Proportions and incidence of locally advanced cervical cancer: a global systematic literature review

Background Optimal treatment of cervical cancer is based on disease stage; therefore, an understanding of the global epidemiology of specific stages of locally advanced disease is needed. Objective This systematic literature review was conducted to understand the global and region-specific proportions of patients with cervical cancer with locally advanced disease and to determine the incidence of the locally advanced disease. Methods Systematic searches identified observational studies published in English between 2010 and June 10, 2020, reporting the proportion of patients with, and/or incidence of, locally advanced stages of cervical cancer (considered International Federation of Gynecology and Obstetrics (FIGO) IB2–IVA). Any staging criteria were considered as long as the proportion with locally advanced disease was distinguishable. For each study, the proportion of locally advanced disease among the cervical cancer population was estimated. Results The 40 included studies represented 28 countries in North or South America, Asia, Europe, and Africa. Thirty-eight studies reported the proportion of locally advanced disease among populations with cervical cancer. The estimated median proportion of locally advanced disease among all cervical cancer was 37.0% (range 5.6–97.5%; IQR 25.8–52.1%); estimates were generally lowest in North America and highest in Asia. Estimated proportions of ≥50% were reported in nine studies from Asia, Europe, Brazil, and Morocco; estimates ≤25% were reported in six studies from Asia, United States, Brazil, and South Africa. Locally advanced disease was reported for 44% and 49% of women aged >70 and ≥60 years, and 5–100% of younger women with cervical cancer. A greater proportion of locally advanced disease was reported for Asian American (19%) versus White women (8%) in one United States study. Two of five studies describing the incidence of locally advanced disease reported rates of 2–4/100 000 women among different time frames. Conclusion This review highlights global differences in proportions of locally advanced cervical cancer, including regional variance and disparities according to patient race and age.


Supplementary Methods
The search strategies shown below were created to support this locally advanced cervical cancer epidemiology systematic literature review as well as one focused on the natural history of locally advanced cervical cancer. Only the epidemiology publications are reported in this article. EMBASE, MEDLINE (PubMed), and Cochrane databases were searched using the search strategies below. Because some studies are not appropriately indexed in electronic databases, bibliographic searching and pearl growing techniques were used to identify any potentially relevant studies that were not captured by database searches. Search: ("observational" OR "prospective" OR "retrospective" OR "crosssectional" OR "cross sectional" OR "longitudinal") AND ("study" OR "studies" OR analys*) Search: "locally advanced" OR "local advanced" OR (local* AND "advanced") OR "stage one" OR "stage two" OR "stage three" OR "stage four" OR "stage ib2" OR "stage iib" OR "stage iiia" OR "stage iiib" OR "stage iva" OR "stage 1b2" OR "stage 2b" OR "stage 3a" OR "stage 3b" OR "stage 4a" OR ("stage" AND ("ib2" OR "iib" OR "iiia" OR "iiib" OR "iva" OR "1b2" OR "2b" OR "3a" OR "3b" OR "4a")) OR ("stage" AND ("ib2" OR "iib" OR "iiia" OR "iiib" OR "iva" OR "1b2" OR "2b" OR "3a" OR "3b" OR "4a")) OR "non-metastatic" OR "non metastatic" OR "lacc" Cochrane search strategy run on June 10, 2020 The following conferences were also searched for relevant abstracts from meetings held English language was a criterion from the beginning of the systematic literature review process and was used as an exclusion criterion in database search queries.
FIGO, International Federation of Gynecology and Obstetrics.

Data extraction
The following information was extracted from the final set of published reports, where available: study details (sample size, inclusion/exclusion criteria, disease stage, stage classification criteria, treatment details, study limitations, time-frame of data collection, data source, location), patient demographics (age, race/ethnicity), clinical characteristics (histology, prior therapy), the proportion of patients with locally advanced stages of cervical cancer, prevalence (rate, odds ratio, risk ratio), and incidence (rate, risk ratio).

Calculation of the Proportion of Locally Advanced Cervical Cancer
The Surveillance, Epidemiology, and End Results summary stage categorizes the extent of cancer spread in a basic set of criteria. In the past, this classification system has also been referred to as General Stage, California Stage, historic stage, and Surveillance, Localized tumor WITH regional lymph node involvement. Involvement of the following types of lymph nodes: para-aortic, iliac NOS, paracervical, parametrial, sacral NOS, regional NOS. Includes FIGO stages IIIC1, IIIC2, IIIC NOS.

Regional
(both direct extension and regional lymph nodes involved) Any combination of codes 2 and 3 above.  Estimated proportion for each study (ES) and the 95% confidence intervals are plotted according to data source (registry, multicenter institution, or single institution). Overlapping timeframes and duplicate data from the same study have been removed. Red triangles represent the range of the subtotal estimated proportion, and the red dashed line represented the overall estimated proportion of locally advanced cervical cancer from this dataset. Heterogeneity of studies is reflected in the I 2 value; a score of >60% = high heterogeneity. Single center studies provided the most unreliable data with the largest variance (estimated range, 6-97%). N indicates the total number of women with cervical cancer. NR, not reported.  Recommendation

Title
Indicate the study's design with a commonly used term in the title (e.g cohort, case-control, cross sectional)

Authors
Contact details for the corresponding author

Study design
Description of the study design (e.g cohort, case-control, cross sectional)

Objective
Specific objectives or hypothesis

Participants
Cohort study-Give the most important eligibility criteria, and the most important sources and methods of selection of participants. Describe briefly the methods of follow-up Case-control study-Give the major eligibility criteria, and the major sources and methods of case ascertainment and control selection Cross-sectional study-Give the eligibility criteria, and the major sources and methods of selection of participants Cohort study-For matched studies, give matching and number of exposed and Report appropriate measures of variability and uncertainty (e.g., odds ratios with confidence intervals)

General interpretation of study results
Checklist items were obtained from the EQUATOR network website: https://www.equator-network.org/reporting-guidelines/strobe-abstracts/.  11 12a 12b 12c 12d 12e 13a 13b 13c 14a 14b 14c 15 16a 16b 16c 17 18 19 20 21 22     In the Zahnd 2018 study, only the incidence of localized and distant cervical cancer was compared in urban and rural areas; neither of these stages was considered locally advanced disease according to our method of estimation (ie, only "regional" disease is considered).

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Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

Supplementary
Appendix page 5 10b List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information. 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. N/A

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
Page 7 and Figure 1 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded. 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots.    Figure 2, Tables 1-3 20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect. Availability of data, code and other materials 27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.