cervical cancer thesis

Thesis: Surviving Cervical Cancer: A History of Prevention, Early Detection, and Treatment

Editor's note:

Alexis Darby defended her thesis titled “Surviving Cervical Cancer: A History of Prevention, Early Detection, and Treatment,” in May 2019 in front of committee members Jane Maienschein, Carolina Abboud, and Karin Ellison, earning her a Bachelor’s degree from Barrett, the Honors College. https://repository.asu.edu/items/53339

Cervical cancer, which many physicians as of 2019 consider to be a success in terms of establishing widely used forms of early preventative and diagnostic technologies, experienced a reduction in incidence rates in women by over fifty percent between 1975 and 2016. Cervical cancer does not often present in women with symptoms until it has entered a later stage of the disease. Because of this fact, in the early twentieth century, physicians were often only able to diagnose cervical cancer when either the woman reported complaints or there was a visual confirmation of lesions on the cervix. The symptoms women often reported included vague abdominal pain, bleeding after sex, and abnormal amounts of vaginal discharge, all of which are non-specific symptoms, making it even harder for women to be diagnosed with cervical cancer.

This thesis answers the following question: How does the history of cervical cancer show that prevention helps reduce rates of cancer-related deaths among women? By studying the history of cervical cancer, people can understand how a cancer that was once one of the top killers of women in the US has declined to become one of the lowest through the establishment of and effective communication of early prevention and diagnostics, both among the general public and within the medical community itself. This thesis is organized based on key episodes which were pertinent to the history of cervical cancer, primarily within the United States and Europe. The episodes are organized in context of the shifts in thought regarding cervical cancer and include topics such as vaccine technologies like the Gardasil and Cervarix vaccines, social awareness movements that educated women on the importance of early detection, and analyses of the early preventative strategies and attempts at treating cervical cancer.

After analyzing eleven key episodes, the thesis determined that, through the narrative of early attempts to treat cervical cancer, shifting the societal thought on cancer, evolving the importance of early detection, and, finally, obtaining a means of prevention, the history of cervical cancer does demonstrate that the development of preventative strategies has resulted in reducing cancer-related deaths among women. Understanding what it took for physicians to evolve from simply detecting cervical cancer to being able to prevent it entirely matters because it can change the way we think about managing other forms of cancer.

How to cite

Last modified, share this page.

Cervical Cancer: Etiology, Pathogenesis, Treatment, and Future Vaccines

• February 2002
• Asian Pacific Journal of Cancer Prevention 3(3):207-214
• 3(3):207-214

• University of Louisville

• International Agency for Research on Cancer

Abstract and Figures

Discover the world's research

• 25+ million members
• 160+ million publication pages
• 2.3+ billion citations

• Tanya Kumar
• Ankit Aneja
• Satwant Kaur

• J Cardiovasc Dis Res

• Trichal V K

• Theresa Ofure Okonofua
• Elzarie De Wet
• Parichart Naruphontjirakul
• Farshid Sefat
• Muhamad Syazreen Md Salleh

• Mohammad Kamarulzzaman Bin Ali
• Choo Mun Chye

• Paul D Blumenthal
• Lynne Gaffikin

• BJOG-INT J OBSTET GY
• Sharita D. Womack
• John W. Sellors
• Attila T. Lorincz

• R. Schlegel

• Hetty J Bontkes
• J.M.M. Walboomers

• INT J CANCER
• Klaus Zumbach
• Fjodor Kisseljov
• Olga Sacharova
• Michael Pawlita

• Richard Schlegel

• International Biological Study on Cervical Cancer (IBSCC) Study Group
• Recruit researchers
• Join for free
• Login Email Tip: Most researchers use their institutional email address as their ResearchGate login Password Forgot password? Keep me logged in Log in or Continue with Google Welcome back! Please log in. Email · Hint Tip: Most researchers use their institutional email address as their ResearchGate login Password Forgot password? Keep me logged in Log in or Continue with Google No account? Sign up

• My Shodhganga
• Receive email updates
• Edit Profile

Shodhganga : a reservoir of Indian theses @ INFLIBNET

• Shodhganga@INFLIBNET
• Banaras Hindu University
• Department of Molecular & Human Genetics

Items in Shodhganga are licensed under Creative Commons Licence Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0).

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Open access
• Published: 07 January 2022

Comparative accuracy of cervical cancer screening strategies in healthy asymptomatic women: a systematic review and network meta-analysis

• Teruhiko Terasawa 1 ,
• Satoyo Hosono 2 ,
• Seiju Sasaki 3 ,
• Keika Hoshi 4 ,
• Yuri Hamashima 5 ,
• Takafumi Katayama 6 &
• Chisato Hamashima 7  

Scientific Reports volume  12 , Article number:  94 ( 2022 ) Cite this article

7747 Accesses

15 Citations

Metrics details

• Cancer screening
• Cervical cancer
• Health care

To compare all available accuracy data on screening strategies for identifying cervical intraepithelial neoplasia grade ≥ 2 in healthy asymptomatic women, we performed a systematic review and network meta-analysis. MEDLINE and EMBASE were searched up to October 2020 for paired-design studies of cytology and testing for high-risk genotypes of human papillomavirus (hrHPV). The methods used included a duplicate assessment of eligibility, double extraction of quantitative data, validity assessment, random-effects network meta-analysis of test accuracy, and GRADE rating. Twenty-seven prospective studies (185,269 subjects) were included. The combination of cytology (atypical squamous cells of undetermined significance or higher grades) and hrHPV testing (excepting genotyping for HPV 16 or 18 [HPV16/18]) with the either-positive criterion (OR rule) was the most sensitive/least specific, whereas the same combination with the both-positive criterion (AND rule) was the most specific/least sensitive. Compared with standalone cytology, non-HPV16/18 hrHPV assays were more sensitive/less specific. Two algorithms proposed for primary cytological testing or primary hrHPV testing were ranked in the middle as more sensitive/less specific than standalone cytology and the AND rule combinations but more specific/less sensitive than standalone hrHPV testing and the OR rule combination. Further research is needed to assess these results in population-relevant outcomes at the program level.

Similar content being viewed by others

Cervical screening: ESGO-EFC position paper of the European Society of Gynaecologic Oncology (ESGO) and the European Federation of Colposcopy (EFC)

Benefits, harms and cost-effectiveness of cervical screening, triage and treatment strategies for women in the general population

Should screening for cervical cancer go to primary human papillomavirus testing and eliminate cytology?

Introduction.

Cervical cancer is the fourth most frequently diagnosed cancer and fourth most common cause of cancer-specific mortality in women, with a worldwide estimated prevalence of 570,000 cases and 311,000 associated deaths in 2018 1 , 2 . Observational studies have clearly demonstrated a reduction in the invasive cancer incidence and mortality in well-organized screening programs using cervical cytological testing that have been implemented 3 . Moreover, randomized controlled trials (RCTs) of well-screened populations have shown that strategies incorporating testing for high-risk human papillomavirus (hrHPV) subtypes, which are the central etiological agents of cervical cancer pathogenesis 4 , were, in aggregate, associated with a reduction in the invasive cancer incidence relative to that shown by cytological screening alone 5 . Therefore, current guidelines recommend three primary screening options: cytological testing alone, standalone hrHPV testing, and cytological + hrHPV combination testing (co-testing) 6 , 7 , 8 , 9 , 10 . However, subsequent management strategies for women with positive primary testing are complex. Although specific triage and/or follow-up testing algorithms for primary cytology and co-testing 11 and for primary hrHPV testing 9 have been proposed, the evidence base to improve patient-important outcomes with these algorithms is immature.

The comparative effectiveness of alternative screening strategies should be based on a comprehensive assessment of benefits and harms. Given the low incidence and mortality due to cervical cancer in high-income countries and the challenges associated with conducting de novo large and long-term RCTs, decision modeling is an alternative realistic option to better understand the theoretical utility of the screening options 12 . In this regard, comprehensive synthesis of the screening accuracy, a key model parameter of cytological and hrHPV testing and their available combination algorithms reported in rigorously conducted paired-design studies, is a valuable intermediate step. However, recent meta-analyses have focused on either standalone cytological and/or hrHPV testing 13 , 14 , 15 or a comparison of cytological testing with a specific combination algorithm not proposed in guidelines only 16 .

For those studies that assessed the diagnostic accuracy of selected and different pairs of tests of interest and their combination algorithms, network meta-analysis of diagnostic test accuracy studies is a useful approach that can compare all the assessed tests and combination algorithms in a single analysis 17 . The current study aimed to perform network meta-analysis to quantitatively compare and rank the cross-sectional accuracy of all reported screening algorithms based on cytological and hrHPV testing. We specifically focused on the comparative accuracy of guideline-proposed combination algorithms by examining data derived from primary studies of healthy asymptomatic women that addressed verification bias because such bias is commonly observed in cancer screening accuracy studies.

This extended systematic review is based on an update evidence review conducted for revision of the Japanese Guidelines for Cervical Cancer Screening 18 , 19 . Although the complete evidence review was planned before analysis, no protocol was registered for this extended review. This report followed PRISMA guidelines for diagnostic test accuracy (PRISMA-DTA) 20 and did not require ethics review or patient consent.

Search strategy

We searched OVID MEDLINE and EMBASE for publications between January 1, 1992, and October 14, 2020, with no language restrictions. The search strategies are detailed in the Supplementary methods . Complementarily, the reference lists of eligible studies and relevant review articles were also screened for other appropriate studies.

Study eligibility

Three paired reviewers independently double screened the first 3000 abstracts in a calibration phase. The same reviewers single screened the remaining abstracts. Two reviewers independently determined the eligibility of potential full-text articles, with discrepancies adjudicated by a third reviewer. Only fully paired-design screening studies of cytology and hrHPV testing, either opportunistic or organized screening, aimed at detecting cervical intraepithelial neoplasia ≥ grade 2 (CIN2+) in healthy asymptomatic women were eligible for inclusion. We included all studies that performed either routine colposcopy-directed biopsy or colposcopy and selective biopsy in all screened women to verify target lesions along with studies that performed either of the colposcopy methods among women with protocol-specified screening results and statistical corrections for data from unverified samples. In studies that analyzed both eligible and ineligible populations, only those with relevant and extractable data were included. In case of multiple publications, we included the publication with the largest sample size (see Supplementary methods for more details) .

Data extraction

One reviewer extracted descriptive data, which were independently confirmed by another reviewer. Next, two reviewers independently extracted numerical data, with discrepancies resolved by consensus. We preferred cross-tabulated count data over reported accuracy estimates when both data types were extractable (see Supplementary methods for more details).

Operationalization

Cytology results were standardized according to the Bethesda system 21 , 22 if other classification systems had been used. For studies that used both conventional and liquid-based cytology tests (CC and LBC, respectively), we favored LBC data over CC data; we jointly analyzed both smear preparation methods.

Operationally, hrHPV assays were categorized into four groups: hybridization with signal amplifications of DNA (e.g., Hybrid Capture 2 [HC2], Qiagen, Gaithersburg, MD), polymerase chain reaction (PCR) of DNA from ≥ 13 hrHPV genotypes, amplification of E6/E7 viral messenger RNA (mRNA), and assays identifying DNA or RNA of genotypes, either HPV16 or HPV18 or both (HPV16/18) 23 . For mRNA-based genotyping, since the genotype HPV45 was additionally targeted with HPV16 and HPV18 (HPV16/18/45), we adopted these results. HC2 positivity was defined as ≥ 1.0 relative light units. We did not assess point-of-care testing platforms (e.g., careHPV, Qiagen, Gaithersburg, MD).

We operationally categorized combination tests as follows: (i) combination algorithms based on the OR rule (women with either test positive were categorized as screening positive while women with both tests negative as screening negative) or the AND rule (women with both tests positive were categorized as screening positive while women with at least 1 negative test as negative) 24 ; (ii) thresholds for cytological testing as, e.g., undetermined significance or worse grades (≥ ASCUS), or low- or high-grade squamous intraepithelial lesions or worse grades (≥ LSIL or ≥ HSIL, respectively); and (iii) hrHPV assays (Table 1 ) 6 , 7 , 8 , 9 , 25 . As cross-sectional representation of guidelines-proposed algorithms, we assessed two specific strategies: “ ≥ LSIL OR [hrHPV AND ASCUS]”, which classified only women with cytologic testing ≥ LSIL, or both by cytologic testing ASCUS and hrHPV testing positive as screening positive; and “HPV16/18(/45) OR [hrHPV AND ≥ ASCUS]”, which classified only women with HPV genotypes 16 or 18 (or 45) positive, or both cytologic testing ≥ ASCUS and hrHPV testing positive for non-16/18(/45) hrHPV genotypes as screening positive (Table 1 ).

Quality assessment

Paired independent reviewers double rated the validity of a study using a risk of bias tool for comparative diagnostic accuracy studies (QUADAS-C) 26 , an extension to the existing Quality Assessment of Diagnostic Accuracy Studies 2 tool 27 . Discrepancies were resolved via consensus. Operationally, a study was defined to have low risk of verification bias only when all screened samples had been histologically verified.

Data synthesis and statistical analysis

The primary outcome was sensitivity and specificity for detecting CIN2+. We used their relative risk values for and absolute differences in (Δ) sensitivity and specificity for any paired alternative screening algorithms (e.g., a standalone test vs. a combination algorithm) as measures of comparative accuracy.

Between-study heterogeneity was assessed visually by using crosshair plots of sensitivity and specificity estimates in the receiver operating characteristic (ROC) space 28 . We calculated the average sensitivity and specificity estimates and their derived relative and Δ sensitivity and specificity values with their corresponding 95% credible intervals (CrIs) by using an arm-based, two-stage hierarchical, Bayesian bivariate random-effects network meta-analysis model 29 . Credible regions for the average estimates were constructed by using the standard method 30 . For comparison, we also calculated average sensitivity and specificity estimates separately by using the standard bivariate meta-analysis model for diagnostic accuracy 31 . Hierarchical summary ROC (HSROC) curves were derived on the basis of the estimated parameters 32 .

We performed study-level univariable meta-regression for the following prespecified binary predictors when ≥ 10 studies were available: study location (countries ranked as “very high human development” by the Human Development Index 2017 33 vs. those that were not), study design (histology-based vs. colposcopy-based verification), and type of sample collectors (physicians vs. nonphysicians). Scarce data on young individuals (< 30 years old) precluded meta-regression based on age. Complete details of the methodology, model fitting, choice of prior distributions for parameters assessed, and operational definitions used in sensitivity analyses are provided in the Supplementary methods .

We used the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) tool 34 to assess the certainty of evidence and focused on the comparisons among cytological testing (≥ ASCUS) alone, standalone hrHPV assays, and the guideline-proposed combination algorithms. For calculating false negatives (FNs) and false positives (FPs), we assumed a healthy screening population of 1,000 women in which 20 are CIN2 + (i.e., a prevalence of 2%) 13 .

We did not evaluate funnel-plot asymmetry because the required tests did not permit valid assessment of the extent and impact of missing studies 20 . All analyses were performed by using WinBUGS 1.4.3 (MRC Biostatistics Unit, Cambridge, UK) and Stata/SE 16.1 (Stata Corp, College Station, TX) 35 . We estimated the probability that the true value (i.e., posterior distribution) of relative sensitivity or specificity was ≥ 1 (or ≤ 1) as a measure of superiority of a test over a comparator test. A conventional, frequentist, two-tailed P- value of 0.05 corresponds to a Bayesian posterior probability of 0.025, which we considered to be the threshold of statistical significance.

Study selection

Our literature search identified 15,488 citations, of which 27 prospective studies reported in 35 publications corresponding to 185,269 women were included for the meta-analysis (Supplementary Fig. S1 ) 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 . Supplementary material provides a list of excluded studies.

Characteristics of included studies

All included studies had a prospective design, and 14 studies (52%) were from high-income countries (Table 2 ). The average age of study participants ranged from 25 to 47 years. Data on type of sample collectors was available for 20 studies (74%), with physician collectors in 14 studies and nonphysician providers, typically trained nurses or midwives, in 6 studies. Thirteen studies had used only CC, and 12 had adopted only LBC, whereas two other studies had used both CC and LBC (Table 2 ). Of the four available hrHPV testing subgroups, HC2 was the most commonly reported hrHPV assay (assessed in 20 studies), whereas six studies assessed PCR-based tests, four genotyped for HPV16/18, and three used mRNA-based tests, of which also genotyped for HPV16/18/45. Data on one or more combination algorithm(s) were available in 19 studies (reported in 20 publications; 70%). The most commonly assessed combinations were HC2 AND ≥ ASCUS, which were reported in 10 studies. Reference standards were used for all participants with routine colposcopy-directed biopsy in three studies 36 , 39 , 40 and colposcopy and selective biopsy in six studies (Table 2 ) 54 , 56 , 58 , 59 , 60 , 61 . Other studies performed statistical corrections for data from unverified samples based on the verified samples with colposcopy-directed biopsy in nine studies 41 , 42 , 44 , 45 , 47 , 48 , 50 , 51 , 53 and colposcopy and selective biopsy in nine studies 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 . See Supplementary results and Supplementary Tables S1 – S3 for more details on study, test, and reference standard characteristics.

Risk of bias

Although the studies were predominantly well conducted, their designs varied substantially, and several sources of bias were observed (Supplementary Fig. S2 ), such as lack of blinding of the colposcopists or grading pathologists to the screening results. Additionally, verification bias could not be ruled out in studies that did not perform histological evaluation of all samples.

Topology of direct comparisons of alternative screening algorithms

Figure  1 shows the network of compared algorithms available from the 27 studies, and Supplementary Table S4 shows the numbers of studies and participating women contributing to each comparison. From 25 screening strategies, 300 pairwise comparisons are theoretically constructable. However, the 27 studies provided 337 contrast data (median 6 [min–max, 1–55] contrasts per study) on only 123 unique pairwise comparisons (41% of all theoretically constructable contrasts). A comparison was based on a median of two studies (min–max, 1–14), and only 18 (15%) of 123 comparisons were based on five or more studies. The three most common comparisons were derived from studies that assessed HC2 and ≥ ASCUS; that is, the comparisons on standalone HC2 vs. standalone ≥ ASCUS (14 studies; 84,330 women), ≥ ASCUS alone vs. HC2 OR ≥ ASCUS (10 studies; 53,337 women), and HC2 alone vs. HC2 OR ≥ ASCUS (10 studies; 53,303 women).

Network of eligible comparisons of cervical cancer screening algorithms. The line thickness is proportional to the number of studies comparing the linked pair of screening algorithms. The size of each node is proportional to the number of study participants. ASCH atypical squamous cells cannot exclude high-grade lesion, ASCUS atypical squamous cells of undetermined significance, HC2 Hybrid Capture 2, HPV16/18(/45) genotyping for HPV types 16 or 18 (or 45), HSIL high-grade squamous intraepithelial lesion, LBC liquid-based cytology, LSIL low-grade squamous intraepithelial lesion, mRNA messenger ribonucleic acid, PCR polymerase chain reaction.

Sensitivity and specificity

The sensitivity estimates varied substantially across studies with broad confidence intervals (CIs); the specificity values also varied although their CIs were narrow (Supplementary Fig. S3 ). Large between-study heterogeneity was visually noted in studies of HC2, all thresholds of cytological testing, and their combinations. These results were also reflected in large credible and predictive regions of the average sensitivity and specificity in the separately performed standard bivariate meta-analyses (Supplementary Fig. S4 ). Although data points were limited, heterogeneity was less prominent in PCR and PCR-based combinations. See Supplementary Fig. S5 for the average estimates of screening accuracy based on the standard meta-analysis.

Figure  2 provides the average accuracy estimates and ranking estimated through the network meta-analysis. Overall, the combinations with the OR rule of hrHPV and cytological testing were most sensitive and least specific, whereas combinations with the AND rule of hrHPV and cytological testing were most specific and least sensitive. The rankings estimated in the network meta-analysis reflected the trade-off between sensitivity and specificity by altering the thresholds; lowering the thresholds of cytological testing (e.g., from ≥ HSIL to ≥ ASCUS) led to higher sensitivity but at the cost of reduced specificity, and tightening the thresholds increased specificity at the cost of reduced sensitivity. This behavior resulted in average estimates and rankings for tests or combination algorithms relying on few studies (e.g., HPV16/18- and mRNA-based combinations assessed in only one study each), which were inconsistent with the standard meta-analysis.

Average sensitivity and specificity and ranking of standalone tests and combination algorithms for cervical cancer screening for detecting CIN2+. Point estimates (blue squares) and CrIs (extending lines) are presented (ordered by the ranking of each test/combination’s sensitivity). See Table 1 for the definition of each strategy. ASCH atypical squamous cells cannot exclude high-grade lesion, ASCUS atypical squamous cells of undetermined significance, CrI 95% credible interval, HC2 Hybrid Capture 2, HPV16/18(/45) genotyping for HPV types 16 or 18 (or 45), HSIL high-grade squamous intraepithelial lesion, LBC liquid-based cytology, LSIL low-grade squamous intraepithelial lesion, mRNA messenger ribonucleic acid, PCR polymerase chain reaction.

In the network meta-analysis, PCR OR ≥ ASCUS was most sensitive (1.0; CrI: 0.994–1.0; probability of best sensitivity: 1.0) but was one of the two least specific screening algorithms (0.846; CrI: 0.753–0.907). In contrast, standalone ≥ HSIL and HC2 AND ≥ HSIL were the two most specific (respectively, 0.994 [CrI: 0.990–0.996; probability of best specificity: 0.43] and 0.994 [CrI: 0.989–0.997]; probability of best specificity: 0.50) but were the two least sensitive (respectively, 0.346 [95% CrI: 0.216–0.497] and 0.345 [CrI: 0.183–0.519]) algorithms.

Comparative accuracy

Supplementary Figure S6 , Supplementary Tables S5 and S6 , respectively, summarize the average relative sensitivity and specificity and ΔFNs and ΔFPs estimated based on a population of 1000 healthy women, with a 2% prevalence of CIN2+, across all possible paired comparisons of available standalone tests and combination algorithms.

Comparative accuracy of standalone tests

For cytological testing, the average relative estimates of screening accuracy reflected the effect of altering the thresholds (Fig.  3 a, Supplementary Table S7 ). For example, ≥ ASCUS was more sensitive than ≥ LSIL (relative sensitivity: 0.86 [CrI: 0.69–0.97; Bayesian P (≥ 1) < 0.001]) but less specific than ≥ LSIL (relative specificity: 1.03 [CrI: 1.05–1.02; Bayesian P (≤ 1) < 0.001]). Two studies that directly compared the alternative smear preparation methods showed identical sensitivity and specificity for CC and LBC for each threshold (Supplementary Fig. S7 ).

Network meta-analysis of standalone tests and combination algorithms for cervical cancer screening for detecting CIN2+. Average sensitivity and specific and their 95% credible regions for ( a ) standalone cytology or hrHPV testing, ( b ) HC2-based combination algorithms, ( c ) PCR-based combination algorithms (including PCR-based genotyping for HPV16/18), and ( d ) mRNA-based combination algorithms (including mRNA-based genotyping for HPV16/18/45). Graded colors (black, dark gray, gray, and light gray) indicate cytology with a specific threshold, red indicates HC2, blue indicates PCR-based tests, green indicates HPV16/18, and magenta indicates mRNA-based tests. Triangles and diamonds represent standalone hrHPV testing and cytology, respectively. Circles and squares represent combinations based on the OR-rule and the AND-rule, respectively. For combination algorithms ( b–d ), standalone component hrHPV testing and cytology (≥ ASCUS) are also presented as reference. See Table 1 for the definition of each strategy. ASCH atypical squamous cells cannot exclude high-grade lesion, ASCUS atypical squamous cells of undetermined significance, HC2 Hybrid Capture 2, HPV16/18(/45) genotyping for HPV types 16 or 18 (or 45), HSIL high-grade squamous intraepithelial lesion, LBC liquid-based cytology, LSIL low-grade squamous intraepithelial lesion, mRNA messenger ribonucleic acid, PCR polymerase chain reaction.

HPV16/18 was more specific but less sensitive than the other hrHPV assays (Fig.  3 a, Supplementary Table S7 ). For example, for comparing HPV16/18 with HC2, the relative specificity was 1.06 [CrI: 1.10–1.04; Bayesian P (≤ 1) < 0.001] and relative sensitivity was 0.59 [CrI: 0.36–0.81; Bayesian P (≥ 1) < 0.001]. Among HC2, PCR-based tests, and mRNA-based tests, data were limited as to whether a specific hrHPV assay was more sensitive or specific than any other. For example, although the PCR-based tests appeared more sensitive but less specific than HC2, the CrIs for the relative accuracy crossed 1, the null value (i.e., the relative sensitivity of PCR vs. HC2 was 1.06 [CrI: 0.98–1.15]; Bayesian P (≤ 1) = 0.06) and relative specificity of HC2 vs. PCR was 1.04 [CrI: 0.99–1.11; Bayesian P (≤ 1) = 0.08]).

Compared with standalone cytological testing irrespective of the thresholds, all standalone hrHPV assays other than HPV16/18 were more sensitive but less specific in general (Fig.  3 a, Supplementary Table S7 ). In contrast, the accuracy of HPV16/18 was comparable to cytological testing. For example, the relative specificity for comparing ≥ LSIL with HPV16/18 was 1.0 [CrI: 0.68–1.62; Bayesian P (≥ 1) = 0.50] and relative specificity was 1.01 (CrI: 1.00–1.03; Bayesian P (≤ 1) = 0.10).

Comparative accuracy among combination algorithms based on specific hrHPV assays

The ROC plots of the average accuracy estimates and their credible regions reflected the effect of altering the thresholds in combined cytological testing (i.e., lower thresholds with increased sensitivity and decreased specificity, and higher thresholds with increased specificity and decreased sensitivity) and the effect of combination methods (i.e., the OR rule with increased sensitivity and decreased specificity, and the AND rule with increased specificity and decreased sensitivity) across the subgroups based on alternative hrHPV assays (Fig.  3 b–d). Among 45 pairwise comparisons based on cytology, HC2, and their combinations, most (40 [89%] for sensitivity and 42 [93%] for specificity) showed a significant difference, reflecting the effect of the thresholds and combination methods (Fig.  3 b, Supplementary Table S8 ). Similarly, among 36 pairwise comparisons based on cytology, PCR-based tests, and their combinations, 28 (78%) for sensitivity and 27 (75%) for specificity showed a significant difference (Fig.  3 c, Supplementary Table S9 ). In contrast, 10 pairwise comparisons based on mRNA-based combinations (Fig.  3 d, Supplementary Table S10 ), only five (50%) and four (40%) contrasts for sensitivity and specificity, respectively, were significantly different.

Comparative accuracy and GRADE assessment of guideline-proposed combination algorithms

Data on the guideline-proposed algorithms are available for HC2 and PCR-based tests on “≥ LSIL OR [hrHPV AND ASCUS]” and for mRNA-based tests and PCR-based tests on “HPV16/18(/45) OR [hrHPV AND ≥ ASCUS]”. Table 3 summarizes the comparative accuracy, and Supplementary Table S11 and Table 4 show the GRADE summary of findings on specific tests or combination algorithms and their comparisons, respectively.

In general, the proposed algorithms were less sensitive but more specific than the standalone component hrHPV assays. However, only HC2-based “≥ LSIL OR [hrHPV AND ASCUS]” and PCR-based “HPV16/18 OR [hrHPV AND ≥ ASCUS]” were significantly less sensitive (the average relative sensitivity ranged from 0.74 to 0.79; Bayesian P (≥ 1) ranged from < 0.001 to 0.003) and more specific (the average relative specificity ranged from 1.04 to 1.10; Bayesian P (≤ 1) ranged from < 0.001 to 0.004). These results suggested that the proposed algorithms, compared with their standalone component hrHPV tests, decreased by an average of 44 to 88 FPs but increased 4 to 5 more FNs (very low to low certainty of evidence).

In contrast, the proposed algorithms were in general equally specific but more sensitive than standalone ≥ ASCUS. However, only PCR-based “LSIL OR [hrHPV AND ASCUS]” was significantly less sensitive than ≥ ASCUS alone (the relative sensitivity = 0.73 [CrI: 0.59–0.92; Bayesian P (≥ 1) = 0.004]; four more FNs [CrI: 1–7]; very low certainty of evidence), but evidence as to whether this combination was more specific or less specific than ≥ ASCUS alone was insufficient (relative sensitivity = 0.98 [CrI: 0.96–1.00; Bayesian P (≥ 1) = 0.04]).

Comparative evidence across alternative guideline-proposed algorithms was generally limited. PCR-based “LSIL OR [hrHPV AND ASCUS]” was significantly more specific and less specific than “HPV16/18 OR [hrHPV AND ≥ ASCUS]” (relative sensitivity; 1.04 [CrI: 1.01–1.11]; Bayesian P (≤ 1) < 0.001]; 37 fewer FPs [CrI: 6–92] and relative specificity: 0.84 [CrI: 0.65–0.97]; Bayesian P (≥ 1) < 0.001; three more FNs [CrI: 1–6]; very low certainty of evidence). Although only HC2-based “LSIL OR [hrHPV AND ASCUS]” was more specific than PCR-based “LSIL OR [hrHPV AND ASCUS]” (relative specificity: 1.05 [CrI: 1.01–1.13]; Bayesian P (≤ 1) = 0.007; 46 fewer FPs [CrI: 7–105]; very low certainty of evidence) across-hrHPV assays, comparative data on the guideline-proposed algorithms were insufficient.

Meta-regression and sensitivity analyses

Due to data paucity, meta-regression was undertaken for only HC2, cytological testing, and their OR combination separately. Although high-income countries ( vs. non-high-income countries) for sensitivity of HC2 and sample collection by physicians ( vs. nonphysician collectors) for sensitivity and specificity of ≥ ASCUS were associated with higher estimates, these covariates were no longer associated with higher (or lower) sensitivity or specificity in their combination, HC2 OR ≥ ASCUS (Supplementary Fig. S8 ).

The sensitivity analysis using the model with a common correlation parameter across tests yielded results comparable to those of the main analysis based on the model with test-specific correlation parameters (Supplementary Table S12 ). Relaxing threshold constraints yielded results not compliant with the expected threshold effects in two specific thresholds for cytological testing (≥ LSIL and ≥ ASCH) and unstable results with wide CrIs for sensitivity in four combination algorithms (i.e., mRNA AND ≥ ASCUS, HPV16/18 AND ≥ ASCUS, HPV16/18 OR ≥ ASCUS, “ ≥ LSIL OR [PCR AND ASCUS]”, and “≥ HSIL OR [HC2 AND ≥ ASCUS]”) regardless of whether correlation parameters were separately assumed or not; all of these tests, except for ≥ LSIL, depended on only a few primary studies. With lower deviance information criterion estimates, the models with threshold constraints were deemed to be better-fitting than the models without threshold constraints; however, the differences were < 5, suggesting no definitively preferred model.

To the best of our knowledge, this is the first network meta-analysis that has comprehensively compared and ranked the cross-sectional screening accuracy of standalone cytology or hrHPV testing with combination algorithms for detecting CIN2+. Importantly, this analysis is based on published accuracy estimates from fully paired-design comparative accuracy studies that addressed verification bias. First, our network meta-analysis confirmed and quantified the theoretically expected gain in and trade-off of screening performance when combining two tests 24 , that is, the combinations with the OR rule (i.e., either test positive) of hrHPV and cytological testing were most sensitive and least specific, whereas combinations with the AND rule (i.e., both test positive) of hrHPV and cytological testing were most specific and least sensitive. Second, our network meta-analysis confirmed that the guideline-proposed combination algorithms, HC2-based “≥ LSIL OR [hrHPV AND ASCUS]” and PCR-based “HPV16/18 OR [hrHPV AND ≥ ASCUS]” appeared to compensate the shortcomings of the two component tests if used as standalone, which, though expected theoretically, had never been quantitatively synthesized. Specifically, these proposed algorithms were not as sensitive but more specific than the component standalone hrHPV testing. Similarly, these proposed algorithms appeared equally specific but more sensitive than standalone ≥ ASCUS, though definitive conclusions could not be made due to limited comparative data. Third, sparse, insufficient comparative evidence precluded reliable assessment of the comparative accuracy across these alternative guideline-proposed algorithms.

Effectiveness of screening should be assessed as a whole program consisting of a set of activities 71 . Since the ultimate goal is to maximize participant-relevant benefits and simultaneously minimize harms, accuracy of testing is, though an important measure, only an intermediate parameter. As already elucidated in the previous meta-analyses 13 , 14 , which is congruent with our results, standalone testing for hrHPV using an assay other than HPV 16/18 genotyping, if all screen-positive women underwent colposcopy, would identify more women with CIN2+ than cytological testing alone but at the cost of more healthy women misclassified as CIN2+. The OR rule combinations, the most sensitive group of strategies found in our meta-analysis, if used for primary co-testing (i.e., performing both tests concurrently), would further increase the number of healthy women misclassified as CIN2+ while identifying only a few more women with CIN2+. The consequences of such FP results include unnecessary colposcopy, triage, or repeat testing with cytology, hrHPV, or other tests. Although infections with hrHPV, and HPV16/18 in particular, carry a higher risk of progression than positive cytology 72 , 73 , 74 , 75 , immediate incremental costs and psychological burden incurred due to increased false-positive results may not be justified in low risk screening settings as only a fraction of the identified CIN2+ lesions detected through standalone hrHPV testing or its combinations progress to invasive cancer; the others actually carry a moderate chance of regression 76 . The AND rule combinations, the most specific group of strategies identified in our meta-analysis, may substantially minimize FPs and their negative consequences. However, sensitivity is lower than cytology alone (≥ ASCUS), potentially leading to unignorably large numbers of FNs depending on the prevalence of CIN2+ in a screened population.

As interim recommendations, several protocols for triage and/or repeat testing followed by colposcopy for screen-positive women have been proposed by professional societies. “≥ LSIL OR [hrHPV AND ASCUS]” and “HPV16/18 OR [hrHPV AND ≥ ASCUS]” were cross-sectional representations for two such protocols, respectively, proposed for positive primary cytological testing 11 and primary hrHPV testing 9 . Our meta-analysis found that the accuracy of these combination algorithms were generally ranked in the middle, being more sensitive and less specific than standalone cytology (≥ ASCUS) and the AND rule combinations but more specific and less sensitive than standalone hrHPV testing and the OR rule combination. We also quantified how each combination algorithm increased or decreased the number of FNs and FPs relative to those of another specific standalone test or combination, which is a strength of our study results. However, any benefits and harms associated with specific screening tests or combinations should be formally assessed at the whole program level along with its necessary resources and costs 71 .

We focused on cross-sectional accuracy of initial screening tests or combinations and their immediate consequences. Our accuracy-based arguments necessarily lack long-term outcomes. Given the chance of regression 76 , the results based on our cross-sectional approach may be only relevant in populations with a low participation rate of follow-up testing. Additionally, the positive criteria we adopted for the estimation of accuracy do not necessarily represent the optimal indications of colposcopy in real-life practice; rather the criteria included the joint indications of any additional intervention; i.e., triage and/or repeat testing, colposcopy, and immediate direct treatments jointly. In this regard, a recent expert consensus statement proposed individualized risk-based management decisions based on the combinations of the available screening results 77 .

Colposcopy-directed biopsy is an imperfect test even for routine biopsies on normal-appearing sites 78 and more so for colposcopy and selective biopsy 79 . Despite the theoretical superiority of verification bias-corrected accuracy estimates over naïvely calculated estimates, these corrections are not error-free. Given the complex mechanisms of missing verification 80 and limitations in inverse probability weighting 81 , bias may not necessarily have been corrected in the right direction. In addition, the effect of the excluded observations due to unsatisfactory or missing test results, even though the reported proportions were not substantial, could be unpredictably large. Furthermore, our meta-analysis was based on aggregate data and thus only accounted for the dependence of the two tests at the aggregate data level 82 ; however, a more sophisticated approach to address these limitations would require individual-level data.

Our GRADE assessment used a typical population-based screening context in high-income countries as adopted in a previous review 13 ; however, the large spread of the credible and predictive accuracy values in our study suggests wide-ranging real-life variations, implying that specific scenarios with different risks might yield divergent conclusions. Finally, we did not assess combinations involving newer screening modalities, such as p16/Ki-67 dual-stain-based cytology 83 , as this was beyond the scope of our meta-analysis.

Conclusions

Limited evidence suggests that specific test combinations might complement the weaknesses of standalone cytological or hrHPV screening and help reduce FN and/or FP results. However, the strategies that provide more benefits than harms at reasonable cost in a population need to be assessed at the program level. As comparative evidence on alternative hrHPV assays is sparse, further research is needed to acquire relevant data. Additionally, future research should elucidate long-term outcomes of specific algorithms and acquire data from HPV-vaccinated populations.

Data availability

The data and statistical codes that supports the findings of this study will be shared on reasonable request to the corresponding author.

Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68 , 394–424. https://doi.org/10.3322/caac.21492 (2018).

Article   Google Scholar  

WHO. Human Papillomavirus (HPV) and Cervical Cancer (WHO, 2019).

Google Scholar  

Peirson, L., Fitzpatrick-Lewis, D., Ciliska, D. & Warren, R. Screening for cervical cancer: A systematic review and meta-analysis. Syst. Rev. 2 , 35. https://doi.org/10.1186/2046-4053-2-35 (2013).

Article   PubMed   PubMed Central   Google Scholar  

Crosbie, E. J., Einstein, M. H., Franceschi, S. & Kitchener, H. C. Human papillomavirus and cervical cancer. Lancet 382 , 889–899. https://doi.org/10.1016/s0140-6736(13)60022-7 (2013).

Article   PubMed   Google Scholar  

Ronco, G. et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: Follow-up of four European randomised controlled trials. Lancet 383 , 524–532. https://doi.org/10.1016/s0140-6736(13)62218-7 (2014).

Curry, S. J. et al. Screening for cervical cancer: US Preventive Services Task Force Recommendation Statement. JAMA 320 , 674–686. https://doi.org/10.1001/jama.2018.10897 (2018).

Jeronimo, J., Castle, P. E., Temin, S. & Shastri, S. S. Secondary Prevention of Cervical Cancer: American Society of Clinical Oncology Resource-stratified clinical practice guideline summary. J. Oncol. Pract. 13 , 129–133. https://doi.org/10.1200/jop.2016.017889 (2017).

Sawaya, G. F., Kulasingam, S., Denberg, T. D. & Qaseem, A. Cervical cancer screening in average-risk women: Best practice advice from the Clinical Guidelines Committee of the American College of Physicians. Ann. Intern. Med. 162 , 851–859. https://doi.org/10.7326/m14-2426 (2015).

Huh, W. K. et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: Interim clinical guidance. Obstet. Gynecol. 125 , 330–337. https://doi.org/10.1097/aog.0000000000000669 (2015).

Fontham, E. T. H. et al. Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society. CA Cancer J. Clin. 70 , 321–346. https://doi.org/10.3322/caac.21628 (2020).

Saslow, D. et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J. Clin. 62 , 147–172. https://doi.org/10.3322/caac.21139 (2012).

Dahabreh, I. J., Trikalinos, T. A., Balk, E. M. & Wong, J. B. Methods Guide for Effectiveness and Comparative Effectiveness Reviews (Agency for Healthcare Research and Quality (US), 2016).

Koliopoulos, G. et al. Cytology versus HPV testing for cervical cancer screening in the general population. Cochrane. Database. Syst. Rev. 8 , CD008587. https://doi.org/10.1002/14651858.CD008587.pub2 (2017).

Mustafa, R. A. et al. Systematic reviews and meta-analyses of the accuracy of HPV tests, visual inspection with acetic acid, cytology, and colposcopy. Int. J. Gynaecol. Obstet. 132 , 259–265. https://doi.org/10.1016/j.ijgo.2015.07.024 (2016).

Fokom-Domgue, J. et al. Performance of alternative strategies for primary cervical cancer screening in sub-Saharan Africa: Systematic review and meta-analysis of diagnostic test accuracy studies. BMJ 351 , h3084. https://doi.org/10.1136/bmj.h3084 (2015).

Li, T. et al. Diagnostic value of combination of HPV testing and cytology as compared to isolated cytology in screening cervical cancer: A meta-analysis. J. Cancer Res. Ther. 12 , 283–289. https://doi.org/10.4103/0973-1482.154032 (2016).

Article   CAS   PubMed   Google Scholar  

Biondi-Zoccai, G. (ed.) Diagnostic Meta-analysis: A Useful Tool for Clinical Decision-Making 183–197 (Springer, 2018).

Book   Google Scholar  

Hamashima, C. et al. The Japanese guideline for cervical cancer screening. Jpn. J. Clin. Oncol. 40 , 485–502. https://doi.org/10.1093/jjco/hyq036 (2010).

The Japanese Research Group for Systematic Review and Guideline Development for Cancer Screening. An Evidence Report for the Japanese Guideline for Cervical Cancer Screening 2019 , 1–258 (2020). http://canscreen.ncc.go.jp/guideline/shikyukeireport2019.pdf . Accessed 20 Dec 2021.

McInnes, M. D. F. et al. Preferred reporting items for a systematic review and meta-analysis of diagnostic test accuracy studies: The PRISMA-DTA statement. JAMA 319 , 388–396. https://doi.org/10.1001/jama.2017.19163 (2018).

Denton, K. J. et al. The revised BSCC terminology for abnormal cervical cytology. Cytopathology 19 , 137–157. https://doi.org/10.1111/j.1365-2303.2008.00585.x (2008).

Cirkel, C., Barop, C. & Beyer, D. A. Method comparison between Munich II and III nomenclature for Pap smear samples. J. Turk. Ger. Gynecol. Assoc. 16 , 203–207. https://doi.org/10.5152/jtgga.2015.0147 (2015).

Schiffman, M. et al. Human papillomavirus testing in the prevention of cervical cancer. J. Natl. Cancer Inst. 103 , 368–383. https://doi.org/10.1093/jnci/djq562 (2011).

Macaskill, P., Walter, S. D., Irwig, L. & Franco, E. L. Assessing the gain in diagnostic performance when combining two diagnostic tests. Stat. Med. 21 , 2527–2546. https://doi.org/10.1002/sim.1227 (2002).

Dickinson, J. et al. Recommendations on screening for cervical cancer. CMAJ 185 , 35–45. https://doi.org/10.1503/cmaj.121505 (2013).

Yang, B. et al. Development of QUADAS-C, a risk of bias tool for comparative diagnostic accuracy studies. https://doi.org/10.17605/OSF.IO/HQ8MF (2021).

Whiting, P. F. et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann. Intern. Med. 155 , 529–536. https://doi.org/10.7326/0003-4819-155-8-201110180-00009 (2011).

Phillips, B., Stewart, L. A. & Sutton, A. J. “Cross hairs” plots for diagnostic meta-analysis. Res. Synth. Methods 1 , 308–315. https://doi.org/10.1002/jrsm.26 (2010).

Owen, R. K., Cooper, N. J., Quinn, T. J., Lees, R. & Sutton, A. J. Network meta-analysis of diagnostic test accuracy studies identifies and ranks the optimal diagnostic tests and thresholds for health care policy and decision-making. J. Clin. Epidemiol. 99 , 64–74. https://doi.org/10.1016/j.jclinepi.2018.03.005 (2018).

Harbord, R. M., Deeks, J. J., Egger, M., Whiting, P. & Sterne, J. A. A unification of models for meta-analysis of diagnostic accuracy studies. Biostatistics 8 , 239–251. https://doi.org/10.1093/biostatistics/kxl004 (2007).

Article   PubMed   MATH   Google Scholar  

Chu, H., Nie, L., Cole, S. R. & Poole, C. Meta-analysis of diagnostic accuracy studies accounting for disease prevalence: Alternative parameterizations and model selection. Stat. Med. 28 , 2384–2399. https://doi.org/10.1002/sim.3627 (2009).

Article   MathSciNet   PubMed   Google Scholar  

Arends, L. R. et al. Bivariate random effects meta-analysis of ROC curves. Med. Decis. Making 28 , 621–638. https://doi.org/10.1177/0272989x08319957 (2008).

Human Development Indicators and Indices: 2018 Statistical Update Team. In United Nations Development Programme; 2018 (United Nations Development Programme, 2018).

Schunemann, H. J. et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ 336 , 1106–1110. https://doi.org/10.1136/bmj.39500.677199.AE (2008).

Thompson, J. Bayesian Analysis with Stata (Stata Press, 2014).

MATH   Google Scholar  

Belinson, J. et al. Shanxi Province cervical cancer screening study: A cross-sectional comparative trial of multiple techniques to detect cervical neoplasia. Gynecol. Oncol. 83 , 439–444. https://doi.org/10.1006/gyno.2001.6370 (2001).

Pan, Q. et al. A thin-layer, liquid-based pap test for mass screening in an area of China with a high incidence of cervical carcinoma. A cross-sectional, comparative study. Acta. Cytol. 47 , 45–50. https://doi.org/10.1159/000326474 (2003).

Article   ADS   PubMed   Google Scholar  

Zhao, F. H. et al. A study of cervical cancer screening algorithms. Zhonghua Zhong Liu Za Zhi 32 , 420–424 (2010).

PubMed   Google Scholar  

Cardenas-Turanzas, M. et al. The performance of human papillomavirus high-risk DNA testing in the screening and diagnostic settings. Cancer Epidemiol. Biomark. Prev. 17 , 2865–2871. https://doi.org/10.1158/1055-9965.epi-08-0137 (2008).

Article   CAS   Google Scholar  

Hovland, S. et al. A comprehensive evaluation of the accuracy of cervical pre-cancer detection methods in a high-risk area in East Congo. Br. J. Cancer 102 , 957–965. https://doi.org/10.1038/sj.bjc.6605594 (2010).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Schneider, A. et al. Screening for high-grade cervical intra-epithelial neoplasia and cancer by testing for high-risk HPV, routine cytology or colposcopy. Int. J. Cancer 89 , 529–534 (2000).

Kulasingam, S. L. et al. Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: Comparison of sensitivity, specificity, and frequency of referral. JAMA 288 , 1749–1757 (2002).

Balasubramanian, A. et al. Accuracy and cost-effectiveness of cervical cancer screening by high-risk human papillomavirus DNA testing of self-collected vaginal samples. J. Low. Genit. Tract. Dis. 14 , 185–195. https://doi.org/10.1097/LGT.0b013e3181cd6d36 (2010).

Bigras, G. & de Marval, F. The probability for a Pap test to be abnormal is directly proportional to HPV viral load: Results from a Swiss study comparing HPV testing and liquid-based cytology to detect cervical cancer precursors in 13,842 women. Br. J. Cancer 93 , 575–581. https://doi.org/10.1038/sj.bjc.6602728 (2005).

Mayrand, M. H. et al. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N. Engl. J. Med. 357 , 1579–1588. https://doi.org/10.1056/NEJMoa071430 (2007).

Mayrand, M. H. et al. Randomized controlled trial of human papillomavirus testing versus Pap cytology in the primary screening for cervical cancer precursors: Design, methods and preliminary accrual results of the Canadian cervical cancer screening trial (CCCaST). Int. J. Cancer 119 , 615–623. https://doi.org/10.1002/ijc.21897 (2006).

Li, N. et al. Different cervical cancer screening approaches in a Chinese multicentre study. Br. J. Cancer 100 , 532–537. https://doi.org/10.1038/sj.bjc.6604840 (2009).

Castle, P. E. et al. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: A subanalysis of the ATHENA study. Lancet Oncol. 12 , 880–890. https://doi.org/10.1016/s1470-2045(11)70188-7 (2011).

Stoler, M. H. et al. High-risk human papillomavirus testing in women with ASC-US cytology: Results from the ATHENA HPV study. Am. J. Clin. Pathol. 135 , 468–475. https://doi.org/10.1309/ajcpz5jy6fcvnmot (2011).

Mahmud, S. M. et al. Comparison of human papillomavirus testing and cytology for cervical cancer screening in a primary health care setting in the Democratic Republic of the Congo. Gynecol. Oncol. 124 , 286–291. https://doi.org/10.1016/j.ygyno.2011.10.031 (2012).

Sangrajrang, S. et al. Comparative accuracy of Pap smear and HPV screening in Ubon Ratchathani in Thailand. Papillomavirus. Res. 3 , 30–35. https://doi.org/10.1016/j.pvr.2016.12.004 (2017).

Sangrajrang, S. et al. Human papillomavirus (HPV) DNA and mRNA primary cervical cancer screening: Evaluation and triaging options for HPV-positive women. J. Med. Screen. 26 , 212–218. https://doi.org/10.1177/0969141319865922 (2019).

Kurokawa, T. et al. The ideal strategy for cervical cancer screening in Japan: Result from the Fukui Cervical cancer screening study. Cytopathology 29 , 361–367. https://doi.org/10.1111/cyt.12576 (2018).

Blumenthal, P. D. et al. Adjunctive testing for cervical cancer in low resource settings with visual inspection, HPV, and the Pap smear. Int. J. Gynaecol. Obstet. 72 , 47–53 (2001).

Visual inspection with acetic acid for cervical-cancer screening: Test qualities in a primary-care setting. University of Zimbabwe/JHPIEGO Cervical Cancer Project. Lancet 353 , 869–873 (1999).

Coste, J. et al. Cross sectional study of conventional cervical smear, monolayer cytology, and human papillomavirus DNA testing for cervical cancer screening. BMJ 326 , 733. https://doi.org/10.1136/bmj.326.7392.733 (2003).

de Cremoux, P. et al. Efficiency of the hybrid capture 2 HPV DNA test in cervical cancer screening. A study by the French Society of Clinical Cytology. Am. J. Clin. Pathol. 120 , 492–499. https://doi.org/10.1309/xfuc-pp6m-5xua-94b8 (2003).

Sankaranarayanan, R. et al. Accuracy of human papillomavirus testing in primary screening of cervical neoplasia: Results from a multicenter study in India. Int. J. Cancer 112 , 341–347. https://doi.org/10.1002/ijc.20396 (2004).

Qiao, Y. L. et al. A new HPV-DNA test for cervical-cancer screening in developing regions: A cross-sectional study of clinical accuracy in rural China. Lancet Oncol. 9 , 929–936. https://doi.org/10.1016/s1470-2045(08)70210-9 (2008).

McAdam, M., Sakita, J., Tarivonda, L., Pang, J. & Frazer, I. H. Evaluation of a cervical cancer screening program based on HPV testing and LLETZ excision in a low resource setting. PLoS ONE 5 , e13266. https://doi.org/10.1371/journal.pone.0013266 (2010).

Article   ADS   CAS   PubMed   PubMed Central   Google Scholar  

Quincy, B. L., Turbow, D. J., Dabinett, L. N., Dillingham, R. & Monroe, S. Diagnostic accuracy of self-collected human papillomavirus specimens as a primary screen for cervical cancer. J. Obstet. Gynaecol. 32 , 795–799. https://doi.org/10.3109/01443615.2012.717989 (2012).

Cuzick, J. et al. Management of women who test positive for high-risk types of human papillomavirus: The HART study. Lancet 362 , 1871–1876. https://doi.org/10.1016/s0140-6736(03)14955-0 (2003).

Petry, K. U. et al. Inclusion of HPV testing in routine cervical cancer screening for women above 29 years in Germany: Results for 8466 patients. Br. J. Cancer 88 , 1570–1577. https://doi.org/10.1038/sj.bjc.6600918 (2003).

Gravitt, P. E. et al. Effectiveness of VIA, Pap, and HPV DNA testing in a cervical cancer screening program in a peri-urban community in Andhra Pradesh, India. PLoS ONE 5 , e13711. https://doi.org/10.1371/journal.pone.0013711 (2010).

Moy, L. M. et al. Human papillomavirus testing and cervical cytology in primary screening for cervical cancer among women in rural China: Comparison of sensitivity, specificity, and frequency of referral. Int. J. Cancer 127 , 646–656. https://doi.org/10.1002/ijc.25071 (2010).

Monsonego, J. et al. Evaluation of oncogenic human papillomavirus RNA and DNA tests with liquid-based cytology in primary cervical cancer screening: The FASE study. Int. J. Cancer 129 , 691–701. https://doi.org/10.1002/ijc.25726 (2011).

Ferreccio, C. et al. Screening trial of human papillomavirus for early detection of cervical cancer in Santiago. Chile. Int. J. Cancer 132 , 916–923. https://doi.org/10.1002/ijc.27662 (2013).

Agorastos, T. et al. Primary screening for cervical cancer based on high-risk human papillomavirus (HPV) detection and HPV 16 and HPV 18 genotyping, in comparison to cytology. PLoS ONE 10 , e0119755. https://doi.org/10.1371/journal.pone.0119755 (2015).

Iftner, T. et al. Head-to-head comparison of the RNA-based aptima human papillomavirus (HPV) assay and the DNA-based hybrid capture 2 HPV test in a routine screening population of women aged 30 to 60 years in Germany. J. Clin. Microbiol. 53 , 2509–2516. https://doi.org/10.1128/jcm.01013-15 (2015).

Wu, Q. et al. A cross-sectional study on HPV testing with type 16/18 genotyping for cervical cancer screening in 11,064 Chinese women. Cancer Med. 6 , 1091–1101. https://doi.org/10.1002/cam4.1060 (2017).

Gray, J. A., Patnick, J. & Blanks, R. G. Maximising benefit and minimising harm of screening. BMJ 336 , 480–483. https://doi.org/10.1136/bmj.39470.643218.94 (2008).

Dillner, J. et al. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: Joint European cohort study. BMJ 337 , a1754. https://doi.org/10.1136/bmj.a1754 (2008).

Katki, H. A. et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: A population-based study in routine clinical practice. Lancet Oncol. 12 , 663–672. https://doi.org/10.1016/s1470-2045(11)70145-0 (2011).

Kitchener, H. C. et al. A comparison of HPV DNA testing and liquid based cytology over three rounds of primary cervical screening: Extended follow up in the ARTISTIC trial. Eur. J. Cancer 47 , 864–871. https://doi.org/10.1016/j.ejca.2011.01.008 (2011).

Luyten, A. et al. Early detection of CIN3 and cervical cancer during long-term follow-up using HPV/Pap smear co-testing and risk-adapted follow-up in a locally organised screening programme. Int. J. Cancer 135 , 1408–1416. https://doi.org/10.1002/ijc.28783 (2014).

Tainio, K. et al. Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: Systematic review and meta-analysis. BMJ 360 , k499. https://doi.org/10.1136/bmj.k499 (2018).

Perkins, R. B. et al. 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. J. Low Genit. Tract. Dis. 24 , 102–131. https://doi.org/10.1097/lgt.0000000000000525 (2020).

Wentzensen, N. et al. Multiple biopsies and detection of cervical cancer precursors at colposcopy. J. Clin. Oncol. 33 , 83–89. https://doi.org/10.1200/jco.2014.55.9948 (2015).

Brown, B. H. & Tidy, J. A. The diagnostic accuracy of colposcopy—A review of research methodology and impact on the outcomes of quality assurance. Eur. J. Obstet. Gynecol. Reprod. Biol. 240 , 182–186. https://doi.org/10.1016/j.ejogrb.2019.07.003 (2019).

Naaktgeboren, C. A. et al. Anticipating missing reference standard data when planning diagnostic accuracy studies. BMJ . https://doi.org/10.1136/bmj.i402 (2016).

Cronin, A. M. & Vickers, A. J. Statistical methods to correct for verification bias in diagnostic studies are inadequate when there are few false negatives: A simulation study. BMC Med. Res. Methodol. 8 , 75–75. https://doi.org/10.1186/1471-2288-8-75 (2008).

Menten, J. & Lesaffre, E. A general framework for comparative Bayesian meta-analysis of diagnostic studies. BMC Med. Res. Methodol. 15 , 70. https://doi.org/10.1186/s12874-015-0061-7 (2015).

Wentzensen, N. et al. Clinical evaluation of human papillomavirus screening with p16/Ki-67 dual stain triage in a large organized cervical cancer screening program. JAMA Intern. Med. 179 , 881–888. https://doi.org/10.1001/jamainternmed.2019.0306 (2019).

Download references

Acknowledgements

We thank Dr. Alejandra Castanon (on behalf of Professor Thomas Iftner and Professor Peter Sasieni), Dr. Joel Coste, and Dr. Tetsuji Kurokawa for the provision of the additional information on their original work; and MARUZEN-YUSHODO Co., Ltd. ( https://kw.maruzen.co.jp/kousei-honyaku/ ) for the English language editing.

This work was supported by the National Cancer Center Research and Development Fund from the National Cancer Center, Tokyo, Japan (Grant Numbers 26-A-30, 29-A-16); and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (Grant Number 26460755 to TT and CH).

Author information

Authors and affiliations.

Section of General Internal Medicine, Department of Emergency and General Internal Medicine, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan

Teruhiko Terasawa

Division of Cancer Screening Assessment and Management, Center for Public Health Science, National Cancer Center, Tokyo, Japan

Satoyo Hosono

Center for Preventive Medicine, St. Luke’s International Hospital Affiliated Clinic, Tokyo, Japan

Seiju Sasaki

Center for Public Health Informatics, National Institute of Public Health, Wako, Japan

Keika Hoshi

Department of Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK

Yuri Hamashima

Department of Statistics and Computer Science, College of Nursing Art and Science, University of Hyogo, Hyogo, Japan

Takafumi Katayama

Department of Nursing, Faculty of Medical Technology, Teikyo University, Tokyo, Japan

Chisato Hamashima

You can also search for this author in PubMed   Google Scholar

Contributions

T.T.: conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, software, supervision, validation, visualization, writing—original draft, writing—review & editing. S.H.: conceptualization, investigation, methodology, validation, writing—review & editing. S.S.: conceptualization, investigation, validation, writing—review & editing. K.H.: conceptualization, investigation, validation, visualization, writing—review & editing. Y.H.: conceptualization, investigation, validation, writing—review & editing. T.K.: conceptualization, investigation, validation, writing—review & editing. C.H.: conceptualization, funding acquisition, investigation, methodology, project administration, resources, supervision, validation, writing—review & editing.

Corresponding author

Correspondence to Teruhiko Terasawa .

Ethics declarations

Competing interests.

The authors declare no competing interests.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Supplementary information., rights and permissions.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and permissions

About this article

Cite this article.

Terasawa, T., Hosono, S., Sasaki, S. et al. Comparative accuracy of cervical cancer screening strategies in healthy asymptomatic women: a systematic review and network meta-analysis. Sci Rep 12 , 94 (2022). https://doi.org/10.1038/s41598-021-04201-y

Download citation

Received : 21 July 2021

Accepted : 17 December 2021

Published : 07 January 2022

DOI : https://doi.org/10.1038/s41598-021-04201-y

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Cervical cancer survival prediction by machine learning algorithms: a systematic review.

• Milad Rahimi
• Atieh Akbari
• Hassan Emami

BMC Cancer (2023)

Validation of an on-chip p16ink4a/Ki-67 dual immunostaining cervical cytology system using microfluidic device technology

• Kei Hashimoto
• Tomoo Kumagai
• Kazunori Nagasaka

Scientific Reports (2023)

A unique Levey–Jennings control chart used for internal quality control in human papillomavirus detection

• Xuehong Peng

Virology Journal (2022)

By submitting a comment you agree to abide by our Terms and Community Guidelines . If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Epidemiology of Cervical Cancer

• First Online: 12 January 2019

Cite this chapter

• Anjum Memon 2 &
• Peter Bannister 2  

1142 Accesses

3 Citations

Worldwide, cervical cancer is the fourth most common cancer among women, with an estimated 528,000 new cases (7.9% of cancer in women) and 266,000 deaths (7.5% of cancer deaths in women) in the year 2012 and a 5-year prevalence of 1.5 million cases (9% of women with cancer). About 85% of the cases occur in developing countries, where cervical cancer accounts for 12% of all cancers in women. The cervical and endometrial cancers originate in the uterus but differ drastically in terms of aetiology, clinical presentation and characteristics, prognosis and survival. Cervical cancer is a model of viral carcinogenesis and most common in developing countries, whereas endometrial cancer is a model of hormonal carcinogenesis and most common in developed countries. The aim of this chapter is to provide an overview of key concepts in cancer epidemiology and to describe the global patterns and trends in incidence and mortality, aetiology and prevention of cervical cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save.

• Get 10 units per month
• Download Article/Chapter or eBook
• 1 Unit = 1 Article or 1 Chapter
• Cancel anytime
• Available as PDF
• Read on any device
• Instant download
• Own it forever
• Available as EPUB and PDF
• Durable hardcover edition
• Dispatched in 3 to 5 business days
• Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Cervical Cancer

Cervical Cancer Epidemiology

Memon A. Epidemiological understanding: an overview of basic concepts and study designs. In: Pencheon D, et al., editors. Oxford handbook of public health practice. 2nd ed. Oxford: Oxford University Press; 2006. p. 100–11.

Google Scholar  

Memon A. Epidemiology of gynaecological cancers. In: Shafi M, et al., editors. Gynaecological oncology. Cambridge: Cambridge University Press; 2010. p. 1–13.

Forman D, Bray F, Vrewster D, et al. Cancer incidence in five continents, Vol X (electronic version) Lyon, IARC. 2013. Available from: http://ci5.iarc.fr/CI5-X

Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr

The Surveillance, Epidemiology, and End Results (SEER) Program. Available from: http://seer.cancer.gov

National Cancer Institute. Cervical cancer. 2014. Available from: http://www.cancer.gov/cancertopics/types/cervical

Centers for Disease Control and Prevention (CDC), National Programme of Cancer Registries (NPCR). Available from: http://apps.nccd.cdc.gov/uscs and http://www.cdc.gov/cancer/npcr

Ryerson A, Eheman C, Altekruse S, et al. Annual report to the nation on the status of cancer, 1975–2012, featuring the increasing incidence of liver cancer. Cancer. 2016;122(9):1312–37.

Article   Google Scholar  

Ylitalo N, Stuver S, Adami H. Cervical cancer. In: Hans-Olov A, et al., editors. Textbook of cancer epidemiology. 2nd ed. New York: Oxford University Press; 2008. p. 446–67.

Chapter   Google Scholar  

Cancer Research UK. Available from: http://info.cancerresearchuk.org

Schiffman M, Castle P, Jeronimo J, et al. Human papillomavirus and cervical cancer. Lancet. 2007;370(9590):890–907.

Article   CAS   Google Scholar  

Castle P, Rodriguez A, Burk R, et al. Short term persistence of human papillomavirus and risk of cervical precancer and cancer: population based cohort study. BMJ. 2009;339:b2569.

Crosbie E, Einstein M, Franceschi S, et al. Human papillomavirus and cervical cancer. Lancet. 2013;382(9895):889–99.

Guan P, Howell-Jones R, Li N, et al. Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. Int J Cancer. 2012;131(10):2349–59.

Li N, Franceschi S, Howell-Jones R, et al. Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: variation by geographical region, histological type and year of publication. Int J Cancer. 2011;128(4):927–35.

Cox J. The development of cervical cancer and its precursors: what is the role of human papillomavirus infection? Curr Opin Obstet Gynecol. 2006;18(suppl.1):S5–S13.

Sellors J, Karwalajtys T, Kaczorowski J, et al. Incidence, clearance and predictors of human papillomavirus infection in women. CMAJ. 2003;168(4):421–5.

PubMed   PubMed Central   Google Scholar  

Dunne E, Unger E, Stenberg M, et al. Prevalence of HPV infection among females in the United States. JAMA. 2007;297(8):813–9.

Plummer M, de Martel C, Vignat J, et al. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob Health. 2016;4(9):609–16.

Franceschi S, Herrero R, Clifford G, et al. Variations in the age-specific curves of human papillomavirus prevalence in women worldwide. Int J Cancer. 2006;119(11):2677–84.

De Sanjose S, Diaz M, Castellsague X, et al. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis. 2007;7(7):453–9.

International Collaboration of Epidemiological Studies of Cervical Cancer. Carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. Int J Cancer. 2006; 118 6 :1481–95.

Kapeu A, Luostarinen T, Jellum E, et al. Is smoking an independent risk factor for invasive cervical cancer? A nested case-control study within Nordic biobanks. Am J Epidemiol. 2008;169(4):480–8.

Plummer M, Herrero R, Franceschi S, et al. Smoking and cervical cancer: pooled analysis of the IARC multi-centric case-control study. Cancer Causes Control. 2003;14(9):805–14.

Schiffman M, Brinton L. The epidemiology of cervical carcinogenesis. Cancer. 1995;76(suppl.10):1888–901.

Palefsky J, Holly E. Molecular virology and epidemiology of human papillomavirus and cervical cancer. Cancer Epidemiol Biomark Prev. 1995;4(4):415–28.

CAS   Google Scholar  

Burger M, Hollema H, Gouw A, et al. Cigarette smoking and human papillomavirus in patients with reported cervical cytological abnormality. BMJ. 1993;306(6880):749–52.

International Agency for Research on Cancer. Human papillomavirus. IARC monographs. 2012; 100b:255–313.

De Vuyst H, Gichangi P, Estambale B, et al. Human papillomavirus types in women with invasive cervical carcinoma by HIV status in Kenya. Int J Cancer. 2008;122(1):244–6.

Sun X, Kuhn L, Ellerbrock T, et al. Human papillomavirus infection in women infected with the human immunodeficiency virus. N Engl J Med. 1997;337(19):1343–9.

Rohner E, Sengayi M, Goeieman B, et al. Cervical cancer risk and impact of pap-based screening in HIV-positive women on antiretroviral therapy in Johannesburg, South Africa. Int J Cancer. 2017;141(3):488–96.

Strickler H, Palefsky J, Shah K, et al. Human papillomavirus type 16 and immune status in human immunodeficiency virus-seropositive women. J Natl Cancer Inst. 2003;95(14):1062–71.

Dahlstrom L, Andersson K, Luostarinen T, et al. Prospective seroepidemiologic study of human papillomavirus and other risk factors in cervical cancer. Cancer Epidemiol Biomark Prev. 2011;20(12):2541–50.

Smith J, Bosetti C, Munoz N, et al. Chlamydia trachomatis and invasive cervical cancer: a pooled analysis of the IARC multicentric case-control study. Int J Cancer. 2004;111(3):431–9.

Smith J, Munoz N, Herrero R, et al. Evidence for chlamydia trachomatis as a human papillomavirus cofactor in the etiology of invasive cervical cancer in Brazil and the Philippines. J Infect Dis. 2002;185m(3):324–31.

Wallin K, Wiklund F, Luostarinen T, et al. A population-based prospective study of chlamydia trachomatis infection and cervical carcinoma. Int J Cancer. 2002;101(4):371–4.

Koskela P, Anttila T, Bjorge T, et al. Chlamydia trachomatis infection as a risk factor for invasive cervical cancer. Int J Cancer. 2000;85(1):35–9.

Munoz N, Franceschi S, Bosetti C, et al. Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case-control study. Lancet. 2002;359(9312):1093–101.

Silins I, Ryd W, Strand A, et al. Chlamydia trachomatis infection and persistence of human papillomavirus. Int J Cancer. 2005;116(1):110–5.

Winer R, Hughes J, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med. 2006;354(25):2645–54.

Ursin G, Pike M, Preston-Martin S, et al. Sexual, reproductive and other risk factors for adenocarcinoma of the cervix: results from a population-based case-control study (California, United States). Cancer Causes Control. 1996;7(3):391–401.

Lee J, So K, Piyathilake C, et al. Mild obesity, physical activity, calorie intake, and the risks of cervical intraepithelial neoplasia and cervical cancer. PLoS One. 2013;8(6):e66555.

Garcia-Closas R, Castellsague X, Bosch X, et al. The role of diet and nutrition in cervical carcinogenesis: a review of recent evidence. Int J Cancer. 2005;117(4):629–37.

Peirson L, Fitzpatrick-Lewis D, Ciliska D, et al. Screening for cervical cancer: a systematic review and meta-analysis. Syst Rev. 2013;2:35.

NHS Choices. Available from: http://www.nhs.uk/pages/home.aspx

Landy R, Pesola F, Castanon A, et al. Impact of cervical screening on cervical cancer mortality: estimation using stage-specific results from a nested case-control study. Br J Cancer. 2016;115(9):1140–6.

Leeman A, del Pino M, Molijn A, et al. HPV testing in first-void urine provides sensitivity for CIN2+detection comparable with a smear taken by a clinician or a brush-based self-sample: cross-sectional data from a triage population. BJOG. 2017;124(9):1356–63.

Blake D, Crosbie E, Kitson S. Urinary HPV testing may offer hope for cervical screening non-attenders. BJOG. 2017;124(9):1364.

Download references

Author information

Authors and affiliations.

Department of Primary Care and Public Health, Brighton and Sussex Medical School, Brighton, UK

Anjum Memon & Peter Bannister

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Anjum Memon .

Editor information

Editors and affiliations.

The Joan and Sanford I. Weill Medical College/Graduate School of Medical Sciences, The New York Presbyterian Hospital-Weill Cornell Medical Center, and Sandra and Edward Meyer Cancer Center, Cornell University, New York, NY, USA

Samir A. Farghaly

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Memon, A., Bannister, P. (2019). Epidemiology of Cervical Cancer. In: Farghaly, S. (eds) Uterine Cervical Cancer. Springer, Cham. https://doi.org/10.1007/978-3-030-02701-8_1

Download citation

DOI : https://doi.org/10.1007/978-3-030-02701-8_1

Published : 12 January 2019

Publisher Name : Springer, Cham

Print ISBN : 978-3-030-02700-1

Online ISBN : 978-3-030-02701-8

eBook Packages : Medicine Medicine (R0)

Share this chapter

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Publish with us

Policies and ethics

• Find a journal
• Track your research

Fact sheets

• Facts in pictures
• Publications
• Questions and answers
• Tools and toolkits
• Endometriosis
• Excessive heat
• Mental disorders
• Polycystic ovary syndrome
• All countries
• Eastern Mediterranean
• South-East Asia
• Western Pacific
• Data by country
• Country presence 
• Country strengthening 
• Country cooperation strategies 
• News releases

Feature stories

• Press conferences
• Commentaries
• Photo library
• Afghanistan
• Cholera 
• Coronavirus disease (COVID-19)
• Greater Horn of Africa
• Israel and occupied Palestinian territory
• Disease Outbreak News
• Situation reports
• Weekly Epidemiological Record
• Surveillance
• Health emergency appeal
• International Health Regulations
• Independent Oversight and Advisory Committee
• Classifications
• Data collections
• Global Health Observatory
• Global Health Estimates
• Mortality Database
• Sustainable Development Goals
• Health Inequality Monitor
• Global Progress
• World Health Statistics
• Partnerships
• Committees and advisory groups
• Collaborating centres
• Technical teams
• Organizational structure
• Initiatives
• General Programme of Work
• WHO Academy
• Investment in WHO
• WHO Foundation
• External audit
• Financial statements
• Internal audit and investigations 
• Programme Budget
• Results reports
• Governing bodies
• World Health Assembly
• Executive Board
• Member States Portal
• Fact sheets /

Cervical cancer

• Cervical cancer is the fourth most common cancer in women globally with around 660 000 new cases and around 350 000 deaths in 2022.
• The highest rates of cervical cancer incidence and mortality are in low- and middle-income countries. This reflects major inequities driven by lack of access to national HPV vaccination, cervical screening and treatment services and social and economic determinants.
• Cervical cancer is caused by persistent infection with the human papillomavirus (HPV).  Women living with HIV are 6 times more likely to develop cervical cancer compared to women without HIV.
• Prophylactic vaccination against HPV and screening and treatment of pre-cancer lesions are effective strategies to prevent cervical cancer and are very cost-effective.
• Cervical cancer can be cured if diagnosed at an early stage and treated promptly.
• Countries around the world are working to accelerate the elimination of cervical cancer in the coming decades, with an agreed set of three targets to be met by 2030. 

Globally, cervical cancer is the fourth most common cancer in women, with around 660 000 new cases in 2022. In the same year, about 94% of the 350 000 deaths caused by cervical cancer occurred in low- and middle-income countries. The highest rates of cervical cancer incidence and mortality are in sub-Saharan Africa (SSA), Central America and South-East Asia. Regional differences in the cervical cancer burden are related to inequalities in access to vaccination, screening and treatment services, risk factors including HIV prevalence, and social and economic determinants such as sex, gender biases and poverty. Women living with HIV are 6 times more likely to develop cervical cancer compared to the general population, and an estimated 5% of all cervical cancer cases are attributable to HIV ( 1) . Cervical cancer disproportionately affects younger women, and as a result, 20% of children who lose their mother to cancer do so due to cervical cancer (2) .

Human papillomavirus (HPV) is a common sexually transmitted infection which can affect the skin, genital area and throat. Almost all sexually active people will be infected at some point in their lives, usually without symptoms. In most cases the immune system clears HPV from the body. Persistent infection with high-risk HPV can cause abnormal cells to develop, which go on to become cancer.

Persistent HPV infection of the cervix (the lower part of the uterus or womb, which opens into the vagina – also called the birth canal) if left untreated, causes 95% of cervical cancers. Typically, it takes 15–20 years for abnormal cells to become cancer, but in women with weakened immune systems, such as untreated HIV, this process can be faster and take 5–10 years. Risk factors for cancer progression include the grade of oncogenicity of the HPV type, immune status, the presence of other sexually transmitted infections, number of births, young age at first pregnancy, hormonal contraceptive use, and smoking. 

Boosting public awareness, access to information and services are key to prevention and control across the life course.

• Being vaccinated at age 9–14 years is a highly effective way to prevent HPV infection, cervical cancer and other HPV-related cancers.
• Screening from the age of 30 (25 years in women living with HIV) can detect cervical disease, which when treated, also prevents cervical cancer.
• At any age with symptoms or concerns, early detection followed by prompt quality treatment can cure cervical cancer.

HPV vaccination and other prevention steps

As a priority, HPV vaccines should be given to all girls aged 9–14 years, before they become sexually active. The vaccine may be given as 1 or 2 doses. People with reduced immune systems should ideally receive 2 or 3 doses. Some countries have also chosen to vaccinate boys to further reduce the prevalence of HPV in the community and to prevent cancers in men caused by HPV.

Other important ways to prevent HPV infection include:

• being a non-smoker or stopping smoking
• using condoms
• voluntary male circumcision.  

Cervical screening and treatment of precancers

Women should be screened for cervical cancer every 5–10 years starting at age 30. Women living with HIV should be screened every 3 years starting at age 25. The global strategy encourages a minimum of two lifetime screens with a high-performance HPV test by age 35 and again by age 45 years. Precancers rarely cause symptoms, which is why regular cervical cancer screening is important, even if you have been vaccinated against HPV.

Self-collection of a sample for HPV testing, which may be a preferred choice for women, has been shown to be as reliable as samples collected by healthcare providers.

After a positive HPV test (or other screening method) a healthcare provider can look for changes on the cervix (such as precancers) which may develop into cervical cancer if left untreated. Treatment of precancers is a simple procedure and prevents cervical cancer. Treatment may be offered in the same visit (the see and treat approach) or after a second test (the see, triage and treat approach), which is especially recommended for women living with HIV.

Treatments of precancers are quick and generally painless causing infrequent complications. Treatment steps include colposcopy or visual inspection of the cervix to locate and assess the lesion followed by:

• thermal ablation, which involves using a heated probe to burn off cells;
• cryotherapy, which involves using a cold probe to freeze off the cells;
• LEETZ (large loop excision of the transformation zone), which involves removing your abnormal tissues with an electrically heated loop; and/or
• a cone biopsy, which involves using a knife to remove a cone-shaped wedge of tissue.

Early detection, diagnosis and treatment of cervical cancer

Cervical cancer can be cured if diagnosed and treated at an early stage of disease. Recognizing symptoms and seeking medical advice to address any concerns is a critical step. Women should see a healthcare professional if they notice:

• unusual bleeding between periods, after menopause, or after sexual intercourse
• increased or foul-smelling vaginal discharge
• symptoms like persistent pain in the back, legs, or pelvis
• weight loss, fatigue and loss of appetite
• vaginal discomfort
• swelling in the legs.

Clinical evaluations and tests to confirm a diagnosis are important and will generally be followed by referral for treatment services, which can include surgery, radiotherapy and chemotherapy as well as palliative care to provide supportive care and pain management.

Management pathways for invasive cancer care are important tools to ensure that a patient is referred promptly and supported as they navigate the steps to diagnosis and treatment decisions. Features of quality care include:

• a multidisciplinary team ensuring diagnosis and staging (histological testing, pathology, imaging) takes place prior to treatment decisions;
• treatment decisions in line with national guidelines; and
• interventions are supported by holistic psychological, spiritual, physical and palliative care.

As low- and middle-income countries scale-up cervical screening, more cases of invasive cervical cancer will be detected, especially in previously unscreened populations. Therefore, referral and cancer management strategies need to be implemented and expanded alongside prevention services.

WHO Response

All countries have made a commitment to eliminate cervical cancer as a public health problem. The WHO Global strategy defines elimination as reducing the number of new cases annually to 4 or fewer per 100 000 women and sets three targets to be achieved by the year 2030 to put all countries on the pathway to elimination in the coming decades:

• 90% of girls vaccinated with the HPV vaccine by age 15
• 70% of women screened with a high-quality test by ages 35 and 45
• 90% of women with cervical disease receiving treatment.

Modelling estimates that a cumulative 74 million new cases of cervical cancer can be averted, and 62 million deaths can be avoided by by 2120 by reaching this elimination goal. Explore the cervical cancer knowledge repository for resources from WHO, UN agencies and other partners: Cervical cancer elimination initiative .

Prevention of HPV-associated precancer and cancer is also a key element of WHO’s Global health sector strategy on HIV,   hepatitis and sexually transmitted infections 2022 – 2030 , and the World Health Assembly resolution WHA74.5 (2021) on oral health includes actions on mouth and throat cancers.

• Stelze, Dominik et al. Estimates of the global burden of cervical cancer associated with HIV. The Lancet. 2020. https://doi.org/10.1016/S2214-109X(20)30459-9
• Guida, F., Kidman, R., Ferlay, J. et al. Global and regional estimates of orphans attributed to maternal cancer mortality in 2020. Nat Med 28 , 2563–2572 (2022). https://doi.org/10.1038/s41591-022-02109-2
• Comprehensive cervical cancer control: a guide to essential practice
• HPV vaccination
• Screening & early detection of cancer
• Burden of cervical cancer disease by country (GLOBOCAN)
• WHO's work on cancer
• Cervical cancer elimination day of action
• WHO position paper on HPV vaccines
• WHO-approved HPV tests
• Global strategy to accelerate the elimination of cervical cancer as a public health problem
• Cervical Cancer Elimination Initiative

• Global Cancer Observatory
• Global and regional estimates of orphans attributed to maternal cancer mortality in 2020
• Estimates of the global burden of cervical cancer associated with HIV
• HPV vaccination and the risk of invasive cervical cancer
• Mortality impact of achieving WHO cervical cancer elimination targets: a comparative modelling analysis in 78 low-income and lower-middle-income countries
• Impact of HPV vaccination and cervical screening on cervical cancer elimination: a comparative modelling analysis in 78 low-income and lower-middle-income countries
• Essential Package of Palliative Care for Women With Cervical Cancer: Responding to the Suffering of a Highly Vulnerable Population

Warning: The NCBI web site requires JavaScript to function. more...

An official website of the United States government

The .gov means it's official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you're on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings
• Browse Titles

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Cervical cancer.

Josephine R. Fowler ; Elizabeth V. Maani ; Charles J. Dunton ; David P. Gasalberti ; Brian W. Jack .

Affiliations

Last Update: November 12, 2023 .

• Continuing Education Activity

Cervical cancer, the fourth most common cancer among women worldwide, is caused almost entirely by human papillomavirus (HPV). High-risk types of HPV can lead to cervical intraepithelial lesions which, over time, can progress to cervical cancer. In the United States and other developed countries, most screening and early detection efforts involve HPV testing and Papanicolaou (Pap) smears. HPV testing identifies exposure to both low- and high-risk types of HPV, whereas Pap smears identify abnormal cytology.

Cervical cancer is a largely preventable disease. Primary prevention and screening are the most effective modalities for decreasing the healthcare burden and mortality attributable to cervical cancer. Since 2006, HPV vaccination has been available to prevent cervical cancer. Interprofessional team members must educate young female patients (ideally, prior to initiating sexual activity) and their families about this highly effective vaccine. This activity details primary prevention strategies, screening guidelines, diagnostic evaluations, current staging, and specific treatment modalities for invasive cervical cancer.

• Identify the risk factors, signs, and symptoms of cervical cancer, including the role of high-risk HPV types in its development.
• Apply evidence-based treatment modalities for precancerous cervical lesions, and assess the indications, techniques, potential complications, and follow-up care associated with these interventions.
• Select appropriate treatment modalities for invasive cervical cancer based on patient characteristics, staging, and available options, including surgery, radiation, and chemotherapy.
• Collaborate with the interprofessional team to increase HPV vaccination initiatives and to ensure coordinated and comprehensive care for patients diagnosed with cervical cancer.
• Introduction

Cervical cancer continues to rank among the top gynecologic cancers worldwide. According to current data, it is ranked 14th among all cancers and is the 4th most common cancer among women worldwide. [1] Cervical cancer intervention focuses on primary and secondary prevention. [2] Primary prevention and screening are the best methods to decrease the burden of cervical cancer and mortality.

In the United States and other developed countries, most screening and diagnostic efforts are directed toward the early identification of high-risk human papillomavirus (HPV) lesions through HPV testing and Papanicolaou (Pap) smears. Although HPV testing is not recommended in women younger than 30 years, low-risk younger women should begin screening with Pap tests at age 21 and continue until age 65, per the United States Preventive Services Task Force (USPSTF) recommendations. Newer recommendations offer 3- to 5-year intervals between screenings based on a patient's prior results and the use of Pap and HPV cotesting. [3] [4]  

Like many diseases and cancers, disparities exist in screening, early diagnosis, and timely treatment rates. Screening rates are lower in low socioeconomic and low-resource areas with racial, ethnic, and age variations. Studies show women with obesity and chronic disease may have lower cervical and breast cancer screening rates. A study of ethnic minority women in the United Kingdom reports several barriers to screening, including lack of awareness, fear, embarrassment, shame, and low perceived risk. [5]  Another study reviewing the barriers for Haitian women revealed socioeconomic barriers, language barriers, and a limited understanding of health and disease. [6]  In the United States, cervical cancer mortality is disproportionately higher in black women.

As cervical cancer is a sexually transmitted infection (STI), it is preventable, and the global incidence can be reduced through targeted education, screening, and intervention. Since 2006, vaccination has been available for the prevention of cervical cancer. Vaccination can improve cancer death rates in populations with higher mortality rates and in developing countries where resources may not be available for routine screening. 

Current literature reports that HPV is found in most sexually active people at some point during their lifetime. There are more than 130 types of known HPV, with 20 HPV types identified as cancer-related. HPV exposure rates are only known in women since men are not screened outside of research protocols. HPV types 16 and 18 are the most common HPV types identified in invasive cervical cancer. Population-based HPV prevalence studies show the greatest prevalence of high-risk HPV occurs in adults younger than 25 years, and cervical cancer deaths peak in middle-aged women between 40 and 50 years. Studies have shown that HPV-related cervical disease in women younger than 25 years is largely self-limiting. However, those with coinfection of multiple HPV types may be less likely to have spontaneous clearance and, thus, progress to cancer.

HPV is transmitted by skin-to-skin contact, including during sexual intercourse, hand-to-genital contact, and oral sex. Risk factors for HPV and cervical cancer include young age at sexual initiation, multiple sexual partners, high parity, smoking, herpes simplex, HIV, coinfection with other genital infections, and oral contraceptive use. [7] [8]

• Epidemiology

Persistent HPV infection causes more than 99% of all cervical cancers. Every year, there are more than 500,000 new cases of cervical cancer and approximately 250,000 deaths due to cervical cancer worldwide. Eighty percent of cases occur in developing countries. [9] In the United States, about 4000 women die yearly from cervical cancer. Blacks, Hispanics, and women in low-resource areas have more disparity in evidenced-based care and a significantly higher mortality rate. [10] [11]  Mortality is higher among women not screened in the past 5 years and those without consistent follow-up after identifying a precancerous cervical lesion. Trends show that women with the highest-mortality risk may be less likely to receive HPV vaccination.

• Pathophysiology

More than 75% of cervical cancer cases are due to high-risk HPV types 16 and 18. [12] Other HPV types also can cause malignancy. Some low-risk HPV types, specifically types 6 and 11, cause condylomata acuminate, commonly referred to as anogenital warts. Although there are more than half a million cases of HPV identified annually, most are low-grade infections and will spontaneously resolve within 2 years. The progression of high-grade lesions and cancer is seen in the presence of other carcinogenic risk factors, as previously described.

Within HPV DNA, the oncoproteins E6 and E7 interfere with the critical host cell cycle; specifically, E6 interferes with suppressive tumor protein p53, whereas E7 interferes with retinoblastoma protein (pRB). Additionally, the E5 protein may play a role in immune evasion. These are significant factors in HPV-related neoplasia, including primary vagina cancer. [13]  Oxidative stress and microRNAs are believed to play a role in cervical carcinogenesis. Future research to elucidate the proposed interplay is needed. [12] [14]

• Histopathology

Squamous cell carcinoma and adenocarcinoma are the most common histological subtypes of cervical cancer, with squamous cell carcinoma being vastly more frequent. Adenocarcinoma constitutes approximately 5% of invasive cervical cancers worldwide, although this percentage is increasing in some countries. [15]   Both subtypes result from precursor lesions, cervical intraepithelial neoplasia (CIN), or carcinoma in situ (CIS). Squamous CIS and adenocarcinoma in situ (AIS) are the most immediate precursors to invasive cervical cancer. Adenocarcinoma of the cervix should be carefully distinguished from endometrial adenocarcinoma with immunohistochemistry and HPV in situ hybridization. [16]   

Most malignancies arise from the sqamocolumnar junction of the cervix. Microscopically, anastomosing irregular nests or single tumor cells with stromal inflammation or desmoplasia are present. Lymphovascular invasion (LVI) may also be present. Grading is predicated on nuclear pleomorphism, nucleoli size, mitotic activity, and necrosis, and does not correlate with prognosis. [17]

• History and Physical

Patients with cervical cancer are usually asymptomatic during the early stages. A complete medical history must include a sexual history, including the patient's age at first sexual encounter. Sexual history also includes questions about postcoital bleeding and pain during intercourse. Questions about previous STIs, including HPV and HIV, the number of lifetime sexual partners, tobacco use, and prior vaccination against HPV are all vitally important. [18] Women should also be asked about menstrual patterns, abnormal bleeding, persistent vaginal discharges, irritations, and known cervical lesions. [19]

The physical exam must include a complete evaluation of the external and internal genitalia. Positive exam findings in women with cervical cancer might include a friable cervix, visible cervical lesions, erosions, masses, bleeding with the examination, and fixed adnexa. [20]  Many patients will have no positive findings on physical examination. Screening by Pap and/or HPV testing is essential in the workup and diagnosis of patients with cervical cancer and its precursor lesions.

According to the United States Preventative Services Task Force (USPTF), Pap screening is recommended beginning at age 21; at age 30, HPV testing starts in conjunction with Pap smear cytology. Screening is recommended every 3 years for women with continued negative screening results and those at low risk for cervical cancer. For women older than 30 years, cytology can be done every 5 years with HPV testing. One Level A recommendation for women with low-risk status and consistently negative screenings is discontinuing cervical cytology and HPV testing at age 65. Women who have had a total abdominal hysterectomy, including removal of the cervix for benign disease, do not require subsequent screening. [4]

Colposcopy is the diagnostic procedure of choice for evaluating abnormal cytology and/or persistent high-risk HPV infection. The American Society for Colposcopy and Cervical Pathology (ASCCP) has issued guidance on procedural indications, and their recommended algorithms are considered standard of care. Multiple colposcopic-guided biopsies and endocervical sampling are often indicated, except during pregnancy. [21]  Abnormal colposcopic findings may include acetowhite color change with the application of acetic acid, rich vascularity, atypical vessels, mosaicism, and punctation (see Image.  Invasive Cervical Cancer).

Patients diagnosed with invasive disease require a comprehensive staging workup. The International Federation of Gynecology and Obstetrics (FIGO) staging system employs several methods to stage a patient's disease. Classically, staging was based on the local extent of the tumor, which could be determined with a combination of pelvic examination, cystoscopy, proctoscopy, chest x-ray, intravenous pyrography, and basic labs. More recently, advanced imaging modalities such as MRI and PET scans have been utilized for staging. A pelvic MRI is excellent for detecting local tumor extension and can also be used for monitoring tumor response. PET scans are more sensitive than CT scans for detecting nodal and visceral metastases. This is critical as nodal disease can significantly influence prognosis. [22]

• Treatment / Management

Precancerous lesions are managed conservatively for women younger than 25 years. Most positive findings in women younger than 25 years are low-risk cervical dysplasia and will resolve spontaneously. Colposcopy evaluates persistent, abnormal cytology or lesions suspected to be moderate or high risk. These are managed according to findings.

Low-risk lesions may be observed and reevaluated more frequently, and high-risk lesions are treated based on size, depth, and location. Cryotherapy or excision is performed to manage precancerous lesions limited in size and depth. Conization, laser, or loop electrosurgical excision procedure (LEEP) are used to manage lesions that include the endocervical canal and are more extensive. LEEP may provide better visualization of the squamocolumnar junction and provide the benefit of less bleeding in the outpatient setting. [23]

If invasive cancer is diagnosed, the next step in management is staging to determine further treatment. Staging is based on findings and results from reported signs and symptoms, examination, tissue pathology, and imaging. Grading is based on the size and depth of the cancer and signs of spread to other organs. Treatment of early-stage disease is typically surgical resection, ranging from a conization to a modified radical hysterectomy. However, women with high-risk pathology postresection may require adjuvant treatment with chemotherapy and radiation. Conization or trachelectomy may be an option for women with early-stage disease who desire future fertility. For patients with more advanced disease, concurrent chemoradiation is the standard of care.

• Differential Diagnosis

Evaluating visible cervical lesions for invasive cancer is essential. However, as discussed above, most cervical cancer is asymptomatic and will not present with an overt mass in the early stages. Other possible causes of cervical lesions and/or abnormal bleeding include STIs, cervical polyps or fibroids, and endometriosis. Diagnosis may require further evaluation of symptoms and testing to determine whether the disease is cervical cancer. A diagnostic biopsy is needed to finalize the diagnosis.

Other pathology-determined conditions in the differential diagnosis include carcinosarcoma, epithelioid trophoblastic tumor, placental site nodule, immature squamous metaplasia, and metastatic disease from a noncervical primary tumor. Rarely, a routine Pap smear may identify metastatic cancer on the uterine cervix. [24]

• Surgical Oncology

Surgical resection is offered to patients with early-stage disease confined to the cervix; it can range from relatively noninvasive procedures such as cervical conization to more extensive operations such as radical hysterectomy. Although surgery is the preferred treatment modality for early-stage cervical cancer, it is especially important in younger patients for whom preservation of ovarian function and/or fertility is desired. Surgery is also indicated in select patients with recurrent disease.

Types of Surgery

Cervical conization

Cervical conization is typically indicated in patients with CIS or stage IA1 invasive cervical cancer. Using a scalpel or laser, a cold knife cone (CKC) removes the cervical transformation zone and a portion of the cervix with at least a 3-mm margin. Pathologic evaluation of the margins and assessment of the presence or absence of lymphovascular invasion (LVI) are critical. If a positive margin or LVI is present, reexcision or more invasive surgical treatment may be required.

If no LVI exists on the specimen, lymph node involvement is exceedingly rare, so nodal evaluation is unnecessary. Patients without any adverse pathologic findings may be observed. Recurrence rates are typically <10%, but patients must be followed closely with periodic colposcopy and cytology. Five-year survival rates exceed 95%. Complications include hemorrhage, infection, cervical incompetence, cervical stenosis, and infertility. The complication rate ranges from 2% to 12%. [25] [26]

Radical trachelectomy

Patients who are not candidates for conization due to adverse pathological features or more advanced disease but who desire future fertility are candidates for a radical trachelectomy. The procedure consists of removing most of the cervix, resecting the parametria, and mobilizing the ureters, bladder, and rectum. A 5-mm section of the cervix is preserved for the placement of a cerclage, allowing for future pregnancy. Due to the increased risk of nodal involvement, a lymph node evaluation with a sentinel node biopsy or pelvic lymphadenectomy typically accompanies a radical trachelectomy.

Adverse pathologic features such as positive margins, parametria involvement, lymph node involvement, or meeting Sedlis criteria would necessitate adjuvant treatment with radiotherapy with or without chemotherapy. A vaginal approach or laparotomy can be used, but there are insufficient data on minimally invasive techniques. The 5-year recurrence rate is approximately 5%, and the overall survival rate is 97%. The pregnancy rate postprocedure is 24%, with a live birth occurring in 75% of patients. [27] Complications include cervical suture problems, dysmenorrhea, isthmic stenosis, and vaginal discharge.

Extrafascial hysterectomy

Extrafascial hysterectomy, also known as a Type A radical hysterectomy, has a narrow range of clinical indications. [28] Typically, this surgery is offered to patients with stage IA1 disease who are not interested in future fertility; it involves the removal of the entire cervix and uterus. As ovarian removal is optional, ovarian function can be preserved. The parametria are not resected, and a vaginal approach or laparotomy may be utilized. Lymph node evaluations are not usually performed unless adverse pathologic features are discovered postoperatively. Patients with adverse pathologic features may require a complete parametrectomy or external beam radiotherapy with or without chemotherapy.

Radical hysterectomy

A radical hysterectomy may be considered in almost all early-stage cervical cancer cases when fertility preservation is not desired. The older Piver-Rutledge-Smith classification has been replaced by the Querleu–Morrow system, which simplifies the classification process based solely on the extent of lateral parametria resection. Four types of radical hysterectomy are described (Types A through D). Type A includes a minimal parametrial resection. In contrast, Type D completely resects the paracervical region to the pelvic sidewall. The most commonly performed radical hysterectomies fall in the Type B and C categories, which differ in the transection of the paracervical region at the level of the ureters or internal iliac vessels, respectively. [29]

Minimally invasive approaches have been shown to provide inferior oncologic outcomes compared with more established open approaches in terms of disease-free survival (91% vs 97%) and overall survival (93% vs 99%), with most patients having stage IB1 disease. [30]  Complications include bleeding, infection, venous thromboembolism, pulmonary embolus, small bowel obstruction, vesicovaginal fistula, hydronephrosis, ureteral injury, urinary stress incontinence, and lower extremity edema.

Laparoscopic radical hysterectomy

Although this procedure offers a quicker recovery for the patient, it has been largely abandoned due to poor oncologic outcomes and increased recurrence compared with open surgery. The mechanism for this difference is unknown, but 2 large independent studies have confirmed this finding. [31] [32] [33]

Lymph node evaluation

Detecting lymph node involvement is essential, as it yields important prognostic information and guides therapeutic decision-making. The risk of nodal involvement should guide the decision to evaluate the lymph nodes and is a function of the disease stage (see Table.  Pelvic Nodal Risk by Stage). Para-aortic (PA) nodal risk typically carries one-half the pelvic nodal risk by stage. Although pelvic lymphadenectomies are considered the gold standard, sentinel node biopsies may also be pursued for select early stage I cervical cancer. Generally, sentinel node biopsies are safe and effective. They have been investigated in stage IA1 to stage IIA1 patients with a sensitivity of 92%, a negative predictive value of 98%, less lymphatic morbidity, and no differences in recurrence-free survival. [34] [35] The sentinel node biopsy approach continues to be investigated in large-scale international trials called SENTICOL III (NCT03386734).

Table. Pelvic Nodal Risk by Stage.

Pelvic exenteration

Pelvic exenteration is the most radical surgical procedure for cervical cancer. Indications are confined to patients with central pelvic recurrence after radiotherapy or patients with stage IVA disease who cannot receive radiotherapy. Classically, a total pelvic exenteration includes the removal of the uterus, fallopian tubes, ovaries, vagina, bladder, urethra, and rectum. Reconstruction consists of an ileal conduit, or continent diversion, for the urinary system and an end colostomy for the GI system. Continent diversions include the Indiana and Miami pouch techniques. [36] [37]  

Total exenteration is generally performed for cervical cancer. Variations of this technique include anterior and posterior exenteration, which spare the rectum or the bladder, respectively. Exenteration can be further classified into supralevator and infralevator, depending on whether the urogenital diaphragm and levator muscles are removed. It is important to ensure that the central tumor can be completely resected and there is no metastatic disease. Minimally invasive pelvic exenteration has been described in the literature, although further evaluation of this technique is warranted. [38] [39]  

A neovagina can be formed with a myocutaneuous flap or split-thickness skin graft with an omental J-flap. The posterior supralevator exenteration approach allows for the possibility of maintaining not only urinary function but fecal continence if a colonic anastomosis can be formed. The 5-year survival rate for patients treated with exenteration ranges from 40% to 50% in the recurrent setting. [40]  At 3 and 5 years, local recurrence rates are 84% and 75%, respectively. [41] Survival is not impacted by the type of exenteration performed. [42] Mortality from the operation has fallen dramatically over the last 70 years to less than 5%, but surgical morbidity is over 50%. [41] Early complications include infection, abscess formation, thromboembolism, fistulas, urinary leakage, peritonitis, stoma necrosis, flap necrosis, and stump dehiscence. Late complications include stoma stenosis, incontinence, hydronephrosis, stone formation, chronic pain, and abdominal wall hernia.

Cervical Cancer in Pregnancy

Although cervical cancer is one of the most common malignancies diagnosed in pregnancy, it poses unique staging and treatment challenges in pregnant patients. A maternal-fetal medicine specialist should evaluate patients to discuss fetal risks and potential pregnancy loss. Women must weigh the risk of delaying treatment until after delivery versus proceeding immediately with treatment.

The determination of gestational age is crucial. Minimum fetal viability is approximately 24 weeks gestation, but there is a significant risk of neonatal death or long-term disability in those who survive. Disability-free survival at 25 years increases substantially with advancing gestational age, with 4% of infants born at 22 weeks versus 78% for those born at 28 weeks gestation. In contrast, full-term infants have a disability-free survival of 97%. [43]

While the radiation delivered during a PET or CT scan remains far below the threshold for the development of congenital malformations and pregnancy loss, ionizing radiation in imaging studies should be kept to a minimum in this population. [44] Other imaging modalities, such as ultrasound and MRI, are preferred when appropriate to determine local tumor extent and distant metastatic involvement. However, MRI and ultrasound have a low sensitivity for small nodal metastases. Consequently, more invasive staging techniques may need to be employed.

In patients with a high risk of nodal metastasis, laparoscopic pelvic lymphadenectomy may be performed to establish the disease stage. [45]  The safety of this procedure has only been studied in limited case series, but it can be performed in any trimester (although earlier in the pregnancy is preferred). These techniques may still be employed when advanced imaging is unavailable or contraindicated. In addition, the FIGO staging system continues to allow the use of proctosigmoidoscopy and cystoscopy for local staging of cervical cancer.

Treatment strategies must be individualized and discussed in a multidisciplinary fashion with medical oncologists, radiation oncologists, obstetrician/gynecologists, maternal-fetal medicine specialists, and gynecologic oncologists. Generally, patients with pregnancies at gestational ages under 22 weeks and stage IA1 disease can be treated with conization, but this carries a 15% risk of significant bleeding and spontaneous abortion. Patients with pregnancies at gestational ages above 22 weeks may be able to delay treatment until after delivery if they have early-stage disease. Patients with more advanced disease (>IB1) may receive platinum-based neoadjuvant chemotherapy (cisplatin/paclitaxel) until delivery, followed by a cesarean radical hysterectomy. Limited data suggest this is a safe regimen for both mother and fetus. [46]  Small series indicate approximately a 75% tumor response rate, with 15% of patients experiencing a local recurrence. The risk of fetal toxicity with these regimens is unknown, but complications may include respiratory distress syndrome, malformations, and childhood malignancies. [46]    International guidelines for treatment and fetal preservation have been published. [47]

Immediate treatment is recommended for patients with documented lymph node metastasis, disease progression, or pregnancy termination. If the patient opts to terminate the pregnancy before treatment, definitive treatment recommendations are identical to those of a nonpregnant patient.

• Radiation Oncology

Radiotherapy remains a crucial component in the treatment of cervical cancer. Randomized evidence from the 1990s and early 2000s has established radiotherapy in almost every facet of treatment; it may be utilized as a definitive or adjuvant treatment with or without platinum-based chemotherapy.

Definitive Radiotherapy

Early-stage cervical cancer

Radiotherapy may be utilized as the sole treatment modality in early-stage cervical cancer (stages IA1 to IIA1). External beam radiotherapy (EBRT) with a brachytherapy (BT) boost has less morbidity and equivalent 5- and 20-year overall survival rates (83% and 75%, respectively) compared with radical hysterectomy. [48] [49] Some centers may perform an adjuvant hysterectomy for bulky tumors after chemoradiation therapy. However, most guidelines do not recommend this due to significant complication rates. Recent data suggest that survival rates after chemoradiation therapy and adjuvant hysterectomy are suboptimal. [50]

Advanced cervical cancer

Locally aggressive and/or node-positive diseases are typically treated with definitive concurrent platinum-based chemoradiotherapy followed by a BT boost. The addition of chemotherapy to definitive radiotherapy has resulted in considerable improvement in overall survival compared with radiotherapy alone, with an 8-year overall survival of 67% versus 41%. Improvements in local recurrence and distant metastasis have also been noted. [51]

Postoperative radiotherapy

Radiotherapy with or without chemotherapy is recommended in the postoperative setting when specific pathologic findings are present. These findings are thought to represent an increased risk of recurrence.

Conventionally, the Sedlis criteria guided the use of adjuvant radiotherapy without chemotherapy in postradical hysterectomy patients with at least 2 of the following 3 features: tumor size greater than 4 cm, LVI, or more than one-third stromal invasion. [52] These criteria were meant to identify patients with at least a 30% risk of relapse at 3 years. [53] Patients who met these criteria and were treated with pelvic radiotherapy were noted to have improved progression-free survival (78% vs 65%) and local recurrence (21% vs 14%). [52] More recently, there have been concerns that these criteria may overlook women who might benefit from adjuvant radiotherapy due to such a high threshold. A nomogram incorporating the original Sedlis criteria and tumor histology has been developed to provide a more linear and continuous risk assessment rather than a simple threshold. [53]

Classically, the addition of chemotherapy to radiotherapy was guided by the Peters trial, which randomized patients with positive nodes, involved parametria, or positive surgical margins to radiotherapy alone or radiotherapy with concurrent platinum-based chemotherapy. The addition of chemotherapy resulted in a 10% improvement in overall survival at 4 years and almost a 20% improvement in progression-free survival over the same time frame. [54] More contemporary studies such as the STARS trial have sought to expand the use of chemotherapy in the adjuvant setting in patients meeting either the original Sedlis or Peters criteria. [55]

Delivery Techniques

The 2 major delivery methods include ERBT, directed at the primary tumor and pelvic lymphatics, and BT, in which a sealed radiation source is placed in close proximity to the tumor. 

EBRT techniques include 3-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiotherapy (IMRT). Intact cervical cancer patients’ plans can be employed. A reduction in gastrointestinal and hematological adverse effects has been documented with IMRT in both adjuvant and definitive settings. [56] [57]

ERBT simulation

Patients undergoing EBRT can be placed in the supine position. Accounting for cervical motion is essential when using IMRT. This is accomplished by taking 2 separate scans of patients, first with a full bladder followed by an empty bladder. Prone positioning may also be accomplished using a belly board; however, if there are large daily fraction shifts, IMRT may not be reproducible. Prone positioning may allow for a reduction in the small bowel dose when using IMRT. [58]

ERBT target delineation

Traditionally, pelvic fields were drawn on 2-D x-rays consisting of anterior-posterior (AP)/posterior-anterior (PA) and opposed lateral fields comprising the 4-field box. The superior edge of the field was the bottom of L4 and inferiorly drawn to the bottom of the obturator foramen (or at least 3 cm below the lowest extent of disease). The lateral fields have the same superior/inferior borders, with the anterior border being the anterior pubic symphysis and the posterior border being the sacral hollow, including S2.

More precise delineation of the gross disease and elective volumes can be accomplished in the era of CT-based planning, PET/CT fusions, and IMRT. A gross tumor volume (GTV) consists of gross disease seen on a CT, PET, and physical examination. An internal target volume (ITV) accounts for variation in bladder filling and can also be employed, but this requires the patient to have 2 CT simulations (empty and full bladder). The clinical tumor volume (CTV) 1 expansion includes the entire cervix and uterus (if intact). Planning target volume (PTV) 1 on primary disease is typically 1.5 cm. The CTV2 includes the parametrial tissue, paravaginal tissues, and at least one-half of the upper vagina. If there is vaginal involvement, consideration should be given to covering the entire vagina. This PTV2 expansion should be 1.0 cm. The elective nodal volumes in the CTV3 should include obturator nodes, external iliac nodes, internal iliac nodes, and presacral nodes. If there is lower vaginal involvement, consideration should be given to coverage of the inguinal nodes. PTV expansion on the elective nodes is typically 0.7 cm.

Coverage of the PA nodes may be necessary in cases with evidence of disease in the nodal chain, or in cases in which the patient has a positive pelvic node and will not receive systemic therapy. In those instances, the superior boundary would become the T12/L1 interspace, with the nodal strip ending at the top of the pelvic field L5/S1. [59] [60]

ERBT dosing and dose constraints

The standard whole pelvic dose is 45 to 50.4 Gy, specifically 1.8 to 2.0 Gy per fraction. Any gross nodal disease may be boosted to 60 Gy if possible, given that organs-at-risk (OAR) constraints are not exceeded.

EBRT has dramatically improved with the adoption of IMRT, reducing acute toxicity while maintaining oncologic outcomes. Typical OAR include the rectum, bladder, bowel, femoral heads, and bone marrow. Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC)   dose constraints can be an excellent guide. Typically, with EBRT, doses of 45 to 50 Gy alone will not lead to significant rates of acute bladder or bowel toxicity. [57]

If BT is planned, minimizing these doses during the external beam phase of treatment will allow higher doses to be delivered during the boost phase of treatment. Bone marrow suppression resulting in grades 3 to 4 neutropenia has been demonstrably lower (8.6% vs 27.1%) with image-guided radiotherapy and IMRT. [56] The most common constraints are for bone marrow in the pelvis. [56] [57] [61]

BT can be used alone in early-stage cervical cancer or as a boost after EBRT in more advanced disease (stages IB2 to IVA), as it allows for highly conformal dose delivery to the tumor while minimizing exposure to normal tissues. The dose delivery is controlled by adjusting the dwell times within the delivery device. High dose-rate (HDR) BT (>12 Gy/hr) is the most commonly used technique; however, it requires a radioactive source, usually iridium-192.

Typically, BT is started after the external beam portion of the treatment or interdigitated with EBRT in the last week of treatment. EBRT and BT should not be administered on the same day. Total treatment time (EBRT and BT) should not exceed 8 weeks. Excessive treatment times can result in a 1% per day decline in local control and overall survival.

Before undergoing BT, a review of the patient’s history, physical exam, pathology, and imaging should be conducted. A complete blood count and metabolic panel should be obtained within a week of the procedure. Metabolic derangements should be investigated and corrected before the procedure. Patients with an absolute neutrophil count (ANC) less than 500 mm should not undergo the procedure until their count has recovered. A review of medications, especially anticoagulants, should be completed, and a prothrombin time/international normalized ratio result should be obtained. Careful consideration should be given to holding anticoagulant medications before the procedure. Inpatients confined to bed should be given thromboprophylaxis and sequential compression devices. Bowel preparation should also be reviewed with the patient before the procedure.

BT applicators

There are several applicators that may be used in various clinical scenarios. The ring and tandem is the most common device for intact cervical cancer. The tandem is placed in the cervical canal while the ring is placed inside the vaginal fornices. Tandem and ovoids are utilized similarly but are preferred in patients with a barrel-shaped cervix. Interstitial applicators such as the Syed template can be used in patients with extensive parametria involvement, pelvic sidewall involvement, lower vaginal involvement, or vaginal cuff recurrence. Tandem and cylinder applicators can be used in cases of vaginal stenosis, inability to place a ring or ovoid, or lower vaginal involvement less than 5 mm thick. Modifications to the tandem and ring or vaginal cylinder can also be made to accommodate interstitial needles. [62] [63]

Patient discomfort experienced during the procedure can lead to suboptimal placement of the applicator, longer procedure times, and distress for the patient. An anesthetic is typically required to help optimize patient comfort and procedure mechanics. The types of anesthesia administered vary but may include general anesthesia, spinal anesthesia, epidural anesthesia, intravenous conscious sedation, and oral pain medication.

Placement of an intracavitary applicator for an intact cervix

The patient is placed in the dorsal lithotomy position in stirrups. After adequate sterile preparation of the area, a Foley catheter is inserted, and the balloon is inflated with dilute contrast to allow for detection with CT scan. A speculum is inserted to visualize the cervix, and a uterine sound is used to determine the length of the cavity. This will aid in determining the length and angle of the tandem. A Smit sleeve is occasionally used to maintain the patency of the cervical os but, if not available, serial dilations may be required. Once this is complete, the tandem is inserted, followed by the ring or ovoid. Fiducial markers may also be placed during the procedure to outline the extent of the disease or the opening of the cervical os so it is visible on CT scan. These applicators can be locked so their relative positions do not change.

Displacement of the bladder and rectum is critical to reduce the excess dose and limit toxicity. The packing material can consist of gauze soaked in a radiopaque solution. Applicators fitted with inflatable balloons or separate rectal blades are also available. Anterior packing displaces the bladder, whereas posterior packing displaces the rectum. It is essential to ensure no packing is placed in front of the ring or ovoids, as this will significantly reduce the intended dose.

Once complete, the patient will undergo a CT simulation for 3-D BT planning. Three-dimensional CT-based planning has been shown to have improved overall survival (65% vs 74%) and lower rates of grades 3 to 4 toxicity (23% vs 3%) compared with 2-D planning. [64]   A 1- to 5-mm slice thickness is recommended. [62] [63] More recently, MRI-guided BT has been incorporated into planning for improved tissue delineation, best seen on the T2-weighted fat-suppressed sequences (T2–fast-spin echo) imaging. [65]

Paraxial and para-coronal images should be obtained concerning the cervix-uteri and sagittal images. [66]  These images can also allow for the assessment of chemoradiation response.   Technically, low- and high-intensity magnetic field MRI machines can be used. Patients can be given glucagon before MRI to reduce bowel motion. A pelvic coil is recommended to increase the signal-to-noise ratio. Ideally, a 3-mm slice thickness should be obtained, which helps improve the detection of parametrial involvement, but a slice thickness of less than 5mm is acceptable. The disadvantages of this approach are the increased costs, longer procedure times, and the need for strict compatibility of the materials utilized.

Proper applicator placement should be confirmed with plain radiography or more advanced imaging such as a CT scan or MRI. Adequate placement includes the tandem bisecting the ring/ovoids on AP and lateral imaging, the tandem being one-third to one-half the distance between the sacral promontory and the pubic symphysis, the tip of the tandem being below the sacral promontory, no packing located superior to the ring/ovoids, and no inferior displacement of the ring/ovoids relative to the flange. 

With HDR BT, a remote afterloading technology allows a small iridium source attached to the end of a cable to be robotically driven through multiple channels, stopping at predetermined points (dwell positions) for varying lengths of time. [67]  A Cochrane review failed to show differences between HDR and low dose-rate (LDR) intracavitary brachytherapy (ICBT). Oncologic outcomes included overall survival, disease-free survival, and recurrence-free survival, as well as local control rate, recurrence, and metastasis. There was no difference in treatment-related complications. Regardless, this review recommends HDR ICBT for all clinical stages of cervix cancer due to the advantages of HDR ICBT, including accuracy of the source, applicator positioning, outpatient treatment, and patient convenience. [68]

BT target delineation

As part of 3-D–based planning, contouring the targets is essential. The Groupe Européen de Curiethérapie and the European Society for Radiotherapy and Oncology (GEC-ESTRO) have established standardized terminology regarding target delineation. [66] The high-risk clinical target volume (HR-CTV) consists of the entire cervix and all gross disease at the beginning of BT treatment; the intermediate-risk clinical target volume (IR-CTV) incorporates the HR-CTV and gross disease before any treatment; and the low-risk clinical target volume (LR-CTV), which includes the IR-CTV as well as the entire uterus, upper vagina, entire parametria, and spaces between the bladder and rectum. [69]  Normal OAR should be contoured, including the bladder, rectum, sigmoid colon, and vagina.

BT dose and dose constraints

Ensuring adequate dose to the target is critical and has been shown to lead to improved local control and survival. Dose and fractionation schemes may vary by institutional preference, but they must result in a total equivalent dose in 2 Gy fractions (EQD2) of 85 Gy or higher, assuming 45 Gy was initially delivered to the pelvis. There are several calculators to determine EQD2. One of these, colloquially known as the “Vienna Spreadsheet,” was used by the Effects of a Multifaceted Intervention on Blood Pressure Actions in the Primary Care Environment (EMBRACE) trial group; it provides EQD2 calculations to the target structures and OAR. The most common dose fractionation schemes include 4 x 7 Gy, 5 x 6 Gy, and 6 x 5 Gy, with an EQD2 of approximately 90.1, 88.6, and 83.7 Gy, respectively.

For 3D-based planning, the critical dosimetric parameter is the D90 greater than or equal to 90%. The goal is for 90% of the HR-CTV to be covered by at least 90% of the prescription dose. The EQD2 should be calculated to ensure the total dose received is approximately 85 Gy or higher, although there are instances in which it is acceptable for the EQD2 to be slightly lower. In patients with a complete response before BT or partial response with less than 4 cm in residual disease, an EQD2 above 80 Gy may be used, whereas for those patients with more than 4 cm residual disease, an EQD2 greater than 85 Gy is recommended. [62] [63]

Despite the transition to 3D-based volumetric planning and the continued evolution of BT treatment, 2-D dosimetric reporting systems persist and should be understood. Point A, where the uterine artery crosses the ureter, is located 2 cm up the tandem and 2 cm lateral to the tandem and was originally part of the Manchester system. This point was traditionally where the prescription dose was prescribed, but more recently has become a starting point where dose coverage can be further manipulated in 3-D to ensure coverage of the HR-CTV. Point B, also part of the original Manchester system, is located 2 cm up the tandem and 5 cm from the patient’s midline. This location represents the pelvic side wall lymphatics and typically receives one-third of the prescription dose. It has fallen out of favor and is no longer reported. The isodose lines for typical tandem and ring/ovoid implant should appear pear-shaped. In addition, the International Commission on Radiation Units and Measurements (ICRU 38) specified a bladder and rectal point. The bladder point is located posterior to the Foley balloon that has been pulled down to the neck of the bladder. The rectal point is 5 mm posterior to the vaginal wall.

Doses to OAR must also be carefully documented. Again, it is the cumulative dose of EQD2 that is critical. The dosimetric parameter D2 cc, which represents the highest dose received by 2 ccs of tissue, is commonly used for evaluating a BT plan. The American Brachytherapy Society (ABS) guidelines allow for the D2 cc of the bladder to receive 90 Gy or less EQD2, whereas the D2 cc of the rectum and sigmoid should be 75 Gy or less EQD2. However, recent data suggest that late rectal morbidity may be substantially lower even using a D2 cc of 65 Gy or less. [70]

Radiation Therapy Complications

Long-term toxicity is a concern with any patient receiving radiation therapy. Bowel, rectal, and urinary complications are the most frequent. There does not appear to be a difference in the frequency or severity of complications with respect to age. The greatest risk of late sequelae typically occurs within 3 years of treatment.

Radiation proctitis can result in tenesmus and intermittent bleeding with bowel movements. Postradiation proctitis typically occurs 3 months after treatment at the earliest but may take years to develop. Treatments can include mesalamine or steroid-based suppositories to relieve pain and stop bleeding. Randomized trials have suggested that mesalamine may be slightly more efficacious than steroid-based suppositories. [71]  Other treatments can include a 4% formaldehyde application to control rectal bleeding. In refractory cases, argon plasma laser coagulation may be performed on the offending vessels.

Radiation cystitis can lead to dysuria, urinary frequency, and, in some cases, hematuria. This complication can occur acutely within 2 to 3 weeks of starting radiotherapy and up to 3 years posttreatment.

For acute cystitis, a urinary tract infection must be ruled out; therefore, a urinalysis is an appropriate first step in the diagnosis. A short course of phenazopyridine can be prescribed for dysuria relief, although the urine color change may be alarming for some patients. Patients should be made aware of this change before starting the medication. Urinary frequency can be treated with anticholinergic drugs such as oxybutynin or mirabegron, although caution is advised in elderly patients.

Chronic cystitis has an incidence of 5% to 10%. [72] These patients are more likely to experience hematuria in addition to frequency and dysuria. The severity can range from mild to severe and life-threatening. Mildly symptomatic patients may be managed conservatively. Any antiplatelet or anticoagulation medications the patient takes should be reviewed, and the necessity questioned. A cystoscopy with clot evacuation and irrigation is necessary in more severe cases. During a cystoscopy, formalin instillation can be used to manage intractable hematuria. In refractory cases, hyperbaric oxygen therapy has been utilized and shown to relieve and control bleeding in 92% of patients; however, recurrences may occur. [73]  Barotrauma is a risk associated with this procedure.

Secondary malignancy

Radiation-induced cancers tend to appear several decades after treatment. The overall risk of secondary malignancy is increased with pelvic radiotherapy compared to those treated with surgery alone. Women younger than 50 years had a 40-year cumulative risk of 22% versus 16% for those older than 50 years. [74]  Secondary cancers tend to be confined to the rectum, bladder, lungs, and genitals. Other retrospective studies have shown an increase in leukemia risk, which peaks around 5 to 10 years after treatment. [75] Limiting normal organ doses may help to reduce the risk. 

Ovarian failure

Radiation-induced ovarian failure typically occurs within 6 to 12 months after radiation. Minimum doses for ovarian failure are inversely related to age ranging from 20.3 Gy at birth to 14.3 Gy at the age of 30 years. [76] The doses used for cervical cancer can easily precipitate ovarian failure. Premenopausal patients have several options for preserving ovarian function, namely definitive surgery or ovarian transposition. Laparoscopic ovarian transposition allows the ovaries to be placed outside the radiation field, usually 3 cm away. This procedure is also useful for fertility preservation. The functional preservation rate is approximately 80%. Ovarian cryopreservation is another option. Exogenous hormonal supplementation with estrogen should be considered to prevent osteoporosis and osteopenia and to maintain libido.

Vaginal stenosis

Vaginal stenosis and vaginal canal shortening can develop over months to years after treatment. Stenosis can make it difficult for intercourse and gynecological exams. Consistent use of a vaginal dilator is typically recommended; however, compliance is highly variable. Sexual dysfunction is quite common, ranging from a lack of desire for sexual activity to a lack of adequate vaginal lubrication.

Bone fracture

Pelvic radiotherapy can increase the risk of pelvic fractures, with most fractures occurring at dose levels of 45 to 63 Gy. Bone health is another concern in patients who undergo radiation to the pelvis. Approximately 10% of patients radiated for cervical cancer experience a pelvic fracture. The most common fracture site is the sacrum, most occurring within 2 years after treatment. Bone mineral density scans and appropriate intervention to maintain bone health may help to reduce this risk.

Uterine perforation

Uterine perforation is a complication related to BT applicator insertion and results in excessive doses to normal tissues, poor target coverage, bleeding, and infection. Rates of perforation range from 2% to 18%. [77] [78] [79]  Management is controversial, ranging from postponement of BT to allow for healing to outright abandonment of the procedure. However, treatment delays are known to adversely affect patient outcomes. The risk of vascular and organ injury is low when a blunt instrument causes perforation. Stable patients without signs of infection may be discharged and observed. Prophylactic antibiotics may be prescribed. Signs of hemodynamic instability and infection warrant more aggressive approaches with IV fluids, antibiotics, and surgical exploration.

• Medical Oncology

Definitive Therapy

The Radiation Therapy Oncology Group (RTOG) trials established the utility of platinum-based chemotherapy regimens. Compared with radiotherapy alone, there are consistent overall survival, disease-free survival, and local control advantages. [51] It is postulated that chemotherapy acts as a radiosensitizer. The most common agent used is weekly cisplatin. Single-agent platinum-based regimens have the best progression-free survival and overall survival compared to non-platinum-based regimens and a better toxicity profile than combinations of platinum-based regimens such as cisplatin/5-FU/hydroxyurea. [80] Carboplatin may also be used in patients who cannot tolerate cisplatin. Some practices continue to use a combination of cisplatin/5-FU. This regimen is delivered concurrently with radiotherapy.

Adjuvant Therapy Chemoradiotherapy may be added after surgical resection should the patient have high-risk features. Overall survival and progression-free survival benefits have been demonstrated with the addition of chemotherapy to radiotherapy in certain high-risk postoperative patients. [54]

The use of adjuvant chemotherapy after definitive chemoradiation continues to be investigated in clinical trials. The results have been mixed. Adding adjuvant carboplatin/taxol to chemoradiation for locally advanced cervical cancer resulted in higher rates of grades 3 to 5 toxicity and no difference in overall survival or progression-free survival. Another trial using concurrent and adjuvant cisplatin/gemcitabine demonstrated improved 3-year progression-free survival but markedly higher rates of grades 3 to 4 toxicity and hospitalizations. [81] RTOG 0724 is an ongoing trial investigating the use of adjuvant cisplatin/paclitaxel after definitive chemoradiation in high-risk postoperative patients (NCT00980954).

Recurrence and Metastasis

In recurrent and metastatic disease settings, patients who are not candidates for exenterative surgery or radiotherapy may receive systemic therapy alone. Many patients have previously received single-agent cisplatin-based therapy; therefore, multidrug regimens are typically used. Cisplatin/paclitaxel has been shown to improve progression-free survival in patients with recurrent cervical cancer but yields no difference in median overall survival. [82]  Although other drug combinations such as cisplatin/topotecan, cisplatin/gemcitabine, and cisplatin/vinorelbine are potential options, the Gynecologic Oncology Group (GOG) has suggested that these regimens are not superior to cisplatin/paclitaxel (protocol 204). [83]  Incorporating biological agents such as vascular endothelial growth factor receptor antagonists like bevacizumab into standard chemotherapeutic regimens has improved overall survival. [84]  Immunotherapy with PD-1 inhibition has also been incorporated into chemotherapeutic regimens. Single-agent pembrolizumab has an objective response rate of 12% to 14% in patients with recurrent or metastatic cervical cancer. [85]  Keynote-826, a randomized, double-blinded phase 3 study, demonstrated the addition of pembrolizumab to multidrug chemotherapy improved overall and progression-free survival. [86]  Follow-up subgroup analysis confirmed this finding in a Japanese population. [87]

• Complications

The most commonly used platinum-based drugs are cisplatin and carboplatin. Common adverse effects include neutropenia, thrombocytopenia, anemia, febrile neutropenia, nephrotoxicity, neurotoxicity, and infection. Although cisplatin is the drug of choice, carboplatin can be used in patients who may not tolerate cisplatin, particularly if they already have underlying renal disease.  Carboplatin is thought to have lower efficacy than cisplatin; however, prospective data suggest noninferiority in effectiveness and a statistically significant lower incidence of febrile and nonfebrile neutropenia and creatinine elevation. [88]

Bevacizumab carries the risk of hypertension, hemorrhage, thromboembolic events, renal injury, and ovarian failure in premenopausal women. Pembrolizumab is known for precipitating autoimmune phenomena such as pneumonitis, colitis, hepatitis, nephritis, and endocrinopathies.

The International Federation of Gynecology and Obstetrics (FIGO) staging system was updated in 2018 and remains the dominant staging methodology. The 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual also has a tumor-node-metastasis classification system in which the tumor stages correspond with the FIGO stages; however, it is not regularly used.

FIGO Staging

Classically, FIGO staging would rely on clinical examination, cystoscopy, proctoscopy, hysteroscopy, urography, and plain film x-ray. These relatively basic tests were utilized so developing countries with fewer healthcare resources could adequately stage patients. More recently, advanced imaging techniques such as MRI and PET scans have become part of the staging workup. MRI is preferred for establishing the tumor stage, given superior tissue delineation compared with CT scan with contrast. [89] [90]

Stage I  

• The disease is strictly confined to the cervix, with the A/B designation indicating the depth of invasion (≤5 or >5 mm).

Stage II  

• The disease invades beyond the uterus but has not extended into the lower vagina.
• This stage also has an A/B designation based on involvement of the parametria.

Stage III  

• The disease has extended to the lower one-third of the vagina (IIIA) or to the pelvic side wall and/or hydronephrosis (IIIB).

Classically, nodal disease did not influence the FIGO staging system; however, it has been shown that nodal disease is one of the most important prognostic indicators for reduced 5-year overall survival. [91]  As a result, new stages (IIIC1 and IIIC2) were added to reflect the involvement of pelvic or PA nodes, respectively.

Stage IVA  

• The disease is locally aggressive, involving adjacent organs such as the bladder or rectum. 

Stage IVB  

• The disease has spread to other solid distant organs; this stage can also be indicative of nonregional nodal disease.

Multiple factors contribute to differences in patient outcomes. Potential prognostic factors for cervical cancer patients include disease stage, number of retrieved lymph nodes, use of a uterine manipulator in laparoscopic treatment, age, race, ethnicity, general health before diagnosis, and access to evidence-based care. These prognostic factors highlight opportunities to enhance care and improve overall mortality.

When diagnosed early, the 5-year relative survival rate for cervical cancer is approximately 92%. About 44% of cervical cancer patients are diagnosed at an early stage. Inconsistent screening is an independent risk factor for late diagnosis. [92]  A higher stage at presentation decreases survival and increases the chance of recurrence. The 5-year relative survival rate drops to 60% when cervical cancer is diagnosed after it has spread locally or spread to regional lymph nodes. With distant metastasis at diagnosis, the 5-year relative survival rate is 19%.

Studies show certain surgical factors affect survival. It is believed that the number of retrieved lymph nodes corresponds to the thoroughness of surgical treatment. Research indicates that a higher retrieved lymph node count has a statistically significant positive effect on progression-free survival. For women having laparoscopic surgery, the use of a uterine manipulator is associated with a better prognosis. [93]

Survival rates also differ based on race. The 5-year relative survival rate is 67% for women of all races. Black women tend to have the highest mortality and lowest survival rate, with a 5-year relative survival rate of approximately 56%. [11] [94]

Patient age at diagnosis also contributes to differences in prognosis and survival, independent of disease stage and histology. Older age is associated with lower survival rates. Patients younger than 50 years, aged 50 to 64 years, and 65 years and older have relative 5-year survival rates of 77%, 61%, and 46%, respectively. Studies indicate older women are a high-risk subset, often receive suboptimal treatment, and die more frequently. Even with BT alone, older women with cervical cancer obtain significant survival benefits. [95]

Complications of advanced disease and associated treatments are similar to other cancers. These late complications may include renal failure, hydronephrosis, pain, lymphedema, bleeding disorders, and fistulas (see Image. Secondary Lymphedema). [96]

• Deterrence and Patient Education

Traditional and innovative patient education methods can increase overall awareness of cervical cancer and the need for prevention and early screening. [97] [98]  Literature shows that healthcare professionals may not consistently recommend or discuss HPV vaccination with all target patients. Some women and parents of young daughters may also have reservations about vaccinations that prevent them from being vaccinated. Additional medical education for clinicians serving high-risk populations may increase awareness, prevention, and screening of those patients at risk for the highest mortality. [99]  

Although a patient may prefer counseling directly from the healthcare professional, additional community outreach efforts are necessary. Culturally sensitive information, appropriate language to reach lower health literacy populations, and targeted efforts to reach women not yet sexually active are needed to expand patient awareness and education and to initiate screening beyond the clinical setting. [100] [101]

• Pearls and Other Issues

Primary prevention of cervical cancer involves HPV vaccination to prevent cervical cancer. The estimated effectiveness of HPV vaccination is 90%. [102]  A quadrivalent vaccine that prevents cervical cancer and genital warts caused by low-risk HPV types is widely available in the United States. The recommended and approved age for vaccination is 9 to 45 years for both females and males. Vaccination can significantly impact cervical cancer mortality in women in low-resource areas and those in high-risk racial and ethnic groups. A vaccine covering only HPV-16 and -18 is no longer marketed in the United States. However, its use may continue in areas outside the United States.

• Enhancing Healthcare Team Outcomes

The interprofessional team can provide public health education and multidisciplinary care to improve cervical cancer awareness, prevention, screening, and management. [103] [104] [105]  Primary care clinicians performing cervical cancer screening, colposcopies, and LEEP procedures, must have ongoing dialogues with gynecologists about findings of suspicious cervical lesions, management, and treatment. Appropriate protocols and guidelines across healthcare systems can improve outcomes by optimizing treatment and follow-up. Developing a culturally sensitive system directed at increasing patient-centered education will require the input of diverse healthcare professionals and staff with multilingual skills and cross-cultural competency.

The interprofessional team can optimize the treatment of patients with cervical cancer through communication and coordination of care. Primary care physicians, gynecologists, gynecologic oncologists, radiation oncologists, and advanced practice practitioners provide diagnoses and care plans. Specialty care, ambulatory care, and oncology nurses should work with the team to coordinate care, support patient education, and provide feedback to the rest of the team. Pharmacists should evaluate vaccinations and medications, recognize drug-to-drug interactions, provide patient education, and monitor compliance. Together, the team can improve outcomes for patients with cervical cancer. 

• Review Questions
• Access free multiple choice questions on this topic.
• Comment on this article.

Invasive Cervical Cancer. Colposcopic view of the cervix in a patient with invasive cervical cancer. Centers for Disease Control and Prevention (CDC)

Secondary Lymphedema. Lymphedema related to cervical cancer treatment. Contributed by Molly Nettles, OTR/L, CLT-LANA

Disclosure: Josephine Fowler declares no relevant financial relationships with ineligible companies.

Disclosure: Elizabeth Maani declares no relevant financial relationships with ineligible companies.

Disclosure: Charles Dunton declares no relevant financial relationships with ineligible companies.

Disclosure: David Gasalberti declares no relevant financial relationships with ineligible companies.

Disclosure: Brian Jack declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Fowler JR, Maani EV, Dunton CJ, et al. Cervical Cancer. [Updated 2023 Nov 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

In this Page

Bulk download.

• Bulk download StatPearls data from FTP

Related information

• PMC PubMed Central citations
• PubMed Links to PubMed

Similar articles in PubMed

• Cervical Cancer (Nursing). [StatPearls. 2024] Cervical Cancer (Nursing). Fowler JR, Maani EV, Dunton CJ, Gasalberti DP, Jack BW, Miller JL. StatPearls. 2024 Jan
• Atypical Squamous Cells of Undetermined Significance. [StatPearls. 2024] Atypical Squamous Cells of Undetermined Significance. Ndifon CO, Al-Eyd G. StatPearls. 2024 Jan
• Review Screening for Cervical Cancer With High-Risk Human Papillomavirus Testing: A Systematic Evidence Review for the U.S. Preventive Services Task Force [ 2018] Review Screening for Cervical Cancer With High-Risk Human Papillomavirus Testing: A Systematic Evidence Review for the U.S. Preventive Services Task Force Melnikow J, Henderson JT, Burda BU, Senger CA, Durbin S, Soulsby MA. 2018 Aug
• Anal dysplasia screening: an evidence-based analysis. [Ont Health Technol Assess Ser....] Anal dysplasia screening: an evidence-based analysis. Medical Advisory Secretariat. Ont Health Technol Assess Ser. 2007; 7(4):1-43. Epub 2007 Jun 1.
• Review Screening for Cervical Cancer: A Decision Analysis for the U.S. Preventive Services Task Force [ 2011] Review Screening for Cervical Cancer: A Decision Analysis for the U.S. Preventive Services Task Force Kulasingam SL, Havrilesky L, Ghebre R, Myers ER. 2011 May

Recent Activity

• Cervical Cancer - StatPearls Cervical Cancer - StatPearls

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Connect with NLM

National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894

Web Policies FOIA HHS Vulnerability Disclosure

Help Accessibility Careers