This study is a secondary analysis based on clinical and cost data from a previously published randomized study (1). During 2013–2015 a total of 36 390 women aged 30–49 years planned for regular screening invitation in Uppsala, Sweden, were randomized into two arms; a) repeated self-sampling of vaginal fluid for HPV testing (n = 17 997, HPV self-sampling arm) or to midwife-collected Pap smear for cytological analysis (n = 18 393, Pap smear arm) (1). The study flowchart is shown in Figure 1 and number of women included are shown in Figure 2. Women with previous hysterectomy or current pregnancy were recommended in the invitation letter not to participate in the study. Some of these women nevertheless performed self-sampling and women with previous hysterectomy were excluded after second self-sampling, while the pregnant women were included in this study. A cost-effective analysis (CEA) was performed comparing the alternative screening strategies, based on quantification, effectiveness and cost data. Additional treatment and follow-up data were collected from patient files.
HPV self-sampling arm
Women were sent an invitation with a self-sampling kit for vaginal fluid, including a sampling brush, an FTA card, a step-by-step guide on how to perform the sampling and a pre-addressed and postage-paid return envelope. Women performed the self-sampling and sent the FTA card to the Department of Immunology, Genetics and Pathology at Uppsala University (HPV laboratory) for HPV testing. Women with a positive HPV test result were sent a second self-sampling kit for repeat sampling after 3–6 months. Participation in primary screening was classified as complete when having an analyzed first negative HPV test, or in the case of a first positive HPV test, after repeated HPV testing. Women with two consecutive HPV-positive self-samples were referred to colposcopy. All HPV-negative women were referred back to screening (Figure 1). Details on sampling material, processing and HPV analysis are described in the published study (1).
Pap smear arm
Women were sent an invitation to schedule an appointment at the local midwife clinic, where Pap smear sampling for cytology was performed. Participation in primary screening was classified complete when having an analyzed Pap smear. Women with CIN2+ in cytology were referred to colposcopy. Women with low-grade cervical intraepithelial neoplasia (CIN1) or atypical squamous cells of unknown significance (ASCUS) in cytology were scheduled for repeated Pap smear and HPV test by a midwife after three months. HPV-positive women and women with CIN2+ in cytology were referred to colposcopy, while HPV-negative women without CIN2+ in cytology were referred back to screening (Figure 1). Cytology and histology were performed at the Department of Pathology and Cytology, Uppsala University Hospital. Pap smears and histological diagnoses were classified according to CIN terminology. The highest histological grade found in each patient was used for interpretation.
Women with repeated HPV-positive results, ASCUS/CIN1 cytology and HPV-positive result or CIN2+ cytology were followed up by colposcopy. Here, the squamocolumnar junction and transformation zone were identified, 5% acetic acid and iodine solution were applicated and after visual evaluation, all lesions were biopsied. A Pap smear was collected on all HPV-positive women in the self-sample arm. In cases of transformation zone 3 (TZ3) a sample was also collected for endocervical cytology. Mainly one expert colposcopist performed colposcopies among women in the HPV self-sampling arm, while different colposcopists performed colposcopies in the Pap smear arm.
Treatment of precancerous lesions and cancers
Women with histological CIN2+ were treated ccording to current clinical recommendations. In the Pap smear arm, about one fifth of the women with CIN were treated at a regional hospital (Enköping lasarett, Enköping). The rest of the women with CIN and women with cancer were treated at the Department of Gynecology and Obstetrics, Uppsala University Hospital. Precancerous lesions and micro-invasive cancers were treated by using the loop electrosurgical excision procedure (LEEP), most of them under local anesthesia but some under general anesthesia. Treated women were invited for a follow-up appointment (‘test of cure’) with a midwife or a gynecologist in 4–6 months. At this appointment, the midwives collected a Pap smear and a sample for HPV testing, and in addition to them, the gynecologist also carried out colposcopy. The cancer cases were discussed at a multidisciplinary meeting after requisite radiological investigation, usually chest and abdominal CT scans and a pelvic MR scan. Surgical treatment consisted of either simple or radical hysterectomy or trachelectomy. Radical surgery included excision of the upper vagina and parametria with bilateral pelvic lymphadenectomy beyond removal of the uterus (hysterectomy) or the cervix (trachelectomy). Surgery was performed either by laparotomy or in most cases by means of minimally invasive techniques, such as laparoscopy or robotic-assisted laparoscopic surgery.
Clinical data (at the time of screening invitation and the cytological and histological test results at clinical follow-up) were retrieved from a database at the Department of Pathology and Cytology, Uppsala University Hospital. All events from invitation until diagnosis were noted for each patient in both study arms. The treatment records, including further preoperative assessment and follow-up after treatment in cases of CIN2+, were manually checked in the patient files until 31 December 2018. All events were included after LEEP until the ‘test of cure’ was accepted (HPV-negative and Pap smear cytology <CIN2), or after surgical treatment of cancer, until the first postoperative visit. Possible treatments and follow-up in cases of CIN1 were not included in this analysis.
Cost-effectiveness analysis (CEA) and cost estimation
A CEA was performed using healthcare provider perspective (20). The unit costs for each screening event were retrieved from the HPV laboratory and Uppsala region financial records. Direct medical costs of inpatient and outpatient healthcare were retrieved from the financial records at Uppsala University Hospital. When needed costs were adjusted for inflation by using the consumer price index (CPI) (21) and converted to 2019 Euros (mean annual exchange rate, € 1 = 10.5912 SEK). A cost per screened woman was calculated in each study arm according to the study protocol. Screening strategies (HPV self-sampling vs. Pap smear) were ranked from the lowest to the most costly. Incremental cost-effectiveness ratios (ICERs) per extra screened women were calculated by dividing the cost difference (cost) with the difference in number of screened women (effect) between the two screening arms in the randomized study. At clinical follow-up, also the ICERs per extra detected woman with CIN2+ were calculated. If a screening arm was more costly and less effective than the comparative one, it was defined as strongly dominated. A sensitivity analysis was performed to account for the uncertainty of screen participation and trends in direct medical costs. Moreover, using the cost data we estimated the cost of treatment and follow-up of histological CIN2+.