Introduction

The Americas region ranks third in the world in incidence and mortality from cervical cancer among World Health Organization (WHO) regions with approximately 74,000 women diagnosed with invasive cancer and 37,000 deaths every year. There are significant disparities within the region, with incidence and mortality rates over three times higher in Latin America and the Caribbean than in North America (1).

Cervical cancer screening has reduced cervical cancer mortality in high- and some high-middle income countries (2,3); however, most low- and middle-income countries (LMIC) have not been successful in cervical cancer control. Several factors are associated with the lack of screening effectiveness in these settings, including low screening coverage, low screening quality, and deficient follow-up of positive-screened women (4). Accordingly, the WHO’s initiative for cervical cancer elimination aims to reach, by the year 2030, 90% Human Papilloma Virus (HPV) vaccination coverage for girls under 15 years of age, 70% screening coverage between ages 35 to 45, and 90% treatment of identified precancerous lesions.

Several studies address the status of screening coverage and associated factors and evaluate alternatives to increase women’s participation in cervical cancer screening (5–8). Similarly, multiple reviews analyze the accuracy of screening tests (cytology, HPV, visual inspection) as a measure of screening quality (9). In contrast, there are fewer reports on follow-up of women with a positive screening test, which may be a more decisive determinant of cervical cancer mortality in some settings (4), and, to our knowledge, no systematic review regarding this subject has been carried out for countries in the Americas region. Hence, we developed this protocol to summarize the available data regarding follow-up of women screened for cervical cancer in Pan American Health Organization (PAHO) Member States (10). We consider this systematic review relevant, taking into account not only the recently launched WHO global strategy for cervical cancer elimination, but also the regional plans for cervical cancer control (11,12).

Methods

The protocol is registered in the PROSPERO database (ID: CRD42021281055).

Aim and objectives

This systematic review aims to synthesize and report the existing knowledge about compliance with follow-up recommendations after an abnormal result of cervical cancer screening in the Americas region.

This will be achieved by systematically searching, selecting, and synthesizing the existing knowledge to answer our research question. So, the specific objectives are:

1. To summarize data on compliance with triage testing after positive HPV in the Americas region.

2. To summarize data on compliance with diagnostic work-up (colposcopy/biopsy) as indicated after primary screening or after triage testing in the Americas region.

3. To summarize data on compliance with treatment of cervical pre-cancerous lesions in the Americas region.

4. To summarize data on compliance with subsequent screening rounds after negative screening results in the Americas.

Study design

We designed the protocol according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) (Figure 1).

Search strategy

We will systematically search in PubMed via the Medline and LILACS databases, and, after that, we will conduct updates and searches for grey literature via the TRIP-database and Google Scholar. Cross-referencing will be used to find additional articles for review.

The Participants, Inter­ventions, Comparators, Outcomes (PICO) question was defined to carry out a structured search as indicated in Table 1. Compliance is defined as the percentage of women undergoing the corresponding procedure within the screening algorithm: triage testing, colposcopy/biopsy, ablative or excisional treatment of precancerous lesions, ablative or excisional treatment after positive screening results in screen-and-treat approaches, new screening round after negative screening results. We will remove duplicates and publications will be independently screened based on title and abstract by two members of the research team, and all disagreements will be solved by consensus.

Search terms

1. Population Adult women AND

"Antigua and Barbuda"[Mesh] OR "Argentina"[Mesh] OR "Bahamas"[Mesh] OR "Barbados"[Mesh] OR "Belize"[Mesh] OR "Bolivia"[Mesh] OR "Brazil"[Mesh] OR "Canada"[Mesh] OR "Chile"[Mesh] OR "Colombia"[Mesh] OR "Costa Rica"[Mesh] OR "Cuba"[Mesh] OR "Dominica"[Mesh] OR "Dominican Republic"[Mesh] OR "Ecuador"[Mesh] OR "El Salvador"[Mesh] OR "Grenada"[Mesh] OR "Guatemala"[Mesh] OR "Guyana"[Mesh] OR "Haiti"[Mesh] OR "Honduras"[Mesh] OR "Jamaica"[Mesh] OR "Mexico"[Mesh] OR "Nicaragua"[Mesh] OR "Panama"[Mesh] OR "Paraguay"[Mesh] OR "Peru"[Mesh] OR "Saint Lucia"[Mesh] OR "Saint Vincent and the Grenadines"[Mesh] OR "Saint Kitts and Nevis"[Mesh] OR "Suriname"[Mesh] OR "Trinidad and Tobago"[Mesh] OR "United States"[Mesh] OR "Uruguay"[Mesh] OR "Venezuela"[Mesh] OR “Latin America”[Mesh] OR “South America”[Mesh] OR “North America”[Mesh] OR “Central America”[Mesh] OR "Caribbean Region"[Mesh] OR "West Indies"[Mesh] OR America OR America’s region OR Americas

2. Intervention

("Mass Screening"[Mesh] OR "Early Detection of Cancer"[Mesh] OR "Early Diagnosis"[Mesh] OR "Diagnostic Screening Programs"[Mesh] OR "Papanicolaou Test"[Mesh] OR "Vaginal Smears"[Mesh] OR Cytodiagnosis[Mesh] OR "Human Papillomavirus DNA Tests"[Mesh] OR "HPV tests" OR "Direct visual inspection" OR "VIA" OR "VILI" OR "Visual Inspection with Acetic Acid" OR "Visual Inspection with Lugol Iodine" OR Colposcopy[Mesh] OR screening)

AND

("Uterine Cervical Neoplasms"[Mesh] OR "Uterine Cervical Dysplasia"[Mesh] OR "Cervical Intraepithelial Neoplasia"[Mesh] OR "Cervical cancer" OR "Cervical pre-cancer" OR "Squamous Intraepithelial Lesions of the Cervix"[Mesh]) NOT (metastatic OR "Neoplasm Metastasis"[Mesh] OR "Lymphatic Metastasis"[Mesh] OR "Breast Neoplasms"[Mesh] OR "Colorectal Neoplasms"[Mesh])

3. Outcome

("Follow-up" OR "Follow-up Studies"[Mesh] OR "Lost to Follow-up"[Mesh] OR "Diagnostic work-up" OR "Treatment compliance" OR " Further assessment rate" OR "Patient Compliance"[Mesh] OR “Colposcopy compliance” OR "Treatment Adherence and Compliance"[Mesh])

Eligibility criteria

We will select papers based on the following criteria:

1. No language restrictions.

2. No publication date range defined

3. Full text availability.

4. Studies including adult women. Studies only on adolescents or upper age limit below 25 years old will be excluded.

5. Studies conducted in populations from PAHO affiliated countries.

6. Outcome specified and data on outcomes available as defined in the PICO question.

7. Studies conducted in the general target population. Studies in special populations will be excluded.

8. Type of study.

   1. Cross-sectional surveys based on self-report.

   2. Cross-sectional surveys based on secondary sources (medical records or information systems).

   3. Cohort studies

   4. Intervention studies (randomized and non-randomized). Qualitative studies will be excluded.

Quality appraisal

For all included studies, two independent reviewers will assess the methodological quality and risk of bias. For cross-sectional, descriptive and population-based studies, we will use the 20-item appraisal tool for cross-sectional studies (AXIS) (14). Cohort studies will be assessed using the checklist developed by the Scottish Intercollegiate Guidelines Network (SIGN) (15). We are not looking for the efficacy of interventions to improve follow-up rates—rather, we search data on follow-up rates on regular basis of screening programs; therefore, we will assess intervention studies (randomized and not randomized) with the SIGN tool for cohort studies, which would be more suitable for the objectives of the review.

We will include original research; thus, if a review is found as initial source of information, we will search the data in the original papers. However, we will also retrieve data, if available in the review but not in the original paper, and, in such case, we will assess the review quality with the AMSTAR2 instrument.

Data management

Studies retrieved from the search will be listed in Zotero® to identify duplicates. If a given study is published in different journals but having differences in sub-group analyses or presenting updated data, we will extract data from all reports but only the latest data available will be included in the analysis. If related publications presenting different information are found, they will be included in the analysis indicating that they correspond to a group of reports with the same origin (clustered studies).

We will prepare three data extraction sheets in Microsoft Excel®: the first one to register eligibility criteria for all studies selected for full text review; the second one for detailed data extraction from studies finally included in the review; and the third one to register the quality appraisal in detail.

From each study included, we will extract general information (author, title, year of publication, observation period, database source, type of study, and country). We will also extract data on the methods, including sample size, follow-up (cohort studies), eligibility criteria for the study population, age (range, median, mean), and statistics used for significance analysis. Finally, the outcomes will be extracted as absolute numbers, when available, in addition to the corresponding indicator (prevalence rate, percentage, etc.). Odds ratio and relative risks will be collected only if the comparator is the regular care or no-intervention.

Data analysis

Compliance with follow-up will be estimated as the percentage of women undergoing the corresponding procedure (triage, diagnosis, treatment, new screening round) among those with indication of the procedure (referral) within the screening algorithm. The main outcome will be the global compliance (follow-up) rate summarizing all steps, and additional outcomes will be compliance with triage, compliance with diagnostic workup, compliance with treatment, and compliance with subsequent screening rounds among negative screened women. Depending on availability of information, a composite index will be estimated by adding the women undergoing the procedures in every step until treatment in the numerator and the women referred for the procedures in every step until treatment in the denominator. If detailed data were not available, we will collect data on the global compliance as reported, categorizing the results based on the compliance definition provided. No compliance analysis after treatment will be done and data regarding compliance with subsequent screening rounds after negative screening results will be analyzed separately.

For intervention studies, only data from baseline (for before and after designs) or data from the control arm (for controlled studies) will be included in the general compliance estimates. A sensitive analysis will be carried out with and without data from intervention studies. Data after any intervention under evaluation will be collected and reported separately, and these data will be summarized by type of intervention (health system, provider, patient).

Depending on the results, we will also conduct meta-analysis. We will use Revman5 (Cochrane Collaboration, London, United Kingdom) to prepare our review and possible meta-analysis. For this, we will review heterogeneity and quality of studies in addition to availability of detailed information. We will apply a fixed effects model if the heterogeneity is small and a random effects model if the heterogeneity is high. Variation in values by geographic area (North America, Central America, South America, Caribbean) and type of study are expected. We will use funnel plots (Christmas tree and “trim and fill”) to assess possible publication bias. Since these methods are unreliable if the number of studies is less than ten, we will only apply it if there are more than ten studies available.

We will present data considering quality of studies and geographic representation, including differences in outcomes and variability in studies. Other subgroup analyses will be carried out by type of study (cross-sectional, cohort, intervention), program approach (screen-and-treat, screen-diagnose-treat, screen-triage-diagnose-treat), primary screening test (cytology, HPV, visual inspection), treatment modality (ablative, excisional). Other analyses might be possible depending on specific findings.

Discussion

We anticipate finding valuable information for policy makers in the Americas as we aim to provide new data to support actions to accelerate the elimination of cervical cancer in the region.

A reduced incidence and mortality from invasive cancer is the essential objective of cervical cancer screening. However, the impact of screening depends on program organization, and several intrinsic and contextual factors may influence program performance (16). The large variability in successful screening determinants makes difficult to properly analize the association between program performance and cervical cancer incidence and mortality, particularly when no organizaed program is in place and, consequently, no routine program data are available.

Access to diagnostic workup and treatment of precancerous lesions has been proposed as a key factor for reduced screening effectiveness in Latin America and the Caribbean (4). Most LMIC lack organized population-based screening, and screening algorithms requiring several visits challenge women’s follow-up and adherence in such settings. Thus, to achieve the WHO target goals for cervical cancer elimination, LMIC should overcome barriers to proper access to screening, diagnosis, and treatment of cervical precancer. The requirement of such effort is common to underserved populations in high-income countries.

Our search is targeted to identify publications on compliance with follow-up algorithms and related factors in the Americas. In this review, the use of a Latin American search engine (LILACS), the review of grey literature, and the inclusion of studies in all languages will allow us to identify more reports that might be relevant for LMIC with a high burden of disease. We aim to identify differences in follow-up rates according to income level, sub-region of the Americas continent, screening test, and programmatic approach. We also aim at exploring how the study of the subject evolved over time and to summarize the latest evidence on the topic.

We follow an standard methodology (PRISMA-P) (13) and assess the quality of studies to reduce the risk of bias. We believe that the methodological approach guarantees our conclusions to be based on the best available evidence. To our knowledge, despite the significant amount of literature on the subject, no systematic review has been conducted to synthesize the available information in the Americas region. It is paramount to carry out this review to set baseline values for regional indicators facing the challenges of the WHO cervical cancer elimination strategy (17). In addition, we consider that, by improving the knowledge on the current situation regarding the status of women’s follow-up as a key component of cervical cancer screening programs we will contribute to enhance regional and country specific plans for cervical cancer control.

Disclaimer

Where authors are identified as personnel of the International Agency for Research on Cancer/Pan American Health Organization/World Health Organization, the authors alone are responsible for the views expressed in this document, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/Pan American Health Organization/World Health Organization.

Ethical Considerations

This study will not include human or animal participants; therefore, it does not require ethical approval.

Conflict of interests

No competing interests are declared by the authors.

Funding

This study will be funded by the Pan American Health Organization under a contract with Hospital Universitario San Ignacio in Bogotá, Colombia.

References

Author notes

^a Corresponding author: rmurillo@husi.org.co

Additional information

How to cite: Fernández-Deaza G, Zuluaga M, Maza M, Luciani S, Murillo R. Follow-up of women with abnormal findings of cervical cancer screening in the Americas region: a systematic review protocol. Univ. Med. 2022;63(4). https://doi.org/10.11144/Javeriana.umed63-4.foll

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