Impact of scaled up human papillomavirus vaccination and cervical screening and the potential for global elimination of cervical cancer in 181 countries, 2020–99: a modelling study

Summary

Background

Cervical screening and human papillomavirus (HPV) vaccination have been implemented in most high-income countries; however, coverage is low in low-income and middle-income countries (LMICs). In 2018, the Director-General of WHO announced a call to action for the elimination of cervical cancer as a public health problem. WHO has called for global action to scale-up vaccination, screening, and treatment of precancer, early detection and prompt treatment of early invasive cancers, and palliative care. An elimination threshold in terms of cervical cancer incidence has not yet been defined, but an absolute rate of cervical cancer incidence could be chosen for such a threshold. In this study, we aimed to quantify the potential cumulative effect of scaled up global vaccination and screening coverage on the number of cervical cancer cases averted over the 50 years from 2020 to 2069, and to predict outcomes beyond 2070 to identify the earliest years by which cervical cancer rates could drop below two absolute levels that could be considered as possible elimination thresholds—the rare cancer threshold (six new cases per 100 000 women per year, which has been observed in only a few countries), and a lower threshold of four new cases per 100 000 women per year.

Methods

In this statistical trends analysis and modelling study, we did a statistical analysis of existing trends in cervical cancer worldwide using high-quality cancer registry data included in the Cancer Incidence in Five Continents series published by the International Agency for Research on Cancer. We then used a comprehensive and extensively validated simulation platform, Policy1-Cervix, to do a dynamic multicohort modelled analysis of the impact of potential scale-up scenarios for cervical cancer prevention, in order to predict the future incidence rates and burden of cervical cancer. Data are presented globally, by Human Development Index (HDI) category, and at the individual country level.

Findings

In the absence of further intervention, there would be 44·4 million cervical cancer cases diagnosed globally over the period 2020–69, with almost two-thirds of cases occurring in low-HDI or medium-HDI countries. Rapid vaccination scale-up to 80–100% coverage globally by 2020 with a broad-spectrum HPV vaccine could avert 6·7–7·7 million cases in this period, but more than half of these cases will be averted after 2060. Implementation of HPV-based screening twice per lifetime at age 35 years and 45 years in all LMICs with 70% coverage globally will bring forward the effects of prevention and avert a total of 12·5–13·4 million cases in the next 50 years. Rapid scale-up of combined high-coverage screening and vaccination from 2020 onwards would result in average annual cervical cancer incidence declining to less than six new cases per 100 000 individuals by 2045–49 for very-high-HDI countries, 2055–59 for high-HDI countries, 2065–69 for medium-HDI countries, and 2085–89 for low-HDI countries, and to less than four cases per 100 000 by 2055–59 for very-high-HDI countries, 2065–69 for high-HDI countries, 2070–79 for medium-HDI countries, and 2090–2100 or beyond for low-HDI countries. However, rates of less than four new cases per 100 000 would not be achieved in all individual low-HDI countries by the end of the century. If delivery of vaccination and screening is more gradually scaled up over the period 2020–50 (eg, 20–45% vaccination coverage and 25–70% once-per-lifetime screening coverage by 2030, increasing to 40–90% vaccination coverage and 90% once-per-lifetime screening coverage by 2050, when considered as average coverage rates across HDI categories), end of the century incidence rates will be reduced by a lesser amount. In this scenario, average cervical cancer incidence rates will decline to 0·8 cases per 100 000 for very-high-HDI countries, 1·3 per 100 000 for high-HDI countries, 4·4 per 100 000 for medium-HDI countries, and 14 per 100 000 for low-HDI countries, by the end of the century.

Interpretation

More than 44 million women will be diagnosed with cervical cancer in the next 50 years if primary and secondary prevention programmes are not implemented in LMICs. If high coverage vaccination can be implemented quickly, a substantial effect on the burden of disease will be seen after three to four decades, but nearer-term impact will require delivery of cervical screening to older cohorts who will not benefit from HPV vaccination. Widespread coverage of both HPV vaccination and cervical screening from 2020 onwards has the potential to avert up to 12·5–13·4 million cervical cancer cases by 2069, and could achieve average cervical cancer incidence of around four per 100 000 women per year or less, for all country HDI categories, by the end of the century. A draft global strategy to accelerate cervical cancer elimination, with goals and targets for the period 2020–30, will be considered at the World Health Assembly in 2020. The findings presented here have helped inform initial discussions of elimination targets, and ongoing comparative modelling with other groups is supporting the development of the final goals and targets for cervical cancer elimination.

Funding

National Health and Medical Research Council (NHMRC) Australia, part-funded via the NHMRC Centre of Excellence for Cervical Cancer Control (C4; APP1135172).

Introduction

An estimated 530 000 cervical cancer cases were diagnosed globally in 2012, with 85% of these occurring in less developed regions.¹ The average worldwide age-standardised incidence rate of cervical cancer in 2012 was 14 cases per 100 000 women.¹ First-generation human papillomavirus (HPV) vaccines, including the quadrivalent vaccine, Gardasil (Merck, Kenilworth, NJ, USA), and the bivalent vaccine, Cervarix (GlaxoSmithKline, London, UK), can prevent about 70% and 84% of cervical cancers, respectively (if the potential for cross-protection against certain non-vaccine-included types is confirmed for the bivalent vaccine). A next-generation nonavalent HPV vaccine, Gardasil 9 (Merck), can prevent approximately 90% of cervical cancers. However, these vaccines do not treat pre-existing infections and related cervical abnormalities. Thus, several generations of women need effective cervical screening. In 2016, the American Society of Clinical Oncology (ASCO) released cervical screening guidelines² recommending screening for women aged 30–49 years one to three times per lifetime in lower-resource settings with primary HPV testing, on the basis of very strong evidence that HPV testing is a more effective, reliable, and adaptable method of screening (via the use of self-collected specimens) than traditional cytological methods.

Research in context

Evidence before this study

Although more than 30% of females aged 10–20 years in developed countries have received the human papillomavirus (HPV) vaccine, less than 3% had been vaccinated in less developed regions by 2014. More than 280 million vaccine doses have already been delivered worldwide, and Gavi, The Vaccine Alliance has articulated an aim to deliver another 30–40 million doses per year from 2020 onwards. Resource-stratified guidelines for cervical screening recommend HPV testing at least once per lifetime, even in low-income countries. WHO has called for global action towards scale-up of these proven approaches to cervical cancer prevention, towards the elimination of cervical cancer. However, the effect and timing on cervical cancer incidence of current vaccination coverage rates, the added benefit of Gavi achieving its targets, and the potential global effect of achieving uniform high-coverage HPV vaccination and screening is not well understood. We searched PubMed for studies published from Jan 1, 2010, to Sept 24, 2018, with the search terms “timing” or “timeline”, “cervical cancer”, and “elimination”. English-only publications were included. Only one previous study that estimated the timeline to elimination of cervical cancer in any country was identified; this study, co-authored by some of us, estimated that Australia, a very-high-Human Development Index (HDI) country with early and high coverage implementation of both HPV vaccination and cervical screening, will achieve a cervical cancer incidence of less than four cases in 100 000 women by 2035.

Added value of this study

Given current trends in cervical cancer incidence, and existing screening and vaccination coverage, the number of cervical cancer cases per annum will increase from about 600 000 in 2020, to 1·3 million in 2069, resulting in 44·4 million new cases of cervical cancer during this period, with almost two-thirds of the burden being in countries with low or medium HDI. Widespread coverage of both HPV vaccination and cervical screening from 2020 onwards has the potential to avert up to 12·5–13·4 million further cases by 2070 and could achieve an average cervical cancer incidence of less than four cases per 100 000 in all country HDI categories, by the end of the century. This study highlights that, as we previously found in Australia, elimination of cervical cancer is possible in most countries, provided high-coverage screening and vaccination can be achieved.

Implications of all the available evidence

The Director-General of WHO has announced a call to action for the elimination of cervical cancer as a public health problem, with intent to submit a resolution on a global cervical cancer elimination strategy at the World Health Assembly in 2020. The findings of this study reinforce that high priority should be given to the effective implementation of high-coverage cervical screening and HPV vaccination in low-income and middle-income countries. The study also suggests that if an annual elimination threshold of four cases per 100 000 were to be set, this threshold would be achievable as an average rate in each HDI category by the end of the century, but would not necessarily apply to all individual low-HDI countries. Our findings also imply that extremely rapid and effective scale-up of prevention interventions would be required to reach global average incidence rates approaching four per 100 000 women across all HDI categories by the end of the century.

Globally, considerable disparities exist between countries and within countries in terms of HPV vaccination and cervical cancer screening coverage rates. In 2008, overall screening uptake was reported to be 19% in low-income and middle-income countries (LMICs), compared with 63% in high-income regions.³ HPV vaccination coverage is much lower in LMICs than in high-income countries; by 2014, an estimated 33·6% of girls and women aged 10–20 years in high-income countries had received the full course of the HPV vaccine, compared with 2·7% of such females in LMICs.⁴ Gavi, The Vaccine Alliance, has announced intent to provide support for the bivalent vaccine and quadrivalent vaccine pilot programmes in selected countries, with an aim to support delivery of 30–40 million doses of vaccine annually from 2022.⁵ Assuming a two-dose schedule, this programme could result in up to an additional 15–20 million girls and women vaccinated per annum in these countries (equivalent to 25–35% of the world's 10-year-old population); however, vaccine supply challenges could affect the achievability of these targets.⁶

Offsetting the effects of vaccination are population growth and ageing, which are likely to result in an increase in the number of cervical cancer diagnoses over the remainder of the century, particularly in LMICs, even in regions where cervical cancer incidence rates have been declining.⁷ Cervical cancer incidence has been in constant flux in the past half century, with the risk of cervical cancer in successive generations decreasing in some settings, due to effective cytology screening,7, 8 and increasing in other settings, potentially because of sexual behavioural differences or HPV co-factor exposures in successive cohorts in the absence of screening intervention.9, 10 These existing trends in cervical cancer incidence must be taken into account when considering the impact of future interventions. The long-term interplay of these factors with the time-delayed effects of vaccination, and the potential benefit of screening or adult HPV vaccination in hastening preventive effects, are not well understood.

In May, 2018, the Director-General of WHO called for “coordinated action globally to eliminate cervical cancer”. This call has been supported by several key agencies, with intent to submit a resolution on a global cervical cancer elimination strategy at the World Health Assembly to be held in May, 2020. An elimination threshold in terms of cervical cancer incidence has not yet been defined as part of this process, but an absolute cervical cancer incidence could be chosen for such a threshold. Findings from our recent analysis showed that in view of current prevention efforts, rates of cervical cancer could fall below four cases per 100 000 women by 2021–35 in Australia;¹¹ however, to date, quantitative estimates of the effect of the global implementation of massively scaled up vaccination and screening initiatives on cervical cancer rates and burden of disease (case numbers) are not available. Such estimates provide crucial background to future discussions of an appropriate threshold.

In this context, the current study aimed to predict the global burden of cervical cancer over the remainder of this century under a range of scenarios, including current country-specific uptake of HPV vaccination and screening, as well as the possibility of very rapid (or gradual) scale-up of HPV vaccination and cervical screening worldwide. We aimed to quantify the cumulative potential effects of increased global vaccination and screening coverage on cervical cancer cases averted during the 50 years from 2020–69 and to extend predictions of cervical cancer incidence rates to 2099 to capture the full effect of HPV vaccination, which takes many decades to be observed. Using these predictions, we aimed to identify the earliest years by which cervical cancer rates could drop below two absolute levels, which could be considered as potential elimination thresholds—the rare cancer threshold (six cases per 100 000 women per year as defined in Europe and Australia)12, 13 and a lower threshold (four cases per 100 000 women per year).