A Randomized Controlled Trial Comparing Cure Rates of Cervical Intraepithelial Neoplasia Grade 2 and Higher (CIN2+) Treated With CO2-based Cryotherapy, CropPen, and Thermoablation (UH3)

Cryotherapy is the current gold standard for treatment of precancerous cervical lesions in low resource settings. However, in recent years a number of issues-particularly the use of compressed gas, which requires storage and replenishment of large and potentially dangerous tanks-have emerged as clear limitations. Two technologies-the LMICs-adapted CryoPen®, manufactured and sold by CryoPen®, Inc. (TX, USA), and the thermoablator commercialized by WISAP Medical Technology (Germany) are treatment options for precancerous cervical lesions that run on electricity and avoid the difficulties associated with compressed gas. The LMIC-adapted CryoPen® (hereafter, CryoPen®) differs from previous cryotherapy methods in that it does not require an external source of gas (a tank), since the gas for cooling is built into the system. Thermoablation (also called thermocoagulation) has been used since the 1970s for treatment of cervical lesions. This is treatment with a probe heated to temperatures of 100 to 120ºC. It is also an effective, inexpensive method that does not require high-level healthcare providers.

The purpose of this study is to conduct a randomized non-inferiority clinical trial to compare the CryoPen® and WiSAP thermoablator to CO2-based cryotherapy for the treatment of CIN2 or more severe diagnoses ("CIN2+") but excluding microinvasive or invasive cervical cancer. The primary objective is to compare CIN2+ cure rates after treatment with the LMIC-adapted CryoPen®, the WISAP thermoablator, and CO2-based cryotherapy.

Women will be recruited from the Salvadorian Social Security Hospital (ISSS) in San Salvador, El Salvador, La Liga Contra el Cancer in Lima, Peru and Hospital Universitario San Ignacio in Bogota, Colombia. All are referral sites for women with abnormal cytology.

The investigators will approach approximately 1,602 women with CIN2+ during a 2.5 year enrollment phase (30 months). Assuming an approximately 80% participation rate, approximately 1,281 women will be enrolled- 1,152 (90%) will be eligible for cryotherapy (i.e. no contraindications) and 129 will be ineligible and undergo alternative treatments. The investigators estimate that approximately 20% will be lost to follow-up at the twelve-month visit, so that complete data will be available on a total of 922 women (57.55% of 1,602) treated with either CO2-based cryotherapy, LMIC-adapted CryoPen®, or thermoablation.

Eligible women with biopsy-confirmed CIN2+ will undergo HPV genotyping with next-generation sequencing. The specimen is taken prior to treatment to establish a baseline of which HPV types are present. If a different HPV type is present in the post-treatment specimen, this will be classified as a new rather than persistent infection. Testing will be conducted at the National Cancer Institute in Rockville, MD. Women will be randomly assigned to one of three study arms: