Screening Lung Cancer: Literature Review
Lung Cancer is the most common form of cancer diagnosed worldwide with respect to incidence and mortality. In 2008 in the UK, lung cancer accounted for 6% of all deaths and 22% of all deaths from cancer (Cancer Research UK, 2011). It is the leading cause of cancer related death in both men (24%) and women (21%) (Cancer Research UK, 2011).
The 5-year survival rate is less than 10% in UK has not significantly improved in the past 20 years despite the advances in imaging and non-imaging diagnostic tests, surgical techniques and postoperative management, radiotherapy delivery and new chemotherapeutic agents (Ghosal et al., 2009). People who are at high-risk of having lung cancer in their life-time include smokers, ex-smokers, who have COPD and who have been exposed to industrial carcinogens such as asbestos and silica (Black et al.,2006).
Due to its high prevalence and mortality rates, easily identifiable at-risk population, lung cancer appears to be an ideal candidate for mass screening (Reich et a.,2007), and hence active research has been carried on since the 1950’s to detect lung cancer in an asymptomatic population at an early stage when it is localized and potentially curable (Bach et al.,2007). The efficacy of a screening programme is judged by its capability to reduce disease-specific mortality and improve survival. On reviewing the literature it is evident that lung cancer screening has been an active field of research appealing many, however also a controversial topic. It is debated mainly in terms of cost effectiveness of the services, ideal diagnostic tests, benefits, harms, influence on mortality and survival, study design, inherent biases such as lead-time bias, length time bias, overdiagnosis bias (Patz et a.,2000).
Currently there is no mass screening programme in the UK. “The National Institute for Health and Clinical Excellence (NICE) considers evidence of both clinical and cost effectiveness when deciding on whether or not to sanction the introduction of new NHS treatments or services” (Whynes ,2008).
The aim of this review is to give an overview about the principles underlining screening, to synthesize and evaluate information from recent evidence provided by clinical studies and RCT’s for lung cancer screening and the issues pertaining to it, review the range of diagnostic test best suitable for screening and overall assess the feasibility of a screening programme and test if evidence support the hypothesis that early detection leads to reduction in mortality.
Identification of Studies
Literature search was conducted using electronic databases such as AMED, EMBASE, Ovid MEDLINE(R), [email protected], Science Direct, Google Scholar using search terms: lung carcinoma, lung cancer screening limiting the search from 1995-2011,clinical trials for screening lung cancer was searched without any time limits and past and on-going clinical trials were identified from National Cancer Institute USA and Cancer Research UK using the clinical trials and research search tool. Lung Cancer was searched using the same search terms to identify studies. Reference list of systemic reviews and other studies was scanned. Quality of the studies was judged on their source of publication and the number of times the particular article was cited by others.
Selection of papers
Initial literature search on LCS resulted in a large number of papers with potential titles which were then filtered by selecting papers based on the relevance of the title to the topic and by reading the abstracts. Full papers of the relevant studies were then retrieved and reviewed.
Papers on screening for lung cancer were considered as the theme as opposed to diagnosing and staging of LC.
Primary search for studies included: systemic reviews, RCT’s,non-randomized cohort / case-control studies, economical analysis, smoking cessation and lifestyle changes.
Studies including other interventions such as CXR, sputum cytology, autofluroescence bronchoscopy, LDCT,PET, biomarkers was considered, however LDCT emerged as the modality of choice due to its technical and clinical abilities.
Papers not published in English were excluded.
Data extraction and synthesis
Substantive data was extracted from the papers. Methodological information regarding the information on participants regarding the entry criteria used such as age, smoking history(PY) and status i.e. current or former, sub-group of high–risk patients with COPD and occupational based risk factors was collected. Data from the results of the studies in terms of prevalence, detection, survival and mortality rates was noted along with disease stage and follow-up period.
The primary outcome was to assess the influence of LCS on mortality. Secondary outcomes were the effectiveness of screening clinically and economically, and the impact of screening on lifestyle changes and smoking behavior.
“Screening means testing people for early stages of a disease before they have any symptoms” (Cancer Research UK, 2011). Screening for LC is highly debated due to lack of evidence provided by past RCT’s showing reduction in mortality and due to the high costs for screening LC .
WHO Screening Guidelines
1.) “The condition should be an important health problem
2.) The disease should have significant mortality
3.) There should be a latent phase of the disease
4.) Intervention earlier in the disease process should improve outcomes
5.) The screening test itself should have certain characteristics
6.)The cost of finding a case using the screening technique should be considered in relation to medical expenditure as a whole”
Table 1: WHO Screening Guidelines.
(Reproduced from Ghosal et al, 2009).
Using the electronic databases 42 studies was included and were categorized based on the nature of the study and relating to the endpoint of this review. They were categorized as: Randomized controlled trials (RCT), non randomized cohort/control studies, cost-effectiveness studies and studies that evaluated the impact of screening on smoking behavior and lifestyle.
On reviewing the literature 8 RCT’s were identified that were conducted in the past, which are current and which are on-going. Two large RCTs namely NLST (National Lung Screening Trial) (NLST Team, 2010) conducted in the USA compared LDCT and CXR’s among screened patients and NELSON (Dutch Belgian randomised lung cancer screening trial) (Netherlands Trial Register, 2011) is currently underway in the Netherlands comparing LDCT with no LDCT. Small RCT’s namely LSS (Lung Screening Study) (Gohagan et al., 2004), DEPISCAN (French pilot RCT) (Blanchon et al.,2007), DANTE (Infante et al.,2008), ITALUNG ( Pegna et al.,2009) randomized their study population into two arms in which LDCT was considered as the active arm.
In the UK an randomized trial funded by the NIHR HTA called the UKLS (UK Lung Cancer Screening Trial) (Baldwin et al.,2011) is underway and is based on the initial results of the NLST. It is working closely with the NELSON trial to maximize the data available(NIHR Health Technology Assessment programme,2011).Features of these RCT’s with their aim and outcome have been outlined in Table 2. PLCO is a large RCT studying the impact on mortality reduction by screening patients with CXR(National cancer institute,2011).
Table 2: Noteworthy RCT’s using LDCT for lung cancer screening.
Study & Ref
Study start Year
Aim of the Study
No. of Subjects
No. of subjects in the LDCT arm
No. of subjects in the Control Arm
UKLS[Ongoing]( Baldwin et al.,2011)UK
LDCT vs. Obs2008
The objective of the UKLS trial is to assess whether LDCTscreening and treatment of early lesions will reduce LC mortality in comparison to a control group
without screening and to investigate if LC screening programme could be implemented in UK
while ensuring any benefit exceeds harms in a cost-effective manner.
4000 (28000 if progression criteria met )–
NELSON[Ongoing](Netherlands Trial register, 2011).NL-B-DK
LSCT vs. Obs2003
1. To prove that in a RCT, screening with LDCT in high risk subjects will lead to a 25% decrease in lung cancer mortality.
2. To estimate the impact of lung cancer screening on health related quality of life and smoking cessation;
3. To estimate cost-effectiveness and help policy making.50-75156007915790715 cigs/day > 25 years OR10 cigs/day > 30 yearsNA
LDCT vs. CXR2003
To compare LC mortality of subjects screened with LDCT and with subjects screened with CXR.55-74530002672326733? 30 PYInitial results, shows 20 % fewer lung cancer deaths among trial participants screened LDCT compared to CXR.
ITALUNG-CT (Pegna et al.,2009)Italy
LDCT vs. Obs2004
ITALUNG is a population-based recruitment RCT perspective of pooling data with other RCTs in Europe andUS [14,22] contributing to the cooperative effort for the evaluation
of the efficacy of low-dose CT lung cancer screening.55-6932061613159320 PYPopulation-based enrolment of high-risk subjects for aRCT of lung cancer screening with low-dose CT is feasible. The number
of drop-outs in the group of subjects randomized to the active arm is low.
LSS ( Gohagan et al.,2004)USA
LDCT vs. CXR2002
To assessthe feasibility of conducting a large scale RCT of LDCT
versus CXR for LC screening.55-74331816601658?30 PARCT comparing annual spiral CT to CXR is feasible..
DANTE( Infante et al.,2007)Italy
LDCT vs. CXR + Sputum cytology2001
To determine the efficacy of lung cancer screening with low-dose CT on LC mortality.LC prevalence, incidence, stage distribution, and resectability are secondary endpoints60-74247212761196?20 PYLC Stage I detection rate in the spiral CT arm was 4 times higher than CXR’s.Advance stage tumors were also detected by CT.
High resection rate suggests possible increase in cure rate.
Longer follow up suggested.
Depiscan-France[Pilot RCT results ]( Blanchon et a.,2007).France
LDCT vs. CXR2002
“To determine the feasibility of enrollment byGPs, investigations and diagnostic procedures by university hospital radiologists
and multidisciplinary teams, data management by centralized clinical research assistants,
and anticipate the future management of a large national trial”(Blanchon et a.,2007)50-75621385380? 15 cigs/day for 20 YearsThis pilot trial allows estimating that non-calcified nodules are 10 timesmore often detected by LDCT than from CXR. It concludes that enrollment by GP’s was difficult and expresses the need for a large co-ordinate clinical research team in a trial.
Clinical Effectiveness: Studies
34 studies were included and broken down to different sub-groups: With comparators, without comparators and other methods.RCT by Garg et al.(2002) compared LDCT versus no screening among patients with COPD and smoking history. Non-randomized studies by Henschke et al.(1999,2001,2004,2006)compared LDCT with CXR Swenson et al.(2002,2003,2005) compared CT with sputum cytology, Sobue et al.,2002 compared CT with CXR and sputum cytology. Studies by Pastorino et al.(2003) and Bastarrika et al.(2005) used LDCT along with PET without any comparator group. Futher prospective, non-randomized cohort studies by Sone et al(.2001);Nawa et al.(2002); Diederich et al.(2002,2004); MacRedmond et al.(2004,2006);Novello et al.(2005);Chong et al.(2004); Menezes et al.(2009) were single arm studies using LDCT. Several of these studies have been summarized with their results elsewhere (Yau et al., 2007). A study by Chien et al. (2008)estimated the mean-sojurm time and effect of mortality reduction by LDCT .I-ECAP study (Henschke et al., 2006) reported survival rates of screen diagnosed stage I cancers.The chosen trials sample populations were predominantly male and over the age of 40(Yau et al., 2007). The participants consisted of non-smokers as well as former or current smokers and who have COPD and who have been exposed to asbestos.
Other tests for LCS:
In a bimodality lung cancer surveillance trial in high–risk patients Lowen et al.,(2006) combined autofluorescent bronchoscopy (AFB)and LDCT, findings from AFB were compared to sputum cytology results .186 patients were enrolled who fulfilled the high-risk criteria and 169 completed baseline tests,7% were diagnosed with lung cancer . Bimodality surveillance could detect lung cancer and pre-malignancy in patients with multiple lung cancer risk factors despite sputum cytology findings and AFB proves to be an effective test in high-risk patients (Lowen et al., 2006).
A RCT in UK called the Lung-SEARCH study is looking at detecting early LC using LDCT and fluorescence bronchoscopy in people with COPD (UKCRN,2011).
In a cross-sectional study by Carozzi et al.(2009), potential use of molecular genetic markers for screening and diagnostic purposes were evaluated which could be combined with LDCT . Biomarkers detected in biological fluid help us understand the connection between genetic alternations and/or molecular pathways changes which will help us detect lung cancer earlier and reduce mortality (Carozzi et al., 2009). “Multi-screening approach integrating imaging technique and biomolecular marker could be used to improve screening for lung cancer and is worth of further investigation” (Carozzi. et al.,2009)
The MEDLUNG study in UK is currently underway, looking at detecting early LC amongst high-risk patients using biomarkers (UKCRN,2011)
A systemic review by Black et al., in 2006 assessed the clinical and cost-effectiveness of CT for LC screening, six studies that described full economic evaluation was identified by scanning the reference list. Further two studies evaluating the cost effectiveness in an UK and Australian setup were looked upon. Economic and mathematical models were used to calculate cost-effectiveness ratios based on study assumptions. Characteristics of the economic studies are described in Table 3.
Type of evaluation & synthesis
Period of study
CEA; Total cost for one life saved; total cost for mean life expectancy saved.
Mass screening(indirect CXR for all screened sputum cytology for high-risk individuals) in 1983 & 1993 and CT option
Age- 40-84 years
Marshall et al.,2000
Incremental CEA; incremental cost per LYG
LDCT vs. No screening
Hypothetical cohort of 100,000 high risk-individuals (60-74 years)
Marshall et al.,2001
Incremental CEA & CUA; incremental cost per LY saved and cost per QALY saved.
Annual scan with LDCT vs. no screening
Hypothetical cohort of 100,000 high risk-individuals (60-74 years)
Chirikos et al.,2002
Incremental CEA; incremental cost per LYG; cost per cancer case detected.
5 annual screening with LDCT vs. no screening.
Hypothetical cohort of screened and unscreened patients from general population (Age ? 45-74 years)
Mahadevia et al.,2003
Incremental CUA; incremental cost per QALY gained.
Annual screen with LDCT vs. No screening.
Hypothetical cohort of 100,000 current, quitting & former smokers,
Age ?60; 55 % male.
Wisnivesky et al.,2003
Incremental CEA; incremental cost per LY saved.
Single scan with LDCT vs. No screening.
Cost restricted to 1 year.
Manser et al.,2004
Incremental CEA; incremental cost per LY saved and QALY saved.
5 annual screening with LDCT vs. no screening
Hypothetical cohort of 10000 male; age ? 60
Incremental CEA; incremental cost per QALY gained
Single scan with LDCT vs. no screening, if positive further diagnostic tests to be undergone.
Hypothetical cohort; high-risk male population using values of test parameters from previous clinical studies.
Table 3~: Characteristics of economic evaluation studies (Reproduced from Black et al., 2006) and data from other studies.
Impact on Lifestyle & Smoking Cessation
Lifestyle is a major modifiable cause of cancer and cancer-related mortality (Aalst et al.,2010). A review based on recent evidence published by studies, Aalst et al. (2010) indicated that screening may have a positive outcome hereby promoting healthy lifestyle but also cautions us that it can also encourage people to continue or start an unhealthy lifestyle. Lung cancer screening can prove to be a teachable moment for smoking cessation and may influence people to quit smoking (Taylor et al., 2006).
Mortality rates gives us the true outcome of a test as it is unconfounded by bias (Black et al.,2006). An effective screening programme should be able to identify high-risk groups depending on age, gender, lifestyle and occupation and have high sensitivity and specificity eventually resulting in reduction of mortality.
Studies by Henschke et al.(2000),Nawa et a.(2002), Gohagan et al.(2004),Menezes et al.(2009) reported high sensitivity and specificity above 80%,Sone et al.(2001) and Pastorino et al.,(2003) reported low sensitivities and Swensen et al.(2002) ,Diederich et al.(2002,2004) reported low specificities. Discrepancy resided amongst studies due to the variation in the entry criteria such as age, gender, PY, high-risk sample and threshold values set (?5 – ? 20mm) for detecting suspicious lesions which made it difficult to compare results and determine the ideal criteria for diagnosis of a screening programme.
Prevalence screening with LDCT revealed that majority of cancers reported were Stage I non-small cell lung cancer (53-100 %)(Yau et a.,2007)though advance stage cancers were also reported with other histological types of cancers. ELCAP,DANTE, LSS studies along with Swensen et al.(2002) found that CT was more effective at identifying cancerous NCN’s than CXR’s.It should be noted that CT detects more peripherally located tumors than centrally located ones which are difficult to diagnose(Postmus et al.,2004).
I-ELCAP study (Henschke et al.,2006) reported a 10-year survival rate of 88% for the whole series and 92% for resected stage I patients. By estimating shorter MST in conjunction with other parameters Chien et al.(2008) predicted that 15% mortality reduction can be seen for an annual LDCT screening. Initial results from NLST showed 20 % reduction in mortality in the LDCT arm, however final results are yet to be published(NLST Team,2010). This trial hereby the only RCT to date that has proved clinical effectiveness against mortality reduction.
However it should be noted that operating characteristics can be influenced by high false positive and false negative rates. High FP rates due to detection of benign lesions and lack of standardized threshold for positive screen have been reported thus resulting in low PPV(Yau et al.,2007).This is one of the hurdles in implementing LDCT for LCS.True estimation of TN rates cannot be established due to incomplete follow-up of negative baseline scans and shorter follow-up duration thus leading to high NPV(Yau et al.2007). Accuracy also depends on the ability of the reporting radiologist(Sone et al.,2001).
The assumption that a “stage-shift” would result in decrease in mortality needs to be more carefully evaluated as it would lead to decrease in inoperable cases and an increase in operable cases which means that LC incidence will occur as a result of overdiagnosis bias(Beplor et al.,2003).
Both clinical effectiveness along with cost-effectiveness hurdle needs to be overcome (which presently poses a greater challenge) to fulfill the criteria of a screening programme(Gleeson ,2006)
Inherent biases present in studies i.e. lead-time bias, length bias and over-diagnosis bias and should be accounted for in CEA and analytical methods as they can affect cost-effectiveness ratios (demonstrated by the cost-evaluation studies included) and survival and mortality benefit may be overestimated(Black et al,2006) .If evidence from LCS studies provide health gains in terms of quality and quantity of life with modest additional cost per patient, cost-effectiveness can be justified (Black et al.,2006).More complete and transparent CEA are required (Patz et al.,2000).
According to the HTA report published in 2006 by Black et al., LDCT for screening LC does not meet the accepted NSC criteria due to unsatisfactory clinical and cost –effectiveness evidence. According to NICE the screening programme needs to pass the cost per QALY threshold of ?20,000–30,000 per QALY (NIHCE,2005). However due to the rise in public expectations which adds additional burden on the services provided by NHS, the imbalance between demand versus supply and the rise in cost of health care services, it seems that even if NSC criteria are satisfied implementation of LDCT as a screening programme would be economically and logistically challenging with respect to the capital cost involved in setting up a multi centre nationalized screening programme
Based on this literature review, it has emerged that LDCT is the choice of screening tool for LCS, however integrated imaging with AFB and PET and advances in genomic and proteomic approaches promises to compliment the ability of CT to detect LC(Carozzi et al.2010).Economic decision-making framework should include harms of screening along with the mortality and morbidity associated with it, radiation exposure risks as a result of repeated follow-ups(Black et al.,2006) .Included studies did not account for this. Past and on-going LDCT studies need to be carefully evaluated and screening progrmme should be designed based on the country’s merits and population distribution. NRCT’s have failed to establish reduction in mortality and hence evidence from large RCT’s proving the hypothesis and screening efficacy is of paramount importance for introducing a population screening progrmme. Results are awaited from these RCT’s.
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