The Papanicolaou (Pap) Test
Alternative Screening and Treatment Strategies in Low-Resource Settings

The Papanicolaou (Pap) Test

The Pap test has never been examined in a randomized controlled trial. A large body of consistent observational data, however, supports its effectiveness in reducing mortality from cervical cancer. Both incidence and mortality from cervical cancer have sharply decreased in a number of large populations following the introduction of well-run screening programs.[1-4] In Iceland, the mortality rate declined by 80% for more than 20 years, and in Finland and Sweden by 50% and 34%, respectively.[1,5] Similar reductions have been observed in large populations in the United States and Canada. Reductions in cervical cancer incidence and mortality were proportional to the intensity of screening.[1,5] Mortality in the Canadian provinces was reduced most remarkably in British Columbia, which had screening rates two to five times those of the other provinces.[6]

Case-control studies have found that the risk of developing invasive cervical cancer is three to ten times greater in women who have not been screened.[7-10] Risk also increases with long duration following the last normal Pap test, or similarly, with decreasing frequency of screening.[11,12] Screening every 2 to 3 years, however, has not been found to increase significantly the risk of finding invasive cervical cancer above the risk expected with annual screening.[12,13]

Choice in methods of screening for cervical cancer in resource-limited countries or underserved populations has prompted the evaluation of one-time “screen and treat” approaches for cervical cancer screening.

A clustered randomized controlled trial in rural India evaluated the impact of one-time visual inspection of the cervix with acetic acid (VIA) and immediate colposcopy, directed biopsy, and cryotherapy (where indicated) on cervical cancer incidence and mortality on healthy women aged 30 to 59 years.[14] Fifty-seven clusters (n = 31,343 women) received the intervention, while 56 control clusters (n = 30,958 women) received counseling and education about cervical cancer screening. After 7 years of follow-up, with adjustments for age, education, marital status, parity, and cluster design, there was a 25% relative reduction in cervical cancer incidence in the intervention arm compared with the control group (hazard ratio [HR] = 0.75; 95% confidence interval [CI], 0.55–0.95). Using the same adjustments, cervical cancer mortality rates demonstrated a 35% relative reduction in the intervention arm compared with the control group (HR = 0.65; 95% CI, 0.47–0.89); the age-standardized rate of death due to cervical cancer was 39.6 per 100,000 person-years for the intervention versus 56.7 per 100,000 person-years for the control. This population was essentially screen naive at entry into the study, and demonstrated a much higher overall risk for cervical cancer death (11% of the controls) than that observed in the U.S. population; the applicability of these findings to the United States and similar western health care systems is therefore difficult to assess. Histological diagnosis of cervical lesions happened after treatment had already taken place, and approximately 27% of patients in this trial received cryotherapy for lesions later determined to be nonmalignant.[15]

A study of the feasibility of single-visit management of high-grade cervical lesions was conducted among a predominantly Latina population in California.[16] Women were randomly assigned to a single-visit group (n = 1,716) in which the Pap test was evaluated immediately and treatment administered the same day for women with high-grade squamous intraepithelial lesions (HSIL) or atypical glandular cells of undetermined significance (AGUS) results; or to usual care (n = 1,805), with results of the Pap test provided within 2 to 4 weeks and referrals for treatment based on results. The program was feasible, with a high degree of acceptability and results in 14 of 16 (88%) women with abnormal test results completing treatment by 6 months versus 10 of 19 (53%) women in the usual care arm completing treatment by 6 months. Follow-up at 12 months was also higher among women in the single-visit group with HSIL/AGUS than among those in the usual care arm; among all women, only 36% in each group had a follow-up Pap test at 1 year.

A randomized trial in South Africa evaluated the impact on diagnosis of cervical intraepithelial neoplasia (CIN) 2+ at 6 months with a screen-and-treat approach with VIA and human papillomavirus (HPV) versus delayed evaluation.[17] Women underwent HPV DNA testing and VIA testing (n = 6,555) and then returned in 2 to 6 days and were randomly assigned to one of three groups to receive (1) cryotherapy if the HPV DNA test result was positive (n = 2,163; 473 HPV+ and 467 treated); (2) cryotherapy if the VIA test result was positive (n = 2,227; 492 VIA+ and 482 treated); or (3) delayed evaluation (n = 2,165). At 6 months, CIN 2+ was diagnosed in 0.80% of women in the HPV+/cryotherapy group, in 2.23% of the VIA+/cryotherapy group, and in 3.55% of the delayed evaluation group. Differences in the prevalence of CIN 2+ persisted among the subset of women evaluated at 12 months. For the secondary outcome of CIN 3+, prevalence of CIN 3+ lesions was low among the three groups but followed the same pattern (two cases with HPV DNA group, three cases in the VIA group, and eight cases in the delayed evaluation group).

References

1. Lăără E, Day NE, Hakama M: Trends in mortality from cervical cancer in the Nordic countries: association with organised screening programmes. Lancet 1 (8544): 1247-9, 1987.  [PUBMED Abstract]
   
   
2. Christopherson WM, Lundin FE Jr, Mendez WM, et al.: Cervical cancer control: a study of morbidity and mortality trends over a twenty-one-year period. Cancer 38 (3): 1357-66, 1976.  [PUBMED Abstract]
   
   
3. Miller AB, Lindsay J, Hill GB: Mortality from cancer of the uterus in Canada and its relationship to screening for cancer of the cervix. Int J Cancer 17 (5): 602-12, 1976.  [PUBMED Abstract]
   
   
4. Johannesson G, Geirsson G, Day N: The effect of mass screening in Iceland, 1965-74, on the incidence and mortality of cervical carcinoma. Int J Cancer 21 (4): 418-25, 1978.  [PUBMED Abstract]
   
   
5. Sigurdsson K: Effect of organized screening on the risk of cervical cancer. Evaluation of screening activity in Iceland, 1964-1991. Int J Cancer 54 (4): 563-70, 1993.  [PUBMED Abstract]
   
   
6. Benedet JL, Anderson GH, Matisic JP: A comprehensive program for cervical cancer detection and management. Am J Obstet Gynecol 166 (4): 1254-9, 1992.  [PUBMED Abstract]
   
   
7. Aristizabal N, Cuello C, Correa P, et al.: The impact of vaginal cytology on cervical cancer risks in Cali, Colombia. Int J Cancer 34 (1): 5-9, 1984.  [PUBMED Abstract]
   
   
8. Clarke EA, Anderson TW: Does screening by "Pap" smears help prevent cervical cancer? A case-control study. Lancet 2 (8132): 1-4, 1979.  [PUBMED Abstract]
   
   
9. La Vecchia C, Franceschi S, Decarli A, et al.: "Pap" smear and the risk of cervical neoplasia: quantitative estimates from a case-control study. Lancet 2 (8406): 779-82, 1984.  [PUBMED Abstract]
   
   
10. Herrero R, Brinton LA, Reeves WC, et al.: Screening for cervical cancer in Latin America: a case-control study. Int J Epidemiol 21 (6): 1050-6, 1992.  [PUBMED Abstract]
    
    
11. Celentano DD, Klassen AC, Weisman CS, et al.: Duration of relative protection of screening for cervical cancer. Prev Med 18 (4): 411-22, 1989.  [PUBMED Abstract]
    
    
12. Screening for squamous cervical cancer: duration of low risk after negative results of cervical cytology and its implication for screening policies. IARC Working Group on evaluation of cervical cancer screening programmes. Br Med J (Clin Res Ed) 293 (6548): 659-64, 1986.  [PUBMED Abstract]
    
    
13. Kleinman JC, Kopstein A: Who is being screened for cervical cancer? Am J Public Health 71 (1): 73-6, 1981.  [PUBMED Abstract]
    
    
14. Sankaranarayanan R, Esmy PO, Rajkumar R, et al.: Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: a cluster-randomised trial. Lancet 370 (9585): 398-406, 2007.  [PUBMED Abstract]
    
    
15. Szarewski A: Cervical screening by visual inspection with acetic acid. Lancet 370 (9585): 365-6, 2007.  [PUBMED Abstract]
    
    
16. Brewster WR, Hubbell FA, Largent J, et al.: Feasibility of management of high-grade cervical lesions in a single visit: a randomized controlled trial. JAMA 294 (17): 2182-7, 2005.  [PUBMED Abstract]
    
    
17. Denny L, Kuhn L, De Souza M, et al.: Screen-and-treat approaches for cervical cancer prevention in low-resource settings: a randomized controlled trial. JAMA 294 (17): 2173-81, 2005.  [PUBMED Abstract]
    
    

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