Abstract
The self-sampling human papillomavirus (HPV) test improves participation in cervical cancer screening. However, the ripple effect of this test on participation in the next screening round has not yet been examined. This study, a secondary analysis of the Accelerating Cervical Cancer Elimination by Self-Sampling test (ACCESS) trial, aims to clarify this effect. Women who had not participated in the cervical cancer screening program of Ichihara City for 3 years or more were included. The participants were randomly assigned to intervention (n = 7337) and control groups (n = 7770). In the initial round, the intervention group could perform a self-sampling HPV test or undergo cytology as the primary screening method, while the control group could undergo cytology only. In the next round, both groups could undergo cytology. In intention-to-screen analysis, screening uptake in the next round was 10.0% (95% confidence interval [CI]: 9.3%, 10.7%) in the intervention group and 10.2% (95% CI: 9.5%, 10.8%) in the control group, with no significant difference between groups (p = 0.717). In conclusion, offering a one-time self-sampling HPV test had no effect on screening uptake in the next round, suggesting that the test needs to be offered on an ongoing basis to continuously improve screening uptake.
Introduction
Cervical cancer can be prevented through high-risk human papillomavirus (HPV) vaccination and screening.1,2 However, preventive measures in Japan are insufficient. HPV vaccination had been suspended between June 2013 and March 2022, 3 and the cervical cancer screening participation rate is noticeably low among developed countries. 4 Self-sampling HPV tests are a tool to improve screening uptake.5–8 For example, the Accelerating Cervical Cancer Elimination by Self-Sampling test (ACCESS) randomized controlled trial (RCT) reported that self-sampling HPV tests increased screening uptake by 3.1 times among Japanese individuals. 9 However, the test has not been recommended by guidelines in Japan and is only used on a one-off basis in limited areas. Our questionnaire survey in the ACCESS trial revealed that approximately half of under-screened individuals intended to undergo screening in the future after using a self-sampling HPV test, even if the sampling was performed by a doctor. 10 Given this result, even a one-time self-sampling test may increase subsequent screening uptake by strengthening the motivation for screening. This study, a pre-planned secondary analysis of the ACCESS trial, aimed to determine whether temporary self-sampling HPV tests increase participation in the next round of screening.
Methods
Details of the ACCESS trial are available in previous reports.9,11 The eligibility criteria were as follows: (1) women living in Ichihara City as of 22 December 2020; (2) women aged 30–58 years as of 1 April 2021; (3) even-aged women, comprising the target population for the cervical cancer screening program in Ichihara City; (4) women who had not participated in the city's cervical cancer screening program for 3 years or more.
A diagram of the inclusion and exclusion criteria is shown in Figure S1 (Supplemental material). A total of 20,555 women who met the eligibility criteria were extracted from the Ichihara City database on 22 December 2020. A preliminary explanation letter was sent to all eligible women on 1 February 2021, explaining that they could decline participation (opt-out consent). Women who declined to participate (N = 4283) and those whose pre-invitation letters were returned because of incorrect addresses (N = 12) were excluded. The remaining 16,260 women were randomly assigned to the intervention or control group in a 1:1 ratio on 22 February 2021. The database was locked for this secondary analysis on 18 November 2024. Between randomization and database lock, 808 and 345 women in the intervention and control groups, respectively, declined to participate in the trial. The final number of participants was 7337 and 7770 in the intervention and control groups, respectively.
Participants in the control group could undergo cytology in both 2021 and 2023, while those in the intervention group could undergo either cytology or a self-sampling HPV test in 2021 and cytology in 2023. Participants in the intervention group were sent a second letter for this trial on 10 March 2021, informing them that they could undergo cytology tests or self-sampling HPV tests as their primary screening method. If participants chose the self-sampling HPV test, they were required to order the kit. In response to their ordering, we sent items including a self-sampling kit (Evalyn Brush; Rovers Medical Devices, Netherlands), an instruction manual, and a return-addressed envelope with cash on delivery. The HPV test was performed by an outsourced company (LSI Medience, Tokyo, Japan) using the Cobas 8800 system (Roche Diagnostics, Rotkreuz, Switzerland). If the HPV test results were invalid, the participants were asked to recollect their samples. The outcome was screening uptake in the next round (2023), which was compared under the intention-to-screen analysis. For sensitivity analysis, individuals with atypical squamous cells of undetermined significance or worse in the initial screening round were excluded because they were assumed to be under medical care.
Continuous variables were compared using the t-test, while categorical variables were analyzed using Pearson's chi-square test. The STATA software version 16.1 (STATA LP, College Station, TX, USA) was used, and statistical significance was set at p < 0.05. Ethics statements are provided in Method S1 (Supplemental material). Trial registry: Japan Registry of Clinical Trials, https://jrct.mhlw.go.jp, jRCT1030200276.
Results
Participant characteristics are shown in Table S1 (Supplemental material). The mean age (standard deviation) of the intervention and control groups was 44.6 (8.3) and 44.5 (8.3), respectively. A diagram of cervical cancer screening in the initial and subsequent rounds is shown in Figure S2 (Supplemental material).
In the intervention group, 1190 and 278 individuals underwent the self-sampling HPV test and cytology, respectively, in the initial round. In the control group, 501 individuals underwent cytology. Screening uptake in the next round is summarized in Table 1.
Screening uptake in the next round (2023).
Pearson's chi-square test was used.
CI: confidence interval; HPV: human papillomavirus.
Excluding those with atypical squamous cells of undetermined significance or worse in the initial round of screening.
Comparison between no screening, cytology, and self-sampling HPV test in 2021 in the intervention group.
Comparison between HPV positive, negative, and invalid in 2021 in the intervention group.
Comparison between no screening and cytology in 2021 in the control group.
Comparison between the control and intervention groups.
In the intention-to-screen analysis, screening uptake in the next round was 10.0% in the intervention group (95% confidence interval [CI]: 9.3%, 10.7%) and 10.2% (95% CI: 9.5%, 10.8%) in the control group, with no significant difference between groups (p = 0.717). In both the intervention and control groups, a significant association was observed between screening status in the initial round and screening uptake in the next round (p < 0.001 for both groups). There was no association between self-sampling HPV test results in the initial round and screening uptake in the next round (p = 0.779). The sensitivity analysis results were consistent with the base analysis results.
Discussion
Previous meta-analyses have confirmed that self-sampling HPV tests increase screening uptake in the initial round.5–8 However, few studies have reported a ripple effect of self-sampling HPV tests on participation rates at subsequent screening rounds. The only previous study reported that 24.5% of women with negative self-sampling HPV test results in the initial round of screening underwent subsequent cytology 2 years later. 12 However, this previous study was a single-arm study with a single intervention group. Thus, nothing is known about the ripple effect of offering a self-sampling HPV test on the participation rates in subsequent rounds of screening. This study is the first RCT to evaluate the effect.
In this study, self-sampling HPV tests were provided only in the initial screening round, and in the next round, both groups were offered only cytology. The intention-to-screen analysis results indicate that a one-time self-sampling HPV test has no impact on subsequent screening uptake for the entire population. When self-sampling tests are adopted in practice, such as in Australia and the Netherlands, they are offered at all screening rounds. Therefore, our findings do not apply to such settings. In contrast, in Japan, self-sampling tests are not recommended by guidelines and are offered infrequently and temporarily at the discretion of local governments. This study revealed that temporary self-sampling HPV tests have no ripple effect on subsequent screening uptake, suggesting the need to offer the test on an ongoing basis.
Contrary to expectations of a ripple effect on subsequent screening uptake from self-sampling tests, we had a concern that barriers to cervical cancer screening, such as embarrassment and lack of time, may remain in the next round of screening. The result that screening uptake in the next round was lower in those who underwent self-sampling tests than in those who underwent cytology may reflect this concern. Individuals who chose a self-sampling test in the initial round may have had strong barriers to sampling by a doctor and gave up on undergoing screening when the option for self-sampling was unavailable. Another concern is that participants with negative HPV test results may feel reassured by knowing that they have a low risk of cervical cancer and may be hesitant to undergo subsequent screening. However, this concern appears negligible because screening uptake in the next round was not associated with HPV test results.
This study had some limitations. First, we were unable to accurately identify those receiving medical care in a clinic or hospital based on the results of the initial round of screening who did not need to be screened in the next round. Those who had cytological results of atypical squamous cells of undetermined significance or worse on cervical cancer screening were recommended to undergo clinical follow-up. Therefore, we assumed they would be under medical care and performed a sensitivity analysis excluding them. These results are similar to those of the base analysis, making it unlikely that the presence of participants under medical care skewed the results. Secondly, Japan lacks a comprehensive registration system for cervical cytology. Therefore, the cytology participation rate in the next round may have been underestimated. Third, the generalizability of our study is limited because this trial was conducted in a single municipality. The study's strength lies in being the first RCT to clarify the ripple effect of the self-sampling HPV test on uptake in the next round of screening.
Conclusion
A temporary self-sampling HPV test has no ripple effect on screening uptake in the next round. Self-sampling HPV tests need to be offered on an ongoing basis to further improve screening rates.
Supplemental Material
sj-docx-1-msc-10.1177_09691413251352999 - Supplemental material for Ripple effect of temporary self-sampling HPV test on screening uptake in the next round: A secondary analysis of the ACCESS randomized controlled trial
Supplemental material, sj-docx-1-msc-10.1177_09691413251352999 for Ripple effect of temporary self-sampling HPV test on screening uptake in the next round: A secondary analysis of the ACCESS randomized controlled trial by Misuzu Fujita, Kengo Nagashima, Minobu Shimazu, Misae Suzuki, Ichiro Tauchi, Miwa Sakuma, Setsuko Yamamoto, Hideki Hanaoka, Makio Shozu, Nobuhide Tsuruoka, Tokuzo Kasai and Akira Hata in Journal of Medical Screening
Supplemental Material
sj-xls-2-msc-10.1177_09691413251352999 - Supplemental material for Ripple effect of temporary self-sampling HPV test on screening uptake in the next round: A secondary analysis of the ACCESS randomized controlled trial
Supplemental material, sj-xls-2-msc-10.1177_09691413251352999 for Ripple effect of temporary self-sampling HPV test on screening uptake in the next round: A secondary analysis of the ACCESS randomized controlled trial by Misuzu Fujita, Kengo Nagashima, Minobu Shimazu, Misae Suzuki, Ichiro Tauchi, Miwa Sakuma, Setsuko Yamamoto, Hideki Hanaoka, Makio Shozu, Nobuhide Tsuruoka, Tokuzo Kasai and Akira Hata in Journal of Medical Screening
Footnotes
Acknowledgements
We sincerely appreciate the invaluable help and support of the mayor of Ichihara City Hall, Joji Koide. We also sincerely appreciate the support of the president of the Chiba Foundation for Health Promotion and Disease Prevention, Takehiko Fujisawa, and the staff members Chiori Suzuki, Fumika Kumahara, Fumiya Chiwaki, Hideaki Nagai, Ikumu Matsushita, Kenji Ishii, Makoto Koumi, Michiko Fusaeda, and Saeri Omori. We would like to thank Editage (
) for English language editing.
Author contributions
Misuzu Fujita: conceptualization, data curation, formal analysis, investigation, methodology, project administration, software, visualization, writing—original draft. Kengo Nagashima: conceptualization, formal analysis, methodology, writing—review & editing. Minobu Shimazu, Hideki Hanaoka, Makio Shozu, and Tokuzo Kasai: conceptualization, methodology, writing—review & editing. Misae Suzuki, Ichiro Tauchi, Miwa Sakuma, Setsuko Yamamoto, and Nobuhide Tsuruoka: conceptualization, investigation, methodology, writing—review & editing. Akira Hata: conceptualization, funding acquisition, investigation, methodology, supervision, writing—review & editing.
Consent to participate
To ensure autonomous participation and reduce selection bias as much as possible, opt-out consent was obtained from all participants. In detail, we sent a preliminary explanation letter to all women who met the eligible criteria, informing them that they could decline to participate in this trial. Additionally, we received written consent from participants who underwent self-sampling HPV testing.
Data availability
The datasets analyzed are provided as Supplemental file, Data S1.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical considerations
This trial was approved by the Research Ethics Committees of the Chiba Foundation for Health Promotion and Disease Prevention (approval numbers R2-2 and R2-7), Graduate School of Medicine, Chiba University (approval number 3979), and the Institute of Statistical Mathematics (approval number ISM20-001) and conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects. The Committee for Personal Information Protection of Ichihara City reviewed the plan of this trial on 12 November 2020 and authorized data provision on 15 December 2020.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a Japan Society for the Promotion of Science (JSPS) KAKENHI Grant (Grant number: 20H03906).
Supplemental material
Supplemental material for this article is available online.
References
Supplementary Material
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