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Evidence supporting decision to stop cervical screening in women aged 20–24 years In September 2016, the Ministry of Health announced that the age women begin having cervical smear tests will change from 20 to 25 in 2018 as part of the wider implementation of HPV primary screening. This paper provides a summary of the evidence about cervical screening in women aged 20–24 years and includes an assessment of the harms and benefits of screening in younger women.

Summary of findings The National Screening Unit believes the balance of evidence is in favour of not undertaking cytology screening women aged 20–24 years. There is good evidence that screening women under the age of 25 is not effective and has the potential to cause more harm than good. In summary:  cervical cancer in young women is rare (in both HPV vaccinated and unvaccinated women)  evidence shows screening women aged 20 to 24 years has had little or no impact on the number of cases of cervical cancer or deaths in this age group or up to age 30 (Sasieni et al, 2009) o analysis of New Zealand data demonstrates that cancer incidence rates in women aged 20 to 24 years have not reduced since the introduction of the NCSP o the lack of reduction in cervical cancer rates is consistent with research conducted in other countries such as Australia, the UK and Canada  investigating and treating common cervical abnormalities in young women where the majority resolve without treatment leads to substantial over-treatment with associated anxiety and trauma of treatment, and an increased risk of subsequent premature births  the falling prevalence of cervical abnormalities due to HPV vaccination is predicted to decrease the performance of cytology screening, reducing its sensitivity and positive predictive value so that a larger proportion of women who screen positive will prove to be false positives (Franco et al, 2006) o the decrease in test performance will be exacerbated by challenges of maintaining skills in detecting cell changes when there are lower rates in cell changes where cytology is the primary screening tool  HPV vaccination has already been shown internationally to reduce the prevalence of high grade cervical abnormalities in young women within about 5 to 6 years of HPV vaccine programme implementation, even in countries with low HPV vaccine coverage o In New Zealand, as with other countries, the impact of HPV vaccination was first seen with dramatic reductions in genital warts case numbers o New Zealand’s cervical screening programme data potentially indicates an early decrease in high grade cytology rates in the 20–24 year age group over the 2013/14 period (over this period a proportion of women vaccinated through the catch up vaccination programme starting in 2009 would have started screening)  with the NZ cohort of young women vaccinated since 2009 entering the programme, the balance of harms and benefit will move further away from screening women aged 20 to 24 years. In 2018, 11 and 12 year old girls vaccinated as part of the routine cohort in 2009 will reach 20 and 21 years of age. Accelerated progress in vaccination is anticipated with both boys and girls likely to be offered vaccination from 2017.

Primary HPV screening is not recommended for women aged 20-24 years. HPV prevalence is too high in younger age groups and the specificity of primary HPV screening is too low potentially resulting in unacceptably high referral rates to colposcopy and treatment of inconsequential disease (Peto et al, 2004; Woodman et al, 2001; MASC, 2014).

The summary of evidence to support cessation of screening women aged < 25 years is outlined below including:  international recommendations and guidelines with respect to screening women aged 20-24 years; and a range of evidence cited to support the recommendations  the incidence and mortality of cervical cancer in New Zealand women age 20-24 years

Released September 2016  the impact of New Zealand’s cervical screening programme on cervical cancer incidence and mortality  consideration of the harms and benefits of screening women aged 20-24 years  the impact of HPV vaccination on the performance of cytology screening in women aged 20- 24 years  the impact of HPV vaccination on the incidence of cervical abnormalities  the potential of HPV vaccination to reduce inequities in cervical cancer incidence.

1. Guidelines and screening programmes generally recommend start ages from 20 to 30 years, with organised screening programmes generally recommending a starting age of 25 years. The International Agency for Research on Cancer (IARC) / World Health Organization undertook a review in 2004 and concluded that there is minimal benefit and substantial harm in screening below age 25 years, recommending that organised screening programmes should not start cervical screening before the age of 25 years (IARC, 2005). The European Guidelines recommend that screening should preferentially not start before age 25 or 30 years (Arbyn et al, 2010). Several countries in Europe start screening at these ages, eg the Netherlands and Finland start at age 30 years. France, Belgium, Ireland, Italy, and Norway start at 25 years. The English Advisory Committee on Cervical Screening recommended increasing the screening initiation age from 20 to 25 years in 2003, with the policy change implemented in 2004. Due to public pressure following a small number deaths in UK women under 25 years of age, this decision to initiate screening at 25 years was reviewed, with ratification of the decision by an extraordinary meeting of the Advisory Committee in 2009 (Kitchener, 2015; Sasieni et al, 2015). It was independently upheld in 2012 by the UK National Screening Committee. Following the UK National Screening Committee 2012 recommendation, Wales raised their screening starting age from 20 to 25 years in 2013, and Scotland in 2016. The Australian National Screening Programme was recently reviewed. Their Medical Services Advisory Committee recommended increasing the screening start age to 25 years (previously 18-20 years) alongside implementing primary HPV testing (MSAC, 2014). The new programme will commence on 1 May 2017.

The Canadian Task Force on Preventive Health Care recommended in 2013 against screening women aged 20-24 years, with routine screening strongly recommended from 30 years and a weaker recommendation for 25-29 years (Dickinson et al, 2013). However, most Canadian provinces still offer screening from 21 years as health practitioners transition to the relatively recent recommendations (Popadiuk et al, 2016).

The United States Preventive Services Task Force included consideration of the screening start age in its 2012 review of the evidence for liquid based cytology and high risk HPV cervical screening and reconfirmed its 2003 recommendation to include screening from age 21 years (USPSTF, 2014).

2. Summary of evidence used by other countries to determine their screening starting age More than 90% of new HPV infections at any age regress in 6-18 months with more persistent infection a prerequisite for progression to cervical intraepithelial neoplasia (CIN). HPV infections in woman aged older than 30 years are more likely to be persistent infections of long duration (Crosbie et al, 2013). Cervical cancer usually develops slowly and is preceded by precancerous changes to the cells of cervix. These changes are histologically defined as CIN of varying severity: CIN1, CIN2 and CIN3 (Vesco et al, 2011). CIN1 is an insensitive histopathology sign of infection and/or progression (it is highly subjective and not regarded as a definitive grade); CIN2 includes a heterogeneous group of lesions that may or may not progress to cancer, and CIN3 represents the most clinically relevant lesions and is the best surrogate end point for cervical cancer screening (Crosbie et al, 2013). The English screening programme stopped screening under 25 year olds in 2004.  The decision was largely based on data from a large case control study by Sasieni and colleagues (2003). Their study showed that screening was ineffective in preventing cancer in that age group. Screening detected a large number of low grade lesions, many of which would regress naturally, risking unnecessary treatment (Kitchener, 2015).  Sasieni et al (2003) showed that screening provided substantially less protection from cervical cancer in women 20-34 years compared with older women. Their study also showed that for women under 25 years, the majority of the small number of cancers that did occur - did so in spite of screening.  Subsequent Sasieni et al (2009) led research, using an enlarged dataset, confirmed that screening women 20-24 years was not protective, with little or no impact on rates of cervical cancer up to the age of 30 years. o There was no evidence that screening women aged 22-24 years reduced the incidence of cancer at ages 25-29 (odds ratio 1.11, 95% confidence interval 0.83 to 1.50). o Some uncertainly remained around the impact of screening on advanced cancers in women under 30 years because of their rarity.  Of the 73 women aged 20-24 years diagnosed with cervical cancer from January 1990 to April 2008, few (if any) were reported to be associated with lack of screening, with only five women having never been screened previously (Sasieni et al, 2009). Of note, it has been observed that when cancers do occur in young women a pelvic examination has too often not been performed in primary care, causing an unacceptable delay in referral (Kitchener et al, 2013). The change in England’s screening starting age in 2004 has not lead to an increase in cancer in the 20- 24 year age group when compared to the Wales and Scotland where the screening starting age remained at 20 years (Kitchener et al, 2013).  There was an observed an increase in cervical cancer incidence from 12 to 21 per million and high-grade CIN increased from 472 to 603 per million in women aged 25–29 years in north-east England after the starting age of screening was raised from 20 years to 25 years in 2004. However, the trends in cancer incidence were no greater than those observed in Scotland and Wales over the same period, even though these countries continued to begin screening at 20 years (relative rate 0.98, 95%CI 0.69–1.39) (Patel et al, 2012; Sasieni and Castanon, 2012). The increasing trend was attributed to an increase in background risk factors including the underlying rate of HPV infection, consistent with an increase in other sexually transmitted infections. The Australian National Screening Programme will stop screening women aged 20-24 years in 2017.  The Medical Services Advisory Committee considered a range of evidence from the National Cervical Screening Programme Renewal Evidence Review (MSAC, 2013) in relation to the screening start age. The Review included the systematic reviews undertaken for the US and Canadian Task Forces (outlined below), as well as Australian cervical cancer data and five primary studies examining the impact of cytology screening from 20 to 25 years.

Australian cervical cancer data - effectiveness of screening women aged 20–24 years  The Committee found that for women aged 20–24 years, cervical cancer is very rare, averaging 10 cases per year between 1991 and 2009. o The data indicate that cervical screening has had no to very minimal effect on cervical cancer incidence or mortality, with any reduction in cancer incidence not larger than ~1 cancer avoided per 100,000 women. o Cervical cancer mortality rates have not changed in 5-year periods before and after the screening program was introduced, with rates of between 0–0.2 deaths per 100,000 women

Released September 2016 3  The modelling evaluation in relation to the introduction of primary HPV testing predicted that delaying starting screening from 20 to 25 years had relatively limited to nil effect on incidence (0.6% increase in cervical cancer cases) and mortality of cervical cancer (0.0% increase in death from cervical cancer (MSAC, 2014; MSAC, 2013).

Australian review of primary studies examining the impact of cytology screening on women aged 20 to 25 years.  The Australian review considered the UK case control study by Sasieni et al (2009) which compared the effectiveness of screening in women aged 20-24 years versus 25-29 years. The Review found that this study provided strong evidence that screening women aged under 25 years did not reduce the incidence of cancer in women aged 25 -29 years.  They also considered two UK papers that examined temporal trends in cancer incidence (Patel et al, 2012; Sasieni & Castenon, 2012) that provided evidence that raising the screening start age to 25 years did not lead to an increase in cervical cancer incidence when compared to Wales and Scotland where the screening start age remains at 20 years.  The Australian review of five primary studies examining the impact of changing the cytology screening start age from 20 to 25 years is provided in Appendix 1.

The Canadian Task Force on Preventive Health Care (CTFPH, 2013) recommended screening start at 25 years of age based on a review undertaken by Peirson and colleagues (Peirson et al, 2012; Peirson et al, 2013). Findings included that:  For women below the age of 30 years, despite high participation in screening, the benefit of screening is unclear.  The reviewers cited the UK evidence from Sasieni and colleagues (2009) that there is no protective effect of screening for women who were tested between ages 20 and 21 or ages 22 to 24 years, stating that this was the only study they found that specifically examined screening for women aged 20-24 years.  The evidence review identified 22 studies that reported test accuracy in precancerous lesions, concluding that specificity for cytology was lower and risk of false positives higher for women less than 30 years of age. As a result women younger than 30 years are at higher risk of undergoing additional diagnostic procedures and potentially unnecessary treatment o In Canada, 9.8% of women aged 20 to 29 years have abnormal results, (compared to 1.6% in women aged 60–69 years); 1.5% have a high grade lesion and are referred to colposcopy and possible biopsy, and more than 50% of these women likely receive further treatment (CTFPH, 2013).

The Canadian recommendation to not screen women aged 20–24 years reflected the low incidence of cervical cancer and associated mortality (for the 2002–2006 period incidence was 1.3 per 100,000 and mortality 0.2 per 100,000 population) and the conclusion that the harms of screening outweighed the benefits.

The Canadian Task Force also noted that there has been no reduction in cervical cancer mortality in women aged 20–24 years since screening became widespread in Canada in the 1970s (CTFPH, 2013).

The United States Preventive Services Task Force (USPSTF, 2014) most recent recommendation in 2012 supported the continuation of a screen starting age of 21 years. This decision followed consideration of a review of the evidence for liquid based cytology and high risk HPV cervical screening they commissioned by Vesco and colleagues (2011) from the Agency for Healthcare Research and Quality. The review included evidence for determining the screen start age.  As with the Canadian and Australian evidence reviews, Vesco and colleagues reported a number studies that indicate the prevalence and incidence of HPV infection in women younger than 20 years is high, with most infections cytological abnormalities transient (Woodman et al, 2001; Peto et al, 2004).  The Vesco review included a US study that reported a higher risk of false positives in women younger than 25 years compared with women aged 25 to 29 years (3.1–3.5% vs 2.1%) (Insinga et al, 2004).  The review noted the UK’s move to lifting the screen start age from 20 to 25 years based and the evidence from Sasieni’s study (2009) that screening in women under the age of 25 years had not lead to a reduction in cervical cancer incidence diagnosed prior to 30 years, and the best available evidence indicating no protective effect from screening before age 32 years  Vescoe at al also noted Sigurdsson and colleagues’ (2007) population based study in Iceland which supported screening in their early twenties. It evaluated the value of cervical cancer screening in the 20 to 24 year age group and found no increase in invasive cervical cancer in this age group; however there was suggestion of a shift to earlier disease detection that could potentially be attributed to earlier screening.  The Vesco review considered the natural history of HPV infection and evidence of the slow progression from CIN to cancer; that cervical cancer is rare in younger age groups, and cervical screening has lower detection rates and higher false positive rates than in older women.

However, in contrast to the UK, Canada and Australia, the US Task Force did not adopt a later starting age, judging that the current evidence did not exclude potential benefits outweighing potential harms. Their decision was made in part because of uncertainty around the impact of a lack of a unifying national health system in the US. Also, there had been no studies comparable to the UK studies using US data and they were unsure if results from other countries assessments were generalisable to the US. The US does not have a national coordinated screening programme.

3. There is a low incidence of cervical cancer and associated mortality in New Zealand women aged 20-24 years

 The five year average cervical cancer incidence (2008–2012) for women aged 20–24 years is low with 3.3 (95%CI: 2.1–4.8) cases per 100,000 women (Smith, 2014). o The New Zealand figure is comparable with England where an incidence of about 1:30,000 per year is reported for the 20 to 24 year age group (Kitchener, 2013).  In comparison, the five year average cervical cancer rate for New Zealand women peaks in the 40–44 year age group at 14.1(95%CI:11.6 –16.9) cases per 100,000 (Smith, 2014).  The five year average cervical cancer incidence (2008–2012) for women aged 20–24 years and 25–29 years is similar for Māori and European/Other o For women aged 20–24 years incidence rates per 100,000 were 3.4 (95%CI 1.1–8.0) in Māori, 4.4 (95%CI 2.6–6.8) in European/Other, 0.8 (95%CI 0.0–4.5) in Asian women. There were no cases reported in Pacific women. o The cervical cancer incidence rates in older age groups are higher for Māori and Pacific than European /Other. For Māori women the highest reported incidence was reported in those aged 55–59 with 28.5 (16.9–45.1) cases per 100,000. For the same age group the incidence was 35.4 (16.2–67.1) in Pacific, 11.4 (4.2–24.9) in Asian and 9.2 (6.7–12.2) in European/Other (Smith, 2014). o The differences in relative incidence between these ethnic groups suggests that screening coverage does make a difference in older women, but does not affect cancer incidence in women aged 20 to 24 years.

A recent NSU review of NZ Cancer Registry data to identify women age 20–24 years with a histologically confirmed diagnosis of cervical cancer for the six year period 2008–2013 found 19 squamous cell type carcinomas, an average of 3.2 cases per year (National Screening Unit, 2015a).  Eighteen cases were squamous cell carcinoma (14 microinvasive, 4 invasive), and one was adenosquamous cell carcinoma (invasive).

Released September 2016 5  The 19 squamous cell type cancer cases represent two percent of all cervical cancer cases (n= 974) registered over the 6 year period o 18 of the 19 squamous cell type cancer cases were diagnosed in the 22–24 year age group. o Māori women presented with 21% of the squamous cell type cancer cases (four cases). There was one Asian women and 14 European women.  Mortality data for cervical cancer shows two deaths (type not specified) for the five year period 2008–2012, both deaths occurred in 2011 (2013 data not yet available). The two cases represent 0.96% of all 208 cancer deaths for 2008–2011 (mortality data for 2012 and 2013 not yet available).

Of the 19 squamous cell type carcinomas, two had negative only cytology screening prior to diagnosis of the cancer, four had low grade cytology and13 had either no screening or high grade cytology within six months of diagnosis. Due to small numbers, these findings should be interpreted with caution.

For each squamous cell carcinoma case, a pathologist and colposcopist reviewed the clinical information smear takers provided on the laboratory request forms that accompanied each cervical smear. The purpose of the review was to determine if screening could have prevented the cancer.  In summary, 74% (14 cases) of the 19 squamous cancers were microinvasive carcinoma, which can be more conservatively treated (eg, by cone biopsy) with a very small risk of infertility. However, one cannot predict the point or rate of development of microinvasion to a full state of invasion.  Two of the 19 squamous carcinoma cases (both invasive) had no screening history so are assumed to be direct referral due to symptoms. The remaining 17 cases had cytology. Of the 17 cases with at least one screening event: o the 3 invasive cancer cases had abnormal symptoms (postcoital bleeding (PCB), irregular bleeding, heavy vaginal bleeding, pain, mass) o 1 of the 14 microinvasive cases had abnormal symptoms (PCB and moderate contact bleed) and a high–grade smear o the remaining 13 microinvasive cases did not have abnormal symptoms recorded on the laboratory request and had at least one normal cervical smear test o 11 of the 14 microinvasive cases had a high–grade smear within 6 months of histological diagnosis and the remaining 3 cases had low–grade cytology prior. No microinvasive cases had only a negative cytology history (indicating that screening did not prevent disease).  In conclusion, all of the microinvasive cases were associated with screening results recommending referral according to New Zealand guidelines (either high–grade or two low-grade abnormalities).  Without the screening events, it cannot be determined if the microinvasive cases would have developed to invasive disease before the age of 25 years. However, screening this age group was likely to have been beneficial for these women as morbidity was probably lower with treatment of smaller lesions.

4. There has been no reduction in cervical cancer incidence and mortality in women aged 20– 24 years since the inception of New Zealand’s cervical screening programme

The incidence of invasive cancer is the most informative measure for evaluating the impact of cervical cancer screening programmes (Anttila et al, 2010). Australia’s New South Wales Cancer Council have recently completed an analysis of New Zealand’s trends in cervical cancer incidence since 1985, five years before the commencement of the NCSP, to 2013 (Smith et al, 2016). Key findings are summarised below with the full report provided separately (noting the report is confidential pending publication).

The analysis of cervical cancer trends does not demonstrate any reduction in the number of cancers in the 20–24 year age group since the inception of the NCSP. In contrast, women in the women aged 25 or older have shown a marked and gradual reduction in cervical cancer incidence.

The overall incidence of cervical cancer was 56% (95%CI: 51–60%) lower in the five year period 2009–2013 than it was in the five-year period 1985–1989 immediately prior to the NCSP implementation. Significant reductions were observed in women aged 25–49, 50–69 and 70+ years (Table 1; Figures 1 & 2).

The relative reduction in cervical cancer incidence rates in 2009–2013 compared to 1985–1989 were very similar in Māori and non-Māori women aged 25–49 (50% in Māori women and 52% in non-Māori women) and 50–69 years (65% in Māori women and 69% in non-Māori women)

Rates of cervical cancer in women aged 20–24 have not reduced over the same time period, rather they appear to be increasing.  Incidence appeared to increase after around 1996 in women aged 20–24 years.  The increasing trend was statistically significant for women aged 20–24 overall overall and for non-Māori women (p<0.01 in both cases), but not for Māori women (p=0.3).

The authors observed that their results suggest that cytology-based screening from age 20 years, as recommended within the current NCSP, has “likely had very limited, or no, impact in cervical cancer in women aged 20–24 years in New Zealand, and it has not prevented the observed increase in invasive cancer in this age group since the program was established”.

The findings of a substantial reduction in cervical cancer in women aged 25 and older, in contrast to little or no discernible reduction in women aged less than 25 years, are consistent with evidence from other countries regarding the limited effectiveness of cervical screening women aged younger than 25 years.

Table 1 – Five-year average cervical cancer incidence before the inception of the NCSP in New Zealand (1985-1989) compared to recent data (2009-2013), by age and ethnicity

All women Māori Non-Māori Incidence Incidence Incidence 1985-1989 2009-2013 SRR 95% CI 1985-1989 2009-2013 SRR 95% CI 1985-1989 2009-2013 SRR 95% CI All ages 16.81 7.38 0.44 (0.4 - 0.48) 32.53 14.76 0.45 (0.34 - 0.6) 15.6 6.5 0.42 (0.37 - 0.46) 20-69 22.42 9.90 0.44 (0.4 - 0.49) 46.29 19.86 0.43 (0.33 - 0.56) 20.6 8.6 0.42 (0.37 - 0.47) 20-24 1.29 3.29 2.55 (1.22 - 5.3) 2.51 4.74 1.89 (0.49 - 7.31) 1.1 2.9 2.75 (1.15 - 6.58) 25-49 23.02 11.67 0.51 (0.45 - 0.57) 41.52 20.57 0.50 (0.36 - 0.68) 21.3 10.3 0.48 (0.42 - 0.56) 50-69 27.65 9.33 0.34 (0.28 - 0.4) 65.62 23.22 0.35 (0.22 - 0.56) 25.3 7.9 0.31 (0.25 - 0.38) 70+ 24.04 10.12 0.42 (0.33 - 0.54) 28.66 20.02 0.70 (0.21 - 2.37) 23.9 9.9 0.41 (0.32 - 0.54) SRR = standardised rate ratio, the ratio between the incidence rate in 2009-2013 and 1985-1989. Results for age groups 25-49, 50-69 and 70+ years represent age-standardised incidence rates and a standardised rate ratio; standardising used the 2013 New Zealand Census night female population. Results for ages 20-24 represent age-specific incidence rates and an age-specific incidence rate ratio. Results in bold are significant at P < 0.05 level

Released September 2016 7 Figure 1. Five-year average cervical cancer incidence by age in a) all women; b) Māori women; c) non-Māori women a)

b)

c)

Year is the middle year of the five-year period for which the average is shown. Age-standardising used the 2013 New Zealand Census night female population. Figure 2. Five-year average cervical cancer incidence in women aged 20–69 years by age

a) Māori women

b) Non- Māori women

Year is the middle year of the five-year period for which the average is shown.

5. The harms appear to outweigh the benefits of screening the 20-24 year age group

Recommendations to not screen women aged 20–24 years reflect the low incidence of cervical cancer and associated mortality in this age group, the uncertain benefit of screening for women aged 20–24 years, immediately or at older ages, the high risk of false positives and associated harms compared with screening older women (CTFPH, 2013).

HPV prevalence decreases with age as a result of clearance and reduced opportunity for reinfection. Around 40% of 20–24 year olds are HPV positive falling to about 7% at age 50 (Kitchener et al, 2006). The mean age of acquiring HPV infection and developing CIN3 (around 30 years of age) suggest that it takes about 10 to 15 years to develop a true cancer precursor lesion (Kitchener, 2015). The Australian Medical Services Advisory Committee (MSAC, 2014) summarised the evidence on the natural history of HPV infections and the benefit and harms of screening young women as follows:  the median time to clear an HPV infection is estimated to range from 8–14 months with longer clearance times for prevalent infection (NHMRC, 2005).  there is a relatively high prevalence of HPV infection and a very low incidence and mortality of cervical cancer in young women o Peto et al (2004) reported a decrease in prevalence of oncogenic HPV genotypes as age increases (19% in women younger than 25 years of age to less than 3% in women 40 years of age and older). o Ho et al (1998) reported a point prevalence of around 20–25% among young women (median = 20 ± 3 years of age). o Woodman et al (2001) reported a cumulative prevalence rate of 44% from repeat testing of teenagers over three years  Tabrizi et al (2012) undertook a study on the prevalence of HPV in women aged 18–24 years before and after the introduction of the HPV vaccination program in Australia. This study reported prevalence rates of 47% for all oncogenic HPV genotypes amongst this age group in the pre-vaccination years (2005–2007) and 34.2% post-vaccination years (2010–2011). Australian National Screening Programme data shows no effect on cervical cancer incidence from screening women aged 20–24 years (MSAC, 2014).  Between 1991 and 2009, new cases of cervical cancer in women aged 20–24 years averaged 10 cases a year (range 4 to 17), with around two deaths per annum over the same period.  A number of organised screening programmes in other developed countries that did not screen below age 25 years had similar incidence and mortality There are high levels of investigation and treatment in young women for abnormalities that will likely regress if left untreated.  All high-grade cytology abnormalities are currently recommended to be referred to colposcopy.  Data from the Australian NCSP shows higher rates of high-grade abnormalities detected by cervical screening in women 20–25 years compared to older age groups (2.9% of women aged 20–25 years, 2.3% of women aged 30–34 years and 1.1% of women aged 40–45 years) (MSAC, 2014).

Released September 2016 9  New Zealand 2012 data shows rates of cytologically reported high grade abnormalities (ASC- H and HSIL) as approximately 3.1% for both 20–24 and 25–29 year age groups with a gradual decline in the 30+ age groups (eg, 1.4% for 35–39 year age group), likely reflecting the high prevalence of HPV infections in the younger age groups (National Cervical Screening Programme, 2015a; Smith et al, 2014). A histology sample is often taken during a colposcopy examination to confirm the colposcopic findings.  Australia data show that young women have the highest number of histology tests performed per 100 screening tests compared to older women; women aged 20–29 years have 5.2 histology tests performed compared with 3.0 histology tests in women aged 50–54 years (MSAC, 2014).  NZ figures also show higher numbers of women who had histology performed in the under 30 year age group. For the 12 month period July to December 2014, of the 1,693 women with histology performed within 90 days of a high grade cytology report, 321 (19%) were aged 20–24 years and 413 (24.4%) were aged 25–29 years compared with 95 (5.6%) in those age 50–54 years (Smith et al, 2015). Confirmed high grade abnormalities are usually treated, however these abnormalities may regress if left untreated (NHMRC, 2005).  Progression of cervical intraepithelial neoplasia to cancer is slow with Vesco at al’s (2011) evidence review citing estimates of 20–30% progression over 5 to 10 years  Vesco et al (2011) included the following study findings in their review: o A review of studies of regression, persistence and progression of CIN over 1–25 year follow-up periods found regression or persistence was most common with CIN1 (57% regressed, 32% persisted and 1% progressed). For CIN2 the results were 43%, 35% and 5% respectively; and for CIN3 they were 32%, 56% and >12% respectively (Oster et al,1993). o More recent data indicates that CIN1 does not predict any meaningful risk of CIN3 (Schiffman et al, 2007; Cox et al, 2003) o A Canadian cohort study that managed CIN2 conservatively, reported the majority of cases with mild dysplasia will regress to normal cytology, as will half of those with moderate dysplasia, and that most of the recession occurs within 2 years of diagnosis of dysplasia: For CIN2 there was a 0.3% progression to invasive cancer within two years, 0.7% within five years and 1.2% within 10 years. Regression to normal cytology was reported at 6.9% within two years, 29% within five years and 53.7% within 10 years. Rates of CIN3 progression to invasive cancer were higher with 1.6% within two years, 2.6% within five years, and 9.9% within 10 years (Holowaty et al,1999).  The harms associated with false positive results include anxiety associated with further tests, the need for colposcopy and subsequent treatment that may cause unnecessary harm, in particular future adverse pregnancy outcomes (Peirson et al, 2012; Arbyn et al, 2008; Kyrgiou et al, 2006; cited in MSAC, 2014).

Landy and colleagues (2014) have attempted to quantify the benefits (cancer prevention and down- staging) and harms (recall and excess treatment) of cervical screening starting at 20 years rather than from 25 years.  They used routine screening data, cancer incidence data and national audit data to compare Wales (screening from age 20 years) with England (screening from 25 years).  They considered the number of screening tests, number of women with an abnormal screen, number of referrals to colposcopy, number treated (excision or ablation), number with micro- invasive cervical cancer (stage 1A) and number with frank cervical cancer (stage 1B or worse)  They found that inviting 100,000 women for screening from age 20 compared with age 25 resulted in an extra 119,000 screens, 20,000 extra non-negative results, 8000 extra referrals to colposcopy and an extra 3000 women being treated.  To prevent one frank cancer (stage 1B+) required between 12,500 and 40,000 additional screening tests (depending on the scenario) in the 20–24 age group and treating between 300 and 900 women for cervical intraepithelial neoplasia who would not otherwise be treated. The authors acknowledge that while there is some uncertainty about the numbers of additional 1B or worse cancers that are prevented by starting screening from age 20 years, it is unlikely to be more than about 1 per 10,000 women population.  The authors judged that treating 300 women by loop excision of the transformation zone is not justified to prevent one case of frank cervical cancer given the related complications. For example citing 3.8% severe haemorrhage in a series of 1000 patients treated in Oxford (Hallam et al,1993); 0.6% major complications and 9.1% minor complications in a US study (Dunn et al, 2004); and 67% reporting pain in a UK study (Tombola Group, 2009).  The Landy study did not attempt to quantify the number of women with anxiety or who had preterm deliveries as a result of treatment.

Castanon et al (2014) have confirmed the increased risk of pre-term delivery associated with excision of cervical neoplasia. Overtreatment of screen detected CIN in women aged 20–24 years will mean additional women will deliver prematurely.  Women with abnormal cytology are referred to colposcopy for further investigation. Those found with a high grade CIN on punch biopsy are treated most commonly by large loop excision of the transformation zone (Lletz).  Castanon and colleagues undertook a large case-control study and confirmed almost all published studies findings that large excisions increase the risk of pre-term delivery. The study found a doubling of the risks of both preterm and very preterm births with one in six births in women who had previously had a large excisional procedure at colposcopy pre-term. These results were statistically significant.  The absolute risk for pre-terms births was 15.3% in women with large excisions and 7.2% with a punch biopsy before birth compared with 6.7% in the general population. For very pre- term births, the absolute risk was 6.4% of births in women with very large excisions compared with 2% in small excisions and 1.4% in the general population.

In the US, a guidance panel was convened in response to moves towards primary HPV screening. It included representatives of the Society for Gynaecological Oncology, The American Society of Colposcopy and Cervical Pathology, American College of Obstetricians and Gynecologists, American Cancer Society, American Society of Cytopathology and the College of American Pathologists (Huh et al, 2015).  This group concluded that primary HPV screening should not be initiated prior to 25 years of age.  This panel had concerns regarding the potential harms of beginning HPV primary screening prior to 25 years of age, particularly with regard to the number of colposcopies, despite the increased detection of disease. The panel observed that progression to cancer is uncommon, and the detection of most of the disease found in the 25-29 year age group can be safely deferred until age 30 and older, with it being unclear if the identification of women with CIN3+ at earlier ages would translate into a meaningful reduction in cervical cancer (Huh et al, 2015).

6. Impact of the introduction of the HPV vaccine on cytology performance

The specificity of cervical cytology is high, with for example a meta–analysis that included 60,000 women in 6 different controlled studies demonstrating a specificity of 96.3% for high grade lesions.

Released September 2016 11 However, the sensitivity of cytology is limited with the same study reporting the sensitivity of a single pap smear to detect high grade lesions as only 53% compared to 96.1% with HPV testing (Cuzick et al, 2006). Both the negative predictive value and positive predictive value of a test are directly affected by the prevalence of the condition being screened. The falling prevalence of cervical abnormalities due to HPV vaccination is predicted to decrease the performance of cytology screening, reducing its sensitivity and positive predictive value so that a larger proportion of women who screen positive will prove to be false positives (Franco et al, 2006). The decrease in test performance will be exacerbated by difficulties for cyto-scientists in accurately detecting abnormalities when the prevalence of disease is very low (Freeman-Wang et al, 2016).  A reduction in the proportion of slides with abnormal results and the tedium of reading many more unexceptional slides increases the risk these abnormalities will be missed.  A shift in interpretation may also occur, with over calling of low grade changes as the cyto- scientists fear that clinically relevant abnormalities will be missed, resulting in a loss in specificity and further decline in PPV.  Both these scenarios impact on the cytology sensitivity and specificity (Franco et al, 2006).  It is acknowledged that the threshold at which these effects will have a significant impact on reporting performance is not established. Screening New Zealand women aged 20–24 years will become increasing problematic as the cohort of women vaccinated against HPV types 16 and 18 reaches their 20s. In 2018:  11 and 12 year old girls vaccinated as part of the routine cohort in 2009 will be 20-21 years of age (their overall 3 dose vaccine coverage was around 54% and 2 dose coverage was 56%)  13 to 15 year olds vaccinated as part of catch up cohort in 2009 will be 22–24 years of age.  16 to 20 year olds vaccinated as part of catch up cohort in 2009 will be 25–29 years of age Given screening is questionable in unvaccinated women aged 20–24 years, it is judged as becoming unjustifiable in this age group in the face of increasing vaccination (Sasieni et al, 2009).

7. HPV vaccination has already been shown to reduce the prevalence of genital warts and high grade cervical abnormalities in young women, even when HPV vaccine coverage is low.

Persistent infection with the high risk oncogenic HPV types 16 and 18 accounts for approximately 70% of all types of cervical cancer (Crosbie et al, 2013). A further 20% are caused by HPV types 31, 33, 45, 52 and 58. Types 6 and 11 cause more than 90% of genital warts. In New Zealand the prevalence of HPV 16/18 in confirmed high grade disease is comparable to that seen in Australia and Europe with a recent study reporting a combined prevalence of 62%. The same study reported a positivity rate for any oncogenic HPV infection of 95% (Simonella et al, 2013). The quadrivalent Gardasil® vaccine protects against HPV types 6, 11, 16 and 18. The bivalent vaccine (Cervarix®) protects against HPV types 16 and 18. A new 9-valent Gardasil® vaccine includes 5 additional types (31, 33, 45, 52 and 58) has been recently licensed in the USA (Markowitz et al, 2016), the European Union, Australia and Canada. New Zealand’s Pharmac is currently assessing the 9-valent vaccine, with a move to fund its use for both boys and girls old anticipated for 2017. Only a two dose schedule will be required for those less than 14 years of age, and there will be a catch up programme for young women and men aged up to 26 years. It is likely that most girls aged 12–13 years will be HPV naïve at the time of vaccination. The impact of HPV vaccination will be attenuated in young women aged older than 14 to 15 years vaccinated in catch up groups when these programmes were first implemented. These young women are more likely to have already been sexually active and exposed to HPV at the time of vaccination (Cuzick et al, 2010; Gertig et al, 2013).

HPV Infection is common worldwide. Mot sexually active individuals will acquire the virus at some point, with the lifetime cumulative risk for HPV infection greater than 80% (Dunne et al, 2007). In developed countries prevalence peaks in young women and decreases after 35 years of age (Crosbie et al, 2013) with initial infection usually between 15 and 24 years of age (Schmeler et al, 2016).  A USA study found that in a cohort of sexually active HPV negative young women, 17% were HPV positive within 12 months and 55% within three years of entry into the study. Of those infected, 59% were infected with a high risk strains (Moscicki et al, 2001).  The US estimates that approximately 13% of women aged 15 years have ever had sex (Guttmacher Institute, 2006); and a survey in the UK estimates that 26% of women had sex by age 16 (Wellings et al, 2001).  It is estimated that 30–40% of women in the UK will be sexually active by age 17, and around 70% by age 19 (Cuzick et al, 2010).  In a NZ secondary school study, 24% of women aged 15 years reported they had ever had sex; and 37% by age 16. Approximately 8% reported having had sex by age 13 or less (Clarke et al, 2013). In April 2007, Australia introduced school based quadrivalent HPV vaccination programme targeting women aged 12–13 year old girls. Two-year catch up programmes were offered for 14–17 year old girls in schools and for women aged 18 to 26 year through GPs (Gertig et al, 2013).  Uptake of the quadrivalent vaccine has been high. Nationally 73% of females aged 12–13 years in 2007 were fully vaccinated, with uptake of the first two doses close to 80% (Barbaro et al, 2014).  The lowest rates were in 20–26 year olds with 52% receiving the first dose (cited in Ali et al, 2013).  Just over 73% of young women who turned 15 years of age in 2014 completed the three dose schedule (cited in Saville, 2016). HPV vaccine impact, genital warts – Australia  The impact of vaccination can be seen first with genital warts given the time to develop genital warts after infection is months rather than years (Brotherton et al, 2010).  Two years after the vaccine introduction, genital warts diagnoses at sexual health clinics had declined by 59% among vaccine eligible women aged 12–26 years in 2007 (Donovan et al, 2011). As expected the rates of genital warts in women over 30 years did not decrease.  Australian sexual health clinic data shows a 92.6% drop in the proportions of under 21 year olds with genital warts (from 11.5% to 0.85%) and a 72.6% drop in women aged 21–30 years (from 11.3% to 3.1%) in the vaccination period 2007 to 2011. In 2011 no genital warts diagnoses were seen in women under 21 years of age who reported prior HPV vaccination (Ali et al, 2013). HPV vaccine impact, cervical abnormalities – Australia  Within five years of the implementation of the Australian HPV vaccination program, the declines in HPV prevalence have resulted in a major reduction in histologically confirmed high grade abnormalities, reported both at the ecological level (Brotherton et al, 2011) and through studies linking HPV vaccine and cervical screening registers (Gertig et al, 2013; Crowe et al, 2014).  Declines in the prevalence of biopsy-confirmed high-grade abnormalities were first seen in the youngest age cohorts, and are now gradually being seen in older age groups as the vaccine cohorts become eligible for screening (Brotherton et al, 2015; Saville, 2016). o In Australia from 2004-2006 to 2012, for women younger than 20 years, the rate of CIN2/3 lesions dropped by 53%. In women aged 20–24 years, the rates of high grade lesions were stable until 2010, then they decreased by 21% in 2012 (AHIW 2014). o Early data from the Victorian Cervical Cytology Registry showed a decrease in the number of histologically confirmed high-grade cervical lesions detected in women aged 20–24 from 19.8 per 1,000 in 2008 to 15.7 per 1,000 in 2011 (VCCR, 2011 cited in MSAC, 2013).

Released September 2016 13 o More recent Victorian state data now show a 17% decline in histologically confirmed cervical pre-cancerous lesions over the two year period 2012–2014 in women aged 25 to 29 years (from 18.1/1000 to 15.6/1000; P<0.0001) (Brotherton et al, 2016). o The Victorian data has also been observed to show the first signs of a decline in the underlying rising rates of high grade lesions in the 30–34 year olds as vaccinated cohorts reach this age range. These women were aged 18–26 years when vaccinated through the catch-up program (Brotherton et al, 2016).  Four years after the introduction the HPV vaccine, population data shows a risk reduction of 46% for histologically confirmed high grade lesions and 34% for other cervical abnormalities in young women who were fully vaccinated before attending their first cervical screening (Crowe et al, 2014).  Australia has seen substantial reductions in the prevalence of vaccine preventable HPV types in vaccinated and unvaccinated women, indicating possible herd immunity; and reductions in HPV genotypes not targeted by the vaccine suggesting partial cross protection (Tabrizi et al, 2014). In 2007, the United States introduced the quadrivalent HPV vaccination following licensure in 2006. The vaccine was available for girls aged 11 to 12 years through to 26 years. The bivalent vaccine was approved in 2009. A nine valent vaccine with additional types 31,33,45,52 and 58 was licensed in the USA at the end of 2014. Almost all vaccines used through 2014 were the quadrivalent (Markotwitz et al, 2016). Vaccine coverage has been low, with a 2013 survey showing that of girls aged 13–17 years 57% had received at least one dose and 38% had received three doses (Stokley et al, 2014). HPV vaccine impact – USA  The National Health and Nutrition Examination Study (HNANES), a cross-sectional survey conducted for the Centers for Disease Control and Prevention (CDC), found that: o In the first four years of the vaccine period (2007–2010), and despite low vaccine coverage, there was a 56% decrease in the HPV prevalence among female aged 14 to 19 years compared with the pre vaccine period. (Markowitz et al, 2013).  Extending the analysis of cervicovaginal samples through to 2012, comparing the 2003-2006 pre-vaccine and 2009–2012 post-vaccine periods, NHANES found that: o Within six years of vaccine introduction there was a 64% reduction for the HPV types included in the vaccine in sexually active young women aged 14-19 years, and a 34% reduction in those aged 20–24 years. o The greater decline in the 14–19 year age group was consistent with higher average vaccine uptake reported in this age group.  The decline in vaccine type prevalence was larger than expected based on the US three-dose coverage. The authors suggested the outcome could be due to herd protection and the effectiveness of less than a complete three-dose vaccine course for which there is increasing evidence (Markowitz et al, 2013) In September 2008, the UK introduced a bivalent HPV vaccine effective against HPV types 16 and 18, shifting to the quadrivalent vaccine in 2012. Girls 12–13 years were vaccinated through a school programme and a catch up programme delivered vaccine for those up to 18 years during the following 3 years. In Scotland, where cervical screening starts at age 20 years, immunised women started attending cervical screening in late 2010. Their data has been used to assess early population level impacts of vaccination. In England screening begins at 25 years and the older immunised cohort will not have started cervical screening until later in 2015 (Freeman-Wang et al, 2016). HPV vaccine impact – UK  Scotland’s school based uptake of HPV vaccination has been high, with sustained coverage above 90% for girls in the routine cohort aged 12–13 years  Overall vaccine uptake in the older catch-up group was around 66%. o Uptake was 80% in 13–17 year old girls still at school, and 30% in older girls who had left school (Kavanagh et al, 2014).  Within four years of vaccine introduction, using cervical screening samples and comparing the 2011–2012 period with 2009–2010 (before vaccinated girls were eligible for screening), Scottish population level data shows the prevalence of HPV 16 and 18 had decreased significantly in vaccinated women aged 20. The reduction was from 29.8% (95% CI 28.3, 31.3%) to 13.6% (95% CI 11.7,15.8%). A reduction was also seen in some other high risk types suggesting cross protection against closely related strains (Kavanagh et al, 2014).  For women aged 20–21 years in 2008–2012 and screened through the cervical screening programme a statistically significant reduction in diagnoses of CIN1, 2 and 3 (29%, 50% and 55% respectively) was also observed in association with receiving 3 vaccine doses (Pollock et al, 2014).  A relatively high proportion of the catch up population is likely to have been sexually active before vaccination. The effect on HPV associated disease will be even more dramatic once the routine cohort of 12–13 year olds vaccinated in the school programmes age through, given their higher levels of vaccination coverage and sexual naivety (Pollock et al, 2014).  The 12–13 year old cohorts would have started presenting for smears from age 20 years in late in 2015 (Kavanagh et al, 2014; Pollock et al, 2014), however, the majority will now start screening later as Scotland is moving to a screening initiation age of 25 years in June 2016. In February 2009, New Zealand commenced the school based delivery HPV quadrivalent vaccine, following introduction of the vaccine in September 2008. Girls in year 8 (approx ages 11–12 years) are offered immunisation. An initial catch up programme was offered until the end of 2010 for women born on or after 1 January 1990, that is up to 20 years of age; and the vaccine remains free for women up to 20 years of age.

Immunisation coverage is measured by eligible birth cohort (Ministry of Health, 2014).  Approximately 54% of girls born in 1997 (aged around 12 years in 2009 when the school based programme started) received 3 doses (as of 28 February 2014).  In contrast, 48% of women born in 1991 (aged around 18–19 years of age during 2009) received 3 doses, with a proportion of this age group requiring completion of the schedule outside of school.  Overall coverage is between 51% and 56% across the 1992 to 2000 birth cohorts, for whom vaccinations were generally accessed through the school based programme. International evidence now shows a two-dose vaccine schedule to be efficacious (Dobson et al, 2013) with a number of countries changing to offering two doses instead of three. The UK changed to a two dose schedule in September 2014 (Freeman-Wang et al, 2016).

New Zealand two dose coverage levels are higher than for three doses.  56% of girls aged around 12 years in 2009 received 2 doses (54% for 3 doses)  52% of women aged around 18–19 years in 2009 received 2 doses (48% for 3 doses) HPV vaccine uptake has been higher in young Māori and Pacific women than in the Other ethnic group (non-Māori and non-Pacific) (Ministry of Health, 2014).  For girls aged around 12 years in 2009 (born in 1997) o Three dose coverage was 74% for Pacific, 63% for Māori and 48% for Other o Two dose coverage was 77% for Pacific, 67% for Māori and 50% for Other  For girls aged around 12 years in 2011 (born in 1999) o Three dose coverage was 77% for Pacific, 64% for Māori and 51% for Other o Two dose coverage was 83% for Pacific, 69% for Māori and 53% for Other  For young women around 18–19 years in 2009 (born in 1991) o Three dose coverage was 38% for Māori, 50% for Pacific and 51% for Other o Two dose coverage was 45% for Māori, 57% for Pacific and 54% for Other

Released September 2016 15 The most recent analyses, undertaken by the Ministry of Health in May 2016, indicate coverage is increasing. For the 2002 cohort (aged about 12 years in 2014):  Overall coverage for three doses is 64%, compared with 54% for 12 year olds when the programme started in 2009; and two dose coverage is 68% compared with 56% in 2009  Three dose coverage is 72% for Māori, 69% for Pacific, 72% for Asian and 58% for Other (non-Māori, non-Pacific and non-Asian)  Two dose coverage is 78% for Māori, 76% for Pacific, 76% for Asian and 61% for Other

HPV vaccine impact, genital warts – New Zealand  The impact of HPV vaccination was seen first with reductions in genital warts.  In the Auckland DHB, 51.7% of eligible students (years 8,12 and 13) were vaccinated during 2009. Despite the relatively low levels of vaccine coverage, Auckland sexual health clinic showed an early response to the HPV vaccine programme. o Within two years of vaccine introduction genital warts incidence decreased. Between 2007 and 2010, there was a 63% decline in the incidence of genital warts in women aged less than 20 years (Oliphant et al, 2011; Ali et al, 2013). There were no changes in genital warts incidence in women aged over 20 years. o A 43.7% decrease in genital warts case counts at sexual health clinics was seen between 2009 and 2013; and a 53.4% decrease for Family Planning clinics (ESR, 2016). Decreases were seen in the 15–19 year and 20–24 year age groups, in both males and females, with case numbers remaining stable over the five year period for all other age groups. HPV vaccine impact, cervical abnormalities – New Zealand  As vaccinated cohorts enter the New Zealand screening programme, it is anticipated that the proportion of satisfactory cytology samples reported as HSIL will gradually reduce, and that this will occur in younger age groups first.  Data from cervical screening programme does indicate a small decrease in high grade cytology rates in the 20–24 year age group over the 2013/14 period. Rates in the other age groups are unchanged (Figures 3 & 4) (Smith et al, 2015).  This decline potentially indicates an early impact of HPV vaccination with the 20–24 age group having been eligible for the catch-up vaccination programme four to five years previously (in 2009) when they would have been aged 15 to 20 years. The oldest birth cohorts eligible for vaccination through the publicly funded program would be aged up to 23 or 24 years over the July to December 2014 period (Smith et al, 2015). o The vaccine affect would have been attenuated for the 20–24 year age group group as vaccine coverage in the catch-up cohort was lower at around 48% and a proportion of the cohort would have been sexually active before vaccination.  HSIL rates in women aged less than 20 years are quite variable as there are likely to be far fewer women of this age group attending screening, with routine screening not recommended for women aged less than 20 years (Smith et al, 2015).  A preliminary review of 2015 NCSP cytology data shows a small unexplained increase in high grade changes across all age groups. Final 2015 data and at least 6 to 12 months of 2016 data are required to more fully analyse the most recent trends. The age-wide increase possibly relates to changes in the configuration of laboratory services and/or small shifts in cytology smear reading sensitivity. Figure 3. Trends in the proportion of total satisfactory samples reported as HSIL, by age, 2013–2014 Source: Smith et al, 2015

Figure 4. Cervical Screening Programme longer term trends high grade cytology rates by age group, July 2008–December 2009

Source: Smith et al, 2015

Released September 2016 17 8. The HPV vaccine programme has the potential to improve equity in preventing cervical cancer

Indigenous populations in the four high income countries Australia, New Zealand, Canada and the USA share a common history of colonisation and worse health outcomes than the general population. Cervical cancer incidence is greater in indigenous compared with non-indigenous populations in these four countries where overall rates of cervical cancer are low. Women of lower socioeconomic status are also at high risk of cervical cancer in a number of countries (Barbaro et al, 2014). Lack of access and low participation in screening is partly attributed to the differences, as is delayed or in adequate treatment following diagnosis (Moore et al, 2015; Vasilevska et al, 2012, Kang, 2015).

A 2004 New Zealand study used 1988–1998 cervical cancer incidence data to explore the relationship with socioeconomic deprivation. The study found greater deprivation was associated with increased incidence of cervical cancer in all age groups apart from women aged below 30 years where it “appeared non-existent”. The authors suggested that the benefit of cervical screening is limited in younger women and that the benefits and costs of screening this age group deserved further investigation. The study did not assess the association between ethnicity, cervical cancer incidence and socioeconomic deprivation as the authors judged the ethnicity data to lack sufficient accuracy (McFadden et al, 2004).

Cervical cancer is largely preventable with enhanced screening uptake providing opportunities to reduce cervical cancer risk. HPV vaccination likely provides a particularly important health intervention in low socioeconomic groups and indigenous populations (Vasilevska et al, 2012). However, if women in lower socioeconomic and minority or indigenous ethnic groups are less likely to participate in HPV vaccination programmes, there is concern that current inequities in cervical cancer incidence and mortality may widen (Barabaro et al, 2014).

A recent New Zealand study showed that the overall prevalence of vaccine- included types in CIN2/3 was similar in Māori and non-Māori women, implying the long term effects of vaccination will be similar in the two groups. Given the higher vaccination coverage rates in Māori, it has been suggested that better post vaccination outcomes may be achieved in Māori (Kang et al, 2015).

Addressing inequities in cancer incidence will require at least the same uptake of the HPV vaccine across ethnic groups and socioeconomic status, and also the same cervical screening coverage from 25 years of age upwards. There is no evidence of a gain for Māori or non-Māori women aged 20–24 years from participation in New Zealand’s cervical screening programme.

New Zealand cervical screening coverage increases with age and is higher in the European/Other group compared with Māori, Pacific and Asian ethnic groups.  Overall screening coverage for women aged 25–69 years in the three years prior to 31 March 2016 (hysterectomy adjusted) was 76.6% o 65.8% in the 25–29 year age group, 72.4% in the 30–34 years age group and peaking at 81.2% in the 45 to 49 year age group  The coverage target of 80% was met only in European /Other women at 81.3% in contrast to 76.2% coverage in Pacific, 65.8% in Māori women and 65.1% in Asian o for younger women aged 25–29 years European/Other coverage was 73.4% Māori 63.6%, Pacific, 62.5% and Asian 44.8%  Coverage in the 20 to 24 year age group is lower than for other age groups and should be interpreted with caution, as many women will have had a shorter timeframe in which they were eligible for screening. o Coverage in Māori women aged 20 to 24 years is approximately 41%, Pacific, 34%, Asian 15.7% and European/Other 58% The delivery of HPV vaccination through organised school based programmes has created the opportunity to improve equity in cervical cancer prevention. For example:  In Australia HPV vaccine delivery has been much more equitable than their cervical screening programme (Barbaro et al, 2014). o There is only a 4.1% difference in the rate of full vaccination between the least and most disadvantaged groups (71.5% versus 75.6% uptake). o Furthermore, uptake of the first two doses was highest in the very remote areas of Australia at 81.1%. This result is viewed as promising for improving equity as those in more remote areas are more likely to be indigenous. o In contrast, there was an 18% lower two-year screening participation rate in the least affluent Australian areas (52.1%) compared with the most affluent areas (63.2%) in 2009–2010.  The UK has also seen more equitable HPV vaccination uptake compared with their cervical screening programme where ethnic minority and low socioeconomic groups traditionally have lower rates of screening attendance. o In Scotland, the incidence of cervical cancer is twice as high in the most deprived versus the least deprived groups, with achieving high vaccine equity viewed as important from the outset of their programme. o While women in the HPV vaccine catch-up cohorts living in more deprived areas were less likely to be vaccinated, those vaccinated in the routine cohort aged 12/13 years had high and equitable vaccine uptake across deprivation classes (Sinka et al, 2014).  The USA, by contrast, has no school programmes and vaccination is not fully government funded. Coverage in the wealthiest states with the lowest cervical cancer rates is around three times higher than the states with highest cervical cancer rates (Bach, 2010).  In New Zealand, the HPV vaccination programme, like others based on school delivery, has seen higher HPV vaccination uptake for traditionally disadvantaged groups compared with coverage achieved in the cervical screening programme. o HPV vaccine uptake is higher in young Māori and Pacific women than in European/Other. o This finding is in contrast to New Zealand’s childhood immunisations levels with inequitable coverage for Māori and Pacific children compared with European/Other. o Although the equity gap in HPV vaccination has been reversed overall, there is a larger fall off between doses one and three for Māori and Pacific groups. o The shift to a two dose schedule, in line with international developments, will likely help address the coverage fall off between doses.

9. Conclusion

Cervical screening remains a key component of the prevention of cervical cancer in vaccinated and unvaccinated women as not all oncogenic HPV types are included in the HPV vaccines. However, cervical cancer is rare before the age of 25 years and screening below this age is believed to cause more harm than benefit.

Some clinicians and members of the general public may feel uneasy about not screening young women, particularly stopping screening when it is already offered. This reflects the natural tension when considering an individual patient versus the broader public health approach to minimising cancer risk, when the overall harms and costs of a population wide intervention may become disproportionally high (Castle et al, 2015). Moreover, at the point at which it is proposed to stop offering screening for women aged under 25 years, HPV immunisation is already being offered and provides far better protection against invasive cancer thathann screening in this age group.

Released September 2016 19

The balance of evidence does not support screening in women aged 20 to 24 years. Cervical abnormalities are common this age group. The women are more likely to have a transient HPV infection and less likely to have precancerous lesions, and evidence shows that screening does not reduce their cancer risk. Investigation and treatment of false positive results is associated with anxiety and additional numbers of premature delivery. Hence, a number of countries with centrally led well organised screening programmes similar to New Zealand have changed to a screening initiation age of 25 years. In summary:  Improvements in cervical cancer prevention and control in women aged 20–24 years can be best accomplished through achieving high HPV vaccination uptake across all ethnic and socioeconomic groups and undertaking prompt investigations of young women with symptoms.  Cervical cytology screening is ineffective at preventing cervical cancer in women aged 20–24 years on a population basis.  Cervical abnormalities are particularly common in this age group and the overwhelming majority do not progress to cervical cancer by age 25.  Screening in women aged less than 25 years results in a large number of women being over treated. Harms from over treatment outweigh benefits, including increased anxiety and trauma from colposcopy, and potentially future adverse pregnancy outcomes such as premature labour.  Falling prevalence of cervical abnormalities due to HPV vaccination will decrease the performance of cytology screening, particularly reducing its positive predictive value.  Given screening is questionable in unvaccinated women aged 20–24 years it is unwarranted in the face of vaccination with the burden of HPV infection set to reduce substantially as vaccinated cohorts reach screening age. Even low vaccination coverage has been associated with substantial reductions in cervical abnormalities. References

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Released September 2016 21 Holowaty P, Miller AB, Rohan T, To T. Natural history of dysplasia of the uterine cervix. J Natl Cancer Inst 1999; 91(3). Huh W, Ault K, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Gynecol Oncol 2015; 136:178–182 IARC. IARC Handbooks of Cancer Prevention Volume 10: Cervix Cancer Screening. 2005; Lyon, France: IARC Press

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Released September 2016 23 Stokley S, Jeyarajah J, Yankey D, et al. Immunization Servcies Division, National Center for Immunization and Repsiratory Diseases. CDC Centers for Disease Control and Prevention (CDC) Human papillomavirus vaccination coverage among adolescents, 2007–2013, and post licensure vaccine safety monitoring, 2006–2104 –United Staes. MMWR Morb Mortal Wkly Rep 2014;63(29):620–624 Tabrizi S, Brotherton J, Kaldor J, et al. Fall in human papillomavirus prevalence following a national vaccination program. J Infect Dis 2012;206(11):1645–1651. Tabrizi S, Brotherton J, Kaldor J, et al. Assessment of herd immunity and cross-protection after a human papillomavirus vaccination programme in Australia: a repeat cross-sectional study. Lancet Infect Dis 2014;14:958–966 Tamboloa Group, Sharp L, Cotton S, Cochran C, et al. After-effects reported by women following colposcopy, cervical biopsies and LLETZ: results from the TOMBOLA trial. BJOG 2009;116:1506–1514 USPSTF, Final Recommendation Statement: Cervical Cancer: Screening. US Preventive Services Task Force. 2014. http://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/cervical-cancer-screening

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VCCR. Statistical Report. 2011. Victorian Cervical Cytology Registry cited in MSAC 2013. Appendix 1: The Australian National Cervical Screening Programme review of five primary studies examining the impact of changing the cytology screening start age from 20 to 25 years (MSAC, 2013) The UK case control study reported by Sasieni et al. (2009) provides the highest quality evidence available for a comparison of the effectiveness of screening in women 20–24 years versus 25–29 years. This study observed screening women aged 22–24 years does not lead to a reduction in the incidence of cervical cancer between ages 26.5–30 years. In addition, the risk of cervical cancer was not lower for women with two screening episodes before the age of 25 years versus no screening. In contrast, screening older age groups (from age 32 years) was associated with a substantial reduction in cervical cancer incidence (Table 1). This study provides strong evidence that screening is less effective in women under the age of 25 years than older age groups. Table 1 Relative effectiveness of screening versus no screening for women by age group (Sasieni et al. 2009) A g e

o f

c a n c Age of screening vs Odds ratio e Interpretation no screening (95% CI) r

d i a g n o s i s

2 5 Any screen 22–24 yr – Screening women 22–24 yr does not 2 1.11 (0.83 reduce incidence of a cervical cancer 9 to 1.50) vs nil screen 20–24 yr diagnosis <30 yr y r

2 6 . Two screens 20–22 yr 5 & 23–25 yr – 1.1 ( 0.62 2 vs 1 screening episodes does not reduce 2 to 2.0) cancer diagnosis in age 26.5–29 vs 1st screen 23–25 yr 9

y r

3 5 Any screen 32–34 yr – 3 0.55 (0.44 The effectiveness of screening for 9 to 0.69) women<32 years is not demonstrated. vs nil screen 30–34 yr y r

Released September 2016 25 A g e

o f

c a n c Age of screening vs Odds ratio e Interpretation no screening (95% CI) r

d i a g n o s i s

4 5 – Any screen 42–44 yr Screening older age groups provides 4 0.37 (0.29 substantial risk reduction for women 9 to 0.48) screened in previous 5–8 years vs nil screen 40–44 yr y r

5 5 Any screen 52–54 yr – 5 0.26 (0.19 - 9 to 0.36) vs nil screen 50–54 yr y r

However, despite its large size, due to the very small numbers of cancers in women under the age of 25 years, this study does not definitively exclude the possibility of a small screening benefit in women under the age of 25 years. In particular, study data do not exclude the possibility that screening will shift diagnosis to early microinvasive disease, reducing the (small) risk of being diagnosed with invasive IB+ cancer in subsequent years. Two UK studies of temporal trends in cervical cancer incidence before and after the screening start age was raised to 25 years in England provide evidence that raising the screening start age to 25 years does not lead to an increase in cervical cancer incidence when compared to Wales and Scotland where the screening start age remains at 20 years (Sasieni & Castanon 2012; Patel et al. 2012). As expected, both studies report the incidence of high-grade CIN decreased in women aged 20–24 years after the screening age was raised in 2004, with an associated increase in the incidence of high-grade CIN in women aged 25–29 years. Both studies also documented an increase in cervical cancer incidence after 2004. However, these cancer incidence trends were also observed in the comparator countries that continued to start screening at age 20 years, indicating the impact of factors other than screening age. In addition, analysis of trends of cervical cancer incidence in England by birth cohort indicate that the increase in incidence observed in women in this age group precedes the change in screening start age (Foley et al. 2011) Patel et al. (2012) reported an increase in cervical cancer incidence in young women in both age groups (20–24 years and 25–29 years) relative to women aged >30 years 2005–2009 versus 2000–2004. However, they also documented a similar trend over time in young women in Wales where the screening was unchanged (Table 2). Furthermore, the investigators presented data on the increasing incidence of STD over the same time period in both populations showing higher rates in the English population, indicating the increase in cervical cancer incidence over time may be attributed to changes in risk factors. Table 2 Impact of extending screening start age from 20 to 25 years in 2004 on cervical cancer incidence, 2000–2009 (Patel et al. 2012) C C H er er Cer G vi vi vic Cervic HG- - ca ca al al CIN C l l can cancer I ca ca cer N nc nc er er

I R R

( 9 I 5 R % R

(9 C 5 I % ) I R C Inci R I) b den (9 Inci y ce 5 b den A rat % y ce t Time g e C ti rate i period, e 5 I) m Region /10 m age g /105 e e group r b pe Pre p o y ri vs e Pre interac u ti o post r vs tion p m d 200 i pos e 4 o t d 200 pe a 4 ri n o d a d ag n e d gr

o a u g p e g r o u p

North- 2 432. 0. 3.4 - 2. 0.028 east 0 2 vs 5 vs 18 Englan – 6 (1 d 2 230. 7.0 .0 4 7 ( 9– y 0 4. r . 37 5 ) 1 – 0 .

Released September 2016 27 C C H er er Cer G vi vi vic Cervic HG- - ca ca al al CIN C l l can cancer I ca ca cer N nc nc er er

I R R

( 9 I 5 R % R

(9 C 5 I % ) I R C Inci R I) b den (9 Inci y ce 5 b den A rat % y ce t Time g e C ti rate i period, e 5 I) m Region /10 m age g /105 e e group r b pe Pre p o y ri vs e Pre interac u ti o post r vs tion p m d 200 i pos e 4 o t d 200 pe a 4 ri n o d a d ag n e d gr

o a u g p e g r o u p

6 1 )

- 2 472. 1.3 12. 1. 1. 0.002 5 0 vs 4 0 vs 21 93 – (1 (1 2 603. ( 21. .0 .2 9 0 1 0 8– 8– y . 1. 2. r 2 34 92 4 ) ) – 1 . 4 5 C C H er er Cer G vi vi vic Cervic HG- - ca ca al al CIN C l l can cancer I ca ca cer N nc nc er er

I R R

( 9 I 5 R % R

(9 C 5 I % ) I R C Inci R I) b den (9 Inci y ce 5 b den A rat % y ce t Time g e C ti rate i period, e 5 I) m Region /10 m age g /105 e e group r b pe Pre p o y ri vs e Pre interac u ti o post r vs tion p m d 200 i pos e 4 o t d 200 pe a 4 ri n o d a d ag n e d gr

o a u g p e g r o u p

)

1. 3 51 0 18. 64.9 (1 – 11111111. 4 vs vs .0 - 3 0 - 0.017 8– 4 0 25. 2. y 61.5 5 13 r )

3 10. 5 6 vs 1. Refere - + - - - 00 nce y r 9.8

Released September 2016 29 C C H er er Cer G vi vi vic Cervic HG- - ca ca al al CIN C l l can cancer I ca ca cer N nc nc er er

I R R

( 9 I 5 R % R

(9 C 5 I % ) I R C Inci R I) b den (9 Inci y ce 5 b den A rat % y ce t Time g e C ti rate i period, e 5 I) m Region /10 m age g /105 e e group r b pe Pre p o y ri vs e Pre interac u ti o post r vs tion p m d 200 i pos e 4 o t d 200 pe a 4 ri n o d a d ag n e d gr

o a u g p e g r o u p

1. 2 1

Wales 2. 2 ( 72 0 219. 1 (conte 2.3 (1 – 0 vs . mporar vs .3 2 1 - 0.007 y 1– 4 0 310. 5. y – 5.9 9 62 control r 1 ) group) . 3 3 )

- 2 298. 1. 11. 1. 1. 0.002 C C H er er Cer G vi vi vic Cervic HG- - ca ca al al CIN C l l can cancer I ca ca cer N nc nc er er

I R R

( 9 I 5 R % R

(9 C 5 I % ) I R C Inci R I) b den (9 Inci y ce 5 b den A rat % y ce t Time g e C ti rate i period, e 5 I) m Region /10 m age g /105 e e group r b pe Pre p o y ri vs e Pre interac u ti o post r vs tion p m d 200 i pos e 4 o t d 200 pe a 4 ri n o d a d ag n e d gr

o a u g p e g r o u p

2 3

( 17 82 5 1 (1 (1 – . 5 vs 7 vs .0 .2 2 1 431. 6– 6– 9 3 0 19. 1. 2. y – 8 30 65 r 1 ) ) . 3 5 )

- 3 52.1 1. 16. - 1. 0.086 0 0 33

Released September 2016 31 C C H er er Cer G vi vi vic Cervic HG- - ca ca al al CIN C l l can cancer I ca ca cer N nc nc er er

I R R

( 9 I 5 R % R

(9 C 5 I % ) I R C Inci R I) b den (9 Inci y ce 5 b den A rat % y ce t Time g e C ti rate i period, e 5 I) m Region /10 m age g /105 e e group r b pe Pre p o y ri vs e Pre interac u ti o post r vs tion p m d 200 i pos e 4 o t d 200 pe a 4 ri n o d a d ag n e d gr

o a u g p e g r o u p

(0 – 0 vs .9 3 vs 6– 4 0 1. y 20. 60.9 84 r 1 )

3 15. 5 6 vs 1. Refere - + - - - 00 nce y 14. r 8

Sasieni and Castanon (2012) included a larger sample of cervical cancers reported across England between 2000 and 2010 and compared incidence rates with both Wales and Scotland (and included data to 2011 for comparisons of time trends by year of age in England (Table 4). They reported no difference in the trend of increasing cervical cancer incidence in women aged 25–29 years in England versus Wales and Scotland over this period (RR 0.98, 95% CI 0.69–1.39) (Table 3). Table 3 Impact of extending screening start age from 20 to 25 years in 2004 on cervical cancer incidence: trends per decade in cervical cancer incidence by age group and nation: 2000–2010 (Sasieni & Castanon 2012) A g P e Wales - England Scotland g (RR England vs Wales v (RR (95% (RR (95% r (95% & Scotland al CI) CI) o CI) u u e p

2 0 – 2.16 0. 0.98 (0.75– 1.39 (0.64– 2 (0.82– 0.59 (0.30–1.15) 1 1.29) 3.05) 4 5.66) 2 y r

2 5 – 1.77 0. 2.37 (2.08– 2.96 (1.94– 2 (1.05– 0.98 (0.69–1.39) 9 2.70) 4.53) 9 2.99) 0 y r

3 0 – 1.29 0. 1.49 (1.34– 2.67 (1.90– 3 (0.81– 0.72 (0.54–0.96) 0 1.66) 3.75) 4 2.05) 3 y r

3 5 – 1.15 0. 1.24 (1.12– 2.47 (1.77– 3 (0.77– 0.68 (0.51–0.90) 0 1.38) 3.45) 9 1.73) 1 y r

Table 4 Impact of extending screening start age from 20 to 25 years in 2004 on cervical cancer incidence: number of cancers diagnosed in each financial year by age at diagnosis, England, N=4,079 cancers (Sasieni & Castanon 2012) 2 2 2 2 0 0 0 0 P 0 0 0 1 Tren A 7 8 9 0 v d g / / / / a (RR/ e 2 2 2 2 l yr) 0 0 0 0 u 0 0 1 1 e 8 9 0 1

2 1 1 7 5 0.71 0

Released September 2016 33 2 2 2 2 0 0 0 0 P 0 0 0 1 Tren A 7 8 9 0 v d g / / / / a (RR/ e 2 2 2 2 l yr) 0 0 0 0 u 0 0 1 1 e 8 9 0 1

0 – . 2 0 2 4 0 2

8 y r

2 0 3 1 1 1 . 6 0.96 5 3 1 7 y 4 r

2 0 4 2 1 1 1 . 0.92 3 5 8 7 4 y 3 r

< 2 0 5 1 . 3 4 9 4 1.67 0 6 2 1 y 5 0 r 0 1

2 0 6 4 5 5 5 . 1.08 5 0 7 6 2 y 2 r

2 7 – 0 1 1 2 1 2 . 4 9 3 6 1.05 9 1 7 6 6 3 5 y r

3 0 – 0 2 3 3 3 3 . 9 2 4 0 1.01 4 5 8 2 2 6 8 y r

3 1 1 1 1 1.01 0 5 5 5 5 5 . 2 2 2 2 0 0 0 0 P 0 0 0 1 Tren A 7 8 9 0 v d g / / / / a (RR/ e 2 2 2 2 l yr) 0 0 0 0 u 0 0 1 1 e 8 9 0 1

+ 5 6 8 8 5 y 2 3 5 5 r

In addition, a population-based registry cohort study examined the impact of reducing the start age in Iceland from 25 to 20 years (Sigurdsson 2007, 2010). Overall, the investigators did not find evidence of a reduction in cervical cancer incidence over time in women in 20–24, 25–29 or 30–34-year age groups to demonstrate the effectiveness of lowering the screening start age to 20 years. However, they reported an increased incidence of stage IA cancers in women aged 20–34 years, and reduced incidence stage IIA suggesting a shift to earlier disease detection potentially attributable to earlier screening (Table 5). Table 5 Cervical cancer in Iceland 1964–2008: age-specific incidence rates at ages 20–29 and 20–34 per 100 000 before and after changing the lower age limit from age 25 to 20 in 1988. (Sigurdsson 2010) Scree A Clinical All Stage Stage Stage n g ly cance IA IB IIA+ e detecte rs detect d g Pre Pre Pre ed r Pre vs vs vs vs Pre vs o post post post post Pre vs post u 1988 1988 1988 1988 post 1988 p 1988

2 0 – 2.1 vs 2 2.8 - - - - - 4 p =0.6 y r

2 2.7 vs 2.7 3.0 vs 0 1.1 vs 6.7 vs 6.6 vs 7.6 3.7 vs – 0.2 2 9.7 2.8 2.1 9 p p p p =0.1 =0.00 p =0.00 p =0.2 =0.1 y 8 =0.9 3 r

2 4.7 vs 3.6 2.4 5.2 vs 0 10.7 5.5 vs 8.9 vs vs0.2 10.5 – vs 2.5 4.0 3 13.0 4 p p p p =0.00 p =0.00 <0.00 p =0.2 =0.009 y 5 =0.7 1 1 r

Released September 2016 35 Screen-detected cases are stage IA and subclinical (occult) IB cases; clinical cases are all other cases. P-values for rate differences in 1964–1988 versus 1989–2008. Incidence rate/105 p-value for test of difference in incidence rate by time period Evidence about the relative harms for screening in young versus older women is more definitive. Insinga et al. (2004) demonstrated the risk of false positive cytology results is higher for women aged 20–24 years than women aged 25–29 years and older age groups (Table 6). These results reflect the high prevalence of HPV infection in this age group) and the lower specificity of cytology in women under 30 years. In addition to the inconvenience of further testing for abnormal cytology results where no abnormalities are found on follow-up, in cases where CIN changes lead to treatment, treatment harms in young women, in particular pregnancy adverse outcomes, for lesions that may otherwise regress also need to be taken into account. Table 6 Abnormal cytology tests as a proportion of all routine cytology tests (Insinga et al. 2004)

A N ge gr FP CIN1 CIN2 CIN3 Cytolo o % % % u gy p tests

2 0 – 852 3.5 0.9 0.6 0.2 2 4

2 5 – 1,952 2.1 0.2 0.6 0.6 2 9

3 0 – 5,992 2.6 0.5 0.3 0.4 3 9

- - 1.6 0.1 0.0 0.0

6 0 – 3,543 1.8 0.1 0.0 0.1 6 9

7 0 – 1,657 - - - 7 9

Note: Of 30,936 routine cytology tests, 1,331 were abnormal tests: 51.5% false positive, 29% incomplete follow-up, 19% CIN/cancer In Australia, NCSP data also show that among women aged 20–69 years, women aged 20–24 years have the highest risk of abnormal cytology results, the second highest risk of high-grade histology after women aged 25– 29 years, but the lowest risk of cervical cancer (AIHW, 2013). These data indicate that screening women aged 20–24 years is more likely to lead to further investigation and potentially treatment than older age groups, despite their low risk of cancer. In the absence of direct evidence about the optimal age for starting screening, recommendations require judgments about the age at which screening benefits outweigh the potential for harms. Both the USPSTF and the CTFPHC concluded against screening in women aged 20 and younger based on evidence that this population are at very low risk of cervical cancer, and the harms of tests, procedures and in some cases treatment for potentially transient changes were judged to outweigh the benefits. However, they differed on recommendations for screening women aged 20–24 years due to ongoing uncertainty about the possibility of modest screening benefits in this age group, and uncertainty about the acceptable trade-off between the potential benefits of early detection and treatment versus the potential harms.

Released September 2016 37 Appendix 1 References Australian Institute of Health and Welfare (AIHW). Cervical screening in Australia 2010-2011. Cancer series 76. Cat. no. CAN 72. 2013a. Canberra, AIHW. Foley G, Alston R, Geraci M, et al. Increasing rates of cervical cancer in young women in England: An analysis of national data 1982-2006. Brit J Cancer 2011; 105(1):177-184. Insinga RP, Glass AG, Rush BB. Diagnoses and outcomes in cervical cancer screening: a population-based study. Am J Obstet Gynecol 2004; 191(1):105-113 Patel, A., Galaal, K., Burnley, C., et al. (2012). "Cervical cancer incidence in young women: a historical and geographic controlled UK regional population study." Br J Cancer 106(11). Sasieni, P., Castanon, A. and Cuzick, J. (2009). "Screening and adenocarcinoma of the cervix." Int J Cancer 125(3): 525- 529. Sigurdsson K, Sigvaldason H. Is it rational to start population-based cervical cancer screening at or soon after age 20? Analysis of time trends in preinvasive and invasive diseases. Eur J Cancer 2007; 43(4). Sigurdsson K. Cervical cancer: cytological cervical screening in Iceland and implications of HPV vaccines. Cytopathology 2010; 21(4). Sasieni P, Castanon A. Dramatic increase in cervical cancer registrations in young women in 2009 in England unlikely to be due to the new policy not to screen women aged 20-24. J Med Screen 2012; 19(3):127-132.

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