Study characteristics

Methods

3‐arm RCT

Participants

5060 women (3488 women, ASCUS smear and 1572 women, LSIL smear)

Study arms:

1. Immediate colposcopy (N = 1836; LSIL = 673, ASCUS = 1163)

2. HPV triage (N = 1385; LSIL = 224, ASCUS = 1161)

3. Cytological follow‐up (N = 1839; LSIL = 675, ASCUS = 1164)

Inclusion criteria:

• Cytologic diagnosis of LSIL or ASCUS

• Aged 18 or older

• Able to provide informed consent and likely to participate the full duration of trial

Exclusion criteria:

• Prior hysterectomy or treatment of cervix

• Pregnant at the time

Interventions

All

• Enrollment pelvic examination with collection of HPV‐sample and liquid‐based cytology

• Exit colposcopy at 24 months. Treatment if CIN2 or 3 in biopsy and CIN1 with previous LSIL/ASCUS and HPV+

Colposcopy indications:

1. Immediate colposcopy at the date of recruitment or within 3 weeks. Treatment if CIN2 or 3 in biopsy.

2. Referral to colposcopy if the HPV test positive or missing or if enrolment cytology HSIL. Treatment if CIN2 or 3 in biopsy

3. Referral to colposcopy if cytology HSIL. Treatment if CIN2 or 3 in biopsy

LSIL only

• Due to safety analysis results later all women with initial LSIL smear referred to colposcopy during the trial

• At each follow‐up visit every six months a pelvic examination, cervicography, cervical smear and HPV‐test were done.

Outcomes

• Default rates

• Cumulative CIN2+ & CIN3+ incidence and results at recruitment, during surveillance and at 24 months' exit examination

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Telephone‐based central randomisation service used. Sequence generation not described in detail, but not estimated to induce bias

Allocation concealment (selection bias)

Low risk

Allocation done from central point

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Blinding of participants was not possible and personnel were not blinded of allocation.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of investigators undertaking follow‐up assessments was not described in detail.

"all available clinical information was unmasked and provided to the clinician conducting the exit pelvic examination and colposcopy."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Losses to follow‐up were disclosed (ASCUS: 14.2% at 24 months in the surveillance group, LSIL: 16.3% at 24 months in the surveillance group) and the analyses were conducted as specified a priori. Loss to follow‐up might have introduced only small bias to histology results.

Selective reporting (reporting bias)

Low risk

Pre‐published trial protocol available, outcome reporting done according to protocol

Other bias

High risk

Source of funding reported; competing interests reported. Ethical approval & informed consent from participants obtained. Repeat smear at randomisation visit and exit colposcopy at 24 months, both could potentially introduce detection bias and over inflate the detection rate of pre‐invasive lesions in the cytological surveillance arm at 24 months.

Study characteristics

Methods

4‐arm RCT

Participants

902 women, presenting with mildly or moderately dyskaryotic smear for the first time.

Study arms:

1. Immediate colposcopy +/‐ treatment (n = 227)

2. Surveillance for 6 months (n = 225)

3. Surveillance for 12 months (n = 223)

4. Surveillance for 24 months (n = 227)

Inclusion criteria:

• Mild or moderate dyskaryosis in first abnormal smear

Exclusion criteria:

• None given.

Interventions

Group 1. Immediate colposcopy with biopsies +/‐ treatment (n = 227)

Group 2. 6‐month surveillance (n = 225):

• Cytology and colposcopy with histological diagnosis (biopsy and/or LLETZ) at 6 months

Group 3. 12‐month surveillance (n = 223):

• Surveillance at 6‐month intervals through cytology and colposcopy with histological diagnosis (biopsy and/or LLETZ) at the end of surveillance period

• Immediate LLETZ if severe dyskaryosis in smear or suspicion of microinvasion at colposcopy.

Group 4. 24‐month surveillance (n = 227):

• Surveillance at 6‐month intervals through cytology and colposcopy with histological diagnosis (biopsy and/or LLETZ) at the end of surveillance period

• Immediate LLETZ if severe dyskaryosis in smear or suspicion of microinvasion at colposcopy

Outcomes

• Default rates

  • Defined as those who did not complete the protocol in question

• Histology at the end of each surveillance period

  • From punch biopsy or LLETZ specimen, whichever showed worse lesion

• Final smear test result

• CIN3 prevalence in relation to number of non‐dyskaryotic smears

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"...all eligible women randomised by serial allocation to one of four groups."

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described in sufficient detail

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Blinding of participants was not possible and blinding of personnel was not reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessment not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

109/675 women in the surveillance arms defaulted from study, rates being higher with longer follow‐up (9.8% at 6 months, 15.2% at 12 months, and 23.3% at 24 months). More specific reasons not available. Significant default rates might bias histology results

Selective reporting (reporting bias)

Low risk

Protocol not available. Results still reported comprehensively and reporting considered not to introduce bias

Other bias

High risk

Conflict of interest not reported; source of funding not reported; details of ethical approval not stated. Missing information still considered not to introduce bias

All women in the surveillance arm had colposcopy in addition to smear, which could introduce bias and over inflate the detection rates in the surveillance arm at 6, 12 and 24 months of surveillance

Study characteristics

Methods

2‐arm RCT with Zelen randomisation

Participants

712 women pre‐randomised, with mild dyskaryosis for the first time or recurrent borderline change on routine cervical screening in primary care.

Aged 20 to 60, not pregnant, no abnormal vaginal bleeding

Of 712 pre‐randomised women, 476 decided to participate in the study.

Study arms:

1. No choice arm (n = 243): surveillance for 12 months

2. Choice arm (n = 233)

Inclusion criteria:

• Recurrent borderline or first mild dyskaryotic smear

• Aged 20 to 60

Exclusion criteria:

• Pregnancy

• Abnormal vaginal bleeding

Interventions

Group 1. No‐choice arm (n = 243)

• Cytological surveillance at 6 months & 12 months, with colposcopy +/‐ treatment (LLETZ) if either follow‐up smear abnormal

• General health questionnaire at baseline, 6 months, and 12 months

Group 2. Choice arm (n = 233)

Women were given the opportunity to choose between a) and b):

• choice a) immediate colposcopy (n = 130)

  • immediate colposcopy with biopsies +/‐ treatment (LLETZ)

  • General Health Questionnaire at baseline, at immediate colposcopy, 6 months, and 12 months

• choice b) cytological surveillance (n = 103)

  • Cytological surveillance at 6 months and 12 months, with colposcopy +/‐ treatment (LLETZ) if either follow‐up smear abnormal

  • General Health Questionnaire at baseline, 6 months, and 12 months

Outcomes

• Default rates

  • reported at 6 months and at 12 months

  • defined as women lost to follow‐up at respective time points

• Cumulative histology at the end of 12‐month surveillance period

  • Based on biopsy or LLETZ‐specimen

• Psychological morbidity and anxiety levels (General Health Questionnaire scores)

  • GHQ‐caseness, defined as 4 or more points from the questionnaire

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation into two study arms prior to consent using computer‐generated random numbers

Allocation concealment (selection bias)

Low risk

Central allocation used. In one of the study arms the participants themselves chose the intervention group.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Participants and investigators were not blinded.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Outcome assessment was not blinded.

Incomplete outcome data (attrition bias)
All outcomes

High risk

712 pre‐randomised, 476 participated. Reasons for non‐participation reported, no clear differences between randomisation groups

172/476 were lost to follow‐up, no specific reasons stated. Adequate sample size might not have been achieved for all outcomes.

Selective reporting (reporting bias)

Low risk

Pre‐trial protocol was not available. Results still reported comprehensively

Other bias

High risk

Project funding reported; conflicts of interest not stated. Local ethical approval and informed consent from participants obtained. Missing information still considered not to introduce bias. Used Zelen randomisation, where some participants were able to choose whether to have immediate colposcopy or cytological surveillance, which might well bias the results included here.

Study characteristics

Methods

2‐arm RCT

Participants

353 women with borderline or mild dyskaryotic smear

Study arms:

1. Immediate treatment (n = 182)

2. Surveillance for 24 months (n = 171)

Inclusion criteria:

• Borderline or mild dyskaryotic smear

• Age < 35

• Fully visible TZ and no features of invasion at colposcopy

Exclusion criteria:

• Previous smear more abnormal than mild dyskaryosis

• Previous CIN

• Normal colposcopy at baseline

Interventions

Group 1. Immediate treatment (n = 182)

• ‐ Immediate treatment (LLETZ)

Group 2. Deferred treatment (n = 171)

• Cytological and colposcopic surveillance at 6 month intervals, treatment (LLETZ) at 24 months

• Treatment during surveillance if follow‐up cytology severe dyskaryosis or worse

Outcomes

• Default rates

  • defined as those who did not complete the protocol

• 2. Histology

  • From LLETZ specimen at the immediate treatment

  • From LLETZ specimen at the end of 24m surveillance period

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised using a sequence of random numbers generated by computer.

Allocation concealment (selection bias)

Low risk

Total allocation concealment as randomisation performed individually from a central point.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Blinding participants was not possible and personnel were not blinded to allocation.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Investigators undertaking follow‐up were not blinded.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

36/171 lost to follow‐up in deferred treatment group, 1/181 in the immediate colposcopy group. More specific reasons not reported. The 20% lost to follow‐up in other arm might introduce bias to histology results

Selective reporting (reporting bias)

Low risk

Pre‐trial protocol was not available. Results still reported comprehensively

Other bias

High risk

Individual sources of funding reported, conflicts of interests not declared. Local ethical approval and informed consent from participants obtained. Missing information still considered not to introduce bias. All women in the surveillance arm had deferred treatment at 24 months regardless of cytology, which could introduce bias and over inflate the CIN detection rate in the surveillance‐arm at 24 months.

Study characteristics

Methods

2‐arm RCT

Participants

4439 women, aged 20‐59, with cytological result showing:

Study arms:

1. Cytological surveillance every 6 months up to 3 years (n = 2223)

2. Immediate referral to colposcopy and surveillance according to general guidelines (n = 2216)

Inclusion criteria:

• Borderline nuclear abnormality and borderline or mild dyskaryosis in repeat smear after 6 months (first phase of trial).

• Single borderline nuclear abnormality (second phase)

• Aged 20‐59

Exclusion criteria

• Pregnancy at the time of recruitment

• Previous cervical treatment

Interventions

Group 1. Surveillance arm (n = 2223)

• HPV‐test at recruitment

• Cytological surveillance every 6 months

• Questionnaire regarding anxiety, depression and colposcopy after‐effects every 6 months

• Exit examination at 3 years: colposcopy, and LLETZ if TZ abnormal

Group 2. Immediate colposcopy arm (n = 2216), second randomisation at colposcopy to a) or b)

a) Biopsy and selective recall for LLETZ based on histology on biopsy

• HPV‐test at recruitment

• Questionnaire regarding anxiety, depression and colposcopy after‐effects every 6 months.

• Follow‐up with cytology and / or colposcopy based on local guidelines

• Exit examination at 3 years: colposcopy, and LLETZ if TZ abnormal.

b) Immediate treatment (LLETZ)

• ‐ HPV‐test at recruitment‐

• Questionnaire regarding anxiety, depression and colposcopy after‐effects every 6 months.‐Follow‐up with cytology and / or colposcopy based on local guidelines‐ Exit examination at 3 years: colposcopy, and LLETZ if TZ abnormal.

Outcomes

• Cumulative incidence of CIN grade 2 or more severe disease

  • Based on biopsy or LLETZ‐specimen

• Cumulative incidence of CIN grade 3 or worse

  • Based on biopsy or LLETZ‐specimen

• Anxiety and depression

  • based on 6‐monthly questionnaire

• Other self reported after‐effects

  • based on 6‐monthly questionnaire

• Rates of non‐attendance

  • Defined as non‐attendance at given follow‐up visit, or attended more than 6 months after the appointment

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Touch‐telephone stratified randomisation used

Allocation concealment (selection bias)

Low risk

Allocation done from central point

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Participants not possible to blind. Blinding of personnel not described

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

At exit examination the colposcopist was blinded to the women's initial cytology status, her randomisation and any clinical outcomes.

Blinding of colposcopists or pathologists at other stages was not reported.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Before the first examination 107/2223 in the surveillance arm, 155/2216 in the colposcopy arm were lost to follow‐up. 1296 (58.3%) women in the surveillance arm and 1389 (62.7%) in the colposcopy arm attended the exit examination. Power calculations were based on 4500 participants. The significant loss to follow‐up and differences between arms might introduce bias to histology results.

Selective reporting (reporting bias)

Low risk

Pre‐published trial protocol available, outcome reporting according to protocol.

Other bias

High risk

Source of funding reported; Competing interests reported. Ethical approval & informed consent from participants obtained. All women were invited to an exit examination at 36 months, where colposcopy was performed regardless of smear results. This could introduce bias and over inflate the CIN detection rates in surveillance arm at 36 months.