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RHO archives : Topics : Cervical Cancer Prevention

Annotated Bibliography

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Primary prevention of cervical cancer

Castellsague, X. et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. New England Journal of Medicine 346(15):1105-1112 (2002).
Data from a large multi-center case-control study were pooled to assess whether male circumcision was related to reduced risks of penile human papillomavirus (HPV) and thus subsequent cervical cancer in female partners. Circumcision status was self-reported and HPV status determined by PCR. Authors adjusted for potential confounders that included age at first intercourse and number of sexual partners. Results showed circumcised men had a reduced risk of having HPV infection as compared to uncircumcised men (odds ratio, .37; 95 percent confidence interval, .16 to.85). The study then analyzed the risk of cervical cancer among monogamous women whose husbands had six or more sexual partners and found a reduced risk of cervical cancer among women whose husbands were circumcised (adjusted odds ratio, .42; 95 percent confidence interval, .23 to .79).

Coker, A.L. et al. Barrier methods of contraception and cervical intraepithelial neoplasia. Contraception 45(1):1-10 (1992).
The goal of this U.S. case-control study of 103 cases with biopsy-confirmed, high-grade dysplasia and 258 controls with normal cervical cytology was to examine risk factors for cervical intraepithelial neoplasia (CIN). Study participants were interviewed about their sexual and reproductive history, Pap smear screening, cigarette exposures, and contraceptive use patterns. After adjusting for confounding factors, the authors found that cases were half as likely as controls to ever have used a barrier method (defined as condom, spermicide, or diaphragm) (OR = 0.5; 95% CI = 0.2-0.9). When analyzed separately, condom (OR = 0.5; 95% CI = 0.2-1.0) and diaphragm use (OR = 0.3; 95% CI = 0.1-0.9) both were associated with a decrease in risk, while spermicide use was not.

Grimes, D.A. and Economy, K.E. Primary prevention of gynecologic cancers. American Journal of Obstetrics and Gynecology 172:227-235 (1995).
This review article examines the epidemiologic characteristics of cervical, endometrial, and ovarian cancers as they relate to primary prevention strategies. The review was limited to invasive cancers. Regarding cervical cancer, the authors concluded that avoiding cigarette smoking may protect against cervical cancer and a diet rich in vitamin C may reduce the risk of cervical cancer. They also determined that the long-term use of oral contraceptives was associated with cervical cancer, but noted the difficulty in controlling for the potential effects of cigarette smoking, sexual history, and the frequency of Pap smear screening. The authors also concluded that the use of barrier methods of contraception (studies included diaphragm, condoms, foam, spermicides, and contraceptive jelly) protects against invasive cervical cancer. Finally they noted that since early age at first intercourse, the frequency of intercourse at an early age, and high numbers of sexual partners are all associated with cervical cancer, abstinence and delaying of first intercourse should decrease the risk of cervical cancer.

Hildesheim, A. et al. Barrier and spermicidal contraceptive methods and risk of invasive cervical cancer. Epidemiology 1:226-272 (1990).
The goal of this U.S. case-control study of 479 invasive cervical cancer cases and 788 controls was to examine the effects of barrier and spermicidal methods of contraception on cervical cancer risk. Study participants were interviewed about contraceptive practices as well as other factors that might affect cervical cancer risk, including reproductive history, sexual behavior, Pap smear screening history, and smoking. After adjusting for confounding factors, the authors found no significant association with condom, diaphragm, or vaginal spermicide use. They noted a slight but nonsignificant decrease of cervical cancer with long-term (more than 5 years) diaphragm use (OR = 0.8; 95% CI = 0.4 1.6).

Koutsky, L.A. and Kiviat, N.B. Genital human papillomavirus. In: Sexually Transmitted Diseases. 3rd ed. Holmes, K.K. et al., eds. New York: McGraw-Hill (1999).
This chapter provides a detailed overview of the issues related to genital human papillomavirus, including the definition, prevalence and incidence, geographic distribution, transmission, risk factors, clinical manifestations, management, and prevention.

Mindel, A. and Tideman, R. HPV transmission—still feeling the way [commentary]. Lancet 354:2098-2099 (December 18-25, 1999).
This commentary critically discusses findings by Sonnex et al. that showed a potential for transmission of HPV infection by finger-genital contact. The authors state that finger-genital transmission of HPV is possible, but that transmission would rely on a sequence of events highly unlikely to occur. They note that detection of HPV DNA on fingertips does not necessarily imply the presence of intact, infectious virus. They also note that HPV transmission would require actual finger transfer of a sufficient quantity of live virus and a corresponding breach of genital skin. They conclude the article by stating that finger-genital contact usually is accompanied by genital-to-genital contact, where transmission is far more likely to occur. They recommend condom use as the only intervention currently proven to reduce the risk of HPV transmission.

Sawaya, G.F. et al. Frequency of cervical smear abnormalities within 3 years of normal cytology. Obstetrics and Gynecology 96(2):219-223 (August 2000).
This U.S. study compared cervical screening outcomes at one, two, and three years after screening. While annual Pap smear screening has contributed significantly to a decline in the U.S. mortality rate from cervical cancer, it is less clear whether women in the United States with normal smears need annual follow-up or could be screened less frequently. This study sought to determine the incidence of abnormal smears after normal smears, and to see how rates vary by age and time since the last normal smear. The study analyzed 128,805 women with normal baseline smears and follow-up smears 9 to 36 months later. The study found that women screened within three years of a normal smear all had the same risk of developing high-grade squamous intraepithelial lesion (SIL) or worse, but such results were uncommon. Women under age 30 were more likely to have a low-grade abnormal smear, and the incidence declined with age. The authors concluded that the best screening protocols for women with recent normal Pap smears should be based on comprehensive modeling studies that incorporate the true risks and benefits of repetitive screening.

Sellors, J.W. et al. Comparison of self-collected vaginal, vulvar, and urine samples with physician-collected cervical samples for human papillomavirus testing to detect high-grade squamous intraepithelial lesions. Canadian Medical Association Journal 163(5):513-518 (September 5, 2000).
In this study, 200 women referred to a colposcopy clinic at a teaching hospital in Ontario, Canada, provided self-collected vulvar, vaginal, and urine samples for HPV testing. A physician also collected cervical samples for testing, and the respective test results were compared. Positive HPV test results obtained on vaginal swabs by the women themselves had a 86.2 percent sensitivity for high-grade squamous intraepithelial lesions (HSIL, equivalent to CIN grade II or III), while the cervical samples obtained by the physician showed a sensitivity of 98.3 percent. The sensitivity of self-collected vulvar and urine samples were 62.1 percent and 44.8 percent respectively. The study found the self-sampling methods to be generally acceptable to the women. Given that Pap smear accuracy is far from perfect and that cytology programs are not feasible in many developing countries, the authors conclude by recommending further evaluation of HPV testing using self-collected samples, especially in areas where cytological screening services are limited.

Sellors, J.W., Mahony, J.B., et al. Prevalence and predictors of human papillomavirus infection in women in Ontario, Canada. Canadian Medical Association Journal 163(5):503-508 (September 5, 2000).
This study of 955 Canadian women ages 15 to 49 was undertaken to increase understanding of the natural history of HPV infection. HPV testing showed that women age 20 to 24 years had the highest prevalence of HPV infection at 24 percent. Prevalence dropped with increasing age, to a low of 3.4 percent in women 45 to 49 years old. The risk factors for HPV infection identified in this study are never-married, divorced, or separated status; more than three lifetime sexual partners; more than one partner in the previous year; cigarette smoking; and current use of oral contraceptives. As other studies have found, there also was a strong association between HPV and abnormal cytological results. The authors call for more HPV survey studies to be done in countries with various rates of cervical cancer in order to better assess risk factors, clearance rates, and acquisition of different types of infection over time.

Shepherd, J. et al. Interventions for encouraging sexual lifestyles and behaviours intended to prevent cervical cancer (Cochrane Review). In: The Cochrane Library, Issue 3, 1999. Oxford: Update Software. [See RHO's WHO RHL page for more information.]
This meta-analysis reviews the effectiveness of health education in promoting sexual risk reduction among women in order to reduce transmission of human papillomavirus (HPV). The review included ten studies of education programs, all of which had the primary aim of preventing HIV and other STIs rather than cervical cancer. The review found that educational interventions targeting socially and economically disadvantaged women in which information provision is complemented by sexual negotiation skill development can encourage at least short-term sexual risk reduction behavior. This has the potential to reduce the transmission of HPV and, as a result, the incidence of cervical cancer.

Sonnex, C. et al. Detection of human papillomavirus DNA on the fingers of patients with genital warts. Sexually Transmitted Infections 75(5):317-319 (October 1999).
This study, which detected HPV DNA on the fingers of patients with genital warts, raises the possibility that HPV infection can be transmitted through finger-genital contact. The authors took samples from genital lesions and fingertips of 14 men and 8 women who had genital warts. From the genital samples, they detected HPV DNA in all 8 female samples and 13 of 14 male samples. In a separate testing of samples taken from fingertips of the same subjects, they detected HPV DNA in 3 women and 9 men. The authors further determined that the same type of HPV DNA was present in the genital and finger samples of one woman and five men. Although sexual intercourse is considered to be the usual mode of transmission for genital HPV infection, this study shows that some patients with genital warts carry HPV of the same type on their fingers. This points to a potential for transmission of HPV infection by finger-genital contact.

Thomas, D.B. et al. Human papillomaviruses and cervical cancer in Bangkok. The role of husbands and commercial sex workers. American Journal of Epidemiology 153(8):740-748 (2001).
This article in is the third in a series of three studies on cervical cancer in Bangkok. The results highlights the potential for men to play a role in increasing their wives risk of HPV infection and cervical cancer. According to the findings, women whose husbands report frequent contact with sex workers (280 or more visits over their lifetime) were more than three times as likely to develop invasive cancer than women whose husbands reported no contact with sex workers. The women in the study reported their husband was their only sexual partner throughout their lifetime, leading to the conclusion that their husbands may be acquiring high-risk HPV infection from contact with sex workers and transmitting it to their wives.

Wen, L.M. et al. Risk factors for the acquisition of genital warts: are condoms protective? Sexually Transmitted Infections 75(5):312-316 (1999).
This study, conducted at Australia's largest STI clinic, included 977 patients with genital warts and 977 controls matched by sex and date of clinic attendance. The study goals were to determine risk factors for acquiring genital warts and to determine whether condoms offer protection against infection. Independent risk factors for genital warts were found to be younger age, greater number of lifetime sexual partners (primarily true for men), and smoking (men only). The authors noted that, although previous studies have failed to show a protective effect of condom use, this study found that consistent condom use significantly reduced the risk for both sexes of acquiring genital warts.

World Health Organization (WHO). Primary Prevention of Cervical Cancer. CAN/85.1. Geneva: WHO (October 3-November 2, 1985).
A WHO consulting group met in 1985 to consider possible approaches for primary prevention of cervical cancer. Given that cervical cancer is strongly linked to early onset of sexual activity and multiple sexual partners, the WHO group recommended sex education and studies in sexual behavior, while acknowledging that behavior is difficult to change. They recommended that development of vaccines for HPV be made a high priority, together with further study of the possible contribution of smoking to cervical cancer. They noted that there is no evidence to suggest a protective effect from hygiene, male circumcision, or nutrition, and that data are inconclusive on the role of oral or injectable contraceptives. They recommended that use of barrier methods, particularly condoms, should be encouraged.

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Screening: assessment of alternative approaches

Adab P, McGhee SM, Yanova J, et al. Effectiveness and efficiency of opportunistic cervical cancer screening: comparison with organized screening. Medical Care. 2004;42(6):600-609.
The authors developed a model to assess the effectiveness (percent reduction in incidence) and efficiency (number of smears per case prevented) of opportunistic screening compared to organized screening for cervical cancer prevention. Data on screening history were gathered from a cross-sectional study of 1,826 women aged 20 to 77 years, living in Hong Kong. Authors developed two models based on screening intervals. In the “optimistic” model, they assumed that women with two previous cytology screenings would return for their next screening at the same duration as their last smear. In the “pessimistic” model it was assumed that the interval for the women’s next screening would be 10 years or more. Based on these models, the reduction in incident cases of cervical cancer was between 26 percent (pessimistic model) and 31 percent (optimistic model) with 2,723 and 2,786 screening smears per cancer case prevented, respectively. Authors discussed the benefits of an organized screening program. Effectiveness typically increases with increased coverage of the population, resulting in a reduction of cervical cancer incidence. In their models, increased coverage did not affect efficiency. Reducing the screening interval also results in increased effectiveness but reduced efficiency. The authors concluded that the current Hong Kong screening system is less effective and efficient compared to an organized screening system that could achieve 80 percent coverage at 10-year intervals (effectiveness estimates were based on models in a study produced by the International Agency for Research on Cancer [IARC], 1986).

Basu, P.S. et al. Visual inspection with acetic acid and cytology in the early detection of cerivcal neoplasia in Kolkata, India. International Journal of Gynecological Cancer 13:626-632 (2003).
This study analyzes the test characteristics of VIA, VIAM and cytology used for cervical cancer screening in Kolkata (Calcutta), India. A total of 5,881 women were screened using VIA, VIAM, and conventional cytology. True positive disease was defined as CIN 2 or 3 or carcinoma in situ. All women had colposcopic evaluation and biopsies were performed if indicated (1052, 17.9%) to determine final diagnosis. Thus, direct estimation of sensitivities, specificities, and predictive values was possible without the risk of verification bias. More women tested positive with VIA and VIAM than with cytology (18.7% and 17.7% compared to 8.2%). The sensitivity of VIA, VIAM and cytology was 55.7%, 60.7%, and 29.5%, respectively. The specificity of VIA, VIAM and cytology was 82.1%, 83.2%, and 92.3%, respectively. The improvement in sensitivity of VIAM over VIA, although small, was statistically significant (P<0.01), with no reduction or improvement in specificity. The sensitivities of VIA and VIAM are lower in this study than previously reported in other studies, and the authors comment that the use of nonmedical workers as compared to nursing or paramedical professionals may account for some of this difference.

Basu, P. et al. Evaluation of downstaging in the detection of cervical neoplasia in Kolkata, India. International Journal of Cancer 100:92-96 (2002).
This study sought to determine the sensitivity and specificity of downstaging (examining the cervix with the naked eye, also known as "unaided visual inspection") when used to detect cervical lesions. Downstaging was used to screen 6,399 women in Kolkata, India. Direct estimates for sensitivity and specificity were made after colposcopy was performed on all women and biopsies were taken for abnormal lesions. Using a low-threshold to detect high-grade lesions, downstaging had a sensitivity of 48.9 percent and a specificity of 75.8 percent. With a high-threshold downstaging, the sensitivity for detecting high-grade lesions was 31.9 percent and the specificity was 93.3 percent. The low sensitivity, and relatively low specificity when using the low-threshold test, means that large numbers of women would be falsely identified as having cervical neoplasia. On the other hand, the low specificity of the high-threshold test means that the test would miss a large proportion of women with disease. Authors conclude that downstaging is an inadequate test for primary screening for cervical neoplasia.

Belinson, J.L. et al. Cervical cancer screening by simple visual inspection after acetic acid. Obstetrics and Gynecology 98(3):441-444 (September 2001).
This study reports the sensitivity and specificity of using visual inspection with acetic acid (VIA) to screen 1,997 women between the ages of 35 to 45 years in rural Shanxi Province, China. VIA, colposcopy and directed biopsies were performed on all women. Sensitivity of VIA in this setting was equal to or greater than rates reported for conventional cytology. VIA had a sensitivity of 71 percent (61 of 86, 95% CI 60%, 80%) for detecting CIN II and higher and a specificity of 74 percent (1,420 of 1,911, 95% CI 72%, 76%) for detecting CIN II and higher. These results are comparable to the sensitivity and specificity reported in the University of Zimbabwe/Johns Hopkins University study. VIA's specificity for detecting CIN II lesions or higher was similar to specificity rates for colposcopy. Both VIA and colposcopy performed less well on smaller lesions that only appeared in one quadrant. The authors discuss several variables that could affect the performance of VIA, and comment that a region's available resources (human and financial) will help determine what screening tests are appropriate. They conclude that the low-cost, ease of training and implementation, and low infrastructure requirements for point-of-care diagnosis and treatment algorithm make VIA an attractive choice for cervical cancer screening in low-resource settings.

Blumenthal, P.D. et al. Adjunctive testing for cervical cancer in low resource settings with visual inspection, HPV, and the Pap smear. International Journal of Gynecology & Obstetrics 72:47-53 (2001).
The objective of this study was to examine whether performing combinations of visual inspection with acetic acid (VIA), HPV testing, and cytology would improve the specificity of VIA without decreasing its sensitivity. Data from a cervical cancer screening study conducted in Zimbabwe were analyzed using standard calculations of net sensitivity and specificity for the various combinations of the screening tests. Net sensitivity and specificity for VIA combined with HPV was calculated as 63.6 and 81.9 percent, respectively.  The combination of VIA followed by HPV was more effective at detecting women with cervical disease than either Pap smear followed by HPV or HPV followed by Pap smear. Combining VIA in sequence with another test also produced fewer false positives than using VIA alone. The authors comment that using VIA as the first test in a sequence has the benefit of immediate results, making it possible to perform a second test in the same visit, an important consideration in developing country settings. It is not possible, however, to have the immediate results from using either HPV or Pap smear as a second test. The authors conclude that making management decisions based on VIA alone, in settings where there is considerable loss to follow-up when women need to return for a second clinic visit, merits serious consideration.

Chirenje, Z.M. et al. Situation analysis for cervical cancer diagnosis and treatment in East, Central and Southern African countries. Bulletin of the World Health Organization 79(2):127-132 (2001).
This study collected interview and questionnaire data from randomly selected primary health care centers, district hospitals, provincial and tertiary hospitals in Kenya, Lesotho, Uganda, United Republic of Tanzania, and Zimbabwe during an eight-month period of 1997. The results revealed that although most countries had a basic infrastructure to support Pap smear screening, coverage was extremely low in all countries and women frequently presented with advanced-stage disease. Frequently cited reasons for the low screening coverage included a lack of policy guidelines on cervical cancer screening, an inconsistent stock of materials, and an inadequate number of trained cytotechnicians. Only 42 percent of district and provincial hospitals had treatment facilities for cone biopsies, but only 31 percent of provincial hospitals actually performed the procedure. Cryotherapy, a relatively inexpensive, reliable, and simple procedure, was only available in 4 percent of hospitals and health centers. These results highlight the great need for increased cervical cancer screening efforts in the region.

Coppleson, M. et al. An electronic approach to the detection of precancer and cancer of the uterine cervix: a preliminary evaluation of Polarprobe. International Journal of Gynecological Cancer 4:79-83 (1994).
This article describes preliminary results of an electronic device for detection of cervical cancer and its precursors, known as the Polarprobe. The Polarprobe is a computerized diagnostic instrument consisting of a pen-sized probe that is inserted into the vagina and moved across the cervix. The probe is attached to a portable computer that processes electrical and optical properties of cervical tissue and compares the information with data from normal or abnormal tissue. The study established recognition algorithms from analysis of results of 106 volunteers and then tested 77 additional volunteers. When comparing Polarprobe diagnosis with concurrently obtained histologic-colposcopic diagnosis, concordance between the two was 85 percent for low-grade intraepithelial abnormalities, 90 percent for high-grade abnormalities, and 99 percent for cancer.

Cullins, V. et al. Cervical cancer prevention using visual screening methods. Reproductive Health Matters 7(14):134-143 (1999).
Among the range of screening techniques being studied for use in low-resource settings, direct visual inspection (DVI)—also referred to as visual inspection with acetic acid (VIA)—is thought to have good potential for screening and treatment in one visit. However, the authors say caution is needed when applying a new approach in a mass screening program. DVI appears to have the same sensitivity but lower specificity than Pap smears, and could lead to overtreatment of many women who do not have disease. The standard forms of treatment (cryosurgery, laser ablation, or loop electrosurgical excision) all result in an open cervical ulcer that takes three to four weeks to heal. Prior to widespread screening using DVI studies need to determine (1) the complication rate of treatment when performed by mid-level clinicians; (2) the co-morbidity of treatment in a population where STIs and HIV are endemic; and (3) the acceptability of a screening program in which up to one-third of women will be unnecessarily treated. The relative risks and benefits of widespread DVI screening need to be carefully evaluated.

Denny, L. et al. Two-stage cervical cancer screening: An alternative for resource-poor settings. American Journal of Obstetrics and Gynecology 183 (2):383-388 (2000).
By using two screening tests sequentially to screen for cervical cancer, this study sought to reduce unnecessary treatment. A total of 1,423 women from Cape Town, South Africa, were screened using direct visual inspection with acetic acid with and without magnification, HPV DNA testing, cytological testing, and cervicography. Any woman with an abnormality on any test was referred for colposcopy. When used alone these tests respectively identified 24, 26, 23, and 23 cases of high-grade squamous intraepithelial lesion or cancer per 1,000 women. The respective tests would also classify 182, 71, 137, and 112 women without disease as having an abnormal result (false positives). When direct visual inspection was used first, and only women with an abnormal result screened with HPV DNA testing, cytological testing, or cervicography, the number of cases identified dropped to 18, 16, and 18 per 1,000 women, respectively (lower sensitivity). However, the number of false positives also dropped significantly (greater specificity). Different settings would favor the use of different combinations of screening tests, but the two-stage approach offers an alternative to screening for cervical cancer in the absence of colposcopy.

Gaffikin, L. et al. Safety, acceptability, and feasibility of a single-visit approach to cervical-cancer prevention in rural Thailand: a demonstration project. Lancet 361:814-820 (March 8, 2003). [Erratum published in the Lancet 361(9373):1994 (June 7, 2003).]
This article assesses an innovative approach to cervical cancer prevention in a rural community in Thailand. 12 nurses were trained to test women for cervical lesions using visual inspection with acetic acid (VIA). Women who tested positive after VIA were counseled by the nurses and offered treatment with cryotherapy. Overall 5999 women were tested with VIA. 798 women tested positive (VIA test-positive rate, 13.3 percent) and of those 618 were eligible for immediate treatment with cryotherapy. 609 of the 618 accepted immediate treatment. A total of 756 women received cryotherapy (either immediate or postponed). Women were counseled about potential side effects and complications and were instructed to return if any symptoms developed that could indicate a potential complication. Follow-up visits were scheduled for 3 months and 1 year post-treatment. 629 women returned for their first scheduled follow-up visit. Overall the majority of women were highly satisfied with the VIA and cryotherapy treatment and few complications arose. There were no major complications (admission, transfusion, or major surgery) needed as a result of the treatment. Unscheduled visits were made by 33 (4.4 percent) of the 756 women, and among those 33 women 17 needed a conservative outpatient procedure (2.2 percent of the total treated). Authors conclude that a VIA + cryotherapy single-visit approach is safe, effective, and feasible for programs in developing countries.

Gaffikin, L. et al. Performance of visual inspection with acetic acid for cervical cancer screening: a qualitative summary of evidence to date. Obstetrical and Gynecological Survey 58(8):543-550 (2003).
This article provides a qualitative summary of the key findings from original research studies on visual inspection with acetic acid (VIA). Authors conducted a systematic review of the literature using a PubMed search to identify relevant journal articles from 1982 through 2002. Overall, 16 articles were eligible for review. In seven of the 16 studies, data were available that allowed for the calculation of sensitivity and specificity of VIA. Based on the data from these seven studies, the authors present ranges, unweighted, and weighted averages (weighted averages based on the number of participants in the study) for the sensitivity and specificity. For VIA’s sensitivity the range was from 66 to 96 percent; unweighted average, 82 percent; weighted average, 81 percent. For VIA’s specificity the range was from 64 to 98 percent; unweighted average, 82 percent; weighted average, 83 percent. Overall these results reflect VIA performance when used to screen over 34,000 women in general health care settings in both developed and developing countries. Authors conclude that these data demonstrate that VIA’s performance is similar to, and possibly superior to, cytology in identifying women with CIN when used in the same setting. More evidence is needed, however, on the long-term programmatic effectiveness in reducing cervical cancer.

Lazcano-Ponce, E.C. et al. Cervical cancer screening in developing countries: why is it ineffective? The case of Mexico. Archives of Medical Research 30:240-250 (1999).
This evaluation of the Mexican national cervical screening program seeks to explain why the program (established in 1974) has failed to decrease cervical cancer mortality in Mexico. They authors found that the low effectiveness of screening is due primarily to issues surrounding Pap smear quality and coverage. Pap quality is low: 64 percent of a random sample of specimens lacked endocervical cells, and false-negative indices from reading centers ranged between 10 and 54 percent. The authors also found that women tend to seek screening only after they are symptomatic, rather than as a preventative measure. Pap smear coverage is particularly low in rural areas (30 percent compared to 64 percent of women age 15-49 in Mexico City). Qualitative research has highlighted additional difficulties, including a preference for female providers and a perception that public services are impersonal and lack necessary privacy. In rural areas, the authors found the perception of cancer and death to be synonymous; they also found that women were reluctant to risk disapproval from their sexual partners by seeking testing. The authors offer a proposal to reorganize Mexico's screening program through five main strategies: (1) increased coverage; (2) improved quality control of how cervical smears are taken; (3) better interpretation of Pap tests; (4) guaranteed treatment for those whose tests show abnormalities; and (5) improved follow-up.

Mandelblatt, J.S. et al. Costs and benefits of different strategies to screen for cervical cancer in less-developed countries. Journal of the National Cancer Institute 94(19):1469-1481 (October 2, 2002).
This study examines the costs and benefits of screening strategies used in cervical cancer prevention in less-developed countries. Using data from Thailand and a population-based model, the study evaluated the costs and benefits of seven strategies including visual inspection with acetic acid (VIA), Pap smear, and human papillomavirus (HPV) testing alone and in combination with other techniques. Compared with no screening (or screening programs that are not well organized), all strategies showed a reduction in mortality from cervical cancer, although the life years saved (LYS) and costs varied considerably. When the authors compared each strategy with the next less costly strategy, they found the least expensive option was screening with VIA, in five-year intervals. This strategy cost $517 per LYS and saved the greatest number of lives. Other strategies had reasonable cost-benefit results depending on maintaining high levels of follow-up. For example, if Pap smear sensitivity reached 80 percent and if 90 percent of women were seen for follow-up, then Pap smear may be a reasonable alternative. The authors emphasize the usefulness of cost-effectiveness data such as these to inform decision-making around health policies.

Megevand, E. et al. Acetic acid visualization of the cervix: an alternative to cytologic screening. Obstetrics & Gynecology 88(3):383-386 (September 1996).
This prospective study of 2,426 women in a squatter area in Cape Town, South Africa, investigated the value of visual inspection of the cervix using acetic acid as an alternative to cytologic screening. All women with a positive visual inspection screening or a positive cytology were referred for colposcopy and biopsy. Histology was obtained on all women with positive results on either test. The authors reported that 76 women had positive visual inspection results; of these, subsequent smears revealed squamous intraepithelial lesions (SIL) in 61 and no evidence of SIL in 15. The remaining 2,350 women had negative visual inspection results. Of these, however, 254 had positive cervical smears; only 11 of these had high-grade SIL on histology-confirmed cytology. Visual screening detected 20 of the 31 women (64%) who had high-grade SIL on both cytology and histology. The authors concluded that in situations where cytology-based screening for precancerous lesions is not available, visual inspection with acetic acid warrants consideration as an alternative screening method.

Meijer, C.J.L.M. et al. Screening for cervical cancer: should we test for infection with high-risk HPV? [commentary] Canadian Medical Association Journal 163(5):535-538 (September 5, 2000).
The authors comment on two Canadian studies by Sellors et al., and summarize the relationship between high-risk human papillomavirus (HPV) infection and the development of cervical cancer. Persistent infection with high-risk HPV can lead to cervical intraepithelial neoplasia (CIN), which then progresses to more severe CIN infection in some women, and to invasive cervical cancer in a subset of these women. The average period from initial infection with HPV to invasive cancer is estimated at 15 years. Infection with high-risk HPV is associated with increased sexual activity and changing sexual partners. However, because of the presence of transient infection in younger women, the authors suggest that women 30 years or older be screened with a test for high-risk HPV instead of or, in some cases, in addition to the Pap test. While not as effective as cytological screening, self-screening for HPV may be appropriate for women who do not participate in routine screening programs. The authors suggest that a "once-in-a-lifetime" HPV screen of 35-year-old women using self-collected samples could reduce cervical cancer in developing countries.

Murthy, N.S. et al. Estimation of reduction in life-time risk of cervical cancer through one life-time screening. Neoplasma 40(4):255-258 (1993).
Given the recommendation by the World Health Organization (WHO) in 1986 that countries with limited resources should aim to screen every woman once in her lifetime, this study attempted to determine at what age that screening could cause the greatest overall reduction in mortality from cervical cancer. The study, using data from three cities in India, compared rates of cervical cancer incidence in unscreened women with incidence in women screened once in their lifetime at different ages (between ages 20 and 64). The authors found that screening at age 45 would be most effective, factoring in the number of cervical cancer cases prevented and the number of productive years of life saved.

Nene, B.M. et al. Early detection of cervical cancer by visual inspection: a population-based study in rural India. International Journal of Cancer 68:770-773 (1996).
The goal of this study was to evaluate the use of unaided visual inspection by trained paramedical workers (PW) in detecting cervical cancer in poor-resource settings. Two PWs examined 1,954 women from the Maharashtra State, India, who were then seen by a gynecologist. PWs scored 1,120 (57.3%) and 118 (6%) women as having abnormal cervices using the low- and high-threshold criteria respectively, similar to the scores obtained by the gynecologist (1,162 and 113 respectively). The sensitivity values of visual inspection to detect cervical cancer by PWs using the low- and high-threshold criteria were 90 percent and 60 percent respectively; specificity values were 42.8 percent and 94.2 percent respectively. Similar values of sensitivity and specificity were also observed by the gynecologist. The authors concluded that unaided visual inspection probably is not a useful procedure for cervical cancer control. The cost savings achieved by 40 to 50 percent of visually normal women not requiring cytology examinations will be offset by those needing repeat examinations, colposcopy, and biopsy.

Ottaviano, M. and La Torre, P. Examination of the cervix with the naked eye using acetic acid test. American Journal of Obstetrics & Gynecology 143:139-142 (1982).
This study of 2,400 patients between the ages of 18 and 65 in Florence, Italy, evaluated the use of visual inspection and colposcopy before and after the application of acetic acid and compared the results of the two techniques. Before the application of acetic acid, they found that no clinical diagnosis, except overt carcinoma, was possible either with visual inspection or with the colposcope. In the comparison between "naked-eye" visual inspection with acetic acid (VIA) and colposcopy with acetic acid, VIA identified 307 of 312 women (98.4%) colposcopically assessed as having an atypical transformation zone. VIA also identified 1,568 of 1,584 (98.9%) of cases where colposcopy identified the cervix as normal. The authors concluded that the detection of precancerous cervical lesions should not depend on the possession of a colposcope.

Pengsaa, P. et al. A self-administered device for cervical cancer screening in northeast Thailand. Acta Cytologica 41(3):749-754 (May 1997).
The goals of this study were to compare results of screening through a self-scraping device against a routine scraping method and to evaluate the acceptance of this new device among a group of rural women from Northeast Thailand. A total of 552 women participated in the study. The women were trained to use the self-scraping device and were reexamined by a gynecologist using the routine scraping method one week later. In both cases, the specimens were stained as Pap smears. The self-scraping method detected 13 abnormal Pap readings, 11 of which were confirmed by physician examination. No false negative readings were found, but the self-scraping method was not as accurate as physician examination for detection of inflammation. Responses to questionnaires about the device showed general acceptance among the women. The authors concluded that in areas where trained medical personnel are not available to carry out regular tests, the self-scraping method can be a useful screening tool.

Richart, R. Screening: the next century. Cancer 76:1919-1927 (November 15, 1995).
This article provides a comprehensive overview of existing and potential screening methods for application in both developing and developed countries. In addition to Pap smears, technologies reviewed for developing countries include unaided visual inspection with and without acetic acid (downstaging), aided visual inspection, and cervicography. Automated Pap machines and HPV DNA tests also are reviewed in the context of both high- and low-resource settings. The author addresses the effectiveness of various screening options as well as the likelihood that they will be available and cost-effective in high- and low-resource settings.

Sankaranarayanan R, Basu P, Wesley RS, et al. Accuracy of visual screening for cervical neoplasia: results from an IARC multi-centre study in India and Africa. International Journal of Cancer. 2004;110:907-913.
This article reports results from 11 cross-sectional studies of cervical cancer screening of 54,981 women in nine centers in Africa and India through the International Agency for Research on Cancer (IARC). Study participants were women aged 25 to 65. All women received VIA, VILI, and colposcopy, with biopsy if indicated. Female health workers trained in the testing procedures performed VIA and VILI. Medical staff performed colposcopy. All providers were blinded to the results of the previous screening test. The pooled sensitivity of VIA for detecting HSIL was 76.8 percent (95% CI: 74.2-79.4%) and the specificity was 85.5 percent (95% CI: 85.2-85.8%). Across the study centers, the sensitivity ranged from 56.1 to 93.9 percent. The specificity ranged from 74.2 to 93.8 percent. For VILI, the pooled sensitivity for detecting HSIL was 91.7 percent (95% CI: 89.7-93.4%) and the specificity was 85.4 percent (95% CI: 85.1-85.7%). Across the study centers, the sensitivity for VILI ranged from 76.0 to 97.0 percent. The specificity ranged from 73.0 to 91.3 percent. Overall, VILI appears to be the more sensitive test although the specificities of the two tests are similar.

Sankaranarayanan R, Rajkumar R, Theresa R, et al. Initial results from a randomized trial of cervical visual screening in South India. International Journal of Cancer. 2004;109:461-467.
Authors conducted a cluster-randomized trial in the Dindigul District of Tamil Nadu, India, to evaluate the efficacy of VIA screening for cervical cancer prevention in an unscreened high-risk population. Villages were randomized into an intervention group that received a single round of VIA screening and a control group. Overall, 30,577 eligible women aged 30 to 59 participated in the intervention arm, and 30,167 eligible women participated in the control arm. In the intervention arm, 2,939 women (9.6%) were screen-positive with VIA and received colposcopy. Of those, 2,777 had biopsy. CIN I was diagnosed in 1,778 women, CIN 2-3 in 222, and cervical cancer (detected by screening) in 69. Between May 2000 and April 2003, 97 women in the intervention arm and 34 women in the control arm were diagnosed with cervical cancer. In the intervention arm, 33 percent of cancers were diagnosed in Stage I compared to in the control arm, where 75 percent of cancers were diagnosed in Stage III (no Stage I cancers were diagnosed in the control group). Authors conclude that VIA-based screening is safe, feasible, and acceptable to women in rural settings. The authors plan to follow the study arms for 10 years, collect incidence data from cancer registries, and compile mortality data from death registries to produce as complete an evaluation as possible of the impact of VIA screening on cervical cancer burden.

Sankaranarayanan, R. et al. Test characteristics of visual inspection with 4% acetic acid (VIA) and Lugol’s iodine (VILI) in cervical cancer screening in Kerala, India. International Journal of Cancer 106:404-408 (2003).
This article reports the results from a cross sectional study screening 4,444 women in Kerala India with VIA, VILI, and conventional cytology. Colposcopy was conducted on all screened women allowing for the direct calculation of sensitivities, specificities, and predictive values and eliminating the risk of verification bias. Biopsies were performed as indicated on 1,644 women (37%). Screening tests were carried out by three health workers who were qualified trained cytotechnicians, also trained to perform conventional Pap smear and to perform and interpret results of VIA and VILI tests. Findings of CIN 2 or worse, based on colposcopy or biopsy, was defined as “true disease”. For VIA the sensitivity and specificity when using a low threshold was 88.6 percent and 78.0% respectively. For high-threshold VIA the sensitivity was 82.6% and specificity was 86.5%. VILI’s performance resulted in a sensitivity of 87.2% and a specificity of 84.7%. Finally conventional cytology resulted in a sensitivity of 81.9% and a specificity of 87.8%. The authors conclude that the test characteristics of VIA and VILI in this study signify that both tests are well suited to be used as an alternative to conventional cytology in low-resource settings.

Sankaranarayanan, R., Budukh, A.M., and Rajkumar, R. Effective screening programmes for cervical cancer in low- and middle-income developing countries. Bulletin of the World Health Organization 79 (10):954-962 (2001).
This article reviews the experiences, challenges, successes, and lessons learned from cervical cancer prevention programs in developing countries. The report draws on data from established screening initiatives in South and Central America (Chile, Colombia, Costa Rica, Cuba, Mexico, Brazil, Peru, and Puerto Rico), sub-Saharan Africa (South Africa, Uganda, Zimbabwe, Burkina Faso, Congo, Ghana, Guinea, Kenya, Mali, Niger, and Nigeria), and South and Southeast Asia (India, Thailand, Singapore, Lao People's Democratic Republic, and China). The authors discuss implications and recommendations for both low-income and middle-income countries. They conclude that, regardless of which screening test will be used, the infrastructure, logistics, finances, and manpower required to establish any organized screening program are too great for many low-income developing countries. VIA, however, could be a viable alternative to detect precancerous lesions in low-income areas where cytology is unavailable. For middle-income developing countries, the authors recommend reorganization of poor-quality cytology programs, with an emphasis on screening high-risk women at least once or twice in their lifetime with a highly sensitive test, and aiming for covering 80 percent of the targeted population.

Sankaranarayanan, R. et al. Visual inspection with acetic acid in the early detection of cervical cancer and precursors [letter to the editor]. International Journal of Cancer 80:161-163 (1999).
This letter to the editor reports on the author's ongoing study comparing the performance of visual inspection with acetic acid (VIA) to cervical cytology in detecting cervical lesions in Kerala, India. Study subjects were 1,351 women age 22 to 70 years (mean age 39). VIA (used by nurses) detected 95.8 percent of dysplasias and cancers; cytology detected 62 percent (VIA detected more mild and moderate dysplasias than cytology). The approximate specificity of VIA was 68 percent and that of cytology was 89.5 percent. The author notes that the effectiveness of VIA in detecting precancerous lesions in this setting, as well as the immediacy of VIA results, make it a potentially attractive case-finding tool in developing-country settings.

Sankaranarayanan, R. et al. Visual inspection of the uterine cervix after the application of acetic acid in the detection of cervical carcinoma and its precursors. American Cancer Society 83:2150-2156 (1998).
The goal of this study in Kerala, India, was to compare visual inspection of the cervix after the application of acetic acid (VIA) with cytology as methods for detecting cervical cancer and its precursors. Subjects with positive VIA or Pap smear findings as well as subjects with an abnormal-looking cervix (defined by criteria such as bleeding on touch, suspected growth or ulcer, or other cervical abnormality) were invited for diagnostic evaluation by colposcopy and biopsy if appropriate. Of the 3,000 women in the study, 298 (9.9%) were positive on VIA, 307 (10.2%) had atypia or dysplasia on Pap smears, and 182 (6.1%) were positive on both VIA and cytology. An additional 215 women (7.2%) were referred to colposcopy because they were identified as having an abnormal cervix on speculum exam, although they were negative on VIA and Pap. Of the 51 true positive cases, VIA detected 46 (90.1%) and cytology 44 (86.2%). The approximate specificities were 92.2 percent for VIA and 91.3 percent for cytology. The authors conclude that if VIA continues to show satisfactory results, this technique is likely to be useful in developing countries where it is not feasible to introduce cytology screening and in developed countries as an adjunct to improve sensitivity of cervical cytology.

Schneider, D.L. et al. Cervicography screening for cervical cancer among 8460 women in a high-risk population. American Journal of Obstetrics and Gynecology 180(2, Part 1):290-298 (February 1999).
This study was part of a large, population-based study of the natural history of cervical neoplasia in Guanacaste Province, Costa Rica. It evaluated the effectiveness of cervicography in detecting cervical dysplasia and cancer in 9,062 women age 18 years and older. Two cervigrams were obtained from each woman, in addition to cervical samples for cytological and HPV-DNA testing. The study found that, compared with Pap smears, cervicography was significantly less sensitive, but equally specific. Overall, for detecting high grade SIL or cancer, cervicography had a sensitivity of 49.3 percent and a specificity of 95 percent. In comparison, cytology testing had a sensitivity of 77.2 percent and a specificity of 94 percent. The sensitivity of cervicography was even lower in women over 50 years: 26.9 percent, presumably because of the increased difficulty in viewing the transformation zone in post-menopausal women. While cervicography identified all cancers (many of which were visible on initial physical examination), it detected only 56 of the 117 histologically confirmed cases of high-grade SIL. The authors note that they could increase sensitivity by changing the diagnostic threshold for defining a possible cervigram, but that this would occur at the expense of reduced specificity. In summary, cervicography as used in this study did not appear to be a useful tool for detecting high-grade SIL.

Sellors, J. et al. Assessment of the cervix after acetic acid wash: Inter-rater agreement using photographs. Obstetrics and Gynecology 99:635-640 (2002).
This study sought to evaluate clinicians' agreement on assessing the cervix after visual inspection with acetic acid (VIA). Three clinicians viewed 144 cervical photographs taken after application of acetic acid and rated them according to VIA categories of negative, positive, or suspicious. Agreement among the pairs of raters was in the moderate to substantial range and was similar to other studies of inter-rater agreement in colposcopy, cervical cytology, and cervical histology.

Spitzer, M. Cervical screening adjuncts: recent advances. American Journal of Obstetrics and Gynecology 179(2):544-556 (August 1998).
This article reviews six technologies that have been proposed as ways to improve the effectiveness of cervical cancer screening: automated cytologic screening, fluid-based technology (e.g., ThinPrep), HPV testing, cervicography, speculoscopy, and the Polarprobe. The author begins by noting that use of the Pap smear in developed countries has resulted in a major reduction of cervical cancer deaths, and that regular screening of at-risk populations is the best way to reduce cervical cancer incidence. He concludes that use of automated cytologic screening may prove to be an effective approach to primary screening, although wide-scale testing in various settings needs to be implemented. He states that there is insufficient evidence to conclude that fluid-based technologies for producing monolayer slides are superior to standard Pap screening approaches. HPV testing may hold promise for use in multiple test screening protocols, and as a primary screening tool for women older than 35. The author concludes that cervicography and speculoscopy are unlikely to be useful in large-scale screening efforts. The Polarprobe is an "in development" technology that measures voltage decay and the scattering of light through cervical tissue. It uses a vaginal probe and computer algorithm to process electrical and optical information and determine the likelihood that tissue is abnormal. The author notes that preliminary results with the Polarprobe are promising (see Coppleson, 1994).

Suba, E.J. et al. De novo establishment and cost-effectiveness of Papanicolaou cytology screening services in the Socialist Republic of Vietnam. Cancer 91(5):928-939 (March 1, 2001).
Using a decision model, this study analyzes the cost-effectiveness of a Pap smear screening program in Vietnam and measures outcomes of life expectance, cervical carcinoma incidence, cost per woman, and cost-effectiveness. The results of the analysis suggest that annual nationwide costs to initiate Pap screening services at five-year intervals will average less that $150,000. Maintenance costs are estimated at $0.092 per woman per year. Cervical cancer incidence and mortality rates could be reduced by 43 percent with five-year screening intervals and 70 percent participation. The author concludes that the data support the cost-effectiveness of establishing widespread Pap smear cervical cancer screening programs, especially since the newer alternative screening techniques are still being tested.

University of Zimbabwe/JHPIEGO Cervical Cancer Project. Visual inspection with acetic acid for cervical-cancer screening: test qualities in a primary-care setting. Lancet 353(9156):869-873 (March 13, 1999). Available at: www.thelancet.com if you have a subscription to the Lancet. Also available online with commentary (free of charge) through ReproLine at www.reproline.jhu.edu/english/3cc/3lancet/lanceta.htm)
The study involved screening by trained nurse-midwives of almost 11,000 women attending 15 primary care clinics in Zimbabwe and found that, in identifying HGSIL and above, visual inspection with acetic acid (VIA) had a sensitivity of 76.6 percent and a specificity of 64.1 percent. The comparable results for Pap smears were 44.3 percent sensitivity and 90.6 percent specificity. As the accompanying Lancet commentary notes, the study provides valuable data on the feasibility and effectiveness of alternative screening approaches in developing-country primary health care settings, and confirmed the relative sensitivity of VIA in comparison to Pap smears in some settings. The commentary also addressed the potential for other new approaches, including HPV screening, and noted the relatively low specificity of VIA in comparison to Pap smears and the potential for overtreatment. The article authors also commented on the ongoing need to carefully assess the implications for programs and patients of a high false positive rate.

Varghese, C. et al. Cervical cancer control in developing countries: beyond visual inspection. Journal of Cytology 17(2):97-101 (2000).
This study compared visual inspection (VI) of the uterine cervix with Pap smear results in two populations in South India. VI was found to have low sensitivity and specificity in detecting cervical dysplasia in women attending an out-patient gynecological clinic (28%, and 81%) as well as among a population-based cohort study (64%, and 51%). The authors argue that given the high "false negative" rate for VI, many cases of dysplasia would go undiagnosed. Although VI has been proposed as an appropriate tool in low-resource settings, to do VI properly the facility should have privacy, water, and electricity—all of which may be lacking in many sites. Both diagnostic and treatment services are limited in many sites, and many women fail to comply with referral subsequent to VI. For these reasons, the authors do not support the concept of cervical cancer control through VI in developing countries.

Wesley, R. et al. Evaluation of visual inspection as a screening test for cervical cancer. British Journal of Cancer 75(3):436-440 (1997).
The goal of this study was to evaluate the performance of visual inspection by trained paramedical workers in detecting precursor cervical lesions and cancer in resource-poor settings. In the study, 2,843 married women in Kerala, India, were subjected to visual inspection of the cervix and a cytology examination. Of these, 1,279 (45%) and 179 (6.3%) women were found to have a positive visual inspection using the low- and high-threshold criteria. With a low threshold, sensitivity and specificity values for detecting moderate dysplasia and above were 65.8 percent and 55.3 percent respectively; the values for detecting severe dysplasia and above were 71.9 percent and 55.3 percent respectively and 92.3 percent and 55.2 percent respectively for invasive cancer. With a high threshold, the sensitivity values decreased significantly and the specificity increased to about 94 percent. The authors concluded that the use of unaided visual inspection does not appear very promising as a preselection procedure for cytology or as a low technology measure for cervical cancer control and that the procedure is unlikely to be cost-effective.

Winkler, J.L. et al. Confirmation of cervical neoplasia using a hand-held, lighted magnification device. Lancet 81(1):35-40 (April 2003).
In low-resource settings where visual inspection with acetic acid (VIA) is being used to test women for cervical lesions, confirmatory methods such as colposcopy are often limited or unavailable. VIA with magnification (VIAM) is being explored as a confirmatory test in some settings. This study assessed the performance of VIAM using the AviScope™ device, a hand-held, monocular scope. A total of 127 women attending 3 colposcopy clinics in Seattle, Washington, had VIAM, colposcopy, and biopsy and endocervical curettage if indicated. All women had been referred for colposcopy because they previously had received a positive Pap smear result. Colposcopically directed biopsy identified 40 women with CIN 2, CIN 3, or carcinoma. The AviScope correctly identified 24 of these 40 women, giving it a sensitivity of 60 percent. Specificity of the AviScope was 69 percent, with it correctly identifying as negative 60 of 87 cases. To date, studies on VIAM have produced conflicting results. The authors of this study caution that although these current results are promising, the actual clinical utility has yet to be determined. The authors suggest, however, that the accuracy of the device could be improved with more extensive provider experience, higher powered magnification, or a different light source.

Zahm, D.M. et al. Colposcopic appearance of cervical intraepithelial neoplasia is age dependent. American Journal of Obstetrics and Gynecology 179(5):1298-1304 (November 1998).
This study evaluated the effect of a patient's age on results of Pap smears, HPV diagnostics, and colposcopy. The U.S. study evaluated 967 women undergoing routine screening in a gynecologic practice. The key finding of the study was that colposcopic results seemed less reliable in women older than 35 with histologically confirmed cervical intraepithelial neoplasia. Colposcopically "positive" results included acetowhite lesions with a higher degree of opacity, a less regular surface, a longer intercapillary distance, and sharper borders between acetowhite and normal epithelium. Among patients with confirmed intraepithelial neoplasia, 54 percent of women younger than age 35 had colposcopic results consistent with the diagnosis, compared with 32 percent of women age 35 years or older. The authors noted that this result may be linked to the thinner cervical epithelium associated with older age. The study also found higher rates of HPV positivity among women less than 35 years old compared with women 35 years or older.

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Treatment: evaluation of simple approaches

Alliance for Cervical Cancer Prevention (ACCP). Effectiveness, Safety, and Acceptability of Cryotherapy: A Systematic Literature Review. Seattle, Washington: PATH (2003). Available at: www.path.org/files/RH_cryo_white_paper.pdf.
This review assesses the available evidence on the effectiveness, safety, and acceptability of cryotherapy for use in treating precancerous cervical lesions. Twelve months after treatment, cryotherapy is approximately 90 percent effective in treating HSIL. Cryotherapy generally produces a lower cure rate for larger lesions and lesions that extend into the cervical canal. Complications associated with cryotherapy are minimal. Data suggest that cryotherapy is safe, with very little risk of major complications such as severe bleeding and pelvic inflammatory disease. The most frequent side effect is a profuse watery vaginal discharge for up to four weeks. Other side effects such as pain and cramping during and after the procedure are generally mild.

Andersen, E.S. and Husth, M. Cryosurgery for cervical intraepithelial neoplasia: 10-year follow-up. Gynecologic Oncology 45:240-242 (1992).
The goal of this study was to evaluate the long-term results of cryotherapy treatment of CIN. Some 261 patients in Denmark were evaluated over a 5-10 year period following cryotherapy. The authors reported an overall cure rate after 5 years of 83.5 percent. Consistent with findings elsewhere, the cure rates of patients with CIN III were significantly lower than those with CIN I and CIN II. Patients with endocervical involvement had lower cure rate as well. The authors concluded that this long-term study had demonstrated the effectiveness of cryotherapy, but cautioned that it also confirmed the need for other treatment methods for patients with endocervical involvement and for careful follow-up, given the risk of treatment failure.

Bishop, A. et al. Cervical Dysplasia Treatment: Key Issues for Developing Countries. Bulletin of PAHO 30(4):378-386 (1996).
While in industrialized countries there has been a trend toward more conservative treatment of cervical intraepithelial dysplasia (CIN), a recent survey found this is not true in many less-developed countries. In order to determine the availability of CIN treatment interventions, and to get an overview of current practices, PATH (Program for Appropriate Technology in Health) collected 110 responses from 33 countries. Worldwide, cone biopsy and hysterectomy are used most widely to treat CIN, and are thought by respondents to be most effective for treating severe dysplasia. In many settings, all grades of CIN are treated. Cryotherapy and loop electrosurgical excision procedure (LEEP) are used more often in Asia, the Caribbean, and Latin American than in other areas. These findings suggest that by making low-cost treatment using cryotherapy and LEEP more widely available, more women could be treated and better use made of scarce resources. The results also suggest that current practices involving treatment of all CIN cases should be reevaluated to ensure that the most appropriate and cost-effective treatment protocols are being used.

Bishop, A. et al. Cervical Dysplasia Treatment in Developing Countries: A Situation Analysis. Seattle: PATH (July 1995).
This extensive review summarizes issues related to cervical dysplasia treatment in developing countries, including appropriate treatment strategies and technologies, a survey of current CIN treatment practices in developing countries, treatment costs analyses, and guidelines for establishing a treatment plan of action.

Burger, R.A. et al. Single-visit program for cervical cancer prevention in a high-risk population. Obstetrics and Gynecology 86(4, Part 1):491-498 (October 1995).
The three goals of this study were to screen and treat—in a single visit—women at increased risk for cervical cancer, to determine the feasibility of this single-visit approach, and to evaluate its acceptability to study participants. Some 126 women in southern California, USA, were recruited for the study through Spanish-language media; all had at least one risk factor for cervical cancer and most reported some barrier, usually cost, to obtaining health care. The single-visit program included a Pap smear; immediate cytologic evaluation; and, for those with cytology results consistent with low- or high-grade SIL, a loop electrosurgical excision or biopsy. Patients who underwent excision or biopsy were asked to return in two weeks for evaluation. The study found the See and Treat approach to be feasible and well accepted. Overtreatment (i.e., no histologic abnormality identified in the excised specimen) occurred in an estimated 5 percent of patients, a figure the authors deemed acceptable given the trade-off of convenient, effective, inexpensive care that does not rely on follow-up visits.

Flannelly, G. et al. A study of treatment failures following large loop excision of the transformation zone for the treatment of cervical intraepithelial neoplasia. British Journal of Obstetrics and Gynecology 104(6):718-722 (June 1997).
The goals of this study were to examine the long term efficacy of large loop excision of the transformation zone (LLETZ) in the treatment of CIN and to evaluate the relative diagnostic merits of colposcopy and cytology in the follow up of these women. The study examined cytology, colposcopy, and histology records of the first 1,000 women treated with LLETZ in the Colposcopy Clinic, Aberdeen Royal Infirmary, Scotland, from 1989 to 1991. A total of 2,812 woman years of follow-up were obtained. The recurrent rate of CIN was 27/1,000 woman years and the cumulative recurrent rate at four years was 10.1 per 100 women. Of the women with abnormal colposcopy and proven CIN, 47 percent had a concurrent smear that did not show dyskaryosis. The authors concluded that LLETZ is effective in treatment for CIN, and colposcopy was useful in the follow-up of these woman and expedited the treatment of persistent disease. They recommend that any follow-up protocol should include a colposcopic assessment and cytological follow up for at least four years following treatment.

Hulman, G. et al. Frequency of cervical intraepithelial neoplasia following large loop excision of the transformation zone. Journal of Clinical Pathology 51:375-377 (1998).
This retrospective study of 669 women in the United Kingdom assessed the risk of persistent/recurrent CIN following treatment by large loop excision of the transformation zone (LLETZ). With LLETZ biopsies, physicians must preserve as much healthy tissue as possible while ensuring that the CIN has been completely removed. Since doctors may be unable to determine the full extent of CIN presence in the endocervical canal, LLETZ biopsies may be incomplete or equivocal. This study found that the persistence/recurrence of CIN was significantly lower in cases where complete excision had occurred. The study also found that persistence/recurrence increased by grade of CIN (for example, from 6.7 percent of patients with CIN1 to 21.7 percent of patients with CIN3). The authors conclude that physicians should carefully follow up on patients with either high-grade CIN or incomplete or equivocal excision.

Keijser, K. et al. Diathermy loop excision in the management of cervical intraepithelial neoplasia: diagnosis and treatment in one procedure. American Journal of Obstetrics and Gynecology166(4):1281-1287 (April 1992).
This Dutch study found diathermy loop excision (another term for LEEP) to be an effective, efficient, and inexpensive technique for diagnosis and treatment of CIN. In the study, 424 women found to have slight to severe dysplasia (CIN grades 1-3) were treated with a stainless steel, rectangular loop used to excise lesions from the cervix and endocervical canal. Over a three- to eight-year follow-up period (median 4.8 years), the study found an overall cure rate of over 92 percent 81 percent after one treatment, the remaining 11 percent after two or three treatments. The authors characterized these results as in the same range with cryocoagulation and laser techniques, but noted that diathermy loop excision is an outpatient method, requiring no general anesthesia and far less training and expensive equipment. They also found diathermy loop excision to be effective for treatment of lesions in the endocervical canal and calculated the method's diagnostic accuracy rate at 99 percent, with no evidence of an effect on fertility or pregnancy outcome.

Kleinberg, M.J. et al. A cost-effectiveness analysis of management strategies for cervical intraepithelial neoplasia grades 2 and 3. American Journal of Obstetrics and Gynecology 188:1186-1188 (2003).
This article reports the results of an analysis of the cost-effectiveness of various management strategies for CIN 2 and 3, including observation, cryotherapy, loop electrosurgical excision procedure (LEEP), carbon dioxide laser ablation, cold-knife conization, and total vaginal hysterectomy. The analysis was conducted using a decision model for a hypothetical cohort of 100,000 women with CIN 2 or CIN 3. Costs were based on US dollars in 2001. Outcome probabilities used in the model were based on available published literature. Three strategies proved cost-effective for managing CIN 2 and CIN 3: cryotherapy, LEEP, or total vaginal hysterectomy. Of the three, cryotherapy was the least expensive while still offering an effective treatment. Cryotherapy had a total cost for CIN 2 of US$41 million with a cure rate of 94.9% (1,454 cancers prevented) compared to LEEP’s total cost of $75 million and cure rate of 95.9% (1473 cancers prevented). For CIN 3 cryotherapy’s total cost was $46 million, with a cure rate of 91.3 % compared to LEEP’s cost of $91 million and cure rate of 93.9%. The authors suggest that cryotherapy’s cost and effectiveness make it an appropriate treatment choice in less-developed settings.

Megevand, E. et al. Can cervical cancer be prevented by a see, screen, and treat program? A pilot study. American Journal of Obstetrics and Gynecology 174(3):923-928 (March 1996).
The goal of this prospective study was to determine the feasibility of providing cervical cancer diagnosis and treatment on site through a mobile clinic at the time of screening or with minimal delay. A total of 5,054 women attended a mobile clinic in Cape Town, South Africa, where they received a free Pap smear and information about cervical cancer and its prevention. In phase 1 of the study, women diagnosed with high-grade squamous intraepithelial lesion were referred to a nearby clinic for colposcopy and treatment. In phase 2, colposcopy and treatment were given on site. Thirty-four percent of 86 women with high-grade lesions in phase 1 attended the colposcopy clinic and received proper treatment (default rate 66%). In contrast, 97 percent of 33 women with high-grade lesions in phase 2 attended the clinic and received proper treatment (default rate 3%). The authors emphasized that education is an essential component in any successful screening program. They concluded that most women will undergo colposcopy and treatment when screening results are obtained quickly and when a colposcopy facility is located at the screening site.

Mitchell, M.F. et al. A randomized clinical trial of cryotherapy, laser vaporization, and loop electrosurgical excision for treatment of squamous intraepithelial lesions of the cervix. Obstetrics & Gynecology 92(5):737-744 (1998).
The goal of this randomized clinical trial was to compare the complications and cure rates of three methods of treating squamous intraepithelial lesions (SIL) of the cervix. The analysis compared data from 390 women randomly assigned to treatment with cryotherapy, laser vaporization, or loop electrosurgical excision after grouping by SIL grade, endocervical gland involvement, and lesion size. Patients were followed for a period of 6-37 months with a mean of 16 months. The authors found no statistically significant differences in the complication rates, the persistence of disease within six months of treatment, or the recurrence of disease at least six months after treatment among the three groups. They did find that the risk of persistent disease was eighteen times higher (risk ratio [RR], 18.9; 95 percent confidence interval [CI], 3.2, 110.6) among women with lesions more than two-thirds the size of the surface area of the cervix. They also found that recurrent disease was higher among women who were 30 years and older (RR, 2.1; 95% CI = 1.2, 4.3), women positive for HPV types 16 or 18 (RR, 2.1; 95% CI = 1.1,4.0), and women with a prior history of treatment for CIN (RR, 2.1; 95% CI = 1.1, 3.9). The authors concluded that these three treatment methods had comparable rates of success and complications for the period of follow-up in this study.

Olatunbosun, O.A. et al. Outcome of cryosurgery for cervical intraepithelial neoplasia in a developing country. International Journal of Gynecology and Obstetrics 38:305-310 (1992).
In this Nigerian study, 73 women diagnosed with CIN were treated by cryosurgery. After a five-year follow-up period, the cure rate was 90 percent, excluding 22 women lost to follow-up. The authors characterized these results as comparable with those reported for other destructive methods and commended cryosurgery as a simple, low-cost, outpatient treatment approach, without serious side-effects or effects on pregnancy outcome. They emphasized, however, the importance of proper pretreatment evaluation and the need for long-term follow-up of patients. They also recommended against the use of cryosurgery for CIN with glandular involvement, given its limited depth of destruction.

Paraskevaidis, E. et al. Cervical intraepithelial neoplasia outcomes after large loop excision with clear margins. Obstetrics and Gynecology 95(6):828-831 (June 2000).
The goals of this case-control study in Greece were to determine the risk of cervical intraepithelial neoplasia (CIN) recurrence in women treated with large loop excision, and to determine risk factors that could lead to better follow-up care. Women treated with loop excision for CIN with clear margins who had adequate follow-up and in whom no subsequent lesions were found (controls) were compared with women who presented with subsequent CIN (cases). Of the 635 women studied, 31 (4.9%) were diagnosed with subsequent lesions. Women over age 40 were found to be at increased risk for recurrence of CIN. The study also found that women with satellite lesions detected before initial treatment and those with glandular involvement were significantly more likely to have a recurrence. The study concluded that large loop excision treatment for women with clear margins and no risk factors is very effective. Follow-up for these women could be less intensive and they could return to normal screening after 12 months. Women who have clear margins but also have any of the identified risk factors should continue with current follow-up protocols.

von Gruenigen, V. et al. Bacteriology and Treatment of Malodorous Lower Reproductive Tract in Gynecologic Cancer Patients. Obstetrics and Gynecology 96(1):23-27 (July 2000).
This prospective case-cohort study evaluated the bacteriology of lower reproductive tract cancers, and the impact of treatment on the quality of life of patients. Gram stain, saline preparations, tumor pH, and anaerobic and aerobic tumor cultures were taken from thirteen patients with malodorous gynecologic cancers, and thirteen with nonmalodorous cancers at the University of Texas Southwestern Medical Center at Dallas. The majority of these (21) had cervical cancer. Most patients with odor had bacterial vaginosis (8 of 13, or 62%). All patients with malodorus tumors were treated with topical metranidazole for seven days. Of the eight patients diagnosed with bacterial vaginosis prior to treatment, none had bacterial vaginosis after treatment, and seven of the thirteen reported no odor after treatment. This small, non-controlled study indicates that patients with malodorous pelvic tumors might benefit from treatment with the topical antibiotic metranidazole.

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