Cervical cancer screening improvements with self-sampling during the COVID-19 pandemic

  1. Miriam Elfström
  2. Penelope Grace Gray
  3. Joakim Dillner  Is a corresponding author
  1. Center for Cervical Cancer Elimination, F46, Pathology and Cancer Diagnostics, Medical Diagnostics Karolinska, Karolinska University Hospital and Division of Cervical Cancer Elimination, CLINTEC, Karolinska Institutet, Sweden
  2. Regional Cancer Center of Stockholm-Gotland, Cancer Screening Unit, Sweden, Sweden

Abstract

Background:

At the onset of the COVID-19 pandemic cervical screening in the capital region of Sweden was canceled for several months. A series of measures to preserve and improve the cervical screening under the circumstances were instituted, including a switch to screening with HPV self-sampling to enable screening in compliance with social distancing recommendations.

Methods:

We describe the major changes implemented, which were (1) nationwide implementation of HPV screening, (2) switch to primary self-sampling instead of clinician sampling, (3) implementation of HPV screening in all screening ages, and (4) combined HPV vaccination and HPV screening in the cervical screening program.

Results:

A temporary government regulation allowed primary self-sampling with HPV screening in all ages. In the Stockholm region, 330,000 self-sampling kits were sent to the home address of screening-eligible women, instead of an invitation to clinician sampling. An increase in organized population test coverage was seen (from 54% to 60% in just 1 year). In addition, a national campaign for faster elimination of cervical cancer with concomitant screening and vaccination for women in ages 23–28 was launched.

Conclusions:

The COVID-19 pandemic necessitated major changes in the cervical cancer preventive strategies, where it can already be concluded that the strategy with organized primary self-sampling for HPV has resulted in a major improvement of population test coverage.

Funding:

Funded by the Swedish Association of Local Authorities and Regions, the Swedish Cancer Society, the European Union’s Horizon 2020 Research and Innovation Program, the Swedish government, and the Stockholm county.

Editor's evaluation

This is a valuable piece of work given the scope of the intervention(s) and the precedent it sets i.e. a crisis can in fact accelerate positive changes in screening that have been academic possibilities rather than practical realities. The evidence is solid since data were obtained from the national cervical screening registry during the pandemic. The work will be of broad interest to researchers and policy makers involved in cervical cancer screening.

https://doi.org/10.7554/eLife.80905.sa0

Introduction

Prior to the COVID-19 pandemic outbreak in spring 2020, the Swedish cervical cancer prevention efforts consisted of invitations for screening at maternity clinics at an interval of 3–7 years. The National Board of Health and Welfare decided in 2015 that screening of 30- to 70-year-old women should primarily be performed with an HPV test and screening of 23- to 29-year-old women with cytology (National Board of Health and Welfare, 2015). However, 5 years later when surveyed during the autumn of the pandemic, 5/21 regions in Sweden had still not implemented the national program. Self-sampling targeting long-term non-attenders as a method to increase population coverage was recommended but was rarely used (Swedish National Cervical Screening Registry, 2021). There was school-based vaccination of both girls and boys (with high population coverage) (National Board of Health and Welfare, 2022) but no consideration of strategies for an even faster strategy to eliminate cervical cancer by concomitant screening and vaccination of young women (Dillner et al., 2021). Although HPV testing has been shown to have higher sensitivity in all age groups and higher specificity for women aged 30 or older compared to cytology-based screening, it was previously not recommended below 30 years of age largely because of the high prevalence of HPV infections, most of which will be cleared without causing cellular lesions or cancer, leading to overdiagnosis and overtreatment (Arbyn et al., 2012; Leinonen et al., 2009; Ronco et al., 2014). However, an increasing proportion of young women that are entering the screening program have been vaccinated, resulting in lower HPV prevalences and lower predictive values of screening (Lei et al., 2020b). Cellular abnormalities among young, vaccinated women are still seen, but typically contain only non-progressive HPV types (Kann et al., 2020).

In April of 2020 all non-emergency healthcare was stopped in the capital region of Sweden because of a severe COVID-19 outbreak. Consequently, 192,000 cervical cancer screening invitations with appointments were canceled. In June the same year, the screening program was allowed to restart but the midwife clinics could not be used for screening as usual, to avoid crowding. The Swedish National Board of Health and Welfare enacted a temporary regulation that (1) allowed for primary self-sampling instead of clinician-based sampling and (2) allowed for primary HPV-based screening in all ages between 23 and 70 years of age. It is well known that when self-samples are analyzed using an HPV assay based on polymerase chain reaction, the sensitivity is not inferior to samples taken by medically trained staff (Arbyn et al., 2018) and that self-sampling can be used to increase population coverage of screening, with improved attendance among under-screened and hard-to-reach women (Elfström et al., 2019; Winer et al., 2019).

Methods

Study population and data collection

Most data in this report derive from publicly available data on new Swedish regulations and strategies used during the pandemic (major official websites https://www.socialstyrelsen.se and https://www.regeringen.se). Results on population coverage and number of screening invitations/self-sampling kits sent are derived from the website of the Swedish National Cervical Screening Registry of Sweden (https://www.nkcx.se/). The registry collects all data on cervical screenings and invitations in Sweden and compares the data to aggregated data from the population registry to calculate the population test coverage of screening (Elfström et al., 2016). To evaluate the contribution of clinician taken samples or self-samples on the population test coverage of the organized screening program, the population coverage was calculated stratified by mode of sampling (self-sampled or clinician sampled) by year, age group, and calendar year.

The registry linkages using the NKCx were approved by the National Ethical Review Agency of Sweden (decision number 2023-00289-02). The agency is appointed directly by the government of Sweden, chaired by a senior judge and has the authority to determine requirements for consent, was not required for this study. Key factors in the ethical consideration include whether the integrity risks were minimal (strong security measures and limited access to data) and benefits and disadvantages of the research. In this case, population-based estimates were sought, which by definition means that the entire population is studied.

Results

The number of cervical screening invitations sent per month in the Stockholm region during 2019 and 2020 is shown in Figure 1. The formal decision to cancel all screening was effective April–June 2020, during which time there was a severe COVID-19 outbreak in the Stockholm region (Pimenoff et al., 2021). When screening was re-initiated in the second half of 2020, only a limited number of invitations were allowed per screening station in order to avoid crowding (Figure 1). During the second half of 2020, only women invited for their first cervical screen and women due for follow-up after abnormal screening results were invited to clinician sampling. Clinician-based sampling was also recommended for women who were pregnant when they received their invitation to self-sampling. There were preparations for a switch to primary self-sampling as the prime screening modality, which was launched in March 2021. Except for women at first cervical screen, pregnant women and follow-up after abnormal screens, self-sampling kits were mailed to all eligible women in the population (direct send instead of invitation to maternity care clinic – no requirement of having to order the kit). A detailed description of the self-sampling kits and their use can be found in Elfström et al., 2019.

Number of invitations to cervical cancer screening in Stockholm by month and year.

LabID 088 is Karolinska University Hospital (Stockholm region). Numbers on the X-axis refer to calendar month.

The organized screening program is based on first generating a list of eligible women who (1) are resident in the catchment area (in this case the greater Stockholm region, with about 2 million resident inhabitants), (2) did not take a cervical test during the recommended age-specific screening interval (3 years 23–49 years of age, 7 years 50–70 years of age). This is assessed by importing of files with tests performed from all laboratories (both public and private) in the region and comparing the sampling dates and the personal identification numbers with the population registry of resident women (3) checking that they did not opt out of the screening program. This is not common, but out of the 732,276 resident women in the eligible target ages, 2655 women (0.4%) had opted out of the program. In the switch that was implemented in March 2021, the previous policy of sending an invitation letter with an appointment time for cervical screening at a local Maternity Care clinic was for most women (see above) replaced by sending of a self-sampling kit (including instructions and a pre-paid return envelope). During 2021, approximately 320,000 self-sampling kits were mailed. There was an increase in the population coverage of the organized cervical screening program, from 54% to 60% (Table 1). The improvement was seen in most age groups and the population test coverage levels approached the test coverage levels in the year before the COVID-19 outbreak when the program was canceled (Table 1). There has been a steady increase in population test coverage over the past decade (Figure 2). The trend was broken during the pandemic, but the trend seems to be restored in 2021 (Figure 2).

Test coverage of organized cervical screening among women in the Stockholm Gotland region, Sweden between the years 2013 and 2021.
Table 1
Test coverage of organized cervical screening (% of total population tested) in the Stockholm and Gotland region during 2013–2021 stratified by age group.

The target age group of the program was 23–60 years of age until 2015 and 23–70 years of age from 2015 onwards. Program cancellation due to the COVID-19 pandemic occurred in April 2020 and the switch to primary screening with self-sampling was implemented in March 2021.

Test coverage (%)
Age group (years)
Year23–7023–2526–3031–4041–5051–6061–70
201347.774.760.058.656.949.30.25
201448.777.259.759.557.651.50.27
201551.177.359.859.258.853.910.3
201654.078.262.561.061.057.714.7
201756.280.664.262.362.461.617.4
201858.283.666.563.164.263.120.3
201960.585.468.264.665.962.727.9
202054.381.762.356.757.257.625.4
202159.688.969.662.362.259.632.6

Because population test coverage is calculated over the length of a full screening interval, most of the population test coverage was still attributable to tests taken already before the pandemic. As shown in Table 2, about two thirds of the coverage was still attributable to clinician-based sampling also in the age groups 26–70 where there had been no possibility for organized screening using clinician taken samples (except for pregnant women) since the start of the pandemic.

Table 2
Test coverage of organized cervical screening stratified by mode of index sampling (clinician taken samples or self-sampling) in the Stockholm Gotland region during 2013–2021 stratified by age group.
Absolute test coverage (%) from index samples taken by clinician
Age class
Year23–7023–2526–3031–4041–5051–6061–70
201347.774.760.058.656.949.30.25
201448.777.259.759.557.651.50.27
201551.177.359.859.258.853.910.3
201654.078.262.561.061.057.714.7
201756.280.664.262.362.461.617.4
201858.283.666.563.164.263.120.3
201960.085.468.264.165.361.927.5
202053.181.762.355.755.555.424.2
202141.086.846.241.339.542.719.8
Absolute test coverage (%) from index sample taken by self-sampling
Age class
Year23–7023–2526–3031–4041–5051–6061–70
20130.000.000.000.000.000.000.00
20140.000.000.000.000.000.000.00
20150.000.000.000.000.000.000.00
20160.000.000.000.000.000.000.00
20170.000.000.000.000.000.000.00
20180.000.000.000.000.000.000.00
20190.460.000.000.490.600.780.37
20201.220.000.000.481.642.261.16
202118.62.1723.421.022.716.912.8

As Sweden uses an annual call & recall system, a certain proportion of the population test coverage is attributable to participation by previous non-attenders (Table 3). The proportion of the test coverage that was attributable to long-term non-attenders taking self-samples was 3.9%, a large part of the overall increase in population test coverage seen (Table 3). Note that self-samples were not used at all before 2019 and were used only in a small scale project targeting non-attenders in 2019–2020 (Table 3).

Table 3
Absolute test coverage (%) of organized cervical screening due to attendance of prior long-time non-attenders stratified by mode of index sampling (clinician taken samples or self-sampling) in the Stockholm Gotland region during 2013–2021 stratified by age group.
Absolute test coverage (%) attributable to previous long-time non-attenders* giving clinician taken samples
Age class
Year23–7023–2526–3031–4041–5051–6061–70
20134.09Na3.018.794.453.470.02
20144.26Na3.089.214.743.500.03
20154.54Na3.049.585.093.730.57
20164.95Na3.0110.25.624.190.93
20175.30Na3.3110.75.894.601.20
20185.71Na3.8111.36.155.011.49
20195.76Na3.8311.55.894.911.81
20205.11Na3.6110.24.964.301.49
20213.57Na2.407.143.193.241.13
Absolute test coverage (%) attributable to previous long-time non-attenders* giving self-samples
Age class
Year23–7023–2526–3031–4041–5051–6061–70
20130.00Na0.000.000.000.000.00
20140.00Na0.000.000.000.000.00
20150.00Na0.000.000.000.000.00
20160.00Na0.000.000.000.000.00
20170.00Na0.000.000.000.000.00
20180.00Na0.000.000.000.000.00
20190.46Na0.000.490.590.770.00
20201.21Na0.000.481.622.241.14
20213.86Na1.535.834.554.082.70
  1. *

    Long-time non-attenders are defined as women who have no history of any screening samples (neither by organized nor disorganized screening) prior to the index organized screening sample for 7.5 years (for those aged 23–49 years old) or 9.5 years (for those aged 50–70 years old).

The increased attendance using self-sampling among prior non-attenders is particularly evident when population coverage is expressed as a proportion of the sampling mode (Table 4). Whereas the proportion of the test coverage attributable to clinician sampling of prior non-attenders has always been less than 10% of the samples, >20% of the population test coverage attributable to self-sampling was attributable to prior non-attenders (Table 4).

Table 4
Proportion (%) of the test coverage attributable to previous long-time non-attenders stratified by mode of index sampling (clinician taken samples or self-sampling) in the Stockholm Gotland region during 2013–2021 stratified by age group.
Proportion (%) of test coverage (clinician taken index samples) attributable to previous long-time non-attenders*
Age class
Year23–7023–2526–3031–4041–5051–6061–70
20138.59na5.0115.07.827.0310.0
20148.76na5.1515.58.236.819.63
20158.88na5.0816.28.656.925,52
20169.17na4.8316.79.217.256.31
20179.42na5.1617.29.447.486.93
20189.81na5.7317.99.587.947.36
20199.59na5.6217.99.027.946.56
20209.62na5.8018.48.937.776.17
20218.72na5.1917.38.087.585.70
Proportion (%) of test coverage (self-sampled index samples) attributable to previous long-time non-attenders*
Age class
Year23–7023–2526–3031–4041–5051–6061–70
202120.7na6.5427.820.024.121.0
  1. *

    Long-time non-attenders are defined as women who have no history of any screening samples (including via both organized and disorganized screening) prior to the index organiszed screening sample for 7.5 years (for those aged 23–49 years old) or 9.5 years (for those aged 50–70 years old).

As self-sampling cannot be used for cytology, only for HPV testing, the need to use self-sampling promoted a change to more widespread use of HPV testing. Although HPV testing had been mandated from age 30 and upwards already in 2015, in 2020 there were still 5 counties that did not use it. This changed and since autumn 2021 all counties in Sweden now use primary HPV screening. In the age groups below 30, HPV screening had not previously been recommended because of concerns about over-screening in an age where HPV infections were common. However, HPV prevalences are dropping because of vaccination and the emergency interim guidelines had now allowed HPV screening in all ages.

After the pandemic, permanent regulations were issued that came into effect on 2022-07-01. These allow choice between primary self-sampling and sampling by a clinician and have also changed the age for HPV screening to be mandated between 23 and 70 years of age. In other words, the changes that were required because of the pandemic have resulted in that huge and permanent improvements could be implemented.

Launch of an even faster cervical cancer elimination campaign

The EVEN FASTER concept for rapid cervical cancer elimination is based on concomitant HPV vaccination and HPV screening targeting the age groups where the HPV infection is spread (have an effective reproductive number >1) (Dillner et al., 2021). HPV vaccination without concomitant testing is most effective among subjects before sexual debut, as they are HPV negative and the vaccine does not prevent infections that have already occurred (Lei et al., 2020a). However, among women after sexual debut who test HPV negative, the vaccine is equally effective as among subjects before sexual debut (Apter et al., 2015). By concomitant vaccination and HPV screening, HPV negative women will reap the full benefit of protection by vaccination and the HPV-positive women can be followed up as usual in the screening program (and are thus also protected against cervical cancer). Although the first version of the concept of concomitant screening and vaccination was published 7 years ago (Bosch et al., 2016), there had been no consideration of whether to actually implement it.

After the acute phase of the epidemic, the setting changed. There was a large screening deficit and multiple strategies were needed in order to ensure that it could be managed without adverse effects for the women. Also, very effective mass vaccination campaigns against COVID-19 had been successfully launched and the switch to self-sampling resulted in that Maternity Care Clinics were interested in advancing their offer for in-person visits by providing both vaccination and screening to women coming for their first screening visit.

It is expected that if there is a strong reduction in the circulation of cancer-causing HPV types, the screening and follow-up efforts can be concentrated to those few women who still test positive for oncogenic HPV types thus greatly improving the ability to cope with the screening deficit and enabling Sweden to faster reach the WHO target of elimination of cervical cancer.

Discussion

A large COVID-19 outbreak in the Stockholm region necessitated concentration of healthcare to emergency care and cancer screening was canceled. We describe that the major measures taken to mitigate the screening deficit (organized primary self-sampling and an even faster campaign with concomitant screening and vaccination) resulted in several important and lasting improvements of the cervical cancer prevention program in Sweden.

The roll-out of primary self-sampling was done in the context of routine screening which means that decisions were made consecutively and the program was adapted as needed to meet the changing dynamics of the pandemic. Therefore, this analysis of the response was completed post hoc. Given that Sweden has a comprehensive registry of all invitations (including mailing of self-sampling materials) and all cervical tests performed in the country, it was possible to perform a detailed description and evaluation of the switch retrospectively. The national even faster campaign with concomitant screening and vaccination was launched as a formal Phase IV trial with the protocol registered at clinicaltrials.gov where everyone interested can read the details.

In the US, there was a 94% reduction of cervical cancer screenings during the initial phase of the pandemic compared to the same period the previous years, and although the screening has partially recovered since then, the cervical cancer screening rates are still 10% below pre-pandemic levels (Mast et al., 2022). Likewise, in England a 43–91% drop per month of received screening samples was observed during the period April to June 2020 and by April 2021 there was still 6.4% fewer samples than expected (Castanon et al., 2022). Thus, although there was a prompt re-initiation of screening through re-opening of screening services and catch-up screening during the period following the initial phase of the pandemic, the impact of the disruption was significant. This contrasts with our findings where the disruption was used as an opportunity to advance the program, with lasting improvements already materializing as a greatly improved screening coverage, lower costs of sample taking and increased use of HPV vaccines.

Self-sampling in cervical screening is well known to improve participation among women who seldom or never attended screening (Sultana et al., 2016). The increase in population coverage seen is at least in part due to that the sending of self-sampling kits resulted in improved attendance in particular among previously non-attending women.

As the cancellation of non-emergency healthcare also involved canceling of follow-up and treatment of newly detected screen-positive women, it has been speculated that a rise in cervical cancer would result (Castanon et al., 2022; Daniels et al., 2021). We could, however, not see any such effect in incidence data from the Swedish Cancer Registry (https://www.socialstyrelsen.se/), probably because non-emergency healthcare was allowed again in June 2020 after a less than 3 months disruption.

In summary, the major COVID-19 outbreak necessitated several emergency changes to the cervical screening program. These have resulted in several major and lasting improvements of the cervical cancer prevention strategy that are likely to promote an accelerated elimination of HPV and cervical cancer.

Data availability

The data in this report derive from publicly available data on new Swedish regulations and strategies used during the pandemic (major official websites https://www.socialstyrelsen.se/ and https://www.regeringen.se/). Results on population coverage and number of screening invitations/self-sampling kits sent are derived from the website of the Swedish National Cervical Screening Registry of Sweden (https://www.nkcx.se/).

References

  1. Book
    1. National Board of Health and Welfare
    (2015)
    Screening for Cervical Cancer - Recommendation and Assessment Documentation
    National Board of Health and Welfare.
  2. Book
    1. National Board of Health and Welfare
    (2022)
    Screening for Cervical Cancer
    National Board of Health and Welfare, Stockholm. Sweden.

Decision letter

  1. Johannes Berkhof
    Reviewing Editor; Amsterdam UMC Location VUmc, Netherlands
  2. Eduardo L Franco
    Senior Editor; McGill University, Canada
  3. Johannes Berkhof
    Reviewer; Amsterdam UMC Location VUmc, Netherlands
  4. Kate Cuschieri
    Reviewer; NHS Lothian, United Kingdom

Our editorial process produces two outputs: (i) public reviews designed to be posted alongside the preprint for the benefit of readers; (ii) feedback on the manuscript for the authors, including requests for revisions, shown below. We also include an acceptance summary that explains what the editors found interesting or important about the work.

Decision letter after peer review:

Thank you for submitting your article "Cervical cancer screening improvements with self- sampling during the COVID-19 pandemic" for consideration by eLife. Your article has been reviewed by 3 peer reviewers, including Johannes Berkhof as Reviewing Editor and Reviewer #1, and the evaluation has been overseen by a Senior Editor. The following individual involved in review of your submission has agreed to reveal their identity: Kate Cuschieri (Reviewer #3).

As is customary in eLife, the reviewers have discussed their critiques with one another. What follows below is the Reviewing Editor's edited compilation of the essential and ancillary points provided by reviewers in their critiques and in their interaction post-review. Please submit a revised version that addresses these concerns directly. Although we expect that you will address these comments in your response letter, we also need to see the corresponding revision clearly marked in the text of the manuscript. Some of the reviewers' comments may seem to be simple queries or challenges that do not prompt revisions to the text. Please keep in mind, however, that readers may have the same perspective as the reviewers. Therefore, it is essential that you attempt to amend or expand the text to clarify the narrative accordingly.

Essential revisions:

1) This paper has strong points and uses a rich data set but all three reviewers agree that the conclusion about the effect of primary HPV self-sampling on screening coverage, in particular among underscreened women, is too strong. The authors do not convincingly show that coverage under self-sampling is better than before the pandemic nor that self-sampling has led to improved participation in previously non-attending women. Conclusions should be in line with the presented data and all requests for more detailed information about self-sampling coverage data should be carefully addressed by the authors. The paper would benefit from characterizing the population of HPV self-sampling participants, in particular by showing data on the time to previous screen.

2) With regard to the HPV EVEN FASTER concept, this approach is interesting and novel but may be difficult to understand. A few more details on the concept would be helpful for the reader as well as more information on the implementation status of the national campaign (reviewer #1 and #2).

Reviewer #1 (Recommendations for the authors):

The data are interesting, but the analysis and presentation are rather crude. The scientific value of the paper in its current form is limited.

1. Data in figure 1 and Table 1 seem to come from different sources, but do not match. Why was the reduction in screening coverage only 4% when there were only a small number of invitations in April 2020 – Dec 2020?

2. The most obvious reason that the screening coverage in 2021 was back at pre-pandemic levels is that the number of invitations was normal again. Please add monthly figures of year 2021 to Figure 1 to illustrate this.

3. In the abstract, the claim is made that a strategy with organized primary self-sampling has resulted in a major improvement of population test-coverage. The increase was only 4% compared to year 2020 (which is not a major improvement), was not observed in the age range 51-60, and levels did not exceed pre-pandemic screening coverage levels. Therefore, it seems fair to conclude that the improvement was achieved because women were re-invited for screening again. Other countries probably showed similar screening coverage patterns without primary self-sampling when there was no concern anymore about crowding (because of availability of vaccines). Please tone down the claim in the abstract.

4. The authors also indicate in the discussion that self-sampling may reach underscreened women. The paper would benefit from showing year 2021 coverage data stratified by time to previous screen.

5. To gain insight into the acceptance of primary self-sampling, please present year 2021 data on the number of women that sent in a self-sampling kit and the number of women indicating that they preferred a provider-collected test.

6. The authors compare their coverage results with other countries (UK and US) where screening rates remained lower than expected. It is questionable whether this has anything to do with primary self-sampling as countries strongly differ in culture, attitude, trust in authorities, health systems etc. It is imaginable that in some countries, the introduction of self-sampling would actually lead to a decrease in screening coverage because of a low trust in the accuracy of a self-collection test. Please elaborate on this in the discussion.

7. A big concern about the Covid19 pandemic is that women who received an invitation in the first year of the pandemic did not show up at all. Were some of these women re-invited for self-sampling in 2021?

8. The authors describe the launch of a concomitant vaccination and screening campaign. No data are presented to show that this campaign was successful. The statement that Maternity Care Clinics expressed interest seems to indicate that this strategy has not yet been implemented and/or endorsed by the health authorities.

Reviewer #2 (Recommendations for the authors):

My detailed comments are below.

Methods

Perhaps worth stating the formula used to calculate coverage in the methods for clarity.

Some of the methods mentioned in the abstract are in the results in the main manuscript.

Results

In March 2021 when self-sampling was launched as the primary test was that excluding first attenders, those on follow-up and pregnant? If so worth clarifying as currently not clear.

Further ahead you state the self-sample strategy was implemented in February 2021, is this a discrepancy?

It was not clear whether the strategy to test and vaccinate at the same appointment was implemented or whether there is evidence that maternity clinics would like to do this but it has not been implemented. I think a bit more background on EVEN FASTER is needed in the methods (or result), I didn't realise it was part of a trial till the discussion.

Also perhaps clarify whether you wait for the HPV result prior to vaccinating or whether you vaccinate regardless of the HPV results.

How did laboratories 1 to 3 manage to maintain invitation levels similar to pre-covid but the others did not?

Discussion

There was not enough evidence presented in the manuscript to conclude that "The most likely explanation for the large increase in population coverage seen is that the sending of self-sampling kits resulted in improved attendance in particular among previously non-attending women."

The fact that coverage was very similar to that observed pre-pandemic suggests that the roll-out of self-sampling may have brought in those that were due to attend in 2020 but were either not invited or were not keen to go in person due t COVID. No evidence is presented on previous screening history of people returning a self-sample.

Similarly, no evidence was presented on cervical cancer rate, could the authors at least reference national cancer registration? Also, I would worry that the increase in cancer will come in 2023 onwards among women who missed a whole screening round.

Figure 1 title includes "Laboratory_ID==088" – please delete or add footnote to explain.

Reviewer #3 (Recommendations for the authors):

I enjoyed reading this manuscript – some comments are below.

Re "It is well known that when self-samples ……can be used to increase population coverage of screening, with improved attendance among under-screened and hard-to-reach women".

I think this is a slight generalisation/overstatement – the magnitude of increase in coverage v much varies according to geography/setting; there have been some exercises/programmes where offering self sampling vs status quo (ie reminder letter) has been modest at best e.g. [The STRATEGIC trial. J Med Screen. 2018 Jun;25(2):88-98].

Re "Although HPV-testing has been shown to have higher sensitivity in all age groups and higher specificity for women aged 30 or older compared to cytology-based screening." Again, this is a nitpick but historically the specificity of cytology in women over 30 has exceeded that of HPV testing in countries that had national, organised cytology based programmes with investment in EQA, training mandates etc.

I appreciate this is a concise manuscript and that one could revert to (15), but as a standalone piece, I was a little unclear on who exactly was eligible/invited for self sampling- I have mentioned this in the public commentary. I sentence or two of explanation would likely cover it.

https://doi.org/10.7554/eLife.80905.sa1

Author response

Essential revisions:

1) This paper has strong points and uses a rich data set but all three reviewers agree that the conclusion about the effect of primary HPV self-sampling on screening coverage, in particular among underscreened women, is too strong. The authors do not convincingly show that coverage under self-sampling is better than before the pandemic nor that self-sampling has led to improved participation in previously non-attending women. Conclusions should be in line with the presented data and all requests for more detailed information about self-sampling coverage data should be carefully addressed by the authors. The paper would benefit from characterizing the population of HPV self-sampling participants, in particular by showing data on the time to previous screen.

In the revised article we have added exactly this information, by performing individual-level registry linkages.

2) With regard to the HPV EVEN FASTER concept, this approach is interesting and novel but may be difficult to understand. A few more details on the concept would be helpful for the reader as well as more information on the implementation status of the national campaign (reviewer #1 and #2).

This was not a main subject of the paper, merely mentioned as another positive side-effect of the Covid pandemic. It is indeed a novel concept and for a more comprehensive understanding, a whole paper should be dedicated to it.

Reviewer #1 (Recommendations for the authors):

The data are interesting, but the analysis and presentation are rather crude. The scientific value of the paper in its current form is limited.

1. Data in figure 1 and Table 1 seem to come from different sources, but do not match. Why was the reduction in screening coverage only 4% when there were only a small number of invitations in April 2020 – Dec 2020?

Coverage is calculated over a screening interval. For example, if the screening interval is 5 years and during 1 year no samples are taken at all – the coverage will go down by 20%.

2. The most obvious reason that the screening coverage in 2021 was back at pre-pandemic levels is that the number of invitations was normal again. Please add monthly figures of year 2021 to Figure 1 to illustrate this.

The system was changed from sending invitations to sending out self-sampling kits instead.

3. In the abstract, the claim is made that a strategy with organized primary self-sampling has resulted in a major improvement of population test-coverage. The increase was only 4% compared to year 2020 (which is not a major improvement), was not observed in the age range 51-60, and levels did not exceed pre-pandemic screening coverage levels. Therefore, it seems fair to conclude that the improvement was achieved because women were re-invited for screening again. Other countries probably showed similar screening coverage patterns without primary self-sampling when there was no concern anymore about crowding (because of availability of vaccines). Please tone down the claim in the abstract.

We do not have data on what other countries did and what effect it might have had in other places. We have demonstrated that for us, this intervention did solve the problem.

4. The authors also indicate in the discussion that self-sampling may reach underscreened women. The paper would benefit from showing year 2021 coverage data stratified by time to previous screen.

This has been added to the revised version.

5. To gain insight into the acceptance of primary self-sampling, please present year 2021 data on the number of women that sent in a self-sampling kit and the number of women indicating that they preferred a provider-collected test.

There was no option for women to indicate that they preferred a provided-collected test.

6. The authors compare their coverage results with other countries (UK and US) where screening rates remained lower than expected. It is questionable whether this has anything to do with primary self-sampling as countries strongly differ in culture, attitude, trust in authorities, health systems etc. It is imaginable that in some countries, the introduction of self-sampling would actually lead to a decrease in screening coverage because of a low trust in the accuracy of a self-collection test. Please elaborate on this in the discussion.

Formally, anything is possible. We have shown that when a reasonably large population-based program switched strategy, the strategy switch was successful.

7. A big concern about the Covid19 pandemic is that women who received an invitation in the first year of the pandemic did not show up at all. Were some of these women re-invited for self-sampling in 2021?

If by “invitation” is meant “received a self-sampling kit by mail”, then all women due for screening during 2020 who did not attend did received the self-sampling kit in 2021.

8. The authors describe the launch of a concomitant vaccination and screening campaign. No data are presented to show that this campaign was successful. The statement that Maternity Care Clinics expressed interest seems to indicate that this strategy has not yet been implemented and/or endorsed by the health authorities.

The Even Faster campaign was only mentioned briefly as another positive effect of the Covid epidemic. Going into the details of it is outside the scope of this paper, but I can assure the readers that it is implemented (>100,000 participants so far) and duly endorsed by the health authorities.

Reviewer #2 (Recommendations for the authors):

My detailed comments are below.

Methods

Perhaps worth stating the formula used to calculate coverage in the methods for clarity.

Some of the methods mentioned in the abstract are in the results in the main manuscript.

Results

In March 2021 when self-sampling was launched as the primary test was that excluding first attenders, those on follow-up and pregnant? If so worth clarifying as currently not clear.

Yes, we have rewritten the wording to make this more clear.

Further ahead you state the self-sample strategy was implemented in February 2021, is this a discrepancy?

The policy switch had some piloting before full implementation.

It was not clear whether the strategy to test and vaccinate at the same appointment was implemented or whether there is evidence that maternity clinics would like to do this but it has not been implemented. I think a bit more background on EVEN FASTER is needed in the methods (or result), I didn't realise it was part of a trial till the discussion.

The Even Faster campaign was only mentioned briefly as another positive effect of the Covid epidemic. Going into the details of it is outside the scope of this paper, but I can assure the readers that it is implemented (>100,000 participants so far) and duly endorsed by the health authorities.

Also perhaps clarify whether you wait for the HPV result prior to vaccinating or whether you vaccinate regardless of the HPV results.

The Even Faster campaign was only mentioned briefly as another positive effect of the Covid epidemic. Going into the details of it is outside the scope of this paper, but in previously published papers on the concept it is clear that vaccination and testing is done at the same time (no waiting for results).

How did laboratories 1 to 3 manage to maintain invitation levels similar to pre-covid but the others did not?

The numbers on the X-axis referred to months of the year. 1,2,3 are January-March when screening went on as usual, before it was stopped. We have revised the Figure legend to make this more clear.

Discussion

There was not enough evidence presented in the manuscript to conclude that "The most likely explanation for the large increase in population coverage seen is that the sending of self-sampling kits resulted in improved attendance in particular among previously non-attending women."

The fact that coverage was very similar to that observed pre-pandemic suggests that the roll-out of self-sampling may have brought in those that were due to attend in 2020 but were either not invited or were not keen to go in person due t COVID. No evidence is presented on previous screening history of people returning a self-sample.

In the revised version, we have added this data (by individual-level registry linkages).

Similarly, no evidence was presented on cervical cancer rate, could the authors at least reference national cancer registration? Also, I would worry that the increase in cancer will come in 2023 onwards among women who missed a whole screening round.

This has been added.

Figure 1 title includes "Laboratory_ID==088" – please delete or add footnote to explain.

Changed as requested.

Reviewer #3 (Recommendations for the authors):

I enjoyed reading this manuscript – some comments are below.

Re "It is well known that when self-samples ……can be used to increase population coverage of screening, with improved attendance among under-screened and hard-to-reach women".

I think this is a slight generalisation/overstatement – the magnitude of increase in coverage v much varies according to geography/setting; there have been some exercises/programmes where offering self sampling vs status quo (ie reminder letter) has been modest at best e.g. [The STRATEGIC trial. J Med Screen. 2018 Jun;25(2):88-98].

The statement was our best assessment of the literature, as also indicated by systematic reviews.

Re "Although HPV-testing has been shown to have higher sensitivity in all age groups and higher specificity for women aged 30 or older compared to cytology-based screening." Again, this is a nitpick but historically the specificity of cytology in women over 30 has exceeded that of HPV testing in countries that had national, organised cytology based programmes with investment in EQA, training mandates etc.

This was how we had interpreted the data. Formal meta-analyses on this point is outside the scope of this paper.

I appreciate this is a concise manuscript and that one could revert to (15), but as a standalone piece, I was a little unclear on who exactly was eligible/invited for self sampling- I have mentioned this in the public commentary. I sentence or two of explanation would likely cover it.

We have tried to be as clear as possible that everyone eligible for screening was instead sent a self-sampling kit. Maybe the question is about the exceptions: that provider-collected sampling of pregnant women in maternity care continued and that the first screens for women entering the program (at age 23-25) was still by invitation to provider collected sampling, We have tried to describe this more clearly now.

https://doi.org/10.7554/eLife.80905.sa2

Article and author information

Author details

  1. Miriam Elfström

    1. Center for Cervical Cancer Elimination, F46, Pathology and Cancer Diagnostics, Medical Diagnostics Karolinska, Karolinska University Hospital and Division of Cervical Cancer Elimination, CLINTEC, Karolinska Institutet, Stockholm, Sweden
    2. Regional Cancer Center of Stockholm-Gotland, Cancer Screening Unit, Sweden, Stockholm, Sweden
    Contribution
    Conceptualization, Data curation, Formal analysis, Validation, Investigation, Project administration, Writing – review and editing
    Competing interests
    No competing interests declared
  2. Penelope Grace Gray

    Center for Cervical Cancer Elimination, F46, Pathology and Cancer Diagnostics, Medical Diagnostics Karolinska, Karolinska University Hospital and Division of Cervical Cancer Elimination, CLINTEC, Karolinska Institutet, Stockholm, Sweden
    Contribution
    Data curation, Formal analysis, Validation, Writing – review and editing
    Competing interests
    No competing interests declared
  3. Joakim Dillner

    Center for Cervical Cancer Elimination, F46, Pathology and Cancer Diagnostics, Medical Diagnostics Karolinska, Karolinska University Hospital and Division of Cervical Cancer Elimination, CLINTEC, Karolinska Institutet, Stockholm, Sweden
    Contribution
    Conceptualization, Resources, Supervision, Funding acquisition, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing – review and editing
    For correspondence
    Joakim.Dillner@ki.se
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8588-6506

Funding

Swedish Association of Local Authorities and Regions

  • Joakim Dillner

Cancerfonden (20 1199 UsF 02 H)

  • Joakim Dillner

Horizon 2020 Framework Programme (847845)

  • Miriam Elfström
  • Joakim Dillner

Swedish Government

  • Joakim Dillner

Stockholm County

  • Joakim Dillner

The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.

Acknowledgements

We thank the staff of the regional cancer center Stockholm Gotland for discussions and extraordinary efforts to maintain screening and cervical cancer prevention under difficult circumstances.

We also thank the staff of the Swedish National cervical screening registry for careful data collection and analyses as well as for openly sharing everything on internet.

Finally, we thank Helena Andersson for assistance in preparing the manuscript.

The work of the Swedish National Cervical Screening registry was supported by the Swedish Association of Local Authorities and Regions and the Swedish Cancer Society (20 1199 UsF 02 H). Miriam Elfström and Joakim Dillner are supported by the European Union’s Horizon 2020 Research and Innovation Program, RISCC under grant agreement No. 847845. The Swedish even faster campaign is supported by the Swedish government and by the Stockholm county.

The funding agencies have had no role in the design, execution, or interpretation of the study or in the decision to submit for publication.

Ethics

The publication of official statistics by the National Cervical Screening Registry is supported by these ethical permissions: Swedish Ethical Review Authority. Ref numbers: 2011/1026-31/4 and 2023-00289-02. The registry linkages using the NKCx were approved by the National Ethical Review Agency of Sweden (decision number 2023-00289-02). The agency is appointed directly by the government of Sweden, chaired by a senior judge and has the authority to determine requirements for consent, was not required for this study.

Senior Editor

  1. Eduardo L Franco, McGill University, Canada

Reviewing Editor

  1. Johannes Berkhof, Amsterdam UMC Location VUmc, Netherlands

Reviewers

  1. Johannes Berkhof, Amsterdam UMC Location VUmc, Netherlands
  2. Kate Cuschieri, NHS Lothian, United Kingdom

Version history

  1. Received: June 8, 2022
  2. Preprint posted: July 23, 2022 (view preprint)
  3. Accepted: November 16, 2023
  4. Version of Record published: December 12, 2023 (version 1)

Copyright

© 2023, Elfström et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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  1. Miriam Elfström
  2. Penelope Grace Gray
  3. Joakim Dillner
(2023)
Cervical cancer screening improvements with self-sampling during the COVID-19 pandemic
eLife 12:e80905.
https://doi.org/10.7554/eLife.80905

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https://doi.org/10.7554/eLife.80905

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