in progress

Final Research Plan

Cervical Cancer: Screening

March 17, 2022

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.

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Figure 1 is the analytic framework that depicts the three Key Questions (KQs) to be addressed in the systematic review. The figure addresses the comparative effectiveness of different screening strategies on precancer detection, cancer incidence, or morbidity/mortality (KQ1), as well as the test accuracy of and adherence to self-collection hrHPV vaginal samples (KQ2). Additionally, the comparative harms of the different cervical cancer screening strategies is displayed (KQ3).

  1. What is the comparative effectiveness of different cervical cancer screening strategies (i.e., test, mode of collection, and interval of testing) on precancer detection, cancer incidence, morbidity, or mortality?
    1. Does the comparative effectiveness vary by population (e.g., by age, gender, race and ethnicity, or human papillomavirus [HPV] vaccination status)?
  2. What is the test accuracy of and adherence to self-collected high-risk HPV vaginal samples?
    1. Does the test accuracy or adherence vary by population (e.g., by age, gender, race and ethnicity, or HPV vaccination status)?
  3. What are the comparative harms of different cervical cancer screening strategies (i.e., test, mode of collection, and interval of testing)?
    1. Do the comparative harms vary by population (e.g., by age, gender, race and ethnicity, or HPV vaccination status)?

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

  1. What is the comparative test accuracy of high-risk HPV tests used in U.S.-based clinical practice?
  2. Can extended genotyping and other triage technologies (e.g., DNA methylation testing and immunostaining for p16/Ki67) for abnormal high-risk HPV or cytology screening results reduce burden of testing and diagnostic procedures?
  3. What are the social risk factors (e.g., race, racism, socioeconomic status, insurance status, or geography) or other risk factors (e.g., history of sexual trauma, smoking, or vaccination status) that contribute to inequities in cervical cancer screening, incidence, and health outcomes?
  4. What are barriers and implementation considerations (e.g., for the health system, clinician, or patient) to screening and followup testing?
  5. Are there effective interventions or strategies to improve screening rates and followup to abnormal screening results?

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.

Category Included Excluded
Aim Studies targeting cervical cancer screening Use of HPV or cytology testing for posttreatment surveillance or other purposes
Populations Persons who have a cervix (any age), including persons at increased risk for cervical cancer or morbidity/mortality from cervical cancer (e.g., by race and ethnicity, income/socioeconomic status, insurance, geography, history of sexual trauma, smoking history, or HPV vaccination status) Surveillance studies conducted exclusively in persons with HIV, with in utero exposure to diethylstilbestrol, or with previous treatment for cervical cancer or a high-grade precancerous lesion
Interventions KQs 1, 3:
  • Test: Any test strategy using hrHPV assay* with or without cytology
  • Specimen type: Cervical, vaginal, or urine
  • Mode of collection: Self- or clinician-collected hrHPV samples
  • Intervals of testing: Any interval of screening

KQ 2: Self-collected hrHPV sample

 Non-hrHPV screening strategies
Comparators KQs 1, 3: Any alternate test (including cytology only) and/or assay, mode of collection, or interval of testing

KQ 2:

  • Clinician-collected hrHPV sample
  • Reference standard
 No screening
Outcomes KQ 1:
  • Precancerous lesions (i.e., CIN2+, CIN3+)
  • Invasive cervical cancer (squamous cell carcinoma or adenocarcinoma)
  • Mortality (all-cause or cervical cancer)
  • Quality of life or other cancer-related morbidity

KQ 2:

  • Test accuracy (e.g., sensitivity, specificity, false-positive rate, and false-negative rate)
  • Adherence to screening

KQ 3:

  • Rates of false-positive and false-negative screening test results
  • Lack of adherence to screening
  • Rates of colposcopy and/or biopsy and related procedural harms
  • Adverse effects on sexual health
  • Psychological harms (e.g., stigma, labeling, partner discord, and depression/anxiety)
  
Study designs KQs 1, 3:
  • Individual patient data meta-analyses and systematic reviews
  • Randomized, controlled trials; controlled clinical trials
  • Nonrandomized studies with unbiased selection and contemporaneous controls

KQ 2:

  • Diagnostic test accuracy studies
  • Participation trials (for adherence only)
 KQs 1, 3:
  • Pre-post studies
  • Nonrandomized studies with historical controls
  • Case reports
  • Case series
  • Narrative reviews
  • Editorials

KQ 2: Diagnostic test accuracy studies without a reference standard
Setting Primary care (e.g., internal medicine, family medicine, orobstetrics/gynecology), other settings generalizable to primary care (e.g., university-based health clinics, mobile clinics, sexually transmitted infection clinics, or family planning clinics), or any setting for self-collection of samples

 
Country Countries with cervical cancer screening programs comparable to those of the United States and categorized as “Very High” or equivalent on the 2020 Human Development Index (as defined by the  United Nations Development Programme) Countries not categorized as “Very High” on the Human Development Index or not applicable to U.S. clinical settings or populations
Language English only Non-English publications
Quality Fair- or good-quality, according to USPSTF design-specific criteria Poor-quality, according to USPSTF design-specific criteria

* HPV tests approved by the U.S. Food and Drug Administration include: the Hybrid Capture 2 High-Risk HPV DNA Test (Qiagen, Hilden, Germany); cobas HPV Test (Roche Molecular Systems, Inc., Pleasanton, CA); APTIMA® HPV and HPV 16, 18/45 Assays (Hologic, Inc., Madison, WI); Cervista™ HPV 16/18 and Cervista™ HR HPV (Hologic, Inc., Madison, WI); and Onclarity HPV™ (Becton Dickinson, Franklin Lakes, NJ).

Abbreviations: CIN2+=cervical intraepithelial neoplasia grade 2; CIN3+=cervical intraepithelial neoplasia grade 3; HPV=human papillomavirus; hrHPV=high-risk human papillomavirus; KQ=key question; USPSTF=U.S. Preventive Services Task Force.

The draft Research Plan was posted on the USPSTF Web site for public comment from October 28 to November 24, 2021. In response to public comment, the USPSTF included pregnant persons in the population of interest and added a contextual question addressing extended genotyping and use of biomarkers following abnormal hrHPV or cytology screening results. In addition, the USPSTF revised the contextual questions and inclusion criteria for clarity. The USPSTF made no other substantive changes that altered the scope of the review.

The USPSTF intends to commission a decision model to accompany this evidence review.