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Innovative Approaches to Cervical Cancer Prevention

Paul D. Blumenthal, MD, MPH; Patricia Ringers, PhD; Noel McIntosh, MD, ScD; Lynne Gaffikin, DrPH Authors and Disclosures Posted: 12/06/2001; Medscape General Medicine. 2001;3(4) 2001 Medscape

Introduction
The article recently published by Sankaranarayanan and colleagues[1] provides an interesting, informative, and timely glimpse at the struggle to devise resource-appropriate interventions for an important public health problem. In many countries, cervical cancer is the most common cause of cancer death among women. The cause of cervical cancer is generally acknowledged to be the sexually transmitted human papillomavirus (HPV); as a sexually transmitted disease (STD), cervical cancer is responsible for more deaths than all other STDs combined, with the recent exception of HIV/AIDS.[2] This is particularly tragic because the vast majority of the estimated 231,000 annual cervical cancer deaths worldwide[3] are preventable. Dr. Sankaranarayanan and colleagues correctly relate that despite over 30 years of effort, very little headway toward reducing cervical cancer deaths has been made in the majority of developing countries. Why is this? Some of the findings from their review help answer this question. Low-resource countries need to invest now in strategies to improve women's health, not wait for the capacity of their health infrastructure to approach that of an industrialized country. In this light, Dr. Sankaranarayanan and his colleagues suggest that to reduce the morbidity and mortality associated with cervical cancer, low-resource countries must consider "planned investments" into prevention strategies, that have not, to date, been effective.[1]As the article suggests, population growth alone will strain extant cervical cancer prevention health infrastructures, so the critical question is whether cost-effective prevention programs can feasibly be introduced and maintained in low-resource countries where large numbers of women still die from cervical cancer. Dr. Sankaranarayanan and associates suggest that for cervical cancer, an approach that targets high-risk women with a simple, good-quality test, even if only offered once or twice in a lifetime, is more realistic and likely to be more cost-effective in low-resource settings than an approach dependent on a test that is not consistently available and/or for which a complex logistical and/or laboratory infrastructure is required. For example, cytology (Pap smear), the cornerstone test of successful screening programs in industrialized countries, requires laboratory facilities, consumables, and consistent, reliable mechanisms for follow-up that are beyond the resources of many countries. As such, it is likely to be "performed inadequately and inefficiently among the population." Which tests or approaches do hold promise for these settings? Vaccines that prevent or treat HPV infection are under development and, ultimately, may be the answer to this important public health problem. However, large-scale vaccine implementation is still years away in the countries that need it the most. An approach with tremendous potential entails testing for the presence of HPV on the cervix (or in the vagina). Widely regarded in industrialized countries as a possible primary screening tool, HPV testing is sensitive and in time could be implemented in developing countries. Currently, however, test costs are relatively high. In addition, with existing HPV testing technology, results are not immediately available. Therefore, the likelihood of high loss to follow-up of positive cases remains a formidable problem. Linking HPV testing with a safe, effective, feasible method of treating positive cases is a critical consideration for the establishment of any successful cancer prevention program. The authors state that visual inspection of the cervix with acetic acid wash (VIA) "may be considered a suitable early detection test in the context of early clinical diagnosis [of cervical cancer or dysplasia] in low-income countries." Indeed, more than 15 studies have documented the test performance characteristics of this simple, easy-to-learn, inexpensive test.[4] All available studies report negative predictive values of over 95%, meaning that

a woman can be tested and confidently discharged with little need for frequent, repeat testing. Indeed, if a woman is tested at about age 40 (an appropriate age for a once-in-a-lifetime screening approach), a negative VIA result means it is very unlikely she will ever get or die from cervical cancer. For women testing positive with VIA, the likelihood of their being truly afflicted with cancer or precancerous lesions varies depending on the prevalence of disease in the target population. For the clinician trained never to treat a patient without a "diagnosis," combining VIA testing with an immediate offer of treatment (such as cryotherapy or LEEP for precancerous lesions) presents a dilemma. VIA results are reported as either test negative or test positive (the latter usually differentiated as suspected cancer vs suspected precancerous lesion). VIA testing, therefore, does not yield a definitive "diagnosis." For many developing countries, however, the capacity to provide histologic diagnoses or even colposcopic confirmation of suspected lesions is extremely limited -- usually to only urban centers, and even there only on a limited basis). Thus, a management approach immediately linking a safe method of treatment with the results of a relatively good screening test "could be judged to be ethical because of the huge reduction in the risk of cervical cancer so achieved."[5] Loss to follow-up post-testing is an issue central to the findings of 2 recent reports on the costeffectiveness of alternative cervical cancer prevention strategies.[6,7] The authors of both studies utilized a state transition Markov computer model and local disease prevalence and resource data from a developing country to estimate the cost-effectiveness (in terms of reduced disease incidence/mortality) of a variety of preventive approaches. In both studies, VIA with immediate cryotherapy was the most cost-effective (defined as fewest dollars spent per life-year saved). In both studies, the sensitivity of VIA (consistently reported in the literature above 60%, average value approximately 75%), coupled with the proven effectiveness of cryotherapy and the fact that both screening and treatment procedures were provided in a single visit, were critical factors contributing to the cost-effectiveness of this approach (as compared with other approaches that require multiple visits or confirmatory testing). Screening coverage in the cost-effectiveness models (base case) as assumed to be 100% -- a challenge with any approach, given that the estimated proportion of women screened within the past 5 years in developing countries is only 5%.[8] In the South Africa analysis,[6] an HPV test provided once in a lifetime with immediate offer of treatment for those with positive test results resulted in a higher reduction in cervical cancer incidence than a single visit approach using VIA, but at a higher cost; for the latter, the cost of a single visit was low enough that the approach resulted in cost savings compared with providing no screening at all.[6] Where HPV testing is affordable and loss to follow-up unlikely, an HPV-based approach is promising. If the cost of HPV testing continues to drop and results become immediately obtainable, this approach offers even more promise. In the interim, where resources are truly scarce, the lower costs associated with VIA-based approaches, despite the lower predicted effectiveness, may make them the most feasible option and, therefore, a possibly attractive one for local policy makers. Although the VIA-based single-visit approach is imperfect in that considerable numbers of women are offered treatment who do not actually have disease (and is offered without a confirmatory diagnosis), this limitation, and the cost of treating false positives, has been taken into account in the above cost-effectiveness analyses. Single-visit approaches limit the burden on already strained healthcare systems by minimizing the need for followup. (Women with large lesions still need referring to higher levels of the system for adequate treatment.) For countries with fledgling referral systems, this approach allows for phased investment in the capacity to diagnose and treat early invasive cancers and large precancerous lesions as well as increased screening coverage. While a single-visit approach seems to be the most cost-effective option for low-resource settings, it is clear that countries have differing public health needs. Health indicators of each country must be considered, and the burden of cervical disease must be weighed against the burden of other preventable diseases. Public health officials in countries suffering large population losses as a result of HIV/AIDS may not elect to invest monies in clinical programs directed at cervical cancer prevention. As Dr. Sankaranarayanan and colleagues suggest, it may

be more appropriate to embark on a program of public education and awareness of the disease. However, where public health officials do elect to invest limited resources in preventing cervical cancer deaths, safe, effective, and low-cost alternatives are clearly needed to yield the greatest reduction in cervical cancer morbidity and mortality for the amount of money they can afford to invest. Recently, with funding from the Bill and Melinda Gates Foundation, 5 international agencies (Engender Health, IARC, JHPIEGO, PAHO, and PATH) joined forces to create the Alliance for Cervical Cancer Prevention. Their shared goal is to prevent cervical cancer in developing countries. They, along with many other organizations dedicated to this goal, are testing various alternative approaches to cervical cancer prevention that are both costeffective and feasible to implement in low-resource settings. Results from ongoing field studies will complement current and future cost-effective computer simulations, providing important additional information for public health officials responsible for allocating limited health resources. If we work collaboratively to implement innovative prevention approaches tailored to local conditions, the elimination of cervical cancer in low- and middle-income countries may yet become a reality.