Effects of the Ameliorated Pap Test on Cervical Cancer Screening Participation: a Multicenter Randomized Controlled Trial

Participants: This project expects to include women just before they undergo Pap smear screening at the NTUH Healthcare System in 2026. We include eligible women aged 25 or above who have not yet undergone Pap tests in 2026. Excluded are those who have ongoing menstruation and those who are pregnant or incapable of understanding the numeric pain scales. Women who have any active cancer at study entry (defined as cancer diagnosed or treated within the previous 6 months, recurrent, regionally advanced or metastatic cancer), previous hysterectomy, previous pelvic surgery or radiotherapy, active vaginal or uterus infection, and analgesic use within 24 hours are excluded due to potential interference with pain intensity. The study protocol was approved by the NTUH Research Ethics Committee. During the recruitment process, every eligible participant is fully informed of this trial's aim, design, and content, except for the intervention details. All participants should provide written informed consent. This study is conducted according to the Declaration of Helsinki and is registered at ClinicalTrials.gov.

Sample size estimation: The investigators estimate to recruit at least 248 participants (180 at the NTUH, 68 at the NTUH Hsin-Chu, Bei-Hu, Yunlin, and Cancer Center branches), 50% (124) of whom are randomized to the intervention group, to reach 90% power for the detection of an increase in 3-year cervical cancer screening participation from 30% to 50% at the 5% level of significance.

Randomization and blinding: Eligible participants are randomly assigned to either the group receiving the traditional Pap test or the modified Pap test. Computer-generated random numbers are employed for simple randomization with a 1:1 allocation ratio. All participants are kept unaware of any information about group allocation throughout the study period. The operators performing the procedure are not informed by the assistants whether to intervene until a specimen is prepared for cervical cytology. The delayed disclosure of the group allocation until this step ensures that the operators standardize the insertion and opening phases of the Pap test. Cytopathologists who analyze the specimens are blinded to the study.

The modified and traditional Pap tests: All operators experienced in techniques for performing a Pap test should attend workshops for a standard operating procedure. The operators include family physicians and gynecologists. A well-trained research assistant is also responsible for ensuring standardization of procedures to eliminate interoperator variability. During the Pap test, there is a privacy curtain separating participants from the operators. An operator separates the labia with hand and then gently inserts the saline-lubricated speculum sideways. The speculum is rotated 90 degrees and opened to achieve an optimal view of the cervix. Then an operator fixes the speculum to obtain the cell samples by brushes. The above-standardized procedures are the same between the two groups. After preparing a specimen for conventional cytology, an operator loosens the locking nut of the speculum, partially closes the blade, rotates the speculum 90 degrees back to its original insertion orientation, and then removes the speculum in the control group receiving the traditional Pap test. For the intervention group receiving the modified Pap test, instead of immediately removing the speculum just after rotating back the speculum, an operator still fixes the speculum in the vagina for 15 seconds. Participants receiving the modified Pap test do not realize what is going on during the 15-second step because they are behind the privacy curtain. Procedurally, the subsequent addition of a non-painful step after specimen collection does not affect specimen quality.

Interview, Anthropometric Indices, and Anxiety scores: The investigators review the medical records after getting informed consent. In addition to pain evaluations, this project collects information about tobacco use, alcohol consumption, socioeconomic status, marital status, parity, sexually active status, menopause, predicted pain of Pap smears, psychological stress, anxiety score, analgesic use, current medications, and medical history through standardized personal interviews. Body height and weight are measured using a standard stadiometer, and body mass index is calculated. Blood pressure is measured with an electronic sphygmomanometer while the patient is seated after resting for at least five minutes. Psychological stress is assessed using the Brief Symptom Rating Scale -5 (BSRS-5). The BSRS-5 includes items of anxiety, depression, hostility, interpersonal sensitivity, and insomnia measured by a 5-point Likert-type scale of 0-4. Normal, slight, and great mental stress is defined by the sum of BSRS-5 scores ≤ 5, 6-9, and ≥10, respectively. The anxiety score is obtained using the Generalized Anxiety Disorder 7-item (GAD-7). GAD-7 total score for the seven items ranges from 0 to 21 (0-4: minimal anxiety. 5-9: mild anxiety. 10-14: moderate anxiety. 15-21: severe anxiety). Based on a meta-analysis, some experts have recommended considering using a cut-off of 8 to optimize sensitivity without compromising specificity.