Abstract
BackgroundCervical cancer is caused by Human Papilloma viruses (HPV) and is preceded by precursor stages: Cervical Intraepithelial Neoplasia (CIN). CIN is mostly found in women in their reproductive age and treated with a Loop Electrosurgical Excision Procedure (LEEP). The recurrence or residual disease rate after treatment is up to 17%. These women have a lifelong increased risk of recurrent CIN, cervical cancer and other HPV related malignancies. Furthermore, LEEP treatments are associated with complications such as premature birth. Limited data show that prophylactic HPV vaccination at the time of LEEP reduces recurrence rates, therefore leading to a reduction in repeated surgical interventions and side effect like preterm birth.The primary study objective is to evaluate the efficacy of the nonavalent HPV vaccination in women with a CIN II-III (high-grade squamous intraepithelial lesion (HSIL) lesion who will undergo a LEEP in preventing recurrent CIN II-III after 24 months.MethodsThis study is a randomised, double blinded, placebo controlled trial in 750 patients without prior HPV vaccination or prior treatment for CIN and with histologically proven CIN II-III (independent of their hrHPV status) for whom a LEEP is planned. Included patients will be randomised to receive either three injections with nonavalent (9 HPV types) HPV vaccine or placebo injections (NaCL 0.9%) as a comparator. Treatment and follow-up will be according the current Dutch guidelines. Primary outcome is recurrence of a CIN II or CIN III lesion at 24 months. A normal PAP smear with negative hrHPV test serves as surrogate for absence of CIN. At the start and throughout the study HPV typing, quality of life and cost effectiveness will be tested.DiscussionAlthough prophylactic HPV vaccines are highly effective, little is known about the effectivity of HPV vaccines on women with CIN. Multiple LEEP treatments are associated with complications. We would like to evaluate the efficacy of HPV vaccination in addition to LEEP treatment to prevent residual or recurrent cervical dysplasia and decrease risks of repeated surgical treatment.Trial registrationMedical Ethical Committee approval number: NL66775.078.18. Affiliation: Erasmus Medical Centre. Dutch trial register: NL 7938. Date of registration 2019-08-05.
Highlights
Cervical cancer is caused by Human Papilloma viruses (HPV) and is preceded by precursor stages: Cervical Intraepithelial Neoplasia (CIN)
Cervical cancer is preceded by Cervical Intraepithelial Neoplasia (CIN) of the cervix and caused by high risk Human Papilloma Viruses [2]
CIN II is mild dysplasia and CIN III severe dysplasia, both known as high-grade squamous intraepithelial lesion (HSIL)
Summary
Setting and study design The VACCIN study is a randomised multicenter, double blinded, placebo controlled trial in female patients with histological diagnosed CIN II or CIN III and treated with LEEP. After histologic diagnosis of CIN II-III for which a LEEP is necessary, patients will be counselled for participating in this study. General practitioners may refer women with intermenstrual or postcoital bleeding This includes women younger than those in the national screening program for cervical cancer. In- and exclusion criteria Women are eligible for participation if they are eighteen years old or above, histologically proven CIN II or III and will be treated with a LEEP. Randomisation will use random permuted blocks of sizes 2 and 4 Both doctor and patient will be blinded for treatment allocation. Study objectives and outcome The primary objective is: The efficacy of nonavalent HPV vaccination in women with a CIN II-III lesion who underwent a LEEP in preventing recurrent CIN II-III after at 24 months follow-up. Cost-effectiveness analysis from a societal perspective: intramural and extramural medical costs questionnaire (iMCQ) and productivity cost questionnaire (iPCQ) will be performed at the start of the study, at 2 months and after 24 months
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