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Background: Targeted therapies for advanced non-small cell lung cancer (NSCLC) with oncogenic drivers have caused a paradigm shift in care. Biomarker testing is needed to assess eligibility for these therapies. Pulmonologists often perform bronchoscopy, providing tissue for both pathologic diagnosis and biomarker analysis. We performed this survey to define the existing knowledge and practices regarding the pulmonologists' role in biomarker testing for advanced NSCLC., Research Question: What is the current knowledge and practice of pulmonologists regarding biomarker testing and targeted therapies in advanced NSCLC?, Study Design and Methods: This cross-sectional study was performed using an electronic survey of a random sample of 7,238 pulmonologists. Questions focused on diagnostic steps and biomarker analyses for NSCLC., Results: A total of 453 pulmonologists responded. Respondents vary by reported lung cancer patient volume, ranging from 51% evaluating one to four new cases per month to 19% evaluating > 10 cases per month. Interventional training, academic practice setting, and higher volume of endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) were associated with increased knowledge of practice guidelines for the number of recommended passes during EBUS-TBNA (P < .05). Academic pulmonologists more commonly performed or referred for EBUS-TBNA than community pulmonologists (96% and 83%, respectively; P < .0005). Higher testing rates were associated with interventional training, academic setting, and the presence of an institutional policy, whereas lower testing rates were associated with general pulmonologists, practice in community settings, and lack of a guiding institutional policy (P < .05)., Interpretation: Substantial differences among pulmonologists' evaluation of advanced NSCLC, variation in knowledge of available biomarkers and the importance of targeted therapies, and differences in institutional coordination likely lead to underutilization of biomarker testing. Interventional training appears to drive improved knowledge and practice for biomarker testing more than practice setting. Improvements are needed in tissue acquisition and interdisciplinary coordination to ensure universal and comprehensive testing for eligible patients., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: This phase I/II trial was designed to determine the maximally tolerated dose of thoracic radiotherapy as part of a combined modality approach. This report includes the long-term outcomes of patients treated on this study. The phase II portion was never completed, as RTOG-0617 opened before it was concluded., Methods: In this study, the maximally tolerated dose was defined as 74 Gy of radiation in 37 fractions. Twenty-five patients with unresectable NSCLC were treated with 2-Gy daily fractions and concurrent weekly carboplatin and paclitaxel. Of these patients, 20 had stage III disease and five had stage I or II disease., Results: Patients were followed until death or for a minimum of 5 years in the case of survivors. The median and 5-year survivals were 42.5 months and 20% for all patients, 52.9 months and 40% in patients with stages I or II disease, and 39.8 months and 15% in patients with stage III disease., Conclusions: The median survival of the stage III patients was quite favorable. We believe that this may have been due to a robust central review program of radiotherapy plans before treatment, ensuring compliance with protocol guidelines along with very low exposure of the heart to radiotherapy. Further improvements in 5-year survival will likely require research on both systemic therapy and thoracic radiotherapy. Potential therapeutic modalities that may aid in these efforts include immunotherapy, targeted therapy, improved imaging, adaptive radiotherapy, simultaneous integrated boost techniques, novel dose fractionation regimens, and charged particle therapy., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Although preoperative chemotherapy (cisplatin-etoposide) and radiotherapy, followed by surgical resection, is considered a standard of care for superior sulcus cancers, treatment is rigorous and relapse limits long-term survival. The Southwest Oncology Group-Intergroup Trial S0220 was designed to incorporate an active systemic agent, docetaxel, as consolidation therapy., Methods: Patients with histologically proven and radiologically defined T3 to 4, N0 to 1, M0 superior sulcus non-small cell lung cancer underwent induction therapy with cisplatin-etoposide, concurrently with thoracic radiotherapy at 45 Gy. Nonprogressing patients underwent surgical resection within 7 weeks. Consolidation consisted of docetaxel every 3 weeks for 3 doses. The accrual goal was 45 eligible patients. The primary objective was feasibility., Results: Of 46 patients registered, 44 were eligible and assessable; 38 (86%) completed induction, 29 (66%) underwent surgical resection, and 20 (45% of eligible, 69% surgical, and 91% of those initiating consolidation therapy) completed consolidation docetaxel; 28 of 29 (97%) underwent a complete (R0) resection; 2 (7%) died of adult respiratory distress syndrome. In resected patients, 21 of 29 (72%) had a pathologic complete or nearly complete response. The known site of first recurrence was local in 2, local-systemic in 1, and systemic in 10, with 7 in the brain only. The 3-year progression-free survival was 56%, and 3-year overall survival was 61%., Conclusions: Although trimodality therapy provides excellent R0 and local control, only 66% of patients underwent surgical resection and only 45% completed the treatment regimen. Even in this subset, distant recurrence continues to be a major problem, particularly brain-only relapse. Future strategies to improve treatment outcomes in this patient population must increase the effectiveness of systemic therapy and reduce the incidence of brain-only metastases., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: EarlyCDT(®)-Lung may enhance detection of early stage lung cancer by aiding physicians in assessing high-risk patients through measurement of biological markers (i.e., autoantibodies). The test's performance characteristics in routine clinical practice were evaluated by auditing clinical outcomes of 1613 US patients deemed at high risk for lung cancer by their physician, who ordered the EarlyCDT-Lung test for their patient., Methods: Clinical outcomes for all 1613 patients who provided HIPAA authorization are reported. Clinical data were collected from each patient's treating physician. Pathology reports when available were reviewed for diagnostic classification. Staging was assessed on histology, otherwise on imaging., Results: Six month follow-up for the positives/negatives was 99%/93%. Sixty-one patients (4%) were identified with lung cancer, 25 of whom tested positive by EarlyCDT-Lung (sensitivity=41%). A positive EarlyCDT-Lung test on the current panel was associated with a 5.4-fold increase in lung cancer incidence versus a negative. Importantly, 57% (8/14) of non-small cell lung cancers detected as positive (where stage was known) were stage I or II., Conclusions: EarlyCDT-Lung has been extensively tested and validated in case-control settings and has now been shown in this audit to perform in routine clinical practice as predicted. EarlyCDT-Lung may be a complementary tool to CT for detection of early lung cancer., (Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

The treatment of advanced non-small cell lung cancer has been with systemic chemotherapy and usually consists of a platinum doublet chemotherapy. The identification of somatic driver mutations has resulted in new drugs that target these mutations. This report discusses the two most important new targeted therapy drugs for the treatment of advanced non-small cell lung cancer that have these driver mutations.

Background: In an effort to evaluate the single agent activity of temsirolimus in previously untreated non-small-cell lung cancer, the North Central Cancer Treatment Group undertook a frontline "window-of-opportunity" study., Methods: Patients received 25 mg of temsirolimus administered intravenously as a weekly 30 minute infusion, on a 4-week cycle. Based on a two-stage Fleming design, the treatment would be promising if at least four of the first 25 evaluable patients in stage I or at least six of the 50 evaluable patients at the end of stage II have a confirmed response. Fresh tumor biopsies were obtained to evaluate predictive markers of temsirolimus activity., Results: A total of 55 patients were enrolled with 52 patients being evaluable. The median age was 64 years. Adverse events (grade 3/4) occurring in 33 patients included dyspnea (12%), fatigue (10%), hyperglycemia (8%), hypoxia (8%), nausea (8%), and rash/desquamation (6%). The clinical benefit rate was 35% with four patients achieving a confirmed partial response and 14 patients with stable disease for 8 weeks or more. The 24-week progression-free survival rate was 25%. Median progression-free survival and overall survival were 2.3 and 6.6 months, respectively. Expression of p70s6 kinase, phospho-p70s6 kinase, Akt, phospho-Akt, and phosphatase and tensin homolog mutation did not correlate with clinical outcome., Conclusions: Temsirolimus given as a single agent in frontline therapy in patients with non-small-cell lung cancer was tolerable and demonstrated clinical benefit but did not meet the primary objective in this study. Patient selection will be needed to enhance the efficacy.

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., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Autoantibody profiling is a developing approach that incorporates immune recognition of myriad aberrant cancer proteins into a single diagnostic assay. We have previously described methodology to screen T7-phage NSCLC-cDNA libraries for phage-expressed proteins recognized by NSCLC-associated antibodies, and developed a multiplex assay that has excellent ability to discriminate NSCLC from control samples. This follow-up report describes the development and testing of a diagnostic autoantibody assay that uses seven amino-acid peptides as capture proteins. A random-peptide M13-phage library was screened for proteins recognized by cancer-associated antibodies. One hundred twenty-one NSCLC case and control samples were divided into two groups for training and validation, or alternately, evaluated sequentially in a leave-one-out analysis. Candidate antibody-markers were ranked by statistical discrimination between cases and controls. Receiver-Operating-Characteristic (ROC-AUC) suggested the predictive potential of various marker combinations. A five-marker combination (AUC = 0.982) afforded 90% sensitivity and 73% specificity in a training-and-testing strategy. Leave-one-out validation provided similar class prediction. Data confirm the potential of antibody profiling to provide high levels of cancer prediction. Random peptide libraries offer a universal source of capture proteins for antibody profiling that obviates the need for tumor-specific library construction and abrogates inherent problems with tumor heterogeneity during biomarker discovery.

Purpose of Review: Considerable advances in genomics, transcriptomics and proteomics have in the recent years transformed our understanding of the molecular mechanisms involved in the pathogenesis of lung cancer and are in the process of revolutionizing our approach to its diagnosis and treatment. Although these techniques have traditionally been described in the context of large volume biopsies from surgically resected tumors, significant technical advances allow their application to smaller samples obtained bronchoscopically, often the only samples available in advanced lung cancer., Recent Findings: Recent data support the use of advanced molecular techniques as an adjunct to conventional histologic examinations of bronchoscopy specimens in the following situations: early diagnosis and screening of nonsmall cell lung cancer by fluorescent in-situ hybridization techniques in particular; accurate histologic diagnosis via novel immunohistochemistry markers; and prognosis and prediction of response to targeted and conventional chemotherapeutic agents., Summary: Molecular biology techniques are increasingly applied to smaller biopsy specimens obtained via bronchoscopy, allowing for their use in advanced, unresectable nonsmall cell lung cancer. Although these techniques have not yet entered the clinical practice arena, they will likely become an unavoidable complement to conventional morphologic examinations and allow for individualized diagnostic and therapeutic approach to lung-cancer patients.

Introduction: We evaluated the role of glutathione-related genotypes on overall survival, time to progression, adverse events, and quality of life (QOL) in stage IIIB/IV non-small cell lung cancer patients who were stable or responding from initial treatment with platinum-based chemotherapy and subsequently randomized to receive daily oral carboxyaminoimidazole or a placebo., Methods: Of the 186 total patients, 113 had initial treatment with platinum therapy and DNA samples of whom 46 also had QOL data. These samples were analyzed using six polymorphic DNA markers that encode five important enzymes in the glutathione metabolic pathway. Patient QOL was assessed using the Functional Assessment of Cancer Therapy-Lung and the UNISCALE QOL questionnaires. A clinically significant decline in QOL was defined as a 10% decrease from baseline to week-8. Multivariate analyses were used to evaluate the association of the genotypes on the four endpoints., Results: Patients carrying a GCLC 77 genotype had a worse overall survival (hazard ratio (HR) = 1.5, p = 0.05). Patients carrying the GPX1-CC genotype had a clinically significant decline in the UNISCALE (odds ratio (OR): 7.5; p = 0.04), total Functional Assessment of Cancer Therapy-Lung score (OR: 11.0; p = 0.04), physical (OR: 7.1; p = 0.03), functional (OR: 5.2; p = 0.04), and emotional well-being constructs (OR: 23.8; p = 0.01)., Conclusions: Genotypes of glutathione-related enzymes, especially GCLC, may be used as host factors in predicting patients' survival after platinum-based chemotherapy. GPX1 may be an inherited factor in predicting patients' QOL. Further investigation to define and measure the effects of these genes in chemotherapeutic regimens, drug toxicities, disease progression, and QOL are critical.

Objective: Patients with schizophrenia sometimes receive substandard medical care. This study explored such disparities among lung cancer patients with underlying schizophrenia., Methods: This retrospective study focused on patients with pre-existing schizophrenia (or in some instances schizoaffective disorder) and a lung cancer diagnosis made between 1980 and 2004. 'Disparity' was defined as a patient's having been prescribed less aggressive therapy for a potentially curable cancer based on state-of-the-art treatment standards for the time and for the cancer stage. Qualitative methods were used to assess healthcare providers' decision-making., Results: 29 patients were included. The median age was 59 years; 38% were men. Twenty-three had non-small cell lung cancer and 6 small cell lung cancer; 17 had potentially curable cancers. Five of 17 had a 'disparity' in cancer care: (1) no cancer therapy was prescribed because of chronic obstructive pulmonary disease; (2) no cancer therapy was prescribed because of infection; (3) no chemotherapy was prescribed because the patient declined it; radiation was provided; (4) no chemotherapy was prescribed because of the patient's schizophrenia symptoms; radiation was administered; and (5) no surgery was performed because of disorientation from a lobotomy; radiation was prescribed. Comments from healthcare providers suggest reflection and ethical adjudication in decision-making., Conclusion: Schizophrenia was never the sole reason for no cancer treatment in patients with potentially curable lung cancer. This study provides the impetus for others to begin to assess the effect of schizophrenia on lung cancer management in other healthcare settings., ((c) 2007 John Wiley & Sons, Ltd.)

Purpose: This study assessed whether maintenance therapy with carboxyaminoimidazole (CAI), compared to placebo, prolonged overall survival in stage IIIB/IV NSCLC patients who had tumour regression or stable disease after treatment with one chemotherapy regimen., Methods: After completion of chemotherapy, patients were randomized to receive daily oral CAI at 250mg or placebo. Treatment continued until patient refusal, disease progression or unacceptable adverse event (AE). Quality of life (QOL) was assessed by UNISCALE and Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L)., Results: Registration was halted early for slow accrual (targeted 360, randomized 186: 94 CAI, 92 placebo). All patients were off active treatment at time of analyses. Non-haematologic AEs (primarily grade 1, 2) observed significantly more often in the CAI group included fatigue (54.5% versus 29.3%), anorexia (31.1% versus 13.0%), nausea (62.2% versus 30.4%), vomiting (32.2% versus 14.1%), neurosensory (60.0% versus 44.6%) and ataxia (33.3% versus 16.3%). Patients discontinued treatment for AEs, death on study or refusal more often in the CAI group (36.0% versus 8.7%, p<0.0001). No significant differences in survival or time to progression were observed (median: CAI versus placebo: 11.4 months versus 10.5 months, log rank p=0.54; 2.8 months versus 2.4 months, log rank p=0.50). More patients receiving CAI reported a clinically significant (10-point) decline in QOL particularly on the functional (58% versus 37%, p=0.05) construct of FACT-L and UNISCALE (72% versus 51%, p=0.04)., Conclusion: The addition of CAI following chemotherapy does not provide clinical benefit or improvement in QOL over placebo in advanced NSCLC.

Objective: To develop evidence-based guidelines on best available treatment options for patients with stage IIIB non-small cell lung cancer (NSCLC)., Methods: A review was conducted of published English-language (abstract or full text) phase II or phase III trials and guidelines from other organizations that address management of the various categories of stage IIIB disease. The literature search was provided by the Duke University Center for Clinical Health Policy Research and supplemented by any additional studies known by the authors., Results: Surgery may be indicated for carefully selected patients with T4N0-1M0. Patients with N3 nodal involvement are not considered to be surgical candidates. For individuals with unresectable disease, good performance score, and minimal weight loss, treatment with combined chemoradiotherapy results in better survival than radiotherapy (RT) alone. Concurrent chemoradiotherapy seems to be associated with improved survival compared with sequential chemoradiotherapy. Multiple daily fractions of RT when combined with chemotherapy have not been shown to result in improved survival compared with standard once-daily RT combined with chemotherapy. The optimal chemotherapy agents and the number of cycles of treatment to combine with RT are uncertain., Conclusion: Prospective trials are needed to answer important questions, such as the role of induction therapy in patients with potentially resectable stage IIIB disease. Future trials are needed to answer the questions of optimal chemotherapy agents and radiation fractionation schedule. The role of targeted novel agents in combination with chemoradiotherapy is just starting to be investigated.

Background: The objective of this study was to assess the value of combined-modality therapy in elderly patients by comparing the differences in outcome between patients who received radiotherapy (RT) alone and patients who received RT plus chemotherapy for stage III nonsmall cell lung cancer (NSCLC)., Methods: The North Central Cancer Treatment Group performed 2 recent Phase III trials for stage III NSCLC. The first trial, NCCTG 90-24-51, included 3 arms: once-daily RT (QDRT) alone, twice-daily RT (BIDRT) alone, and concurrent chemotherapy plus BIDRT. The second trial, NCCTG 94-24-52, included 2 arms and compared concurrent chemotherapy with either QDRT or BIDRT. The chemotherapy arms of both trials included etoposide and cisplatin administered concurrently with RT. Only the patients aged >/=65 years (elderly) who participated in those trials were included in this analysis., Results: Of the 166 elderly patients who were included in this analysis, 37 patients received RT alone, and 129 patients received concurrent chemotherapy plus RT. The median and 5-year survival rates were 10.5 months and 5.4% for the RT alone group compared with 13.7 months and 14.7% for the RT plus chemotherapy group (log-rank P = .05). Patients who received RT plus chemotherapy experienced significantly greater severe toxicity (grade >/=3) compared with patients who received RT alone (89.9% vs 32.4%; P < 0.01)., Conclusions: Elderly patients who participated in these trials appeared to gain a survival advantage from RT and chemotherapy compared with RT alone. As is the case with younger patients, this benefit came at the cost of additional toxicity.

Purpose: To evaluate the combination of sorafenib and gefitinib in patients with advanced non-small cell lung cancer., Experimental Design: In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21 days followed by a 7-day washout with crossover to the other agent for an additional 21 days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed., Results: Thirty-one patients were treated (n=12, part A; n=19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib C(max) (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n=8, part A; n=12, part B) had stable disease >or=4 months. The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily., Conclusions: Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non-small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.

Background: Fluorodeoxyglucose positron emission tomography (FDG-PET) is sensitive for detection of neoplastic solitary pulmonary nodules but may have decreased sensitivity for detection of carcinoid tumors. Our purpose was to determine the sensitivity of FDG-PET to detect pulmonary carcinoid tumors., Methods: We performed a retrospective review of our institutional results regarding FDG-PET in the setting of thoracic carcinoid neoplasms. We identified 16 patients with a pathologic diagnosis of bronchial carcinoid who had an antecedent FDG-PET (from 2000 to 2004). All patients but one presented with pulmonary nodule(s)., Results: Sixteen patients had a diagnosis of carcinoid tumor, typical in 11 patients and atypical in 5 patients. The mean greatest pathologic dimension was 2.08 cm (range, 1.0 to 8.3 cm). Overall positron emission tomography (PET) sensitivity was 75% (12 true-positive and 4 false-negative results). The mean (+/- SD) size of carcinoids with false-negative PET results was not significantly different from carcinoids with true-positive results (1.6 +/- 0.81 cm and 2.35 +/- 1.87 cm, p = 0.54). Fifteen of 16 patients were staged pathologically, and positive nodes were found in 2 of these patients. PET lymph node staging agreed with pathologic staging in one stage 4 patient with positive lymph nodes and distant metastasis, but PET results were false negative in the other patient who had N2 with micrometastatic disease; stage IIIA., Conclusions: FDG-PET imaging is useful for evaluation of typical and atypical thoracic carcinoid tumors. Although overall PET sensitivity for detection of carcinoid tumors is somewhat reduced as compared to non-small cell lung cancer, it is much higher than prior reports suggest.

In the United States, lung cancer kills more men and woman than the next three most common cancers combined. Unfortunately, the long-term outcome of lung cancer is still dismal with a 5-year survival rate of 15%. However, significant improvements in median survival times and 1-year and 2-year survival rates have been achieved in the last decade. This progress has been accomplished not only because of better surgical techniques but also because of the use of platinum-based regimens with newer chemotherapy agents and, more recently, targeted therapy. The role of chemotherapy as an integral part of the treatment of lung cancer has expanded significantly, particularly in the last few years with the proven benefit of adjuvant chemotherapy. For advanced stage non-small cell lung cancer (NSCLC), chemotherapy prolongs survival and improves quality of life in patients with good performance status, and appears to provide symptomatic improvement in patients with decreased performance status. Platinum-based doublet chemotherapy regimens are now the standard of care in patients with advanced stage NSCLC, and non-platinum-based combination therapies are reasonable alternatives in certain populations. The combination of the vascular endothelial growth factor inhibitor bevacizumab and chemotherapy has proven to prolong survival. As agents such as monoclonal antibodies, small molecules inhibitors of tyrosine kinase, and direct inhibitors of proteins involved in lung cancer proliferation are being developed and tested, we are optimistic that these agents will result in improvement in the survival and quality of life of lung cancer patients.

Background: A pooled analysis was performed to examine the impact of pretreatment factors on overall survival (OS) and time to progression (TTP) in patients with advanced-stage nonsmall cell lung cancer (NSCLC) and to construct a prediction equation for OS using pretreatment factors., Methods: A pooled data set of 1053 patients from 9 North Central Cancer Treatment Group trials was used. Age, gender, Eastern Cooperative Oncology Group performance status (PS), tumor stage (Stage IIIB vs. Stage IV), body mass index (BMI), creatinine level, hemoglobin (Hgb) level, white blood cell (WBC) count, and platelet count were evaluated for their prognostic significance in both univariate and multivariate analyses by using a Cox proportional-hazards model., Results: Patients who had high WBC counts, low Hgb levels, PS >0, BMI < 18.5 kg/m2, and TNM Stage IV disease had significantly worse TTP and OS. Patients who had Stage IV disease with a high WBC count had a particularly poor prognosis. An equation to predict the OS of patients with Stage IV NSCLC based on pretreatment PS, BMI, Hgb level, and WBC count was constructed., Conclusions: In addition to the widely accepted prognostic factors of PS, BMI, and disease stage, both of the readily available laboratory parameters of Hgb level and WBC count were found to be significant prognostic factors for OS and TTP in patients with advanced-stage NSCLC. The authors' prediction equation can be used to evaluate the benefit of a treatment in Phase II trials by comparing the observed survival of a cohort with its expected survival by using the patients' own prognostic factors in place of comparisons with historic data that may have substantially different baseline patient characteristics.

Background: A blood test for non-small cell lung cancer (NSCLC) may be a valuable tool for use in a comprehensive lung cancer screening strategy. Here we report the potential of autoantibody profiling to detect early-stage and occult NSCLC., Methods: T7-phage NSCLC cDNA libraries were screened with patient plasma to identify phage-expressed proteins recognized by tumor-associated antibodies. Two hundred twelve immunogenic phage-expressed proteins, identified from 4000 clones, were statistically ranked for their individual reactivity with 23 stage I cancer patient and 23 risk-matched control samples. All 46 samples were used as a training set to define a combination of markers that were best able to distinguish patient from control samples; this set of classifiers was then examined using leave-one-out cross-validation. Markers were then used to predict probability of disease in 102 samples from the Mayo Clinic CT Screening Trial (six prevalence cancer samples, 40 drawn 1 to 5 years before diagnosis, and 56 risk-matched controls)., Results: Measurements of the five most predictive antibody markers in 46 cases and controls were combined in a logistic regression model that yielded area under the receiver operating characteristics curve of 0.99; leave-one-out validation achieved 91.3% sensitivity and 91.3% specificity. In testing this marker set with samples from the Mayo Clinic Lung Screening Trial, we correctly predicted six of six prevalence cancers, 32 of 40 cancers from samples drawn 1 to 5 years before radiographic detection on incidence screening, and 49 of 56 risk-matched controls., Conclusions: Antibody profiling may be a useful tool for early detection of NSCLC.

Introduction: This pooled analysis was performed to examine the impact of pretreatment factors on severe (grade 3 or higher) adverse events (AE) in patients with advanced stage non-small cell lung cancer (NSCLC)., Methods: A pooled data set of 1053 participants from nine North Central Cancer Treatment Group clinical trials was used. Age, gender, performance status, tumor stage, body mass index, serum creatinine levels, hemoglobin levels, white blood cell counts, and platelet counts were evaluated univariately and multivariately using logistic regression. The magnitude of the effects of the pretreatment factors after adjusting for type of chemotherapy agent (platinum versus no platinum) was explored in the final multivariate model., Results: Women and older participants had a significantly greater risk for experiencing severe hematologic and non-hematologic AE. Participants with performance status >0 had an increased risk for severe non-hematologic AE. For every one unit (10/L) increase in pretreatment white blood cell count, there was an 11% reduction in the odds of experiencing a severe hematologic AE. The magnitude of these effects on the end points remained similar after adjusting for type of chemotherapy agent., Conclusions: Pretreatment factors of gender, age, performance status, and hematologic parameters were significant predictors of severe AE among patients with advanced stage NSCLC. This suggests the need to control or adjust for factors that predispose patients to an increased risk of severe AE. These findings can aid in tailoring therapy to individual patients and in the proper design of future clinical trials.

Purpose: To answer the question, "should elderly non-small-cell lung cancer patients be offered elderly-specific trials?", Patients and Methods: The North Central Cancer Treatment Group (NCCTG) performed a pooled analysis of elderly patients who participated in elderly-specific trials (required age > or = 65 years) and age-unspecified trials (required age > or = 18 years). Between 1998 and 2000, all NCCTG non-small-cell lung cancer (NSCLC) patients with incurable cancer, age > or = 65 years, and receiving first-line chemotherapy were included. A total of 118 elderly patients participated in elderly-specific trials, and 108, in age-unspecified trials. Demographics and outcomes were compared based on trial type., Results: The median age of elderly patients in elderly-specific trials was greater: median (range): 73 years (65 to 87) and 70 years (65 to 85), respectively (P < .001), as was the percentage older than 80 years: 17% and 3%, respectively (P = .0008). Median survival times were 232 and 302 days, respectively (P = .08). After adjustment for baseline age, Eastern Cooperative Oncology Group performance score, cancer stage, and body mass index, this survival difference was not statistically significant (hazard ratio = 1.25; P = .16). Grade 3 or worse nonhematologic adverse event rates were greater in age-unspecified trials (81% v 57%, respectively; P < .001), as were grade 3 or worse hematologic events (68% v 10%, respectively; P < .001)., Conclusion: Elderly patients in NSCLC elderly-specific trials suffered lower rates of severe adverse events with no statistically significant differences in survival. It seems that elderly-specific trials are providing quality care and helping to define optimal cancer therapy in the elderly, particularly among the "oldest of the old."

Rationale: Phenotypic and genotypic heterogeneity of lung cancer likely precludes the identification of a single predictive marker and suggests the importance of identifying and measuring multiple markers., Objectives: We describe the use of a fluorescent protein microarray to identify and measure multiple non-small cell lung cancer-associated antibodies and show how simultaneous measurements can be combined into a single diagnostic assay., Methods: T7 phage cDNA libraries of non-small cell lung cancer were first biopanned with plasma samples from normal subjects and patients with non-small cell lung cancer to enrich the component of tumor-associated proteins, and then applied to microarray slides. Two hundred twelve immunogenic phage-expressed proteins were identified from roughly 4,000 clones, using high-throughput screening with patient plasmas and assayed with 40 cancer and 41 normal plasma samples. Twenty patient and 21 normal plasma samples were randomly chosen and used for statistical determination of the predictive value of each putative marker. Statistical analysis identified antibody reactivity to seven unique phage-expressed proteins that were significantly different (p < 0.01) between patient and normal groups. The remaining 20 patient and 20 normal plasma samples were used as an independent test of the predictive ability of the selected markers., Main Results: Measurements of the 5 most predictive phage proteins were combined in a logistic regression model that achieved 90% sensitivity and 95% specificity in prediction of patient samples, whereas leave-one-out statistical analysis achieved 88.9% diagnostic accuracy among all 81 samples., Conclusion: Our data indicate that antibody profiling is a promising approach that could achieve high diagnostic accuracy for non-small cell lung cancer.

Purpose: A randomized three-arm phase II study was undertaken to evaluate the optimum administration schedule of pemetrexed and gemcitabine in chemotherapy-naïve patients with non-small-cell lung cancer., Patients and Methods: Patients were randomly assigned to three schedules of pemetrexed 500 mg/m2 plus gemcitabine 1,250 mg/m2, separated by a 90-minute interval, on a 21-day cycle as follows: schedule A, pemetrexed followed by gemcitabine on day 1 and gemcitabine on day 8; schedule B, gemcitabine followed by pemetrexed on day 1 and gemcitabine on day 8; and schedule C, gemcitabine on day 1 and pemetrexed followed by gemcitabine on day 8., Results: One hundred fifty-two eligible patients (schedule A, n = 59; schedule B, n = 31, and schedule C, n = 62) received a median of five (schedule A), two (schedule B), and four (schedule C) treatment cycles. Overall, 66% of patients experienced grade 3 or 4 neutropenia. Common grade 3 and 4 nonhematologic toxicities were dyspnea (11%), fatigue (16%), and transaminase elevation (9%). Schedule A seemed less toxic compared with schedule C (grade 3 or 4 events: 86% v 94%, respectively; P = .19; grade 4 events: 39% v 48%, respectively; P = .30). Schedule B was closed at interim analysis for inferior efficacy. Schedule A, with a confirmed response rate of 31% (95% CI, 20% to 45%), met the protocol-defined efficacy criteria, whereas schedule C, with a confirmed response rate of 16.1% (95% CI, 11% to 34%), did not. Median survival time and time to progression were 11.4 and 4.4 months, respectively, with no observable difference between the arms., Conclusion: Pemetrexed and gemcitabine administered as outlined for schedule A met the protocol-defined efficacy criteria, was less toxic compared with the other treatment schedules, and should be further evaluated.

Objective: The objective of our study was to retrospectively review the PET results of non-small cell lung carcinomas detected on screening chest CT in a high-risk population., Conclusion: PET findings were negative in 32% of the cases of non-small cell carcinomas that were detected on screening CT in a high-risk patient population. These tumors were small, low-grade, or both. The most common histology was bronchioloalveolar cell carcinoma. The role of PET in evaluating screening-detected indeterminate nodules in a high-risk population may be more limited than in a general population.

Lung cancer is the leading cause of cancer mortality and is usually discovered at an advanced stage, when treatment is generally not effective. Many researchers have investigated the value of screening for lung cancer, which would theoretically allow earlier detection and more effective treatment. Unfortunately, no trials of screening strategies for lung cancer have shown a mortality benefit, and as a result, no major medical organization currently recommends screening. Research continues to seek proof of the benefit of screening as new techniques are developed, including low-dose spiral computed tomography (CT), autofluorescence bronchoscopy, and advanced techniques of sputum analysis. Although there are promising data on the sensitivity of these newer screening methods, especially low-dose CT, for detecting early lung cancer, none of the published trials are controlled, and they have not yet proven a decrease in mortality. There are ongoing randomized, controlled trials aiming to demonstrate a mortality benefit. Patients who are interested in being screened for lung cancer should be encouraged to participate in well-designed clinical trials whenever possible.

Purpose: Many studies have highlighted the aberrant expression and prognostic significance of individual proteins in either the Rb (particularly cyclin D1, p16INK4A, and pRb) or the p53 (p53 and p21Waf1) pathways in non-small cell lung cancer. We hypothesize that cumulative abnormalities within each and between these pathways would have significant prognostic potential regarding survival., Experimental Design: Our study population consisted of 106 consecutive surgically resected cases of predominantly early-stage non-small cell lung cancer from the National Cancer Institute-Mayo Clinic series, and assessment of proteins involved both immunohistochemical (cyclin D1, p21Waf1, pRb, p16INK4A, and p53) and mutational analysis (p53) in relationship to staging and survival., Results: Cyclin D1 overexpression was noted in 48% of the tumors, p16INK4A negative in 53%, pRb negative in 17%, p53 immunopositive in 50%, p53 mutation frequency in 48%, and p21(Waf1) overexpression in 47%, none with prognostic significance. Cyclin D1 overexpression in pRb-negative tumors revealed a significantly worse prognosis with a mean survival of 2.3 years (P = 0.004). A simultaneous p53 mutation dramatically reduced the mean survival time to 0.9 years (P = 0.007). Cyclin D1 overexpression with either a p53 mutation or a p53 overexpression was also associated with a significantly poorer prognosis (P = 0.0033 and 0.0063, respectively)., Conclusions: Some cumulative abnormalities in the Rb and p53 pathways (e.g., cyclin D1 overexpression and p53 mutations) significantly cooperate to predict a poor prognosis; however, the complexity of the cell cycle protein interaction in any given tumor warrants caution in interpreting survival results when specific protein abnormalities are taken in isolation.

Background: Weight loss predicts a poor prognosis for patients with non-small-cell lung cancer. Tumor necrosis factor alpha (TNFalpha) is a mediator of this weight loss, yet no studies have tested infliximab, an IgG monoclonal antibody that blocks the binding of TNFalpha to its p55 and p75 receptors, for this indication. The safety and pharmacokinetics of infliximab in combination with docetaxel, a commonly used chemotherapy agent for non-small-cell lung cancer, were explored in this pilot study., Methods/results: Four patients with metastatic non-small-cell lung cancer were treated initially with infliximab 5 mg/kg per day intravenously once a week on weeks 1, 3 and 5, and docetaxel 36 mg/m2 per day intravenously once a week on weeks 1, 2, 3, 4, 5 and 6 of an 8-week treatment cycle. Therapy was well tolerated with no grade 4 or 5 adverse events. Maximal serum concentrations of infliximab at 1, 3 and 5 weeks were (mean+/-SD) 108+/-11, 135+/-19, and 139+/-6 microg/ml, respectively, and appeared similar to historical concentrations from non-cancer patients not receiving concomitant chemotherapy (144+/-68 microg/ml). One patient manifested weight stability. One patient manifested a partial tumor response, one stable disease, and two disease progression. Median survival within the cohort was 203 days (range 111 to 324 days)., Conclusions: The above combination appears safe, and docetaxel does not appear to increase serum concentrations of infliximab. A larger study testing the role of this combination for weight loss in non-small-cell lung cancer patients is ongoing and utilizes the doses described above.

Background: Gender has been reported as a predictor for nonsmall cell lung cancer (NSCLC) survival. Most of the reports are limited to selected groups of patients. The magnitude of gender effect on NSCLC survival across disease stage, tumor histology, and therapies needs to be further characterized., Methods: A cohort of 4,618 patients diagnosed with NSCLC was prospectively enrolled and actively followed. Vital status of each patient was verified through multiple complementary sources. Cox proportional hazards models were developed to compare postdiagnosis survival between genders adjusting for age at diagnosis, tumor histology and grade, stage, pack-years smoked, and treatment received (resection, radiation, or chemotherapy)., Results: There were 2,724 men (59%) and 1,894 women (41%), with a median age at diagnosis of 68 years in men and 66 in women (p < 0.01). More men smoked and were heavier smokers than women. Adenocarcinoma was the most frequent histology in both genders. No difference was found in stage and treatment between genders. The estimated survival in men was 51% (95% CI: 49%, 53%) and 15% (95% CI: 12%, 17%) at one and five years, respectively, and in women was 60% (95% CI: 58%, 62%) and 19% (95% CI: 16%, 22%). Men were at a significantly increased risk of mortality compared to women following a diagnosis of NSCLC (adjusted relative risk: 1.20, 95% CI: 1.11, 1.30), particularly for patients with stage III/IV disease or adenocarcinoma., Conclusions: Male gender is confirmed to be an independent unfavorable prognostic indicator for NSCLC survival.

The purpose of this study was to determine the tumor response rate and toxicity profile of low-dose weekly carboplatin and paclitaxel in advanced non-small-cell lung cancer (SCLC) patients 65 or more years of age. Forty-nine patients 65 years of age or more with advanced non-SCLC with a median age of 73 years (range: 65-85) and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 in 31%, 47%, and 22% of patients, respectively, were treated and evaluated. Patients received carboplatin (AUC = 2) and paclitaxel 50 mg/m2 on days 1, 8, and 15 of a 4-week cycle. The overall confirmed tumor response rate was 14% (95% CI: 4.7%, 32.5%) with no complete responses. The 1-year survival rate was 31% (95% CI: 20%, 48%). There was one treatment-related death, and there were two grade IV allergic reactions to chemotherapy. No other grade IV or V treatment-related toxicities were observed. There were only three episodes of grade III myelosuppression. Low-dose weekly carboplatin and paclitaxel, as prescribed in this trial, provides modest activity in the treatment of advanced non-SCLC patients 65 or more years of age. However, the relatively mild toxicity profile observed in this trial suggests that this regimen might remain an option for patients at increased risk for myelosuppression or with a poor performance status.

Purpose: The North Central Cancer Treatment Group performed a phase III trial to determine whether chemotherapy plus either bid radiation therapy (RT) or daily (qd) RT resulted in a better outcome for patients with stage III non-small-cell lung cancer (NSCLC). No difference in survival was identified between the two arms. This secondary analysis was performed to examine the relationship between patient age and outcome., Patients and Methods: Two hundred forty-six patients were randomized to receive etoposide plus cisplatin and either RT qd or split-course RT bid. This retrospective study compared the outcomes of patients aged >/=70 years ("elderly patients") with those of younger individuals. Of the 244 assessable patients, 63 (26%) were elderly, and 181 (74%) were younger individuals., Results: The 2-year and 5-year survival rates were 39% and 18%, respectively, in patients younger than 70 years, compared with 36% and 13%, respectively, in elderly patients (P =.4). Grade 4+ toxicity occurred in 62% of patients younger than 70 years compared with 81% of elderly patients (P =.007). Grade 4+ hematologic toxicity occurred in 56% of patients younger than 70 years, compared with 78% of elderly patients (P =.003). Grade 4+ pneumonitis occurred in 1% of those younger than 70 years, compared with 6% of elderly patients (P =.02)., Conclusion: Toxicity, especially myelosuppression and pneumonitis, was more pronounced in the elderly patients receiving combined-modality therapy for locally advanced NSCLC. Despite increased toxicity, elderly patients have survival rates equivalent to younger individuals. Therefore, fit, elderly patients with locally advanced NSCLC should be encouraged to receive combined-modality therapy, preferably on clinical trials with cautious, judicious monitoring. Future studies should explore ways to decrease toxicity of therapy in elderly patients.

Background: Performance scores predict benefits and toxicities from chemotherapy. Among older cancer patients, however, many investigators have empirically called for a detailed assessment of activities of daily living, claiming that the utility of performance scores is limited in this older population. This study's goals were therefore twofold: (1). to explore the predictive capability of an activities questionnaire and of performance score with respect to chemotherapy's toxicity and efficacy; (2). to describe the daily activities of older patients as they undergo chemotherapy for incurable metastatic lung cancer., Methods: As part of a multi-institutional therapeutic trial, this study included 48 patients >or=65 years of age with metastatic non-small-cell lung cancer. All were assigned an Eastern Cooperative Oncology Group (ECOG) performance score and completed an activity questionnaire (Voorrips) prior to the initiation of carboplatin and paclitaxel. Patients were monitored for toxicity (CTC, version 2) and cancer status., Results: Within this cohort, ECOG performance scores were poor at predicting grade 3 or worse toxic events ( P=0.71, Mantel-Haenszel chi-squared). In contrast, the activity questionnaire categories did predict grade 3 or worse toxicity ( P=0.03) with a positive association observed between greater levels of activity and lower toxicity rates. Neither instrument predicted 90-day disease progression, although there was a trend that suggested a positive association between favorable scores and lower progression rates ( P=0.051). Patients described a broad range of daily activities., Conclusion: Activity questionnaires capture a broad range of data that may prove useful in predicting toxicity among older cancer patients.

Stage IIIB includes patients with T4, any N, M0, and any T, N3, M0. Surgery may be indicated only for carefully selected T4N0M0 patients with or without neoadjuvant chemotherapy or chemoradiotherapy. Patients with N3 lymph node involvement are not considered as surgical candidates. For patients with unresectable disease, good performance score, and minimal weight loss, treatment with combined chemotherapy and radiotherapy has resulted in better survival than treatment with radiotherapy alone. Multiple daily fractions of radiotherapy have not resulted in improved survival compared with standard fractionation once daily. Concurrent chemoradiotherapy appears to be associated with improved survival compared with sequential chemotherapy and radiotherapy. Treatment of stage IIIB due to malignant pleural effusion is addressed in the section that deals with stage IV disease.

Purpose: This Phase III study was performed to determine whether chemotherapy plus b.i.d. or q.d. radiotherapy (RT) resulted in superior survival for patients with Stage III non-small-cell lung cancer (NSCLC)., Methods and Materials: Patients with Stage III NSCLC and an Eastern Cooperative Oncology Group performance status of