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The Proceedings of the American Thoracic Society 6:233-241 (2009)
© 2009 The American Thoracic Society
doi: 10.1513/pats.200809-110LC
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Current Treatments for Advanced Stage Non–Small Cell Lung Cancer

Thomas E. Stinchcombe1 and Mark A. Socinski1

1 Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina

Correspondence and requests for reprints should be addressed to Tom Stinchcombe, M.D., Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Physicians Office Building, 3rd Floor, 170 Manning Drive, Cb 7305, Chapel Hill, NC 27599-7305. E-mail: Thomas_Stinchcombe{at}med.unc.edu

ABSTRACT

Lung cancer remains the leading cause of cancer mortality in the United States, and the majority of patients will have non–small cell lung cancer (NSCLC) and will present with locally advanced or metastatic disease. In the United States, the most common histology is adenocarcinoma, followed by squamous cell, large cell, and not otherwise specified. For patients with a preserved performance status (PS), double agent platinum-based therapy extends survival, improves quality of life (Qol), and reduces disease-related symptoms. The addition of a third cytotoxic agent increases toxicity without any clinical benefit. However, the addition of a targeted agent (bevacizumab, an antiangioegenesis agent, or cetuximab, an antibody against the epidermal growth factor receptor [EGFR]) to platinum-based therapy has yielded an improvement in survival compared with platinum-based therapy alone. To receive bevacizumab, patients are required to have nonsquamous histology, a PS of 0 or 1, and no evidence of brain metastases, hemoptysis, uncontrolled hypertension, and no need for therapeutic anticoagulation. The benefits of chemotherapy for patients with a poor performance status are less well defined, and the current recommendations are for treatment with single-agent chemotherapy. Elderly patients (defined as age ≥ 70 yr) derive a survival and Qol benefit from chemotherapy treatment, and for the majority of elderly patients single-agent chemotherapy is the standard. However, elderly patients with a good performance status and without co-morbidities can tolerate platinum-based therapy without excessive toxicity and appear to derive a survival benefit similar to that in younger patients. Recently, a separate population of patients defined by a light or never-smoking history has been identified. This patient population appears to have unique clinical and molecular characteristics, and may benefit from initial therapy with an EGFR tyrosine kinase inhibitor. Once patients have progressed on first-line therapy there are three agents available (docetaxel, pemetrexed, and erlotinib), but the efficacy of pemetrexed appears to be limited to patients with nonsquamous histology. Despite the improvements in care and number of therapeutic agents available, the survival for patients with advanced-stage NSCLC remains modest; novel approaches are required and participation in clinical trials should be encouraged.

Key Words: chemotherapy • targeted therapy • elderly • never smoking • poor performance status

Lung cancer is the leading cause of cancer mortality in the United States, and it is estimated that in 2008 more patients will die from lung cancer than prostate, breast, and colorectal cancer combined (1). Approximately 85% of the patients with lung cancer will have non–small cell lung cancer (NSCLC), which is frequently subdivided into the squamous, adenocarcinoma, large cell, and not otherwise specified (NOS) histologies. The most common histologies on recent cooperative groups trials in the United States are: adenocarcinoma (~ 50% of cases), squamous cell (~ 20%), and large cell (~ 10%) (2). The majority of the patients will have locally advanced or metastatic disease at the time of diagnosis (3, 4). Patients with malignant pleural and pericardial effusions are classified as stage IIIB under the current staging system, but have a prognosis and undergo treatment similar to that of patients with metastatic disease. In addition to the patients who present with advanced-stage disease, a significant percentage of the patients who present with early-stage disease will subsequently relapse with metastatic disease (5). Thus, the majority of patients who receive the diagnosis of NSCLC will receive chemotherapy for advanced disease.

In patients with advanced-stage NSCLC, the patient's performance status (PS) is used to estimate a patient's prognosis, as well as the patient's tolerance of and the potential benefit from chemotherapy. The Eastern Cooperative Oncology Group (ECOG) or Zubrod and Karnofsky (6, 7) scales are frequently used in oncology. While there may be subtle differences depending on the scale used, in general a good performance status is defined as asymptomatic or ambulatory but restricted from strenuous activities, and the standard of care for this patients population is treatment with double-agent chemotherapy (8, 9). Treatment with chemotherapy has been shown to extend survival, reduce disease-related symptoms, and improve quality of life (Qol) in comparison to best supportive care (BSC) in this patient population (8, 9). Patients with a poor performance status, often defined as ambulatory and active more than 50% of the time but unable to carry out work activities, have a worse prognosis, and the role of chemotherapy in this patient population is less certain. The current recommendations is that patients with a poor performance status receive single-agent chemotherapy (8, 9). Patients who are only capable of limited self care and confined to a bed or chair more than 50% of the time or incapable of self care BSC is the standard. Thus, a detailed history of the patient's daily activities and a careful assessment of his or her performance status are critical to selection of the appropriate therapy.

The standard therapy for patients with advanced-stage disease is platinum-based double-agent chemotherapy. Trials comparing different platinum-based combinations have, in general, revealed equal efficacy and differing toxicity profiles (10). This led to the belief that we had reached a "therapeutic plateau" with standard cytotoxic chemotherapy (11). Recent trials have investigated the addition of a "targeted agent" in combination with platinum-based chemotherapy. These agents are active against a specific pathway involved in the pathogenesis and metastases of NSCLC, and the hope is that these agents will have greater activity and reduced toxicity compared with standard cytotoxic chemotherapy. Recently two phase III trials have compared a platinum-doublet chemotherapy with and without bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor (VEGF) in chemotherapy-naïve patients (i.e., first-line therapy). This agent prevents the binding of VEGF to VEGF receptors, which inhibits the growth of new blood vessels, causes regression of existing vasculature, and normalizes the tumor vasculature, which enhances the delivery of chemotherapy to the tumor (12, 13). One trial demonstrated a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) (14), and a second trial revealed a statistically significant improvement in PFS (15). The trial by Sandler and coworkers, ECOG 4599, led to the approval of bevacizumab in combination with carboplatin and paclitaxel in advanced NSCLC (14). Activation of the EGFR pathway initiates a process that promotes tumor cell proliferation, angiogenesis, decreased apoptosis, and the development of metastasis (16). The development of agents that inhibit or inactivate this pathway has been an area of active investigation in oncology. A phase III trial that compared a platinum doublet with and without cetuximab, a monoclonal antibody directed at the epidermal growth factor receptor (EGFR), in chemotherapy-naïve patients revealed a statistically significant improvement in OS (17). In patients who have progressed after one or two previous chemotherapy regimens (i.e., second- and third-line therapy), treatment with the oral EGFR tyrosine kinase inhibitor (TKI) has been shown to improve survival compared with BSC (18). This agent inhibits the EGFR pathway by binding to the intracellular domain and tyrosine kinase and inhibiting downstream signaling. In addition to these trials, numerous other targeted therapies are currently in development and being investigated in clinical trials.

FIRST-LINE THERAPY

Chemotherapy
The benefit of first-line chemotherapy in patients with a good PS is well established; however, significant debate existed about the optimal number of agents, selection of agents, and the duration of therapy. The optimal number of agents was assessed in a meta-analysis performed by Delbaldo and colleagues that included 13,601 patients from 65 trials; treatment with two chemotherapy drugs yielded a superior response and survival rates compared with single-agent chemotherapy (Table 1) (19). The addition of a third cytotoxic agent did not improve survival and resulted in greater toxicity in comparison to two chemotherapy agents (19). The greater toxicity associated with the addition of a third cytotoxic agent may have compromised the efficacy due to the fact that patients may have received fewer cycles or required more frequent dose reductions related to toxicity. Thus, most trials currently in development are using a double-agent chemotherapy platform, and the addition of a targeted agent with a different toxicity profile.


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  		TABLE 1. SELECT META-ANALYSIS OF CHEMOTHERAPY IN ADVANCED NSCLC

 
The current standard is a platinum agent in combination with a second agent, generally paclitaxel gemcitabine, vinorelbine, and docetaxel, and more recently pemetrexed in patients with nonsquamous histology (8–10, 20). However, there continues to be a debate about the proper selection of the platinum agent. Two meta-analyses have been performed comparing cisplatin versus carboplatin. Both have revealed a superior response with cisplatin-based therapies compared with carboplatin-based therapies, but similar OS (21, 22). In the meta-analysis by Ardizzoni and coworkers, carboplatin treatment was associated with a non–statistically significant increase in the HR for mortality relative to treatment with cisplatin (hazard ratio [HR], 1.07; 95% confidence interval [CI], 0.99–1.15; P = 0.10) (22). In subgroup analyses, patients with nonsquamous histology and patients treated with the modern or third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR, 1.12; 95% CI, 1.01–1.23 and HR, 1.11; 95% CI, 1.01–1.21, respectively) (22). In the meta-analysis by Hotta and colleagues, cisplatin-based therapy was associated with a nonsignificant improvement in survival (HR, 1.050; 95% CI, 0.907–1.216; P = 0.515) (21). A subset analysis revealed a superior survival with cisplatin in combination with a newer agent (paclitaxel, gemcitabine, and docetaxel) than with carboplatin and a newer agent (HR, 1.106; 95% CI, 1.005–1.218; P = 0.039). These meta-analyses indicate that cisplatin is the more active agent when combined with current chemotherapy agents. Both meta-analyses revealed an increased rate of nausea, vomiting, and renal toxicity with cisplatin-based therapy. Carboplatin-based therapy was associated with an increased rate of thrombocytopenia. At this time, both therapies are considered acceptable, and proponents of cisplatin-based therapy cite the improved efficacy, and the proponents of carboplatin cite the reduced toxicity of carboplatin. Many North American physicians and Cooperative Groups prefer carboplatin-based therapies, while European physicians and clinical investigators favor cisplatin-based therapies.

The optimal duration of platinum-based therapies has been an area of investigation as well. Five trials have compared a shorter duration of platinum-based therapy (three or four cycles) with a longer duration of therapy (six cycles or until disease progression) (23–27). Four trials (23–25, 27) have revealed equivalent survival with a shorter duration of therapy, and toxicity has been equivalent (25, 27) or greater with the longer duration of therapy (23, 24). The quality of life has been equivalent (23, 25) or better with the shorter duration of therapy (24, 27). A fifth trial compared four cycles versus six cycles of carboplatin-based therapy, and the preliminary results revealed a significant improvement in overall survival with the longer course of therapy (26). The cumulative data of these phase III trials favors a shorter course of platinum-based therapy given the similar OS observed between the two treatment strategies, and the risk of additional toxicity and reduced quality of life with a longer duration of therapy.

The Role of Targeted Agents in First-line Treatment
There was tremendous initial enthusiasm for the integration of targeted agents into the treatment of advanced NSCLC; however, after the sobering results of several phase III trials, it became apparent that the integration of targeted agents would be more difficult than anticipated. For example, the EGFR TKI therapies gefitinib and erlotinib had shown promising activity in phase II trials (28–30), and four phase III trials of chemotherapy with and without EGFR TKI therapy were performed (31–34). Unfortunately, none of these trials revealed a survival benefit with the addition of EGFR TKI therapies to the standard chemotherapy. These trials illustrated that it was unlikely that targeted therapies were going to benefit the entire population of patients with NSCLC, and the proper selection of patients based on clinical or molecular characteristics would be essential to the further development of targeted agents.

Bevacizumab.
The first targeted agent that demonstrated a survival benefit in first-line therapy was bevacizumab. A three-arm randomized phase II trial (n = 99) compared standard chemotherapy (carboplatin and paclitaxel) versus bevacizumab at a dose of 7.5 mg/kg and 15 mg/kg every 3 weeks (35). The primary end-point was time to tumor progression, and the patients on the 15 mg/kg treatment arm had a statistically significant higher response rate and longer TTP compared with patients on the standard chemotherapy alone. Some significant bevacizumab-related toxicity was observed on the trial, including hypertension, proteinuria, and bleeding. The bleeding consisted of mucocutaneous bleeding as well as pulmonary hemorrhage, which appeared to be associated with squamous histology. Four of the 13 patients with squamous histology experienced severe pulmonary hemorrhage.

As a result of this trial, the ECOG initiated ECOG 4599, a phase III trial comparing carboplatin and paclitaxel versus carboplatin and paclitaxel with bevacizumab at a dose of 15 mg/kg every 3 weeks (14). Patients with squamous histology, brain metastases, uncontrolled hypertension, and clinically significant cardiac disease were excluded. Patients with hemoptysis of greater than or equal to 0.5 teaspoon were excluded after the trial had been initiated. Eight hundred seventy-eight patients were enrolled, and patients treated on the bevacizumab-containing arm had a statistically higher response rate, progression-free survival, and overall survival (Table 2). On the bevacizumab-containing treatment arm in comparison to the carboplatin and paclitaxel arm, significantly higher rates of hypertension (7% versus 0.7%), proteinuria (3.1. versus 0%), febrile neutropenia (5% versus 2%), and hemorrhage (4.4 versus 0.7%) were observed. There were significantly more treatment-related deaths on the bevacizumab-containing arm (n = 15) compared with the carboplatin and paclitaxel arm (n = 2). The results of this trial led the United States Food and Drug Administration (FDA) to approve bevacizumab in advanced NSCLC for patients with nonsquamous histology.


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  		TABLE 2. SELECT PHASE III TRIALS COMPARING CHEMOTHERAPY VS CHEMOTHERAPY AND A TARGETED AGENT

 
A phase III trial performed in Europe, referred to as the AVAIL trial, investigated the efficacy of bevacizumab at 7.5 mg/kg and 15 mg/kg every 3 weeks in combination with cisplatin and gemcitabine compared with cisplatin and gemcitabine (15, 36). The bevacizumab 7.5 mg/kg and 15 mg/kg arms were compared with chemotherapy alone, and this trial was not designed to detect a difference in efficacy of the two different doses of bevacizumab. The trial was initially designed with the primary endpoint of OS, but the primary endpoint was changed to progression-free survival after the trial had been initiated. A total of 1,047 were randomized between the three arms, and the trial revealed that patients receiving treatment on the bevacizumab-containing arms did experience a modest but a statistically significant improvement in PFS, but a statistically significant difference in OS was not observed (Table 2). Potential explanations for the discrepant results include differences in the patient population enrolled on the trials, differences in the rate of second-line therapies, and the different statistical design between the two trials. This trial has raised issues about the clinical benefit of the addition of bevacizumab in combination with cisplatin-based therapy.

Cetuximab.
Another targeted agent that has demonstrated activity in the first-line setting is the monoclonal antibody cetuximab. A randomized phase II trial (n = 86) compared the activity of chemotherapy with cisplatin and vinorelbine with and without cetuximab (37). This trial demonstrated the safety of the combination, and the response rates, median PFS, and OS were numerically higher on the cetuximab-containing treatment arm. This led to the development of a phase III trial (known as the FLEX trial) with the primary endpoint of OS comparing cisplatin and vinorelbine with and without cetuximab (Table 2) (17). Patients were required to have EGFR expression by immunohistiochemistry (IHC), and 85% of the patients screened demonstrated EGFR expression. There are currently multiple biomarkers being investigated for the predicting clinical benefit of anti-EGFR direct therapies including IHC, fluorescence in situ hybridization (FISH), and activating EGFR mutations. The optimal biomarker or set of biomarkers for predicting clinical benefit or resistance has yet to be determined, and the technical methods for testing biomarkers has yet to be standardized. The use of IHC on this trial may impact the development of future trials and selection of patients for cetuximab therapy outside of a clinical trial.

Patients with a performance status of two (18% of the patients enrolled) and squamous histology (33% of patients enrolled) were eligible, but patients with brain metastases were excluded. Patients randomized to the cetuximab-containing arm demonstrated a statistically significant higher response rate and an improvement in OS (Table 2). There was no difference in PFS between the two treatment arms. Patients on the cetuximab-containing arm compared with the chemotherapy arm did experience a statistically significant higher rate of febrile neutropenia (22% versus 15%), grade 3/4 acne-like rash (10% versus < 1%), diarrhea (5% versus 2%), and infusion-related reactions (4% versus < 1%). The rate of treatment related deaths on the cetuximab and chemotherapy arms were similar (3% and 2%, respectively).

A second phase III trial of carboplatin and taxane therapy (either paclitaxel or docetaxel at the discretion of the treating physician) with and without cetuximab with the primary endpoint of progression-free survival by independent radiologic review has been performed (Table 2) (38). The patients were not selected on the basis of EGFR expression by IHC, and this trial was substantially smaller than the FLEX trial (676 versus 1,125 patients, respectively). Similar to the FLEX trial, no statistically significant difference in the PFS was observed. When this trial was initially presented, OS data were not available, but a subsequent press release (39) indicated that a statistically significant difference in OS was not observed. The HR observed on this trial was similar to the HR observed on the FLEX trial, and this trial was not sufficiently powered to detect a difference in OS.

At this time cetuximab is currently not approved by the FDA for treatment of advanced NSCLC within the United States, and it anticipated a decision about approval will occur in 2009.

SECOND-LINE THERAPY

Second-line therapy is generally referred to therapy given after disease progression after first-line therapy. Approximately 40 to 50% of patients enrolled on first-line trials have subsequently received second-line therapy (14, 23). Patients with a good PS, non-squamous histology and female gender appear to be more likely to receive second-line therapy (40). There are currently three agents approved by the FDA for second-line therapy; two cytotoxic chemotherapy agents, docetaxel and pemetrexed, and the EGFR TKI, erlotinib. Docetaxel was the first agent approved based on two phase III trials (Table 3). The TAX 317 compared treatment with docetaxel versus BSC, and the initial docetaxel dose was 100 mg/m2 every 3 weeks, but when excessive toxicity was observed the trial was amended and the dose reduced to 75 mg/m2 every 3 weeks. Patients receiving docetaxel at 75 mg/m2 experienced a significantly longer time to tumor progression, median survival time, and a higher 1-year survival rate (41). The second phase III trial, TAX 320, compared docetaxel at two different doses, 100 mg/m2 and 75 mg/m2 every 3 weeks with the control arm of older chemotherapy agents of vinorelbine or ifosfamide (42). While the overall survival was not different among the three treatment groups, the 1-year survival rate was significantly higher on the treatment arm of docetaxel 75 mg/m2. These trials led to FDA approval of docetaxel and established docetaxel at 75 mg/m2 every 3 weeks as the standard of care. Subsequent trials have investigated docetaxel on a weekly schedule in comparison to the every-three-week schedule. A recent meta-analysis compared the two schedules and found equivalent efficacy, and a similar rate of anemia, thrombocytopenia, and nonhematologic toxicities (43). The rate of febrile neutropenia was significantly lower on the weekly schedule, and this schedule may be an option for patients who are at increased risk of infectious complications.


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  		TABLE 3. SELECT PHASE III TRIALS OF SECOND-LINE TREATMENT OF NSCLC

 
Pemetrexed was subsequently approved in the second-line setting on the basis of a phase III noninferiority trial comparing pemetrexed versus docetaxel 75 mg/m2 every 3 weeks (44). This trial differed from other second-line trials in that patients were only allowed to have received one previous line of therapy for advanced disease. Pemetrexed had a statistically significant lower rate of neutropenia, febrile neutropenia, and neutropenia with infections and a similar rate of grade 3 or 4 nonhematologic toxicities. Based on the similar clinical activity of pemetrexed compared with docetaxel, and the lower rate of myelosuppression, the FDA approved pemetrexed for treatment in the second-line setting (45). A retrospective analysis revealed that in patients with squamous histology treatment with pemetrexed compared with docetaxel yielded an inferior OS (HR, 1.563; 95% CI, 1.079–2.264; median survival time of 6.2 and 7.4 mo, respectively) (46). In contrast, in patients with nonsquamous histology, treatment with pemetrexed compared with docetaxel yielded a superior survival (HR, 0.778; 95% CI, 0.607–0.997; median survival time of 9.3 and 8.0 mo, respectively). The treatment by histology interaction test was statistically significant (P = 0.001). These data, in combination with prospective data from another trial (20), are suggestive that the activity of pemetrexed is limited to patients with nonsquamous histology, and the FDA has recently changed the indication of pemetrexed to patients with nonsquamous histology.

Erlotinib was approved by the FDA on the basis of the National Cancer Institute of Canada BR.21 trial, which compared erlotinib versus BSC in patients who had progressed on one line of therapy and were not candidates for further chemotherapy, and/or who had progressed on two lines of therapy (18). This trial revealed a statistically significant improvement in PFS and OS with erlotinib in comparison to best supportive care. Erlotinib was well tolerated, with the principal toxicities being rash and diarrhea, and a low rate of myelosuppression and nausea and vomiting was observed. Erlotinib is approved in the second- as well as third-line treatment settings, and the fact that it is an oral agent may be more convenient for some patients. Early experience with the EGFR TKI therapies erlotinib and gefitinib revealed that some patients experienced a rapid and tremendous response to therapy, and that these response were associated with a history of never-smoking, female sex, Asian ethnicity, and adenocarcinoma histology (47). The clinical subgroups were subsequently found to have a higher prevalence of activating EGFR mutations in the tyrosine kinase domain that was associated with a high response rate to this EGFR TKI therapy (48–50). A separate analysis of the BR.21 revealed that smoking status appeared to be the most powerful predictor of survival benefit of erlotinib: never-smokers (defined as < 100 cigarettes in the entire lifetime) had a significantly higher survival rate (HR, 0.4; P < 0.01) (51). Current investigations are trying to determine the combination of clinical and molecular factors that will predict a survival benefit for EGFR TKI therapy.

In summary, the response rate observed on second-line trials is approximately 10%, the median survival times are 6 to 8 months, and 1-year survival rates are approximately 30% for all three agents. While the median survival time observed on BR.21 was numerically lower than the median survival times observed on TAX 317 and the trial by Hanna and coworkers (44), BR included patients with a performance status of 3 and a higher percentage of patients that had received two previous therapies; therefore, variation in patient populations may have contributed to this difference. While the efficacy appears similar, significant differences in toxicity exist between the three agents. Docetaxel has a higher rate of myelosuppression than pemetrexed and erlotinib, and erlotinib has a higher rate of nonhematologic toxicity than pemetrexed and docetaxel, predominantly related to the higher rate of rash and diarrhea. Currently many physicians select the second-line agent on the basis of physician and patient preference, patient co-morbidities, the toxicities associated with the therapy, and convenience. For the patients with a history of never-smoking, erlotinib may be considered the preferred second-line agent. Pemetrexed should only be used in patients with nonsquamous histology.

UNIQUE PATIENT POPULATIONS

Elderly
Age of 70 years or more is used in most lung cancer trials to define elderly, and the median age of diagnosis of lung cancer in the United States is 69 years (52). The number of elderly patients who are expected to receive the diagnosis of lung cancer is expected to increase as this segment of the population increases (53). Elderly patients are often underrepresented on clinical trials (54, 55), and there is some concern that the patients enrolled on clinical trials may not be representative of the general elderly patient population (i.e., the "fit" elderly). This problem is further compounded by the fact that there is significant variability in the definition of a "fit" and "unfit" elderly patient. To better define the elderly patient population, many trials employ an assessment of co-morbidities (56, 57) in addition to the standard trial eligibility criteria.

Previously there had been a concern that the elderly may experience excessive toxicity from therapy, and/or that treatment may have only modest benefit. The Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) randomly assigned patients more than 70 years old to vinorelbine versus BSC (Table 4) (58). This trial revealed a significant improvement in one-year survival rate and Qol for patients who received vinorelbine, and toxicity was acceptable. The role of double-agent chemotherapy in elderly patients has been investigated in two trials. A trial by Frasci and colleagues (59) revealed a benefit of the combination of gemcitabine and vinorelbine compared with vinorelbine alone; but a larger trial, the Multicenter Italian Lung Cancer in the Elderly Study (MILES) (60), did not reveal a benefit of combination therapy over single-agent gemcitabine or vinorelbine. The results of the MILES trial led Italian investigators to recommend single-agent therapy for elderly patients.


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  		TABLE 4. SELECT PHASE III CLINICAL TRIALS IN ELDERLY PATIENTS

 
Retrospective data comparing the results of younger patients with older patients who participated in large randomized trials is available (61–65). It is important to note that these trials were not designed to investigate the effect of age on treatment, the elderly population represented a minority of the patients enrolled (15–30%), and all these trials used a platinum-based doublet, which may have caused physicians to carefully select the elderly patients who were enrolled on the trials. In general, these trials have revealed similar toxicity and survival between the two age groups. The retrospective analysis by Langer and coworkers revealed that elderly patients experienced more leukopenia and neuropsychiatric complications, but efficacy results were not significantly different when compared with the younger cohort (63). A subset analysis was performed of the three-arm TAX 326 trial, which compared docetaxel in combination with carboplatin and cisplatin in comparison to the reference arm of cisplatin and vinorelbine (62). The age cutoff of 65 years or more was used in this analysis, and 401 of the 1,218 patients were defined as elderly. The combination of cisplatin and docetaxel, compared with the reference regimen, yielded a statistically significant 3-month improvement in median survival and consistent benefit in 1-year and 2-year survival rates. The survival results observed on the carboplatin and docetaxel treatment arm were similar to those in the reference regimen. Cancer and Leukemia Group B (CALGB) trial 9730 performed a randomized trial of carboplatin and paclitaxel versus paclitaxel, and patients were stratified by stage, age, and PS (65). A total of 155 elderly patients (27%) were enrolled, and there was no significant difference in response or survival between the elderly and the younger patients. When the elderly subset were analyzed by treatment arm, the nonsignificant difference in survival observed in the overall study patient population was also observed in the elderly subset.

In summary, age alone should not dictate treatment-related decisions in patients with advanced NSCLC, and elderly patients with a good PS improved OS and Qol when treated with chemotherapy compared with supportive care alone. Single-agent therapy remains the standard therapy, but it is clear that elderly patients with a good PS and without co-morbidities can tolerate double-agent therapy. However, to date no elderly-specific trial has demonstrated a survival advantage for platinum-based double-agent therapy compared with single-agent therapy. Unfortunately, there is a paucity of data on the benefits and toxicity for patients who are aged 80 years or greater.

Poor Performance Status
Retrospective analyses in the 1980s suggested that patients with advanced-stage NSCLC and poor PS experience substantial toxicity and derived limited or no benefit from chemotherapy (66, 67). As a result of these analyses, patients with a PS of 2 were excluded from many platinum-based trials. A subsequent analysis of an ECOG trial of 1,594 revealed a high incidence of adverse events, including five deaths, but the overall toxicity experienced by patients with PS of 2 was not significantly different than that experienced by patients with a PS of 0 or 1 (66). The median survival time of 4.1 months and 1-year survival rate of 19% were substantially inferior to those of patients with PS of 0 or 1. A subsequent ECOG phase II trial investigated attenuated dose of cisplatin/gemcitabine and carboplatin/paclitaxel in patients with PS of 2 (n = 102). The median survival times were 6.8 months and 6.1 months, respectively, and the 1-year survival rates were 25% and 19%, respectively. There was no statistical difference between the two treatment groups, and the survival figures were longer than historical controls. CALGB trial 9730 compared carboplatin and paclitaxel versus paclitaxel alone, and 99 patients with a PS of 2 were enrolled. The median survival time and 1-year survival rate of patients with a PS of 2 were 3.0 months and 14%, respectively, which were significantly lower than those of the patients with PS of 0 or 1. However, when the survival rates of the patients with PS of 2 were analyzed by treatment arm, patients who received double-agent therapy had a significantly higher median survival time (4.7 versus 2.4 mo) and superior 1-year survival rate (18% versus 10%) compared with patients who were treated with single-agent therapy. A retrospective review of patients with a poor performance status who received carboplatin and paclitaxel on two clinical trials revealed a similar median survival time and 1-year survival rate of 4.9 months and 21%, respectively (68). The rate of toxicities observed in the good performance and poor performance status patients was similar. More recently, a prospective phase III trial comparing single-agent gemcitabine versus carboplatin and gemcitabine in the PS 2 patient population was performed (69). The primary endpoint was median survival time, and a total of 170 patients were enrolled. The median PFS on the single-agent and double-agent arms were 2.79 and 4.11, respectively (P = 0.234); the median survival times observed were 5.2 and 6.7, respectively (P = 0.367). The rate of grade 3 or 4 toxicity was greater on the double-agent arm, and the Qol was similar between the two arms. At this time, single- or double-agent chemotherapy are reasonable treatment options, but our practice has been to treat with single-agent therapy.

Never- or Light Smoking Patient Population
Tobacco use is the most common etiologic agent for lung cancer, but is estimated that in the United States approximately 10 to 15% of cases of lung cancer occur in patients who have never smoked, and the prevalence of lung cancer in never-smokers is higher in Asia (70). The rate of never-smoking lung cancer is higher among women than among men, and adenocarcinoma is the most likely histology (71, 72). This patient population has some unique clinical and molecular characteristics and more recently has been considered a separate disease population. Patients with lung cancer with a light or never-smoking history appear to have a better prognosis than patients who are former or current smokers, and the prognosis has been associated with the number of pack-years (73). Patients with a never- or light smoking history also have a higher rate of EGFR mutations, and these mutations have been associated with response to EGFR-TKI therapy (50, 51, 74). However, patients with a history of never-smoking may have KRAS mutations at a significant rate; these mutations have been associated with resistance to EGFR TKI therapy (75–77). These data are suggestive that this subgroup of patients may have significant molecular heterogeneity.

In a retrospective review of patients treated on phase III trial of carboplatin and paclitaxel with and without erlotinib, patients with a history of never-smoking (n = 72) who received carboplatin and paclitaxel with erlotinib experienced a substantial improvement in overall survival compared with patients who received carboplatin and paclitaxel (n = 44); median overall survival of 22.5 versus 10.1 months (HR, =0.49; 95% CI, 0.28–0.85) (32). These data have raised the question of whether these patients may benefit from initial therapy with an EGFR TKI in combination with chemotherapy or from EGFR TKI therapy alone. The Cancer and Leukemia Group B is performing a randomized phase II trial comparing erlotinib alone and in combination with carboplatin and paclitaxel in patients with never- or light smoking history to investigate this clinical question (78).

The Iressa Pan Asia Study (IPASS) was a phase III trial that compared the treatment with the EGFR TKI therapy gefitinib (trade name Iressa) versus carboplatin and paclitaxel in chemotherapy-naïve never- or light smokers (n = 608) in Asia (79). This trial differs from the CALGB trial, since it was a direct comparison of EGFR TKI therapy and standard cytotoxic chemotherapy alone in a select patient population, and it was a phase III trial. The primary endpoint was the noninferiority of gefitinib in comparison to carboplatin and paclitaxel for PFS. Gefitinib demonstrated superior PFS compared with chemotherapy (HR, 0.74; 95% CI, 0.65–0.85; P < 0.0001), exceeding the primary objective. Preliminary OS data was similar for gefitinib, carboplatin, and paclitaxel (HR, 0.91; 95% CI, 0.76–1.10; median overall survival time of 18.6 versus 17.3 mo). Qol improvement rates were significantly higher in patients who received gefitinib compared with patients who received carboplatin and paclitaxel. On subset analysis in the patients with an activating EGFR mutation, the PFS was significantly longer with gefitinib than carboplatin and paclitaxel (HR, 0.48; 95% CI, 0.36–0.64; P < 0.0001). However, in patients without activating EGFR mutations, the PFS was significantly shorter with gefitinib than with carboplatin and paclitaxel (HR, 2.85; 95% CI, 2.05–3.98; P < 0.0001). The prevalence of activating EGFR mutations was probably higher on this trial than a similar trial performed outside of Asia. However, these results could change the treatment paradigm in advanced in NSCLC, and patients who have activating EGFR may receive EGFR TKI therapy as initial therapy. This trial also represents the model for future drug development in NSCLC in which a targeted agent is given in a clinically or molecularly selected patient population that has a high likelihood of benefit from the therapy.

CONCLUSIONS

For patients with advanced-stage NSCLC and a preserved performance status, platinum-based doublets are the standard of care; however, patients with advanced-stage disease are beginning to be divided into different treatment subsets. For patients who do not have a contraindication to bevacizumab, the combination with platinum-based therapy is a therapeutic option. It is anticipated that cetuximab in combination with a platinum-based therapy will be approved by the FDA in the upcoming year, which may provide an additional therapeutic option for patients with all histologic subtypes. In the near future, patients with evidence of an activating EGFR mutation may receive first-line therapy with an EGFR TKI. Once a patient's disease progresses, there are currently three agents (docetaxel, pemetrexed, and erlotinib) approved for use in the second-line setting, but the activity of pemetrexed appears to be limited to the nonsquamous patient population. Single-agent therapy remains the standard for elderly patients and patients with a poor performance status, and future clinical trials will need to be developed for these patient populations. Despite the recent therapeutic improvements, the overall survival for most patients with advanced-stage disease remains modest, and clinical trials that investigate the activity of novel agents, and incorporate patient selection based on clinical and molecular factors, are required.

FOOTNOTES

Conflict of Interest Statement: T.E.S. has received lecture fees from Lilly Oncology and Genentech. He has received grants from Bristol-Meyers, Lilly Oncology, Bayer, and Abrexis Bioscience. M.A.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form September 25, 2008; accepted in final form October 12, 2008)

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