Final Research Plan

Cervical Cancer: Screening

October 29, 2015

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 will be 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 28 until June 24, 2015 at 5:00 p.m., ET.

*Excludes high-risk populations (e.g., women who are HIV-positive), pregnant women, women without a cervix, and women who have had a hysterectomy with removal of the cervix.

Text Description.

This figure is the analytic framework that depicts the two Key Questions (KQs) to be addressed by the systematic review. The figure illustrates how cervical cancer screening programs among women age 21 years or older with a cervix may improve health outcomes (KQ 1) and have possible harms (KQ 2).

  1. What is the effectiveness of human papillomavirus (HPV) testing, with or without cytology, as a primary screening strategy for reducing cervical cancer mortality (KQ 1.0) and incidence (KQ 1.1) compared with currently recommended screening strategies for women in the United States?
    1. Does the effectiveness of HPV testing to reduce cervical cancer outcomes vary by subpopulation (e.g., age, race/ethnicity, screening history, HPV immunization status, and socioeconomic status)?
    2. For each primary screening strategy, how does the rescreening interval relate to future cancer incidence or progression?
    3. Does the appropriate rescreening interval for each primary screening strategy vary by subpopulation (e.g., age, race/ethnicity, screening history, HPV immunization status, and socioeconomic status)?
  2. What are the potential adverse effects of HPV testing, with or without cytology, as a primary screening strategy compared with currently recommended screening strategies for women in the United States?
    1. Do the adverse effects vary by subpopulation (e.g., age, race/ethnicity, and HPV immunization status)?
    2. Do the adverse effects vary by screening strategy, including by rescreening interval?

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

  1. What is the accuracy of and relative adherence to self-collected HPV specimens compared with clinically-collected HPV specimens?
  2. What are the important assay-related issues, including differences in test performance characteristics, of the HPV tests used in clinical trials?
  3. What are the regression rates of cervical intraepithelial neoplasia (CIN)3?
  4. What is the current practice for treatment of CIN2 or CIN3?
  5. What are the rates of colposcopy- and biopsy-related harms (e.g., pain, discomfort, bleeding, and infection) from diagnostic evaluation and other harms associated with current treatments of screen-detected precancerous or cancerous cervical lesions?

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).

  Included Excluded
Aim KQs 1, 2: Studies targeting cervical cancer screening or development of cervical cancer over time KQs 1, 2: Use of HPV or cytology testing for posttreatment surveillance or other purposes
Populations KQs 1, 2: Females age ≥21 years who have a cervix KQs 1, 2:
  • High-risk populations (e.g., women who are HIV-positive)
  • Women without a cervix
  • Women who have had a hysterectomy with the removal of the cervix
  • Pregnant women
Interventions KQs 1, 2:
  • Primary HPV screening strategies*:
    • Alone
    • In combination with cytology (cotesting)
    • In combination with cytology triage of positive HPV (reflex cytology)
  • Self- or clinician-collected HPV specimens, collected at home or in a clinic
KQs 1, 2: Nonprimary HPV screening strategies (e.g., primary cytology-based screening, cytology with HPV triage [reflex HPV])
Comparators KQs 1, 2: Comparative effectiveness (i.e., cytology-based [conventional or liquid-based] or other primary HPV screening strategies [cotesting, reflex cytology, or reflex HPV]) KQs 1, 2: Comparative effectiveness of cytology-based screening strategies (liquid-based cytology vs. conventional cytology alone); cytology with HPV triage vs. cytology-based screening strategies
Outcomes KQ 1:
  • Early detection of disease (CIN3+)
  • Invasive cancer
  • Mortality (all-cause or cervical cancer)
  • Improved quality of life

The following hierarchy1 of outcomes for new cervical cancer screening methods will be used:

Rank 1: Cervical cancer mortality (quality-adjusted life-years gained)
Rank 2: Cervical cancer morbidity/stage IB+ incidence
Rank 3: Cervical cancer incidence (including microinvasive)
Rank 4: Reduced CIN3+ incidence or p16 immunohistochemistry-associated high-grade squamous intraepithelial lesion incidence2
Rank 5: Increased detection of CIN3+ (or CIN2+)

  • More CIN3+ detection overall (cumulative CIN3+)
  • More CIN2+ detection followed by less CIN3+ detection at subsequent screening (Note: CIN2+ detection may include overdiagnosis)
Rank 6: Increased test positivity with increased, similar, or minimally reduced positive predictive value

KQ 2:

  • Rates of false-positive and false-negative screening test results
  • Rates of colposcopy and/or biopsy
  • Labeling
  • Stigma (e.g., sexually transmitted infection)
  • Partner discord
  • Psychological distress (e.g., anxiety)
  • Reduced quality of life
Study Designs KQs 1, 2:
  • Systematic reviews and meta-analyses
  • Randomized, controlled trials; controlled clinical trials
  • Cohort studies, including patient registries
KQs 1, 2:
  • Case-control studies
  • Case reports
  • Case series
  • Narrative reviews
  • Editorials
Setting KQs 1, 2: Primary care (e.g., internal medicine, family medicine, obstetrics/gynecology) or other settings generalizable to primary care (e.g., university-based health clinics, mobile clinics, sexually transmitted infection clinics, family planning clinics) KQs 1, 2:
  • Community/university research laboratories or other nonmedical centers
  • Correctional facilities
  • Worksites
  • Inpatient/residential facilities
Country KQs 1, 2: Countries with cervical cancer screening programs comparable to those of the United States and categorized as “Very High” or equivalent on the 2014 Human Development Index (as defined by the  United Nations Development Programme) KQs 1, 2: Countries not categorized as “Very High” on the Human Development Index or not applicable to U.S. clinical settings or populations
Language KQs 1, 2: English only KQs 1, 2: Non-English publications
Quality KQs 1, 2: Fair- or good-quality, according to USPSTF design-specific criteria KQs 1, 2: Poor-quality, according to USPSTF design-specific criteria

*Primary screening strategies refer to the use of a certain type of test in the first step of a screening approach.
HPV tests approved by the U.S. Food and Drug Administration include: the Hybrid Capture 2 High-Risk HPV DNA Test (Digene Corp., Gaithersburg, MD), cobas HPV Test (Roche Molecular Systems, Inc., Pleasanton, CA), APTIMA® HPV Assay (E6/E7 mRNA) (Gen-Probe Inc., San Diego, CA), Cervista™ HPV 16/18 (Hologic, Inc., Madison, WI), and Cervista™ HR HPV.

The draft Research Plan for this topic was posted on the USPSTF Web site for public comment from May 28 to June 24, 2015. The USPSTF addressed most comments by clarifying and providing further details on the interventions, comparators, and outcomes in the table of inclusion and exclusion criteria. No major changes were made to the scope of the review or the approach to synthesizing the evidence.

The USPSTF has commissioned a decision model to supplement the systematic evidence review on screening for cervical cancer, as it did for the previous topic update in 2012. The decision model is a mathematical simulation that projects the health outcomes that result from alternative interventions for prevention, diagnosis, and treatment. For example, a decision model can describe the expected population health outcomes of a clinical preventive service over a lifetime horizon rather than the more limited range of years generally captured by clinical trials. Inputs into the decision model will include data from the systematic evidence review, which will provide the best available information on the linkages between screening and outcomes of interest. In conjunction with the evidence review, the decision model will help the USPSTF examine how the benefits and harms of cervical cancer screening strategies may vary by the different screening strategies, starting and stopping ages, and time interval between screening. The model will also investigate how individual-level factors—adherence to recommended screening, surveillance strategies, and prior use of preventive strategies—may affect the benefits and harms of different cervical cancer screening approaches.

For more information about how the USPSTF uses decision models in formulating its recommendations, please refer to the USPSTF procedure manual, available at

1.   Arbyn M, Ronco G, Cuzick J, et al. How to evaluate emerging technologies in cervical cancer screening? Int J Cancer. 2009;125(11):2489-96. PMID: 19626591.
2.   Darragh TM, Colgan TJ, Cox JT, et al. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis. 2012;16(3):205-42. PMID: 22820980.