Human papillomavirus DNA testing as a screen for cervical cancer: a meta-analysis of randomized controlled trials

Purpose: The aim was to evaluate the effectiveness of cervical screening when HPV DNA testing is implemented. Materials and Methods: Medline (PubMed) was searched and experts were contacted for references. Odds ratio (OR) and 95% confidence intervals (CI) were used as measures of effect sizes. Results: The rate of CIN3 and worse decreased about twofold, from 1.19% in round 1 to 0.67% in round 2, and CIN2 decreased from 1.70% in round 1 to 0.80% in round 2. When primary cervical screening with LBC was combined with HPV testing, there was a statistically significant reduction in the detection of CIN2 and CIN3+ at the next screening round compared with liquid-based cytology (LBC) alone. Conclusions: HPV DNA-based screening is more effective than cytology in CIN3 and invasive cervical cancers, by detecting persistent high-grade lesions earlier, and providing a longer low-risk period. However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2.

Human papillomavirus; Cervical cancer; Screening

[1] Thorsteinsson K., Ladelund S., Jensen-Fangel S., Katzenstein T.L., Johansen I.S., Pedersen G., et al.: “Incidence of cervical dysplasia and cervical cancer in women living with HIV in Denmark: comparison with the general population”. HIV Med., 2016, 17, 7.

[2] Holst S., Wohlfahrt J., Kjaer S.K., Kamper-Jorgensen M., Kern P., Andersson M., et al.: “Cervical cancer screening in Greenland, 1997- 2011: Screening coverage and trends in the incidence of high-grade cervical lesions”. Gynecol. Oncol., 2016, pii: S0090-8258(16) 30085-3.

[3] Peto J., Gilham C., Fletcher O., Matthews F.E.: “The cervical cancer epidemic that screening has prevented in the UK”. Lancet, 2004, 364, 249.

[4] Cuzick J., Clavel C., Petry K.U., Meijer C.J.L.M., Hoyer H., Ratnam S., et al.: “Overview of the European and North American studies on HPV testing in primary cervical cancer screening”. Int. J. Cancer, 2006, 119, 1095.

[5] Anttila A., Kotaniemi-Talonen L., Leinonen M., Hakama M., Laurila P., Tarkkanen J., et al.: “Rate of cervical cancer, severe intraepithelial neoplasia, and adenocarcinoma in situ in primary HPV DNA screening with cytology triage: randomised study within organised screening programme”. BMJ, 2010, 340, c1804.

[6] van den Akker-van Marle M.E., van Ballegooijen M., van Oortmarssen G..J, Boer R., Habbema J.D.: “Cost-effectiveness of cervical cancer screening: comparison of screening policies”. J. Natl. Cancer Inst., 2002, 94, 193.

[7] Cuzick J., Clavel C., Petry K.U., Meijer C.J., Hoyer H., Ratnam S., et al.: “Overview of the European and North American studies on HPV testing in primary cervical cancer screening”. Int. J. Cancer, 2006, 119, 1095.

[8] Liberati A., Altman D.G., Tetzlaff J., Mulrow C., Gotzsche P.C., Ioannidis J.P., et al.: “The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration”. BMJ, 2009, 339, b2700.

[9] Kitchener H.C., Almonte M., Thomson C., Wheeler P., Sargent A., Stoykova B., et al.: “HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial”. Lancet Oncol., 2009, 10, 672.

[10] Leinonen M., Nieminen P., Kotaniemi-Talonen L., Malila N., Tarkkanen J., Laurila P., et al.: “Age-specific evaluation of primary human papillomavirus screening vs conventional cytology in a randomized setting”. J. Natl. Cancer Inst., 2009, 101, 1612.

[11] Stoler M.H., Wright T.C., Jr., Sharma A., Apple R., Gutekunst K., Wright T.L., et al.: “High-risk human papillomavirus testing in women with ASC-US cytology: results from the ATHENA HPV study”. Am. J. Clin. Pathol., 2011, 135, 468.

[12] Ronco G., Giorgi-Rossi P., Carozzi F., Confortini M., Dalla Palma P., Del Mistro A., et al.: “Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial”. Lancet. Oncol., 2010, 11, 249.

[13] Rijkaart D.C., Berkhof J., Rozendaal L., van Kemenade F.J., Bulkmans N.W.J., Heideman D.A.M., et al.: “Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial”. Lancet Oncol., 2012, 13, 78.

[14] Ogilvie G.S., Krajden M., van Niekerk D.J., Martin R.E., Ehlen T.G., Ceballos K., et al.: “Primary cervical cancer screening with HPV testing compared with liquid-based cytology: results of round 1 of a randomised controlled trial — the HPV FOCAL Study”. Br. J. Cancer , 2012, 107, 1917.

[15] Ronco G., Dillner J., Elfstrom K.M., Tunesi S., Snijders P.J., Arbyn M., et al.: “Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials”. Lancet, 2014, 383, 524.

[16] Arbyn M., Bergeron C., Klinkhamer P., Martin-Hirsch P., Siebers A.G., Bulten J.: “Liquid compared with conventional cervical cytology - A systematic review and meta-analysis”. Obstet. Gynecol., 2008, 111, 167.

[17] Siebers A.G., Klinkhamer P.J.J.M., Arbyn M., Raifu A.O., Massuger L.F.A.G., Bulten J.: “Cytologic Detection of Cervical Abnormalities Using Liquid-Based Compared With Conventional Cytology A Randomized Controlled Trial”. Obstet. Gynecol., 2008, 112, 1327.

[18] Ronco G., Cuzick J., Pierotti P., Cariaggi M.P., Dalla Palma P., Naldoni C., et al.: “Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening: randomised controlled trial”. BMJ, 2007, 335, 28.

[19] Arbyn M., Buntinx F., Van Ranst M., Paraskevaidis E., Martin- Hirsch P., Dillner J.: “Virologic versus cytologic triage of women with equivocal pap smears: A meta-analysis of the accuracy to detect high-grade intraepithelial neoplasia”. J. Natl. Cancer Inst., 2004, 96, 280.

[20] Tjalma W.A., Fiander A., Reich O., Powell N., Nowakowski A.M., Kirschner B., et al.: “Differences in human papillomavirus type distribution in high-grade cervical intraepithelial neoplasia and invasive cervical cancer in Europe”. Int. J. Cancer, 2013, 132, 854.

[21] de Cremoux P., de la Rochefordiere A., Savignoni A., Kirova Y., Alran S., Fourchotte V., et al.: “Different outcome of invasive cervical cancer associated with high-risk versus intermediate-risk HPV genotype”. Int. J. Cancer, 2009, 124, 778.