Resected Early-stage Non-small Cell Lung Cancer Research Articles

Erythropoietin and erythropoietin receptor coexpression is associated with poor survival in stage I non-small cell lung cancer

7655 Background: The role of erythropoietin (EPO) and its receptor (EPO-R) in tumor biology is under active investigation. This study was designed to evaluate the prognostic impact of EPO and EPO-R expression in stage I non-small cell lung cancer (NSCLC) patients. Methods: EPO and EPO-R expression in 158 tumor samples from resected stage I NSCLC was evaluated using immunohistochemistry and tissue-array technology. Disease specific survival time was calculated from the date of surgery to death from cancer-related causes. Results: EPOR and EPO were highly expressed in 20.9% and 35.4% of the tumors respectively. High EPO-R compared to negative or low level of expression was associated with a poor 5-year disease specific survival (60.6% versus 80.8%, logrank test: p=0.01). High EPO compared to negative and low level of expression was associated with a trend toward a poor 5-year disease specific survival (69.6% versus 80.4%, logrank test: p=0.13). High level of EPO-R and EPO coexpression compared to other groups of patients was associated with a poor 5- year disease specific survival (50.0% versus 80.0% of survival at the end of follow-up, logrank test: p=0.005). In multivariate analysis for disease specific survival, high level of EPO-R and EPO coexpression was an independent prognostic factor for disease specific survival (HR 2.214, 95% CI: 1.012–4.848, p=0.046). Conclusions: These results establish for the first time the pejorative prognostic value of EPO and EPO-R expression in early stage resected NSCLC and suggest a potential paracrine and/or autocrine role of endogenous EPO in NSCLC aggressiveness. No significant financial relationships to disclose.

Extent of nodal dissection and patient age impact recurrence-free survival (RFS) after surgery for non-small cell lung cancer (NSCLC)

7613 Background: Factors influencing the pattern of disease relapse after curative surgical resection in early stage NSCLC is unknown. We sought to evaluate the effect of tumor- and patient-related characteristics on the pattern of disease recurrence (local relapse and/or metastatic disease) and survival in relation to surgical resection for NSCLC. Methods: A consecutive retrospective series of 488 patients seen at Mayo Clinic Rochester who had complete resection of NSCLC between 1997 and 1998 was utilized. Cox proportional hazards model was used to evaluate the effect of age, gender, smoking status, TNM stage, number of lymph node (LN) involved, number of LN resected, and histopathologic diagnosis on RFS. Logistic regression was used to evaluate the effect on recurrence or death within the first 2 years after surgical resection. Results: Data on 342 patients with a median follow-up of 85 months (range: 0.1 to 162) are reported. 60% were male, and 81% had N0 stage at diagnosis. There were 26 (7.6%) never smokers. Median number of LN resected was 20 (interquartile range [IQR]: 14–29). Median age at surgery was 71 years (IQR: 64 to 76). A bi-modal pattern of local recurrence (N=62) after surgery for early stage NSCLC was observed, with 57% of patients having a local recurrence within 2 years and 21% of patients having a local recurrence from 5–7 years post-surgery. The median duration from surgery to first documented recurrence was 16 months (IQR: 8 to 39). While age, N stage, number of LN involved, and T stage were significant predictors of RFS univariately, only lesser LN resected (p=0.008), older age (p<0.0001) and higher T-stage (p=0.003) were significant adverse predictors of RFS in the multivariate analysis when adjusted for all factors. Higher T-Stage was associated with a significantly increased risk of recurrence or death within the first 2 years after surgical resection (p =0.004). Updated results using data from all 488 patients will be presented in the meeting. Conclusions: A trend towards a bimodal distribution of local recurrences after surgical resection of early stage NSCLC was observed. Increased number of LN resected, younger age and lower T stage were associated with better RFS. No significant financial relationships to disclose.

Epidermal Growth Factor ReceptorMutation Testing in the Care of Lung Cancer Patients

As the literature about epidermal growth factor receptor (EGFR) mutations grows and screening for mutations becomes increasingly integrated into clinical care, it is important to examine how best to do somatic mutational analyses and how best to use the test results in clinical decision making. We began offering mutation screening by comprehensive direct sequence analysis of exons 18 to 24 of the tyrosine kinase domain of EGFR in August 2004 as part of clinical cancer care and protocol therapy at our institutions. All identified potential mutations are confirmed with three to five independent PCRs of the original genomic DNA sample and, if not previously noted in the literature, are compared with the patient's germ-line DNA to ensure the finding is somatic. We formally analyzed the first 100 patients to undergo EGFR sequence analysis and found that testing was feasible and significantly affected the treatment of patients with non-small cell lung cancer (NSCLC). Patients harboring EGFR mutations were significantly more likely to receive recommendations for therapy with EGFR tyrosine kinase inhibitors (i.e., gefitinib or erlotinib) than patients without mutations. However, negative EGFR test results did not prevent physicians from administering these agents to selected patients. Ideally, a standardized technique for mutation testing could be developed, with demonstrated reproducibility and validity. Clinical trials incorporating molecular diagnostics are ongoing to assess the efficacy of EGFR tyrosine kinase inhibitors as first-line therapy for metastatic NSCLC and as adjuvant therapy for early-stage resected NSCLC. It is likely that mutation testing and other molecular analyses will be most useful in these two clinical situations.

Multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of recombinant MAGE-A3 vaccine as adjuvant therapy in stage IB/II MAGE-A3-positive, completely resected, non-small cell lung cancer (NSCLC)

7019 Background: About half of the patients with completely resected early-stage NSCLC will relapse. Adjuvant chemotherapy reduces the number of relapses at the expense of substantial toxicity. Activity of MAGE-A3 vaccination (i.e. recombinant MAGE-A3 protein and a potent GSK immunological adjuvant) has been proven in advanced melanoma. As about 35% of NSCLCs express the MAGE-A3 antigen, post-operative MAGE-A3 vaccination may be a targeted, well tolerated, and effective adjuvant therapy. Methods: Patients with completely resected, MAGE-A3 positive (assessed by quantitative RT-PCR), stage pIB or pII were 2:1, double-blind, randomly assigned to postoperative MAGE-A3 vaccination or placebo. Vaccination was started ≥6 weeks after surgery, with 5 vaccinations at 3-week intervals, followed by 8 vaccinations every 3 months. Randomization was stratified for stage (IB vs. II), histology (squamous vs. other), and lymph node procedure (sampling vs. dissection). Other anti-cancer adjuvant therapy was not allowed. Primary endpoint was time-to-recurrence, other endpoints were recurrence rates at different times, and survival. A sample size of 180 patients (120 active, 60 placebo) was chosen, to achieve 48% power (α=10%) to detect a 10% difference, assuming a 40% recurrence rate at month 30 in the placebo group (log rank test). A thorough interim efficacy analysis by an independent statistician (blinded to investigators and sponsor) is planned for 18 months after completion of recruitment. Results: 35% of 1,089 biopsies from 59 sites were MAGE-A3 positive. In two years, 182 patients were randomized (121 stage IB, 61 stage II). Overall, treatment was well tolerated, with high protocol compliance. Data collection for the interim efficacy analysis was initiated on December 19th, 2005. Median follow-up was 21 months, with 62 recurrences recorded. Conclusions: This study confirms expression of MAGE-A3 antigen in 35% of early NSCLC cases, and demonstrates good tolerability of postoperative MAGE-A3 vaccination. Efficacy results of the interim analysis will be available in February 2006. [Table: see text]

Prognostic Value of Fluorodeoxyglucose Positron Emission Tomography in Non-small Cell Lung Cancer: A Review

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer morbidity and mortality. Adjuvant chemotherapy improves survival in resected early-stage NSCLC. However, a significant proportion of patients with early-stage lung cancer are cured by surgery alone. There are no reliable clinical or molecular markers to predict outcomes after surgery in early-stage NSCLC. Positron emission tomography with 2-[F]fluoro-2-deoxy-D-glucose (FDG-PET) improves the accuracy of staging work-up in NSCLC. The standardized uptake value, a commonly used semiquantitative measure of FDG uptake, correlates with tumor doubling time and indices of cell cycling. Therefore, FDG-PET may be a useful predictor of outcome independent of its role in tumor staging. In this review, we critically examine the published studies on the utility of FDG-PET as a prognostic tool in patients with NSCLC and provide direction for future research.

Adjuvant Chemotherapy for Early-Stage Non-small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related mortality in the developed world. Non-small cell lung cancer (NSCLC) represents 85% of cases of lung cancer, and patients have a poor 5-year survival rate. Approximately one third of NSCLC patients present with early-stage disease that is amenable to potentially curative resection and multimodality therapy. Several randomized trials now have confirmed the survival benefit with adjuvant platinum-based chemotherapy, as seen in the 1995 meta-analysis from the NSCLC Collaborative Group. The International Adjuvant Lung Cancer Collaborative Group Trial demonstrated a 4.5% improvement in survival for patients with stage I to III NSCLC. Studies from Japan have reported an improvement of 15.4% in the 5-year survival rate among patients with T1N0 disease after they had received adjuvant therapy with a combination of platinum and uracil-tegafur, and an improvement in the 5-year survival of 11% rate favoring chemotherapy with uracil-tegafur in a subgroup analysis of patients with T2N0 disease. Two recently published meta-analyses have estimated a relative risk reduction in mortality of 11 to 13% at 5 years. Significant improvement in the long-term survival rate has been demonstrated for patients with stage IB and II disease by the Cancer and Leukemia Group B 9633 trial (4-year survival rate, 12%) and the The National Cancer Institute of Canada Clinical Trials Group BR.10 trial (5-year survival rate, 15%; risk reduction for recurrence, 40%). Thus, there is compelling evidence to now recommend adjuvant platinum-based combination chemotherapy for patients after resection of early-stage NSCLC.

Patient Subsets Benefiting from Adjuvant Therapy Following Surgical Resection of Non–Small Cell Lung Cancer

Adjuvant chemotherapy is the standard of therapy for some patients with stages I, II, and III breast and colon cancer. The therapeutic efficacy of adjuvant chemotherapy following surgical resection of early stage non-small cell lung cancer (NSCLC) has been less clear. A meta-analysis was reported in 1995 of patients who underwent surgical resection for early stage NSCLC and were then randomized to either observation or chemotherapy. This meta-analysis showed a 13% reduction in the hazard ratio of death, leading to a 5% absolute improvement in survival 5 years after the start of adjuvant cisplatin-based chemotherapy treatment compared with observation only. Multiple prospective randomized trials for patients with NSCLC were planned and undertaken to attempt to validate the observations of the meta-analysis. Six trials with > or =150 patients with early stage NSCLC (stages I-IIIA) on each arm have been reported in the last 2 years. Four of the six trials show a survival advantage for the patients with early stage NSCLC treated with adjuvant chemotherapy compared with those who underwent observation. The survival benefit in these four studies varies from a 4% to a 16% survival advantage at 4 to 5 years after the start of chemotherapy. The hazard ratio of death for the patients treated with chemotherapy ranged from 0.61 to 0.86 compared with patients on observation. Thus, the information available at the current time supports the administration of chemotherapy for patients with stages IB and II NSCLC. Further research will be needed to define the role of adjuvant chemotherapy and its use in conjunction with chest radiotherapy for the treatment of patients with resected stages IA and IIIA NSCLC.

Mutational profiling of the oncogenome in non-small cell lung cancer (NSCLC)

7021 Background: Cancers arise from a multistage process during which tumor cells acquire activating mutations in proto-oncogenes and inactivating mutations in tumor suppressor genes. In NSCLC, somatic mutations have been detected in genes such as EGFR, HER2, PIK3CA, BRAF, KRAS, and p53. Two of these mutations are now known to have direct clinical relevance; mutations in the EGFR tyrosine kinase domain are associated with tumor responses to targeted therapies such as gefitinib and erlotinib (Lynch et al, NEJM ’04, Paez et al, Science ’04, Pao et al, PNAS ’04), while KRAS mutations are found in tumors refractory to these agents (Pao et al, PLoS Med ‘05). Moreover, EGFR and KRAS mutations are mutually exclusive (Shigematsu et al, JNCI ‘04). To identify new predictors of response as well as novel targets for therapy, we have initiated a comprehensive large-scale re-sequencing analysis of genes potentially mutated in NSCLC, i.e. the NSCLC oncogenome. Methods: Genomic DNA was extracted from 188 early-stage resected untreated NSCLCs. All tumors were obtained on IRB-approved protocols and with patients’ consent. High-throughput PCR-based re-sequencing was performed on a high priority list of ∼100 genes, with particular focus on genes in the ERBB signaling pathway. Results: Thus far, 110 tumors have been analyzed for EGFR (exons 2–28) and KRAS2 (exons 1–6) mutations. 11 tumors (10%) had EGFR mutations (exons 19 and 21), while 19 (17%) had KRAS mutations (exon 2). EGFR and KRAS mutations were mutually exclusive. No mutations were identified among 11 never smokers analyzed for changes in FLT3 (exons 2–24). Conclusions: Mutational profiling of NSCLC can distinguish clinically relevant molecular subsets of lung cancer, and may reveal novel targets for therapy. Further re-sequencing of the NSCLC oncogenome is in progress. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech AstraZeneca AstraZeneca

The Role of Adjuvant Chemotherapy for Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the United States. Patients with early stage NSCLC have a reasonable chance of cure with surgery, but unfortunately, fewer than half of all newly diagnosed NSCLC patients are surgical candidates. In addition, less than half of all patients treated with surgical resection alone are ultimately cured of their disease. As a result, several studies have emerged over the past decade examining the role of adjuvant chemotherapy as a means of improving outcomes in early-stage NSCLC. This article highlights the background and rationale, as well as the major findings, of each of these studies, namely, the British Medical Journal meta-analysis, the Adjuvant Lung Project Italy study, the Japanese Lung Cancer Research Group study, the International Adjuvant Lung Cancer Trial, the Cancer and Leukemia Group B 9633 study, and the JBR.10 study. From these collective studies, a new standard of care has emerged in the treatment of early-stage resected NSCLC: the use of adjuvant platinum-based chemotherapy.

Adjuvant and neoadjuvant therapy in non-small cell lung cancer

The 5-year survival rates for patients with non-small cell lung cancer (NSCLC) ranges from 9% to 61% following resection, depending on clinical stage; survival rates post-surgery (pathologic stage) range from 25% to 67%. Most stage I and II patients eventually experience recurrent disease: two thirds occur systemically, one third locally. Surgical resection remains the standard of care in early stage NSCLC, although the role of surgery in stage IIIA [N 2 ] disease is controversial. Despite resection, the vast majority of lung cancer patients will experience recurrent and/or metastatic disease; therefore, supplementing surgery with adjuvant therapy is a rational treatment strategy. Recent data indicate that adjuvant chemotherapy should now be considered the standard of care for the treatment of patients with completely resected early stage NSCLC, with the single exception of patients with stage IA disease, where the prognosis is relatively favorable and there is currently no evidence supporting the efficacy of adjuvant therapy. While recent data from trials of adjuvant chemotherapy have shown promising results, no study has yet compared the utility of adjuvant versus neoadjuvant, or induction, chemotherapy. From the current data, more than 90% of patients receiving neoadjuvant chemotherapy undergo the planned surgical resection. Neoadjuvant chemotherapy may also downstage the disease before surgery and decrease perioperative tumor seeding, and molecularly targeted approaches with neoadjuvant therapy appear promising.

Tumour CEA as predictor of better outcome in squamous cell carcinoma of the lung

High levels of serum carcinoembryonic antigen (S-CEA) are considered a negative prognostic factor in non-small-cell lung cancer (NSCLC), while the prognostic value of tumour CEA (T-CEA) is unknown. We investigated the prognostic role of T-CEA in radically resected early stage NSCLC. We measured preoperative S-CEA levels and T-CEA in 146 patients with stage 1-2 NSCLC, and analysed their influence on survival. In patients positive for T-CEA, 3-year survival was 80%, compared to 65% in T-CEA-negative patients (p=0.03). After stratification by histology, T-CEA positivity was prognostic of better survival in squamous cell carcinoma (SCC) (p=0.024) but not in adenocarcinomas (ADK) (p=0.87). Multiple Cox regression analysis showed that T-CEA positivity was an independent predictor of better survival in patients with early stage NSCLC (p=0.02). In SCC patients, the magnitude of the hazard ratio was confirmed even if the precision of the estimate is decreased (p=0.06). In conclusion, T-CEA expression appears to be an important prognostic factor in early stage SSC of the lung.

Adjuvant therapy for resected non-small-cell lung cancer: recent advances, emerging agents, and lingering questions.

Survival rates for all stages of non-small-cell lung cancer (NSCLC) are dismal. Despite complete resection of early-stage NSCLC, many patients have recurrence at distant metastatic sites, reinforcing the need for effective systemic adjuvant therapy. Chemotherapy, and more recently, targeted therapies, have been evaluated in the adjuvant setting. Although initial trials did not suggest improved survival, a 1995 meta-analysis favored adjuvant cisplatin-based chemotherapy. The recently published International Adjuvant Lung Trial confirms this finding and suggests a new standard of care. In this paper we review data on adjuvant chemotherapy and limitations of recent clinical trials, including those with targeted therapies. We also address the most effective and least toxic regimens for adjuvant chemotherapy and the subsets of patients likely to derive the most benefit.

Adjuvant chemotherapy after complete resection for early stage NSCLC

Less than 20–25% of non-small cell lung cancer (NSCLC) patients present with stage I or II disease are best treated by surgical resection. Long-term survival in NSCLC remains poor also in these early stages: the 5-year survival rate of patients who undergo complete surgical resection is only 40 to 50%. The majority of post-surgical relapses are distant metastases with the risk of a local recurrence after complete resection being less than 10%. Postoperative treatments, including chemotherapy, radiotherapy or both, have been widely evaluated during the last decades and, unfortunately, none has demonstrated any significant impact on survival. Data regarding large-scale adjuvant chemotherapy trials, closed for the accrual almost four to five years ago, will be fully available soon and, hopefully, a specific meta-analysis will be performed.

Multidetector-row CT of lung cancer screening.

L UNG CANCER IS currently the most common cause of cancer death in men and women in the United States. ~,2 Despite the development of effective multimodality treatments, mortality from primary lung cancer has continued to rise over the past 3 decades; approximately 85% of those who develop lung cancer die from i t) More Americans die from lung cancer than colon, breast, and prostate cancers combined. Small-cell lung cancer accounts for approximately 25% of lung cancers. Small-cell lung cancer is usually a systemic disease at initial presentation because of its aggressive nature with early dissemination throughout the body. Outcome is not improved by screening. Non-small-cell lung cancer (NSCLC) accounts for approximately 75% of all lung cancers. The prognosis in patients with NSCLC follows surgical stage at the time of diagnosis. Overall, 5-year survival from lung cancer remains less than 15%3; however, patients with surgically resected early-stage NSCLC have 5-year survival rates of up to 70% or more. 4 Five-year survival in a cohort of 598 patients with surgically resected stage I tumors was recently reported as 75%; however, when stratified by TNM tumor classification, patients with T1 tumors fared better than those with T2 tumors, with 5-year survival rates of 82% and 68%, respectively. 4,5 Small tumor size at time of diagnosis and treatment is associated with longer survival, particularly when tumors are less than 1 cm in diameter. This improvement in survival forms the primary rationale for the early detection of lung cancer using multidetector computed tomography (MDCT) screening.

Irinotecan in non-small-cell lung cancer: status of ongoing trials.

Irinotecan possesses significant single-agent activity in non-small-cell lung cancer (NSCLC) and is active in combination with either cisplatin or carboplatin. Two phase III trials completed in Japan have suggested that the combination of irinotecan/cisplatin yields superior survival rates in stage IV NSCLC patients compared to vindesine/cisplatin. The principal toxicities of the irinotecan/cisplatin regimen are neutropenia and diarrhea. This regimen is currently being tested in Japan against regimens commonly used in the United States, such as cisplatin/gemcitabine, cisplatin/vinorelbine, and carboplatin/paclitaxel. These studies include evaluation of monthly as well as weekly schedules of cisplatin in combination with irinotecan as well as a triplet regimen of irinotecan/carboplatin/paclitaxel. Ongoing trials are evaluating these regimens as well as irinotecan/carboplatin and several nonplatinum-based irinotecan-containing doublets in both the first- and second-line treatment of advanced NSCLC. Several ongoing trials are attempting to integrate irinotecan with thoracic radiation therapy in stage III NSCLC. These trials are using irinotecan-containing regimens as induction and concurrent therapy with thoracic radiation therapy. Irinotecan is also being evaluated in the preoperative setting in early-stage resectable NSCLC. Many of these trials are also incorporating celecoxib, a potent inhibitor of the cyclooxygenase-2 pathway, in combination with irinotecan-containing regimens in both advanced as well as early-stage NSCLC. Future trials should focus on the integration of the new targeted agents in combination with irinotecan-containing regimens in all stages of NSCLC.

Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer.

The aim of this study was to investigate the prognostic importance of codon 12 K-ras mutations in patients with early-stage non-small-cell lung cancer (NSCLC). We identified 260 patients with surgically resected stage I (n = 193) and stage II (n = 67) NSCLC with at least a 5-year follow-up. We performed polymerase chain reaction analysis of DNA obtained from paraffin-embedded NSCLC tissue, using mutation-specific probes for codon 12 K-ras. K-ras mutations were detected in 35 of 213 assessable specimens (16.4%). K-ras mutations were detected in 27 of 93 adenocarcinomas (29.0%), one of 61 squamous cell carcinomas (1.6%), five of 39 large-cell carcinomas (12.8%), and two of 20 adenosquamous carcinomas (10%) (P = .001). G to T transversions accounted for 71% of the mutations. There was no statistically significant difference in overall survival for all patients with K-ras mutations (median survival, 39 months) compared with patients without K-ras mutations (median survival, 53 months; P = .33). There was no statistically significant difference in overall or disease-free survival for subgroups with stage I disease, adenocarcinoma, or non-squamous cell carcinoma or for specific amino acid substitutions. The median survival time for stage II patients with K-ras mutations was 13 months, compared with 38 months for patients without K-ras mutations (P = .03). Codon 12 K-ras mutations were more common in adenocarcinomas than in squamous cell carcinomas. For the subgroup with stage II NSCLC, there was a statistically significant adverse effect on survival for the presence of K-ras mutations. However, when the entire group was considered, the presence of K-ras mutations was not of prognostic significance in this cohort of patients with resected early-stage NSCLC.

Cyfra 21-1 as a Biologic Marker of Non-small Cell Lung Cancer: Evaluation of Sensitivity, Specificity, and Prognostic Role

<i>Background:</i> Cytokeratins are epithelial markers whose expression is not lost during malignant transformation. Cyfra 21-1 is a cytokeratin-19 fragment that is soluble in serum and may be a useful circulating tumor marker. <i>Study objective:</i> The aims of this study were (1) to confirm sensitivity and specificity of Cyfra 21-1 in detecting non-small cell lung cancer (NSCLC) and especially the squamous cell subtype, (2) to assess the potential relationship between Cyfra 21-1 and disease stage of the disease in NSCLC, and (3) to evaluate prognostic effect of Cyfra 21-1 in NSCLC. <i>Methods:</i> An immunoradiometric assay of serum Cyfra 21-1 was performed in 161 patients with lung cancers and 71 others with benign lung diseases. The ability of Cyfra 21-1 to detect different histologic subtypes of lung cancer vs benign lung diseases was assessed through receiver operating characteristic (ROC) curves and comparisons with other tumor markers such as carcinoembryonic antigen, neuron-specific enolase, and squamous cell carcinoma antigen. Comparisons of Cyfra 21-1 levels according to histologic subtype and disease stage were done using Kruskal-Wallis test. Independent prognostic value of Cyfra 21-1 was studied with a multivariate analysis of survival (Cox's model). <i>Results:</i> Using a threshold of 3.3 ng/mL for Cyfra 21-1, sensitivity and specificity were, respectively, 0.59 and 0.94 in NSCLC, 0.68 and 0.94 in the subgroup of the squamous cell carcinoma, and 0.19 and 0.94 in small cell lung cancer. Cyfra 21-1 levels were significantly higher in advanced NSCLC than in early-stage disease. All 29 patients with serum concentrations >32 ng/mL had stage IIIB-IV and only one of 14 patients with stage I-II disease had Cyfra 21-1 level >18 ng/mL. In the multivariate analysis of survival, Cyfra 21-1 was an independent prognostic factor along with performance status and disease stage in NSCLC. <i>Conclusions:</i> Cyfra 21-1 is a sensitive and specific tumor marker of NSCLC, especially of squamous cell subtype. It also reflects the extent of the disease and has an independent prognostic role along with performance status and disease stage in NSCLC. <i>Implications:</i> A high level of Cyfra 21-1 in apparently early-stage NSCLC should be an indication for more extensive workup before thoracotomy. The independent prognostic role of Cyfra 21-1 level may be useful in stratifying populations with advanced NSCLC or early-stage resected NSCLC as elevated Cyfra 21-1 levels might identify those patients at high risk for treatment failure.