Mortality impact of achieving WHO cervical cancer elimination targets: a comparative modelling analysis in 78 low-income and lower-middle-income countries

Introduction

In 2018, an estimated 570 000 cases of cervical cancer were diagnosed, and 311 000 women died from the disease.¹ Although cervical cancer has been relatively well controlled for several decades in many high-income countries, mainly because of cervical screening initiatives and effective cancer treatment services, it remains the most common cause of cancer-related death among women in 42 countries, most of which are low-income and lower-middle-income countries (LMICs).²

Prophylactic vaccines against oncogenic human papillomavirus (HPV) have been available in most high-income countries from 2006 onwards. First-generation vaccines directly protect against oncogenic HPV types 16 and 18 in individuals naive for those types, and these HPV types are responsible for approximately 70% of invasive cervical cancers.3, 4 More recently, broader-spectrum protection against the types responsible for up to 90% of cervical cancers has been shown either via direct protection against a larger proportion of types (second-generation 9-valent vaccine) or via cross-protection against non-vaccine included types (bivalent vaccine).5, 6 However, because vaccines are primarily targeted at pre-adolescents or young adolescents, it is expected to take several decades after deployment in a population before their full benefits in terms of cancer prevention are realised, and a substantial impact of vaccines on cervical cancer incidence or mortality outcomes is yet to be observed. To date, vaccine coverage in LMICs has been low overall, with an estimated 3% of the primary targeted population of young girls in less developed regions vaccinated by 2014.⁷ By 2016, only 14% of LMICs had established vaccination programmes.⁸

Many high-income countries are transitioning, or considering transitioning, from cervical cytology to primary HPV testing for cervical screening, which is generally a more effective and cost-effective approach to screening.9, 10, 11 Initiatives for both HPV vaccination and screening have been introduced in the context of broad access to diagnostic, precancer treatment, cancer treatment, and supportive and palliative care services in high-income countries, and the combination of early detection via screening and effective treatment with surgery, chemotherapy, and radiotherapy has meant that net 5-year survival for cervical cancer is around 60–70% or greater in several high-income countries.¹² However, in LMICs, uptake of cervical screening has been low and inconsistent, and population-level access to cancer care is generally poor. As a consequence of these differentials in access to cervical screening and treatment, the majority of deaths (91%) from cervical cancer currently occur in LMICs and upper-middle-income countries, and 60% of deaths are in LMICs.¹ Access to supportive and palliative care services for people in LMICs is poor,¹³ and thus the majority of women dying from cervical cancer do so with little or no supportive care or pain relief.

In May, 2018, the Director-General of WHO announced a call to action to eliminate cervical cancer as a public health problem, and in January, 2019, the WHO Executive Board requested that a draft global strategy to achieve elimination be developed. The draft global strategy being developed by WHO, with its partners, includes triple-intervention targets for scale-up of vaccination, screening, precancer treatment, and invasive cancer treatment in all countries; these targets specify 90% coverage of HPV vaccination, 70% coverage of twice-lifetime screening, and 90% access to cervical precancer and cancer treatment services and palliative care, by 2030.¹⁴ To inform the strategic planning process, the WHO Cervical Cancer Elimination Modelling Consortium (CCEMC) was formed and has done comparative modelling of potential intervention scenarios in all 78 LMICs. In the accompanying Article published in The Lancet,¹⁵ CCEMC predictions of the impact of HPV vaccination, screening, and precancer treatment strategies on cervical cancer incidence and cases averted are presented; the analysis found that elimination by 2120 at a threshold of four cases per 100 000 women was possible in all 78 LMICs if girls-only vaccination was combined with twice-lifetime screening. This strategy was predicted to reduce age-standardised incidence across 78 LMICs by 97% and to avert more than 74 million cervical cancer cases over the next century.¹⁵ The analysis concluded that adding screening with high uptake to vaccination will expedite reductions in cervical cancer incidence and the number of cases averted, and will be necessary to eliminate cervical cancer in countries with the highest burden.

The aims of the current analysis were to model cancer treatment scale-up in addition to HPV vaccination and cervical screening and to assess the impact of achieving the 90–70–90 triple-intervention targets on cervical cancer mortality and deaths averted over the next century on the path to elimination. The cervical cancer elimination initiative has been framed within the context of the UN Sustainable Development Goals (SDGs) to support the realisation of SDG target 3.4—a one-third reduction in premature mortality from non-communicable diseases by 2030.¹⁶ Therefore, we also assessed the potential for the cervical cancer elimination strategy to deliver a one-third reduction in premature mortality from cervical cancer by 2030.

Methods

Results

Predictions from the three models were broadly consistent for all scenarios. Figure 1 shows the summary results across the models for the reduction in age-standardised mortality from 2020 to 2120, table 2 depicts these findings as numerical snapshots of the rates and relative reductions compared to the status quo scenario over time, and the reductions in premature mortality in women aged 30–69 years. Snapshots of the age-specific findings in 2020, 2070, and 2120 for each of the three CCEMC models are shown in the appendix (pp 11–25).

Figure 2A depicts annual cervical cancer deaths over time and figure 2B provides information about the cumulative cervical cancer deaths averted. Table 3 summarises these findings for the cumulative deaths and deaths averted over the periods 2020–2030, 2020–2070, and 2020–2120, for all core and supplementary scenarios.

In 2020, the predicted age-standardised rate for cervical cancer mortality across all 78 LMICs was 13·2 (range 12·9–14·1) per 100 000 women. By 2030, vaccine-only strategies would have minimal impact on cervical cancer mortality, which would remain at 13·2 (12·9–14·0) deaths per 100 000 women, corresponding to a 0·1% (0·1–0·5) reduction, averting a median of 620 deaths across all 78 LMICs by 2030 (rounded to 0·0 million in table 3). However, scaling up twice-lifetime cancer screening and treatment in addition to vaccination would result in a mortality rate of 8·5 (8·2–10·8) by 2030, corresponding to a 34·2% (23·3–37·8) reduction, averting 300 000 (300 000–400 000) deaths, mainly due to the impact of improved access to cancer treatment. In this 10-year timeframe, vaccination plus once-lifetime screening or twice-lifetime screening and treatment scale-up would lead to similar mortality reductions. For further information about the relative contribution of the interventions, see the appendix (pp 33–40).

By 2070, girls-only vaccination would lead to a mortality rate of 5·0 (range 4·5–5·4) per 100 000 women, corresponding to a reduction of 61·7% (61·4–66·1), averting 4·8 million (4·1–4·8) deaths, but scaling up once-lifetime screening and treatment in addition to vaccination would result in a rate of 1·4 (1·4–2·2) per 100 000 women, corresponding to a reduction of 88·9% (84·0–89·3), averting 13·3 million (13·1–13·6) deaths. By 2070, girls-only vaccination, twice-lifetime screening, and treatment would result in a mortality rate of 1·0 (0·9–1·6) per 100 000 women, corresponding to a reduction of 92·3% (88·4–93·0), averting 14·6 million (14·1–14·6) deaths. Compared to girls-only vaccination with catch-up to age 14 years (S1), extended-multi-age cohort vaccination to 25 years (S4) would result in increased intermediate-term mortality benefits, bringing forward the benefits of vaccination by about a decade (figure 1). At the high levels of vaccination coverage for girls assumed in the analysis, additional vaccination of boys at age 9 years (S5) would have minimal additional impact on cervical cancer mortality in women over the next 50 years and would have similar intermediate-term benefits to girls-only vaccination by 2070 (figure 1, figure 3 , table 2).

By 2120, girls-only vaccination would result in a mortality rate of 1·3 (range 1·3–1·9) per 100 000 women, corresponding to a mortality reduction of 89·5% (86·6–89·9), averting 45·8 million (44·7–46·4) deaths. By 2120, a mortality rate of 0·2 (0·2–0·5) per 100 000 women, corresponding to a reduction of 98·6% (96·5–98·6), would be achievable with the WHO triple-intervention strategy, averting 62·6 million (62·1–62·8) deaths. If screening were done once per lifetime instead of twice, 60·8 million (60·2–61·2) deaths would be averted over the same period. The specific estimate for the incremental benefit of the twice-lifetime versus once-lifetime screening package over this period was 1·6 million (1·3–2·5) additional deaths averted, with most of these additional deaths averted before 2070. Compared to girls-only vaccination alone, 16·8 million (16·4–17·4) additional deaths would be averted via the triple-intervention strategy by 2120.

In terms of premature mortality outcomes (deaths at age 30–69 years), the triple-intervention strategy would result in rate reductions of 33·9% (range 24·4–37·9) by 2030, 96·2% (94·3–96·8) by 2070, and 98·6% (96·9–98·8) by 2120 (table 2).

Figure 3 shows the regional results across the models for the reduction in age-standardised mortality from 2020 to 2120. The highest mortality rates in 2020, at approximately 30 per 100 000 women, are in sub-Saharan Africa, followed by Latin America and the Caribbean (approximately 16 per 100 000 women). These regions are predicted to have the greatest absolute reductions in mortality rates over the next two decades if the triple-intervention strategy can be successfully scaled up; by 2040, cervical cancer mortality in sub-Saharan Africa could be reduced by more than two-thirds to less than ten per 100 000 women, and in Latin America and the Caribbean it could be reduced to approximately six per 100 000 women. Details about the age-specific cervical cancer incidence and mortality rates in 2020, 2070, and 2120 for each region are provided in the appendix (pp 11–25).

With the WHO triple-intervention strategy, over the next 10 years, about half (48% [range 45–55]) of deaths averted would be in sub-Saharan Africa and almost a third (32% [29–34]) would be in South Asia (including India); over the next century, almost 90% of deaths averted would be in these regions (appendix p 26).

The appendix (pp 27–32) provides information at the country level for the predicted impact of the WHO triple-intervention strategy. In all countries, the median estimates of mortality rates by 2120 approach 1 per 100 000 women or lower.

The findings for model-specific, explanatory, and sensitivity analyses are provided in the appendix (pp 11–25, 33–43). Overall, the findings were concordant between models. The only notable difference was in the level of herd immunity predicted at older ages for unvaccinated individuals, which probably relate to underlying differences in assumptions around assortative sexual mixing among different age groups and different behaviour groups; we consider that the model variation in this area provides a useful reflection of true uncertainty in outcomes. The explanatory results demonstrated that the main benefits by 2030 were via cancer treatment scale-up, and that screening would lead to substantial mortality reductions beyond those conferred by vaccination and cancer treatment scale-up from 2030 to 2070–80. The results of the sensitivity analysis show that the choice of standard population is an important driver for rate estimates and also showed that, for deaths averted, differences between individual model estimates were much smaller than the unavoidable uncertainties in future population projections over the next century.

Discussion

In this analysis, we have quantified, for the first time, the number of women's lives that could be saved by the successful implementation of the WHO global strategy for cervical cancer elimination. This report complements our parallel analysis on cervical cancer incidence.¹⁵ Importantly, by extending the analysis to encompass mortality outcomes, we have quantified the impact of scaling up cancer treatment. Taken together, these two modelling analyses show that successful implementation of the WHO 90–70–90 triple-intervention strategy by 2030 would reduce cervical cancer incidence to 0·7 (0·6–1·6) per 100 000 women¹⁵ and mortality to 0·2 (0·2–0·5) per 100 000 women across all 78 LMICs by 2120. This outcome, which is only achievable through a multi-sectoral and integrated approach across the continuum of cancer care, would represent extraordinary reductions in cervical cancer incidence (97% reduction) and mortality (99% reduction). Consequently, around 74·1 million cervical cancer cases and 62·6 million deaths would be averted, representing an enormous gain in terms of both quality of life and lives saved.

A major strength of this study is that we used a comparative approach involving well established model platforms that have been previously validated with data from multiple countries and that have jointly informed many national vaccination and cervical screening policy decisions. Predictions from the three models were broadly consistent for all scenarios, even over a century-long projection period. Our results for vaccination-only strategies are generally consistent with a recent analysis of the shorter-term impact on likely radiotherapy demand in LMICs,²⁶ which estimated that bivalent HPV vaccination of girls aged 12 years would only result in a 3·9% reduction in incident cervical cancer cases from 2015 to 2035. In line with our findings, the analysis found that incremental scale-up of radiotherapy in LMICs in the shorter term (up to 2035) would yield substantial health gains. Our sensitivity analysis demonstrated that for deaths averted, the variations generated by the differences in models were much smaller than uncertainties due to population size and structure over the next century. The sensitivity analysis also demonstrated that rates are somewhat sensitive to the choice of standard population used; this emphasises the importance of using the 2015 World Female Population for calculating cervical cancer incidence and mortality rates for comparability with our findings and across countries.

There were also some limitations to our analysis. The quality and availability of data about access to cancer treatment services, effective delivery of treatment, stage-distribution at diagnosis, and survival are variable for LMICs. Our modelling of survival was based on the latest data from major WHO reviews and we used updated DIRAC radiotherapy machine density as a surrogate for radiotherapy capacity and treatment access; this approach is reflective of the importance of radiotherapy as a cornerstone of effective treatment for cervical cancer and in line with the approach used by recently published models and the 2015 Lancet Oncology Commission on expanding global access to radiotherapy.26, 27 Furthermore, each modelling group independently did country-level model calibration of stage-specific survival to the best available mortality estimates from GLOBOCAN 2018. We incorporated a calibrated quality factor into the final estimated country-specific and stage-specific survival assumptions, which encompasses data limitations in treatment delivery information as well as variations in treatment delivery from established protocols and recommendations, equipment and infrastructure maintenance and logistics, and treatment abandonment due to financial stress or for other reasons. We did not take into account treatment improvements over time, assuming that mortality benefits resulting from cancer treatment scale-up by 2030 will be only due to the delivery of existing, effective treatment modalities, and not to emerging or hypothetical improvements in treatment beyond what is proven to be effective on a large scale in health services in high-income countries today.

Another limitation is that we did not explicitly model HPV infection, precancer and cervical cancer in women living with HIV. Increased progression to precancer and invasive cancer and reduced clearance of HPV is known to occur in women living with HIV, and this group is at increased risk of developing invasive cervical cancer, although this risk might now be partly or largely countered by the beneficial effects of antiretroviral therapy in many settings.28, 29 A separate collaborative group sponsored and coordinated by WHO is analysing the effects of HIV burden on estimates of cervical cancer elimination timing in selected countries. Current WHO cervical screening recommendations specify more frequent screening in women living with HIV,³⁰ and thus the mortality benefits we predicted are likely to depend on successful implementation of more intensive strategies for screening in high HIV-burden settings.

We did not include vaccination of boys or adult women in our core scenarios, because neither strategy has been found to be universally cost-effective even in high-income countries, and neither approach is recommended as part of the draft WHO elimination strategy. WHO's Strategic Advisory Group of Experts on Immunisation (SAGE) has recommended that vaccinating boys or older women should be delayed until current vaccine supply constraints are alleviated.³¹ Priority should be given to vaccination of young girls since this strategy will generate the greatest health benefits overall; boys will derive protection via herd immunity if high-coverage vaccination can be achieved in girls, and older women will be offered protection via scale-up of screening and treatment services. In this analysis, we did not explicitly consider cost-effectiveness, although previous work has shown the cost-effectiveness of combined vaccination and cervical screening approaches in various upper-middle-income countries and LMICs.32, 33 Cost-effectiveness will be required to weigh the trade-offs of the different strategies assessed here, including the incremental costs and benefits of vaccinating boys and doing two cervical screening tests instead of one in a lifetime. We found that the additional benefit of twice-lifetime versus once-lifetime screening was 1·6 million more deaths averted over a century, but the differences in cases averted is much higher.¹⁵ Thus, the incremental improvement in quality of life from including a second screen is likely to be substantial. Furthermore, our findings for screening are in the context of rapid and effective scale-up of cancer treatment. If cancer treatment is not as broadly available as we assumed, the incremental benefits of additional cancer prevention via increasing screening to two tests in a lifetime would be larger. Finally, the incremental benefits of a second screen are higher when considered over the next 50 years rather than 100 years, because if vaccination is scaled up successfully then screening will provide the most benefit in the next 50–60 years. In the future, it will be important to assess the potential for future de-intensification of cervical screening, since our findings suggest that this could be considered in some countries after about 2070–80, when the full benefits of vaccination for mortality outcomes are becoming realised. The ongoing work of the CCEMC is focused on more detailed analysis of the incremental benefits of the strategies and on quantifying cost-effectiveness for the 78 LMICs; we are also analysing a larger number of more nuanced alternative scenarios at a country level, including optimal triage policy. In general terms, more detailed country-level analyses, taking into account specific local factors important for the effective delivery of vaccination and screening interventions, will continue to be required, and should be viewed as an important complement to the current large-scale analysis.

The WHO scale-up targets for elimination can be considered aspirational. Many challenges will need to be overcome, including vaccine and screening test supply and delivery challenges, and the infrastructure challenges associated with scale-up of invasive cancer diagnostics, treatment, and supportive and palliative care services. If scale-up is achieved more slowly than we have assumed, then reductions in mortality will be correspondingly delayed. With respect to HPV vaccination, the assumed scaled up 90% coverage rate is broadly in line with data suggesting that global coverage of other vaccines in LMICs (including measles, poliomyelitis, hepatitis B and diphtheria-tetanus-pertussis) is 84–90%.³⁴ Our analysis for screening broadly applies to a wide range of clinically validated HPV tests that can achieve benchmark sensitivity and specificity. Testing could be done either at a central laboratory or in a point of care environment, with clinician-collected or self-collected samples; the sensitivity of PCR-based self-collected tests has been shown to be comparable to that of clinician-collected samples.³⁵ In principle, our findings also apply to any future screening test with similar performance to that of primary HPV testing. For example, machine learning approaches for analysing digitised cervical images hold promise in some settings.³⁶ Our modelling of screening assumed that the majority (90%) of HPV-positive women were treated, with visual assessment for treatment done only to exclude the possibility of a frank cancer or a large precancerous lesion (which would require referral). Therefore, our findings for the impact of the cervical screening and referral pathway are likely to represent the maximum attainable benefit. In practice, resource-stratified guidelines recommend different approaches in different settings and, where possible, women are triaged to treatment to minimise the potential harms, which include psychosocial impact, potential overtreatment, and a possible impact on obstetric outcomes. WHO is revising its guidelines for cervical screening and has already revised its guidelines for precancer treatment to take into account the latest evidence and the elimination strategy.30, 37

One of our main findings is that although achieving cervical cancer elimination per se will take many decades, the benefits of scaling up to the WHO elimination coverage targets will start to be realised within a decade. Key to this insight is an understanding of the timing of the effects of each intervention. Over the next 10–20 years, scaling up cancer treatment services will have the greatest impact because thousands of women in LMICs are being diagnosed every year with cervical cancer but have no access to adequate treatment. With appropriate treatment, survival prospects for early-stage and locally advanced cervical cancer are high. As a linked issue, offering appropriate palliative care to women who require it is an ethical and moral imperative. Over the intermediate term (the next 50–60 years), cervical screening will make an important contribution to outcomes, and over the longer term the full benefits of vaccination will be realised. The realisation of the major benefits of screening and vaccination over the intermediate and longer term will, however, require immediate action to implement these initiatives.

Scaling up to national vaccination, screening, and cancer treatment services in LMICs will be greatly facilitated by the successful realisation of universal health coverage in countries (SDG target 3.8). The 2019 Political Declaration of the UN high-level meeting on universal health coverage reaffirmed that health is a precondition for, and an outcome and indicator of, all dimensions of sustainable development, and countries strongly recommitted to achieving universal health coverage by 2030.³⁸ Building resilient and sustainable health systems could also be facilitated by the cervical cancer elimination initiative.³⁹ For example, cervical screening initiatives might be able to support or build on HIV services, since women receiving antiretroviral therapy return for refills regularly. Opportunities exist to link screening with sexual and reproductive health services, potentially increasing both uptake of screening and of contraception services. The elimination initiative could assist with building cancer literacy and addressing stigma in communities, and scaling up treatment as well as supportive and palliative care services for cervical cancer should have positive implications for various other tumour types. Access to universal health coverage will be a key underlying factor for the achievement of SDG goal 3.4, to reduce premature mortality from non-communicable diseases by a third by 2030. We have shown that, when considered at a level across all 78 LMICs, the cervical cancer elimination initiative will specifically support efforts to achieve this target. More broadly, the elimination agenda will support a reduction in poverty (SGD1), an increase in gender equality (SDG5), and reduction in inequalities (SDG10). Thus, successful implementation of the elimination initiative will have both nearer-term and enduring positive consequences, not only for women but also for their families and broader society.

In conclusion, these findings emphasise the importance of acting now on three fronts to scale up HPV vaccination, screening, and treatment for cervical cancer. In the next 10 years, achieving substantial reductions in cervical cancer mortality will depend on successful scale-up of cancer treatment services in LMICs, and supportive and palliative care will need to be scaled up alongside such services. Implementing the WHO strategy towards cervical cancer elimination will result in large-scale mortality reductions and more than 62 million women's lives saved over the next century in LMICs. These findings have informed the draft WHO global strategy for cervical cancer elimination, which will be presented to the WHO Executive Board in February, 2020, and thereafter considered at the World Health Assembly in May, 2020.

Supplementary Material