Suresh S. Ramalingam, MD

	Non—small cell lung cancer (NSCLC) is diagnosed at an early stage, when it is amenable to surgical resection in approximately 20% to 25% of cases.

 Surgical resection is standard treatment for early-stage NSCLC. Approximately 40% of patients with early-stage NSCLC are unable to undergo surgery due to comorbid medical conditions. Of patients who undergo surgery, 60% to 70% experience recurrences at systemic sites and 20% to 40% suffer local failures. Recurrence of disease is attributed to micrometastatic disease present at the time of diagnosis. Adjuvant chemotherapy is administered postoperatively with the goal of eradicating micrometastatic disease and improving long-term disease-free survival (DFS) and overall survival (OS).

	Although a number of clinical trials conducted over the years suggested a survival benefit with adjuvant chemotherapy, the evidence was not conclusive. The outlook on adjuvant chemotherapy started to change after data were published from a meta-analysis conducted by the Non—Small Cell Lung Cancer Collaborative Group in 1995, which reviewed 14 trials of adjuvant lung cancer therapy (N = 4357).

 The analysis included 8 trials involving cisplatin-based chemotherapy (n = 1394). The analysis reported a 5% reduction (95% confidence interval [CI], —0.5%-7%) in the absolute risk of death at 5 years (hazard ratio [HR], 0.87; 

 = .08) with cisplatin-based chemotherapy. This finding led to large prospective clinical trials that demonstrated benefits with adjuvant chemotherapy.

	Since platinum-based chemotherapy regimens have been established as the standard for the treatment of advanced NSCLC,

 they have also become the mainstay of therapy in the adjuvant setting. In this review, we summarize the current evidence regarding the role of chemotherapy for NSCLC in the adjuvant setting and provide recommendations for routine clinical practice.

PHASE III CLINICAL TRIALS OF ADJUVANT CHEMOTHERAPY FOR RESECTED NSCLC

	A number of phase III studies have been conducted in the past 2 decades to evaluate the role of postoperative chemotherapy in early-stage NSCLC. These trials differ from each other in distribution of tumor stage, chemotherapy regimen, and use of postoperative radiotherapy (PORT). As a result, some studies showed a survival benefit with adjuvant therapy, while others noted no improvement in outcomes (

	The Eastern Cooperative Oncology Group (ECOG) 3590 study randomized 488 patients with resected stage II or IIIA NSCLC to receive PORT alone (n = 242) or combined with 4 cycles of cisplatin and etoposide (n = 246).

 This phase III trial is unique among the recent adjuvant chemotherapy trials in that it included PORT as a standard part of therapy. Only 69% of patients in the combination therapy arm received all 4 cycles of chemotherapy. This is in keeping with other NSCLC trials of adjuvant chemotherapy, in which a significant number of patients did not receive all planned cycles of chemotherapy. The planned total dose of radiotherapy (50.4 Gy) was delivered to 82% of patients in the combined therapy arm and 84% of those in the radiation-only arm.

	The addition of chemotherapy to thoracic radiation offered no survival benefit, with a median OS of 38 months in the combination arm versus 39 months in the PORT-only group (

 = .56). Patterns of recurrence did not differ significantly between the groups.

	In an effort to assess the value of cisplatin-based chemotherapy in NSCLC, British researchers for BLT (Big Lung Trial) randomized patients with stage I-III NSCLC to receive 3 cycles of chemotherapy or no chemotherapy in conjunction with their primary treatment (ie, surgery, radiotherapy, or best supportive care), which was determined by disease stage.

 Of the 381 patients who underwent surgery, 192 were randomized to chemotherapy; 3% of patients received neoadjuvant chemotherapy and 97% had adjuvant chemotherapy. The 189 patients in the control arm did not receive any chemotherapy. The treating physician had the discretion to select from among 4 cisplatin-based chemotherapy regimens: cisplatin plus mitomycin and ifosfamide; cisplatin plus mitomycin and vinblastine; cisplatin and vindesine; or cisplatin and vinorelbine (Navelbine). Chemotherapy and PORT were administered sequentially for those patients in the surgery arm who received adjuvant PORT.

	The primary endpoint of OS was not improved with adjuvant chemotherapy (HR, 1.02; 

 = .90). More than 75% of patients treated in this trial received a 3-drug regimen; triplet regimens are known to have an inferior therapeutic index compared with standard doublet regimens. The majority of patients in this study had stage I NSCLC, a setting in which adjuvant chemotherapy appears to be least beneficial.

	The ALPI (Adjuvant Lung Cancer Project Italy) trial enrolled 1209 patients with completely resected stage I, II, or IIIA NSCLC and randomized them to treatment with a combination of cisplatin, mitomycin, and vindesine or to observation.

 Patients were permitted to receive PORT according to the local institutional policy. The trial was designed to detect a 20% relative improvement in OS or an absolute benefit of 7%. The median duration of follow-up was 64.5 months.

	No statistically significant difference in OS was observed between the treatment and control arms (HR, 0.96; 

 = .59). A trend toward improved progression-free survival (PFS) was observed with the addition of adjuvant chemotherapy (HR, 0.89; 

 = .13). Patients were prospectively evaluated for molecular markers p53, Ki-67, and KRAS codon 12 mutations; investigators found no statistically significant association between any of the tumor markers and OS.

National Cancer Institute of Canada Clinical Trials Group JBR.10

	The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) conducted a phase III randomized trial to determine the benefit of adjuvant chemotherapy in patients with resected stage IB or stage II (T2N0, T1N1, or T2N1) NSCLC.7 The trial was later expanded to include several American cooperative groups, including the Cancer and Leukemia Group B (CALGB), the Southwestern Oncology Group (SWOG), and ECOG. The study was designed with an 80% power to detect a 10% improvement in overall survival. In total, 482 patients were randomized to 4 cycles of adjuvant chemotherapy with cisplatin and vinorelbine or to observation.

	The median duration of follow-up was 5.3 years for the observation group and 5.1 years for the chemotherapy group, with patients receiving a median of 3 cycles of treatment. Recurrence-free survival was significantly decreased in the chemotherapy group (HR, 0.60; 

 <.001). Median OS was significantly prolonged in the chemotherapy group compared with the observation arm (95 mo vs 73 mo, respectively; HR, 0.69; 

 = .04). The investigators performed a subgroup analysis of OS benefit by stage of disease. They found no statistically significant benefit associated with chemotherapy in patients with stage IB NSCLC (

 = .79), but patients with stage II NSCLC derived significant benefit.

	In early 2010, the investigators published long-term follow-up data, accrued during a median of 9.3 years. The data confirmed initial results of the trial, showing a persistent benefit from adjuvant chemotherapy (HR, 0.78; 

 = .04), including prolongation of disease-specific survival (HR, 0.73; P = .03).

 As observed in the earlier analysis, investigators noted a correlation between benefit from chemotherapy and stage of disease at enrollment. Patients with stage II disease who received chemotherapy demonstrated a significant OS benefit (HR, 0.68; 

 = .01) compared with their counterparts in the observation arm, while patients with stage IB disease showed no OS benefit versus the subgroup of patients with stage IB disease in the observation cohort (HR, 1.03; 

	A subset analysis of patients with stage IB disease found that patients with tumors >4 cm benefited from adjuvant chemotherapy compared with observation, but the level of benefit was not statistically significant (HR, 0.66; 95% CI, 0.39-1.14; 

 = .133). For patients with tumors <4 cm, adjuvant chemotherapy appeared detrimental (HR, 1.73; 95% CI, 0.98-3.04; 

 = .56). The 5-year OS rate for patients with tumors ≥4 cm was 59% in the observation group and 79% in the chemotherapy arm.

	IALT (International Adjuvant Lung Trial) compared adjuvant cisplatin-based chemotherapy with observation for patients with resected stage I, II, or IIIA NSCLC.

 The primary endpoint was OS, and secondary endpoints consisted of DFS, the incidence of second primary cancers, and adverse effects. Although the study was closed early because of slow accrual, a total of 1867 patients were randomized to receive chemotherapy (n = 932) or observation (n = 935). For patients in the chemotherapy arm, treating physicians could add one of 4 different agents to cisplatin: etoposide, vinorelbine, vindesine, or vinblastine. Patients with pathologic stage N1 or N2 disease were allowed to receive PORT after completion of chemotherapy if they had been assigned to treatment and after randomization if they were assigned to observation. In the chemotherapy group, 74% of patients received at least a 240 mg/m

 cumulative dose of cisplatin and 8% did not receive chemotherapy. Compared with the observation arm, the chemotherapy group had better median OS (HR, 0.86; 

 <.03) and a higher 5-year OS rate (40.5% vs 44.5%, respectively). Disease-free survival was also significantly higher in the chemotherapy group (HR, 0.83; 

	Long-term follow-up data from the IALT study was published in January 2010, which showed a persistent trend toward improved survival with chemotherapy (HR, 0.91; 

 The benefit in OS seen with chemotherapy use remained statistically significant for up to 5 years (HR, 0.86; 

 = .01); however, the OS benefit did not persist beyond 5 years (HR, 1.45; 

 = .04). After 5 years, the rate of non—lung cancer-related mortality was higher in the chemotherapy arm. This was not attributable to secondary malignancies, and the reasons behind the increase are unclear.

Adjuvant Navelbine International Trialist Association

	ANITA (Adjuvant Navelbine International Trialist Association) was a European multinational study of adjuvant vinorelbine plus cisplatin versus observation in patients with resected stage IB-IIIA NSCLC.

 A total of 840 patients were randomized to chemotherapy (n = 407) or observation (n = 433). PORT was permitted at the discretion of the treating provider. Median duration of follow-up was 76 months. Median survival was 65.7 months for patients in the chemotherapy arm and 43.7 months for patients in the observation arm (HR, 0.80; 

 = .017). The absolute long-term OS benefit with the use of chemotherapy was 8.6% at 5 years and 8.4% at 7 years. Patients with stage IB disease did not appear to benefit from chemotherapy, with a 5-year OS rate of 62% in the chemotherapy group versus 64.5% in the observation group (HR, 1.10; CI, 0.76-1.57). In patients with stage II disease, investigators reported a trend toward significant benefit for patients randomized to chemotherapy versus those randomized to observation, with a 5-year OS rate of 51% versus 39%, respectively (HR, 0.71; CI, 0.49-1.03). Patients with stage IIIA disease in the chemotherapy arm experienced significantly prolonged survival, with a 5-year OS rate of 42% versus 26% in the observation group (HR, 0.69; CI, 0.53-0.90). The results of the subset analysis were not conclusive; the test to determine the interaction between stage of disease and chemotherapy did not reach statistical significance (

	Investigators also conducted an unplanned analysis of the subset of patients who received PORT. A greater number of patients in the observation group received PORT than in the chemotherapy group. PORT was associated with a favorable outcome in patients with N1 and N2 nodal status. For the N1 patients randomized to observation, the rate of 5-year survival was 43% for those who received PORT versus 31% for those who did not; for N2 patients who received PORT, the 5-year survival rate was 21% compared with 17% for those who did not. This finding aligns with evidence from other studies in support of a role for PORT following chemotherapy in patients with resected N2 disease.

	The Cancer and Leukemia Group B (CALGB) 9633 study compared carboplatin-based adjuvant chemotherapy with observation, with OS as the primary endpoint. It is the only study conducted exclusively in patients with stage IB disease.

 CALGB 9633 was specifically designed to identify the benefit of adjuvant chemotherapy in patients with high-risk stage I disease (T2N0). Data equating carboplatin with cisplatin in advanced-stage NSCLC underlay the research team’s decision to use carboplatin with paclitaxel.

	The Data Safety Monitoring Board terminated the study early after an interim safety analysis crossed the previously specified stopping boundary for efficacy, demonstrating an HR for OS of 0.62 (CI, 0.44-0.89; 

 = .014). The study’s targeted accrual was 384 patients; by the time it closed, 344 patients had been randomized, with 173 assigned to chemotherapy and 171 assigned to observation. The median duration of follow-up at the time of final analysis was 74 months, at which point investigators observed a nonsignificant trend toward improved OS favoring chemotherapy (HR, 0.83; 

 = .125). The median OS for patients treated with chemotherapy was 95 months compared with 78 months for patients in the observation group. Improvement in DFS was noted in the chemotherapy arm, but this also failed to achieve statistical significance (HR, 0.80; 

 = .065). Nearly 85% of patients in the adjuvant chemotherapy group received planned doses that were considerably higher than those associated with cisplatin-based regimens.

	An exploratory analysis of the benefit of chemotherapy by tumor size was conducted, and it found evidence that having a tumor ≥4 cm is a determinant of prognosis. Based on this, investigators stratified patients into 2 subgroups for their analysis—one group consisted of patients with tumors <4 cm and the other had patients with tumors ≥4 cm. A significant advantage with chemotherapy was observed in patients with tumors ≥4 cm (HR, 0.69; 

	A number of hypotheses have been offered for the negative overall results of the study: the small sample size left the study inadequately powered, patients with stage IB disease do not benefit from chemotherapy, and the combination of carboplatin and paclitaxel is an inferior regimen. The data from the CALGB 9633 subanalysis, along with the lack of benefit seen with adjuvant chemotherapy in patients with tumors <4 cm in the JBR.10 study, suggest that observation alone is optimal for this group following surgery.

 Lung Adjuvant Cisplatin Evaluation Meta-Analysis

	The LACE (Lung Adjuvant Cisplatin Evaluation) meta-analysis of data from 5 recent studies was conducted to evaluate postoperative cisplatin-based chemotherapy in patients with completely resected NSCLC and to identify any subgroups that derive greater benefit from adjuvant chemotherapy.

 Data were collected for individual patients (N = 4584) enrolled in 5 large trials of adjuvant chemotherapy: BLT, ANITA, JBR.10, IALT, and CALGB 9633. The primary endpoint was OS, and secondary endpoints consisted of DFS, lung cancer—related deaths, non–lung cancer–related deaths, delivery of planned chemotherapy, and toxicity. The overall median duration of follow-up was 5.2 years (range per trial, 4.7-5.9 y).

	Adjuvant chemotherapy was associated with an 11% reduction in the risk of death (HR, 0.89; 

 = .005). The absolute survival benefit at 3 and 5 years was 3.9% and 5.4%, respectively. A 16% improvement in DFS was also noted (HR, 0.84; 

 <.001), with an absolute benefit of 5.8% and 5.8% at 3 and 5 years, respectively.

	The meta-analysis revealed a decrease in lung cancer deaths in patients treated with chemotherapy, with an absolute benefit of 6.9% at 5 years (HR, 0.82; 

 <.001). Patients in the chemotherapy arm had higher rates of non—lung cancer–related deaths (HR, 1.36; 

 = .004). The increase in risk of death for patients treated with chemotherapy occurred predominantly in the first 6 months of follow-up (HR, 2.31; 

 <.001) and was probably related to pulmonary or cardiovascular events or treatment-related toxicity.

	Investigators noted a significant correlation between stage of disease and benefit from chemotherapy. Patients with stage IA disease did not derive any significant benefit from chemotherapy and might even have been harmed by it (HR, 1.4; 95% CI, 0.95-2.06). The researchers observed a trend toward improved OS in patients with stage IB disease (HR, 0.93; 95% CI, 0.78-1.10). A clear advantage with adjuvant chemotherapy was observed in patients with stage II (HR, 0.83; 95% CI, 0.73-0.95) and stage III disease (HR, 0.83; 95% CI, 0.72-0.94). Chemotherapy had a detrimental effect on patients with World Health Organization performance status (PS) of 2, while patients with better PS (eg, PS 0) derived greater benefit from chemotherapy.

	An analysis of the LACE database was conducted to determine whether elderly patients derive the same benefit as younger patients from adjuvant chemotherapy.

 Patients were divided into 3 age groups: <65 years, 65 to 69 years, and >70 years. Patients’ baseline characteristics differed between groups. The cohort of patients aged <65 years included a greater proportion of women and had higher percentages of patients with better PS, a history of pneumonectomy, and an adenocarcinoma diagnosis. All of these differences were statistically significant. Overall, the elderly patients (aged ≥70 y) and those aged <70 years derived similar benefit from adjuvant chemotherapy even though the older patients received fewer cycles of chemotherapy and a lower total dose of cisplatin. Rates of toxicity did not differ significantly between the 3 age groups. Based on this analysis, chemotherapy should be offered to elderly individuals who are otherwise fit enough to receive platinum-based therapy. Given the small number of patients aged >75 years in the trials included in the meta-analysis, prospective studies are needed to investigate adjuvant chemotherapy in elderly patients.

	In the setting of advanced disease, carboplatin has been shown to be noninferior to cisplatin. The CISCA (Cisplatin vs Carboplatin) meta-analysis included individualized patient data from 9 randomized trials comparing carboplatin with cisplatin as a first-line treatment in patients with advanced NSCLC.

 Patients with advanced-stage disease had a significantly better response rate with cisplatin than with carboplatin (30% vs 24%, respectively; 

 <.001). Overall, outcomes were slightly worse for patients treated with carboplatin (HR, 1.07; 95% CI, 0.99-1.15; 

 = .100), but the difference was not statistically significant. Carboplatin was inferior to cisplatin in terms of OS in the subset of patients with nonsquamous tumors (HR, 1.12; 95% CI, 1.01-1.23) and those treated with third-generation regimens (HR, 1.11; 95% CI, 1.01-1.21). This meta-analysis suggests that in the setting of advanced disease, cisplatin is slightly superior to carboplatin. Because of carboplatin’s favorable tolerability profile and the ease of administering it in the outpatient setting, carboplatin remains the backbone of treatment for advanced NSCLC in the United States. In the adjuvant setting even a small improvement in efficacy might make a difference for patients who are being treated with curative intent, and therefore cisplatin is preferred. In the single adjuvant trial that used carboplatin, no OS benefit was observed, which might be due in part to carboplatin’s inferior efficacy compared with cisplatin. Based on the current evidence, cisplatin is recommended for patients who have no contraindications.

	A second subgroup analysis of LACE was conducted to examine the role of adjuvant treatment with a combination of cisplatin and vinorelbine.

 This analysis found a significant 8.9% improvement in OS at 5 years (HR, 0.80; 95% CI, 0.70-0.91; 

 <.001). Once again, the benefit varied according to the stage of disease. Stage I patients saw minimal OS benefit, but stage II and stage III patients experienced a significant increase in OS at 5 years (11.6% and 14.7%, respectively). Compared with other treatment regimens used in the LACE analysis, the doublet of cisplatin and vinorelbine was superior (

 = .04). Based on these observations, a cisplatin/vinorelbine regimen is a proven approach for adjuvant chemotherapy in patients with early-stage NSCLC. However, given the favorable toxicity profile of newer agents such as taxanes, gemcitabine (Gemzar), and pemetrexed (Alimta) and their comparable efficacy in advanced disease, it is reasonable to use any of these drugs in combination with cisplatin as adjuvant therapy.

	Potential prognostic and predictive markers are being evaluated to identify patients at greater risk for recurrence of NSCLC and patients who might derive a greater benefit from chemotherapy. The excision repair cross-complementation 1 (ERCC1) enzyme plays a key role in nucleotide excision repair and is associated with removal of DNA adducts caused by platinum compounds. ERCC1 levels have been shown to be prognostic for NSCLC patients treated with chemotherapy.

 The ribonucleotide reductase M1 (RRM1) enzyme is involved in DNA synthesis; it is responsible for catalyzing the synthesis of deoxyribonucleotides from ribonucleotides. Increased levels of RRM1 have been associated with resistance to gemcitabine.

	A retrospective study evaluated formalin-fixed, paraffin-embedded tissues from patients with NSCLC who were treated with gemcitabine alone or combined with cisplatin.

 Investigators determined ERCC1, RRM1, and epidermal growth factor receptor (EGFR) gene-expression levels for 87% of the samples. Median OS was longer for patients with low ERCC1 levels than for those with higher ERCC1 levels (17.3 mo vs 10.9 mo, respectively; 

 = .0032). When only those patients who received cisplatin were considered, the predictive power of ERCC1 was greater, with OS of 23.0 months for patients with low ERCC1 levels compared with 12.4 months for those with higher MST levels (

 = .001). ERCC1 was not predictive of survival in patients treated with single-agent gemcitabine. A similar improvement in OS was also observed for patients with low levels of RRM1 expression versus those with higher levels (13.9 mo vs 10.9 mo, respectively; 

	These observations were substantiated by an analysis of ERCC1 expression levels in 761 tumor samples from patients enrolled in the IALT study; 355 tumors were ERCC1-positive and 446 tumors were ERCC1-negative.

 Patients with ERCC1-negative tumors derived significant benefit from cisplatin-based chemotherapy (HR, 0.65; 95% CI, 0.50-0.86; 

 = .002). No improvement was observed with adjuvant chemotherapy in patients who had ERCC1-positive tumors (HR 1.14; 95% CI, 0.84-1.55; 

 = .4). In patients who were not treated with chemotherapy, ERCC1 expression was a positive predictor of prolonged survival (HR, 0.66; 95% CI, 0.49-0.90; 

	To assess the feasibility of prospectively testing ERCC1 and RRM1 levels in patients with resectable NSCLC, SWOG is conducting a clinical trial for patients with stage IA or IB tumors ≥2 cm. Chemotherapy is being selected according to the patient’s level of expression of ERCC1 and RRM1. Patients expressing low levels of both enzymes will receive adjuvant cisplatin-based chemotherapy, while those expressing high levels will be assigned to observation. In Europe, 2 ongoing randomized studies are evaluating treatment selection based on molecular markers.

 The results of these ongoing studies will provide definitive information regarding the utility of these biomarkers in selecting treatment.

	Gene expression profiles are also being used for risk-stratification of patients following surgery.

 The lung metagene model was developed to help identify patients at high risk of lung cancer recurrence with greater accuracy than currently used clinical predictors. Based on promising early results with the model, CALGB is conducting a phase III study (CALGB 30506) to evaluate its utility in identifying patients with stage I NSCLC likely to benefit from chemotherapy.

 Patients will be randomized to receive cisplatin-based chemotherapy or observation and stratified according to their lung metagene score (LMS). The study’s primary endpoints include the benefit of adjuvant chemotherapy in patients with stage I disease, the benefit of chemotherapy in patients with a high LMS, and survival difference between patients with a high LMS and those with a low LMS.

Epidermal Growth Factor Receptor Inhibitors

	Various clinical trials are underway to determine the role of targeted agents and other novel therapies in the adjuvant setting. The National Cancer Institute of Canada (NCI-C) conducted a phase III BR.19 study to examine the role of the EGFR tyrosine kinase inhibitor gefitinib (Iressa) in the adjuvant treatment of NSCLC.

 Patients with completely resected stage IB, II, or IIIA NSCLC were randomized to receive gefitinib or placebo for 2 years. Patients who previously received adjuvant platinum-based chemotherapy were allowed to participate. The study’s primary endpoint was OS. BR.19 was closed prematurely following early reports from other studies and from clinicians in routine practice of gefitinib causing interstitial pneumonitis, but it is hoped that the data will provide helpful information regarding the use of EGFR inhibitors as adjuvant therapy.

	RADIANT (Randomized Double-Blind Trial in Adjuvant NSCLC With Tarceva), a similarly designed study, recently completed accrual.

 This ongoing phase III trial has enrolled patients with completely resected EGFR-positive tumors that were detected by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). Patients with stage IB-IIIA NSCLC were eligible, even if they had received adjuvant chemotherapy. Patients have been randomized to receive placebo or erlotinib (Tarceva) for 2 years. The primary endpoint of the study is DFS; secondary endpoints are OS and safety.

	Bevacizumab (Avastin) is an angiogenesis inhibitor and plays a key role in the treatment of patients with advanced NSCLC. The ongoing ECOG E1505 study seeks to define the role of bevacizumab in the adjuvant setting.

 Patients with completely resected stage IB-IIIA NSCLC are being randomized to 4 cycles of cisplatin-based adjuvant chemotherapy with or without bevacizumab; patients in the bevacizumab arm who do not experience disease progression will continue on bevacizumab for 1 year as maintenance therapy. The primary endpoint of the study is OS.

	A vaccine-based strategy to improve survival is also in advanced stages of investigation. The MAGRIT (MAGE-A3 as Adjuvant NSCLC Immunotherapy) study is enrolling patients with resected stage IB-IIIA NSCLC whose tumors test positive for melanoma antigen (MAGE)-A3, present in various tumor types. Patients who received adjuvant chemotherapy previously are still eligible for the study. Patients are randomized to receive a novel MAGE-A3 antigen-specific cancer immunotherapeutic (ASCI) or placebo.

 During a 27-month period, patients will receive 13 injections of the immunotherapy or placebo. The primary endpoint of MAGRIT is DFS; OS and lung cancer—specific survival are among the study’s secondary endpoints. MAGRIT was launched following promising data from an earlier randomized phase II study investigating MAGE-A3 ASCI.

	Adjuvant platinum-based chemotherapy is clearly beneficial for patients with resected stage II-IIIA NSCLC, and it is associated with an increase in 5-year survival of ~10%. In patients with stage IB disease, adjuvant chemotherapy appears to provide a modest benefit to those whose tumors are >4 cm. The use of 3 to 4 cycles of cisplatin-based chemotherapy should be considered the standard approach for patients with stage IB (>4 cm tumor), II, and IIIA disease who have undergone resection. While the treatment of early-stage NSCLC has greatly changed in recent years, much work is needed to improve the overall cure rate. The use of individualized treatment approaches, the addition of molecularly targeted agents, and the development of newer drugs are necessary elements for improving outcomes for patients with early-stage NSCLC.

Articles

Non-small cell lung cancer (NSCLC) is diagnosed at an early stage, when it is amenable to surgical resection in approximately 20% to 25% of cases.

Adjuvant Therapy for Non-Small Cell Lung Cancer: Impact of Recent Clinical Trials on Community Practice

The treatment of early-stage non–small-cell lung cancer (NSCLC) has undergone a paradigm shift recently with the addition of systemic therapy to local therapy. The use of cisplatin-based chemotherapy following surgery is now a standard approach for patients with stage II–IIIA disease. In this issue of ONCOLOGY, Gray et al present an overview of neoadjuvant approaches to the treatment of early-stage NSCLC. The paper outlines various advantages associated with earlier initiation of systemic therapy for patients with surgically resectable disease. In addition to those mentioned by the authors, we would like to highlight two important areas that make the neoadjuvant approach more attractive for the treatment of lung cancer.


The first issue relates to the better ability to deliver chemotherapy in the preoperative setting. In the randomized clinical trials conducted in the postoperative setting, only about 60% to 70% of patients were able to receive the planned courses of chemotherapy.[1,2] This is likely due to the invasive nature of the surgery and longer recovery times with lung cancer surgery. In addition, the presence of smoking-related comorbid illness in a majority of lung cancer patients contributes to the difficulty in completion of planned chemotherapy. Notably, the meta-analysis of adjuvant chemotherapy studies found the dose of cisplatin to be an important determinant of outcome.[3]

Therefore, the preoperative setting might be more suited for delivery of optimal dose and number of cycles of chemotherapy. In the Southwest Oncology Group (SWOG) 9900 study, 80% of patients received all three cycles of planned chemotherapy in the preoperative setting.[4]

The second major advantage of the preoperative approach is the ability to evaluate novel molecularly targeted agents to obtain additional insights into the mechanism(s) of action and assess the degree of target modulation in the tumor. Agents that target specific molecular pathways such as inhibitors of the epidermal growth factor receptor are already in routine clinical use. A variety of other novel compounds are in various phases of development. For targeted agents, it is important to establish target modulation and determine any dose-response effects before large-scale clinical trials are initiated to evaluate efficacy. This requires paired tumor biopsies before and after administration of a novel agent, which is often not feasible in lung cancer. The risk of pneumothorax, unfavorable tumor location and presence of comorbid illness are major limiting factors in lung cancer patients for obtaining paired biopsies.

As an alternative, administration of a novel agent for a brief of period of time in the preoperative period, followed by evaluation of the molecular effects on the harvested tumor tissues (at surgery) is an attractive approach. Nikolinakos and colleagues reported on a study that involved the administration of pazopanib, a vascular endothelial growth factor receptor inhibitor, for 2 to 6 weeks before surgery for NSCLC patients with resectable disease.[5] This study identified a variety of circulating angiogenic factors that were correlated with reduction in tumor size. The molecular studies on the tumor tissues have not yet been reported. Notably, only 19 patients were included in this trial.

Our group is conducting a similar study with everolimus (Afinitor), an inhibitor of the mammalian target of rapamycin (mTOR) pathway, in patients with resectable disease. Following a diagnostic baseline tumor biopsy, patients are treated with 3 weeks of oral therapy with everolimus and then undergo surgical resection. Molecular events that are both upstream and downstream of mTOR are evaluated and compared between the baseline and the posttreatment specimens.

These biomarker-driven “window of opportunity” studies require a relatively small sample size, but yield a great deal of mechanistic insights into the targeted pathways relevant to novel agents. For proven agents such as erlotinib (Tarceva), a brief duration of therapy in selected patients might achieve tumor downstaging when used as preoperative therapy. It is our view that this approach should be aggressively pursued to guide drug development in lung cancer.


Gray and colleagues rightly point out the limitations to the routine use of preoperative therapy despite the availability of supportive data from phase III studies in their paper. The results of the Neoadjuvant/Adjuvant Taxol (paclitaxel) Carboplatin Hope (NATCH) study, the first randomized comparison of preoperative vs postoperative chemotherapy in early-stage NSCLC were presented recently.[6] Approximately 600 patients were randomized to the regimen of carboplatin and paclitaxel for three cycles administered either before or after surgery. The third arm of the trial was surgery alone. Though patients with stage I, II, or IIIA NSCLC were eligible, approximately 75% had stage I disease. The investigators found a trend toward superior 5-year disease-free survival-the primary endpoint of the study-in the neoadjuvant arm. In particular, delivery of chemotherapy was achieved in 90% of patients in the neoadjuvant arm compared to only 66% in the adjuvant therapy arm. The lack of a clear survival advantage to systemic therapy in this study is not surprising given the high proportion of stage I patients enrolled, in whom the benefit with adjuvant chemotherapy is still not firmly established.

A phase III study that was initiated in the United States to compare adjuvant vs neoadjuvant therapy was unfortunately closed early due to poor accrual. This study was designed to compare the administration of cisplatin-docetaxel for three cycles either before or after surgery for early-stage NSCLC. One of the main hurdles to accrual was the prevailing practice of taking patients with suspected lung cancer to surgery without a preoperative diagnostic biopsy. Since a diagnosis of lung cancer was necessary for patients to be enrolled in this study, many of the potentially eligible patients were unable to participate due to the lack of a diagnostic biopsy. It is important to arrive at a consensus regarding the need for a diagnostic biopsy before surgery to facilitate the conduct of future studies in the preoperative setting.


Gray et al describe data from the use of combinations of three cytotoxic agents. Such regimens are associated with a higher degree of toxicity and did not result in a clear survival advantage in studies conducted in patients with advanced-stage disease.[7] In the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis, the use of three-drug combinations was shown to result in a lower dose of cisplatin being administered as adjuvant therapy. Since cisplatin remains the cornerstone of therapy for lung cancer, the three-drug combinations would not be ideal for adjuvant or neoadjuvant therapy.

Alternatively, the addition of a rational molecularly targeted agent might be more suited for combination with platinum-based doublet regimens. The Eastern Cooperative Oncology Group is conducting a phase III study (ECOG 1505) to evaluate the utility of adding bevacizumab (Avastin), a monoclonal antibody against the vascular endothelial growth factor, to cisplatin-based doublets for patients with surgically resected NSCLC (stages IB–IIIA). The emergence of cisplatin/pemetrexed (Alimta) as an efficacious regimen for nonadenocarcinoma histology in advanced NSCLC[8] has led to the inclusion of this as one of the chemotherapy backbones for the ECOG 1505 study. It is hoped that better tolerated regimens such as cisplatin/pemetrexed would be more suited for combination with molecularly targeted agents both in the preoperative and neoadjuvant settings.

Though not described in the article, Zheng and colleagues from the authors’ group have pursued novel biomarker-driven strategies to define patient populations susceptible to platinum-based chemotherapy.[9] Their work on the use of ERCC1 and RRM1 as both predictive and prognostic markers has led to a prospective phase II study by the Southwest Oncology Group for biomarker-based treatment selection in patients with resected NSCLC.


In summary, a number of new approaches to eradicate micrometastasis in early-stage NSCLC are currently being pursued. The neoadjuvant approach has many potential advantages and has been proven to improve survival compared to surgery alone. Individualization of treatment based on risk of recurrence and susceptibility to specific chemotherapeutic agents are other highly promising avenues toward improved outcome for patients with early-stage NSCLC.

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

1. Arriagada R, Bergman B, Dunant A, et al: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350:351-360, 2004.
2. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352:2589-2597, 2005.
3. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung Adjuvant Cisplatin Evaluation: A pooled analysis by the LACE Collaborative Group. J Clin Oncol 26:3552-3559, 2008.
4. Pisters KM, Vallieres E, Bunn PA, et al: S9900: Surgery alone or surgery plus induction (ind) paclitaxel/carboplatin (PC) chemotherapy in early stage non-small cell lung cancer (NSCLC): Follow-up on a phase III trial (abstract 7520). J Clin Oncol 25(18S):389s, 2007.
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The treatment of early-stage non–small-cell lung cancer (NSCLC) has undergone a paradigm shift recently with the addition of systemic therapy to local therapy. The use of cisplatin-based chemotherapy following surgery is now a standard approach for patients with stage II–IIIA disease.

Suresh S. Ramalingam, MD

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