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.

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.

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.

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.

Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group.

PURPOSE: Several recent trials have shown a significant overall survival (OS) benefit from postoperative cisplatin-based chemotherapy in patients with non-small-cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation was to identify treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy. PATIENTS AND METHODS: Individual patient data were collected and pooled from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in completely resected patients that were conducted after the 1995 NSCLC meta-analysis. The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analyzed using hazard ratios (HRs) and log-rank tests stratified by trial. RESULTS: With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82 to 0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95 to 2.06; HR for stage IB = 0.93; 95% CI, 0.78 to 1.10; HR for stage II = 0.83; 95% CI, 0.73 to 0.95; and HR for stage III = 0.83; 95% CI, 0.72 to 0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70 to 0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80 to 1.07), or other (HR = 0.97; 95% CI, 0.84 to 1.13). Chemotherapy effect was higher in patients with better performance status. There was no interaction between chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or planned total dose of cisplatin. CONCLUSION: Postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC.

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.

Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis.

PURPOSE: To replicate an earlier National Cancer Institute of Canada (NCIC) trial that examined the effect on survival of the timing of thoracic radiotherapy (TRT) in patients with limited disease small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients received three cycles of cyclophosphamide, doxorubicin, and vincristine alternating with three cycles of etoposide and cisplatin. Three hundred twenty five chemotherapy- and radiotherapy-naïve patients were randomly assigned to either early TRT administered concurrently in the second cycle or late TRT administered concurrently with the sixth cycle; the dose was 40 Gy in 15 fractions over 3 weeks. RESULTS: TRT was received by 92% and 82% of patients in the early and late arms, respectively (P = .01). Sixty-nine percent of patients in the early arm received all six courses of chemotherapy compared with 80% in the late arm (P = .003). There was no evidence of a survival difference; median overall survival time was 13.7 and 15.1 months in the early and late arms, respectively (P = .23). In a meta-analysis of all eight trials that compared early and late TRT, there were three in which the proportion of patients who completed their planned chemotherapy was similar between the TRT arms (hazard ratio [HR] = 0.73; 95% CI, 0.62 to 0.86) and five in which proportionally fewer patients in the early TRT arm completed their chemotherapy (HR = 1.06; 95% CI, 0.97 to 1.17). CONCLUSION: This study failed to show a survival advantage for early TRT with chemotherapy in limited-stage SCLC, unlike the NCIC trial. However, the results of a meta-analysis suggest that it is essential to ensure that the delivery of chemotherapy is optimal when administered with early TRT.