Eduardo Lazcano
Director of the Research Center for Population Health
National Institute for Public Health (INSP)

The Cancer Battle and Cost-Effective Interventions

Wed, 09/07/2016 - 15:06

At the end of the 80's, cervical cancer constituted one of the principal public health problems in Mexico. Given this, during the 1990s a line of research on cervical cancer was created at the National Institute of Public Health (INSP) of Mexico, with three principal areas: as the basis for later operational research, evaluation of processes and quality of care within the national cervical cancer detection program based on cytology (Papanicolaou or Pap smears); development of research using a case-control design, to identify associated factors including human papillomavirus (HPV) infection as well as epidemiological research on the impact of the cervical cancer early detection program; and the first population-based studies to characterize HPV DNA genotypes in healthy women in Mexico.

The initial scientific findings demonstrated that Mexico’s national cervical cancer detection program had fairly severe quality issues, including low-quality cytology specimen collection, given that close to 60 percent of a randomly selected sample of cytology (Pap smear) slides lacked endocervical cells, mucus and metaplastic cells, making them of little use for diagnostic purposes. Likewise, research established that there was an extremely high rate of false negative results on Pap smears. In spite of these findings, cytology did have a protective effect in terms of secondary prevention of cervical cancer in Mexico.

Given this, our research team used qualitative and quantitative approaches to identify the principal barriers to accessibility in the cervical cancer early detection program as well as limitations in local program processes. Our research group developed the first population-based regional studies to characterize the presence of HPV DNA in different age groups in Mexico. This research established that HPV is endemic in the Mexican population and has a bimodal distribution by age; that is, the highest frequency is reached before age 25 and a second peak in frequency occurs after age 65.

In 2006, the Ministry of Health commissioned the INSP to carry out two large demonstration studies to evaluate the utility of the HPV test in Mexico. These studies included over 250,000 Mexican women and demonstrated that clinical and self-sampled HPV tests have greater sensitivity than cytology. Community-based studies showed that a single yearly HPV test is more sensitive than two Pap tests in a year. A randomized, communitybased trial showed that HPV tests done on vaginal samples that were self-collected at home were four times more sensitive than cervical cytology as practiced in healthcare facilities located in rural areas in Mexico. In addition, this self-sampled test is low-cost, allows semiautomatized analysis, is easy to implement and has a lower false negative rate than cytology. Advantages include that it can be done either at home or at a local clinic or health center and this, in combination with the high acceptability of self-sampled tests, allows for increased coverage.

Mexico has adopted evidence-based public health policy and practice for the prevention and control of cervical cancer, including detection of and vaccination against HPV in all regions and socioeconomic groups, albeit targeting specific age groups. In 2006 the HPV test was introduced for primary detection in the country’s 150 most disadvantaged municipalities. Based on scientific evidence produced by the INSP, laboratory infrastructure for HPV DNA analysis has been established throughout most of Mexico in recent years for Seguro Popular and ISSSTE patients. Over 5 million HPV tests have been processed, concentrating principally on women above 35 years of age. Women with positive HPV results are referred for cytology. The INSP is carrying out triage studies that will provide evidence on what the best diagnostic referral processes are for these women.

Universal vaccination against HPV among girls between 10 and 11 years old was introduced in Mexico in 2012 with an alternative, extended vaccine schedule. The INSP recommended an HPV vaccination program using a preliminary extended schedule of 0-6-60 months, and later confirmed that the third dose would not be necessary. As of 2014 the policy proposed by the World Health Organization is to provide two doses before the age of 15, which has been implemented in over 80 countries including Mexico thanks to initiatives such as that recommended by the INSP.

A clinical trial implemented by the INSP to evaluate the immunogenicity and non-inferiority of alternative HPV vaccination schedules showed that vaccineinduced antibody titers were significantly higher after administration of two doses in girls 9-10 years old than after three doses in women 18-24 years old at 24 months after the last dose. The INSP research group is analyzing the immune response observed at 48, 51 and 61 months within that clinical trial. In collaboration with Mexico’s National Center for the Prevention and Control of HIV and AIDS (CENSIDA), the INSP will evaluate pilot programs focusing on introduction of universal HPV vaccination among women and men with HIV. This research will explore acceptability of the target population and among health professionals as well as accessibility and organizational issues in implementing vaccines through the national program of Ambulatory Centers for Prevention and Care of AIDS and sexually transmitted infections (Capasits).

Cervical cancer prevention and control programs that are opportunistic, as is the case for Mexico, face a series of challenges in terms of efficiency when followingup diagnosis and treatment for women with HPV or positive cytology. During the initial phases of HPV test implementation, in areas where quality control and follow-up processes for cervical cytology were especially deficient, women with positive HPV test results were sent directly to colposcopy. The result was a system overload with higher probabilities of over-diagnosis and over-treatment.

The principal problem Mexico’s cervical cancer prevention and control program faces is the high proportion of false negative results for cytology and a loss to follow-up of close to 50 percent after initial testing. Given this, at present women with a positive HPV test are referred for a Pap smear, which requires high-quality cytology and improved colposcopy to reach the necessary levels of diagnostic sensitivity.

In Mexico and the Latin American region more research is needed on the best triage strategy for HPV positive women, which should employ biomarkers with a better predictive value for development of disease. Such a study, called FRIDA, is being carried out in Mexico, in a projected universe of 100,000 women. This is the most ambitious initiative of its kind worldwide and is being developed through collaboration between the INSP and the Epidemiologic Research Unit of IMSS of the central Mexican state of Morelos. Infrastructure for this research has been set up within the HPV molecular biology laboratory at the INSP that will allow evaluation of the utility of tests for clinical management as triage strategies, including HPV 16 and 18 typing as well as convention liquid cytology. The research will also explore cellular markers for cancer progression such as E6 oncoprotein for HPV 16 and 18 as well as p16INK4a/Ki67 biomarkers.

A new cervical cancer prevention and control paradigm will also be researched through a strategy that a group of international experts has called the HPV-FASTER approach. This approach consists of including women up to 30 years or older in vaccination programs and pairing this with at least one HPV screening test in this same age group. The previously mentioned INSP-IMSS group will coordinate a study in Tlalpan, in the southern part of Mexico City, focusing on producing evidence on potential benefits to adult women of a combination of HPV vaccination and screening based on testing of highrisk HPV DNA. This could have an enormous positive impact since it allows exploration of the possibility for extending screening intervals in cancer prevention and control programs.

Given these initiatives, the INSP group has established itself as one of the principal innovators in cervical cancer prevention and control programs at a global level. This research group is on the cutting edge of the INSP’s mission to increase social equity and protect the population’s health by generating and disseminating scientific evidence, in that it has proposed organized social responses and achieved their implementation to contribute to important reductions in cervical cancer’s impact on the community.