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1.  Evaluation of the Lung Cancer Risks at Which to Screen Ever- and Never-Smokers: Screening Rules Applied to the PLCO and NLST Cohorts 
PLoS Medicine  2014;11(12):e1001764.
Martin Tammemägi and colleagues evaluate which risk groups of individuals, including nonsmokers and high-risk individuals from 65 to 80 years of age, should be screened for lung cancer using computed tomography.
Please see later in the article for the Editors' Summary
Background
Lung cancer risks at which individuals should be screened with computed tomography (CT) for lung cancer are undecided. This study's objectives are to identify a risk threshold for selecting individuals for screening, to compare its efficiency with the U.S. Preventive Services Task Force (USPSTF) criteria for identifying screenees, and to determine whether never-smokers should be screened. Lung cancer risks are compared between smokers aged 55–64 and ≥65–80 y.
Methods and Findings
Applying the PLCOm2012 model, a model based on 6-y lung cancer incidence, we identified the risk threshold above which National Lung Screening Trial (NLST, n = 53,452) CT arm lung cancer mortality rates were consistently lower than rates in the chest X-ray (CXR) arm. We evaluated the USPSTF and PLCOm2012 risk criteria in intervention arm (CXR) smokers (n = 37,327) of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). The numbers of smokers selected for screening, and the sensitivities, specificities, and positive predictive values (PPVs) for identifying lung cancers were assessed. A modified model (PLCOall2014) evaluated risks in never-smokers. At PLCOm2012 risk ≥0.0151, the 65th percentile of risk, the NLST CT arm mortality rates are consistently below the CXR arm's rates. The number needed to screen to prevent one lung cancer death in the 65th to 100th percentile risk group is 255 (95% CI 143 to 1,184), and in the 30th to <65th percentile risk group is 963 (95% CI 291 to −754); the number needed to screen could not be estimated in the <30th percentile risk group because of absence of lung cancer deaths. When applied to PLCO intervention arm smokers, compared to the USPSTF criteria, the PLCOm2012 risk ≥0.0151 threshold selected 8.8% fewer individuals for screening (p<0.001) but identified 12.4% more lung cancers (sensitivity 80.1% [95% CI 76.8%–83.0%] versus 71.2% [95% CI 67.6%–74.6%], p<0.001), had fewer false-positives (specificity 66.2% [95% CI 65.7%–66.7%] versus 62.7% [95% CI 62.2%–63.1%], p<0.001), and had higher PPV (4.2% [95% CI 3.9%–4.6%] versus 3.4% [95% CI 3.1%–3.7%], p<0.001). In total, 26% of individuals selected for screening based on USPSTF criteria had risks below the threshold PLCOm2012 risk ≥0.0151. Of PLCO former smokers with quit time >15 y, 8.5% had PLCOm2012 risk ≥0.0151. None of 65,711 PLCO never-smokers had PLCOm2012 risk ≥0.0151. Risks and lung cancers were significantly greater in PLCO smokers aged ≥65–80 y than in those aged 55–64 y. This study omitted cost-effectiveness analysis.
Conclusions
The USPSTF criteria for CT screening include some low-risk individuals and exclude some high-risk individuals. Use of the PLCOm2012 risk ≥0.0151 criterion can improve screening efficiency. Currently, never-smokers should not be screened. Smokers aged ≥65–80 y are a high-risk group who may benefit from screening.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Lung cancer is the most commonly occurring cancer in the world and the most common cause of cancer-related deaths. Like all cancers, lung cancer occurs when cells acquire genetic changes that allow them to grow uncontrollably and to move around the body (metastasize). The most common trigger for these genetic changes in lung cancer is exposure to cigarette smoke. Symptoms of lung cancer include a persistent cough and breathlessness. If lung cancer is diagnosed when it is confined to the lung (stage I), the tumor can often be removed surgically. Stage II tumors, which have spread into nearby lymph nodes, are usually treated with surgery plus chemotherapy or radiotherapy. For more advanced lung cancers that have spread throughout the chest (stage III) or the body (stage IV), surgery is rarely helpful and these tumors are treated with chemotherapy and radiotherapy alone. Overall, because most lung cancers are not detected until they are advanced, less than 17% of people diagnosed with lung cancer survive for five years.
Why Was This Study Done?
Screening for lung cancer—looking for early disease in healthy people—could save lives. In the US National Lung Screening Trial (NLST), annual screening with computed tomography (CT) reduced lung cancer mortality by 20% among smokers at high risk of developing cancer compared with screening with a chest X-ray. But what criteria should be used to decide who is screened for lung cancer? The US Preventive Services Task Force (USPSTF), for example, recommends annual CT screening of people who are 55–80 years old, have smoked 30 or more pack-years (one pack-year is defined as a pack of cigarettes per day for one year), and—if they are former smokers—quit smoking less than 15 years ago. However, some experts think lung cancer risk prediction models—statistical models that estimate risk based on numerous personal characteristics—should be used to select people for screening. Here, the researchers evaluate PLCOm2012, a lung cancer risk prediction model based on the incidence of lung cancer among smokers enrolled in the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Specifically, the researchers use NLST and PLCO screening trial data to identify a PLCOm2012 risk threshold for selecting people for screening and to compare the efficiency of the PLCOm2012 model and the USPSTF criteria for identifying “screenees.”
What Did the Researchers Do and Find?
By analyzing NLST data, the researchers calculated that at PLCOm2012 risk ≥0.0151, mortality (death) rates among NLST participants screened with CT were consistently below mortality rates among NLST participants screened with chest X-ray and that 255 people with a PLCOm2012 risk ≥0.0151 would need to be screened to prevent one lung cancer death. Next, they used data collected from smokers in the screened arm of the PLCO trial to compare the efficiency of the PLCOm2012 and USPSTF criteria for identifying screenees. They found that 8.8% fewer people had a PLCOm2012 risk ≥0.0151 than met USPSTF criteria for screening, but 12.4% more lung cancers were identified. Thus, using PLCOm2012 improved the sensitivity and specificity of the selection of individuals for lung cancer screening over using UPSTF criteria. Notably, 8.5% of PLCO former smokers with quit times of more than 15 years had PLCOm2012 risk ≥0.0151, none of the PLCO never-smokers had PLCOm2012 risk ≥0.0151, and the calculated risks and incidence of lung cancer were greater among PLCO smokers aged ≥65–80 years than among those aged 55–64 years.
What Do These Findings Mean?
Despite the absence of a cost-effectiveness analysis in this study, these findings suggest that the use of the PLCOm2012 risk ≥0.0151 threshold rather than USPSTF criteria for selecting individuals for lung cancer screening could improve screening efficiency. The findings have several other important implications. First, these findings suggest that screening may be justified in people who stopped smoking more than 15 years ago; USPSTF currently recommends that screening stop once an individual's quit time exceeds 15 years. Second, these findings do not support lung cancer screening among never-smokers. Finally, these findings suggest that smokers aged ≥65–80 years might benefit from screening, although the presence of additional illnesses and reduced life expectancy need to be considered before recommending the provision of routine lung cancer screening to this section of the population.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001764.
The US National Cancer Institute provides information about all aspects of lung cancer for patients and health-care professionals, including information on lung cancer screening (in English and Spanish)
Cancer Research UK also provides detailed information about lung cancer and about lung cancer screening
The UK National Health Service Choices website has a page on lung cancer that includes personal stories
MedlinePlus provides links to other sources of information about lung cancer (in English and Spanish)
Information about the USPSTF recommendations for lung cancer screening is available
doi:10.1371/journal.pmed.1001764
PMCID: PMC4251899  PMID: 25460915
2.  U.S. Primary Care Physicians’ Lung Cancer Screening Beliefs and Recommendations 
Background
No high-quality study to date has shown that screening reduces lung cancer mortality, and expert groups do not recommend screening for asymptomatic individuals. Nevertheless, lung cancer screening tests are available in the U.S., and primary care physicians (PCPs) may have a role in recommending them to patients.
Purpose
This study describes U.S. PCPs’ beliefs about and recommendations for lung cancer screening, and examines characteristics of PCPs who recommend screening.
Methods
A nationally representative survey of practicing PCPs was conducted in 2006–2007. Mailed questionnaires assessed PCPs’ beliefs about lung cancer screening guidelines and the effectiveness of screening tests, and whether PCPs would recommend screening for asymptomatic patients. Data were analyzed in 2009.
Results
Nine hundred and sixty-two PCPs completed the survey (absolute response rate=70.6%; cooperation rate=76.8%). One quarter said that major guidelines support lung cancer screening. Two thirds said that low–radiation dose spiral CT (LDCT) is very or somewhat effective in reducing lung cancer mortality in current smokers; LDCT was perceived as more effective than chest × ray or sputum cytology. Responding to vignettes describing asymptomatic patients of varying smoking exposure, 67% of PCPs recommended lung cancer screening for at least one of the vignettes. Most PCPs recommending screening said they would use chest × ray; up to 26% would use LDCT. In adjusted analyses, PCPs’ beliefs and practice style were strongly associated with their lung cancer screening recommendations.
Conclusions
Many PCPs’ lung cancer screening beliefs and recommendations are inconsistent with current evidence and guidelines. Provider education regarding lung cancer screening’s evidence base and guideline content is indicated.
doi:10.1016/j.amepre.2010.07.004
PMCID: PMC3133954  PMID: 20965378
3.  Screening and Rapid Molecular Diagnosis of Tuberculosis in Prisons in Russia and Eastern Europe: A Cost-Effectiveness Analysis 
PLoS Medicine  2012;9(11):e1001348.
Daniel Winetsky and colleagues investigate eight strategies for screening and diagnosis of tuberculosis within prisons of the former Soviet Union.
Background
Prisons of the former Soviet Union (FSU) have high rates of multidrug-resistant tuberculosis (MDR-TB) and are thought to drive general population tuberculosis (TB) epidemics. Effective prison case detection, though employing more expensive technologies, may reduce long-term treatment costs and slow MDR-TB transmission.
Methods and Findings
We developed a dynamic transmission model of TB and drug resistance matched to the epidemiology and costs in FSU prisons. We evaluated eight strategies for TB screening and diagnosis involving, alone or in combination, self-referral, symptom screening, mass miniature radiography (MMR), and sputum PCR with probes for rifampin resistance (Xpert MTB/RIF). Over a 10-y horizon, we projected costs, quality-adjusted life years (QALYs), and TB and MDR-TB prevalence. Using sputum PCR as an annual primary screening tool among the general prison population most effectively reduced overall TB prevalence (from 2.78% to 2.31%) and MDR-TB prevalence (from 0.74% to 0.63%), and cost US$543/QALY for additional QALYs gained compared to MMR screening with sputum PCR reserved for rapid detection of MDR-TB. Adding sputum PCR to the currently used strategy of annual MMR screening was cost-saving over 10 y compared to MMR screening alone, but produced only a modest reduction in MDR-TB prevalence (from 0.74% to 0.69%) and had minimal effect on overall TB prevalence (from 2.78% to 2.74%). Strategies based on symptom screening alone were less effective and more expensive than MMR-based strategies. Study limitations included scarce primary TB time-series data in FSU prisons and uncertainties regarding screening test characteristics.
Conclusions
In prisons of the FSU, annual screening of the general inmate population with sputum PCR most effectively reduces TB and MDR-TB prevalence, doing so cost-effectively. If this approach is not feasible, the current strategy of annual MMR is both more effective and less expensive than strategies using self-referral or symptom screening alone, and the addition of sputum PCR for rapid MDR-TB detection may be cost-saving over time.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Tuberculosis (TB)—a contagious bacterial disease—is a major public health problem, particularly in low- and middle-income countries. In 2010, about nine million people developed TB, and about 1.5 million people died from the disease. Mycobacterium tuberculosis, the bacterium that causes TB, is spread in airborne droplets when people with active disease cough or sneeze. The characteristic symptoms of TB include fever, a persistent cough, and night sweats. Diagnostic tests include sputum smear microscopy (examination of mucus from the lungs for M. tuberculosis bacilli), mycobacterial culture (growth of M. tuberculosis from sputum), and chest X-rays. TB can also be diagnosed by looking for fragments of the M. tuberculosis genetic blueprint in sputum samples (sputum PCR). Importantly, sputum PCR can detect the genetic changes that make M. tuberculosis resistant to rifampicin, a constituent of the cocktail of antibiotics that is used to cure TB. Rifampicin resistance is an indicator of multidrug-resistant TB (MDR-TB), the emergence of which is thwarting ongoing global efforts to control TB.
Why Was This Study Done?
Prisons present unique challenges for TB control. Overcrowding, poor ventilation, and inadequate medical care increase the spread of TB among prisoners, who often come from disadvantaged populations where the prevalence of TB (the proportion of the population with TB) is already high. Prisons also act as reservoirs for TB, recycling the disease back into the civilian population. The prisons of the former Soviet Union, for example, which have extremely high rates of MDR-TB, are thought to drive TB epidemics in the general population. Because effective identification of active TB among prison inmates has the potential to improve TB control outside prisons, the World Health Organization recommends active TB case finding among prisoners using self-referral, screening with symptom questionnaires, or screening with chest X-rays or mass miniature radiography (MMR). But which of these strategies will reduce the prevalence of TB in prisons most effectively, and which is most cost-effective? Here, the researchers evaluate the relative effectiveness and cost-effectiveness of alternative strategies for screening and diagnosis of TB in prisons by modeling TB and MDR-TB epidemics in prisons of the former Soviet Union.
What Did the Researchers Do and Find?
The researchers used a dynamic transmission model of TB that simulates the movement of individuals in prisons in the former Soviet Union through different stages of TB infection to estimate the costs, quality-adjusted life years (QALYs; a measure of disease burden that includes both the quantity and quality of life) saved, and TB and MDR-TB prevalence for eight TB screening/diagnostic strategies over a ten-year period. Compared to annual MMR alone (the current strategy), annual screening with sputum PCR produced the greatest reduction in the prevalence of TB and of MDR-TB among the prison population. Adding sputum PCR for detection of MDR-TB to annual MMR screening did not affect the overall TB prevalence but slightly reduced the MDR-TB prevalence and saved nearly US$2,000 over ten years per model prison of 1,000 inmates, compared to MMR screening alone. Annual sputum PCR was the most cost-effective strategy, costing US$543/QALY for additional QALYs gained compared to MMR screening plus sputum PCR for MDR-TB detection. Other strategies tested, including symptom screening alone or combined with sputum PCR, were either more expensive and less effective or less cost-effective than these two options.
What Do These Findings Mean?
These findings suggest that, in prisons in the former Soviet Union, annual screening with sputum PCR will most effectively reduce TB and MDR-TB prevalence and will be cost-effective. That is, the cost per QALY saved of this strategy is less than the per-capita gross domestic product of any of the former Soviet Union countries. The paucity of primary data on some facets of TB epidemiology in prisons in the former Soviet Union and the assumptions built into the mathematical model limit the accuracy of these findings. Moreover, because most of the benefits of sputum PCR screening come from treating the MDR-TB cases that are detected using this screening approach, these findings cannot be generalized to prison settings without a functioning MDR-TB treatment program or with a very low MDR-TB prevalence. Despite these and other limitations, these findings provide valuable information about the screening strategies that are most likely to interrupt the TB cycle in prisons, thereby saving resources and averting preventable deaths both inside and outside prisons.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001348.
The World Health Organization provides information (in several languages) on all aspects of tuberculosis, including general information on tuberculosis diagnostics and on tuberculosis in prisons; a report published in the Bulletin of the World Health Organization in 2006 describes tough measures taken in Russian prisons to slow the spread of TB
The Stop TB Partnership is working towards tuberculosis elimination; patient stories about tuberculosis are available (in English and Spanish)
The US Centers for Disease Control and Prevention has information about tuberculosis, about its diagnosis, and about tuberculosis in prisons (some information in English and Spanish)
A PLOS Medicine Research Article by Iacapo Baussano et al. describes a systematic review of tuberculosis incidence in prisons; a linked editorial entitled The Health Crisis of Tuberculosis in Prisons Extends beyond the Prison Walls is also available
The Tuberculosis Survival Project, which aims to raise awareness of tuberculosis and provide support for people with tuberculosis, provides personal stories about treatment for tuberculosis; the Tuberculosis Vaccine Initiative also provides personal stories about dealing with tuberculosis
MedlinePlus has links to further information about tuberculosis (in English and Spanish)
doi:10.1371/journal.pmed.1001348
PMCID: PMC3507963  PMID: 23209384
4.  Screening for lung cancer: a systematic review and meta-analysis of controlled trials 
Thorax  2003;58(9):784-789.
Background: Lung cancer is a substantial public health problem in western countries. Previous studies have examined different screening strategies for lung cancer but there have been no published systematic reviews.
Methods: A systematic review of controlled trials was conducted to determine whether screening for lung cancer using regular sputum examinations or chest radiography or computed tomography (CT) reduces lung cancer mortality. The primary outcome was lung cancer mortality; secondary outcomes were lung cancer survival and all cause mortality.
Results: One non-randomised controlled trial and six randomised controlled trials with a total of 245 610 subjects were included in the review. In all studies the control group received some type of screening. More frequent screening with chest radiography was associated with an 11% relative increase in mortality from lung cancer compared with less frequent screening (RR 1.11, 95% CI 1.00 to 1.23). A non-statistically significant trend to reduced mortality from lung cancer was observed when screening with chest radiography and sputum cytological examination was compared with chest radiography alone (RR 0.88, 95% CI 0.74 to 1.03). Several of the included studies had potential methodological weaknesses. Controlled studies of spiral CT scanning have not been reported.
Conclusions: The current evidence does not support screening for lung cancer with chest radiography or sputum cytological examination. Frequent chest radiography might be harmful. Further methodologically rigorous trials are required before any new screening methods are introduced into clinical practice.
doi:10.1136/thorax.58.9.784
PMCID: PMC1746815  PMID: 12947138
5.  Risk Prediction for Breast, Endometrial, and Ovarian Cancer in White Women Aged 50 y or Older: Derivation and Validation from Population-Based Cohort Studies 
PLoS Medicine  2013;10(7):e1001492.
Ruth Pfeiffer and colleagues describe models to calculate absolute risks for breast, endometrial, and ovarian cancers for white, non-Hispanic women over 50 years old using easily obtainable risk factors.
Please see later in the article for the Editors' Summary
Background
Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer.
Methods and Findings
Using data on white, non-Hispanic women aged 50+ y from two large population-based cohorts (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO] and the National Institutes of Health–AARP Diet and Health Study [NIH-AARP]), we estimated relative and attributable risks and combined them with age-specific US-population incidence and competing mortality rates. All models included parity. The breast cancer model additionally included estrogen and progestin menopausal hormone therapy (MHT) use, other MHT use, age at first live birth, menopausal status, age at menopause, family history of breast or ovarian cancer, benign breast disease/biopsies, alcohol consumption, and body mass index (BMI); the endometrial model included menopausal status, age at menopause, BMI, smoking, oral contraceptive use, MHT use, and an interaction term between BMI and MHT use; the ovarian model included oral contraceptive use, MHT use, and family history or breast or ovarian cancer. In independent validation data (Nurses' Health Study cohort) the breast and ovarian cancer models were well calibrated; expected to observed cancer ratios were 1.00 (95% confidence interval [CI]: 0.96–1.04) for breast cancer and 1.08 (95% CI: 0.97–1.19) for ovarian cancer. The number of endometrial cancers was significantly overestimated, expected/observed = 1.20 (95% CI: 1.11–1.29). The areas under the receiver operating characteristic curves (AUCs; discriminatory power) were 0.58 (95% CI: 0.57–0.59), 0.59 (95% CI: 0.56–0.63), and 0.68 (95% CI: 0.66–0.70) for the breast, ovarian, and endometrial models, respectively.
Conclusions
These models predict absolute risks for breast, endometrial, and ovarian cancers from easily obtainable risk factors and may assist in clinical decision-making. Limitations are the modest discriminatory ability of the breast and ovarian models and that these models may not generalize to women of other races.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2008, just three types of cancer accounted for 10% of global cancer-related deaths. That year, about 460,000 women died from breast cancer (the most frequently diagnosed cancer among women and the fifth most common cause of cancer-related death). Another 140,000 women died from ovarian cancer, and 74,000 died from endometrial (womb) cancer (the 14th and 20th most common causes of cancer-related death, respectively). Although these three cancers originate in different tissues, they nevertheless share many risk factors. For example, current age, age at menarche (first period), and parity (the number of children a woman has had) are all strongly associated with breast, ovarian, and endometrial cancer risk. Because these cancers share many hormonal and epidemiological risk factors, a woman with a high breast cancer risk is also likely to have an above-average risk of developing ovarian or endometrial cancer.
Why Was This Study Done?
Several statistical models (for example, the Breast Cancer Risk Assessment Tool) have been developed that estimate a woman's absolute risk (probability) of developing breast cancer over the next few years or over her lifetime. Absolute risk prediction models are useful in the design of cancer prevention trials and can also help women make informed decisions about cancer prevention and treatment options. For example, a woman at high risk of breast cancer might decide to take tamoxifen for breast cancer prevention, but ideally she needs to know her absolute endometrial cancer risk before doing so because tamoxifen increases the risk of this cancer. Similarly, knowledge of her ovarian cancer risk might influence a woman's decision regarding prophylactic removal of her ovaries to reduce her breast cancer risk. There are few absolute risk prediction models for ovarian cancer, and none for endometrial cancer, so here the researchers develop models to predict the risk of these cancers and of breast cancer.
What Did the Researchers Do and Find?
Absolute risk prediction models are constructed by combining estimates for risk factors from cohorts with population-based incidence rates from cancer registries. Models are validated in an independent cohort by testing their ability to identify people with the disease in an independent cohort and their ability to predict the observed numbers of incident cases. The researchers used data on white, non-Hispanic women aged 50 years or older that were collected during two large prospective US cohort studies of cancer screening and of diet and health, and US cancer incidence and mortality rates provided by the Surveillance, Epidemiology, and End Results Program to build their models. The models all included parity as a risk factor, as well as other factors. The model for endometrial cancer, for example, also included menopausal status, age at menopause, body mass index (an indicator of the amount of body fat), oral contraceptive use, menopausal hormone therapy use, and an interaction term between menopausal hormone therapy use and body mass index. Individual women's risk for endometrial cancer calculated using this model ranged from 1.22% to 17.8% over the next 20 years depending on their exposure to various risk factors. Validation of the models using data from the US Nurses' Health Study indicated that the endometrial cancer model overestimated the risk of endometrial cancer but that the breast and ovarian cancer models were well calibrated—the predicted and observed risks for these cancers in the validation cohort agreed closely. Finally, the discriminatory power of the models (a measure of how well a model separates people who have a disease from people who do not have the disease) was modest for the breast and ovarian cancer models but somewhat better for the endometrial cancer model.
What Do These Findings Mean?
These findings show that breast, ovarian, and endometrial cancer can all be predicted using information on known risk factors for these cancers that is easily obtainable. Because these models were constructed and validated using data from white, non-Hispanic women aged 50 years or older, they may not accurately predict absolute risk for these cancers for women of other races or ethnicities. Moreover, the modest discriminatory power of the breast and ovarian cancer models means they cannot be used to decide which women should be routinely screened for these cancers. Importantly, however, these well-calibrated models should provide realistic information about an individual's risk of developing breast, ovarian, or endometrial cancer that can be used in clinical decision-making and that may assist in the identification of potential participants for research studies.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001492.
This study is further discussed in a PLOS Medicine Perspective by Lars Holmberg and Andrew Vickers
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information about breast cancer, ovarian cancer, and endometrial cancer;
Information on the Breast Cancer Risk Assessment Tool, the Surveillance, Epidemiology, and End Results Program, and on the prospective cohort study of screening and the diet and health study that provided the data used to build the models is also available on the NCI site
Cancer Research UK, a not-for-profit organization, provides information about cancer, including detailed information on breast cancer, ovarian cancer, and endometrial cancer
The UK National Health Service Choices website has information and personal stories about breast cancer, ovarian cancer, and endometrial cancer; the not-for-profit organization Healthtalkonline also provides personal stories about dealing with breast cancer and ovarian cancer
doi:10.1371/journal.pmed.1001492
PMCID: PMC3728034  PMID: 23935463
6.  Lung cancer screening: from imaging to biomarker 
Biomarker Research  2013;1:4.
Despite several decades of intensive effort to improve the imaging techniques for lung cancer diagnosis and treatment, primary lung cancer is still the number one cause of cancer death in the United States and worldwide. The major causes of this high mortality rate are distant metastasis evident at diagnosis and ineffective treatment for locally advanced disease. Indeed, approximately forty percent of newly diagnosed lung cancer patients have distant metastasis. Currently, the only potential curative therapy is surgical resection of early stage lung cancer. Therefore, early detection of lung cancer could potentially increase the chance of cure by surgery and underlines the importance of screening and detection of lung cancer. In the past fifty years, screening of lung cancer by chest X-Ray (CXR), sputum cytology, computed tomography (CT), fluorescence endoscopy and low-dose spiral CT (LDCT) has not improved survival except for the recent report in 2010 by the National Lung Screening Trial (NLST), which showed a 20 percent mortality reduction in high risk participants screened with LDCT compared to those screened with CXRs. Furthermore, serum biomarkers for detection of lung cancer using free circulating DNA and RNA, exosomal microRNA, circulating tumor cells and various lung cancer specific antigens have been studied extensively and novel screening methods are being developed with encouraging results. The history of lung cancer screening trials using CXR, sputum cytology and LDCT, as well as results of trials involving various serum biomarkers, are reviewed herein.
doi:10.1186/2050-7771-1-4
PMCID: PMC3776246  PMID: 24252206
7.  Randomized controlled trials of the efficacy of lung cancer screening by sputum cytology revisited: a combined mortality analysis from the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Lung Study 
Cancer  2009;115(21):5007-5017.
Background
Two randomized controlled trials of lung cancer screening initiated in the 1970's, the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Lung Study, compared one arm which received annual chest x-ray and four-monthly sputum cytology (dual-screen) to a second arm which received annual chest x-ray only. Previous publications from these trials reported similar lung cancer mortality between the two groups. However, these findings were based on incomplete follow-up, and each trial on its own was underpowered to detect a modest mortality benefit.
Methods
We estimated the efficacy of lung cancer screening with sputum cytology in an intention-to-screen analysis of lung cancer mortality, using combined data from these trials (n=20,426).
Results
Over one-half of squamous cell lung cancers diagnosed in the dual-screen group were identified by cytology; these cancers tended to be more localized than squamous cancers diagnosed in the x-ray only arm. After nine years of follow-up, lung cancer mortality was slightly lower in the dual-screen than in the x-ray only arm (rate ratio (RR) 0.88, 95% confidence interval (CI) 0.74-1.05). Reductions were seen for squamous cell cancer deaths (RR 0.79, 95% CI 0.54-1.14) and in the heaviest smokers (RR 0.81, 95% CI 0.67-1.00). There were also fewer deaths from large cell carcinoma in the dual-screen group, though the reason for this is unclear.
Conclusions
These data are suggestive of a modest benefit of sputum cytology screening, though we cannot rule out chance as an explanation for these findings.
doi:10.1002/cncr.24545
PMCID: PMC2767423  PMID: 19637354
lung cancer; screening; sputum cytology; chest x-ray
8.  Early detection for lung cancer. New tools for casefinding. 
Canadian Family Physician  2001;47:537-544.
OBJECTIVE: To review data from published population trials and clinical practice guidelines on screening for lung cancer to provide a recommendation for early detection of lung cancer. QUALITY OF EVIDENCE: Literature was searched via MEDLINE using the MeSH headings "lung neoplasm," "mass screening," "thoracic radiography," and "sputum." Only prospective randomized controlled trials with large numbers of subjects were selected. MAIN MESSAGE: Risk of lung cancer among long-term heavy smokers continues even years after stopping smoking. Risk is highest in smokers with chronic obstructive pulmonary disease. Canadian clinical practice guidelines currently recommend that sputum cytology examination and chest radiography (CXR) not be used for lung cancer screening. This guideline was deducted from four randomized population trials in the 1970s that have serious limitations and applies to asymptomatic adults only. A CXR and sputum cytology examination are indicated in symptomatic current and former smokers older than 45 years with a smoking history of 30 pack-years or more and airflow obstruction defined as a forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) of 70% or less and a FEV1 lower than 70%. Curative treatment is available for early lung cancer. Substantial advances in innovative technologies for early detection using low-dose spiral CT and newer sputum tests have been made in the last three decades. Additional studies are under way to evaluate these new technologies. CONCLUSION: Primary care physicians have an important role in identifying people at risk of developing lung cancer and in supporting research to evaluate new screening technology.
PMCID: PMC2018399  PMID: 11281087
9.  A survey on pulmonary screening practices among otolaryngology-head & neck surgeons across Canada in the post treatment surveillance of head and neck squamous cell carcinoma 
Background
Post treatment lung screening for head and neck cancer patients primarily focuses on the distant metastasis and a high rate of second primary can also be expected. The best screening tool and timing for this purpose is controversial. We sought out to assess the current practice and beliefs among Canadian Head and Neck Surgeons.
Methods
After Ethical Board approval, a nationwide survey was conducted through the Canadian Society of Otolaryngology (CSO) among head and neck surgeons regarding their practices for pulmonary screening in HNSCC patients.
Results
Our CSO survey among Otolaryngology-head and neck surgeons showed that 26 out of 32 respondents perform routine lung screen, out of which 23 (88%) feel that chest radiography should be preferred. The majority of respondents felt that lung screening could impact beneficially on mortality. For symptomatic patients, low-dose spiral CT was the preferred modality (48%), followed by PET/CT scan (14%) and sputum cytology (14%). In high-risk asymptomatic patients (current smoker, radiation exposure, family history and advanced HNSCC), 31% of respondents performed a CXR. The same percentage performed a low dose CT, while 19% relied on PET scan. A further 19% of respondents did not perform any screening in high-risk patients. Most respondents (77%) had more than 10 years practice since graduation from medical school and came from the provinces of Quebec, Ontario and Alberta.
Conclusion
Chest radiography remains the preferred modality for lung screening and was believed to be impacting beneficially on lung mortality. The recent literature does not seem to be in agreement with those beliefs. Further studies to establish which modality is best and concurrent nation-wide education are warranted.
doi:10.1186/s40463-015-0057-7
PMCID: PMC4323133  PMID: 25649793
Head and neck cancer; Pulmonary screening; Survey; Canadian head and neck surgeons
10.  Lung Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial 
Background
The 5-year overall survival rate of lung cancer patients is approximately 15%. Most patients are diagnosed with advanced-stage disease and have shorter survival rates than patients with early-stage disease. Although screening for lung cancer has the potential to increase early diagnosis, it has not been shown to reduce lung cancer mortality rates. In 1993, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was initiated specifically to determine whether screening would reduce mortality rates from PLCO cancers.
Methods
A total of 77 464 participants, aged 55–74 years, were randomly assigned to the intervention arm of the PLCO Cancer Screening Trial between November 8, 1993, and July 2, 2001. Participants received a baseline chest radiograph (CXR), followed by three annual single-view CXRs at the 10 US screening centers. Cancers were classified as screen detected and nonscreen detected (interval or never screened) and according to tumor histology. The positivity rates of screen-detected cancers and positive predictive values (PPVs) were calculated. Because 51.6% of the participants were current or former smokers, logistic regression analysis was performed to control for smoking status. All statistical tests were two-sided.
Results
Compliance with screening decreased from 86.6% at baseline to 78.9% at the last screening. Overall positivity rates were 8.9% at baseline and 6.6%–7.1% at subsequent screenings; positivity rates increased modestly with smoking risk categories (Ptrend < .001). The PPVs for all participants were 2.0% at baseline and 1.1%, 1.5%, and 2.4% at years 1, 2, and 3, respectively; PPVs in current smokers were 5.9% at baseline and 3.3%, 4.2%, and 5.6% at years 1, 2, and 3, respectively. A total of 564 lung cancers were diagnosed, of which 306 (54%) were screen-detected cancers and 87% were non–small cell lung cancers. Among non–small cell lung cancers, 59.6% of screen-detected cancers and 33.3% of interval cancers were early (I–II) stage.
Conclusions
The PLCO Cancer Screening Trial demonstrated the ability to recruit, retain, and screen a large population over multiple years at multiple centers. A higher proportion of screen-detected lung cancers were early stage, but a conclusion on the effectiveness of CXR screening must await final PLCO results, which are anticipated at the end of 2015.
doi:10.1093/jnci/djq126
PMCID: PMC2873186  PMID: 20442215
11.  An evaluation of screening for lung cancer in Niigata Prefecture, Japan: a population-based case–control study 
British Journal of Cancer  2001;85(9):1326-1331.
Although an annual screening programme for lung cancer has been carried out widely in Japan since 1987, there is insufficient evidence to confirm its efficacy in terms of reducing mortality. In order to evaluate the efficacy of the lung cancer screening which has been widely carried out in Japan since 1987, a case–control study was conducted in Niigata Prefecture, Japan. In the study area, chest X-ray examinations for all participants and sputum cytology for high-risk participants were offered annually. Case subjects, who had died from lung cancer (174), and control subjects matched by sex, year of birth, residence and smoking status (801), who had been alive at the time of diagnosis of the corresponding case, were selected from the National Health Insurance holders. Screening histories of the subjects were compared between cases and matched controls for the identical calendar period before the time of diagnosis of the cases. The odds ratio of death from lung cancer for those screened within 12 months vs those not screened was 0.401 (95% CI: 0.272–0.591) with adjustment by smoking index. Our results suggest that annual lung cancer screening might reduce mortality from lung cancer by approximately 60%. © 2001 Cancer Research Campaign
doi:10.1054/bjoc.2001.2060
PMCID: PMC2375248  PMID: 11720469
lung cancer; screening; case–control study; efficacy
12.  Cancer Screening: A Mathematical Model Relating Secreted Blood Biomarker Levels to Tumor Sizes  
PLoS Medicine  2008;5(8):e170.
Background
Increasing efforts and financial resources are being invested in early cancer detection research. Blood assays detecting tumor biomarkers promise noninvasive and financially reasonable screening for early cancer with high potential of positive impact on patients' survival and quality of life. For novel tumor biomarkers, the actual tumor detection limits are usually unknown and there have been no studies exploring the tumor burden detection limits of blood tumor biomarkers using mathematical models. Therefore, the purpose of this study was to develop a mathematical model relating blood biomarker levels to tumor burden.
Methods and Findings
Using a linear one-compartment model, the steady state between tumor biomarker secretion into and removal out of the intravascular space was calculated. Two conditions were assumed: (1) the compartment (plasma) is well-mixed and kinetically homogenous; (2) the tumor biomarker consists of a protein that is secreted by tumor cells into the extracellular fluid compartment, and a certain percentage of the secreted protein enters the intravascular space at a continuous rate. The model was applied to two pathophysiologic conditions: tumor biomarker is secreted (1) exclusively by the tumor cells or (2) by both tumor cells and healthy normal cells. To test the model, a sensitivity analysis was performed assuming variable conditions of the model parameters. The model parameters were primed on the basis of literature data for two established and well-studied tumor biomarkers (CA125 and prostate-specific antigen [PSA]). Assuming biomarker secretion by tumor cells only and 10% of the secreted tumor biomarker reaching the plasma, the calculated minimally detectable tumor sizes ranged between 0.11 mm3 and 3,610.14 mm3 for CA125 and between 0.21 mm3 and 131.51 mm3 for PSA. When biomarker secretion by healthy cells and tumor cells was assumed, the calculated tumor sizes leading to positive test results ranged between 116.7 mm3 and 1.52 × 106 mm3 for CA125 and between 27 mm3 and 3.45 × 105 mm3 for PSA. One of the limitations of the study is the absence of quantitative data available in the literature on the secreted tumor biomarker amount per cancer cell in intact whole body animal tumor models or in cancer patients. Additionally, the fraction of secreted tumor biomarkers actually reaching the plasma is unknown. Therefore, we used data from published cell culture experiments to estimate tumor cell biomarker secretion rates and assumed a wide range of secretion rates to account for their potential changes due to field effects of the tumor environment.
Conclusions
This study introduced a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays. Assuming physiological data on CA125 and PSA from the literature, the model predicted detection limits of tumors that were in qualitative agreement with the actual clinical performance of both biomarkers. The model may be helpful in future estimation of minimal detectable tumor sizes for novel proteomic biomarker assays if sufficient physiologic data for the biomarker are available. The model may address the potential and limitations of tumor biomarkers, help prioritize biomarkers, and guide investments into early cancer detection research efforts.
Sanjiv Gambhir and colleagues describe a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays.
Editors' Summary
Background.
Cancers—disorganized masses of cells that can occur in any tissue—develop when cells acquire genetic changes that allow them to grow uncontrollably and to spread around the body (metastasize). If a cancer (tumor) is detected when it is small, surgery can often provide a cure. Unfortunately, many cancers (particularly those deep inside the body) are not detected until they are large enough to cause pain or other symptoms by pressing against surrounding tissue. By this time, it may be impossible to remove the original tumor surgically and there may be metastases scattered around the body. In such cases, radiotherapy and chemotherapy can sometimes help, but the outlook for patients whose cancers are detected late is often poor. Consequently, researchers are trying to develop early detection tests for different types of cancer. Many tumors release specific proteins—“cancer biomarkers”—into the blood and the hope is that it might be possible to find sets of blood biomarkers that detect cancers when they are still small and thus save many lives.
Why Was This Study Done?
For most biomarkers, it is not known how the amount of protein detected in the blood relates to tumor size or how sensitive the assays for biomarkers must be to improve patient survival. In this study, the researchers develop a “linear one-compartment” mathematical model to predict how large tumors need to be before blood biomarkers can be used to detect them and test this model using published data on two established cancer biomarkers—CA125 and prostate-specific antigen (PSA). CA125 is used to monitor the progress of patients with ovarian cancer after treatment; ovarian cancer is rarely diagnosed in its early stages and only one-fourth of women with advanced disease survive for 5 y after diagnosis. PSA is used to screen for prostate cancer and has increased the detection of this cancer in its early stages when it is curable.
What Did the Researchers Do and Find?
To develop a model that relates secreted blood biomarker levels to tumor sizes, the researchers assumed that biomarkers mix evenly throughout the patient's blood, that cancer cells secrete biomarkers into the fluid that surrounds them, that 0.1%–20% of these secreted proteins enter the blood at a continuous rate, and that biomarkers are continuously removed from the blood. The researchers then used their model to calculate the smallest tumor sizes that might be detectable with these biomarkers by feeding in existing data on CA125 and on PSA, including assay detection limits and the biomarker secretion rates of cancer cells growing in dishes. When only tumor cells secreted the biomarker and 10% of the secreted biomarker reach the blood, the model predicted that ovarian tumors between 0.11 mm3 (smaller than a grain of salt) and nearly 4,000 mm3 (about the size of a cherry) would be detectable by measuring CA125 blood levels (the range was determined by varying the amount of biomarker secreted by the tumor cells and the assay sensitivity); for prostate cancer, the detectable tumor sizes ranged from similar lower size to about 130 mm3 (pea-sized). However, healthy cells often also secrete small quantities of cancer biomarkers. With this condition incorporated into the model, the estimated detectable tumor sizes (or total tumor burden including metastases) ranged between grape-sized and melon-sized for ovarian cancers and between pea-sized to about grapefruit-sized for prostate cancers.
What Do These Findings Mean?
The accuracy of the calculated tumor sizes provided by the researchers' mathematical model is limited by the lack of data on how tumors behave in the human body and by the many assumptions incorporated into the model. Nevertheless, the model predicts detection limits for ovarian and prostate cancer that broadly mirror the clinical performance of both biomarkers. Somewhat worryingly, the model also indicates that a tumor may have to be very large for blood biomarkers to reveal its presence, a result that could limit the clinical usefulness of biomarkers, especially if they are secreted not only by tumor cells but also by healthy cells. Given this finding, as more information about how biomarkers behave in the human body becomes available, this model (and more complex versions of it) should help researchers decide which biomarkers are likely to improve early cancer detection and patient outcomes.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050170.
The US National Cancer Institute provides a brief description of what cancer is and how it develops and a fact sheet on tumor markers; it also provides information on all aspects of ovarian and prostate cancer for patients and professionals, including information on screening and testing (in English and Spanish)
The UK charity Cancerbackup also provides general information about cancer and more specific information about ovarian and prostate cancer, including the use of CA125 and PSA for screening and follow-up
The American Society of Clinical Oncology offers a wide range of information on various cancer types, including online published articles on the current status of cancer diagnosis and management from the educational book developed by the annual meeting faculty and presenters. Registration is mandatory, but information is free
doi:10.1371/journal.pmed.0050170
PMCID: PMC2517618  PMID: 18715113
13.  Cervical Screening at Age 50–64 Years and the Risk of Cervical Cancer at Age 65 Years and Older: Population-Based Case Control Study 
PLoS Medicine  2014;11(1):e1001585.
Peter Sasieni and colleagues use a population-based case control study to assess the risk of cervical cancer in screened women aged over 65 years to help inform policy on the upper age of cervical cancer screening.
Please see later in the article for the Editors' Summary
Background
There is little consensus, and minimal evidence, regarding the age at which to stop cervical screening. We studied the association between screening at age 50–64 y and cervical cancer at age 65–83 y.
Methods and Findings
Cases were women (n = 1,341) diagnosed with cervical cancer at age 65–83 y between 1 April 2007 and 31 March 2012 in England and Wales; age-matched controls (n = 2,646) were randomly selected from population registers. Screening details from 1988 onwards were extracted from national databases. We calculated the odds ratios (OR) for different screening histories and subsequent cervical cancer. Women with adequate negative screening at age 65 y (288 cases, 1,395 controls) were at lowest risk of cervical cancer (20-y risk: 8 cancers per 10,000 women) compared with those (532 cases, 429 controls) not screened at age 50–64 y (20-y risk: 49 cancers per 10,000 women, with OR = 0.16, 95% CI 0.13–0.19). ORs depended on the age mix of women because of the weakening association with time since last screen: OR = 0.11, 95% CI 0.08–0.14 at 2.5 to 7.5 y since last screen; OR = 0.27, 95% CI 0.20–0.36 at 12.5 to 17.5 y since last screen. Screening at least every 5.5 y between the ages 50 and 64 y was associated with a 75% lower risk of cervical cancer between the ages 65 and 79 y (OR = 0.25, 95% CI 0.21–0.30), and the attributable risk was such that in the absence of screening, cervical cancer rates in women aged 65+ would have been 2.4 (95% CI 2.1–2.7) times higher. In women aged 80–83 y the association was weaker (OR = 0.49, 95% CI 0.28–0.83) than in those aged 65–69 y (OR = 0.12, 95% CI 0.09–0.17). This study was limited by an absence of data on confounding factors; additionally, findings based on cytology may not generalise to human papillomavirus testing.
Conclusions
Women with adequate negative screening at age 50–64 y had one-sixth of the risk of cervical cancer at age 65–83 y compared with women who were not screened. Stopping screening between ages 60 and 69 y in women with adequate negative screening seems sensible, but further screening may be justifiable as life expectancy increases.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Nearly one in ten cancers diagnosed in women occur in the cervix, the structure that connects the womb to the vagina. Every year, more than a quarter of a million women (mostly in developing countries) die because of cervical cancer, which occurs only after the cervix has been infected with human papillomavirus (HPV) through sexual intercourse. In the earliest stages of cervical cancer, abnormal cells begin to grow in the cervix. Cells with low-grade abnormalities (changes that often revert to normal), cells with high-grade abnormalities (which are more likely to become cancerous), and cancer cells can all be detected by collecting a few cells from the cervix and examining them under a microscope. This test forms the basis of cervical screening, which has greatly reduced cervical cancer deaths in countries with a national screening program by ensuring that cervical abnormalities are detected at an early, treatable stage. In the UK, for example, since the start of a cervical screening program in 1988 in which women aged 25–64 years are called for testing every 3–5 years, the incidence of cervical cancer (the number of new cases per year) has almost halved at a time when sexually transmitted diseases have more than doubled.
Why Was This Study Done?
Currently, there is little consensus about the age at which cervical screening should stop, and minimal evidence about the impact of cervical screening on the incidence of cervical cancer in older women. In this population-based case control study (a study that compares the characteristics of all the cases of a disease in a population with the characteristics of matched individuals without the disease), the researchers examine the association between screening in women aged 50–64 years and cervical cancer in women aged 65–83 years. They ask whether well-screened women with a history of negative results and no evidence of high-grade abnormalities are at sufficiently low risk of cervical cancer that screening can be stopped at age 65 years, and whether women who are regularly screened (at least once every 5.5 years) between the ages of 50 and 64 years are subsequently at reduced risk of cervical cancer.
What Did the Researchers Do and Find?
The researchers randomly selected two age-matched controls for every woman aged 65–83 years who was diagnosed with cervical cancer between 2007 and 2012 in England and Wales. The researchers included 1,341 women with cervical cancer and 2,646 controls. They extracted each woman's cervical screening details from national databases and calculated the association between screening history and subsequent cervical cancer. Women with adequate negative screening at age 65 years (at least three tests at age 50–64 years with the last one over age 60, the last three of which were negative, and no evidence of high-grade abnormalities) were at the lowest risk of cervical cancer (20-year risk of eight cancers per 10,000 women) compared with unscreened women (20-year risk of 49 cancers per 10,000 women). That is, women who were not screened at age 50–64 years were six times more likely to develop cervical cancer between the ages of 65 and 83 years than women who were screened. The risk of developing cervical cancer among adequately negatively screened women increased with age and with time since the last screen. Finally, the researchers estimate that in the absence of any cervical screening, the rate of cervical cancer among women aged 65–79 years would be 23 cases per 100,000 woman-years, 2.4 times higher than the current rate.
What Do These Findings Mean?
These findings show that women who exited the screening program in England and Wales with a history of adequate negative screening between the ages of 50 and 64 years were at a very low risk of being diagnosed with cervical cancer at the age of 65 years or older. The “protection” provided by screening was greatest for women aged 65–69 years and decreased steadily with increasing age and with time since the last negative screen. Because the researchers did not have any information on other characteristics that might have affected cervical cancer risk (for example, number of sexual partners), the women who were screened may have shared other characteristics that reduced their risk of developing cervical cancer. Moreover, these findings, which are based on microscopic examination of cells, may not generalise to the HPV-based screening programs that many countries are considering. Despite these limitations, the researchers conclude that, for now, it seems sensible to continue screening at least until age 60 years and not beyond age 69 years in women with adequate negative screening, but that given increasing life expectancy, screening in older women might be justified in the future.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001585.
This study is further discussed in a PLOS Medicine Perspective by Anne Rositch and colleagues
The US National Cancer Institute provides information about cervical cancer for patients and for health professionals, including information on cervical screening (in English and Spanish)
The US Centers for Disease Control and Prevention also has information about cervical cancer and about cervical screening
The UK National Health Service Cervical Screening Programme website has detailed information and statistics on cervical screening in England
The UK National Health Service Choices website has pages on cervical cancer (including a personal story about cervical cancer) and on cervical screening (including personal comments about screening)
Cancer Research UK provides detailed information about all aspects of cervical cancer
More information about cervical cancer and screening is available from the Macmillan cancer charity
MedlinePlus provides links to additional resources about cervical cancer and screening (in English and Spanish)
Personal stories about cervical cancer and about cervical screening are available through the charity Healthtalkonline
doi:10.1371/journal.pmed.1001585
PMCID: PMC3891624  PMID: 24453946
14.  Effect of Flexible Sigmoidoscopy-Based Screening on Incidence and Mortality of Colorectal Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
PLoS Medicine  2012;9(12):e1001352.
A systematic review and meta-analysis of randomized trials conducted by B. Joseph Elmunzer and colleagues reports that that flexible sigmoidoscopy-based screening reduces the incidence of colorectal cancer in average-risk patients, as compared to usual care or no screening.
Background
Randomized controlled trials (RCTs) have yielded varying estimates of the benefit of flexible sigmoidoscopy (FS) screening for colorectal cancer (CRC). Our objective was to more precisely estimate the effect of FS-based screening on the incidence and mortality of CRC by performing a meta-analysis of published RCTs.
Methods and Findings
Medline and Embase databases were searched for eligible articles published between 1966 and 28 May 2012. After screening 3,319 citations and 29 potentially relevant articles, two reviewers identified five RCTs evaluating the effect of FS screening on the incidence and mortality of CRC. The reviewers independently extracted relevant data; discrepancies were resolved by consensus. The quality of included studies was assessed using criteria set out by the Evidence-Based Gastroenterology Steering Group. Random effects meta-analysis was performed.
The five RCTs meeting eligibility criteria were determined to be of high methodologic quality and enrolled 416,159 total subjects. Four European studies compared FS to no screening and one study from the United States compared FS to usual care. By intention to treat analysis, FS-based screening was associated with an 18% relative risk reduction in the incidence of CRC (0.82, 95% CI 0.73–0.91, p<0.001, number needed to screen [NNS] to prevent one case of CRC = 361), a 33% reduction in the incidence of left-sided CRC (RR 0.67, 95% CI 0.59–0.76, p<0.001, NNS = 332), and a 28% reduction in the mortality of CRC (relative risk [RR] 0.72, 95% CI 0.65–0.80, p<0.001, NNS = 850). The efficacy estimate, the amount of benefit for those who actually adhered to the recommended treatment, suggested that FS screening reduced CRC incidence by 32% (p<0.001), and CRC-related mortality by 50% (p<0.001).
Limitations of this meta-analysis include heterogeneity in the design of the included trials, absence of studies from Africa, Asia, or South America, and lack of studies comparing FS with colonoscopy or stool-based testing.
Conclusions
This meta-analysis of randomized controlled trials demonstrates that FS-based screening significantly reduces the incidence and mortality of colorectal cancer in average-risk patients.
Please see later in the article for the Editors' Summary
Editor's Summary
Background
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Regular CRC screening has been shown to reduce the risk of dying from CRC by 16%, and CRC screening can identify early stage cancers in otherwise healthy people, which allows for early treatment and management of the disease. Screening for colorectal cancer is frequently performed using a flexible sigmoidoscopy (FS), which is a thin, flexible tube with a tiny camera and light on the end, allowing a doctor to look at the inside wall of the bowel and remove any small growths or polyps. Although screening may detect early cancers, the life-saving and health benefits of screening are uncertain because the polyp may not necessarily progress. This could lead to anxiety and unnecessary interventions and treatments amongst those screened. Randomized controlled trials (RCTs) are needed to determine all of the risks involved in cancer screenings, however the guidelines that recommend FS-based screening do not rely upon RCT data. Recently, the results of four large-scale RCTs evaluating FS screening for CRC have been published. The conflicting results with respect to the incidence and mortality of CRC in these studies have called into question the effectiveness of endoscopic screening.
Why Was This Study Done?
The results of RCTs measuring the risks and outcomes of CRC screening have shown varying estimates of the benefits of using FS screening. If better estimates of the risks and benefits of FS screening are developed, then the current CRC screening guidelines may be updated to reflect this new information. In this study, the authors show the results of a meta-analysis of published RCTs, which more precisely estimates the effects of FS-based screening on the incidence and mortality of colorectal cancer.
What Did the Researchers Do and Find?
The researchers used the Medline and Embase databases to find relevant studies from 1966 to May 28, 2012. After screening 3,319 citations and 29 potentially relevant articles, five RCTs of high methodologic quality and 416,159 total subjects evaluating the effect of FS screening on the incidence and mortality of CRC were identified. The data were extracted and random effects meta-analysis was performed. The meta-analysis revealed that FS-based screening was associated with an 18% relative risk reduction in the incidence of CRC (0.82, 95% CI 0.73–0.91, p<0.001, number needed to screen (NNS) to prevent one case of CRC = 361), a 33% reduction in the incidence of left-sided CRC (RR 0.67, 95% CI 0.59–0.76, p<0.001, NNS = 332), and a 28% reduction in the mortality of CRC (RR 0.72, 95% CI 0.65–0.80, p<0.001, NNS = 850). The amount of benefit for those who adhered to the recommended treatment suggested that FS screening reduced CRC incidence by 32% (p<0.001), and CRC-related mortality by 50% (p<0.001).
What Do These Findings Mean?
This meta-analysis of RCTs evaluating the effect of FS on CRC incidence and mortality demonstrates that a FS-based strategy for screening is very effective in reducing the incidence and mortality of CRC in patients. The current recommendations for endoscopic screening are based on observational studies, which may not accurately reflect the effect of FS-based screening on the incidence and mortality of CRC. Here, the authors performed a systematic review and meta-analysis of five recent RCTs to better estimate the true effect of FS-based screening on the incidence and mortality of CRC. Thus, the results of this meta-analysis may affect health policy, and directly impact patients and clinicians.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001352.
Cancer research UK provides comprehensive information about screening for colorectal cancers as does the UK National Screening Committee
PubMed Health has general information about colon cancer
The National Cancer Institute also has comprehensive resources on colorectal cancer and treatment
The Mayo Clinic provides an overview of all aspects of colon cancer
doi:10.1371/journal.pmed.1001352
PMCID: PMC3514315  PMID: 23226108
15.  "Risk homeostasis"or "teachable moment"? the interaction between smoking behavior and lung cancer screening in the Mayo Lung Project 
The chest X-ray lung cancer screening program of Mayo Lung Project (MLP) yielded mixed results of improved lung case survival but no improvement in lung cancer mortality. This paper analyzes the smoking patterns of study participants in order to examine possible behavioral ramifications of periodic lung cancer screening. Using a longitudinal difference-of-difference model, we compared the smoking behavior, in terms of current smoker status among all subjects and the intensity of smoking among those continuing smokers, between those who received periodic lung cancer screening and those who received usual-care. In both arms of this lung cancer screening trial, there was a sizable decline in cigarette smoking one year after participants received baseline prevalence screening. There was no significant difference in current smoker status between the intervention group receiving periodic X-ray screening and the control group receiving usual care. While we detect that the continuing smokers in the intervention group smoked more than their counterparts in the control group, the magnitude of the difference is not sufficient to explain a substantial difference in lung cancer incidence between the two groups. Our study shows that periodic lung screening in MLP did not decrease smoking behavior beyond the observed decline following the initial prevalence screening conducted at baseline for both the intervention and control groups. Our results also indicate, paradoxically, that participants assigned to the intervention group smoked more cigarettes per day on average than those in the control group. Lung cancer screening programs need additional cessation components to sustain the abstinence effect typically observed following initial lung screening.
doi:10.1186/1617-9625-9-2
PMCID: PMC3033237  PMID: 21255463
16.  Socioeconomic Inequalities in Lung Cancer Treatment: Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(2):e1001376.
In a systematic review and meta-analysis, Lynne Forrest and colleagues find that patients with lung cancer who are more socioeconomically deprived are less likely to receive surgical treatment, chemotherapy, or any type of treatment combined, compared with patients who are more socioeconomically well off, regardless of cancer stage or type of health care system.
Background
Intervention-generated inequalities are unintended variations in outcome that result from the organisation and delivery of health interventions. Socioeconomic inequalities in treatment may occur for some common cancers. Although the incidence and outcome of lung cancer varies with socioeconomic position (SEP), it is not known whether socioeconomic inequalities in treatment occur and how these might affect mortality. We conducted a systematic review and meta-analysis of existing research on socioeconomic inequalities in receipt of treatment for lung cancer.
Methods and Findings
MEDLINE, EMBASE, and Scopus were searched up to September 2012 for cohort studies of participants with a primary diagnosis of lung cancer (ICD10 C33 or C34), where the outcome was receipt of treatment (rates or odds of receiving treatment) and where the outcome was reported by a measure of SEP. Forty-six papers met the inclusion criteria, and 23 of these papers were included in meta-analysis. Socioeconomic inequalities in receipt of lung cancer treatment were observed. Lower SEP was associated with a reduced likelihood of receiving any treatment (odds ratio [OR] = 0.79 [95% CI 0.73 to 0.86], p<0.001), surgery (OR = 0.68 [CI 0.63 to 0.75], p<0.001) and chemotherapy (OR = 0.82 [95% CI 0.72 to 0.93], p = 0.003), but not radiotherapy (OR = 0.99 [95% CI 0.86 to 1.14], p = 0.89), for lung cancer. The association remained when stage was taken into account for receipt of surgery, and was found in both universal and non-universal health care systems.
Conclusions
Patients with lung cancer living in more socioeconomically deprived circumstances are less likely to receive any type of treatment, surgery, and chemotherapy. These inequalities cannot be accounted for by socioeconomic differences in stage at presentation or by differences in health care system. Further investigation is required to determine the patient, tumour, clinician, and system factors that may contribute to socioeconomic inequalities in receipt of lung cancer treatment.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Lung cancer is the most commonly occurring cancer worldwide and the commonest cause of cancer-related death. Like all cancers, lung cancer occurs when cells begin to grow uncontrollably because of changes in their genes. The most common trigger for these changes in lung cancer is exposure to cigarette smoke. Most cases of lung cancer are non-small cell lung cancer, the treatment for which depends on the “stage” of the disease when it is detected. Stage I tumors, which are confined to the lung, can be removed surgically. Stage II tumors, which have spread to nearby lymph nodes, are usually treated with surgery plus chemotherapy or radiotherapy. For more advanced tumors, which have spread throughout the chest (stage III) or throughout the body (stage IV), surgery generally does not help to slow tumor growth and the cancer is treated with chemotherapy and radiotherapy. Small cell lung cancer, the other main type of lung cancer, is nearly always treated with chemotherapy and radiotherapy but sometimes with surgery as well. Overall, because most lung cancers are not detected until they are quite advanced, less than 10% of people diagnosed with lung cancer survive for 5 years.
Why Was This Study Done?
As with many other cancers, socioeconomic inequalities have been reported for both the incidence of and the survival from lung cancer in several countries. It is thought that the incidence of lung cancer is higher among people of lower socioeconomic position than among wealthier people, in part because smoking rates are higher in poorer populations. Similarly, it has been suggested that survival is worse among poorer people because they tend to present with more advanced disease, which has a worse prognosis (predicted outcome) than early disease. But do socioeconomic inequalities in treatment exist for lung cancer and, if they do, could these inequalities contribute to the poor survival rates among populations of lower socioeconomic position? In this systematic review and meta-analysis, the researchers investigate the first of these questions. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 46 published papers that studied people with lung cancer in whom receipt of treatment was reported in terms of an indicator of socioeconomic position, such as a measure of income or deprivation. Twenty-three of these papers were suitable for inclusion in a meta-analysis. Lower socioeconomic position was associated with a reduced likelihood of receiving any treatment. Specifically, the odds ratio (chance) of people in the lowest socioeconomic group receiving any treatment was 0.79 compared to people in the highest socioeconomic group. Lower socioeconomic position was also associated with a reduced chance of receiving surgery (OR = 0.68) and chemotherapy (OR = 0.82), but not radiotherapy. The association between socioeconomic position and surgery remained after taking cancer stage into account. That is, when receipt of surgery was examined in early-stage patients only, low socioeconomic position remained associated with reduced likelihood of surgery. Notably, the association between socioeconomic position and receipt of treatment was similar in studies undertaken in countries where health care is free at the point of service for everyone (for example, the UK) and in countries with primarily private insurance health care systems (for example, the US).
What Do These Findings Mean?
These findings suggest that patients in more socioeconomically deprived circumstances are less likely to receive any type of treatment, surgery, and chemotherapy (but not radiotherapy) for lung cancer than people who are less socioeconomically deprived. Importantly, these inequalities cannot be explained by socioeconomic differences in stage at presentation or by differences in health care system. The accuracy of these findings may be affected by several factors. For example, it is possible that only studies that found an association between socioeconomic position and receipt of treatment have been published (publication bias). Moreover, the studies identified did not include information regarding patient preferences, which could help explain at least some of the differences. Nevertheless, these results do suggest that socioeconomic inequalities in receipt of treatment may exacerbate socioeconomic inequalities in the incidence of lung cancer and may contribute to the observed poorer outcomes in lower socioeconomic position groups. Further research is needed to determine the system and patient factors that contribute to socioeconomic inequalities in lung cancer treatment before clear recommendations for changes to policy and practice can be made.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001376.
The US National Cancer Institute provides information about all aspects of lung cancer for patients and health care professionals (in English and Spanish); a monograph entitled Area Socioeconomic Variations in U. S. Cancer Incidence, Mortality, Stage, Treatment, and Survival, 19751999 is available
Cancer Research UK also provides detailed information about lung cancer and links to other resources, such as a policy statement on socioeconomic inequalities in cancer and a monograph detailing cancer and health inequalities in the UK
The UK National Health Service Choices website has a page on lung cancer that includes personal stories about diagnosis and treatment
MedlinePlus provides links to other US sources of information about lung cancer (in English and Spanish)
doi:10.1371/journal.pmed.1001376
PMCID: PMC3564770  PMID: 23393428
17.  Computed Tomography Screening for Lung Cancer: Has It Finally Arrived? Implications of the National Lung Screening Trial 
Journal of Clinical Oncology  2013;31(8):1002-1008.
The National Lung Screening Trial (NLST) has provided compelling evidence of the efficacy of lung cancer screening using low-dose helical computed tomography (LDCT) to reduce lung cancer mortality. The NLST randomized 53,454 older current or former heavy smokers to receive LDCT or chest radiography (CXR) for three annual screens. Participants were observed for a median of 6.5 years for outcomes. Vital status was available in more than 95% of participants. LDCT was positive in 24.2% of screens, compared with 6.9% of CXRs; more than 95% of all positive LDCT screens were not associated with lung cancer. LDCT detected more than twice the number of early-stage lung cancers and resulted in a stage shift from advanced to early-stage disease. Complications of LDCT screening were minimal. Lung cancer–specific mortality was reduced by 20% relative to CXR; all-cause mortality was reduced by 6.7%. The major harms of LDCT are radiation exposure, high false-positive rates, and the potential for overdiagnosis. This review discusses the risks and benefits of LDCT screening as well as an approach to LDCT implementation that incorporates systematic screening practice with smoking cessation programs and offers opportunities for better determination of appropriate risk cohorts for screening and for better diagnostic prediction of lung cancer in the setting of screen-detected nodules. The challenges of implementation are considered for screening programs, for primary care clinicians, and across socioeconomic strata. Considerations for future research to complement imaging-based screening to reduce the burden of lung cancer are discussed.
doi:10.1200/JCO.2012.43.3110
PMCID: PMC3589698  PMID: 23401434
18.  Bridging the clinical gaps: genetic, epigenetic and transcriptomic biomarkers for the early detection of lung cancer in the post-National Lung Screening Trial era 
BMC Medicine  2013;11:168.
Lung cancer is the leading cause of cancer death worldwide in part due to our inability to identify which smokers are at highest risk and the lack of effective tools to detect the disease at its earliest and potentially curable stage. Recent results from the National Lung Screening Trial have shown that annual screening of high-risk smokers with low-dose helical computed tomography of the chest can reduce lung cancer mortality. However, molecular biomarkers are needed to identify which current and former smokers would benefit most from annual computed tomography scan screening in order to reduce the costs and morbidity associated with this procedure. Additionally, there is an urgent clinical need to develop biomarkers that can distinguish benign from malignant lesions found on computed tomography of the chest given its very high false positive rate. This review highlights recent genetic, transcriptomic and epigenomic biomarkers that are emerging as tools for the early detection of lung cancer both in the diagnostic and screening setting.
doi:10.1186/1741-7015-11-168
PMCID: PMC3717087  PMID: 23870182
Biomarker; Diagnostics; Early detection; Epigenetics; Genetics; Lung cancer; Screening; Transcriptomics
19.  Use of lung cancer screening tests in the United States: results from the 2010 National Health Interview Survey 
Background
Prior to evidence of efficacy, lung cancer screening was being ordered by many physicians. The National Lung Screening Trial (NLST), which demonstrated a 20 percent reduction in lung cancer mortality among those randomized to receive low-dose computed tomography (LDCT), will likely lead to increased screening use.
Methods
We estimated the prevalence of chest x-ray and CT use in the United States using data from the 2010 National Health Interview Survey (NHIS). Subjects included 15,537 NHIS respondents aged ≥40 years without prior diagnosis of lung cancer. Estimates of the size of the U. S. population by age and smoking status were calculated. Multivariate logistic regression examined predictors of test use adjusting for potential confounders.
Results
Twenty-three percent of adults reported chest x-ray in the previous year, and 2.5 percent reported chest x-ray specifically to check for lung cancer; corresponding numbers for chest CT were 7.5 and 1.3 percent. Older age, black race, male gender, smoking, respiratory disease, personal history of cancer, and having health insurance were associated with test use. Approximately 8.7 million adults in the United States would be eligible for LDCT screening according to NLST eligibility criteria.
Conclusions and Impact
Monitoring of trends in the use of lung screening tests will be vital to assess the impact of NLST and possible changes in lung cancer screening recommendations and insurance coverage in the future. Education of patients by their physicians, and of the general public, may help ensure that screening is used appropriately, in those most likely to benefit.
doi:10.1158/1055-9965.EPI-12-0343
PMCID: PMC3392469  PMID: 22573798
lung cancer; screening; chest x-ray; low-dose helical computed tomography; national survey
20.  A Cost-Utility Analysis of Lung Cancer Screening and the Additional Benefits of Incorporating Smoking Cessation Interventions 
PLoS ONE  2013;8(8):e71379.
Background
A 2011 report from the National Lung Screening Trial indicates that three annual low-dose computed tomography (LDCT) screenings for lung cancer reduced lung cancer mortality by 20% compared to chest X-ray among older individuals at high risk for lung cancer. Discussion has shifted from clinical proof to financial feasibility. The goal of this study was to determine whether LDCT screening for lung cancer in a commercially-insured population (aged 50–64) at high risk for lung cancer is cost-effective and to quantify the additional benefits of incorporating smoking cessation interventions in a lung cancer screening program.
Methods and Findings
The current study builds upon a previous simulation model to estimate the cost-utility of annual, repeated LDCT screenings over 15 years in a high risk hypothetical cohort of 18 million adults between age 50 and 64 with 30+ pack-years of smoking history. In the base case, the lung cancer screening intervention cost $27.8 billion over 15 years and yielded 985,284 quality-adjusted life years (QALYs) gained for a cost-utility ratio of $28,240 per QALY gained. Adding smoking cessation to these annual screenings resulted in increases in both the costs and QALYs saved, reflected in cost-utility ratios ranging from $16,198 per QALY gained to $23,185 per QALY gained. Annual LDCT lung cancer screening in this high risk population remained cost-effective across all sensitivity analyses.
Conclusions
The findings of this study indicate that repeat annual lung cancer screening in a high risk cohort of adults aged 50–64 is highly cost-effective. Offering smoking cessation interventions with the annual screening program improved the cost-effectiveness of lung cancer screening between 20% and 45%. The cost-utility ratios estimated in this study were in line with other accepted cancer screening interventions and support inclusion of annual LDCT screening for lung cancer in a high risk population in clinical recommendations.
doi:10.1371/journal.pone.0071379
PMCID: PMC3737088  PMID: 23940744
21.  Sensitivity and specificity of lung cancer screening using chest low-dose computed tomography 
British Journal of Cancer  2008;98(10):1602-1607.
Lung cancer screening programmes using chest X-ray and sputum cytology are routinely performed in Japan; however, the efficacy is insufficient. Screening using low-dose computed tomography (CT) is a more effective approach and has the potential to detect the disease more accurately. A total of 7183 low-dose CT screening tests for 4689 participants and 36 085 chest X-ray screening tests for 13 381 participants were conducted between August 1998 and May 2002. Sensitivity and specificity of lung cancer screening were calculated by both the detection method and the incidence method by linkage of the screening database and the Cancer Registry database. The preclinical detectable phase was assumed to be 1 year. Sensitivity and specificity by the detection method were 88.9 and 92.6% for low-dose CT and 78.3 and 97.0% for chest X-ray, respectively. Sensitivity of low-dose CT by the incidence method was 79.5%, whereas that of chest X-ray was 86.5%. Lung cancer screening using low-dose CT resulted in higher sensitivity and lower specificity than traditional screening according to the detection method. However, sensitivity by the incidence method was not as high as this. These findings demonstrate the potential for overdiagnosis in CT screening-detected cases.
doi:10.1038/sj.bjc.6604351
PMCID: PMC2391122  PMID: 18475292
sensitivity; specificity; lung cancer; screening
22.  Early diagnosis of lung cancer 
F1000Prime Reports  2013;5:12.
A large randomized controlled trial, The National Lung Screening Study (NLST), has demonstrated that screening with low-dose spiral computed tomography saved lives from lung cancer when compared with screening with chest radiographs. This is the first test showing efficacy in screening for lung cancer as previous trials of chest radiographs and sputum cytology failed to result in fewer deaths with screening. This review will examine the problem of lung cancer, the issues presented by screening, and the results of computed tomography (CT) studies for lung cancer screening. Now that CT screening has been shown to be effective, implementation of screening becomes the next step.
doi:10.12703/P5-12
PMCID: PMC3616602  PMID: 23585930
23.  Identification of lung cancer with high sensitivity and specificity by blood testing 
Respiratory Research  2010;11(1):18.
Background
Lung cancer is a very frequent and lethal tumor with an identifiable risk population. Cytological analysis and chest X-ray failed to reduce mortality, and CT screenings are still controversially discussed. Recent studies provided first evidence for the potential usefulness of autoantigens as markers for lung cancer.
Methods
We used extended panels of arrayed antigens and determined autoantibody signatures of sera from patients with different kinds of lung cancer, different common non-tumor lung pathologies, and controls without any lung disease by a newly developed computer aided image analysis procedure. The resulting signatures were classified using linear kernel Support Vector Machines and 10-fold cross-validation.
Results
The novel approach allowed for discriminating lung cancer patients from controls without any lung disease with a specificity of 97.0%, a sensitivity of 97.9%, and an accuracy of 97.6%. The classification of stage IA/IB tumors and controls yielded a specificity of 97.6%, a sensitivity of 75.9%, and an accuracy of 92.9%. The discrimination of lung cancer patients from patients with non-tumor lung pathologies reached an accuracy of 88.5%.
Conclusion
We were able to separate lung cancer patients from subjects without any lung disease with high accuracy. Furthermore, lung cancer patients could be seprated from patients with other non-tumor lung diseases. These results provide clear evidence that blood-based tests open new avenues for the early diagnosis of lung cancer.
doi:10.1186/1465-9921-11-18
PMCID: PMC2832627  PMID: 20146812
24.  Screening Mammography for Women Aged 40 to 49 Years at Average Risk for Breast Cancer 
Executive Summary
Objective
The aim of this review was to determine the effectiveness of screening mammography in women aged 40 to 49 years at average risk for breast cancer.
Clinical Need
The effectiveness of screening mammography in women aged over 50 years has been established, yet the issue of screening in women aged 40 to 49 years is still unsettled. The Canadian Task Force of Preventive Services, which sets guidelines for screening mammography for all provinces, supports neither the inclusion nor the exclusion of this screening procedure for 40- to 49-year-old women from the periodic health examination. In addition to this, 2 separate reviews, one conducted in Quebec in 2005 and the other in Alberta in 2000, each concluded that there is an absence of convincing evidence on the effectiveness of screening mammography for women in this age group who are at average risk for breast cancer.
In the United States, there is disagreement among organizations on whether population-based mammography should begin at the age of 40 or 50 years. The National Institutes of Health, the American Association for Cancer Research, and the American Academy of Family Physicians recommend against screening women in their 40s, whereas the United States Preventive Services Task Force, the National Cancer Institute, the American Cancer Society, the American College of Radiology, and the American College of Obstetricians and Gynecologists recommend screening mammograms for women aged 40 to 49 years. Furthermore, in comparing screening guidelines between Canada and the United States, it is also important to recognize that “standard care” within a socialized medical system such as Canada’s differs from that of the United States. The National Breast Screening Study (NBSS-1), a randomized screening trial conducted in multiple centres across Canada, has shown there is no benefit in mortality from breast cancer from annual mammograms in women randomized between the ages of 40 and 49, relative to standard care (i.e. physical exam and teaching of breast-self examination on entry to the study, with usual community care thereafter).
At present, organized screening programs in Canada systematically screen women starting at 50 years of age, although with a physician’s referral, a screening mammogram is an insured service in Ontario for women under 50 years of age.
International estimates of the epidemiology of breast cancer show that the incidence of breast cancer is increasing for all ages combined, whereas mortality is decreasing, though at a slower rate. These decreasing mortality rates may be attributed to screening and advances in breast cancer therapy over time. Decreases in mortality attributable to screening may be a result of the earlier detection and treatment of invasive cancers, in addition to the increased detection of ductal carcinoma in situ (DCIS), of which certain subpathologies are less lethal. Evidence from the SEER cancer registry in the United States indicates that the age-adjusted incidence of DCIS has increased almost 10-fold over a 20-year period (from 2.7 to 25 per 100,000).
The incidence of breast cancer is lower in women aged 40 to 49 years than in women aged 50 to 69 years (about 140 per 100,000 versus 500 per 100,000 women, respectively), as is the sensitivity (about 75% versus 85% for women aged under and over 50, respectively) and specificity of mammography (about 80% versus 90% for women aged under and over 50, respectively). The increased density of breast tissue in younger women is mainly responsible for the lower accuracy of this procedure in this age group. In addition, as the proportion of breast cancers that occur before the age of 50 are more likely to be associated with genetic predisposition as compared with those diagnosed in women after the age of 50, mammography may not be an optimal screening method for younger women.
Treatment options vary with the stage of disease (based on tumor size, involvement of surrounding tissue, and number of affected axillary lymph nodes) and its pathology, and may include a combination of surgery, chemotherapy, and/or radiotherapy.
Surgery is the first-line intervention for biopsy confirmed tumours. The subsequent use of radiation, chemotherapy, or hormonal treatments is dependent on the histopathologic characteristics of the tumor and the type of surgery. There is controversy regarding the optimal treatment of DCIS, which is noninvasive.
With such controversy as to the effectiveness of mammography and the potential risk associated with women being overtreated or actual cancers being missed, and the increased risk of breast cancer associated with exposure to annual mammograms over a 10-year period, the Ontario Health Technology Advisory Committee requested this review of screening mammography in women aged 40 to 49 years at average risk for breast cancer. This review is the first of 2 parts and concentrates on the effectiveness of screening mammography (i.e., film mammography, FM) for women at average risk aged 40 to 49 years. The second part will be an evaluation of screening by either magnetic resonance imaging or digital mammography, with the objective of determining the optimal screening modality in these younger women.
Review Strategy
The following questions were asked:
Does screening mammography for women aged 40 to 49 years who are at average risk for breast cancer reduce breast cancer mortality?
What is the sensitivity and specificity of mammography for this age group?
What are the risks associated with annual screening from ages 40 to 49?
What are the risks associated with false positive and false negative mammography results?
What are the economic considerations if evidence for effectiveness is established?
The Medical Advisory Secretariat followed its standard procedures and searched these electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and the International Network of Agencies for Health Technology Assessment.
Keywords used in the search were breast cancer, breast neoplasms, mass screening, and mammography.
In total, the search yielded 6,359 articles specific to breast cancer screening and mammography. This did not include reports on diagnostic mammograms. The search was further restricted to English-language randomized controlled trials (RCTs), systematic reviews, and meta-analyses published between 1995 and 2005. Excluded were case reports, comments, editorials, and letters, which narrowed the results to 516 articles and previous health technology policy assessments.
These were examined against the criteria outlined below. This resulted in the inclusion of 5 health technology assessments, the Canadian Preventive Services Task Force report, the United States Preventive Services Task Force report, 1 Cochrane review, and 8 RCTs.
Inclusion Criteria
English-language articles, and English and French-language health technology policy assessments, conducted by other organizations, from 1995 to 2005
Articles specific to RCTs of screening mammography of women at average risk for breast cancer that included results for women randomized to studies between the ages of 40 and 49 years
Studies in which women were randomized to screening with or without mammography, although women may have had clinical breast examinations and/or may have been conducting breast self-examination.
UK Age Trial results published in December 2006.
Exclusion Criteria
Observational studies, including those nested within RCTs
RCTs that do not include results on women between the ages of 40 and 49 at randomization
Studies in which mammography was compared with other radiologic screening modalities, for example, digital mammography, magnetic resonance imaging or ultrasound.
Studies in which women randomized had a personal history of breast cancer.
Intervention
Film mammography
Comparators
Within RCTs, the comparison group would have been women randomized to not undergo screening mammography, although they may have had clinical breast examinations and/or have been conducting breast self-examination.
Outcomes of Interest
Breast cancer mortality
Summary of Findings
There is Level 1 Canadian evidence that screening women between the ages of 40 and 49 years who are at average risk for breast cancer is not effective, and that the absence of a benefit is sustained over a maximum follow-up period of 16 years.
All remaining studies that reported on women aged under 50 years were based on subset analyses. They provide additional evidence that, when all these RCTs are taken into account, there is no significant reduction in breast cancer mortality associated with screening mammography in women aged 40 to 49 years.
Conclusions
There is Level 1 evidence that screening mammography in women aged 40 to 49 years at average risk for breast cancer is not effective in reducing mortality.
Moreover, risks associated with exposure to mammographic radiation, the increased risk of missed cancers due to lower mammographic sensitivity, and the psychological impact of false positives, are not inconsequential.
The UK Age Trial results published in December 2006 did not change these conclusions.
PMCID: PMC3377515  PMID: 23074501
25.  Screening for HIV-Associated Tuberculosis and Rifampicin Resistance before Antiretroviral Therapy Using the Xpert MTB/RIF Assay: A Prospective Study 
PLoS Medicine  2011;8(7):e1001067.
In a prospective study, Stephen Lawn and colleagues find that pre-ART screening with Xpert MTB/RIF increased tuberculosis case detection by 45% compared to smear microscopy in HIV-positive patients at high risk of TB risk. AE competing interests must also pull through to the proof. “The Academic Editor, Madhukar Pai, declares that he consults for the Bill & Melinda Gates Foundation (BMGF). The BMGF supported FIND which was involved in the development of the Xpert MTB/RIF assay. He also co-chairs the Stop TB Partnership's New Diagnostics Working Group that was involved in the WHO endorsement of the Xpert assay.” Linked: Scott pmed.1001061; Evans pmed.1001064; Dowdy pmed.1001063
Background
The World Health Organization has endorsed the Xpert MTB/RIF assay for investigation of patients suspected of having tuberculosis (TB). However, its utility for routine TB screening and detection of rifampicin resistance among HIV-infected patients with advanced immunodeficiency enrolling in antiretroviral therapy (ART) services is unknown.
Methods and Findings
Consecutive adult HIV-infected patients with no current TB diagnosis enrolling in an ART clinic in a South African township were recruited regardless of symptoms. They were clinically characterised and invited to provide two sputum samples at a single visit. The accuracy of the Xpert MTB/RIF assay for diagnosing TB and drug resistance was assessed in comparison with other tests, including fluorescence smear microscopy and automated liquid culture (gold standard) and drug susceptibility testing. Of 515 patients enrolled, 468 patients (median CD4 cell count, 171 cells/µl; interquartile range, 102–236) produced at least one sputum sample, yielding complete sets of results from 839 samples. Mycobacterium tuberculosis was cultured from 81 patients (TB prevalence, 17.3%). The overall sensitivity of the Xpert MTB/RIF assay for culture-positive TB was 73.3% (specificity, 99.2%) compared to 28.0% (specificity, 100%) using smear microscopy. All smear-positive, culture-positive disease was detected by Xpert MTB/RIF from a single sample (sensitivity, 100%), whereas the sensitivity for smear-negative, culture-positive TB was 43.4% from one sputum sample and 62.3% from two samples. Xpert correctly identified rifampicin resistance in all four cases of multidrug-resistant TB but incorrectly identified resistance in three other patients whose disease was confirmed to be drug sensitive by gene sequencing (specificity, 94.1%; positive predictive value, 57%).
Conclusions
In this population of individuals at high risk of TB, intensive screening using the Xpert MTB/RIF assay increased case detection by 45% compared with smear microscopy, strongly supporting replacement of microscopy for this indication. However, despite the ability of the assay to rapidly detect rifampicin-resistant disease, the specificity for drug-resistant TB was sub-optimal.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Tuberculosis (TB)—a contagious bacterial infection that mainly affects the lungs—is a leading cause of illness and death among people who are infected with HIV, the virus that causes AIDS by destroying the immune system, which leaves infected individuals susceptible to other infections. TB is caused by Mycobacterium tuberculosis, which is spread in airborne droplets when people with the disease cough or sneeze. Its symptoms include a persistent cough, weight loss, and night sweats. Diagnostic tests for TB include chest X-rays, sputum smear analysis (microscopic examination of mucus coughed up from the lungs for M. tuberculosis bacilli), and mycobacterial liquid culture (the growth of M. tuberculosis from sputum and determination of its drug sensitivity). TB can be cured by taking several drugs daily for six months, although the recent emergence of multidrug-resistant TB (MDR-TB) is making the disease increasingly hard to treat.
Why Was This Study Done?
TB is a major problem in clinics that provide antiretroviral therapy (ART) for HIV-positive people in resource-limited settings. Not only is it a major cause of sickness and mortality in those affected by it, but TB (especially MDR-TB) can also spread to other patients attending the same clinic for health services. Rapid diagnosis and appropriate treatment are very important to reduce these risks. Unfortunately, sputum smear analysis—the mainstay of TB diagnosis in resource-limited settings—only detects about a fifth of TB cases when used as a screening tool before initiating ART. Chest X-rays are costly and don't always detect TB, and liquid culture—the gold standard method for TB diagnosis—is costly, technically difficult, and slow. Consequently, the World Health Organization (WHO) recently endorsed a new test for the investigation of patients suspected of having TB, especially in regions where HIV infection and MDR-TB are common. Xpert MTB/RIF is an automated DNA test that detects M. tuberculosis and DNA differences that make the bacteria resistant to the drug rifampicin (an indicator of MDR-TB) within 2 hours. In this study, the researchers investigate whether Xpert MTB/RIF could be used as a routine screening test to increase TB detection among HIV-positive people initiating ART.
What Did the Researchers Do and Find?
The researchers collected sputum from HIV-infected adults with no current TB diagnosis enrolling at an ART clinic in a South African township where HIV infection and TB are both common. They then compared the diagnostic accuracy of Xpert MTB/RIF (performed at a centralized laboratory) with that of several other tests, including liquid culture (the reference test). Nearly a fifth of the patients had culture-positive TB. Xpert MTB/RIF identified three-quarters of these patients (a sensitivity of 73.3%). By contrast, the sensitivity of smear microscopy was 28%. The new test's specificity (the proportion of patients with a negative Xpert MTB/RIF result among patients without TB) was 99.2%. That is, Xpert MTB/RIF had a low false-positive rate. Notably, Xpert MTB/RIF detected all cases of smear-positive, culture-positive TB but only 43.4% of smear-negative, culture-positive cases from a single sputum sample; it detected 62.3% of such cases when two sputum samples were analyzed. Finally, Xpert MTB/RIF correctly identified rifampicin resistance in all four patients who had MDR-TB but incorrectly identified resistance in three patients with drug-sensitive TB.
What Do These Findings Mean?
In this population of HIV-positive patients with a high TB risk, pre-ART screening with Xpert MTB/RIF increased case detection by 45% compared to smear microscopy, a finding that needs confirming in other settings. Importantly, Xpert MTB/RIF reduced the delay in diagnosis of TB from more than 20 days to two days. This delay would be reduced further by doing the assay at ART clinics rather than at a centralized testing facility, but the diagnostic accuracy of point-of-care testing needs evaluating. Overall, these findings (and those of an accompanying article by Scott et al. that examines the performance of Xpert MTB/RIF in an area where HIV infection is common) support the replacement of smear microscopy with Xpert MTB/RIF for pre-ART TB screening (provided misdiagnosis of rifampicin resistance can be reduced). These findings also suggest that routine screening with Xpert MTB/RIF could reduce the risk of MDR-TB outbreaks in HIV care and treatment settings and improve outcomes for HIV-positive patients with MDR-TB who currently often die before a diagnosis of TB can be made.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001056.
This study is further discussed in a PLoS Medicine Perspective by Carlton Evans; a related PLoS Medicine Research Article by Scott et al. is also available
WHO provides information (in several languages) on all aspects of tuberculosis, including general information on tuberculosis diagnostics and specific information on the Xpert MTB/RIF test; further information about WHO's endorsement of Xpert MTB/RIF is included in a recent Strategic and Technical Advisory Group for Tuberculosis report
WHO also provides information about tuberculosis and HIV
The US National Institute of Allergy and Infectious Diseases has detailed information on tuberculosis and HIV/AIDS
The US Centers for Disease Control and Prevention also has information about tuberculosis, including information on the diagnosis of and on tuberculosis and HIV co-infection
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV-related tuberculosis (in English and Spanish)
doi:10.1371/journal.pmed.1001067
PMCID: PMC3144215  PMID: 21818180

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