Should surgery be part of the multimodality treatment for stage IIIB non-small cell lung cancer?

BACKGROUND: Traditionally, treatment for stage IIIB (T4N2M0 and T1-4N3M0) NSCLC consists in definitive chemoradiation. Surgery is used only anecdotally. Here, we studied outcome for patients treated with multimodality including surgery. METHODS: Patients who underwent surgery for stage IIIB between 2000 and 2015 were retrospectively reviewed and data analyzed. Patients were selected for surgery if they would tolerate multimodality treatment, the tumor was deemed upfront resectable, and N2-N3 involvement was limited to a non-bulky single site. Survival was calculated from the date of surgery until last follow-up. Univariate and multivariate analysis were performed to identify prognostic factors. RESULTS: During the study period, 5416 patients underwent resection for NSCLC in our center. Sixty patients (1%) had clinical stage IIIB. Thirty-two patients had T4N2 NSCLC involving the carina and/or superior vena cava (n = 25, 78%), left atrium (n = 5, 16%), or other (n = 2, 6%). Half of the 28 patients with N3-disease had supraclavicular node involvement. Pneumonectomy was performed in 27 patients (45%). Twenty-nine patients (48%) had induction therapy, with chemotherapy alone. Adjuvant therapy was administered to 52 patients (87%), mostly chemoradiation. Complete resection rate was 92%. Post-operative mortality was 3%. Three- and 5-year overall survivals were 51% and 39%, respectively. Multivariate analysis identified incomplete resection (P = 0.008) and absence of adjuvant treatment (P = 0.032) as poor survival prognostic factors. CONCLUSIONS: Surgery can be considered as a component of multimodality therapy in highly selected patients with stage IIIB NSCLC based on encouraging 5-year survival of 39%.

ERCC1 isoform expression and DNA repair in non-small-cell lung cancer.

BACKGROUND: The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation. METHODS: We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage. RESULTS: We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance. CONCLUSIONS: Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.).

Adjuvant chemotherapy for resected early-stage non-small cell lung cancer.

BACKGROUND: To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010. OBJECTIVES: To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapyB. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapyin patients with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival. SEARCH METHODS: We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, handsearching relevant meeting proceedings and by discussion with trialists and organisations. SELECTION CRITERIA: We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment. DATA COLLECTION AND ANALYSIS: We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status. MAIN RESULTS: We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low. AUTHORS' CONCLUSIONS: Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out.

Association of Molecular Profiles and Mutational Status With Distinct Histological Lung Adenocarcinoma Subtypes. An Analysis of the LACE-Bio Data.

BACKGROUND: Adjuvant chemotherapy (AC) is indicated for stage II and stage III lung adenocarcinomas (ADC). Using the LACE Bio II database, we analyzed the distribution of various mutations across the subtypes of ADCs and studied the prognostic and predictive roles of PD-L1, TMB, and Tumor Infiltrating Lymphocytes (TILs). MATERIALS AND METHODS: Clinical and genomic data from the LACE Bio II data were extracted. Patients were divided into ADC subtypes, in which the grouping was done based on their known clinical behavior (Lepidic [LEP], Acinar/Papillary [ACI or PAP], Micropapillary/Solid [MIP or SOL], Mucinous [MUC] and Others). Kaplan-Meier (KM) and log-rank test were used to compare survival based on PD-L1, TMB, TILs and combinations of TMB with PD-L1 and TILs. Adjusted Hazard Ratios (HR) were analyzed with Overall Survival (OS), Disease-Free Survival (DFS) and Lung Cancer-Specific Survival (LCSS) as endpoints. RESULTS: A total of 375 ADC patients were identified. MIP/SOL was the subtype most commonly positive for various biomarkers. PD-L1 Negative/high TMB was associated with better outcomes in terms of OS (HR = 0.46 [0.23-0.89], P = .021) and DFS (HR = 0.52 [0.30-0.90], P = .02), relative to PD-L1 Negative/low TMB. High TMB predicted worse outcome with AC use in terms of OS (ratio of hazard ratio rHR = 2.75 [1.07-7.04], P = .035). Marked TILs had better outcome with AC for DFS (rHR = 0.22 [0.06-0.87], P = .031 and LCSS (rHR = 0.08 [0.01-0.66], P = .019) respectively. There was also a beneficial effect of AC among patients with Marked TILs/low TMB in terms of DFS (rHR = 0.06 [0.01-0.53], P = .011). CONCLUSION: High TMB has a prognostic role in resectable lung ADC. The high TMB group had a poor outcome with AC, suggesting that this group may be better served with immune checkpoint therapy.

Non-small-cell lung cancer.

In the decade since the last Lancet Seminar on lung cancer there have been advances in many aspects of the classification, diagnosis, and treatment of non-small-cell lung cancer (NSCLC). An international panel of experts has been brought together to focus on changes in the epidemiology and pathological classification of NSCLC, the role of CT screening and other techniques that could allow earlier diagnosis and more effective treatment of the disease, and the recently introduced seventh edition of the TNM classification and its relation to other prognostic factors such as biological markers. We also describe advances in treatment that have seen the introduction of a new generation of chemotherapy agents, a proven advantage to adjuvant chemotherapy after complete resection for specific stage groups, new techniques for the planning and administration of radiotherapy, and new surgical approaches to assess and reduce the risks of surgical treatment.

WITHDRAWN: Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease.

BACKGROUND: Randomized trials have demonstrated that adding a drug to a single-agent or to a two-agent regimen increased the tumor response rate in patients with advanced non-small cell lung cancer (NSCLC), although its impact on survival remains controversial. OBJECTIVES: To evaluate the clinical benefit of adding a drug to a single-agent or two-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC. SEARCH METHODS: There were no language restrictions. Searches of MEDLINE and EMBASE were performed using the search terms non-small cell lung carcinoma/drug therapy, adenocarcinoma, large-cell carcinoma, squamous-cell carcinoma, lung, neoplasms, clinical trial phase III, and randomized trial. Manual searches were also performed to find conference proceedings published between January 1982 and June 2006. SELECTION CRITERIA: Data from all randomized controlled trials performed between 1980 and 2006 (published between January 1980 and June 2006) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, one-year survival rate, and toxicity rate were calculated using the fixed-effect model. Pooled median ratios (MRs) for median survival also were calculated using the fixed-effect model. ORs and MRs lower than unity (< 1.0) indicate a benefit of a doublet regimen compared with a single-agent regimen (or a triplet regimen compared with a doublet regimen). MAIN RESULTS: Sixty-five trials (13601 patients) were eligible. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR 0.42, 95% confidence interval [CI] 0.37 to 0.47, P < 0.001) and one-year survival (OR 0.80, 95% CI 0.70 to 0.91, P < 0.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI 0.79 to 0.89, P < 0.001). An increase also was observed in the tumor response rate (OR 0.66, 95% CI 0.58 to 0.75, P < 0.001) in favor of the triplet regimen, but not for one-year survival (OR 1.01, 95% CI 0.85 to 1.21, P = 0.88). The median survival ratio was 1.00 (95% CI 0.94 to 1.06, P = 0.97). AUTHORS' CONCLUSIONS: Adding a second drug improved tumor response and survival rate. Adding a third drug had a weaker effect on tumor response and no effect on survival.

Prognostic and predictive effect of KRAS gene copy number and mutation status in early stage non-small cell lung cancer patients.

BACKGROUND: In the current analysis, we characterize the prognostic significance of KRAS mutations with concomitant copy number aberrations (CNA) in early stage non-small cell lung cancer (NSCLC), and evaluate the ability to predict survival benefit from adjuvant chemotherapy. METHODS: Clinical and genomic data from the LACE (Lung Adjuvant Cisplatin Evaluation)-Bio consortium was utilized. CNAs were categorized as Gain (CN ≥2) or Neutral (Neut)/Loss; KRAS status was defined as wild type (WT) or mutant (MUT). The following groups were compared in all patients and the adenocarcinoma subgroup, and were correlated to survival endpoints using a Cox proportional hazards model: WT + Neut/Loss (reference), WT + Gain, MUT + Gain and MUT + Neut/Loss. A treatment-by-variable interaction was added to evaluate predictive effect. RESULTS: Of the 946 (399 adenocarcinoma) NSCLC patients, 41 [30] had MUT + Gain, 145 [99] MUT + Neut/Loss, 125 [16] WT + Gain, and 635 [254] WT + Neut/Loss. A non-significant trend towards worse lung cancer-specific survival (LCSS; HR =1.34; 95% CI, 0.83-2.17, P=0.232), DFS (HR =1.34; 95% CI, 0.86-2.09, P=0.202) and OS (HR =1.59; 95% CI, 0.99-2.54, P=0.055) was seen in KRAS MUT + Gain patients relative to KRAS WT + Neut/Loss patients. A negative prognostic effect of KRAS MUT + Neut/Loss was observed for LCSS (HR =1.32; 95% CI, 1.01-1.71, P=0.038) relative to KRAS WT + Neut/Loss on univariable analysis, but to a lesser extent after adjusting for covariates (HR =1.28; 95% CI, 0.97-1.68, P=0.078). KRAS MUT + Gain was associated with a greater beneficial effect of chemotherapy on DFS compared to KRAS WT + Neut/Loss patients (rHR =0.33; 95% CI, 0.11-0.99, P=0.048), with a non-significant trend also seen for LCSS (rHR =0.41; 95% CI, 0.13-1.33, P=0.138) and OS (rHR =0.40; 95% CI, 0.13-1.26, P=0.116) in the adenocarcinoma subgroup. CONCLUSIONS: A small prognostic effect of KRAS mutation was identified for LCSS, and a trend towards worse LCSS, DFS and OS was noted for KRAS MUT + Gain. A potential predictive effect of concomitant KRAS mutation and copy number gain was observed for DFS in adenocarcinoma patients. These results could be driven by the small number of patients and require validation.

DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy.

BACKGROUND: Adjuvant cisplatin-based chemotherapy improves survival among patients with completely resected non-small-cell lung cancer, but there is no validated clinical or biologic predictor of the benefit of chemotherapy. METHODS: We used immunohistochemical analysis to determine the expression of the excision repair cross-complementation group 1 (ERCC1) protein in operative specimens of non-small-cell lung cancer. The patients had been enrolled in the International Adjuvant Lung Cancer Trial, thereby allowing a comparison of the effect of adjuvant cisplatin-based chemotherapy on survival, according to ERCC1 expression. Overall survival was analyzed with a Cox model adjusted for clinical and pathological factors. RESULTS: Among 761 tumors, ERCC1 expression was positive in 335 (44%) and negative in 426 (56%). A benefit from cisplatin-based adjuvant chemotherapy was associated with the absence of ERCC1 (test for interaction, P=0.009). Adjuvant chemotherapy, as compared with observation, significantly prolonged survival among patients with ERCC1-negative tumors (adjusted hazard ratio for death, 0.65; 95% confidence interval [CI], 0.50 to 0.86; P=0.002) but not among patients with ERCC1-positive tumors (adjusted hazard ratio for death, 1.14; 95% CI, 0.84 to 1.55; P=0.40). Among patients who did not receive adjuvant chemotherapy, those with ERCC1-positive tumors survived longer than those with ERCC1-negative tumors (adjusted hazard ratio for death, 0.66; 95% CI, 0.49 to 0.90; P=0.009). CONCLUSIONS: Patients with completely resected non-small-cell lung cancer and ERCC1-negative tumors appear to benefit from adjuvant cisplatin-based chemotherapy, whereas patients with ERCC1-positive tumors do not.

Adjuvant or induction cisplatin-based chemotherapy for operable lung cancer.

Despite aggressive surgical management, 5-year survival rates of patients with non-small-cell lung cancer (NSCLC) range from 73% for those with pathologic stage IA to 25% for stage IIIA. Given the low survival rate associated with treatment by surgery alone, numerous trials have investigated the use of induction or adjuvant strategies with chemotherapy or thoracic irradiation, either alone or in combination. A meta-analysis published in 1995 showed that cisplatin-based regimens produce the best adjuvant chemotherapy results in NSCLC patients, and this finding has been validated by three large randomized trials. Neoadjuvant chemotherapy offers theoretical advantages over adjuvant chemotherapy, including improved patient compliance, a smaller primary tumor, and pathologic evaluation of treatment efficacy. However, most large randomized trials of neoadjuvant chemotherapy have failed to show statistically significant results. This article reviews the pros and cons of each strategy, current guidelines, and treatment methods that are being explored.

LACE-Bio: Validation of Predictive and/or Prognostic Immunohistochemistry/Histochemistry-based Biomarkers in Resected Non-small-cell Lung Cancer.

BACKGROUND: Complete resection of non-small-cell lung cancer (NSCLC) offers the potential for cure after surgery and adjuvant chemotherapy. Patients may not benefit and may experience severe toxicity. There are no validated molecular tools to allow better patient selection. MATERIALS AND METHODS: The LACE-Bio (LACE [Lung Adjuvant Cisplatin Evaluation]) project includes 4 trials (International Adjuvant Lung Cancer Trial [IALT], Adjuvant Navelbine International Trialist Association [ANITA], JBR10, and Cancer and Leukemia Group B (CALGB)-9633). Immunohistochemistry biomarkers shown in one trial to have a prognostic/predictive effect on overall survival were tested. RESULTS: The majority of the promising biomarkers could not be validated; the prognostic effect of tumor infiltrating lymphocytes and ß-tubulin was confirmed. Potential causes include tissue fixation, storage, the use of tissue microarrays, and varying reagent/antibody batches. CONCLUSIONS: Immunohistochemistry assays from single trials may be misleading and require validation before being used for patient selection. LACE-Bio-2 is evaluating potential genomic biomarkers that may allow more precise selection of patients with NSCLC for adjuvant chemotherapy in NSCLC.

Multidrug resistance proteins do not predict benefit of adjuvant chemotherapy in patients with completely resected non-small cell lung cancer: International Adjuvant Lung Cancer Trial Biologic Program.

PURPOSE: The purpose of our study was to determine whether multidrug resistance proteins (MRP) are of prognostic and/or predictive value in patients who were enrolled into the International Adjuvant Lung Cancer Trial (IALT). EXPERIMENTAL DESIGN: Expression of MRP1 and MRP2 was immunohistochemically assessed in tumor specimens obtained from 782 IALT patients. Prognostic and predictive analyses were based on Cox models adjusted for clinical and pathologic variables. RESULTS: MRP1 expression was considered positive in 364 (47%) patients and MRP2 expression in 313 (40%) patients. MRP2-positive patients had a significantly shorter overall survival than MRP2-negative patients in the total patient population [adjusted hazard ratio for death, 1.37; 95% confidence interval (95% CI), 1.09-1.72; P = 0.007]. There was no significant association between MRP1 expression and overall survival. Neither MRP1 nor MRP2 predicted response to adjuvant cisplatin-based chemotherapy. CONCLUSIONS: MRP2 expression is an independent prognostic factor in patients with completely resected non-small cell lung cancer but neither MRP1 nor MRP2 was of predictive value in patients enrolled into the IALT.

Genome-wide copy number analyses of samples from LACE-Bio project identify novel prognostic and predictive markers in early stage non-small cell lung cancer.

BACKGROUND: Adjuvant chemotherapy (ACT) provides modest benefit in resected non-small cell lung cancer (NSCLC) patients. Genome-wide studies have identified gene copy number aberrations (CNA), but their prognostic implication is unknown. METHODS: DNA from 1,013 FFPE tumor samples from three pivotal multicenter randomized trials (ACT vs. control) in the LACE-Bio consortium (median follow-up: 5.2 years) was successfully extracted, profiled using a molecular inversion probe SNP assay, normalized relative to a pool of normal tissues and segmented. Minimally recurrent regions were identified. P values were adjusted to control the false discovery rate (Q values). RESULTS: A total of 976 samples successfully profiled, 414 (42%) adenocarcinoma (ADC), 430 (44%) squamous cell carcinoma (SCC) and 132 (14%) other NSCLC; 710 (73%) males. We identified 431 recurrent regions, with on average 51 gains and 43 losses; 253 regions (59%) were ≤3 Mb. Most frequent gains (up to 48%) were on chr1, 3q, 5p, 6p, 8q, 22q; most frequent losses (up to 40%) on chr3p, 8p, 9p. CNA frequency of 195 regions was significantly different (Q≤0.05) between ADC and SCC. Fourteen regions (7p11-12, 9p21, 18q12, and 19p11-13) were associated with disease-free survival (DFS) (univariate P≤0.005, Q<0.142), with poorer DFS for losses of regions including CDKN2A/B [hazard ratio (HR) for 2-fold lower CN: 1.5 (95% CI: 1.2-1.9), P<0.001, Q=0.020] and STK11 [HR =2.4 (1.3-4.3), P=0.005, Q=0.15]. Chromosomal instability was associated with poorer DFS (HR =1.5, P=0.015), OS (HR =1.2, P=0.189) and lung-cancer specific survival (HR =1.7, P=0.003). CONCLUSIONS: These large-scale genome-wide analyses of gene CNA provide new candidate prognostic markers for stage I-III NSCLC.

Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer.

BACKGROUND: On the basis of a previous meta-analysis, the International Adjuvant Lung Cancer Trial was designed to evaluate the effect of cisplatin-based adjuvant chemotherapy on survival after complete resection of non-small-cell lung cancer. METHODS: We randomly assigned patients either to three or four cycles of cisplatin-based chemotherapy or to observation. Before randomization, each center determined the pathological stages to include, its policy for chemotherapy (the dose of cisplatin and the drug to be combined with cisplatin), and its postoperative radiotherapy policy. The main end point was overall survival. RESULTS: A total of 1867 patients underwent randomization; 36.5 percent had pathological stage I disease, 24.2 percent stage II, and 39.3 percent stage III. The drug allocated with cisplatin was etoposide in 56.5 percent of patients, vinorelbine in 26.8 percent, vinblastine in 11.0 percent, and vindesine in 5.8 percent. Of the 932 patients assigned to chemotherapy, 73.8 percent received at least 240 mg of cisplatin per square meter of body-surface area. The median duration of follow-up was 56 months. Patients assigned to chemotherapy had a significantly higher survival rate than those assigned to observation (44.5 percent vs. 40.4 percent at five years [469 deaths vs. 504]; hazard ratio for death, 0.86; 95 percent confidence interval, 0.76 to 0.98; P<0.03). Patients assigned to chemotherapy also had a significantly higher disease-free survival rate than those assigned to observation (39.4 percent vs. 34.3 percent at five years [518 events vs. 577]; hazard ratio, 0.83; 95 percent confidence interval, 0.74 to 0.94; P<0.003). There were no significant interactions with prespecified factors. Seven patients (0.8 percent) died of chemotherapy-induced toxic effects. CONCLUSIONS: Cisplatin-based adjuvant chemotherapy improves survival among patients with completely resected non-small-cell lung cancer.

Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study.

PURPOSE: Erlotinib has proven activity in pretreated patients with advanced non-small cell lung cancer (NSCLC). We evaluated erlotinib in the frontline treatment of advanced NSCLC and assessed biological predictors of outcome. EXPERIMENTAL DESIGN: In this phase II study, chemotherapy-naive patients with stage IIIB/IV NSCLC received oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity occurred. Tumor response was assessed every 6 weeks, and samples were analyzed for potential molecular markers of treatment response and survival. The primary end point was the proportion of patients without disease progression after 6 weeks of treatment. RESULTS: Fifty-three patients were eligible. The overall rate of nonprogression at 6 weeks was 52.8% (28 of 53 patients). Tumor response rate was 22.7%, with 1 complete response, 11 partial responses, and 16 cases of stable disease. Responses were seen across most patient clinical characteristics. The median duration of tumor response was 333 days; median overall survival was 391 days; and median time to disease progression was 84 days. Erlotinib was well tolerated, the main treatment-related adverse events being mild-to-moderate rash and diarrhea. Histologic material for biological studies was available in 29 cases. Four of five responders and one patient with stable disease had a classic epidermal growth factor receptor tyrosine kinase mutation. Two progressing patients exhibited epidermal growth factor receptor point mutations (one with T790M mutation), and K-ras mutations were detected in 10 nonresponders. CONCLUSIONS: Erlotinib shows significant antitumor activity in the first-line treatment of advanced NSCLC and may be a viable alternative to chemotherapy. Patient selection cannot easily be based on clinical or biological variables.

Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease.

BACKGROUND: Randomized trials have demonstrated that adding a drug to a single-agent or to a two-agent regimen increased the tumor response rate in patients with advanced non-small cell lung cancer (NSCLC), although its impact on survival remains controversial. OBJECTIVES: To evaluate the clinical benefit of adding a drug to a single-agent or two-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC. SEARCH STRATEGY: There were no language restrictions. Searches of MEDLINE and EMBASE were performed using the search terms non-small cell lung carcinoma/drug therapy, adenocarcinoma, large-cell carcinoma, squamous-cell carcinoma, lung, neoplasms, clinical trial phase III, and randomized trial. Manual searches were also performed to find conference proceedings published between January 1982 and June 2006. SELECTION CRITERIA: Data from all randomized controlled trials performed between 1980 and 2006 (published between January 1980 and June 2006) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, one-year survival rate, and toxicity rate were calculated using the fixed-effect model. Pooled median ratios (MRs) for median survival also were calculated using the fixed-effect model. ORs and MRs lower than unity (< 1.0) indicate a benefit of a doublet regimen compared with a single-agent regimen (or a triplet regimen compared with a doublet regimen). MAIN RESULTS: Sixty-five trials (13601 patients) were eligible. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR 0.42, 95% confidence interval [CI] 0.37 to 0.47, P < 0.001) and one-year survival (OR 0.80, 95% CI 0.70 to 0.91, P < 0.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI 0.79 to 0.89, P < 0.001). An increase also was observed in the tumor response rate (OR 0.66, 95% CI 0.58 to 0.75, P < 0.001) in favor of the triplet regimen, but not for one-year survival (OR 1.01, 95% CI 0.85 to 1.21, P = 0.88). The median survival ratio was 1.00 (95% CI 0.94 to 1.06, P = 0.97). AUTHORS' CONCLUSIONS: Adding a second drug improved tumor response and survival rate. Adding a third drug had a weaker effect on tumor response and no effect on survival.