported that compared outcomes of patients 70 years of age or older with those of younger patients.[23] Elderly patients who were physically fit were able to tolerate platinum-based chemotherapy as well as younger patients. In the study, all patients were randomized to one of a variety of platinumbased therapies and evaluated for response and drug tolerance. Clinical response (partial or complete) to therapy was 21.5% in younger patients and 23.3% in patients ≥70 years of age. Median time to progression was 4.37 months in younger patients compared with 4.30 months in elderly patients, with 1-ear survival of 38% and 29%, respectively, and 2-ear survival of 14% and 12%, respectively. Both patient populations showed similar functional declines, with the elderly exhibiting a higher incidence of cardiovascular and respiratory comorbidities and experiencing more leukopenia and neuropsychiatric toxicity. The authors concluded that advanced age alone should not preclude the use of chemotherapy for elderly non-mall-cell lung cancer patients with good performance status.[ 23] It is unclear whether two-drug combinations are preferred over singleagent therapy in the elderly. Several third-generation chemotherapeutic agents appear to be effective in improving survival of patients with advanced non-small-cell lung cancer over the age of 70. The trial by the Elderly Lung Cancer Vinorelbine Study Group (ELVIS) demonstrated that single-agent vinorelbine was superior to best supportive care with significantly superior survival and quality of life for elderly patients.[24] In a phase III trial conducted by the Southern Italy Cooperative Oncology Group (SICOG), the combination of vinorelbine and gemcitabine was superior to vinorelbine alone in elderly patients older than 70. Median survival with the combination was 21 weeks, compared with 18 weeks for singleagent vinorelbine.[25] The 1-year survival rate was also superior in the two drug arm. These results conflicted with those from the Multicenter Italian Lung Cancer in the Elderly Study (MILES), in which patients with advanced non- small-cell lung cancer were randomized to receive one of three treatments: single-agent gemcitabine, single-agent vinorelbine, or the combination.[26] Early results indicated that both gemcitabine and gemcitabine plus vinorelbine produced the best response rates (18.4%), and the trial was continued to a final enrollment of 700 patients. However, further evaluation of all patients has shown that the combination regimen provided no statistically significant benefit with respect to median survival or 1-year survival compared with single-agent vinorelbine and was associated with more toxicity. Hence, this study demonstrated that the vinorelbine/gemcitabine combination does not offer a significant advantage over single-agent vinorelbine or gemcitabine. These and other similar results have led investigators to believe that chemotherapy should be considered for elderly patients with good performance status (0 or 1). Platinum-based combinations should be considered for those elderly patients with a good performance status, but single agents may be preferable for those patients with comorbid diseases or who have performance status of 2. Novel Therapies for Advanced- Stage Non-Small-Cell Lung Cancer With the increased use of platinumas well as non-platinum-based firstline regimens, the number of patients who still have a good performance status after first-line therapy seeking additional therapy after relapse has increased,[ 27] while the number of second- line therapies is limited. Thus, identifying novel therapies for the treatment of non-small-cell lung cancer is critical to improve outcomes for these patients. Given that some investigators believe a plateau has been reached with cytotoxic chemotherapy in the treatment of advanced non- small-cell lung cancer, novel biologicbased therapies may provide further advances by virtue of their unique mechanisms of action (Table 3). While some of the molecular mechanisms underlying the pathologic processes of lung cancer remain unknown, several cellular and biologic advances have identified a number of molecules and cellular pathways in volved in the regulation of tumor growth and proliferation. In non- small-cell lung cancer, novel therapies directed against certain molecular targets may improve survival and quality of life beyond that achieved with chemotherapeutic agents. Selected biological agents under investigation for treatment of non-small-cell lung cancer are presented in Table 3. Some of the more actively researched molecular- based inhibitors include anti- epidermal growth factor receptor (anti- EGFR) inhibitors, antiangiogenesis agents, and antisense therapies, which are discussed below. Epidermal Growth Factor Receptor Inhibitors
The epidermal growth factor receptor (EGFR, also known as ErbB1 or HER1) appears to play a critical role in tumorigenesis because of its abundant expression on cancer cells and its ability to stimulate cellular pathways that increase cell proliferation, decrease cell death (apoptosis), and increase angiogenesis.[28] Treatment with EGFR inhibitors is associated with a decrease in tumor cell proliferation and/or viability in vitro and in vivo.

• Gefitinib-Gefitinib (Iressa), one of the first members in this new class of selective EGFR tyrosine kinase inhibitors, blocks EGFR activity (autophosphorylation) and subsequent signal transduction mechanisms that regulate proliferation, metastasis, and angiogenesis.[29] Gefitinib(Drug information on gefitinib) is orally active, and has been associated with a low side effect profile-primarily acneiform rash and diarrhea. Two multicenter, randomized, dosecomparative phase II trials of gefitinib as monotherapy in patients with locally advanced or metastatic non- small-cell lung cancer have been conducted. The Iressa Dose Evaluation in Advanced Lung Cancer Trial-1 (IDEAL-1) was conducted in Japan, Europe, South Africa, and Australia. Eligible patients had received one or two previous chemotherapy regimens, one of which was to have been platinum- based.[30] The IDEAL-2 trial, conducted in the United States, required patients to have received at least two prior chemotherapy regimens containing a platinum agent and docetaxel given separately or concurrently.[ 31] In the IDEAL-1 trial, 210 patients were randomized to receive gefitinib at a daily oral dose of 250 mg (n = 103) or 500 mg (n = 106) (one patient did not receive treatment at the 250-mg dose).[30] Overall response rates of 18.4% and 19.0% were observed for patients receiving the 250- and 500-mg doses, respectively. For patients who responded, median duration of response was more than 3 months, and median survival times were 7.6 and 8.0 months for the 250- and 500-mg dose groups, respectively. In IDEAL-2, of the 216 patients randomized, 102 patients were treated with a daily oral dose of 250 mg of gefitinib and 114 patients received a dose of 500 mg of gefitinib.[31] Responses were observed in 11.8% of patients treated with 250 mg of gefitinib and 8.8% of patients treated with 500 mg. Median survival was 6.1 and 6.0 months for patients in the 250- and 500-mg groups, respectively. Symptom improvement on the IDEAL trials occurred rapidly; the median time to improvement for both treatment groups was 8 days in IDEAL-1, and 10 days and 9 days in the 250- and 500-mg groups, respectively, in IDEAL-2. Symptom improvement occurred in 40.3% and 43.1% of patients who received 250- mg gefitinib in the IDEAL-1 and IDEAL-2 studies, respectively.[32] For the patients receiving 500 mg/d, 37% of the IDEAL-1 participants and 35.1% of the IDEAL-2 participants had symptom improvement.[32] In both studies a substantially greater proportion of patients with an objective tumor response or stable disease showed improvements in symptoms compared with patients who had progressive disease. There was also a positive association between symptom response and survival; patients with improvements in symptoms had greater survival. Based on the results of these clinical trials, particularly IDEAL-2, gefitinib was approved for use in the United States in the treatment of patients with non-small-cell lung cancer in the third-line setting. Improvements in quality of life were also seen in these trials. Overall, the quality-of-life improvement rate was 23.9% and 21.9% for the 250- and 500-mg/d dose groups, respectively, on IDEAL-1, and 34% and 23% for the 250- and 500-mg/d dose groups, respectively, on IDEAL-2.[32] As with symptom improvement, quality-of-life improvement was recorded in a greater percentage of patients who achieved an objective response followed by those with stable disease. These results indicate that treatment with singleagent gefitinib had a positive impact on symptoms and quality of life in patients with advanced non-small-cell lung cancer. Combination therapy with gefitinib has also been evaluated in the Iressa NSCLC Trials Assessing Combination Treatment (INTACT-1 and INTACT- 2). These two randomized, multicenter phase III trials were conducted in chemotherapy- naive patients to determine if the combination of gefitinib and chemotherapy would show additive or synergistic antitumor effects. In INTACT- 1, patients with stage III/IV non-small-cell lung cancer were randomized to treatment with gemcitabine at 1,250 mg/m² administered on days 1 and 8 and cisplatin at 80 mg/m² on day 1, or to the same chemotherapy regimen combined with 250 or 500 mg/d of gefitinib. Patients in INTACT-2 were randomized to receive carboplatin at AUC 6 plus paclitaxel at 225 mg/m² administered every 3 weeks with or without the same doses of gefitinib. Although the combination of gefitinib and platinum chemotherapy doublets was well tolerated in both studies, no statistically significant increase in response rate, survival, or time to worsening of symptoms was demonstrated with the addition of this EGFR inhibitor.[33,34]
• Erlotinib-Erlotinib-Erlotinib (Tarceva) is a quinazoline small-molecule tyrosine kinase inhibitor that exhibits its effect at nanomolar concentrations. In a phase I study, patients with advanced solid malignancies refractory to conventional chemotherapy were treated with erlotinib.[35] Forty patients were enrolled, four of whom had non- small-ell lung cancer. Diarrhea and skin rash were the primary toxicities that precluded treatment with doses greater than 150 mg/d. Among patients with advanced, platinum-refractory non-small-cell lung cancer, 14.3% had an objective response and 28.6% had stable disease.[35] A phase II trial evaluating erlotinib at 150 mg/d enrolled 56 patients with progressive, recurrent non-small-cell lung cancer previously treated with a platinum-based chemotherapy regimen.[ 36] Eight patients (14.3%) achieved response (one complete, seven partial; six confirmed at week 12 and beyond), 16 patients (28.6%) had stable disease lasting ≥ 12 weeks, and 28 patients (57.1%) had documented progression of their underlying malignancy. Toxicities included rash and diarrhea, and were generally mild. Only a single patient required transient dose reductions due to skin toxicity.
• Cetuximab-Cetuximab (Erbitux) is a mouse-human chimerized monoclonal antibody that specifically binds to the EGFR, thereby inhibiting downstream signal transduction pathways.[ 37] In preclinical in vivo and in vitro studies, cetuximab(Drug information on cetuximab) has been shown to enhance radiosensitivity, promote radiation-induced apoptosis, decrease cell proliferation, inhibit radiation- induced damage repair, and inhibit tumor angiogenesis. Furthermore, cetuximab has been shown to enhance cytotoxicity when combined with various chemotherapeutic agents.[37] In the clinical setting, phase I studies of cetuximab alone and in combination with cisplatin have been reported.[ 38] Baselga et al presented a summary of three initial studies, which included a single-dose trial of cetuximab (CP02-9401), a weekly multiple-dose trial (once weekly for 4 weeks) (CP02-9502), or weekly in combination with cisplatin (CP02- 9503). In CP02-9503, patients were restricted to those who had head and neck cancers (n = 16) and non-smallcell lung cancer (n = 6). A total of 52 patients were treated in these three studies. In the CP02-9401 and CP02- 9502 studies, cetuximab was administered intravenously at doses ranging from 5 to 100 mg/m². In CP02-9503, cetuximab doses ranged from 5 to 400 mg/m² given weekly with addition of cisplatin, every 4 weeks, at 60 mg/m² 1 hour following cetuximab administration. Initially, three patients were treated with 100 mg/m² of cisplatin, but two experienced grade 3 or higher toxicities; the dose was therefore reduced to 60 mg/m². Overall, cetuximab was well tolerated, with five episodes of grade 3 or higher toxicity occurring with 317 doses of cetuximab. The most frequent adverse reactions included fever and chills, asthenia, transaminase elevations, nausea, and skin toxicities (flushing [4 cases], seborrheic dermatitis [1 case], and acneiform rash [6 cases]). A phase II study of cetuximab in combination with docetaxel in chemotherapy- refractory patients with advanced non-small-cell lung cancer was reported.[39] Cetuximab was administered at 400 mg/m² IV during the first week followed by 250 mg/m² IV weekly. Docetaxel was adminis tered at 75 mg/m² IV every 3 weeks. Twenty-five patients had been enrolled at the time of the report, and 20 patients were evaluable for response. Preliminary results showed that after two cycles of therapy, four patients had a partial response and six had stable disease. Toxicities included acneiform rash (grade 2/3) in five patients and febrile neutropenia (grade 2/3) in two patients. A phase II open-label, multicenter, nonrandomized study has been designed to evaluate the safety and toxicity of chemotherapy with cetuximab in patients with stage IIIA/B non- small-cell lung cancer. Other objectives are to determine the survival rate with this regimen in comparison to established regimens, and to determine the potential correlation of EGFR expression with survival rate. In this study, patients will initially receive cetuximab at 400 mg/m² IV on day 1. Beginning on day 8, cetuximab at 250 mg/m² plus paclitaxel at 45 mg/ m² and carboplatin at AUC 2 will be delivered weekly for 7 weeks during concurrent radiation therapy (63.0 Gy in 34 daily fractions over 7 weeks). Concurrent cetuximab plus chemotherapy/ radiation therapy will be followed by 3 weeks of single-agent cetuximab at 250 mg/m²/wk. Patients then receive two cycles of paclitaxel at 200 mg/m² and carboplatin at AUC 6 every 3 weeks, plus cetuximab at 250 mg/m²/wk for 6 weeks. This study plans to accrue a minimum of 70 patients.