Sequential screening for lung cancer in a high-risk group: randomised controlled trial: LungSEARCH: a randomised controlled trial of Surveillance using sputum and imaging for the EARly detection of lung Cancer in a High-risk group.

BACKGROUND: Low-dose computed tomography (LDCT) screening detects early-stage lung cancer and reduces mortality. We proposed a sequential approach targeted to a high-risk group as a potentially efficient screening strategy. METHODS: LungSEARCH was a national multicentre randomised trial. Current/ex-smokers with mild/moderate chronic obstructive pulmonary disease (COPD) were allocated (1:1) to have 5 years surveillance or not. Screened participants provided annual sputum samples for cytology and cytometry, and if abnormal were offered annual LDCT and autofluorescence bronchoscopy (AFB). Those with normal sputum provided annual samples. The primary end-point was the percentage of lung cancers diagnosed at stage I/II (nonsmall cell) or limited disease (small cell). RESULTS: 1568 participants were randomised during 2007-2011 from 10 UK centres. 85.2% of those screened provided an adequate baseline sputum sample. There were 42 lung cancers among 785 screened individuals and 36 lung cancers among 783 controls. 54.8% (23 out of 42) of screened individuals versus 45.2% (14 out of 31) of controls with known staging were diagnosed with early-stage disease (one-sided p=0.24). Relative risk was 1.21 (95% CI 0.75-1.95) or 0.82 (95% CI 0.52-1.31) for early-stage or advanced cancers, respectively. Overall sensitivity for sputum (in those randomised to surveillance) was low (40.5%) with a cumulative false-positive rate (FPR) of 32.8%. 55% of cancers had normal sputum results throughout. Among sputum-positive individuals who had AFB, sensitivity was 45.5% and cumulative FPR was 39.5%; the corresponding measures for those who had LDCT were 100% and 16.1%, respectively. CONCLUSIONS: Our sequential strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the efficiency of lung cancer screening.

Research in progress--LungSEARCH: a randomised controlled trial of surveillance for the early detection of lung cancer in a high-risk group.

Low-dose CT screening for lung cancer is effective but expensive. Therefore, cheaper or more focused screening strategies may be required. LungSEARCH is a randomised prospective trial of 1568 high-risk individuals (ie, current or former moderate to heavy smokers with mild/moderate COPD) who undergo either annual sputum cytology/cytometry testing or no screening. Those with abnormal sputum then receive annual CT and fluorescent bronchoscopy for the remainder of 5 years, to identify early stage lung cancer. It is hoped that these simple initial tests could identify those requiring expensive CT scans, and the aim is to demonstrate a stage shift towards early stage cancers.Trial registration numbers ISRCTN: ISRCTN80745975, clinicaltrials.gov: NCT00512746.

Attitudes to participation in a lung cancer screening trial: a qualitative study.

BACKGROUND: Earlier diagnosis of lung cancer is key to reducing mortality. New evidence suggests that smokers have negative attitudes to screening and participation in lung cancer screening trials is poor (<1 in 6 of those eligible). Understanding participation is important since uptake in screening trials is likely to predict uptake in screening programmes. A qualitative study of people accepting and declining participation in the Lung-SEARCH screening trial was conducted. Two questions were addressed: Are the screening methods offered acceptable to patients? Why do some people take part and others decline? METHODS: The qualitative study used semi-structured interviews with 60 respondents from three groups: (a) trial participants providing an annual sputum sample; (b) trial participants with a sputum sample showing abnormal cytology and thus undergoing annual CT scanning and bronchoscopy; and (c) those declining trial participation. RESULTS: Most respondents (48/60, 80%) viewed sputum provision, CT scanning and bronchoscopy as largely acceptable. Those declining trial participation described fear of bronchoscopy, inconvenience of travelling to hospitals for screening investigations and perceived themselves as having low susceptibility to lung cancer or being too old to benefit. Patients declining participation discounted their risk from smoking and considered negative family histories and good health to be protective. Four typological behaviours emerged within those declining: 'too old to be bothered', 'worriers', 'fatalists' and 'avoiders'. CONCLUSION: Sputum provision, CT scanning and bronchoscopy are largely acceptable to those participating in a screening trial. However, the decision to participate or decline reflects a complex balance of factors including acceptability and convenience of screening methods, risk perception, altruism and self-interest. Improving practical and changing cognitive aspects of participation will be key to improving uptake of lung cancer screening.

Screening for lung cancer: is this the way forward?

While low-dose CT scans have been shown to detect greater numbers of early lung cancers than conventional CXR, the first randomized trial of CT versus CXR screening in more than 50 000 subjects has shown a 20% reduction in mortality with CT. There are several other randomized trials in progress. CT scanning may be a useful technique for identifying lung cancer at an earlier stage and may reduce mortality. However, before it can be used on a wider scale, issues such as overdiagnosis bias, cost-effectiveness, false positive findings of multiple noncalcified nodules and the willingness of the relevant population to accept CT scanning need to be evaluated. There is still very little information on the cost per life-year saved as a result of CT scanning, as the data to date is very imprecise. There is no evidence that screening programs influence smoking rates despite the inclusion of cessation programs in many trials. Furthermore, if CT screening is adopted, much work is needed to persuade individuals at high risk, mostly current or former heavy smokers with some airflow obstruction, to participate in a screening program.

Lung cancer: progress in diagnosis, staging and therapy.

Lung cancer remains one of the greatest medical challenges with nearly 1.5 million new cases worldwide each year and a growing tobacco epidemic in the developing world. This review summarizes briefly the current status in growing areas of clinical research. The value of screening for early disease is not yet established and trials to see if mortality can be improved as a result are in progress. Better and more accurate staging will both streamline investigation and prove cost-effective once ultrasound-guided biopsy and aspiration of mediastinal nodes become universally accepted. This, allied to the new staging classification, will improve selection of cases for surgery, intensive multimodality therapy and for adjuvant treatment postoperatively. Much still needs to be done to refine staging as within a particular stage group, the outcome shows great variation. More information is needed on the genetic make-up in some groups of tumours and not just their size; that is, more biological data on tumour growth patterns are likely to be at least as discriminating. The place of the stem cell theory of tumorigenesis is also explored in this paper. Finally, targeted therapy for advanced non-small-cell lung cancer is highlighted as a development with early promise, but still much clarification is required, before it can be considered as a universal approach in late disease.

Ensuring the right PET scan for the right patient.

Guidelines issued by the National Institute for Clinical Excellence (NICE) in the England and Wales recommend that rapid access to (18)F-deoxyglucose positron emission tomography (FDG-PET) is made available to all appropriate patients with non-small-cell lung cancer (NSCLC). The clinical evidence for the benefits of PET scanning in NSCLC is substantial, showing that PET has high accuracy, sensitivity and specificity for disease staging, as well as pre-therapeutic assessment in candidates for surgery and radical radiotherapy. Moreover, PET scanning can provide important information to assist in radiotherapy treatment planning, and has also been shown to correlate with responses to treatment and overall outcomes. If the government cancer waiting time targets are to be met, rapid referral from primary to secondary healthcare is essential, as is early diagnostic referral within secondary and tertiary care for techniques such as PET. Studies are also required to explore new areas in which PET may be of benefit, such as surveillance studies in high-risk patients to allow early diagnosis and optimal treatment, while PET scanning to identify treatment non-responders may help optimise therapy, with benefits both for patients and healthcare resource use. Further studies are needed into other forms of lung cancer, including small-cell lung cancer and mesothelioma. In conclusion, PET scanning has the potential to improve the diagnosis and management of lung cancer for many patients. Further studies and refinement of guidelines and procedures will maximise the benefit of this important technique.

Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes: ACCP evidenced-based clinical practice guidelines (2nd edition).

BACKGROUND: This chapter of the guidelines is intended to provide an evidence-based assessment of the initial evaluation of patients recognized as having lung cancer and the recognition of paraneoplastic syndromes. METHODS: The current medical literature that is applicable to this issue was identified by a computerized search and was evaluated using standardized methods. Recommendations were framed using the approach described by the Health and Science Policy Committee of the American College of Chest Physicians. RESULTS: Patients with lung cancer usually present with multiple symptoms, both respiratory related and constitutional. There is usually a time delay between symptom recognition by the patient and the ultimate diagnosis of lung cancer by the physician. Whether this time delay impacts prognosis is unclear, but delivering timely and efficient care is an important component in its own right. Lung cancer may be accompanied by a variety of paraneoplastic syndromes. These syndromes may not necessarily preclude treatment with a curative intent. CONCLUSIONS: The initial evaluation of the patient with known or suspected lung cancer should include an assessment of symptoms, signs, and laboratory test results in a standardized manner as a screen for identifying those patients with paraneoplastic syndromes and a higher likelihood of metastatic disease.

Lung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial.

BACKGROUND: The diagnosis and staging of lung cancer is an important process that identifies treatment options and guides disease prognosis. We aimed to assess endobronchial ultrasound-guided transbronchial needle aspiration as an initial investigation technique for patients with suspected lung cancer. METHODS: In this open-label, multicentre, pragmatic, randomised controlled trial, we recruited patients who had undergone a CT scan and had suspected stage I to IIIA lung cancer, from six UK centres and randomly assigned them to either endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) or conventional diagnosis and staging (CDS), for further investigation and staging. If a target node could not be accessed by EBUS-TBNA, then endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was allowed as an alternative procedure. Randomisation was stratified according to the presence of mediastinal lymph nodes measuring 1 cm or more in the short axis and by recruiting centre. We used a telephone randomisation method with permuted blocks of four generated by a computer. Because of the nature of the intervention, masking of participants and consenting investigators was not possible. The primary endpoint was the time-to-treatment decision after completion of the diagnostic and staging investigations and analysis was by intention-to-diagnose. This trial is registered with ClinicalTrials.gov, number NCT00652769. FINDINGS: Between June 10, 2008, and July 4, 2011, we randomly allocated 133 patients to treatment: 66 to EBUS-TBNA and 67 to CDS (one later withdrew consent). Two patients from the EBUS-TBNA group underwent EUS-FNA. The median time to treatment decision was shorter with EBUS-TBNA (14 days; 95% CI 14-15) than with CDS (29 days; 23-35) resulting in a hazard ratio of 1·98, (1·39-2·82, p<0·0001). One patient in each group had a pneumothorax from a CT-guided biopsy sample; the patient from the CDS group needed intercostal drainage and was admitted to hospital. INTERPRETATION: Transbronchial needle aspiration guided by endobronchial ultrasound should be considered as the initial investigation for patients with suspected lung cancer, because it reduces the time to treatment decision compared with conventional diagnosis and staging techniques. FUNDING: UK Medical Research Council.

Measurement of changes in cytochrome oxidase redox state during obstructive sleep apnea using near-infrared spectroscopy.

STUDY OBJECTIVES: To use near-infrared spectroscopy to investigate the effect of obstructive sleep apnea on cytochrome oxidase, the terminal enzyme of the mitochondrial respiratory chain. DESIGN: Observational study. SETTING: Teaching hospital sleep unit. PATIENTS: Subjects with diagnosed moderate to severe obstructive sleep apnea were recruited from the sleep clinic. INTERVENTIONS: Subjects were invited to attend 2 daytime sleep-study sessions, which included near-infrared monitoring of cerebral oxygenation and cytochrome-oxidase oxidation state. In addition, in study session 1, full polysomnography was performed (8 subjects, 303 apneas), and in study session 2, arterial oxygen saturation, cerebral blood flow velocity, and blood pressure were monitored (7 subjects, 287 apneas). MEASUREMENTS AND RESULTS: In study session 1, mean (+/- SD) cytochrome-oxidase changes ranged from 0.48 +/- 0.08 microM to 0.13 +/- 0.05 microM. The magnitude of cytochrome-oxidase change correlated significantly with the magnitude of change in the cerebral tissue oxygenation index (P < .001). In study session 2, there were significant correlations between arterial oxygen-saturation changes and cytochrome-oxidase redox changes and between Doppler cerebral blood flow velocity changes and cytochrome-oxidase redox changes (P < .001 and P = .001, respectively). CONCLUSIONS: Changes in directly measured cerebral tissue saturation and changes in arterial saturation and cerebral blood flow velocity (the 2 main factors affecting cerebral oxygenation) are associated with changes in cytochrome-oxidase oxidation state. The reduced cerebral oxygenation that occurs during obstructive sleep apnea is associated with changes in the intracellular redox state.

Symptomatic gastroesophageal reflux in subjects with a breathing sleep disorder.

STUDY OBJECTIVES: A link between gastroesophageal reflux (GER) and obstructive sleep apnea (OSA) has been suggested; however, the prevalence and frequency of symptomatic GER and the influence of OSA severity on GER are not known. DESIGN AND PATIENTS: Two hundred seventy-one subjects referred for overnight sleep studies were investigated for subjects with a breathing sleep disorder, occurrence of symptomatic GER, potential risk factors for both conditions, and comorbidity using a validated questionnaire. RESULTS: Overall, 160 of the 228 respondents (73%; 135 subjects with OSA and 93 subjects who snore) reported GER-related symptoms, with heartburn and/or acid regurgitation being the leading symptoms. No evidence of a difference in the occurrence of symptomatic GER between subjects who snore and subjects with OSA was observed (odds ratio [OR], 1.21; 95% confidence interval [CI], 0.7 to 2.1). Furthermore, the occurrence of reflux symptoms was not influenced by the severity of OSA (OR per 10 4% arterial oxygen saturation [SaO(2)] dips per hour, 0.98; 95% CI, 0.8 to 1.1). Self-reported comorbidity was higher in subjects with OSA compared with subjects who snore (p = 0.02), but none of the potential risks produced an association with the presence of reflux symptoms in this sample of patients with a breathing sleep disorder. CONCLUSION: We conclude that symptomatic GER is common in subjects with a breathing sleep disorder, but there was no difference between those with OSA and subjects who snore.

Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes.

This chapter describes the components of the initial evaluation for a patient either suspected or known to have lung cancer. The components of the initial evaluation are based on the recognized manifestations of localized lung cancer, ie, symptoms referable to the primary tumor, intrathoracic spread of lung cancer, and patterns of metastatic dissemination. Features of the history and physical signs may be useful indicators of the extent of disease. A standardized evaluation, relying on symptoms, signs, and routinely available laboratory tests, can serve as a useful screen for metastatic disease. Also described are the common features of the various paraneoplastic syndromes associated with lung cancer.

The physiologic evaluation of patients with lung cancer being considered for resectional surgery.

The preoperative physiologic assessment of a patient being considered for surgical resection of lung cancer must consider the immediate perioperative risks from comorbid cardiopulmonary disease, the long-term risks of pulmonary disability, and the threat to survival due to inadequately treated lung cancer. As with any planned major operation, especially in a population predisposed to atherosclerotic cardiovascular disease by cigarette smoking, a cardiovascular evaluation is an important component in assessing perioperative risks. Measuring the FEV(1) and the diffusing capacity of the lung for carbon monoxide (DLCO) measurements should be viewed as complementary physiologic tests for assessing risk related to pulmonary function. If there is evidence of interstitial lung disease on radiographic studies or undue dyspnea on exertion, even though the FEV(1) may be adequate, a DLCO should be obtained. In patients with abnormalities in FEV(1) or DLCO identified preoperatively, it is essential to estimate the likely postresection pulmonary reserve. The amount of lung function lost in lung cancer resection can be estimated by using either a perfusion scan or the number of segments removed. A predicted postoperative FEV(1) or DLCO < 40% indicates an increased risk for perioperative complications, including death, from lung cancer resection. Exercise testing should be performed in these patients to further define the perioperative risks prior to surgery. Formal cardiopulmonary exercise testing is a sophisticated physiologic testing technique that includes recording the exercise ECG, heart rate response to exercise, minute ventilation, and oxygen uptake per minute, and allows calculation of maximal oxygen consumption (.VO(2)max). Risk for perioperative complications can generally be stratified by .VO(2)max. Patients with preoperative .VO(2)max > 20 mL/kg/min are not at increased risk of complications or death; .VO(2)max< 15 mL/kg/min indicates an increased risk of perioperative complications; and patients with .VO(2)max < 10 mL/kg/min have a very high risk for postoperative complications. Alternative types of exercise testing include stair climbing, the shuttle walk, and the 6-min walk. Although often not performed in a standardized manner, stair climbing can predict .VO(2)max. In general terms, patients who can climb five flights of stairs have O(2)max > 20 mL/kg/min. Conversely, patients who cannot climb one flight of stairs have .VO(2)max < 10 mL/kg/min. Data on the shuttle walk and 6-min walk are limited, but patients who cannot complete 25 shuttles on two occasions will have .VO(2)max < 10 mL/kg/min. Desaturation during an exercise test has been associated with an increased risk for perioperative complications. Lung volume reduction surgery (LVRS) for patients with severe emphysema is a controversial procedure. Some reports document substantial improvements in lung function, exercise capability, and quality of life in highly selected patients with emphysema following LVRS. Case series of patients referred for LVRS indicate that perhaps 3 to 6% of these patients may have coexisting lung cancer. Anecdotal experience from these case series suggest that patients with extremely poor lung function can tolerate combined LVRS and resection of the lung cancer with an acceptable mortality rate and good postoperative outcomes. Combining LVRS and lung cancer resection should probably be limited to those patients with heterogeneous emphysema, particularly emphysema limited to the lobe containing the tumor.

Mediastinal staging of NSCLC with endoscopic and endobronchial ultrasound.

Mediastinal staging of non-small-cell lung cancer (NSCLC) is of paramount importance. It distinguishes operable from inoperable disease, guides prognosis and allows accurate comparison of outcomes in clinical trials. Noninvasive imaging modalities for mediastinal staging include CT, PET and integrated PET-CT. Mediastinoscopy is considered the current gold standard; however, each of these techniques has limitations in sensitivity or specificity. These inadequacies mean that 10% of operations performed with curative intent in patients with NSCLC are futile, owing to inaccurate locoregional lymph-node staging. Endoscopic and endobronchial ultrasound-guided mediastinal lymph-node aspiration are important and promising innovative techniques with reported sensitivities and specificities higher than standard investigations. The role of these techniques in mediastinal lymph-node staging is evolving rapidly and early data suggest that they may diminish the need for invasive surgical staging of the mediastinum. Furthermore, these are outpatient procedures that do not require general anesthesia and may be combined safely in the same sitting, for optimal accuracy of mediastinal staging. We propose a new algorithm for the diagnosis and staging of NSCLC, based on the current evidence, which incorporates endoscopic and endobronchial ultrasound as a first investigation after CT in patients with intrathoracic disease.

Complications of lung cancer treatment.

In most cases lung cancer is incurable, but treatment is prolonging life for many and sustaining quality of life. Inevitably, disease-related symptoms develop with disease progression, and it can be difficult to differentiate these from treatment-induced complications. This is particularly true for pulmonary complications because tumor progression occurs most frequently in the lungs, and separating the effects of the disease from those induced by treatment (chemotherapy, radiotherapy) is often very difficult. This chapter identifies the main complications around surgical resection of lung cancer, highlighting the importance of expert postoperative care. For palliative treatments such as radiotherapy and chemotherapy, complications are related to the planned intensity of proposed therapy, the performance status of the patients, and patient age. Treatment of the elderly sufferer, now representing almost 50% of new cases, is poorly researched, but therapy-related complications are commoner in those aged over 70 years by ~20% when compared with their younger counterparts. Even during palliative care great attention has to be taken to minimize side effects of commonly used medications.