Although it is recommended that smokers undergoing surgery for lung cancer quit smoking to reduce post-operative complications, few studies have examined patterns of smoking in the peri-operative period. The goals of this study were to determine: 1) patterns of smoking during post-operative recovery, 2) types of cessation strategies used to quit smoking, and 3) factors related to smoking after lung cancer surgery.
Data were collected from 94 patients through chart review, tobacco, health-status, and symptom questionnaires at 1, 2, and 4-months after surgery. Smoking status was assessed through self-report and urinary cotinine measurement.
Eighty-four patients (89%) were ever-smokers and 35 (37%) reported smoking at diagnosis. Thirty-nine (46%) ever-smokers remained abstinent, 13 (16%) continued smoking at all time-points, and 32 (38%) relapsed. Ten (46%) of those who relapsed were former-smokers and had not smoked for at least 1-year. Sixteen (46%) of those who were smoking at diagnosis received cessation assistance with pharmacotherapy being the most common strategy. Factors associated with smoking during recovery were younger age and quitting smoking ≤ six-months before the diagnosis of lung cancer. Factors that were marginally significant were lower educational level, male gender, lower number of comorbidities, and the presence of pain
Only half of those who were smoking received assistance to quit prior to surgery. Some patients were unable to quit and relapse rates post-surgery were high even among those who quit more than 1-year prior. Innovative programs incorporating symptom management and relapse prevention may enhance smoking abstinence during post-operative care.
lung cancer; thoracic surgery; smoking cessation; symptom management
Performance status (PS) is a commonly used factor in determining the appropriateness for chemotherapy of patients with non-small cell lung cancer (NSCLC). The prevalence of poor PS and impact of chemotherapy on survival among NSCLC patients has not been studied in community populations.
Patients and Methods
Insured patients, aged 50+ years, diagnosed with advanced stage NSCLC between 2000 and 2007 were identified via tumor registry (n=292) and linked to electronic medical records, automated medical claims, and Census tract information. A multivariate Cox proportional hazards model was used to determine the factors associated with survival.
Of 292 stage IIIB-IV patients, 82 (28%) had PS 3 or 4, and 39% of PS 3–4 patients received first line chemotherapy. Those who received chemotherapy lived 4.8 months compared to 2.4 months for those who did not. Factors associated with a reduced likelihood of death included receipt of chemotherapy (hazard ratio [HR], 0.64), and female gender (HR, 0.71).
Modern chemotherapy may be associated with positive effects on survival for poor PS patients, as for good PS patients. Further trials, especially randomized trials, in this neglected subgroup are indicated.
chemotherapy; non-small cell lung cancer; performance status; survival; advanced stage; guidelines
Relative to best supportive care alone, cytotoxic chemotherapy has an established role in prolonging overall survival (OS) in patients with or without previous treatment for metastatic non-small cell lung cancer (NSCLC). OS has been the principal endpoint influencing regulatory decisions regarding targeted therapies for metastatic NSCLC, including the vascular endothelial growth factor monoclonal antibody bevacizumab in the frontline setting and the epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib in patients after prior treatment. Progression-free survival (PFS), another common endpoint in oncology clinical trials, has been discussed as a potential surrogate for OS in metastatic NSCLC. A number of phase III clinical trials of investigational targeted agents for treatment of metastatic NSCLC are ongoing, with OS designated as the primary endpoint in some cases and PFS in others. Both endpoints have been developed largely to evaluate outcomes in unselected populations in which a fraction of patients are anticipated to derive significant benefit. New approaches are being considered for the evaluation of targeted agents. Recent high profile trials have been designed to assess PFS using a randomized discontinuation design and disease control rate after 8 weeks of treatment. With a series of recent advances towards increasingly personalized biomarker-directed anticancer therapies, the appropriateness of the traditional regulatory approach has been questioned.
lung cancer; progression-free survival; overall survival; surrogate endpoint; disease control rate; clinical research
Maintenance therapy is a new treatment paradigm for advanced non-small cell lung cancer (NSCLC). We conducted a meta-analysis of randomized studies with single agent maintenance therapy.
An electronic literature search of public databases (MEDLINE, EMBASE, Cochrane library) and manual search of relevant conference proceedings was performed. A formal meta-analysis was conducted using Comprehensive Meta Analysis software (Version 2.0). Outcome data were pooled and reported as hazard ratio (HR). The primary outcome of interest was overall survival (OS) and secondary outcome was progression free survival (PFS).
Twelve studies were included (5 meeting abstracts, 7 full manuscripts) with a total of 4286 patients (maintenance arm/control arm- 2449/1837, median age 61 years, males -69 %). The OS (HR 0.86, 95% confidence intervals [CI] 0.80-0.92; P=0.0003) and PFS (HR 0.80, 95% CI 0.77-0.84; P<0.0001) were superior with maintenance therapy. ‘Switch’ maintenance was associated with significant OS and PFS improvement (OS HR 0.84, 95% CI 0.77-0.91; P=0.00026; PFS HR 0.62, 95% CI 0.57-0.67; P<0.0001). Despite a modest improvement in PFS (HR 0.90, 95%CI 0.85-0.95; P=0.007), “continuation” maintenance was not associated with survival benefit (HR 0.927, 95%CI 0.78-1.09; P=0.33). Improvements in OS and PFS were observed with both EGFR-targeted agents (HR 0.83, 95% CI 0.74-0.92; P=0.004; HR 0.64, 95% CI 0.58-0.71 P<0.0001) and cytotoxic agents (HR 0.89, 95% CI 0.80-0.98; P=0.018; HR 0.85, 95% CI 0.80-0.89; P < 0.0001).
Single agent maintenance therapy improves overall survival, though statistical significance was only noted with ‘switch’ maintenance.
Maintenance therapy; non-small cell lung cancer; NSCLC; EGFR; pemetrexed; erlotinib; gefitinib
The anti-proliferative effects of 1α,25-dihydroxyvitamin D3 (1,25-D3, calcitriol, the active form of vitamin D) are mediated by the nuclear vitamin D receptor (VDR). In the present study, we characterized VDR expression in lung adenocarcinoma (AC).
We examined VDR mRNA expression using a quantitative real-time PCR (qRT-PCR) in 100 patients who underwent surgery for lung AC. In a subset of these patients (n = 89), we examined VDR protein expression using immunohistochemistry. We also examined the association of VDR protein expression with circulating serum levels of 25-hydroxyvitamin D3 (25-D3) and 1,25-D3. The antiproliferative effects and cell cycle arrest of 1,25-D3 were examined using lung cancer cell lines with high (SKLU-1) as well as low (A549) expression of VDR mRNA.
Higher VDR expression correlates with longer survival after adjusting for age, sex, disease stage and tumor grade (HR 0.73, 95% CI 0.58–0.91). In addition, there was a positive correlation (r = 0.38) between serum 1,25-D3 and tumor VDR protein expression. A greater anti-proliferative effect of 1,25-D3 was observed in high compared to low VDR-expressing cell lines; these effects corresponded to G1 cell cycle arrest; this was associated with a decline in cyclin D1, S-phase kinase protein 2 (Skp2), retinoblastoma (Rb) and minichromosome maintenance 2 (MCM2) proteins involved in S-phase entry.
Increased VDR expression in lung AC is associated with improved survival. This may relate to a lower proliferative status and G1 arrest in high VDR-expressing tumors.
VDR; Vitamin D; 1,25-D3; Lung Adenocarcinoma; Survival
Few studies have examined the association between non-steroidal anti-inflammatory drug (NSAID) use and risk of small cell lung cancer (SCLC); among them, findings are mixed. Recently, we found that use of NSAIDs was differentially associated with lung cancer risk by histology. Here, we examine, more comprehensively, the association between individual NSAIDs and SCLC risk. 75,546 residents of western Washington State, ages 50–76, completed a baseline questionnaire in 2000–2002 and reported on their use of individual NSAIDs over the past 10 years. NSAID use was categorized as non-users, low (<4 days/week or <4 years), and high (≥4 days/week and ≥4 years). 111 SCLC were identified through linkage to a population-based cancer registry. Multivariable-adjusted Cox proportional hazards models including strong adjustment for smoking were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Compared to non-use, high use of regular-strength aspirin was associated with an elevated risk of SCLC (HR 1.78, 95% CI: 1.05–3.02; P-trend = 0.03). Findings for low-dose aspirin were elevated but did not reach statistical significance. Use of non-aspirin NSAIDs was not associated with SCLC risk. Our findings provide further indication of heterogeneity in the association between aspirin and lung cancer morphologies. Large, prospective studies with comprehensive assessments of NSAID use and smoking history and data on both men and women, are needed in order to better understand the association between use of aspirin and SCLC.
Aspirin; Ibuprofen; NSAID; Small cell lung cancer
Lung cancer is the leading cause of cancer mortality for men and women in the United States and is a growing worldwide problem. Protection against lung cancer is associated with higher dietary intake of fruits and vegetables, according to recent large epidemiologic studies. One strategy for lung cancer chemoprevention focuses on the use of agents to modulate the metabolism and disposition of tobacco, environmental and endogenous carcinogens through upregulation of detoxifying phase II enzymes. We summarize the substantial evidence that suggests that induction of phase II enzymes, particularly the glutathione S-transferases, plays a direct role in chemoprotection against lung carcinogenesis. The engagement of the Keap1–Nrf2 complex regulating the antioxidant response element (ARE) signaling pathway has been identified as a key molecular target of chemopreventive phase II inducers in several systems. Monitoring of phase II enzyme induction has led to identification of novel chemopreventive agents such as the isothiocyanate sulforaphane, and the 1,2-dithiole-3-thiones. However, no agents have yet demonstrated clear benefit in human cell systems, or in clinical trials. Alternative strategies include: (a) using intermediate cancer biomarkers for the endpoint in human trials; (b) high-throughput small molecule discovery approaches for induced expression of human phase II genes; and (c) integrative approaches that consider pharmacogenetics, along with pharmacokinetics and pharmacodynamics in target lung tissue. These approaches may lead to a more effective strategy of tailored chemoprevention efforts using compounds with proven human activity.
Lung cancer; Phase II enzymes; Chemoprevention; Induction; Phytochemicals
We previously reported data on the safety, tolerability, and recommended phase II dose of obatoclax mesylate in conjunction with topotecan in patients with advanced solid tumor malignancies. Preliminary efficacy data suggested activity in patients with recurrent small cell lung cancer (SCLC). Based on these data, we performed a phase II study of obatoclax mesylate plus topotecan in patients with relapsed SCLC to assess efficacy.
This was an open-label, single-arm, phase II extension of obatoclax mesylate plus topotecan in patients with relapsed SCLC. Obatoclax mesylate was given intravenously (IV) at a dose of 14 mg/m2 on days 1 and 3 with IV topotecan at 1.25 mg/m2 on days 1–5 of an every 3-week cycle. The primary end-point of this study was overall response rate.
Nine patients with recurrent SCLC were enrolled into the first stage of the study. Patients received a median of 2 cycles of treatment. All patients were evaluable for the primary end-point of overall response. There were no partial or complete responses. Five patients (56%) had stable disease. The remaining four patients (44%) developed progressive disease. The most common grade 3 or 4 adverse events included thrombocytopenia (22%), anemia (11%), neutropenia (11%), and ataxia (11%).
Obatoclax mesylate added to topotecan does not exceed the historic response rate seen with topotecan alone in patients with relapsed SCLC following the first-line platinum-based therapy.
Obatoclax mesylate; Topotecan; Small cell lung cancer (SCLC); Apoptosis
Chemotherapy prolongs survival and improves quality of life (QOL) for good performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Targeted therapies may improve chemotherapy effectiveness without worsening toxicity. SGN-15 is an antibody–drug conjugate (ADC), consisting of a chimeric murine monoclonal antibody recognizing the Lewis Y (Ley) antigen, conjugated to doxorubicin. Ley is an attractive target since it is expressed by most NSCLC. SGN-15 was active against Ley-positive tumors in early phase clinical trials and was synergistic with docetaxel in preclinical experiments. This Phase II, open-label study was conducted to confirm the activity of SGN-15 plus docetaxel in previously treated NSCLC patients.
Sixty-two patients with recurrent or metastatic NSCLC expressing Ley, one or two prior chemotherapy regimens, and PS ≤ 2 were randomized 2:1 to receive SGN-15 200 mg/m2/week with docetaxel 35 mg/m2/week (Arm A) or docetaxel 35 mg/m2/week alone (Arm B) for 6 of 8 weeks. Intrapatient dose-escalation of SGN-15 to 350 mg/m2 was permitted in the second half of the study. Endpoints were survival, safety, efficacy, and quality of life.
Forty patients on Arm A and 19 on Arm B received at least one treatment. Patients on Arms A and B had median survivals of 31.4 and 25.3 weeks, 12-month survivals of 29% and 24%, and 18-month survivals of 18% and 8%, respectively. Toxicity was mild in both arms. QOL analyses favored Arm A.
SGN-15 plus docetaxel is a well-tolerated and active second and third line treatment for NSCLC patients. Ongoing studies are exploring alternate schedules to maximize synergy between these agents.
Immunoconjugate; Targeted therapy; NSCLC; Lewis Y; SGN-15; Monoclonal antibody
The neutrophil elastase (NE) gene encodes a powerful serine protease that is involved in the process of normal tissue turnover, natural host defense or tissue damage in acute and chronic inflammatory disorders. Furthermore, NE was suggested as one of the determinant factors of individual susceptibility to lung cancer resulting from imbalance between α1-antitrypsin (AT) and NE. To determine whether NE plays a role in risk for lung cancer, we screened polymorphisms in the promoter region of the NE gene and assessed the role of the NE polymorphisms in the risk for lung cancer. We confirmed three previously identified polymorphisms which are located at −903, −741, and extra 52 bp STS relative to the transcription initiation site. In addition, two new polymorphisms at −832 (G/T) and −789 (C/T) were identified. Their rare allelic frequencies of new polymorphism are 0.02 and 0.01, respectively, among Caucasians. The prevalence of the NE −903 (T/T) and (T/G) genotypes were 0.88 and 0.12 in controls as compared to 0.96 and 0.04 in lung cancer patients using genomic DNA isolated from 113 Caucasian lung cancer cases and 131 controls. A significant increase in lung cancer risk was observed for expected high NE activity genotypes (OR = 3.2, 95% CI = 1.02–10.3) as compared to low NE activity genotypes. These results were consistent with previous in vitro functional analysis, which reported an approximately two-fold increase enzyme expression with the −903T/−741G allele as compared to the −903G/−741A variant. These results confirm that the NE promoter region polymorphisms may influence in risk for lung cancer.
Neutrophil elastase; Lung cancer; Genetic polymorphism; Cancer susceptibility
Disagreements between cancer patients and their caregivers about treatment and care can affect the patient’s physical and mental well-being. Therefore it is important to understand if oncologists can accurately identify the presence of patient-caregiver decisional conflict. This study examined assessments made by lung cancer patients, their caregivers, and their oncologists regarding patient-caregiver disagreements concerning treatment and care decisions.
Participants and methods
We assessed the extent to which the patient, caregiver, and oncologist reported disagreement between the patient and the family member regarding treatment decisions in 134 patient-caregiver-oncologist triads. Descriptive statistics were used to explore rates of concordance amongst all possible combinations of raters. Loglinear models were tested for 3-way agreement.
Most patient-caregiver pairs, 82.1% (n=110), reported agreement concerning presence or absence of decisional conflict. Oncologists were more successful in detecting absence of conflict than the presence of conflict. When the caregiver and the oncologist agreed, it was regarding the absence of conflict (64.9%), rather than the presence of conflict. In 10.6 % (n = 15) of cases, oncologists reported that conflictual relationships negatively impacted their ability to provide patient care.
Recent models of cancer patient care promote including the caregiver fully in the process while respecting the primacy of the patient’s perspective. However, these models assume that the oncologist will recognize when disagreements exist and be able to assist in conflict resolution. The degree to which the oncologist identified that conflict exists and implications for their ability to provide patient care when familial disagreements existed are discussed.
lung cancer; family caregivers; treatment; decision making; conflict; patient care
We sought to determine the mechanisms of downregulation of the airway transcription factor Foxa2 in lung cancer and the expression status of Foxa2 in non-small-cell lung cancer (NSCLC).
A series of 25 lung cancer cell lines were evaluated for Foxa2 protein expression, FOXA2 mRNA levels, FOXA2 mutations, FOXA2 copy number changes and for evidence of FOXA2 promoter hypermethylation. In addition, 32 NSCLCs were sequenced for FOXA2 mutations and 173 primary NSCLC tumors evaluated for Foxa2 expression using an immunohistochemical assay.
Out of the 25 cell lines, 13 (52%) had undetectable FOXA2 mRNA. The expression of FOXA2 mRNA and Foxa2 protein were congruent in 19/22 cells (p=0.001). FOXA2 mutations were not identified in primary NSCLCs and were infrequent in cell lines. Focal or broad chromosomal deletions involving FOXA2 were not present. The promoter region of FOXA2 had evidence of hypermethylation, with an inverse correlation between FOXA2 mRNA expression and presence of CpG dinucleotide methylation (p<0.0001). In primary NSCLC tumor specimens, there was a high frequency of either absence (42/173, 24.2%) or no/low expression (96/173, 55.4%) of Foxa2. In 130 patients with stage I NSCLC there was a trend towards decreased survival in tumors with no/low expression of Foxa2 (HR of 1.6, 95%CI 0.9–3.1; p=0.122).
Loss of expression of Foxa2 is frequent in lung cancer cell lines and NSCLCs. The main mechanism of downregulation of Foxa2 is epigenetic silencing through promoter hypermethylation. Further elucidation of the involvement of Foxa2 and other airway transcription factors in the pathogenesis of lung cancer may identify novel therapeutic targets.
lung cancer; non-small-cell lung cancer; Foxa2; methylation; transcription factors; epigenetic; downregulation; adenocarcinoma; mutation; prognosis
The impact of age on prognosis in advanced stage non-small cell lung cancer (NSCLC) may differ by sex.
Patients and methods
Eligible patients (N = 1590) from E1594, a 4-arm platinum-based chemotherapy trial, and E4599 (carboplatin/paclitaxel ± bevacizumab) chemotherapy arm were divided into male and female cohorts and separated into age groups of <60 or ≥60 years old. Eligible E4599 patients (N = 850) were similarly separated by age and sex and by treatment (±bevacizumab). Survival was calculated separately for each cohort.
The median survival time (MST) for women ≥60 years old treated with chemotherapy alone on E1594 and E4599 was 11.6 months versus 9.0 months for women <60 (p = 0.03). MST was 7.4 and 8.3 months for men ≥60 and <60 years old respectively (NS). In E4599 the age <60 by bevacizumab treatment interaction was statistically significant (p = 0.03) for women (younger had greater benefit), with no age effect in men.
In this unplanned, exploratory subgroup analysis of advanced stage NSCLC ECOG trials, women ≥60 years old treated with chemotherapy live longer than men and younger women. In contrast, bevacizumab survival benefit was more pronounced in men of any age and in younger women on E4599.
Age/sex interactions; Bevacizumab; Chemotherapy; Sex/gender differences; NSCLC; Prognostic factors
Smoking cessation among cancer patients is critical for improving outcomes. Understanding factors associated with smoking abstinence after the diagnosis of cancer can provide direction to develop and test interventions to enhance cessation rates. The purpose of this study was to identify determinants of smoking outcomes among cancer patients.
Standardized questionnaires were used to collect data from 163 smokers or recent-quitters (quit ≤ 6 mo) at study entry of which 132 and 121 had data collected at 3 and 6-months. Biochemical verification was conducted with urinary cotinine and carbon monoxide. Descriptive statistics, Cronbach alpha coefficients, Pearson correlations, Fisher’s exact test, and multivariable logistic regression were used for analyses.
Seven-day-point-prevalence-abstinence (PPA) rates were 90/132 (68%) at 3-months; 46/71 (65%) among lung and 44/61 (72%) among head and neck cancer patients, whereas 7-day-PPA rates were 74/121 (61%) at 6-months; 31/58 (53%) among lung and 43/63 (68%) among head and neck cancer patients. Continuous abstinence rates were 63/89 (71%) at 3-months; 32/45 (71%) among lung and 31/44 (70%) among head and neck cancer patients, whereas continuous abstinence rates were 46/89 (52%) at 6-months; 18/45 (40%) among lung and 28/44 (64%) among head and neck cancer patients. Lower cancer-related, psychological and nicotine withdrawal symptoms were associated with increased 7-D-PPA abstinence rates at 3 and 6 months in univariate models. In multivariable models, however, decreased craving was significantly related with 7-day-PPA at 3-months and decreased craving and increased self-efficacy were associated with 7-D-PPA at 6-months. Decreased craving was the only factor associated with continuous abstinence at 6-months.
Smoking outcomes among lung and head and neck cancer patients appear to have remained the same over the last two decades despite the availability of an increased number of pharmacotherapy options to treat tobacco dependence. Decreased craving and increased self-efficacy were the most consistent factors associated with improved smoking outcomes but symptom control may also play a role in optimal management. Use of combined, and/or higher doses of pharmacotherapy along with behavioral interventions that increase self-efficacy and manage symptoms may promote enhanced cessation rates.
smoking cessation; tobacco dependence; lung cancer; head and neck cancer; smoking cessation interventions; symptom management; craving
Platinum-based doublet chemotherapy is the traditional treatment of choice for advanced non-small cell lung cancer (NSCLC); however, the efficacy of these regimens has reached a plateau. Increasing evidence demonstrates that patients with sensitizing mutations in the epidermal growth factor receptor (EGFR) experience improved progression-free survival and response rates with first-line gefitinib or erlotinib therapy relative to traditional platinum-based chemotherapy, while patients with EGFR-mutation negative tumors gain greater benefit from platinum-based chemotherapy. These results highlight the importance of molecular testing prior to the initiation of first-line therapy for advanced NSCLC. Routine molecular testing of tumor samples represents an important paradigm shift in NSCLC therapy and would allow for individualized therapy in specific subsets of patients. As these and other advances in personalized treatment are integrated into everyday clinical practice, pulmonologists will play a vital role in ensuring that tumor samples of adequate quality and quantity are collected in order to perform appropriate molecular analyses to guide treatment decisions. This article provides an overview of clinical trial data supporting molecular analysis of NSCLC, describes specimen acquisition and testing methods currently in use, and discusses future directions of personalized therapy for patients with NSCLC.
Epidermal growth factor receptor (EGFR); Kirsten rat sarcoma viral oncogene homolog (KRAS); molecular testing; personalized medicine; tyrosine kinase inhibitors; non-small cell lung cancer
To investigate the prognostic importance of functional capacity and exercise behavior in patients with metastatic non-small cell lung cancer (NSCLC).
Patients and methods
Using a prospective design, 118 consecutive participants with histologically confirmed metastatic (inoperable) NSCLC and Eastern Cooperative Oncology group (ECOG) 0–3 completed a six-minute walk test to assess functional capacity and questionnaire that assessed self-reported exercise behavior. Cox proportional models were used to estimate the risk of all-cause mortality according to six-minute walk distance (6MWD) (<358.5 m, 358.5–450 m, ≥450 m) and exercise behavior (MET-hrs wk−1) categories with adjustment for important covariates.
Median follow-up was 26.6 months; 77 deaths were reported during this period. Functional capacity was an independent predictor of survival (Ptrend = 0.003) and added incremental prognostic value beyond that provided by PS plus other traditional markers of prognosis (Ptrend = 0.025). Compared with patients achieving a 6MWD <358.5 m, the adjusted hazard ratio (HR) for all-cause mortality was 0.61 (95% CI, 0.34–1.07) for a 6MWD of 358.5–450 m, and 0.48 (95% CI, 0.24–0.93) for a 6MWD >450 m. In unadjusted analysis, there was a borderline significant effect of exercise behavior on survival (p = 0.052). Median survival was 12.89 months (95% CI, 9.11–21.05 months) for those reporting <9 MET-hrs wk−1 compared with 25.63 months (95% CI, 11.28 to ∞ months) for those reporting ≥9 MET-hrs wk−1.
Functional capacity is a strong independent predictor of survival in advanced NSCLC that adds to the prediction of survival beyond traditional risk factors. This parameter may improve risk stratification and prognostication in NSCLC.
Prognosis; Functional assessment; Exercise; Cardiorespiratory fitness; Survival
Tumor recurrence is the major cause of death in lung cancer treatment. To date, there is no clinically applied gene expression-based model to predict the risk for tumor recurrence in non-small cell lung cancer (NSCLC). We sought to embed crosstalk with major signaling pathways into biomarker identification. Three approaches were used to identify prognostic gene signatures from 442 lung adenocarcinoma samples. Candidate genes co-expressed with 6 or 7 major NSCLC signaling hallmarks were identified from genome-wide coexpression networks specifically associated with different prognostic groups. From these candidate genes, the first approach selected genes significantly associated with disease-specific survival using univariate Cox model. The second approach used random forests to refine the gene signatures; and the third approach used Relief algorithm to form the final gene sets. A total of 21 gene signatures were identified using these three approaches. These gene signatures generated significant prognostic stratifications (log-rank P < 0.05 in Kaplan-Meier analyses; Hazard Ratio >1, P< 0.05) in all tumors, stage I only, and in stage I patients not receiving chemotherapy in all training and test sets. In multivariate analyses with age, gender, race, smoking history, cancer stage, and tumor differentiation, a 10-gene signature had a hazard ratio of 3.23 (95% CI: [1.48, 7.06]), which was a more significant prognostic factor than other clinical factors, except cancer stage (III vs. I; with no significant difference). All identified 21 gene signatures outperformed other lung cancer signatures evaluated in the Director's Challenge Study. This study is an important step toward personalized prognosis of tumor recurrence and patient selection for adjuvant chemotherapy, with significant impact on down-stream clinical applications.
lung adenocarcinoma; gene co-expression networks; biomarker identification; signaling pathways; prognostic stratification; tumor recurrence; metastasis; non-small cell lung cancer
Evidence-based guidelines recommend chemotherapy for medically fit patients with stage II–IV non-small cell lung cancer (NSCLC). Adherence to chemotherapy guidelines has rarely been studied among large populations, mainly because performance status (PS), a key component in assessing chemotherapy appropriateness, is missing from claims-based datasets. Among a large cohort of patients with known PS, we describe first line chemotherapy use relative to guideline recommendations and identify patient factors associated with guideline concordant use.
Patients and Methods
Insured patients, ages 50+, with stage II–IV NSCLC between 2000–2007 were identified via tumor registry (n=406). Chart abstracted PS, automated medical claims, Census tract information, and travel distance were linked to tumor registry data. Chemotherapy was considered appropriate for patients with PS 0–2. Multivariate logit models were fit to evaluate patient characteristics associated with chemotherapy over- and under-use per guideline recommendations. Tests of statistical significance were two sided.
Overall compliance with first line chemotherapy guidelines was 71%. Significant (p<0.05) predictors of chemotherapy underuse (19%) included increasing age (odds ratio [OR], 1.09), higher income (OR, 1.02), diagnosed before 2003 (OR, 2.05), and vehicle access (OR, 6.96) in the patient’s neighborhood. Significant predictors of chemotherapy overuse (10%) included decreasing age (OR, 0.92), diagnosed after 2003 (OR, 3.24), and higher income (OR, 1.05) in the patient’s neighborhood.
Among NSCLC patients 29% do not receive guideline recommended chemotherapy treatment missing opportunities for cure or beneficial palliation, or receiving chemotherapy with more risk of harm than benefit. Care concordant with guidelines is influenced by age, economic considerations such as income and transportation barriers.
guideline adherence; non-small cell lung cancer; chemotherapy; performance status; underuse; overuse
CT plays an important role in diagnosis of lung cancer, however has been limited by uncertain diagnostic rate for early stage of non–small-cell lung cancer (NSCLC), particularly central tumors. Genetic analysis of sputum has proven to be useful in diagnosis of NSCLC. We proposed to evaluate efficacy of combing CT and genetic analysis of sputum for noninvasive diagnosis of stage I NSCLC. Genomic copy changes of a panel of lung cancer-related genes, HYAL2, FHIT, p16, and SP-A were analyzed by a mini-chip in sputum from 33 patients with stage I NSCLC and 49 cancer-free controls. The genetic and CT diagnoses were compared with surgical-pathologic stage. CT had higher sensitivity (85%) in detection of lung cancer compared with the mini-chip (70%) (p<0.05), while there was no significant difference in specificity between the two tests (89 vs. 92%, p=0.09). Similarly, CT showed considerably higher sensitivity (93%) in identifying peripheral tumors than did the mini-chip (64%) (p<0.05), whereas there was no difference in specificity between them (98 vs. 96%, p=0.28). However, in detecting central tumors, CT had lower specificity (90%) compared with the mini-chip (98%) (P<0.05), although its sensitivity (79%) was higher than that of the mini-chip (73%) (P=0.05). Combining both tests offered higher sensitivity (91%) than did any single one (85%, 70%, all <0.05), while still keeping 92% sensitivity. In particular, this combined approach yielded higher sensitivity, specificity, and accuracy for diagnosing central cancers compared with CT alone (all p<0.05). The integration of the genetic assay with CT led to improvements in noninvasive diagnosis of stage I NSCLCs, especially central tumors.
Genetic analysis; sputum; CT; lung cancer; diagnosis
Many epidemiological studies show the benefit of fruits and vegetables on reducing risk of lung cancer, the leading cause of cancer death in the United States. Previously, we demonstrated that cigarette smoke exposure (SM)-induced lung lesions in ferrets were prevented by a combination of low dose of β-carotene, α-tocopherol (AT), and ascorbic acid (AA). However, the role of a combination of AT and AA alone in the protective effect on lung carcinogenesis remains to be examined. In the present study, we investigated whether the combined AT (equivalent to ∼100 mg/day in the human) and AA (equivalent to ∼210 mg/day) supplementation prevents against SM (equivalent to 1.5 packs of cigarettes/day) induced lung squamous metaplasia in ferrets. Ferrets were treated for 6 weeks in the following three groups (9 ferrets/group): (i) Control (no SM, no AT+AA), (ii) SM alone, and (iii) SM+AT+AA. Results showed that SM significantly decreased concentrations of retinoic acid, AT, and reduced form of AA, not total AA, retinol and retinyl palmitate, in the lungs of ferrets. Combined AT+AA treatment partially restored the lowered concentrations of AT, reduced AA and retinoic acid in the lungs of SM-exposed ferrets to the levels in the control group. Furthermore, the combined AT+AA supplementation prevented SM-induced squamous metaplasia [0 positive /9 total ferrets (0%) vs. 5/8 (62%); p <0.05] and cyclin D1 expression (p < 0.05) in the ferret lungs, in which both were positively correlated with expression of c-Jun expression. Although there were no significant differences in lung microsomal malondialdehyde (MDA) levels among the three groups, we found a positive correlation between MDA levels and cyclin D1, as well as c-Jun expressions in the lungs of ferrets. These data indicate that the combination of antioxidant AT+AA alone exerts protective effects against SM-induced lung lesions through inhibiting cyclin D1 expression and partially restoring retinoic acid levels to normal.
Antioxidants; retinoic acid; cigarette smoke; lung carcinogenesis; cyclin D1
Complete surgical resection is the most effective curative treatment for lung cancer. However, many patients with lung cancer also have severe COPD which increases their risk of postoperative complications and their likelihood of being considered “inoperable.” Preoperative Pulmonary Rehabilitation (PR) has been proposed as an intervention to decrease surgical morbidity but there is no established protocol and no randomized study has been published to date.
We tested two preoperative PR interventions in patients undergoing Lung Cancer resection and with moderate-severe COPD in a randomized single blinded design. Outcomes were length of hospital stay and postoperative complications.
The first study tested 4 weeks of guideline-based PR vs.usual care: that study proved to be very difficult to recruit as patients and providers were reluctant to delay surgery. Nine patients were randomized and no differences were found between arms.
The second study tested ten preoperative PR sessions using a customized protocol with nonstandard components (exercise prescription based on self efficacy, inspiratory muscle training, and the practice of slow breathing) (n=10) vs.usual care (N=9). The PR arm had shorter length of hospital stay by 3 days (p=0.058), fewer prolonged chest tubes (11% vs. 63%, p=0.03) and fewer days needing a chest tube (8.8vs.4.3 days p=0.04) compared to the controlled arm.
A ten-session preoperative PR intervention may improve post operative lung reexpansion evidenced by shorter chest tube times and decrease the length of hospital stay, a crude estimator of post operative morbidity and costs. Our results suggest the potential for short term preoperative Pulmonary Rehabilitation interventions in patients with moderate-severe COPD undergoing curative lung resection. 4 weeks of conventional preoperative PR seems non feasible.
COPD; Pulmonary Rehabilitation; Lung Cancer; Emphysema; Exercise Outcomes; Thoracic Surgery
Tumor size at diagnosis (TSD) indirectly reflects tumor growth rate. The relationship between TSD and smoking is poorly understood. The aim of the study was to determine the relationship between smoking and TSD. We reviewed 1712 newly diagnosed and previously untreated non-small cell lung cancer (NSCLC) patients’ electronic medical records and collected tumor characteristics. Demographic and epidemiologic characteristics were derived from questionnaires administered during personal interviews. Univariate and multivariate linear regression models were used to evaluate the relationship between TSD and smoking controlling for demographic and clinical factors. We also investigated the relationship between the rs1051730 SNP in an intron of the CHRNA3 gene (the polymorphism most significantly associated with lung cancer risk and smoking behavior) and TSD. We found a strong dose dependent relationship between TSD and smoking. Current smokers had largest and never smokers smallest TSD with former smokers having intermediate TSD. In the multivariate linear regression model, smoking status (never, former, and current), histological type (adenocarcinoma vs SqCC), and gender were significant predictors of TSD. Smoking duration and intensity may explain the gender effect in predicting TSD. We found that the variant allele of rs1051730 in CHRNA3 gene was associated with larger TSD of squamous cell carcinoma. In the multivariate linear regression model, both rs1051730 and smoking were significant predictors for the size of squamous carcinomas. We conclude that smoking is positively associated with lung tumor size at the moment of diagnosis.
Lung cancer; tumor size; epidemiologic characteristics; risk factors; CHRNA3
Telomere length plays an important role in chromosomal stability and tumorigenesis, and its measurement in peripheral white blood cell DNA may be a predictor of the development of lung cancer.
Using a new method - monochrome multiplex quantitative PCR -which reduces measurement variability, we compared telomere length relative to standard DNA in white blood cell DNA in 229 incident male lung cancer cases and 229 matched controls within the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male smokers.
Median (10th, 90th percentile) telomere length was 1.13 (0.86, 1.45) in cases and 1.08 (0.85, 1.38) in controls (P = 0.038). Telomere length was inversely associated with pack-years of smoking (Spearman correlation r = −0.16, P = 0.02) among controls. Compared to subjects with shorter telomere length (≤ median), subjects with greater telomere length (> median) had a 1.6-fold (95% CI, 1.06–2.36) increased risk of lung cancer. There was a significant linear relationship between quartiles of telomere length and risk of lung cancer (odds ratios (95% confidence intervals) by quartile: 1.00, 0.98 (0.55–1.73), 1.62 (0.95–2.77), and 1.50 (0.84–2.68); Ptrend = 0.05). In addition, subgroup analysis showed that greater telomere length was associated with increased risk of lung cancer among heavy smokers (> 38 years) (OR, 1.90; 95% CI, 1.00–3.59) but not among light smokers (≤ 38 years) (OR, 1.08; 95% CI, 0.56–2.11) (Pinteraction = 0.01).
Our results suggest that greater telomere length may be associated with higher risk of lung cancer among male smokers.
Telomere length; lung cancer; cohort study
Estrogen signaling pathways may play a significant role in the pathogenesis of non-small cell lung cancers (NSCLC) as evidenced by the expression of aromatase and estrogen receptors (ERα and ERβ) in many of these tumors. Here we examine whether ERα and ERβ levels in conjunction with aromatase define patient groups with respect to survival outcomes and possible treatment regimens. Immunohistochemistry was performed on a high-density tissue microarray with resulting data and clinical information available for 377 patients. Patients were subdivided by gender, age and tumor histology, and survival data was determined using the Cox proportional hazards model and Kaplan-Meier curves. Neither ERα nor ERβ alone were predictors of survival in NSCLC. However, when coupled with aromatase expression, higher ERβ levels predicted worse survival in patients whose tumors expressed higher levels of aromatase. Although this finding was present in patients of both genders, it was especially pronounced in women ≥ 65 years old, where higher expression of both ERβ and aromatase indicated a markedly worse survival rate than that determined by aromatase alone. Conclusion: Expression of ERβ together with aromatase has predictive value for survival in different gender and age subgroups of NSCLC patients. This predictive value is stronger than each individual marker alone. Our results suggest treatment with aromatase inhibitors alone or combined with estrogen receptor modulators may be of benefit in some subpopulations of these patients.
NSCLC; tissue microarray; aromatase; estrogen receptor; immunohistochemistry; prognosis