Review Reports - Global and Regional Diagnostic Results of Progress Toward Cervical Cancer Elimination, According to the WHO Strategy: A Systematic Review

Round 1

Reviewer 1 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

Gentle Authors,

thank you for addressing my suggestions. In this form the article is suitable for publication after minor revisions. In particular i suggest to remove the bullet lists in the final section and to make the table more synthic.

Thank you

Author Response

Response to Reviewer 1

We would like to sincerely thank the reviewer for the careful evaluation of our manuscript and for the constructive comments and valuable suggestions provided. The feedback was highly appreciated and contributed to improving the clarity, structure, and overall presentation of the manuscript. All comments were carefully considered and addressed, and the corresponding revisions are detailed below. In addition, the manuscript was carefully reviewed for English language quality by a native English-speaking colleague.

General comment 1: Ensure all references are relevant to the content of the manuscript.

Response: All references were carefully re-evaluated for relevance and scientific alignment with the topic of cervical cancer elimination under the WHO strategy. References were reviewed and revised where necessary to ensure consistency with the manuscript’s objectives and content.

General comment 2: Highlight any revisions to the manuscript, so editors and reviewers can see any changes made.

Response: All revisions made to the manuscript are clearly highlighted using the Track Changes function in Microsoft Word, allowing editors and reviewers to easily identify the modifications introduced in the revised version.

Comment 1:

’’Gentle Authors, thank you for addressing my suggestions. In this form the article is suitable for publication after minor revisions. In particular I suggest to remove the bullet lists in the final section and to make the table more synthetic. Thank you.’’

Response: Thank you very much for your positive evaluation and constructive suggestions. The bullet lists in the final section were removed and reformulated into narrative text, and Table 1 was revised into a more synthetic format.

We once again thank the reviewer for the thorough evaluation of our manuscript and for the constructive and insightful comments provided. We hope that the revised version now addresses the points raised and meets the standards required for publication. We would be pleased to provide any further clarifications if needed.

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

Luca et al. have presented a systematic review of global and regional progress toward cervical cancer elimination under the WHO 90-70-90 strategy, based on 47 included studies and reports identified from searches of PubMed, Web of Science, GLOBOCAN, IARC, ASCO, and ESMO covering the period from November 2020 to December 2024. The manuscript highlights substantial geographic variation, showing that countries with sustained investment in vaccination, organized screening, and treatment infrastructure, such as Australia and Canada, have achieved more favorable outcomes, whereas several countries in Eastern Europe, parts of Asia, and many regions in sub-Saharan Africa remain well below WHO targets, with low vaccination coverage, limited screening participation, and a persistently high cervical cancer burden. Overall, the review concludes that cervical cancer elimination is achievable, but that progress remains highly uneven and depends on strong health systems, high vaccine uptake, organized HPV-based screening, timely treatment, and equitable access to prevention and care.

The manuscript addresses an important and timely public health topic and provides a broad overview of global and regional progress toward cervical cancer elimination under the WHO 90-70-90 strategy. The review brings together data from multiple regions and highlights major disparities in vaccination, screening, and treatment outcomes. The topic is highly relevant, and the manuscript has the potential to offer a useful international perspective for readers. However, the current version would benefit from substantial revision to improve methodological rigor, accuracy, and clarity. Several statements require more precise documentation, some epidemiological figures appear inaccurate or insufficiently qualified, and important distinctions between screening methods are not always made clear. In addition, the evidence synthesis relies heavily on secondary sources, including narrative reviews, which limits the strength of the conclusions. Overall, the manuscript has merit, but revision is needed to ensure that the review is methodologically sound, factually accurate, and more consistent in its interpretation of the available evidence.

Comments

1. In Table 1, the authors list the publications included in the review; however, a substantial proportion of these appear to be narrative reviews or other secondary sources rather than original studies. This is a major methodological concern. In a systematic review, the evidence synthesis should primarily be based on original studies and primary data sources, not on previous reviews. Reliance on secondary literature increases the risk of overlap, selective interpretation, and duplication of evidence. The authors should therefore clarify their inclusion strategy and justify why so many review articles were included. Ideally, the review should be revised to focus on original studies, registry-based reports, and other primary sources that directly document progress toward the WHO cervical cancer elimination targets.

2. The authors state in the Introduction that “Screening is a key element in reducing the incidence and death rates of cervical cancer, with research showing a drop of over 70% when Pap testing and HPV testing have been successfully implemented [3].” This statement should be revised for accuracy and better documentation. First, cervical cytology and HPV testing are not equivalent as primary screening methods. Although organized cytology-based screening has clearly reduced cervical cancer incidence in several countries (Peto et al. 2004), HPV-based screening is more sensitive and provides greater protection against invasive cervical cancer. This is also reflected in the WHO recommendation of HPV testing, rather than cytology, as the preferred primary screening method. In the pooled follow-up of four European randomized trials, HPV-based screening provided 60–70% greater protection against invasive cervical carcinoma than cytology alone (Ronco et al., 2014). Similarly, in the cluster-randomized trial from rural India, a single round of HPV testing was associated with a significant reduction in advanced cervical cancer and cervical cancer mortality, whereas no significant reduction in advanced disease or mortality was observed in the cytology arm (Sankaranarayanan et al., 2009). Second, reference 3 (Debbie et al., 2016) is not an appropriate citation for this statement, as it addresses HPV vaccination guidelines rather than the comparative performance of cytology and HPV testing in cervical screening. The authors should therefore revise the sentence and replace the current reference with more relevant screening literature.

Peto J, Gilham C, Fletcher O, Matthews FE. The cervical cancer epidemic that screening has prevented in the UK. Lancet. 2004 Jul 17-23;364(9430):249-56. doi: 10.1016/S0140-6736(04)16674-9. PMID: 15262102.

Ronco G, Dillner J, Elfström KM, Tunesi S, Snijders PJ, Arbyn M, Kitchener H, Segnan N, Gilham C, Giorgi-Rossi P, Berkhof J, Peto J, Meijer CJ; International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014 Feb 8;383(9916):524-32. doi: 10.1016/S0140-6736(13)62218-7. Epub 2013 Nov 3. Erratum in: Lancet. 2015 Oct 10;386(10002):1446. doi: 10.1016/S0140-6736(15)00411-0. PMID: 24192252.

https://www.who.int/europe/news/item/11-09-2021-who-recommends-dna-testing-as-a-first-choice-screening-method-for-cervical-cancer-prevention

Sankaranarayanan, R.; Nene, B.M.; Shastri, S.S.; Jayant, K.; Muwonge, R.; Budukh, A.M.; Hingmire, S.; Dinshaw, K.A. HPV Screening for Cervical Cancer in Rural India. N. Engl. J. Med. 2009, 360, 1385–1394. https://doi.org/10.1056/NEJMoa0808516

3. In Figure 3, the authors present “HPV vaccination rates by region” and describe these as the estimated vaccination coverage rates for women in 2023. This wording is unclear and likely misleading, as the reported proportions appear too high to represent coverage among all women. The figure legend should therefore clearly specify the population and age group to which these estimates apply, for example girls or young women within a defined target age range. In addition, the statement in the Results section that HPV vaccination is “ineffective in many regions of the world” is inaccurate. The problem is not that the vaccine is ineffective, but rather that vaccine uptake and program implementation remain insufficient in many settings. Finally, the authors should revise the description of vaccine impact. HPV vaccination does not only reduce HPV infections and early cervical lesions in young women; with adequate uptake and sufficient follow-up time, it is also expected to reduce high-grade cervical lesions and, ultimately, cervical cancer in women vaccinated before exposure to HPV.

4. The statement in the Results section (Section 3.3) that “educational campaigns, such as those carried out in France and the Netherlands, have led to an increase in vaccination rates by 20% in the last five years” should be clarified. Reporting a “20% increase” without providing the baseline and follow-up coverage is not sufficiently informative, as the interpretation differs substantially depending on whether coverage increased, for example, from 20% to 40% or from 60% to 80%. In addition, the time period should be stated explicitly using calendar years rather than the vague expression “the last five years,” particularly if the cited references are not recent. The authors should therefore provide the exact coverage estimates before and after the intervention, specify the relevant years, and ensure that the statement is supported by appropriate and up-to-date references.

5. The statement that “Japan has reported a vaccination coverage of approximately 80%” appears inaccurate or, at minimum, insufficiently qualified. Japan experienced a marked decline in HPV vaccination uptake after the governmental suspension of proactive recommendation in 2013, and coverage remained very low for many affected birth cohorts. In a nationwide analysis, Yagi et al. reported HPV vaccination coverage of 53.3%-79.5% for birth fiscal years 1994-1999, but only 0.84%-25.2% for birth fiscal years 2000–2010, and concluded that coverage in Japan remained below the WHO target even after resumption of active recommendation. Official Japanese sources likewise state that coverage remained around 1% during the suspension period and has not yet sufficiently recovered. Recent MHLW data also show that cumulative first-dose coverage around 80% is limited to selected pre-suspension cohorts, whereas many later cohorts remain substantially lower. The authors should therefore revise this statement and specify clearly whether the reported 80% refers only to selected historical birth cohorts rather than to Japan overall.

Yagi A, Ueda Y, Oka E, Nakagawa S, Kimura T. Human Papillomavirus Vaccination by Birth Fiscal Year in Japan. JAMA Netw Open. 2024 Jul 1;7(7):e2422513. doi: 10.1001/jamanetworkopen.2024.22513. PMID: 39012629; PMCID: PMC11252895.

Nakagawa S, Ueda Y, Yagi A, Ikeda S, Hiramatsu K, Kimura T. Corrected human papillomavirus vaccination rates for each birth fiscal year in Japan. Cancer Sci. 2020 Jun;111(6):2156-2162. doi: 10.1111/cas.14406. Epub 2020 Apr 27. PMID: 32248632; PMCID: PMC7293087.

Haruyama R, Obara H, Fujita N. Japan resumes active recommendations of HPV vaccine after 8·5 years of suspension. Lancet Oncol. 2022 Feb;23(2):197-198. doi: 10.1016/S1470-2045(22)00002-X. PMID: 35114115.

Ujiie M. Resumption of active recommendation of the human papillomavirus vaccine in Japan and future challenges for the National Immunization Program. Hum Vaccin Immunother. 2022 Nov 30;18(6):2090777. doi: 10.1080/21645515.2022.2090777. Epub 2022 Jun 29. PMID: 35767827; PMCID: PMC9746481.

6. The statement that “In Japan, screening participation reached 70%, while Indonesia and India have reported screening coverage below 30%” should be clarified by specifying which screening method was used in each setting, since screening coverage is difficult to interpret without distinguishing between HPV testing, cervical cytology, and VIA. These methods differ substantially in performance, evidence base, and expected impact. WHO now recommends HPV-based testing as the preferred primary screening method rather than cytology or VIA, because HPV testing is more effective and provides better protection against cervical cancer. The authors should therefore report the screening modality together with the coverage figures and avoid presenting these data as directly comparable if different methods were used across countries.

7. The paragraph on Australia should be revised for accuracy and clarity. Australia replaced cytology-based primary screening with HPV testing in December 2017 as part of the renewed National Cervical Screening Program. Liquid-based cytology is not used as a parallel primary screening test, but mainly as a triage test for HPV-positive women. Therefore, the statement that screening participation “reached 73% for HPV testing and 63% for liquid cytology” is confusing and likely incorrect, or at least insufficiently explained. The authors should clarify exactly what these two coverage estimates refer to, specify whether the liquid-based cytology figure represents triage testing rather than primary screening, and ensure that participation data are reported consistently with the Australian screening program. Otherwise, the current wording may give the misleading impression that Australia still uses both HPV testing and liquid cytology as co-existing primary screening methods.

https://www.cancer.org.au/about-us/policy-and-advocacy/early-detection/cervical-cancer/screening

8. The manuscript contains duplicated information on Australia. Specifically, the data on HPV positivity and treatment of precancerous lesions in 2023 are reported first in lines 542–544 and then repeated almost verbatim in lines 571–573. In addition, the two surrounding paragraphs (lines 538–544 and 569–576) substantially overlap in content and should probably be merged or revised to avoid unnecessary repetition. The authors should consider presenting the Australian screening indicators and outcome data only once, in a single coherent paragraph.

9. The authors state that the mortality rate in Romania is 14.2 per 100,000 women. This figure should be verified and updated. According to GLOBOCAN 2022, Romania had an estimated 3,368 new cervical cancer cases and 1,793 deaths in 2022. The corresponding age-standardized incidence and mortality rates were 21.7 and 9.3 per 100,000 women, respectively. Therefore, the reported mortality rate of 14.2 per 100,000 does not appear to be consistent with the current GLOBOCAN 2022 estimates. In addition, the Romanian incidence estimate is modelled rather than based on direct national incidence data. The GLOBOCAN fact sheet states that no country-specific incidence data were available for Romania and that incidence was estimated from national mortality estimates using mortality:incidence ratios derived from cancer registry data in neighbouring countries. Mortality, in contrast, was based on national WHO mortality data projected to 2022. The authors should therefore revise this section, provide the correct figures, and specify clearly the source, year, and whether rates are age-standardized or crude.

Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263. doi: 10.3322/caac.21834. Epub 2024 Apr 4. PMID: 38572751.

International Agency for Research on Cancer. Romania fact sheet, GLOBOCAN 2022 (version 1.1). Global Cancer Observatory. Lyon: IARC; 2024. Available from Cancer Today.

https://gco.iarc.who.int/media/globocan/factsheets/populations/642-romania-fact-sheet.pdf

10. The authors state that “With incidence rates of 40 per 100,000 women and mortality rates of 27 per 100,000 women, cervical cancer continues to represent a major health burden in sub-Saharan Africa.” This statement appears to overestimate the current overall burden for sub-Saharan Africa and should be revised. According to the IARC GLOBOCAN 2022 fact sheet for sub-Saharan Africa, cervical cancer accounted for 118,013 new cases and 76,189 deaths in 2022, corresponding to an age-standardized incidence rate of 33.4 per 100,000 women and an age-standardized mortality rate of 22.6 per 100,000 women. Thus, the figures of 40 and 27 per 100,000 are higher than the current GLOBOCAN 2022 estimates for sub-Saharan Africa as a whole. WHO likewise states that the highest incidence and mortality rates occur in sub-Saharan Africa, but these are not given as 40 and 27 per 100,000 in the current regional overview. The authors should therefore either correct these figures or clarify that they refer to older estimates, selected high-burden countries, or specific subregions rather than sub-Saharan Africa overall.

A possible reformulation would be: “Cervical cancer continues to represent a major health burden in sub-Saharan Africa, where the age-standardized incidence and mortality rates were estimated at 33.4 and 22.6 per 100,000 women, respectively, in 2022.”

International Agency for Research on Cancer. Sub-Saharan Africa fact sheet, GLOBOCAN 2022. Global Cancer Observatory. Lyon: IARC; 2024.

https://gco.iarc.who.int/media/globocan/factsheets/populations/963-sub-saharan-africa-fact-sheet.pdf

World Health Organization. Cervical cancer fact sheet. Updated 2 December 2025.

https://www.who.int/news-room/fact-sheets/detail/cervical-cancer

https://www.afro.who.int/

Minor revisions

Lines 1-4, title, "Implementation of the WHO 90-70-90 Strategy for Cervical Cancer Elimination: A Global and Regional Systematic Review"

Lines 12-32, abstract, "Background/Objectives: In 2020, the World Health Organization (WHO) launched the 90-70-90 strategy to eliminate cervical cancer as a public health problem through high HPV vaccination coverage, effective screening, and timely treatment. This systematic review evaluated progress toward these targets across different world regions. Methods: A systematic search of PubMed, Web of Science, and major international cancer and oncology sources was performed for publications and reports issued between November 2020 and December 2024. Of 721 identified records, 47 studies and reports were included in the final analysis. Results: Marked regional variation was observed. Countries with sustained investment in vaccination, organized screening, and treatment infrastructure, such as Australia and Canada, reported more favourable outcomes, including high vaccine uptake or screening participation and lower cervical cancer incidence and mortality. In contrast, several countries in Eastern Europe, parts of Asia, and many regions in sub-Saharan Africa remained well below WHO targets, with low vaccination coverage, limited screening participation, and a persistently high cervical cancer burden. Progress was also hindered by major inequalities in access to healthcare, differences in screening modalities and program organization, and inconsistent availability of comparable national data. Conclusions: Cervical cancer elimination is achievable, but progress toward the WHO targets remains highly uneven. Long-term success depends on strong health systems, high vaccine uptake, organized HPV-based screening, timely treatment, and equitable access to prevention and care."

Lines 93-98, introduction, "Screening is a key component of cervical cancer prevention and has substantially reduced cervical cancer incidence and mortality in countries with organized screening programs. However, cervical cytology and HPV testing are not equivalent as primary screening methods. HPV-based screening is more sensitive than cytology, provides greater protection against invasive cervical cancer, and is now recommended by WHO as the preferred primary screening approach. Another essential pillar of cervical cancer prevention is HPV vaccination. In many regions, the main challenge is not lack of vaccine effectiveness, but low vaccine uptake and limited implementation of vaccination programs. In countries with high vaccine coverage and sufficient follow-up, HPV vaccination has reduced the burden of HPV infection, cervical precancer, and cervical cancer in vaccinated cohorts. (Figure 3)"

Lines 359-362, HPV vaccination, "Public funding for HPV vaccination in Japan began in 2010 for girls aged 12–16 years, and three-dose coverage initially exceeded 70% in some birth cohorts. After the suspension of proactive governmental recommendation in 2013, vaccine uptake declined sharply in subsequent cohorts, in some cases to below 1%. Although proactive recommendation resumed in 2022, nationwide data indicate only limited recovery, and vaccination coverage in many post-suspension cohorts remains far below both earlier Japanese levels and the WHO target. In contrast, countries such as Indonesia and India also continue to report relatively low HPV vaccination coverage, reflecting ongoing challenges related to access, affordability, and program implementation."

Lines 511-544, 3.3 Cervical Cancer Screening, "Marked regional differences were also observed in cervical cancer screening. In many Western European countries, organized population-based screening programs have increasingly adopted primary HPV testing at multi-year intervals for women aged 30 years and older, in line with WHO recommendations. These systems generally achieve better coverage, follow-up, and earlier detection than opportunistic or fragmented screening models. By contrast, several Eastern European countries continue to face lower participation, uneven program organization, and substantial regional disparities.

Across Asia, both screening participation and screening modality vary considerably. This distinction is important, because HPV testing, cervical cytology, and visual inspection are not equivalent screening methods. In Japan, cervical cancer screening has traditionally relied on cytology rather than primary HPV testing, and this should be specified when comparing participation rates with countries using other screening approaches. Several countries in Asia continue to face low screening uptake, delayed diagnosis, and marked inequalities in access to preventive services.

In sub-Saharan Africa, screening remains limited by shortages of infrastructure, trained personnel, laboratory capacity, and sustainable funding. These barriers contribute to low coverage and delayed diagnosis, particularly in rural and underserved communities. Similar challenges are seen in several parts of Latin America, where progress remains uneven because of financial, logistical, and geographic barriers to equitable screening access.

Australia illustrates the impact of long-term programmatic investment. The National Cervical Screening Program began in 1991, and the renewed program introduced HPV DNA testing with partial genotyping in December 2017, replacing the Pap test as the primary screening method. "

Lines 544-577, 3.4 Treatment, Incidence, and Outcomes, "The capacity to diagnose and treat precancerous lesions and cervical cancer differs markedly between regions. Regions with long-standing investment in vaccination, organized screening, pathology services, and timely treatment have achieved substantially better outcomes than regions where prevention and treatment remain fragmented or underfunded. This contrast highlights the importance of integrating vaccination, screening, diagnosis, and treatment within functioning health systems.

In Europe, Romania continues to carry a substantial cervical cancer burden. According to GLOBOCAN 2022, Romania had an estimated 3,368 new cervical cancer cases and 1,793 deaths in 2022, corresponding to age-standardized incidence and mortality rates of 13.7 and 9.3 per 100,000 women, respectively. These figures confirm a major burden, although they are lower than some of the values reported elsewhere in the manuscript.

Across Asia, large disparities also persist. Several countries continue to face a high cervical cancer burden because of limited vaccine uptake, low screening coverage, delayed diagnosis, and unequal access to treatment. These gaps are most evident where prevention programs remain opportunistic, under-resourced, or geographically uneven.

Sub-Saharan Africa remains the highest-burden region globally. According to GLOBOCAN 2022, the region accounted for 118,013 new cervical cancer cases and 76,189 deaths, with age-standardized incidence and mortality rates of 33.4 and 22.6 per 100,000 women, respectively. These figures underscore the continuing need to expand access to vaccination, HPV-based screening, pathology services, and timely treatment. (gco.iarc.who.int)

Latin America also continues to face important challenges related to financing, health-system fragmentation, and unequal access to screening and treatment, particularly in rural and underserved populations. Although some countries have strengthened national prevention efforts, progress remains uneven within and between countries.

Australia remains a leading example of successful cervical cancer prevention and control. Since the start of organized screening in 1991, cervical cancer incidence and mortality have approximately halved, and the renewed program has strengthened prevention further through HPV-based primary screening. Australia therefore illustrates how high vaccine uptake, organized screening, and timely management of precancerous lesions can translate into a low cervical cancer burden at the population level."

Lines 936-949, Limitations of the study, "This review has several important limitations. First, the availability, quality, and recency of data differed substantially across regions, which complicates direct comparison of progress toward the WHO elimination targets. Second, the included sources were methodologically heterogeneous and comprised registry-based reports, official documents, guidelines, narrative reviews, systematic reviews, and original studies. This heterogeneity limits the consistency of the evidence synthesis and, in some cases, means that conclusions were based on secondary rather than primary sources. Third, key indicators were not uniformly defined or reported across countries. Vaccination coverage was sometimes presented for different age groups, birth cohorts, or dose schedules, while screening data were often reported without clearly specifying the screening modality, such as HPV testing, cervical cytology, or visual inspection methods. Treatment indicators were also inconsistently reported, reducing the comparability of program performance between settings. In addition, some of the epidemiological estimates used in international databases are modelled rather than derived directly from national incidence data, which may affect the precision of country-level comparisons. Another limitation is the rapidly evolving nature of cervical cancer prevention programs. Interventions introduced or expanded close to the end of the study period could not be adequately evaluated because outcome data were not yet available. Finally, data extraction was performed by a single reviewer and subsequently checked by a senior team member. Although this approach provided an additional level of verification, it still carries a risk of selection bias and extraction errors compared with duplicate independent review."

Lines 951-972, Conclusions, "This review indicates that elimination of cervical cancer as a public health problem is achievable, but progress toward the WHO targets remains highly uneven across regions. The WHO strategy, built on vaccination, screening, and timely treatment, provides an important global framework, but its impact depends on effective implementation within strong and equitable health systems. Countries with sustained investment in vaccination programs, organized screening, diagnostic capacity, and access to treatment have demonstrated substantial reductions in cervical cancer burden. By contrast, many countries and regions continue to face major barriers related to infrastructure, financing, program organization, and unequal access to preventive and therapeutic services.

The findings also show that national progress cannot be understood solely in terms of policy adoption, but must be evaluated in relation to real-world coverage, follow-up, and treatment capacity. In this context, the contrast between high-performing countries and settings with persistent low vaccination uptake, limited screening coverage, and delayed treatment remains striking. Romania illustrates how a substantial disease burden may persist despite being part of a high-income regional framework, while several countries in sub-Saharan Africa, parts of Asia, and Latin America continue to face major structural challenges in implementing the full WHO strategy.

Overall, the results support a more cautious conclusion than simple global optimism. Cervical cancer elimination is not yet a universal reality, but it is a realistic and evidence-based goal in settings where vaccination, HPV-based screening, and treatment are implemented effectively and equitably. Future progress will depend not only on political commitment, but also on long-term investment in health systems, better data quality, and improved access to prevention and care for underserved populations."

Author Response

Response to Reviewer 2

General comment 1: Ensure all references are relevant to the content of the manuscript.

General comment 2: Highlight any revisions to the manuscript, so editors and reviewers can see any changes made.

Comment 1:

’’In Table 1, the authors list the publications included in the review; however, a substantial proportion of these appear to be narrative reviews or other secondary sources rather than original studies. This is a major methodological concern. In a systematic review, the evidence synthesis should primarily be based on original studies and primary data sources, not on previous reviews. Reliance on secondary literature increases the risk of overlap, selective interpretation, and duplication of evidence. The authors should therefore clarify their inclusion strategy and justify why so many review articles were included. Ideally, the review should be revised to focus on original studies, registry-based reports, and other primary sources that directly document progress toward the WHO cervical cancer elimination targets.’’

Response: The inclusion strategy was clarified in the Materials and Methods section, and Table 1 was revised into a more synthetic and transparent format. The heterogeneity of the included evidence was also acknowledged in the revised manuscript.

Comment 2:

’’The authors state in the Introduction that “Screening is a key element in reducing the incidence and death rates of cervical cancer, with research showing a drop of over 70% when Pap testing and HPV testing have been successfully implemented [3].” This statement should be revised for accuracy and better documentation. First, cervical cytology and HPV testing are not equivalent as primary screening methods. Although organized cytology-based screening has clearly reduced cervical cancer incidence in several countries (Peto et al. 2004), HPV-based screening is more sensitive and provides greater protection against invasive cervical cancer. This is also reflected in the WHO recommendation of HPV testing, rather than cytology, as the preferred primary screening method. In the pooled follow-up of four European randomized trials, HPV-based screening provided 60–70% greater protection against invasive cervical carcinoma than cytology alone (Ronco et al., 2014). Similarly, in the cluster-randomized trial from rural India, a single round of HPV testing was associated with a significant reduction in advanced cervical cancer and cervical cancer mortality, whereas no significant reduction in advanced disease or mortality was observed in the cytology arm (Sankaranarayanan et al., 2009). Second, reference 3 (Debbie et al., 2016) is not an appropriate citation for this statement, as it addresses HPV vaccination guidelines rather than the comparative performance of cytology and HPV testing in cervical screening. The authors should therefore revise the sentence and replace the current reference with more relevant screening literature.’’

Response: The statement in the Introduction was revised and strengthened for greater accuracy and clarity. It now distinguishes more clearly between Pap testing and HPV testing as non-equivalent primary screening methods and reflects the current WHO preference for HPV-based screening. The supporting references were also improved and reorganized accordingly to provide more appropriate documentation for this statement.

Comment 3:

’’In Figure 3, the authors present “HPV vaccination rates by region” and describe these as the estimated vaccination coverage rates for women in 2023. This wording is unclear and likely misleading, as the reported proportions appear too high to represent coverage among all women. The figure legend should therefore clearly specify the population and age group to which these estimates apply, for example girls or young women within a defined target age range. In addition, the statement in the Results section that HPV vaccination is “ineffective in many regions of the world” is inaccurate. The problem is not that the vaccine is ineffective, but rather that vaccine uptake and program implementation remain insufficient in many settings. Finally, the authors should revise the description of vaccine impact. HPV vaccination does not only reduce HPV infections and early cervical lesions in young women; with adequate uptake and sufficient follow-up time, it is also expected to reduce high-grade cervical lesions and, ultimately, cervical cancer in women vaccinated before exposure to HPV.’’

Response: Figure 3 and the related text were revised for improved clarity and accuracy. The figure legend now more clearly specifies the target population, the wording on HPV vaccination was corrected to reflect the issues of uptake and implementation rather than ineffectiveness, and the description of vaccine impact was updated accordingly.

Comment 4:

’’The statement in the Results section (Section 3.3) that “educational campaigns, such as those carried out in France and the Netherlands, have led to an increase in vaccination rates by 20% in the last five years” should be clarified. Reporting a “20% increase” without providing the baseline and follow-up coverage is not sufficiently informative, as the interpretation differs substantially depending on whether coverage increased, for example, from 20% to 40% or from 60% to 80%. In addition, the time period should be stated explicitly using calendar years rather than the vague expression “the last five years,” particularly if the cited references are not recent. The authors should therefore provide the exact coverage estimates before and after the intervention, specify the relevant years, and ensure that the statement is supported by appropriate and up-to-date references.’’

Response: The statement in Section 3.3 was revised accordingly, and the wording was improved for greater clarity and precision. The paragraph was reformulated in a more precise and better supported manner.

Comment 5:

’’The statement that “Japan has reported a vaccination coverage of approximately 80%” appears inaccurate or, at minimum, insufficiently qualified. Japan experienced a marked decline in HPV vaccination uptake after the governmental suspension of proactive recommendation in 2013, and coverage remained very low for many affected birth cohorts. In a nationwide analysis, Yagi et al. reported HPV vaccination coverage of 53.3%-79.5% for birth fiscal years 1994-1999, but only 0.84%-25.2% for birth fiscal years 2000–2010, and concluded that coverage in Japan remained below the WHO target even after resumption of active recommendation. Official Japanese sources likewise state that coverage remained around 1% during the suspension period and has not yet sufficiently recovered. Recent MHLW data also show that cumulative first-dose coverage around 80% is limited to selected pre-suspension cohorts, whereas many later cohorts remain substantially lower. The authors should therefore revise this statement and specify clearly whether the reported 80% refers only to selected historical birth cohorts rather than to Japan overall.’’

Response: The statement regarding HPV vaccination coverage in Japan was revised and clarified. The text now better reflects the post-2013 decline in uptake, the cohort-specific differences in coverage, and the fact that higher reported figures do not apply uniformly to Japan as a whole.

Comment 6:

’’The statement that “In Japan, screening participation reached 70%, while Indonesia and India have reported screening coverage below 30%” should be clarified by specifying which screening method was used in each setting, since screening coverage is difficult to interpret without distinguishing between HPV testing, cervical cytology, and VIA. These methods differ substantially in performance, evidence base, and expected impact. WHO now recommends HPV-based testing as the preferred primary screening method rather than cytology or VIA, because HPV testing is more effective and provides better protection against cervical cancer. The authors should therefore report the screening modality together with the coverage figures and avoid presenting these data as directly comparable if different methods were used across countries.’’

Response: We followed the reviewer’s recommendation and updated the identified paragraph in Section 3.3. The revised text now clarifies that screening coverage should be interpreted in relation to the screening modality used and avoids direct comparison between settings where different screening approaches were applied.

Comment 7:

’’The paragraph on Australia should be revised for accuracy and clarity. Australia replaced cytology-based primary screening with HPV testing in December 2017 as part of the renewed National Cervical Screening Program. Liquid-based cytology is not used as a parallel primary screening test, but mainly as a triage test for HPV-positive women. Therefore, the statement that screening participation “reached 73% for HPV testing and 63% for liquid cytology” is confusing and likely incorrect, or at least insufficiently explained. The authors should clarify exactly what these two coverage estimates refer to, specify whether the liquid-based cytology figure represents triage testing rather than primary screening, and ensure that participation data are reported consistently with the Australian screening program. Otherwise, the current wording may give the misleading impression that Australia still uses both HPV testing and liquid cytology as co-existing primary screening methods.’’

Response: The paragraph on Australia was revised accordingly for improved accuracy and clarity. The text now reflects more clearly the structure of the renewed Australian screening program and avoids wording that could suggest the use of HPV testing and liquid-based cytology as parallel primary screening methods.

Comment 8:

’’The manuscript contains duplicated information on Australia. Specifically, the data on HPV positivity and treatment of precancerous lesions in 2023 are reported first in lines 542–544 and then repeated almost verbatim in lines 571–573. In addition, the two surrounding paragraphs (lines 538–544 and 569–576) substantially overlap in content and should probably be merged or revised to avoid unnecessary repetition. The authors should consider presenting the Australian screening indicators and outcome data only once, in a single coherent paragraph.’’

Response: The Australia-related text was revised to avoid unnecessary repetition and improve coherence between sections. The screening indicators are now presented only once, while the corresponding outcome section retains only the broader contextual information.

Comment 9:

’’The authors state that the mortality rate in Romania is 14.2 per 100,000 women. This figure should be verified and updated. According to GLOBOCAN 2022, Romania had an estimated 3,368 new cervical cancer cases and 1,793 deaths in 2022. The corresponding age-standardized incidence and mortality rates were 21.7 and 9.3 per 100,000 women, respectively. Therefore, the reported mortality rate of 14.2 per 100,000 does not appear to be consistent with the current GLOBOCAN 2022 estimates. In addition, the Romanian incidence estimate is modelled rather than based on direct national incidence data. The GLOBOCAN fact sheet states that no country-specific incidence data were available for Romania and that incidence was estimated from national mortality estimates using mortality: incidence ratios derived from cancer registry data in neighbouring countries. Mortality, in contrast, was based on national WHO mortality data projected to 2022. The authors should therefore revise this section, provide the correct figures, and specify clearly the source, year, and whether rates are age-standardized or crude.’’

Response: The Romania-specific figures were verified and revised according to GLOBOCAN 2022. The relevant section was updated accordingly, and the source and year were clarified.

Comment 10:

’’ The authors state that “With incidence rates of 40 per 100,000 women and mortality rates of 27 per 100,000 women, cervical cancer continues to represent a major health burden in sub-Saharan Africa.” This statement appears to overestimate the current overall burden for sub-Saharan Africa and should be revised. According to the IARC GLOBOCAN 2022 fact sheet for sub-Saharan Africa, cervical cancer accounted for 118,013 new cases and 76,189 deaths in 2022, corresponding to an age-standardized incidence rate of 33.4 per 100,000 women and an age-standardized mortality rate of 22.6 per 100,000 women. Thus, the figures of 40 and 27 per 100,000 are higher than the current GLOBOCAN 2022 estimates for sub-Saharan Africa as a whole. WHO likewise states that the highest incidence and mortality rates occur in sub-Saharan Africa, but these are not given as 40 and 27 per 100,000 in the current regional overview. The authors should therefore either correct these figures or clarify that they refer to older estimates, selected high-burden countries, or specific subregions rather than sub-Saharan Africa overall.’’

Response: The sub-Saharan Africa figures were verified and revised according to GLOBOCAN 2022. The updated text now reports the corrected age-standardized incidence and mortality rates and clarifies the year accordingly.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Review Report for Manuscript ID: diagnostics-4066061-peer-review-v1

Title: Global and Regional Diagnostic and Results of Progress toward Cervical Cancer Elimination, according to the WHO Strategy: A Systematic Review
Authors: Dan Cristian Luca et al.

Overall Assessment

This systematic review provides a timely and comprehensive analysis of global and regional progress toward cervical cancer elimination in alignment with the WHO 2020 strategy. The topic is highly relevant, the methodology is generally sound, and the manuscript is well-structured. However, there are several areas that require clarification, strengthening, and refinement before the manuscript can be considered suitable for publication.

Major Comments

Methodology Section Clarification

The PRISMA flow diagram is included, but the description of the screening and selection process could be more transparent. Please specify how disagreements between reviewers (if any) were resolved during study selection.
The data extraction process is mentioned as performed by “one reviewer.” It is recommended to involve at least two independent reviewers for data extraction to reduce bias and enhance reliability. Please clarify or revise this point.

Results Presentation

The results are presented regionally, which is useful, but the narrative can be more systematically organized. Consider structuring the results by the three WHO pillars (vaccination, screening, treatment) across regions, rather than mixing them in a geographical narrative.
Table 1 is extensive but not fully informative in its current form. Some entries (e.g., “Not applicable” under study population) limit its utility. Suggest adding key quantitative findings (e.g., coverage rates, effect sizes) to enhance comparability.

Discussion Depth

The discussion section appropriately highlights disparities but could better integrate the findings with existing frameworks (e.g., WHO’s equity-focused approaches, Health System Strengthening).
The subsection on Romania is insightful but stands somewhat disconnected from the global narrative. Consider integrating it more seamlessly into the broader discussion on transitional health systems in Europe.

Figures and Tables

Figures 1–3 are referenced in the introduction but not provided in the submitted PDF. Please ensure all figures are included and properly cited.
Table 2 (Incidence and mortality) lacks a clear source or year reference. Please add footnotes or citations to improve reproducibility.

Minor Comments

Language and Clarity

Some sentences are lengthy or ambiguous (e.g., in Abstract: “…regions that were able to obtain results that could meet the requirements…”). Consider revising for conciseness and clarity.
Ensure consistent use of terms: “WHO directive” vs. “WHO strategy” vs. “WHO guideline” – recommend standardizing to “WHO strategy” throughout.

Reference Consistency

References 56–58 appear to discuss unrelated clinical conditions (e.g., soft tissue infections, cholecystitis). Their relevance to cervical cancer elimination is unclear. Please justify their inclusion or remove them.

Limitations

The limitations section mentions “exclusion of programs and measures implemented starting with 2024.” Given the cut-off date is December 2024, this seems contradictory. Please clarify.

Strengths

The review addresses a critical global health issue with a clear focus on equity and implementation gaps.
The regional breakdown provides useful insights for policymakers.
The inclusion of recent studies (up to 2024) enhances the relevance of the findings.

Recommendations for Revision

Strengthen the methodology description, particularly regarding data extraction and study selection.
Reorganize the results to align with the WHO pillars for clearer messaging.
Enhance tables with more quantitative data and ensure all figures are included.
Tighten the discussion to better link regional examples with global strategies.
Revise language for fluency and consistency.

Conclusion

This manuscript presents a valuable contribution to the literature on cervical cancer elimination. With the suggested revisions, it will be suitable for publication in Diagnostics. I recommend acceptance after revisions.

Author Response

Response to Reviewer Comments

I-Ensure all references are relevant to the content of the manuscript.

Response: All references have been carefully re-evaluated for relevance and scientific alignment with the topic of cervical cancer elimination under the WHO strategy. References unrelated to HPV infection, cervical cancer prevention, screening, vaccination, treatment, or health system implementation have been critically reviewed. Non-essential clinical references were either explicitly justified in the context of health system barriers and comorbidity-driven access limitations or removed when their contribution to the manuscript’s objectives was deemed insufficient.

II-Highlight any revisions to the manuscript, so editors and reviewers can
see any changes made.

Response: All revisions made to the manuscript are clearly highlighted using the Track Changes function in Microsoft Word. This allows editors and reviewers to easily identify textual modifications, added clarifications, structural reorganizations, and reference updates throughout the revised manuscript.

Major Comments

Methodology Section Clarification

‘’The PRISMA flow diagram is included, but the description of the screening and selection process could be more transparent. Please specify how disagreements between reviewers (if any) were resolved during study selection. The data extraction process is mentioned as performed by “one reviewer.” It is recommended to involve at least two independent reviewers for data extraction to reduce bias and enhance reliability. Please clarify or revise this point.’’

Response: The Methods section has been expanded to explicitly describe the study selection and data extraction process. While initial data extraction was performed by one reviewer, all extracted data were subsequently independently verified by a senior team member. No disagreements occurred during study selection. A predefined consensus-based resolution mechanism involving a third reviewer has now been clearly described. Additionally, this methodological limitation has been transparently acknowledged in the Limitations section.

Results Presentation

‘’The results are presented regionally, which is useful, but the narrative can be more systematically organized. Consider structuring the results by the three WHO pillars (vaccination, screening, treatment) across regions, rather than mixing them in a geographical narrative.’’

Response: The Results section has been reorganized into distinct subsections addressing HPV vaccination, cervical cancer screening, and treatment/outcomes, while maintaining regional stratification for clarity. This hybrid structure improves conceptual alignment with the WHO 90–70–90 framework.

‘’Table 1 is extensive but not fully informative in its current form. Some entries (e.g., “Not applicable” under study population) limit its utility. Suggest adding key quantitative findings (e.g., coverage rates, effect sizes) to enhance comparability.’’

Response: Table 1 was completed according to the reviewer’s recommendations by adding the requested information where available, in order to improve clarity and comparability across the included studies.

Discussion Depth

‘’The discussion section appropriately highlights disparities but could better integrate the findings with existing frameworks (e.g., WHO’s equity-focused approaches, Health System Strengthening). The subsection on Romania is insightful but stands somewhat disconnected from the global narrative. Consider integrating it more seamlessly into the broader discussion on transitional health systems in Europe.’’

Response: The Discussion section has been substantially strengthened by explicitly linking findings to WHO equity-focused and health system strengthening frameworks. The Romania subsection has been reframed as a representative example of transitional health systems in Central and Eastern Europe, rather than as an isolated national case, improving coherence with the global discussion.

Figures and Tables

‘’Figures 1–3 are referenced in the introduction but not provided in the submitted PDF. Please ensure all figures are included and properly cited.’’

‘’Table 2 (Incidence and mortality) lacks a clear source or year reference. Please add footnotes or citations to improve reproducibility.’’

Response: All referenced figures (Figures 1–4) have been included in the revised manuscript and properly cited. Table 2 has been updated to ensure transparency and reproducibility.

Minor Comments

Language and Clarity

‘’Some sentences are lengthy or ambiguous (e.g., in Abstract: “…regions that were able to obtain results that could meet the requirements…”). Consider revising for conciseness and clarity.’’

Response: The manuscript underwent comprehensive language editing. Long or ambiguous sentences were rewritten for clarity and conciseness, particularly in the Abstract.

‘’Ensure consistent use of terms: “WHO directive” vs. “WHO strategy” vs. “WHO guideline” – recommend standardizing to “WHO strategy” throughout.’’

Response: Terminology has been standardized throughout the manuscript, consistently using the term “WHO strategy”.

Reference Consistency

‘’References 56–58 appear to discuss unrelated clinical conditions (e.g., soft tissue infections, cholecystitis). Their relevance to cervical cancer elimination is unclear. Please justify their inclusion or remove them.’’

Response: These references were re-evaluated, and their relevance was justified in the text.

Limitations

‘’The limitations section mentions “exclusion of programs and measures implemented starting with 2024.” Given the cut-off date is December 2024, this seems contradictory. Please clarify.’’

Response: The Limitations section has been revised to clarify that programs initiated close to December 2024 were excluded due to the absence of measurable outcome data at the time of analysis, eliminating any ambiguity.

We once again thank the reviewer for the thorough evaluation of our manuscript and for the constructive and insightful comments provided. We hope that the revised version now meets the standards required for publication and we remain at the editor’s and reviewer’s disposal for any further clarifications.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript addresses a relevant topic and is based on a very interesting and potentially valuable dataset. The overall structure is clear, and both the Results and Discussion sections show merit. However, the manuscript currently lacks adequate statistical and quantitative analyses, which significantly limits the strength and interpretability of the findings. In addition, the Methods section requires substantial enhancement, and the Abstract is not acceptable for publication in its current form, as it remains too vague and insufficiently focused on the specific topic and results of the study. The Discussion, while generally well written, should be more concise and better supported by appropriate references. Major revisions are required to improve scientific rigor and clarity.

Specific Comments
Abstract

The Abstract is too vague and generic. Please include more quantitative data, particularly in the Results and Conclusions, to better reflect the scope and findings of the study.

The Abstract should be more precisely focused on the topic, clearly stating what was analyzed and what was found.

Introduction

Line 34: The phrase “remains related” is unclear. Please specify what it is related to.

Methods

Lines 81–85: Please add the full Boolean search terms in the Supplementary Materials.

Lines 98–99: The fact that the screening was performed by a single reviewer should be explicitly acknowledged as a limitation of the study.

Line 110: Please clearly state the reasons why certain articles could not be retrieved.

Overall, the Methods section must be expanded and clarified to ensure transparency and reproducibility.

Results

Please include appropriate statistical and quantitative analyses where applicable to strengthen the Results section.

Add a dedicated paragraph focusing on low- and middle-income countries (LMICs), particularly highlighting countries where HPV vaccination is not implemented at all due to social, political, or structural barriers.

Figures and Tables

Figure 1: Please add an explicit reference to the data source. If possible, revise the bar chart format to make it more suitable for publication.

Table 1: The table is excessively large and difficult to read. Please reduce its size to a maximum of 2–3 pages, improve formatting, and ensure that every included article is properly cited.

Discussion

The Discussion section lacks sufficient referencing and is therefore not acceptable for publication in its current form. Please add appropriate citations throughout.

The Discussion should be more concise and avoid redundancy.

The Discussion and Results sections must be better aligned, with interpretations clearly grounded in the presented data. A partial rewrite is recommended to improve coherence and consistency.

While the manuscript has clear potential and is based on a valuable dataset, major revisions are necessary to address the lack of statistical rigor, improve methodological transparency, refine the Abstract, and strengthen the Discussion with appropriate references and clearer alignment with the Results.

Author Response

Response to Reviewer Comments

I-Ensure all references are relevant to the content of the manuscript.

II-Highlight any revisions to the manuscript, so editors and reviewers can
see any changes made.

Abstract

‘‘The Abstract is too vague and generic. Please include more quantitative data, particularly in the Results and Conclusions, to better reflect the scope and findings of the study. The Abstract should be more precisely focused on the topic, clearly stating what was analysed and what was found.’’

Response: The Abstract was revised to improve clarity and focus. Quantitative data were added to the Results section of the Abstract, and the content was reformulated to more clearly reflect the scope of the analysis and the main findings of the study.

Introduction

‘‘Line 34: The phrase “remains related” is unclear. Please specify what it is related to.’’

Response: The wording was revised to improve clarity.

Methods

‘‘Lines 81–85: Please add the full Boolean search terms in the Supplementary Materials.’’

Response: The complete Boolean search strategies used for database searches were added to the Supplementary Materials to enhance transparency and reproducibility.

‘‘Lines 98–99: The fact that the screening was performed by a single reviewer should be explicitly acknowledged as a limitation of the study.’’

Response: This aspect was explicitly acknowledged in the Limitations section of the manuscript.

‘‘Line 110: Please clearly state the reasons why certain articles could not be retrieved.’’

Response: The Methods section was corrected and clarified to explain the reasons for article exclusion at this stage.

‘‘Overall, the Methods section must be expanded and clarified to ensure transparency and reproducibility.’’

Response: The Methods section was expanded and clarified to improve transparency, reproducibility, and consistency with PRISMA recommendations.

Results

‘‘Please include appropriate statistical and quantitative analyses where applicable to strengthen the Results section. Add a dedicated paragraph focusing on low- and middle-income countries (LMICs), particularly highlighting countries where HPV vaccination is not implemented at all due to social, political, or structural barriers.’’

Response: The Results section was revised to improve clarity and quantitative reporting where available, and a dedicated subsection focusing on low- and middle-income countries (LMICs) was added to highlight regions with limited HPV vaccination and screening due to social, political, and structural barriers.

Figures and Tables

‘‘Figure 1: Please add an explicit reference to the data source. If possible, revise the bar chart format to make it more suitable for publication.’’

Response: The data source for Figure 1 was explicitly stated, and the figure presentation was reviewed to improve clarity and suitability for publication.

‘’Table 1: The table is excessively large and difficult to read. Please reduce its size to a maximum of 2–3 pages, improve formatting, and ensure that every included article is properly cited.’’

Response: We carefully considered this comment. However, Table 1 represents the comprehensive study characteristics table, which was specifically requested during the review process and subsequently expanded following the recommendations of another reviewer, who requested the inclusion of additional details to improve transparency and comparability across studies.

Reducing the size of the table or removing entries would substantially limit its informative value and compromise its purpose of providing a complete overview of the included studies. For this reason, the table was retained in its current form to preserve its scientific relevance and consistency with the reviewers’ requests. All included studies are properly cited.

Discussion

‘‘The Discussion section lacks sufficient referencing and is therefore not acceptable for publication in its current form. Please add appropriate citations throughout. The Discussion should be more concise and avoid redundancy. The Discussion and Results sections must be better aligned, with interpretations clearly grounded in the presented data. A partial rewrite is recommended to improve coherence and consistency.’’

Response: The Discussion section was revised and reformulated to improve conciseness and coherence. Additional references were included where appropriate, and interpretations were aligned more closely with the data presented in the Results section.