Barriers to lung cancer care: health professionals' perspectives.

PURPOSE: Globally, lung cancer is the most common cancer and the leading cause of cancer death. Problematically, there is a wide variation in the management and survival for people with lung cancer and there is limited understanding of the reasons for these variations. To date, the views of health professionals across relevant disciplines who deliver such care are largely absent. The present study describes Australian health professionals' views about barriers to lung cancer care to help build a research and action agenda for improving lung cancer outcomes. METHODS: Qualitative semi-structured interviews were undertaken with a multidisciplinary group of 31 Australian health professionals working in lung cancer care for an average of 16 years (range 1-35 yrs.; SD = 10.2) seeing a mean of 116 patients annually. RESULTS: Three superordinate themes were identified: illness representations, cultural influences, and health system context. Illness representations included three themes: symptoms attributed as smoking-related but not cancer, health-related stigma, and therapeutic nihilism. Cultural influence themes included Indigenous health care preferences, language and communication, and sociodemographic factors. Health system context included lack of regional services and distance to treatment, poor care coordination, lack of effective screening methods, and health professional behaviours. CONCLUSIONS: Fractured and locally isolated approaches routinely confound responses to the social, cultural and health system complexities that surround a diagnosis of lung cancer and subsequent treatment. Improving outcomes for this disadvantaged patient group will require government, health agencies, and the community to take an aggressive, integrated approach balancing health policy, treatment priorities, and societal values.

A survey of lung cancer in rural and remote Aboriginal and Torres Strait Islander communities in Queensland: health views that impact on early diagnosis and treatment.

BACKGROUND: Lung cancer incidence, mortality and hospitalisation rates are higher for Indigenous Australians compared with non-Indigenous Australians and increase again when living in more remote areas. If Indigenous Australians are made more aware of lung cancer through better access to health services and programmes, lung cancer outcomes might improve. AIM: We aimed to survey the level of lung cancer awareness in rural and remote Aboriginal and Torres Strait Islander communities and discover perceived barriers to timely diagnosis and treatment of lung cancer. METHODS: Interviews were conducted in three discrete outer regional and remote Aboriginal communities and one urban setting in Queensland. Participants included Aboriginal and Torres Strait Islander peoples from three target population groups: patients referred for medical treatment with symptoms suspicious of lung cancer or confirmed lung cancer; Indigenous health workers; community members aged 18 years and over. Participants gave written, informed consent. RESULTS: Of 51 community members and 14 Indigenous health workers, 32 reflected they knew very little about lung cancer, 60 cited smoking as the cause of lung cancer and 54 recognised warning symptoms as a prompt to seek healthcare. Indigenous health workers were not able to describe a healthcare pathway that would apply to a patient with suspected lung cancer. CONCLUSION: The two main barriers identified as impacting on quality healthcare were communication and follow-up processes. These could be addressed by service improvement activities.

Realising opportunities for evidence-based cancer service delivery and research: linking cancer registry and administrative data in Australia.

The traditional roles of Australian cancer registries have been incidence, mortality and survival surveillance although increasingly, roles are being broadened to include data support for health-service management and evaluation. In some Australian jurisdictions, cancer stage and other prognostic data are being included in registry databases and this is being facilitated by an increase in structured pathology reporting by pathology and haematology laboratories. Data linkage facilities are being extended across the country at national and jurisdictional level, facilitating data linkage between registry data and data extracts from administrative databases that include treatment, screening and vaccination data, and self-reported data from large population cohorts. Well-established linkage protocols exist to protect privacy. The aim is to gain better data on patterns of care, service outcomes and related performance indicators for health-service management and population health and health-services research, at a time of increasing cost pressures. Barriers include wariness among some data custodians towards releasing data and the need for clearance for data release from large numbers of research ethics committees. Progress is being made though, and proof of concept is being established.

Queensland Lung Cancer Screening Study: rationale, design and methods.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality in Australia. Screening using low-dose computed tomography (LDCT) can reduce lung cancer mortality. The feasibility of screening in Australia is unknown. This paper describes the rationale, design and methods of the Queensland Lung Cancer Screening Study. AIMS: The aim of the study is to describe the methodology for a feasibility study of lung cancer screening by LDCT in Australia. METHODS: The Queensland Lung Cancer Screening Study is an ongoing, prospective observational study of screening by LDCT at a single tertiary institution. Healthy volunteers at high risk of lung cancer (age 60-74 years; smoking history ≥30 pack years, current or quit within 15 years; forced expiratory volume in 1s ≥50% predicted) are recruited from the general public through newspaper advertisement and press release. Participants receive a LDCT scan of the chest at baseline, year 1 and year 2 using a multidetector helical computed tomography scanner and are followed up for a total of 5 years. Feasibility of screening will be assessed by cancer detection rates, lung nodule prevalence, optimal management strategies for lung nodules, economic costs, healthcare utilisation and participant quality of life. CONCLUSIONS: Studying LDCT screening in the Australian setting will help us understand how differences in populations, background diseases and healthcare structures modulate screening effectiveness. This information, together with results from overseas randomised studies, will inform and facilitate local policymaking.

Screening for activating EGFR mutations in surgically resected nonsmall cell lung cancer.

The clinical applicability of screening surgically resected nonsmall cell lung cancer (NSCLC) tumour tissue and serum for activating epidermal growth factor receptor (EGFR) mutation is unknown. Furthermore, the comparative accuracy of inexpensive EGFR mutation tests, mutant-enriched (ME)-PCR and high-resolution melt (HRM) has not been determined. Lung tumour DNA from 522 surgically resected stage I-IV NSCLC and matched serum DNA from a subset of 64 subjects was analysed for EGFR mutations in exons 19 and 21 using ME-PCR and HRM. Additionally, 97 subjects had previous EGFR DNA sequencing data available for comparison. ME-PCR and HRM detected EGFR mutations in 5% (27 out of 522) of tumour samples. Compared to DNA sequencing, ME-PCR had a sensitivity of 100% and specificity of 99%, while HRM had 100% sensitivity and specificity. Six subjects with EGFR mutation tumours had matched serum, where ME-PCR detected mutations in three samples and HRM in two samples. In the cohort of never-smoker subjects, those with EGFR mutated tumours had worse survival compared with wild-type tumours (30 versus 49 months; p=0.017). ME-PCR and HRM have similar accuracy in detecting EGFR mutations but the prognostic implications of the mutations in resected NSCLC warrants further study.

Exploratory study of the 'weekend effect' for acute medical admissions to public hospitals in Queensland, Australia.

AIMS: To determine whether in-hospital deaths of patients admitted through emergency departments with acute exacerbations of chronic obstructive pulmonary disease (COPD), acute myocardial infarction, intracerebral haemorrhage and acute hip fracture are increased by weekend versus weekday admission (the 'weekend effect'). METHODS: We performed a retrospective analysis of statewide administrative data from public hospitals in Queensland, Australia, during the 2002/2003-2006/2007 financial years. The primary outcome was 30-day in-hospital mortality. The secondary outcome of 2-day in-hospital mortality helped determine whether increased mortality of weekend admissions was closely linked to weekend medical care. RESULTS: During the study period, there were 30 522 COPD, 17 910 acute myocardial infarction, 4183 acute hip fracture and 1781 intracerebral haemorrhage admissions. There was no significant weekend effect on 30-day in-hospital mortality for COPD (adjusted risk ratio = 0.92, 95% CI: 0.81-1.04, P= 0.222), intracerebral haemorrhage (adjusted risk ratio = 1.01, 95% CI: 0.86-1.16, P= 0.935) or acute hip fracture (adjusted risk ratio = 0.78, 95% CI: 0.54-1.03, P= 0.13). There was a significant weekend effect for acute myocardial infarction (adjusted risk ratio = 1.15, 95% CI: 1.03-1.26, P= 0.007). Two-day in-hospital mortality showed similar results. CONCLUSION: This is the first Australian study on the 'weekend effect' (in a cohort other than neonates), and the first study worldwide to assess specifically the weekend effect among COPD patients. Observed patterns were consistent with overseas research. There was a significant weekend effect for myocardial infarction. Further research is needed to determine whether location (e.g. rural), clinical (e.g. disease severity) and service provision factors (e.g. access to invasive procedures) influence the weekend effect for acute medical conditions in Australia.

Genetic association study of CYP1A1 polymorphisms identifies risk haplotypes in nonsmall cell lung cancer.

Lung cancer remains a leading cause of disease globally, with smoking being the largest single cause. Phase I enzymes, including cytochrome P(450), family 1, subfamily A, polypeptide 1 (CYP1A1), are involved in the activation of carcinogens, such as polycyclic aromatic hydrocarbons, to reactive intermediates that are capable of binding covalently to DNA to form DNA adducts, potentially initiating the carcinogenic process. The aim of the present study was to investigate the association of CYP1A1 gene polymorphisms and haplotypes with lung cancer risk. A case-control study was carried out on 1,040 nonsmall cell lung cancer (NSCLC) cases and 784 controls to investigate three CYP1A1 variants, CYP1A1*2A (rs4646903; thymidine to cytosine substitution at nucleotide 3801 (3801T>C)), CYP1A1*2C (rs1048943; 2455A>G; substitution of isoleucine 462 with valine (exon 7)) and CYP1A1*4 (rs1799814; 2453C>A; substitution of threonine 461 with asparagine (exon 7)) using PCR restriction fragment length polymorphism methods. The CYP1A1*2A and CYP1A1*2C variants were significantly over-represented in NSCLC cases compared with controls, whereas the CYP1A1*4 variant was under-represented. CYP1A1 haplotypes (in allele order CYP1A1*4, CYP1A1*2C, CYP1A1*2A) CGC and CGT were associated with an increased risk of lung cancer, whereas AAT was associated with decreased lung cancer risk in this population. The present study has identified risk haplotypes for CYP1A1 in NSCLC and confirmed that CYP1A1 polymorphisms are a minor risk factor for NSCLC.

Genetic susceptibility to the respiratory effects of air pollution.

There is large variation between individuals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative stress genes (NQO1, GSTM1, GSTP1) modify respiratory symptoms, lung function, biomarkers and risk of asthma. Inflammatory gene polymorphisms (TNF) influence the lung function response to ozone, and the effect of different levels of ozone on the development of asthma. Polymorphisms in oxidative stress genes (GSTM1, GSTP1) alter the response to combined exposure to ragweed pollen and diesel exhaust particles. Importantly, polymorphisms in an oxidative stress gene (GSTM1) have predicted patients with asthma who benefit from antioxidant supplementation in Mexico City, which has chronically high ozone exposure. Genetic linkage studies of families have not been feasible for studying the effects of air pollution in humans, but some progress has been made with pedigrees of specially bred mice, in identifying chromosomal regions linked to effects of ozone or particles. A high priority now, in addition to avoiding exposure in the most susceptible people, is to clearly identify the most effective and safe chemopreventive agents for individuals who are genetically susceptible to the adverse effects of air pollution (eg, antioxidants to be taken during high ozone levels).

Genetic susceptibility to the respiratory effects of air pollution.

There is large variation between individuals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative stress genes (NQO1, GSTM1, GSTP1) modify respiratory symptoms, lung function, biomarkers and risk of asthma. Inflammatory gene polymorphisms (TNF) influence the lung function response to ozone, and the effect of different levels of ozone on the development of asthma. Polymorphisms in oxidative stress genes (GSTM1, GSTP1) alter the response to combined exposure to ragweed pollen and diesel exhaust particles. Importantly, polymorphisms in an oxidative stress gene (GSTM1) have predicted patients with asthma who benefit from antioxidant supplementation in Mexico City, which has chronically high ozone exposure. Genetic linkage studies of families have not been feasible for studying the effects of air pollution in humans, but some progress has been made with pedigrees of specially bred mice, in identifying chromosomal regions linked to effects of ozone or particles. A high priority now, in addition to avoiding exposure in the most susceptible people, is to clearly identify the most effective and safe chemopreventive agents for individuals who are genetically susceptible to the adverse effects of air pollution (eg, antioxidants to be taken during high ozone levels).

Systematic review of multidisciplinary teams in the management of lung cancer.

BACKGROUND: In several countries, clinical practice guidelines for lung cancer recommend that multidisciplinary (MD) teams should be used to plan the management of all lung cancer patients. We conducted a systematic review to evaluate and critically appraise the effectiveness of multidisciplinary teams for lung cancer. MATERIALS AND METHODS: Medline searches were carried out for the period 1984 to July 2007. We included any study that mentioned team working among specialists with diagnostic and curative therapeutic intent, where members of the team met at a specified time, either in person or by video or teleconferencing, to discuss the diagnosis and management of patients with suspected lung cancer. All study designs were included. We were particularly interested in whether multidisciplinary working improved survival but also considered other outcomes such as practice patterns and waiting times. RESULTS: Sixteen studies met the criteria for inclusion. Statistical pooling was not possible due to clinical heterogeneity. Only two of the primary studies reported an improvement in survival. Both were before-and-after designs, providing weak evidence of a causal association. Evidence of the effect of MD teams was stronger for changing patient management than for affecting survival. Six of the studies reported an increase in the percentage of patients undergoing surgical resection or an increase in the percentage of patients undergoing chemotherapy or radiotherapy with curative intent. CONCLUSION: This systematic review shows limited evidence linking MD teams with improved lung cancer survival. This does not mean that MD teams do not improve survival, merely that currently available evidence of this is limited. It seems intuitively obvious that MD teams should improve outcomes for lung cancer patients, but there are difficulties in conducting randomised trials to show this. The best way forward would be prospective evaluation of the effectiveness of MD teams as they are implemented, paying particular attention to collecting data on potential confounders.

Gene expression of lung squamous cell carcinoma reflects mode of lymph node involvement.

Tumour, node, metastasis staging is essential for lung cancer management. However, similarly staged cancers may have markedly different prognoses, indicating that stage cannot completely explain tumour behaviour. While ipsilateral hilar node involvement is designated N1, the current authors hypothesised that primary tumours involving nodes by direct extension are biologically distinct from those involving nodes through lymphatic metastasis. Microarrays were used to investigate the gene expression profiles of 59 primary lung squamous cell carcinomas, comparing N0 tumours (n = 35), N1 tumours by direct extension (N1d; n = 8), and N1/N2 tumours by lymphatic metastasis (N1/N2m; n = 16). Hierarchical clustering using 125 genes differentially expressed between N0 and N1/N2m tumours found N1d tumours clustered with N0 tumours. Class prediction modelling found the expression profiles of all eight N1d tumours were more similar to N0 than to N1/N2m tumours. The present study demonstrates for the first time that N1 tumours directly invading hilar nodes are genomically different to those that metastasise via lymphatics. Independent reports suggest that tumours with direct, rather than metastatic node involvement have better outcomes. Consequently, the data suggest that there is a need to re-evaluate the N1 staging definition in lung cancer. This is relevant for prognosis prediction and also for clinical management, particularly in selecting those patients most likely to benefit from adjuvant chemotherapy.

Inhaled corticosteroids for stable chronic obstructive pulmonary disease.

BACKGROUND: The role of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) has been the subject of much controversy. Major international guidelines recommend selective use of ICS. Recently published meta-analyses have reported conflicting findings on the effects of inhaled steroid therapy in COPD. OBJECTIVES: The objective of the review is to determine the efficacy of regular use of inhaled corticosteroids in patients with stable COPD. SEARCH STRATEGY: A pre-defined search strategy was used to search the Cochrane Airways Group specialised register for relevant literature. Searches are current as of October 2006. SELECTION CRITERIA: We selected randomised trials comparing any dose of any type of inhaled steroid with a placebo control in patients with COPD. Acute bronchodilator reversibility to short term beta2-agonists and bronchial hyperresponsiveness were not exclusion criteria. The a priori primary outcome was change in lung function. Data on mortality, exacerbations, quality of life and symptoms, rescue bronchodilator use, exercise capacity, biomarkers and safety were also analysed. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: Forty-seven primary studies with 13,139 participants met the inclusion criteria. Medium term use of ICS (> two months and up to six months) resulted in a small improvement in FEV1 in some studies. Long term use of ICS (> six months) did not significantly reduce the rate of decline in FEV1 in COPD patients (weighted mean difference (WMD) 5.80 ml/year with ICS over placebo, 95% CI -0.28 to 11.88, 2333 participants). There was no statistically significant effect on mortality in COPD patients (OR 0.98, 95% CI 0.83 to 1.16, 8390 participants). Long term use of ICS reduced the mean rate of exacerbations in those studies where pooling of data was possible (WMD -0.26 exacerbations per patient per year, 95% CI -0.37 to -0.14, 2586 participants). ICS slowed the rate of decline in quality of life, as measured by the St George's Respiratory Questionnaire (WMD -1.22 units/year, 95% CI -1.83 to -0.60, 2507 participants). Response to ICS was not predicted by oral steroid response, bronchodilator reversibility or bronchial hyper-responsiveness in COPD patients. There was an increased risk of oropharyngeal candidiasis (OR 2.49, 95% CI 1.78 to 3.49, 4380 participants) and hoarseness. The few long term studies that measured bone effects generally showed no major effect on fractures and bone mineral density over 3 years. AUTHORS' CONCLUSIONS: Patients and clinicians should balance the potential benefits of inhaled steroids in COPD (reduced rate of exacerbations, reduced rate of decline in quality of life), against the known increase in local side effects (oropharyngeal candidiasis and hoarseness). The risk of long term adverse effects is unknown.

Cochrane systematic reviews of treatments for lung cancer.

Morbidity and mortality from lung cancer is a major burden to global health. The integration of expert clinical experience, patient preference and high-quality evidence, including Cochrane systematic reviews, can only help improve outcomes from this highly lethal condition.

Cytokine gene polymorphisms in idiopathic pulmonary fibrosis.

Pro- and anti-fibrotic cytokine gene polymorphisms may affect expression of idiopathic pulmonary fibrosis (IPF). The aims of the present case-control study were to examine polymorphisms in the IL-6, transforming growth factor (TGF)-beta 1, tumour necrosis factor (TNF)-alpha and interleukin-1 (IL-1)Ra genes in patients with IPF (n = 22) -compared to healthy controls (n = 140). Genotyping was performed on DNA extracted from peripheral blood lymphocytes, using polymerase chain reaction - restriction fragment length polymorphism with gene polymorphisms determined according to -published techniques. The following sites were examined: (i) IL-1Ra*1-5 (86 bp variable tandem repeat intron 2), (ii) IL-6 (-174G > C), (iii) TNF-alpha (-308G > A) and (iv) TGF-beta 1 (Arg25Pro). The TNF-alpha (-308 A) allele was over-represented in the IPF (p(corr) = 0.004) group compared to controls. Risk of IPF was significant for heterozygotes for: (i) the TNF-alpha (-308 A) allele (A/G) (odds ratio (OR) 2.9; 95% confidence interval (CI) 1.2-7.2; P = 0.02), (ii) homozygotes (A/A) (OR 13.9; 95%CI 1.2-160; P = 0.04) and (iii) carriage of the allele (A/A + A/G) (OR 4; 95%CI 1.6-10.2; P = 0.003). The distribution of alleles and genotypes for IL-6, TGF-beta 1 and IL-1Ra between the two groups was not significantly different. This is the third study to independently confirm that there is a significant association of the TNF-alpha (-308 A) allele with IPF. Further research is needed to assess the utility of cytokine gene polymorphisms as markers of disease -susceptibility.

Lung cancer. 9: Molecular biology of lung cancer: clinical implications.

It has been hypothesised that clinically evident lung cancers have accumulated many different genetic or epigenetic abnormalities in oncogenes and/or tumour suppressor genes. This notion has important clinical ramifications. Recent developments in our knowledge of the molecular biology of lung cancer are reviewed, with particular reference to genetic abnormalities in tumour suppressor gene inactivation and overactivity of growth promoting oncogenes. These changes lead to the "hallmarks of lung cancer". These hallmarks are the new rational targets for early detection, prevention, and treatment of lung cancer.

Mannose-binding lectin gene polymorphism predicts hospital admissions for COPD infections.

Infection frequently causes exacerbations of chronic obstructive pulmonary disease (COPD). Mannose-binding lectin (MBL) is a pattern-recognition receptor that assists in clearing microorganisms. Polymorphisms in the MBL2 gene reduce serum MBL levels and are associated with risk of infection. We studied whether the MBL2 codon 54 B allele affected serum MBL levels, admissions for infective exacerbation in COPD and disease susceptibility. Polymorphism frequency was determined by PCR-RFLP in 200 COPD patients and 104 smokers with normal lung function. Serum MBL was measured as mannan-binding activity in a subgroup of 82 stable COPD patients. Frequency of COPD admissions for infective exacerbation was ascertained for a 2-year period. The MBL2 codon 54 B allele reduced serum MBL in COPD patients. In keeping, patients carrying the low MBL-producing B allele had increased risk of admission for infective exacerbation (OR 4.9, P(corrected)=0.011). No association of MBL2 genotype with susceptibility to COPD was detected. In COPD, serum MBL is regulated by polymorphism at codon 54 in its encoding gene. Low MBL-producing genotypes were associated with more frequent admissions to hospital with respiratory infection, suggesting that the MBL2 gene is disease-modifying in COPD. MBL2 genotype should be explored prospectively as a prognostic marker for infection risk in COPD.

5' CpG island methylation of the FHIT gene is correlated with loss of gene expression in lung and breast cancer.

Allele loss and loss of expression of fragile histidine triad (FHIT), a putative tumor suppressor gene located in chromosome region 3p14.2, are frequent in several types of cancers. Tumor-acquired methylation of promoter region CpG islands is one method for silencing tumor suppressor genes. We investigated 5' CpG island methylation of the FHIT gene in 107 primary non-small cell lung cancer (NSCLC) samples and corresponding nonmalignant lung tissues, 39 primary breast carcinomas, as well as in 49 lung and 22 breast cancer cell lines by a methylation-specific PCR assay. In addition, we analyzed brushes from the bronchial epithelium of 35 heavy smokers without cancer. FHIT methylation was detected in 37% of primary NSCLCs, 31% of primary breast cancers, and 65% of lung and 86% of breast cancer cell lines. The frequency of methylation in small cell and NSCLC cell lines were identical. Methylation was found in 9% of the corresponding nonmalignant lung tissues and in 17% of bronchial brushes from heavy cigarette smokers. FHIT methylation was significantly correlated with loss of FHIT mRNA expression by Northern blot analysis in lung cancer cell lines and with loss of Fhit expression in NSCLC and breast tumors by immunostaining. We conclude that methylation of FHIT is a frequent event in NSCLC and breast cancers and is an important mechanism for loss of expression of this gene. Methylation of FHIT commences during lung cancer pathogenesis and may represent a marker for risk assessment.