Acting on the call for cervical cancer elimination: Planning tools for low- and middle- income countries to increase the coverage and effectiveness of screening and treatment.

INTRODUCTION: Accessible planning tools tailored for low-and middle-income countries can assist decision makers in comparing implementation of different cervical cancer screening approaches and treatment delivery scenarios in settings with high cervical cancer burden. METHODS: The Cervical Precancer Planning Tool (CPPT) was developed by PATH for users to explore and compare the accuracy of screening approaches, what treatment equipment to procure, and how best to deploy treatment equipment in a given country. The CPPT compares four screening approaches: 1) visual inspection with acetic acid (VIA), 2) HPV testing, 3) HPV testing followed by a VIA triage, and 4) HPV testing followed by an enhanced triage test. Accuracy of screening outcomes (e.g., true positives, false positives) is based on published sensitivity and specificity of tests to detect cervical precancerous lesions. The CPPT compares five scenarios for deploying ablative treatment equipment: 1) cervical precancer equipment at every location a woman is screened (single visit approach), 2) equipment only at a hospital level, 3) a single unit of equipment in each district, 4) allowing two districts to share a single unit of equipment, and 5) equipment placed at select district hospitals paired with mobile outreach. Users can customize the CPPT by adjusting pre-populated baseline values and assumptions, including population estimates, screening age range, screening frequency, HPV and HIV prevalence, supply costs, and health facility details. RESULTS: The CPPT generates data tables and graphs that compare the results of implementing each of the four screening and five treatment scenarios disaggregated by HIV status. Outputs include the number and outcomes of women screened, cost of each screening approach, provider time and cost saved by implementing self-sampling for HPV testing, number of women treated, treatment equipment needed by type, and the financial and economic costs for each equipment deployment scenario. CONCLUSION: The CPPT provides practical information and data to compare tradeoffs of patient access and screening accuracy as well as efficient utilization of equipment, skilled personnel, and financial resources. Country decision makers can use outputs from the CPPT to guide the scale-up of cervical cancer screening and treatment while optimizing limited resources.

Evaluation of diagnostic ultrasound use in a breast cancer detection strategy in Northern Peru.

To evaluate the diagnostic impact of point-of-care breast ultrasound by trained primary care physicians (PCPs) as part of a breast cancer detection program using clinical breast exam in an underserved region of Peru. Medical records and breast ultrasound images of symptomatic women presenting to the Breast Cancer Detection Model (BCDM) in Trujillo, Peru were collected from 2017-2018. Performance was measured against final outcomes derived from regional cancer center medical records, fine needle aspiration results, patient follow-up (sensitivity, specificity, positive, and negative predictive values), and by percent agreement with the retrospective, blinded interpretation of images by a fellowship-trained breast radiologist, and a Peruvian breast surgeon. The diagnostic impact of ultrasound, compared to clinical breast exam (CBE), was calculated for actual practice and for potential impact of two alternative reporting systems. Of the 171 women presenting for breast ultrasound, 23 had breast cancer (13.5%). Breast ultrasound used as a triage test (current practice) detected all cancer cases (including four cancers missed on confirmatory CBE). PCPs showed strong agreement with radiologist and surgeon readings regarding the final management of masses (85.4% and 80.4%, respectively). While the triage system yielded a similar number of biopsies as CBE alone, using the condensed and full BI-RADS systems would have reduced biopsies by 60% while identifying 87% of cancers immediately and deferring 13% to six-month follow-up. Point-of-care ultrasound performed by trained PCPs improves diagnostic accuracy for managing symptomatic women over CBE alone and enhances access. Greater use of BI-RADS to guide management would reduce the diagnostic burden substantially.

National implementation of HPV vaccination programs in low-resource countries: Lessons, challenges, and future prospects.

More than 90% of cervical cancer deaths occur in low- and middle-income countries (LMICs), which have limited capacity to mount the comprehensive national screening and precancer treatment programs that could prevent most of these deaths. The development of vaccines against the human papillomavirus (HPV) has dramatically altered the landscape of cervical cancer prevention. As of mid-2020, 56 LMICs (41% of all LMICs) have initiated national HPV vaccination programs. This paper reviews the experience of LMICs that have introduced HPV vaccine into their national programs, key lessons learned, HPV vaccination sustainability and scale-up challenges, and future mitigation measures. As international guidance evolved and countries accumulated experience, strategies for national introduction shifted with regard to target groups, delivery site and timing, preparation and planning, communications and social mobilization, and ultimately monitoring, supervision and evaluation. Despite the successes that LMICs have been able to achieve in reaching large proportions of eligible girls, there are still considerable challenges countries encounter in overcoming rumors, reaching out-of-school girls, completing the vaccine series, estimating target populations, monitoring program performance, and assuring vaccination sustainability. New opportunities, such as the entry of additional vaccine manufacturers and ongoing studies to evaluate one-dose delivery, could help overcome the outstanding barriers to higher coverage and financial sustainability. Effective use of the experience to date and advances on the horizon could enable all LMICs to move towards the coverage levels that are needed to achieve eventual elimination.

Breast cancer early detection and diagnostic capacity in Uganda.

BACKGROUND: Greater than 80% of women presenting for breast cancer treatment in Uganda have late-stage disease, which is attributable to a dysfunctional referral system and a lack of recognition of the early signs and symptoms among primary health care providers, and compounded by the poor infrastructure and inadequate human capacity. Improving the breast health care system requires a systemic approach beginning with situational analysis to identify systematic gaps that prevent sustainable improvements in outcome. METHODS: The authors performed a situational analysis of the breast health care system using methods developed by the Breast Health Global Initiative. Based on their findings, they developed a series of recommendations for strengthening the health system for the early diagnosis of breast cancer based on clinical detection, referral, tissue sampling, and diagnosis. RESULTS: Deficits in the recognition of breast cancer signs and symptoms, the underuse of clinical breast examination as a diagnostic and/or screening tool, the centralization of diagnostic tests (radiology and pathology), reliance on excisional biopsies rather than needle biopsies, and a lack of trained professionals and knowledge of the referral system all contribute to significant health system delays. CONCLUSIONS: To strengthen referral networks and improve the early diagnosis of breast cancer in Uganda, national referral hospitals should provide educational programs to primary health care providers in community health centers (CHCs), at which the majority of women first present with symptoms. At secondary district-level facilities in which imaging and tissue sampling can be performed, the capacity for diagnostic testing could be increased through task shifting of basic interpretation (abnormal vs normal) from specialists to nonspecialists using networking technology to facilitate remote oversight from specialists at the national referral hospitals.

Prevention of cervical and breast cancer mortality in low- and middle-income countries: a window of opportunity.

Breast and cervical cancer are the two most common women's cancers worldwide. Countries have invested for decades in early detection programs for breast and cervical cancer through screening, community education, and opportunistic case detection by health professionals. However, effectiveness in low- and middle-income countries (LMICs) has been limited due to low coverage, insufficient laboratory capacities for diagnosis, health information systems (HIS) that are not designed to track patients or monitor program performance, barriers that inhibit women's uptake of services, and inadequate treatment options. Even where some screening activities exist, there has not been sufficient attention to ensuring completion of appropriate diagnosis and treatment after women receive a positive screening test result or report symptoms suggesting cervical or breast cancer. Because of this failure to provide adequate follow-up care, these women miss the potential benefit from early detection and have a higher than average risk to develop cancer or progress to more advanced cancer stages that could have been avoided. There are several critical steps in a woman's journey from good health to elevated cancer risk, then to cancer prevention or diagnosis, and finally to treatment. There is a window of opportunity that extends from the time a positive finding is identified-by a cervical or breast screening test or recognition of a breast abnormality-to the point when cervical precancer treatment is delivered or a treatment plan for diagnosed breast cancer is initiated. Building on existing health systems and adapting measurable, affordable, and culturally acceptable interventions can achieve a lasting impact. If women can successfully navigate this window of opportunity, they can avoid progression to cervical cancer or greatly reduce the need for invasive treatments for breast cancer and improve their chances for survival and improved quality of life. We propose several actions that can lead us on the path towards reduction of this cancer burden.

Health impact of delayed implementation of cervical cancer screening programs in India: A modeling analysis.

India has the highest burden of cervical cancer in the world. To estimate the consequences of delaying implementation of organized cervical cancer screening, we projected the avertable burden of disease under different implementation scenarios of a screening program. We used an individual-based microsimulation model of human papillomavirus (HPV) infection and cervical cancer calibrated to epidemiologic data from India to project age-specific cancer incidence and mortality reductions associated with screening (once-in-a-lifetime among women aged 30-34 years) with one-visit visual inspection with acetic acid (VIA) and one- and two-visit HPV DNA testing. We then applied these reductions to a population model to project the lifetime cervical cancer cases and deaths averted under different implementation scenarios taking place from 2017 to 2026: (1) immediate implementation of screening with currently available screening tests (one-visit VIA, two-visit HPV testing); (2) immediate implementation of screening with currently available screening tests, with a switch to point-of-care one-visit HPV testing in 5 years; and (3) 5-year delayed implementation of screening with current screening tests or point-of-care HPV testing. Immediate implementation of two-visit HPV testing with a switch to one-visit HPV testing averted 574,100 cases and 382,500 deaths over the lifetimes of 81.4 million 30- to 34-year-old women screened once between 2017 and 2026. Delayed implementation with a one-visit HPV test averted 209,300 cases and 139,100 deaths. Delaying implementation of screening programs in high-burden settings will result in substantial morbidity and mortality among women beyond the age for adolescent HPV vaccination.

Model for Early Detection of Breast Cancer in Low-Resource Areas: The Experience in Peru.

PURPOSE: Late-stage breast cancer detection should be something of the past; however, it is still all too common in low-resource areas, including Peru, where 57% of women diagnosed with cancer are diagnosed at stage III or IV disease. Early detection of breast cancer is feasible in low-resource semirural and rural areas where mammography is rarely accessible. METHODS: PATH collaborated with Peruvian health institutions at local, regional, and national levels to design and implement a model of care for the early detection of breast cancer in Peru. The model includes training health promoters for community outreach, professional midwives in clinical breast exam, doctors to perform fine-needle aspiration biopsy sampling with ultrasound to triage, and patient navigators to ensure patients follow through with treatment. RESULTS: In a northern region of Peru, 400 individuals, including health promoters, midwives, doctors, and volunteers, received early-detection training in two phases. In Peru, local health professionals continue to refine and improve methods and materials using locally available resources, and the Peruvian health information system now includes specific breast cancer detection categories. Despite challenges and limited resources, the model is effective, and partnership with government health administrations improves health systems and benefits the population. CONCLUSION: Given the absence of screening mammography, the public health challenge is to bring breast cancer early detection and diagnostic services closer to women's homes and to ensure appropriate follow-up and care. The model is eminently transferable with appropriate adaptation and should now be tested in other settings within and outside of Peru.

Opportunities and challenges for introducing HPV testing for cervical cancer screening in sub-Saharan Africa.

To protect women against cervical cancer, the World Health Organization recommends that women aged 30 to 49 years be screened with tests that detect human papillomavirus (HPV). If the countries that have the greatest burden of this disease-especially those in sub-Saharan Africa-are not to be left behind, we must understand the challenges they face and identify measures that can help them take full advantage now of innovations that are transforming screening services in wealthier countries. We reviewed policy documents and published literature related to Kenya, Tanzania, and Uganda, and met with key personnel from government and nongovernmental organizations. National policy makers understand the value of HPV testing in terms of its superior sensitivity and the programmatic advantages that could result from using self-collected samples. However, while these countries have national cervical cancer prevention strategies, and some have national departments or units for cervical cancer prevention, screening is rare, funding scarce, and quality low. Age guidelines are not strictly followed, with scarce resources being used to screen many women younger than the recommended ages. Published evidence of the benefits of HPV testing-including performance, safety, and cost-effectiveness-must be provided to ministry of health leaders, along with information on anticipated costs for training personnel, purchasing supplies, providing facility space, and maintaining test kits. Despite the obstacles, a joint effort on the part of global and national stakeholders to introduce molecular screening methods can bring better protection to the women who need it most.

Cost-Effectiveness of Cervical Cancer Screening in Women Living With HIV in South Africa: A Mathematical Modeling Study.

BACKGROUND: Women with HIV face an increased risk of human papillomavirus (HPV) acquisition and persistence, cervical intraepithelial neoplasia, and invasive cervical cancer. Our objective was to determine the cost-effectiveness of different cervical cancer screening strategies among women with HIV in South Africa. METHODS: We modified a mathematical model of HPV infection and cervical disease to reflect coinfection with HIV. The model was calibrated to epidemiologic data from HIV-infected women in South Africa. Clinical and economic data were drawn from in-country data sources. The model was used to project reductions in the lifetime risk of cervical cancer and incremental cost-effectiveness ratios (ICERs) of Pap and HPV DNA screening and management algorithms beginning at HIV diagnosis, at 1-, 2-, or 3-year intervals. Strategies with an ICER below South Africa's 2016 per capita gross domestic product (US$5270) were considered "cost-effective." RESULTS: HPV testing followed by treatment (test-and-treat) at 2-year intervals was the most effective strategy that was also cost-effective, reducing lifetime cancer risk by 56.6% with an ICER of US$3010 per year of life saved. Other cost-effective strategies included Pap (referral threshold: HSIL+) at 1-, 2-, and 3-year intervals, and HPV test-and-treat at 3-year intervals. Pap (ASCUS+), HPV testing with 16/18 genotyping, and HPV testing with Pap or visual triage of HPV-positive women were less effective and more costly than alternatives. CONCLUSIONS: Considering per capita gross domestic product as the benchmark for cost-effectiveness, HPV test-and-treat is optimal in South Africa. At lower cost-effectiveness benchmarks, Pap (HSIL+) would be optimal.

Estimating the value of point-of-care HPV testing in three low- and middle-income countries: a modeling study.

BACKGROUND: Where resources are available, the World Health Organization recommends cervical cancer screening with human papillomavirus (HPV) DNA testing and subsequent treatment of HPV-positive women with timely cryotherapy. Newer technologies may facilitate a same-day screen-and-treat approach, but these testing systems are generally too expensive for widespread use in low-resource settings. METHODS: To assess the value of a hypothetical point-of-care HPV test, we used a mathematical simulation model of the natural history of HPV and data from the START-UP multi-site demonstration project to estimate the health benefits and costs associated with a shift from a 2-visit approach (requiring a return visit for treatment) to 1-visit HPV testing (i.e., screen-and-treat). We estimated the incremental net monetary benefit (INMB), which represents the maximum additional lifetime cost per woman that could be incurred for a new point-of-care HPV test to be cost-effective, depending on expected loss to follow-up between visits (LTFU) in a given setting. RESULTS: For screening three times in a lifetime at 100% coverage of the target population, when LTFU was 10%, the INMB of the 1-visit relative to the 2-visit approach was I$13 in India, I$36 in Nicaragua, and I$17 in Uganda. If LTFU was 30% or greater, the INMB values for the 1-visit approach in all countries was equivalent to or exceeded total lifetime costs associated with screening three times in a lifetime. At a LTFU level of 70%, the INMB of the 1-visit approach was I$127 in India, I$399 in Nicaragua, and I$121 in Uganda. CONCLUSIONS: These findings indicate that point-of-care technology for cervical cancer screening may be worthy of high investment if linkage to treatment can be assured, particularly in settings where LTFU is high.

Primary Prevention of Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Guideline.

PURPOSE: To provide resource-stratified (four tiers), evidence-based recommendations on the primary prevention of cervical cancer globally. METHODS: The American Society of Clinical Oncology convened a multidisciplinary, multinational panel of oncology, obstetrics/gynecology, public health, cancer control, epidemiology/biostatistics, health economics, behavioral/implementation science, and patient advocacy experts. The Expert Panel reviewed existing guidelines and conducted a modified ADAPTE process and a formal consensus-based process with additional experts (consensus ratings group) for one round of formal ratings. RESULTS: Existing sets of guidelines from five guideline developers were identified and reviewed; adapted recommendations formed the evidence base. Five systematic reviews, along with cost-effectiveness analyses, provided evidence to inform the formal consensus process, which resulted in agreement of ≥ 75%. RECOMMENDATIONS: In all resource settings, two doses of human papillomavirus vaccine are recommended for girls age 9 to 14 years, with an interval of at least 6 months and possibly up to 12 to 15 months. Individuals with HIV positivity should receive three doses. Maximal and enhanced settings: if girls are age ≥ 15 years and received their first dose before age 15 years, they may complete the series; if no doses were received before age 15 years, three doses should be administered; in both scenarios, vaccination may be through age 26 years. Limited and basic settings: if sufficient resources remain after vaccinating girls age 9 to 14 years, girls who received one dose may receive additional doses between age 15 and 26 years. Maximal, enhanced, and limited settings: if ≥ 50% coverage in the priority female target population, sufficient resources, and cost effectiveness, boys may be vaccinated to prevent other noncervical human papillomavirus-related cancers and diseases. Basic settings: vaccinating boys is not recommended.It is the view of the American Society of Clinical Oncology that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.

Resource-stratified implementation of a community-based breast cancer management programme in Peru.

Breast cancer incidence and mortality rates continue to rise in Peru, with related deaths projected to increase from 1208 in 2012, to 2054 in 2030. Despite improvements in national cancer control plans, various barriers to positive breast cancer outcomes remain. Multiorganisational stakeholder collaboration is needed for the development of functional, sustainable early diagnosis, treatment and supportive care programmes with the potential to achieve measurable outcomes. In 2011, PATH, the Peruvian Ministry of Health, the National Cancer Institute in Lima, and the Regional Cancer Institute in Trujillo collaborated to establish the Community-based Program for Breast Health, the aim of which was to improve breast health-care delivery in Peru. A four-step, resource-stratified implementation strategy was used to establish an effective community-based triage programme and a practical early diagnosis scheme within existing multilevel health-care infrastructure. The phased implementation model was initially developed by the Breast Cancer Initiative 2·5: a group of health and non-governmental organisations who collaborate to improve breast cancer outcomes. To date, the Community-based Program for Breast Health has successfully implemented steps 1, 2, and 3 of the Breast Cancer Initiative 2·5 model in Peru, with reports of increased awareness of breast cancer among women, improved capacity for early diagnosis among health workers, and the creation of stronger and more functional linkages between the primary levels (ie, local or community) and higher levels (ie, district, region, and national) of health care. The Community-based Program for Breast Health is a successful example of stakeholder and collaborator involvement-both internal and external to Peru-in the design and implementation of resource-appropriate interventions to increase breast health-care capacity in a middle-income Latin American country.

The Cost-Effectiveness of Visual Triage of Human Papillomavirus-Positive Women in Three Low- and Middle-Income Countries.

Background: World Health Organization guidelines support human papillomavirus (HPV) testing alone (followed by treatment with cryotherapy) or in conjunction with visual inspection with acetic acid (VIA) triage testing. Our objective was to determine the cost-effectiveness of VIA triage for HPV-positive women in low-resource settings.Methods: We calibrated mathematical simulation models of HPV infection and cervical cancer to epidemiologic data from India, Nicaragua, and Uganda. Using cost and test performance data from the START-UP demonstration projects, we assumed screening took place either once or three times in a lifetime between ages 30 and 40 years. Strategies included (i) HPV alone, followed by cryotherapy for all eligible HPV-positive women; and (ii) HPV testing with VIA triage for HPV-positive women, followed by cryotherapy for eligible women who were also VIA-positive (HPV-VIA). Model outcomes included lifetime risk of cervical cancer and incremental cost-effectiveness ratios (ICERs; international dollars/year of life saved).Results: In all three countries, HPV alone was more effective than HPV-VIA. In Nicaragua and Uganda, HPV alone was also less costly than HPV-VIA; ICERs associated with screening three times in a lifetime (HPV alone) were below per capita GDP. In India, both HPV alone and HPV-VIA had ICERs below per capita GDP.Conclusions: VIA triage of HPV-positive women is not likely to be cost-effective in settings with high cervical cancer burden. HPV alone followed by treatment may achieve greater health benefits and value for public health dollars.Impact: This study provides early evidence on the cost-effectiveness of HPV testing followed by VIA triage versus an HPV screen-and-treat strategy. Cancer Epidemiol Biomarkers Prev; 26(10); 1500-10. ©2017 AACR.

Evidence-based policy choices for efficient and equitable cervical cancer screening programs in low-resource settings.

Women in developing countries disproportionately bear the burden of cervical cancer. The availability of prophylactic vaccines against human papillomavirus (HPV) types 16 and 18, which cause approximately 70% of cervical cancers, provides reason for optimism as roll-out begins with support from Gavi, the Vaccine Alliance. However, for the hundreds of millions of women beyond the target age for HPV vaccination, cervical cancer screening to detect and treat precancerous lesions remains the only form of prevention. Here we describe the challenges that confront screening programs in low-resource settings, including (1) optimizing screening test effectiveness; (2) achieving high screening coverage of the target population; and (3) managing screen-positive women. For each of these challenges, we summarize the tradeoffs between resource utilization and programmatic attributes. We then highlight opportunities for efficient and equitable programming, with supporting evidence from recent mathematical modeling analyses informed by data from the PATH demonstration projects in India, Nicaragua, and Uganda.

Ending cervical cancer: A call to action.

The outlook for elimination of the scourge of cervical cancer is bright, because we now have the tools to achieve this goal. In recent years human papillomavirus (HPV) vaccination in high-income countries has resulted in dramatic decreases in HPV infection and associated cervical disease. If all countries with a substantial burden of disease introduce the vaccine nationally, we can protect the vast majority of women and girls most at risk. For women who are beyond the vaccination target age, progress has been made in screening and treatment for cervical precancer, but we must accelerate this momentum to reduce incidence and mortality worldwide to the very low rates found in wealthier countries. Human and financial resources must be increased and directed to programs that follow best practices and reach all women, including the marginalized or disadvantaged. Seven key actions are recommended. Now is the time for action at national, regional, and global levels.

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.