Randomized Controlled Trial to Study Interventions to Increase Participation in Cervical Cancer Screening Program
Randomized Controlled Trial to Study Interventions to Increase Participation in Cervical Cancer Screening Program
Women who don't participate in Swedish cytology screening program are a minority of about
 10%, but constitute the majority of those who acquire cervical cancer. Over 50 000 women in
 the Västra Götalandregion have abstained from participation in the program for at least 2
 screening rounds (6 - 10 years, depending om age). We plan to test two promising strategies
 to increase participation. In a study of two different health policies women who have
 defaulted are randomised to receiving a telephone call from a midwife, receive an offer of a
 self-test for HPV or being included in a control group. This is an effectiveness study that
 should give an answer how participation could be increased and give the basis for a
 calculation of the costs involved, before decisions can be made about implementing either
 intervention.
Background

 Cervical cancer today is considered as a disease that to a very large extent is preventable.
 In Sweden cytological screening has been ongoing since the 60:s and this has made cervical
 cancer a rare disease. Several new, but costly, methods like HPV-testing and vaccination has
 been claimed to further reduce cancer incidence, but this has not been scientifically proven
 so far. A recent audit of the Swedish screening program (Andrae 2008) found that the foremost
 risk factor for cervical cancer in the context of the program was non participation. Women
 who do participate are well protected from cervical cancer.

 A Swedish study evaluating different strategies to increase participation found telephone
 contact with defaulters to be the superior intervention (Eaker 2004). This study was done in
 a region of Sweden with lower coverage (Sparén 2007) and less emphasis on efforts to increase
 participation. A study from Kalmar, Sweden, with high coverage did not find an extended yield
 to requests from non-participating women to be cost effective (Oscarsson 2007). Self testing
 for HPV has been advocated as an effective method and there is a kit commercially available
 (Stenvall 2007). The procedure is used as a routine in Uppsala county and marketed to other
 counties.

 Aim To study two possible interventions to increase participation

 Design Randomised controlled trials of two interventions and a control arm

 Hypothesis

 Intervention with a) supportive telephone contact, by a midwife, with women who do not have a
 smear registered for two screening rounds will increase participation, increase uptake of
 precancerous lesions (CIN2+) and is cost effective. b) selftesting for oncogenic
 papillomavirus (HPV) will increase participation and is cost effective.

 Method: selection of study base

 Selection was done by random among women aged 29 - 63 who did not have a pap-smear registered
 within the two recent screening rounds. Women who were excluded from invitation due to total
 hysterectomy and women who could be identified as have immigrated into the region under the
 period were excluded before randomisation. July 1 2008 there was 52362 women who fulfilled
 the first criteria (before exclusions) identified through the Register for Prevention of
 Cervical Cancer in West Sweden. 8800 selected women will be included and randomised to one of
 three arms with the distribution 5:1:5

 Methods: Intervention Arm A: 4000 randomised women fulfilling inclusion criteria receive a
 letter informing them they will be contacted by a midwife by phone, to be offered an
 appointment to take a smear. They can at that stage decline such contact or if they wish
 return contact information (telephone number). A week later the women who have not declined
 will be called by a midwife and offered an appointment for taking a smear. Abnormal smear
 will be followed up with referral to a gynecologist in concordance with normal screening
 routine.

 Arm B: 800 women will be sent an offer of HPV-self sampling (Aprovix, Uppsala, Sweden). By
 regular mail the woman can order a test kit, and return this to the laboratory after
 sampling. The samples will be tested with Hybrid Capture II for high risk HPV. A negative
 result will be communicated to the women. A positive result will be sent to the gynecological
 clinic responsible for the work up of abnormal cytological screening smears in the area were
 the woman lives. The afflicted woman will get information from the clinic and an appointment
 for colposcopy and cytology. Further investigation will be conducted as clinical routine.
 Reminders will be sent to women who have ordered the kit and not returned any sample. In
 order to evaluate the effect of a primary reminder women who have not responded to the
 primary offer within 60 days will receive a reminder.

 Arm C (controls) 4000 women will be controls. No specific action will be taken within the
 study outside routine in the screening program (yearly written reminder when smears are not
 found in the database)

 Methods: Data collection All data about cytology, colposcopy with biopsies and treatment for
 CIN are registered as a routine in the West Sweden Registry for Cervical Cancer Prevention
 and data will be extracted from that registry. Data about HPV-testing will be transferred to
 this registry from the Aprovix laboratory in Uppsala. Man-time needed and costs for material
 and analyses for the different interventions will be registered as base for health economic
 assessments.

 Primary outcomes: Frequency of testing (cytology in arm A and C and HPV-test in arm B).
 Frequency of further assessment of abnormal tests (all arms).

 Secondary outcomes: (Arm A vs arm C) Frequency of abnormal smears. Frequency of treated CIN,
 (CIN1, CIN2 and CIN3, grouped as low grade (CIN1) and high grade (CIN2, CIN3, AIS and
 invasive cancer). Number of invasive cancers and FIGO stadium. Cost of interventions. Cost
 per CIN2+ found. The study is powered to find a 30% difference in primary outcome based on an
 expected 20% participation rate in the control group with 80% power at a significance level
 of 5% for both interventions (A and B compared with C). An expected rate of abnormal smears
 of 7% among these women with no smear recorded 6 or more years will give a 80% power to find
 a 60% relative difference in number of abnormal smears (RR=1,6) when intervention arm A is
 compared with the controls in arm C.

 The results from work up of abnormal tests in arm A will be considered representative for arm
 B as well, given the same level of abnormality.

 The cost per participant and per biopsy with CIN found will be calculated. The cost per found
 and treated high grade CIN will be compared with a reference of estimated €3500 (preliminary
 figure) per CIN2+ that is eradicated.

 Methods:Statistical analysis All analysis will be based on intention to treat. Pearson's Chi2
 and Fischers exact test will be used to compare distribution of categorical variables between
 the groups. One way variances will be used to test differences of means between groups for
 continuous variables. The cumulated probability for outcome vs. follow up time will be
 calculated with Kaplan-Meier analysis. Multiple Cox regression will be used to determine
 relative risks. 95 % confidence intervals will be used throughout and level of significance
 will be calculated two sided as 5%
Inclusion Criteria:

 -  No record of PAP smear in the regional screening register for more than two screening
 rounds (6 - 10 years depending on age).

 -  Evidence in the regional population register that women have been living in the west
 region of Sweden during this time.

 Exclusion Criteria:

 -  Total hysterectomy