Tailoring treatment and follow-up strategies of patients with cervical adenocarcinoma in situ and cervical cancer

This thesis investigated strategies to improve the treatment and follow-up of patients with cervical adenocarcinoma in situ (AIS) and patients with cervical cancer. The work investigated the incidence of cervical AIS, its recurrence and progression to cancer risks after treatment, and diagnostic biomarkers for the follow-up. Additionally, this thesis highlighted important knowledge gaps in the treatment of early-stage cervical cancer and it explored diagnostic approaches in the follow-up of patients with cervical cancer. To provide evidence-based recommendations for the treatment and follow-up of patients with AIS, we performed a Dutch, population-based, retrospective cohort of patients with AIS. The findings showed that the overall 20-year incidence of high-grade dysplasia (AIS, cervical intraepithelial neoplasia [CIN] grade 2 and 3) was highest after a large-loop excision of the transformation zone (LLETZ), followed by a cold-knife conisation (CKC) and a hysterectomy. The 20-year incidence of high-grade dysplasia was similar between LLETZ and CKC after a complete resection of the AIS lesion (i.e. negative surgical margins or no dysplasia present at end of treatment). Following treatment by LLETZ or CKC, co-testing (high-risk human papillomavirus [HPV] testing and cytology) can distinguish patients at high-risk for developing AIS, CIN grade 3 and cervical cancer (AIS/CIN3+) from patients at low-risk. After initial treatment by LLETZ or CKC, it was not cost-effective to perform an additional hysterectomy in patients who completed childbearing. In a literature review we explored four de-escalation strategies for patients with early-stage cervical cancer. These de-escalation strategies aim to reduce treatment-related morbidity without hampering oncological safety. To tailor follow-up care of patients with cervical cancer after fertility-sparing surgery, we performed a Dutch, population-based, retrospective cohort study including 1462 patients with cervical cancer. The findings showed that the incidence of recurrent high-grade cervical dysplasia and cervical cancer (CIN2+) was strongly associated with high-risk HPV and cytology results during follow-up after fertility-sparing surgery. Furthermore, the number of tests in the follow-up could be reduced in patients, who tested high-risk HPV negative with normal or low-grade cytology at 6 months follow-up. In a case-control study, we explored new biomarkers in the follow-up of patients with cervical cancer. In patients without recurrent cervical cancer DNA methylation levels decreased 2-years posttreatment compared to pretreatment in both cervicovaginal self-samples and urine. Furthermore, DNA methylation markers in cervicovaginal self-samples were higher in patients with recurrent cervical cancer compared to patients without recurrent cervical cancer posttreatment. The results of a questionnaire study showed that patients with CIN grade 2 and 3 considered urine and cervicovaginal self-samples as acceptable and reliable sampling methods for cervical cancer screening. In summary, this thesis provided incidence and recurrence rates of patients with AIS in order to improve the strategies for treatment and diagnostic follow-up. Furthermore, this thesis highlighted research directions for the treatment and diagnostic follow-up of patients with cervical cancer. In patients with cervical cancer who test high-risk HPV negative with normal or low-grade cytology after fertility-sparing surgery, the frequency of subsequent follow-up testing with high-risk HPV and cytology can be reduced.