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Final Research Plan

Final Research Plan for Lung Cancer: Screening

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

The final Research Plan is used to guide a systematic review of the evidence by researchers at an Evidence-based Practice Center. The resulting Evidence Review will form the basis of the USPSTF Recommendation Statement on this topic.

The draft Research Plan was available for comment from May 3 until May 30, 2018 at 8:00 p.m., ET.

Analytic Framework

Moving from left to right, this figure depicts the eight key questions (KQs) and research approach that will guide the evidence review described in this research plan. The figure illustrates the overarching question, KQ 1: how does screening for lung cancer with low-dose computed tomography (LDCT) change the incidence of lung cancer and distribution of lung cancer types and stages, and what are the harms associated with screening (KQ 4)? On the left, the population of interest is specified as adults at increased risk of lung cancer. Beneath the population of interest, KQ 2 posits: does the use of risk prediction models for identifying adults at higher risk of lung cancer mortality improve the balance of benefits and harms of screening compared with trial eligibility criteria? The figure then depicts the pathway from screening to the detection of nodules, asking: What is the accuracy of LDCT screening for lung cancer (KQ 3) and what are the associated harms of screening (KQ 4)? Following the detection of nodules, the figure addresses the pathway of workup or surveillance to diagnosis of lung cancer, asking: what are the harms associated with workup or surveillance of nodules (KQ 5)? Following diagnosis of lung cancer, the figure outlines the pathway of treatment to advanced disease, and then to health outcomes of interest, asking: how effective is surgical resection for the treatment of early (stage I) non-small cell lung cancer (KQ 6), and what are the associated harms of treatment (KQ 7)? Alongside the aforementioned pathway, the figure follows the pathway from diagnosis of lung cancer to health outcomes, asking: what is the magnitude of change in all-cause mortality that results from a specified change in lung cancer incidence and change in distribution of lung cancer stages after screening (KQ 8)?

* The evaluation of evidence on treatment will be limited to studies of surgical resection or stereotactic body radiotherapy for stage I non-small cell lung cancer.

Key Questions to Be Systematically Reviewed

1. a. Does screening for lung cancer with low-dose computed tomography (LDCT) change the incidence of lung cancer and the distribution of lung cancer types and stages (i.e., stage shift)?
    b. Does screening for lung cancer with LDCT change all-cause mortality, lung cancer mortality, or quality of life?
    c. Does the effectiveness of screening for lung cancer with LDCT differ for subgroups defined by age, sex, race/ethnicity, presence of comorbid conditions, or other lung cancer risk factors?
    d. Does the effectiveness of screening for lung cancer with LDCT differ by the number or frequency of LDCT scans (e.g., annual screening for 3 years, the protocol used in the National Lung Screening Trial [NLST], vs. other approaches)?
2. Does the use of risk prediction models for identifying adults at higher risk of lung cancer mortality improve the balance of benefits and harms of screening compared with the use of trial eligibility criteria (e.g., NLST criteria) or the 2013 USPSTF recommendations?
3. a. What is the accuracy of screening for lung cancer with LDCT?
    b. Does the accuracy of screening for lung cancer with LDCT differ for subgroups defined by age, sex, race/ethnicity, presence of comorbid conditions, or other lung cancer risk factors?
    c. Does the accuracy of screening for lung cancer with LDCT differ for various approaches to nodule classification (i.e., those based on nodule size and characteristics)?
4. a. What are the harms associated with screening for lung cancer with LDCT?
    b. Do the harms of screening for lung cancer with LDCT differ with the use of Lung-RADS™, I-ELCAP, or similar approaches (e.g., to reduce false-positive results)?
    c. Do the harms of screening for lung cancer with LDCT differ for subgroups defined by age, sex, race/ethnicity, presence of comorbid conditions, or other lung cancer risk factors?
5. a. What are the harms associated with workup or surveillance of nodules?
    b. Do the harms of workup or surveillance of nodules differ with the use of Lung-RADS, I-ELCAP, or similar approaches (e.g., to reduce false-positive results)?
    c. Do the harms of workup or surveillance of nodules differ for subgroups defined by age, sex, race/ethnicity, presence of comorbid conditions, or other lung cancer risk factors?
6. a. What is the effectiveness of surgical resection or stereotactic body radiotherapy (SBRT) for the treatment of early (stage I) non-small cell lung cancer?
    b. Does the effectiveness of surgical resection or SBRT differ for subgroups defined by age, sex, race/ethnicity, or presence of comorbid conditions?
7. a. What are the harms associated with surgical resection or SBRT for the treatment of early (stage I) non-small cell lung cancer?
    b. Do the harms of surgical resection or SBRT differ for subgroups defined by age, sex, race/ethnicity, or presence of comorbid conditions?
8. What is the magnitude of change in all-cause and lung cancer mortality that results from a specified change in lung cancer incidence (and change in distribution of lung cancer stages [i.e., stage shift]) after screening?

Contextual Questions

Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.

1. What are the barriers to implementing lung cancer screening and surveillance in clinical practice in the United States (e.g., barriers to shared decisionmaking, systematically eliciting and documenting a detailed smoking history, systems for tracking nodules and followup, and availability of appropriate LDCT protocols)?
2. a. Are the participants of randomized, controlled trials of lung cancer screening (e.g., NLST) that reported a reduction in all-cause or lung cancer mortality representative of screening-eligible U.S. adults (based on NLST criteria or USPSTF recommendations)?
    b. How do the 5-year survival rate and life expectancy of persons eligible for lung cancer screening in the United States (based on NLST criteria or USPSTF recommendations) compare with those of NLST participants?
    c. Are the settings and providers in randomized, controlled trials of lung cancer screening (e.g., NLST) that reported a reduction in all-cause or lung cancer mortality representative of U.S. health care settings and providers?
3. Does screening for lung cancer with LDCT have unintended benefits from detecting incidental findings (e.g., coronary artery calcium, chronic obstructive pulmonary disease, or extrapulmonary nodules) leading to interventions that improve health outcomes?
4. What is the effectiveness of smoking cessation interventions among patients receiving LDCT screening?

Research Approach

The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Review. Criteria are overarching as well as specific to each of the key questions (KQs).

Category Include Exclude
Populations KQs 1–5, 8: Asymptomatic adults (age ≥18 years)

KQs 6, 7: Adults (age ≥18 years) with early (stage I) non-small cell lung cancer

KQs 1–5, 8: Children; persons with symptoms or prior diagnosis of lung cancer

KQs 6, 7: Children; persons with nonprimary lung cancer or other than stage I lung cancer

Risk prediction KQ 2: Externally validated models including demographic variables, clinical variables, or biomarkers intended for identifying persons at increased risk who are more likely to benefit from screening KQ 2: Models including a single variable or biomarker; models not considering smoking and age (known risk factors for lung cancer)
Screening KQs 1, 3, 4, 8: LDCT* KQs 1, 3, 4, 8: No screening, chest x-ray, sputum cytology, and other screening modalities
Workup or surveillance KQ 5: Computed tomography, biopsy, positron emission tomography, or other tests used after screening  
Interventions KQs 6, 7: Surgical resection or SBRT KQs 6, 7: Chemotherapy, natural therapies, immunotherapy, or targeted molecular therapy
Comparisons KQs 1, 3, 8: Chest x-ray, no screening, or usual care

KQ 2: 2013 USPSTF recommendations or criteria used by trials showing benefit (e.g., NLST)

KQ 3:

  • There is no single gold standard for assessing accuracy
  • Comparison (reference standard) could be subsequent diagnosis of lung cancer within 1 year (likely resulting from repeat imaging and subsequent biopsy), biopsy, or subsequent imaging
  • Sensitivity and false negatives (false reassurance): Typically determined by considering new lung cancer presenting within 1 year of a normal screening study as false negatives  
  • Specificity and false positives: Initial positive LDCT result that is found to be benign with tissue diagnosis or subsequent imaging

KQs 4, 5: Chest x-ray, no screening, usual care, or no comparison group

KQs 6, 7: No comparison group is required; although the review will not assess comparative effectiveness of treatments, comparative effectiveness studies are eligible if they provide data for eligible populations, interventions, and outcomes and meet the other eligibility criteria

KQs 1–3, 8: Studies without a comparison group
Outcomes KQ 1a: Incidence of lung cancer (all stages); distribution of lung cancer types and stages

KQ 1b: All-cause mortality, lung cancer mortality, quality of life, or functional status

KQ 2: Estimated number of deaths from lung cancer or all-cause mortality that can be prevented by screening, estimated screening effectiveness (e.g., number needed to screen), or estimated screening harms

KQ 3: Sensitivity, specificity, and predictive value

KQ 4: Radiation exposure, false-positive results, overdiagnosis, smoking cessation rates, psychosocial harms, incidental findings leading to additional tests and subsequent harms, and unnecessary treatment (e.g., surgical resection for a benign nodule)

KQ 5: Radiation exposure, false-positive results, overdiagnosis, smoking cessation rates, psychosocial harms, incidental findings leading to additional tests and subsequent harms, unnecessary treatment (e.g., surgical resection for a benign nodule), and harms of workup (e.g., biopsy leading to an adverse event)

KQ 6: 5- and 10-year incidence of advanced disease and mortality (survival rates)

KQ 7: Harms of treatment, including mortality, infection, bleeding, bronchopleural fistula, and respiratory failure

KQ 8: All-cause and lung cancer mortality

Costs
Study designs All KQs: Controlled trials

KQ 2: Modeling studies are also eligible; clinical prediction tools must include multiple factors

KQ 3: Studies evaluating accuracy are also eligible

KQs 4, 5, 7: Prospective cohort studies and case-control studies are also eligible

KQ 6: Prospective cohort studies are also eligible

All other study designs

KQ 2: Models including a single variable or biomarker; models not considering smoking and age (known risk factors for lung cancer)

KQs 1–5, 8: Studies with a sample size less than 1,000

KQs 6, 7: For surgery (established standard treatment), studies with a sample size less than 500; for SBRT, no limit on sample size

Study duration KQs 1–5, 7, 8: Any length of time

KQ 6: At least 5 years of followup

KQ 6: Less than 5 years of followup
Settings Published in or after 2001  
Countries Studies conducted in countries categorized as “Very High” on the 2016 Human Development Index (as defined by the United Nations Development Programme) Studies conducted in countries that are not categorized as “Very High” on the 2016 Human Development Index
Language English Languages other than English
Study quality Good or fair quality Poor quality (according to design-specific USPSTF criteria)

* The review will focus on computed tomography but will also search for and include new trials (published since the search cutoff dates of the last review) of other screening modalities. Older studies (before 2013) of other screening modalities will not be carried forward to this update.
Defined as detection of disease that would never progress to produce symptoms or death.
Systematic reviews are excluded from the evidence review. However, separate searches will be conducted to identify relevant systematic reviews and the citations of all studies included in those systematic reviews will be reviewed to ensure that database searches have captured all relevant primary studies.

Abbreviations: LDCT=low-dose computed tomography; NLST=National Lung Screening Trial; SBRT=stereotactic body radiotherapy; USPSTF=U.S. Preventives Services Task Force.

Decision Model Approach

The USPSTF has commissioned a comparative decision modeling analysis to supplement the systematic evidence review on screening for lung cancer, as it did for the previous topic update in 2014. The decision models are mathematical simulations that project the health outcomes resulting from alternative interventions for screening, diagnosis, and treatment. In conjunction with the evidence review, the decision models will help the USPSTF examine the benefits and harms of screening for lung cancer at the population level, reflecting current nodule management and followup guidelines, while accounting for the variability in implementation patterns across the United States. The decision models will also evaluate different start and stop ages, screening intervals, and screening strategies based on individual lung cancer risk, particularly for population subgroups at higher risk for lung cancer.

For more information about how the USPSTF uses decision models in formulating its recommendations, please refer to the USPSTF procedure manual, available at https://www.uspreventiveservicestaskforce.org/Page/Name/procedure-manual.

Response to Public Comment

The draft Research Plan was posted for public comment on the USPSTF Web site from May 3, 2018, to May 30, 2018. In response to comments, the USPSTF clarified that the screening test under consideration is LDCT, not computed tomography, and that KQ 1a covers stage shift (where more cancer cases are detected at an earlier stage). The USPSTF revised the eligibility criteria for KQ 3 to clarify the reference standards for accuracy assessment, revised KQs 4 and 5 to make it clear that I-ELCAP protocols are eligible, revised KQs 6 and 7 to include SBRT as an eligible treatment, and added subgroup questions to KQs 6 and 7. The USPSTF also added a contextual question about smoking cessation interventions among patients receiving LDCT screening. Lastly, the USPSTF added unnecessary treatment (e.g., surgical resection for a benign nodule), bronchopleural fistula, and respiratory failure to the list of eligible harms.

Current as of: August 2018

Internet Citation: Final Research Plan: Lung Cancer: Screening. U.S. Preventive Services Task Force. August 2018.
https://www.uspreventiveservicestaskforce.org/Page/Document/final-research-plan/lung-cancer-screening1

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