Clinical Triage and Treatment of Atypical Glandular Cells (AGC) Detected in Screening

Study Overview
=================
Brief Summary
-----------------
The risk of cervical cancer after diagnosis with atypical glandular cells (AGC) detected by screening is elevated for 15 years after discovery. The current recommendation is that when AGC is detected during screening, referel is made to a gynecologist for colposcopy with biopsy within 3 months after the index test. Repeated tests should be done after one year and after two years and if these are negative, the woman can return to routine screening. Given the increased risk of cancer associated with AGC a new evaluation of the optimal follow-up and treatment of AGC, which is detected during screening, is carried out. In this randomized study, women with AGC will be randomized to routine treatment according to current guidelines or to conization. The aim of the study is to determine which of the two treatments is most effective.

Detailed Description
-----------------
Evidence from a nationwide cohort study demonstrated that the risk of cervical cancer following a diagnosis of AGC detected in screening was elevated for 15 years, particularly the risk of adenocarcinoma. Furthermore, the study suggested that compared to high-grade squamous intraepithelial lesion (HSIL) management, the management of AGC has been suboptimal in Sweden (Wang et al., BMJ 2016). A study conducted in the greater metropolitan region of Stockholm showed that the PPV for high grade lesions was 60% for Human Papillomavirus (HPV) positive AGC detected in screening (Norman et al., BMJ Open, 2017). The new guidelines for cervical cancer prevention were adopted in January of 2017 nationally and in December 2017 in county of Stockholm and outline a clinical management strategy for AGC. The recommendation is that AGC detected in screening, regardless of HPV status, should be referred to a gynecologist for colposcopy with biopsy within 3 months of the index test. For women over the age of 40, an ultrasound and endometrial biopsy is also recommended. Repeat tests should be done at one year and two years, if these are negative then the woman can return to routine screening. The elevated risk for high grade lesions and cancer associated with AGC, coupled with the reality that cervical cancer incidence has increased in Sweden, begs a new evaluation of the optimal clinical management and treatment of AGC detected in screening. Women will be randomized to routine management according to the new guidelines or to an alternative management.

Official Title
-----------------
Clinical Triage and Treatment of Atypical Glandular Cells (AGC) Detected in Screening: Randomized Healthservices Trial

Conditions
-----------------
Uterine Cervical Cancer

Intervention / Treatment
-----------------
* Procedure: Conization
* Procedure: Colposcopy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: give informed consent Women diagnosed with AGC (atypical glandular cells, M69720) and HPV 16/18 positive, detected in cervical screening. Exclusion Criteria: Do not give informed consent HPV negative or none-HPV16/18 positive

Ages Eligible for Study
-----------------
Minimum Age: 23 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active comparator<br>All women ages <41, women ages ≥41 with TZ1 and TZ2, and women ages ≥41 with a desire for further childbearing Clinical management and follow-up according to the national screening guidelines published in 2017 (same as for the comparator group, see below). Women with TZ3 and women ages ≥41 with no desire for further childbearing a. Referral to (diagnostic) excision. The depth of the diagnostic excision will be clinically determined in the trial. It should be with the intent to treat but no so extensive that the risk for side effects increases. The excision should include a cervical abrasion and endometrial sampling. | Procedure: Conization<br>* A cone biopsy to remove abnormal tissue.<br>* Other names: Excision;|
| Placebo Comparator: Placebo comparator<br>Clinical management and follow-up according to the national screening guidelines published in 2017: Colposcopy with biopsy within 3 months, endocervical sample, ultrasound and endometrial biopsy if the woman is ≥40 Colposcopy after 12 months if the first colposcopy and biopsies are normal Cytology and HPV testing at 12 and 24 months if the second colposcopy is normal | Procedure: Colposcopy<br>* Colposcopy with biopsy within 3 months,endocervical sample, ultrasound and endometrial biopsy if the woman is ≥40 Colposcopy after 12 months if the first colposcopy and biopsies are normal Cytology and HPV testing at 12 and 24 months if the second colposcopy is normal<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CIN3+ | Proportion of women with histologically verified HSIL+ (CIN3+) including AIS+ after AGC found in screening | 2-3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CIN2+ | Proportion of women with histologically verified HSIL+ (CIN2+) including AIS+ after AGC found in screening | 2-3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cervical cancer, atypical glandular cells