P. V. Zimmerman

Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen

Purpose: To describe the Food and Drug Administration (FDA) review and approval of erlotinib (Tarceva, OSI Pharmaceuticals, Melville, NY) for treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. Experimental Design: The FDA reviewed raw data in electronic format from a randomized controlled clinical trial comparing erlotinib with placebo in patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. Results: Patients were randomized in a 2:1 ratio (erlotinib, n = 488 and placebo, n = 243). Erlotinib was superior to placebo for survival, progression-free survival, and tumor response rate. Exploratory analyses indicate that epidermal growth factor receptor status may be an important predictor of the erlotinib survival effect. Rash (75% versus 17%) and diarrhea (54% versus 18%) in the erlotnib and placebo group respectively were the most common adverse events. Severe rash occurred in 9% and severe diarrhea in 6% of erlotinib-treated patients and each resulted in study discontinuation in 1% of patients. Dose reductions were required for 10% of patients with rash and 4% of patients with diarrhea. Conclusions: On November 18, 2004, the FDA granted erlotinib regular approval for treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. The applicant has committed to conduct post-marketing clinical trials to assess further the effect of epidermal growth factor receptor expression, measured with immunohistochemical staining, on erlotinib treatment effect.

PLOIDY AS A PROGNOSTIC DETERMINANT IN SURGICALLY TREATED LUNG CANCER

The usefulness of tumour ploidy as a prognostic determinant in lung cancer was evaluated in a group of 100 surgically treated patients. Archival paraffin sections of the tumours were analysed by flow cytometry. 45% of tumours were aneuploid and 55% were diploid. Overall, patients with aneuploid tumours had significantly shorter survival (p less than 0.0005) than those with diploid tumours. The subset of patients without nodal involvement at operation and with diploid tumours had a particularly long survival rate. Of these 45 patients 41 (91%) were alive at 2 years compared with only 16 (55%) of the 29 with aneuploid tumours (p less than 0.05). A group with such a favourable prognosis has not previously been recognised except when staging is based on total mediastinal nodal clearance. Ploidy was found to be independent of age, sex, type of operation, site of primary tumour, histology, or TNM category. On Cox multivariate analysis ploidy was the most important and independent prognostic determinant. Therefore, in patients with operable lung cancer, ploidy should be taken into account in planning of management, in estimation of prognosis, and in stratification for treatment trials.

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).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).

Survival of patients with biopsy-proven usual interstitial pneumonia and nonspecific interstitial pneumonia

This is the first Australian study to examine survival and clinical characteristics in biopsy-proven idiopathic interstitial pneumonia. A cohort of 70 patients from a single institution between January 1990 and December 1999 was reviewed. All patients were Caucasian, 23 (33%) female. Mean age±sd at diagnosis was 60±12 yrs for males and 54±14 yrs for females. A total 24% of patients had never smoked. The histopathological diagnoses were usual interstitial pneumonia (UIP) (n=59), nonspecific interstitial pneumonia (NSIP) (n=7), desquamative interstitial pneumonia (n=3) and acute interstitial pneumonia (n=11). Clinical and functional characteristics of the two main histological subgroups of UIP and NSIP showed significantly older patients in the UIP group and a significantly lower mean forced expiratory volume in one second (FEV1) in the NSIP group. Median survival for UIP was 78 months compared with 178 months for NSIP. No survival difference between treated and untreated patients with UIP was found. Multivariate analysis revealed smoking alone to be predictive of poorer survival. This study demonstrates the best median survival for usual interstitial pneumonia of available series and confirms a survival difference between usual interstitial pneumonia and nonspecific interstitial pneumonia. Furthermore, the reported results may have implications for treatment timing using conventional protocols currently recommended.

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, Pcorrected=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.

Loss of Fhit expression in non-small-cell lung cancer: correlation with molecular genetic abnormalities and clinicopathological features.

The FHIT gene is located at a chromosomal site (3p14.2) which is commonly affected by translocations and deletions in human neoplasia. Although FHIT alterations at the DNA and RNA level are frequent in many types of tumours, the biological and clinical significance of these changes is not clear. In this study we aimed at correlating loss of Fhit protein expression with a large number of molecular genetic and clinical parameters in a well-characterized cohort of non-small-cell lung cancers (NSCLCs). Paraffin sections of 99 non-small-cell carcinomas were reacted with an anti-Fhit polyclonal antibody in a standard immunohistochemical reaction. Abnormal cases were characterized by complete loss of cytoplasmic Fhit staining. The Fhit staining results were then correlated with previously obtained clinical and molecular data. Fifty-two of 99 tumours lacked cytoplasmic Fhit staining, with preserved reactivity in adjacent normal cells. Lack of Fhit staining correlated with: loss of heterozygosity (LOH) at the FHIT 3p14.2 locus, but not at other loci on 3p; squamous histology; LOH at 17p13 and 5q but not with LOH at multiple other suspected tumour suppressor gene loci; and was inversely correlated with codon 12 mutations in K- ras. Fhit expression was not correlated overall with a variety of clinical parameters including survival and was not associated with abnormalities of immunohistochemical expression of p53, RB, and p16. All of these findings are consistent with loss of Fhit protein expression being as frequent an abnormality in lung cancer pathogenesis as are p53 and p16 protein abnormalities and that such loss occurs independently of the commitment to the metastatic state and of most other molecular abnormalities.

Cytokine gene polymorphisms in idiopathic pulmonary fibrosis.

Abstract

A new method for objective identification and measurement of airway lumen in paediatric flexible videobronchoscopy

Background: Accurate measurements of airway and lesion dimensions are important to the developmental progress of paediatric bronchoscopy. The malacia disorders are an important cause of respiratory morbidity in children, but no methods are currently available to measure these lesions or the airway lumen accurately. A new measurement technique is described here. Methods: The magnification power of a paediatric videobronchoscope was defined and a simple and user friendly computer based program (Image J) was used to develop an objective technique (colour histogram mode technique, CHMT) for measurement of the airway lumen. Results: In vivo intra-observer and inter-observer repeatability coefficients for repeated area measurements from 28 images using the Bland-Altman method were 0.9 mm2 and 1.6 mm2, respectively. The average intraclass correlation coefficient for repeated measurements of area was 0.93. In vitro validation measurements using a 2 mm diameter tube resolved radii measurements to within 0.1 mm (coefficient of variability 8%). An “acceptable result” was defined in 92% of 734 images completed with the CHMT alone and 8% with its modification. The success rate for two of three images being within 10% of each other’s area was 100%. Measurements of cricoid cross sectional areas from 116 patients compared with expected airway areas for age derived from endotracheal tube sizes were comparable. Conclusions: The CHMT method of identifying and measuring airway dimensions is objective, accurate, and versatile and, as such, is important to the future development of flexible videobronchoscopy.

Exhaled breath analysis for lung cancer

Early diagnosis of lung cancer results in improved survival compared to diagnosis with more advanced disease. Early disease is not reliably indicated by symptoms. Because investigations such as bronchoscopy and needle biopsy have associated risks and substantial costs, they are not suitable for population screening. Hence new easily applicable tests, which can be used to screen individuals at risk, are required. Biomarker testing in exhaled breath samples is a simple, relatively inexpensive, non-invasive approach. Exhaled breath contains volatile and non-volatile organic compounds produced as end-products of metabolic processes and the composition of such compounds varies between healthy subjects and subjects with lung cancer. Many studies have analysed the patterns of these compounds in exhaled breath. In addition studies have also reported that the exhaled breath condensate (EBC) can reveal gene mutations or DNA abnormalities in patients with lung cancer. This review has summarised the scientific evidence demonstrating that lung cancer has distinct chemical profiles in exhaled breath and characteristic genetic changes in EBC. It is not yet possible to accurately identify individuals with lung cancer in at risk populations by any of these techniques. However, analysis of both volatile organic compounds in exhaled breath and of EBC have great potential to become clinically useful diagnostic and screening tools for early stage lung cancer detection.

Assessment of the clinical usefulness of nebulised ipratropium bromide in patients with chronic airflow limitation.

The effect of adding nebulised ipratropium bromide to bronchodilator treatment was studied in 20 patients with severe chronic airflow limitation. Maintenance theophylline with or without a steroid preparation was continued and comparison made between placebo, nebulised salbutamol, and a combination of nebulised salbutamol and ipratropium. Although the mean FEV1 values showed the combination to produce a small but significant increase in peak bronchodilatation over the effect of salbutamol alone, there were eight patients in whom no clinically useful improvement occurred. The remaining 12 patients did obtain clinically useful improvement in the magnitude or the duration of bronchodilatation (or both) as a result of the added ipratropium. The conclusion is that individual patients with chronic airflow limitation responded to the addition of nebulised ipratropium bromide in a variable way. Patients who could obtain additional benefit from ipratropium need to be identified by an appropriate reversibility study before its inclusion in their bronchodilator treatment.