Risk of cervical cancer after completed post-treatment follow-up of cervical intraepithelial neoplasia: population based cohort study

Abstract

Objective: To compare the risk of cervical cancer in women with histologically confirmed cervical intraepithelial neoplasia who returned to routine screening after having completed post-treatment follow-up with consecutive normal smear test results with women with a normal primary smear test result.

Design: Population based cohort study using data from a nationwide pathology register.

Setting: The Netherlands, 1994 to 2006.

Population: 38,956 women with histologically confirmed intraepithelial neoplasia grades 1 to 3 with completed follow-up after treatment.

Intervention: Routine post-treatment follow-up of cervical intraepithelial neoplasia, recommending smear tests at six, 12, and 24 months.

Main outcome measure: Incidence of cervical cancer in the period from completed follow-up with negative test results after cervical intraepithelial neoplasia to the next primary test. 10-year hazard ratios were compared with periods after normal results for the primary smear test, adjusted for year in follow-up.

Results: 20 cervical cancers were diagnosed during 56,956 woman years after completed follow-up of cervical intraepithelial neoplasia, whereas 1613 cervical cancers were diagnosed during 25,020,697 woman years after a normal primary smear test result. The incidence of 35.1 (95% confidence interval 21.4 to 54.2) per 100,000 woman years and 6.4 (6.1 to 6.8) per 100,000 woman years, respectively, led to an adjusted hazard ratio of 4.2 (95% confidence interval 2.7 to 6.5) for periods after completed follow-up compared with periods after normal primary smear test results. This hazard ratio was increased for all ages. No significant difference in risk of cervical cancer was observed by grade of cervical intraepithelial neoplasia.

Conclusions: An excess risk of cervical cancer previously observed for women treated for cervical intraepithelial neoplasia was also observed in the subgroup of women who completed their post-treatment follow-up with three consecutive normal smear test results. The overall corrected risk of cervical cancer in these women was increased fourfold 35 cases per 100,000 woman years) compared with women with normal primary smear test results (6 per 100,000 woman years).

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that: MR is currently involved in a comparative study of new generation human papillomavirus tests, for which Roche Diagnostics, Genomica, Qiagen, and Gen-Probe provided assays and instrumentations. MR did not receive any salary, compensation, or bonuses for work on any of the projects from any of the companies, and does not hold companies’ stock. Concerning the present paper, there has been no involvement or support from any of the companies. Since 1989 RB has been participating in the screening research group at the Department of Public Health of Erasmus MC. Between 2009 and 2012 he was also director of health economics at Cerner LifeSciences, which is a consultancy that mainly works for the pharmaceutical industry and is part of Cerner that mainly develops and markets healthcare information technology. This research and article were not funded or supported by Cerner or their clients. RB’s institution has received a grant from Health Insurance Executive Board. MvB was the principal investigator until 2008 on a project on the cost effectiveness of human papillomavirus vaccination, financed by GSK (a pharmaceutical company that produces human papillomavirus vaccines against cervical cancer). There has been no collaboration with or support from GSK for the present paper. The authors have no other relationships or activities that could appear to have influenced the submitted work.

Figures

Definition of completed negative test results at follow-up after histologically confirmed cervical intraepithelial neoplasia and counting of woman years at risk for a hypothetical episode. CIN=histologically confirmed cervical intraepithelial neoplasia. a=left censored (excluded) woman years at risk because of ongoing follow-up during which by definition no cervical cancer was diagnosed; b=included woman years at risk. Because for all episodes woman years at risk were also left censored before 1 January 1994, episodes of cervical intraepithelial neoplasia with completed negative follow-up test results were included in the analysis if at least part of b accrued after that date. Restrictions for side analysis (episodes of cervical intraepithelial neoplasia in which follow-up testing followed recommended timing): c=maximum 12 months (recommended six months and an allowed delay of six months); d=18 to 42 months