Because of the limitations that many researchers associate with the Pap smear to screen cervical cancer patients in developing countries, various alternatives are being explored, including visual inspection techniques and human papillomavirus (HPV) screening.
Both have clinical benefits and drawbacks, and researchers and patients must also contend with economic and public education challenges.
Visual Screening with Acetic Acid
The efficacy and practicality of visual-inspection screening are being evaluated using a 3% to 5% acetic acid solution on the cervix. The solution causes abnormal cervical cells to turn white, making it possible to obtain an immediate test result.
“You can say to a woman, ‘You're fine—go home and don't worry,'” said Jacqueline Sherris, PhD, Strategic Program Leader of Reproductive Health at the Program for Appropriate Technology in Health (PATH) in Seattle. Or the health care provider can tell the patient she needs further evaluation. Telling her right away increases the likelihood of her returning in a week for therapy.
Even better, said Dr. Sherris, some programs treat women immediately with cryotherapy. While not perfect, visual inspection differentiates most of the individuals who have disease from those who don't, said Paul Blumenthal, MD, Associate Professor of Gynecology and Obstetrics at Johns Hopkins University School of Medicine and Director of the Cervical Cancer Prevention Program at JHPIEGO, a not-for-profit international public health organization.
Additionally, the immediate treatment gets around the problem of the majority of women not undergoing further follow-up, said Sylvia Robles, MD, MSc, Unit Chief of Non-Communicable Diseases at the Pan American Health Organization (PAHO), part of the World Health Organization.
Some women may want to go home and talk to their families before receiving therapy, but they are more likely to come back knowing their diagnosis, Dr. Robles continued.
She related a recent experience she had in El Salvador where a 34-year-old woman with six children was screened with the acetic acid test and a lesion was found and was treated immediately with cryotherapy.
“She would have developed cancer,” Dr. Robles said. “We haven't seen serious complications in the thousands and thousands of women we've treated so far.”
In truly poor countries, people need some form of low-tech screening, said Eduardo L. Franco, MPH, DrPH, Professor of Epidemiology and Oncology Director in the Division of Cancer Epidemiology at McGill University.
Visual inspection seems to work in Peru, South Africa, and India, he said, adding that it's very efficacious when compared with the Pap test. The sensitivity of detecting high-grade lesions is at least equal to that of cytology, although the specificity may be lower.
In some of Thailand's provinces, JHPIEGO is beginning to implement the alternative approach of visual inspection plus the offer of treatment.
The program is in its initial stages and the start-up costs are high, noted Dr. Blumenthal, adding that $400 million can generally get a program up and running. Programs have to include the cost of human resources, transportation, and technology.
Visual Inspection Using Lugol's Iodine
Another visual test being evaluated involves the use of Lugol's iodine, which stains normal cervical cells brown, leaving abnormal areas a yellowish color. Studies indicate that sensitivity is at least as good as Pap screening, Dr. Sherris said, and as with the acetic acid test, the results can be seen immediately, enabling the patient to be treated with cryotherapy.
Visual inspection with iodine is now under investigation in India and Africa and appears to be working well, Dr. Robles noted.
Training for Visual Inspection
Overall, visual screening training does not take a long time, said Rengaswamy Sankaranarayanan, MD, a staff scientist for the Unit of Descriptive Epidemiology at the International Agency for Research on Cancer in Lyon, France. Dr. Sankaranarayanan has worked on cervical cancer screening research in India and Africa.
Nurses, health care workers, and midwives can generally be trained in one to two weeks. “But quality of training is very important,” he noted. On a long-term basis, the performance of the workers has to be carefully monitored, and they need retraining for quality assurance.
Drawbacks of Visual Inspection
Others have problems with visual inspection, however. “Personally, I do not have much faith in alternative methods such as visual inspection of the cervix,” said Micol Salvetto, MSc, a consultant in Managua, Nicaragua, for the Central American Health Institute, a non-governmental organization with branches in Central America.
“Wherever I have seen countries experimenting with this technique—Peru was one of them—it has invariably translated to a huge amount of work and money invested in pilot programs, which have not yielded the desired results.”
Ms. Salvetto acknowledges the advantage of having an immediate test result, which cytology does not provide, but said she is particularly concerned about nurses making diagnostic decisions: “They would have to make a diagnostic decision, for which I do not think they are qualified,” she said.
Visual inspection also has a low specificity. If treated immediately without a biopsy, many women will receive cryotherapy unnecessarily.
“If these women are not part of a structured system and there is no chance of following them up, the effectiveness of the treatment may never be known,” she said.
While the acetic acid test is an extremely inexpensive and attractive alternative that produces immediate results, it tends to overdiagnose quite significantly and therefore it is not a practical alternative, agreed Hennie Cronjé, MD, Professor in the Department of Obstetrics and Gynecology at the University of the Free State in Bloemfontein, South Africa.
If the specificity of the acetic acid test can be improved, it might be invaluable, he said.
Despite these drawbacks, local governments generally welcome these pilot programs for visual inspection but are unwilling to consider changing the existing system based on a Pap smear, Ms. Salvetto said.
However, neither the pilots nor the international literature have proven a definite advantage of visual inspection, she noted.
“If the money currently spent on piloting techniques of unproved efficiency were invested in the improvement of existing, traditional programs, the health of women in developing countries would greatly improve.”
HPV DNA testing is another area of screening that researchers are investigating for developing countries. Shunro Sonoda, MD, DMedSci., Professor Emeritus of Virology at Kagoshima University in Kagoshima, Japan, and his colleagues are introducing HPV molecular diagnosis with the Pap smear test in developing countries.
Fifty to 70 percent of cases with Grade II-III lesions on the Pap test are positive for HPV DNA, he said, and 80 to 90 percent of cervical cancers are associated with HPV infection.
HPV testing as a primary screening may be effective in women who are in their 30s, 40s, and 50s who have persistent infection, Dr. Sherri said.
A positive result strongly correlates with a precancerous lesion in this population, but younger women would not benefit from such screening, because about 90% have a transient HPV infection of mild dysplasia that will resolve spontaneously.
HPV is a relatively objective test with yes-or-no results that are accurate, while visual tests leave a lot of room for interpretation, Dr. Sherri explained.
The HPV test is sensitive, Dr. Franco said, and “if you don't have the virus, you are free of lesions.”
The self-collection of vaginal samples is another area of interest, Dr. Sherris said. Women need to take a swab and insert it into their vagina, rotate it around several times, remove it, and put it in a collection bottle.
The strategy is easier to implement in some settings than in others. “It's not difficult, but women who are not used to tampons or other intravaginal devices are often uncomfortable with the self-test,” she explained.
HPV testing's impact will be very limited in the short term, said Ms. Salvetto. “Even if it was possible to test for all the known high-risk HPV types, or the most prevalent ones in a country, there is no guarantee that this will result in an invasive lesion in that particular woman,” she noted. This is also not a once in a lifetime test, unless it is used to dismiss older women from a screening program. Having a negative result does not mean that the patient can't acquire the virus in the future, she explained.
HPV testing is expensive and relies on highly specialized laboratory equipment and specific antibodies, which are rarely available in developing countries, she added. “Our own experience with PCR testing for HPV in Nicaragua was not encouraging,” she said.
“I do not see how it could be of any benefit in screening programs, which are still struggling to cope with covering the cost of performing a Pap on all high-risk women.”
Because of its cost, using the test in middle resource countries makes more sense than trying to use it in developing countries, said Dr. Franco.
Dr. Cronjé also acknowledges that the test is expensive. He believes that the development of a cheap on-site HPV test would be beneficial to women.
Continuing and Future Challenges
Regardless of what screening test researchers find works best for a specific population, still to be considered are the economic and public education issues.
For many governments cervical cancer is not a very high priority, Dr. Cronjé noted. Nutrition, AIDS, and tuberculosis are considered to be much more urgent, with the result that there is little money available for control of cervical cancer.
Making a direct cost comparison among the different cervical cancer screening tests is difficult because of the variations in different countries' infrastructures, health care systems, and human and technical resources.
Dr. Sankaranarayanan and his colleagues are evaluating conventional cytology, HPV, and acetic visual testing in a large randomized trial in India. Although results are not yet available, he noted that all the three methods are promising but have different economic implications.
Generally, visual screening methods require less of a financial investment than Pap screening, he said. However, countries that have already invested in cytology screening, such as Chile and Brazil, should make further investments to further improving their programs with internal and external quality controls, and the quality of Pap smear, evaluation, and reporting.
In other countries, such as those in Sub-Saharan Africa, implementing a cytology-based program is not practical because of costs, Dr. Sankaranarayanan noted. These countries may instead benefit from visual inspection. In India, for example, some states may be able to introduce cytology, while in others introducing visual tests may be more economically feasible.
In addition to finding economic support for screening programs, both developing and industrialized countries need to have an understanding of the impact of cervical cancer on the global level.
“We in the United States and developed countries are used to not worrying about this disease,” Dr. Sherris said. “We seldom know someone who has been impacted by it.”
In contrast, more than 60,000 women in India die from cervical cancer each year, she said—women in their 30s and 40s, who have children and who have a role in their community.
In developing countries, health care programs need to encourage women to continue with their care if they have a positive test or don't feel well, Dr. Robles said.
Women must be told exactly why they need to go through the bother of doing an unpleasant test when they believe they are and possibly feel healthy, agreed Ms. Salvetto.
Cultural beliefs and preferences change between countries and among different communities in the same country, she added. An effective screening program should target its campaign accordingly.
Additionally, public education programs need to focus on any needed follow-up visits to health care providers and treatment options.
Partnership Crucial to Success
To help address the challenges inherent in cervical cancer screening, industrialized countries need to partner with scientists in developing countries to increase research capacity and to complement each others' strengths and weaknesses, said Sylvia C. Robles, MD, MSc, Unit Chief of Noncommunicable Diseases for the Pan American Health Organization.
“Scientists around the world can continue to work on looking for ways to test and treat women at lower costs and under difficult circumstances,” concluded Micol Salvetto, MSc, a Nicaragua-based health consultant for the Central American Health Institute.