The investment case for cervical cancer elimination

We already know what causes cervical cancer, how to prevent it, and how to treat it, even in resource‐constrained settings. Inequitable access to human papillomavirus vaccine for girls and screening and precancer treatment for women in low‐ and middle‐income countries is unacceptable on ethical, social, and financial grounds. The burden of cervical cancer falls on the poor and extends beyond the narrow bounds of the family, affecting national economic development and community life, as family resources are drained and poverty tightens its grip. Proven solutions are available and the priorities for the next few years are clear, as shown by the papers in this Supplement. Sustained political commitment and strategic investments in cervical cancer prevention can not only save millions of lives over the next 10 years, but can also pave the way for the broader fight against all cancers.


| INTRODUCTION
We already know what causes cervical cancer, how to prevent it, and how to treat it, even in resource-constrained se ngs. Yet, sadly, every two minutes a woman dies of this disease. The global divide in incidence and mortality for cervical cancer could hardly be more stark. The vast majority of women who develop and die of cervical cancer live in low-and middle-income countries (LMICs), where access to primary and secondary preven on-and care for women with invasive disease, including pallia ve care-remains profoundly limited. The problem fundamentally is social and economic inequality-the solu on is, in large part, sustained poli cal commitment.
If the current genera on of young adolescent girls can be vaccinated against human papillomavirus (HPV), in 20-30 years as they reach the ages when precancerous lesions would normally appear and take hold, they can expect to be nearly free of the threat of cervical cancer. The good news about cross-protec on against HPV types not included in the vaccine and herd immunity for those who missed being vaccinated 1,2 and the recent licensing of a 9-valent vaccine that protects against 90% of the types causing cervical cancer suggests we may be closer to elimina on of this disease than we dreamed possible 10 years ago when the vaccine was first introduced. 3 Despite this exci ng prospect and the hard work it will take to make widespread HPV vaccina on a reality, we cannot forget the millions of adult women and older adolescent girls who were beyond the priority age for vaccina on when it became available in their communi es. These women deserve a chance to have the protec on that screening and preven ve treatment (for precancer) provides-the protec on women in wealthy countries have benefitted from for decades. Arguments to ra onalize this gross inequity of access in the past-the challenges of providing cytology, insufficient trained specialists, compe ng burdens of infec ous disease and obstetric complica ons-can no longer be accepted. Without significantly increased screening and preven ve treatment services, an es mated 19 million women will die from cervical cancer over the next 40 years. 4 There is a backlog of more than 700 million women in low-and lower-middle-income countries who were 20-49 years old in 2015, 5 who are or will reach screening age in the next decade who have not been vaccinated and for the most part have never been screened. The papers in this Supplement highlight the progress that has been made in recent years and, more importantly, the opportuni es that governments now have to apply proven clinical tools and health system approaches to redress this inequity.
This final paper in this Interna onal Journal of Gynecology and Obstetrics (IJGO) Supplement draws on the insights of the expert contribu ons of the preceding papers to construct a compelling case for urgent investment in cervical cancer preven on. Targeted investments that build on recent scien fic advances and best prac ces can support and accelerate na onal efforts to scale-up nascent programs, and ensure essen al services are established with sustainable strategies for disadvantaged women who have, for far too long, borne the heaviest por on of the burden of this preventable disease.

| THE BURDEN OF CERVICAL CANCER IS ON THE POOR
In 2012 there were 528 000 cases and 266 000 deaths from cervical cancer worldwide, 6 a number of deaths not unlike that of women who died from complica ons of pregnancy and childbirth. Maternal mortality rates have greatly improved over the last 15 years, dropping from about 529 000 in 2000 to about 303 000 in 2015 7 ; this is believed to be due at least in part to efforts to meet the Millennium Development Goals. As with maternal mortality, the distribu on of cervical cancer cases is highly skewed, with mortality rates in the Eastern Africa region (27.6 per 100 000: age standardized rate) that are 18 mes higher than in regions with the lowest rates-Australia/New Zealand (1.5) and Western Europe (1.8). 6 There are 38 countries where the most common cancer among women is cervical cancer, and most of those countries are in Sub-Saharan Africa. 8 Women in these countries play significant roles in their families, communi es, and society at large, as caregivers of children and the elderly, wage earners, and major food producers. The impact of serious illness and premature mortality extends far beyond the narrow bounds of the family, affecting na onal economic development as well as community life and draining family resources as poverty ghtens its grip. 9 Many wealthy countries have seen cervical cancer incidence and mortality rates fall drama cally in the past two to three decades, par cularly where effec ve popula on-based screening programs have been established. With the introduc on of HPV vaccines and the con nued delivery of screening services, these countries are already on the path to elimina on of cervical cancer. There are others, however, where screening programs have been weak and changes in sexual lifestyles have increased exposure to HPV, as in Central Asia, 10 or where high HIV rates have exacerbated HPV persistence and progression to cancer, resul ng in rates that are unchanged or rising. 8 If there is no substan al change in the incidence of cervical cancer, the overall number of women predicted to develop the disease each year is es mated to grow to 700 000 by 2030, the last year for achieving the Sustainable Development Goal target to reduce by one-third premature mortality from noncommunicable diseases (NCDs), including cancer, cardiovascular disease, diabetes, and chronic respiratory diseases. 8 It is in LMICs where efforts will make the most difference.

| PROVEN SOLUTIONS ARE AVAILABLE
The licensure of three HPV vaccines and the growing body of evidence that they can be delivered to young adolescent girls in LMICs, building on exis ng pla orms of na onal immuniza on programs, is one of the most exci ng developments of the past decade. As noted in the paper by LaMontagne et al., 11 the impact of the vaccine on immunological and disease endpoints has surpassed our expectaons, including the benefits of herd immunity for the unvaccinated in communi es where vaccine is widely but not universally provided.
The safety of the vaccine, despite numerous unsubstan ated claims by vaccine opponents, con nues to be judged highly sa sfactory by However, the moderate sensi vity and variability of VIA, the heavy burden on overworked healthcare providers, and the cultural issue of modesty have also been revealed as major barriers to scaling up highquality na onal programs based on VIA. As noted by Ogilvie et al., 13 HPV tests designed to minimize infrastructure demands offer the promise of higher sensi vity and reliability, allowing longer intervals between screening and greater disease reduc on. Wherever sufficient resources permit it, the WHO recommends HPV tes ng as the preferred screening method. 12 The ability to perform HPV tes ng with samples collected by women themselves is one of the biggest breakthroughs, with the poten al to revolu onize screening by removing cultural barriers and reducing demands on health worker me.
Despite these advances in screening technology and delivery, they will have limited impact if screening is not followed by effec ve treatment where needed, embedded within programs with resourceappropriate management algorithms. Castle et al. 14  Scaling up all these ac vi es to na onal programs with coverage reaching even the most marginalized popula ons is the ul mate goal, if we are to achieve elimina on of cervical cancer. As Holme et al. 19 report, there is both good news and bad news on this front. Where there were no effec ve na onal programs 10 years ago, we now have several countries forging ahead to expand and adapt pilot programs, even with their limited resources. Countries that had services in major urban areas are star ng to expand to smaller provincial and district facili es and test poten al outreach strategies. However, too many countries are struggling to map out feasible na onal strategies appropriate for their resources and to iden fy partners and donors who will help them get started. There was a longstanding belief that screening programs would not be successful unless they could achieve 80% coverage, 20 but modeling has clearly shown that the impact is linear and that every incremental improvement in coverage has a payoff in disease reduc on, although it may be somewhat less cost-effec ve un l higher levels of coverage can be achieved. If implemented with careful planning, strategic and sustainable financing, robust monitoring and evalua on, and adequate popula on coverage, screening programs can reduce cervical cancer incidence and mortality substan ally. Table 1 draws on the papers in this Supplement to summarize highlights of the progress made in the past decade and remaining priori es.
Addressing these priori es requires the a en on of many different partners at na onal and global levels. Advocacy will be cri cal to this effort. 21

| THE RATIONALE FOR INCREASED INVESTMENT NOW
Campos et al. 22 have calculated the cost of a basic program of vaccinaon, once-in-a-life me screening, and cancer treatment (at current levels) for 50 LMICs, rolled out over a 10-year period. To reach 160 million girls with two doses of vaccine and 170 million women with screening and treatment as needed would cost about US $3.2 billion. The program cost for each woman reached with screening averaged US $9, with costs lower in the low-income countries. What has not been calculated is the cost of inac on-the lives lost each year and the escala ng health costs to the system of trea ng late-stage cancers, a cost that will climb as more women demand cancer treatment rather than accep ng their fate.
With this targeted investment over the next 10 years, we could prevent 5.2 million cervical cancer cases, 3.7 million deaths, and 21.8 million disability-adjusted life years. 22 By any measure, both vaccina on and screening in this basic package are very cost-effec ve. If we con nue to defer ac on-wai ng for be er technologies or for successive cohorts of vaccinated girls from this point onward to take care of the problem-we will be sacrificing the current genera on of women and girls who did not benefit from HPV vaccines.
In addi on to the girls and women who benefit directly, other investments already being made to strengthen health systems-such as upgrading health informa on systems, expanding the health labor force, and modernizing procurement capaci es and supply chainswill have a bigger payoff if we use them wisely to address not only the tradi onal health issues but also previously unaddressed problems like cervical cancer, with high value for money spent.  23 In the same way, the successful control of cervical cancer-the first cancer for which we have effec ve strategies for both primary and secondary preven on applicable in lowerresource se ngs-could be the opening salvo in the ba le against cancer globally, a fight that will be difficult to turn away from even in countries with the least resources. As Bill Foege, leader of the smallpox campaign, noted: "…we are always faced with making sufficient decisions based on insufficient informa on. If we had waited un l all the answers were available, the work on smallpox eradica on would never have started-selec ng the target helped develop the appropriate tools and strategy." 24 In the case of cervical cancer, many of the answers and tools are already available; consensus on the target is emerging-elimina on of cervical cancer as a public health problem.

AUTHOR CONTRIBUTIONS
Both VT and OG developed the original concept. VT created the first dra . Both authors contributed sugges ons and reviewed the final paper.

VT acknowledges par al support from the Bill & Melinda Gates
Founda on; however, the views expressed here are solely those of T A B L E 1 Overview of progress and priori es for cervical cancer preven on.