An Innovative Treatment for Cervical Precancer (UH3)

The purpose of this academic-industrial partnership will compare the CryoPen® and thermoablator to traditional CO2-based cryotherapy for the treatment of cervical precancer in low and middle income countries (LMICs) and investigate whether the cure rates of cervical intraepithelial neoplasia 2 and more severe diagnoses (CIN2+) with these devices are non-inferior compared to that of conventional cryotherapy. The results of this study will affect other research areas by serving as a springboard to exploring treatment alternatives that are amenable to low-resource settings and thus will reach the most vulnerable populations.

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:

A. CO2-based cryotherapy (double freeze), B. CryoPen® (single freeze), or C. Thermoablation for 40 seconds at 100ºC.

At a pre-treatment visit, consented women will receive a pregnancy test as part of the eligibility criteria for enrollment in the study. Pre-vaginal cultures will be collected to be analyzed for bacterial vaginosis, yeast, gonorrhea and chlamydia. The same cultures will be collected at a 6-week follow-up visit. Consented women will be enrolled and undergo a pelvic exam and visual inspection of the cervix following placement of diluted acetic acid on the cervix. Images of the cervix will be taken with a mobile ODT device will be taken before and after treatment. Women deemed ineligible for cryotherapy will undergo LEEP immediately. In the case of suspected cancer, women will be appropriately referred.

Six weeks post-treatment, women who return for a visit for evaluation of treatment side effects; these women will complete a questionnaire to assess the presence of pain or cramps, bleeding, stenosis, watery discharge, malodorous discharge and be evaluated for evidence of cervicitis. In addition, vaginal cultures will be collected and analyzed for bacterial vaginosis, yeast, gonorrhea, and chlamydia.

One year post-treatment, women will return for a follow-up visit to determine residual disease, which is the primary endpoint. Residual disease will be determined by colposcopy and four-quadrant biopsies. In addition, VIA, cytology, and high-risk HPV DNA testing with careHPV will be performed. Genotyping and next-generation sequencing will be repeated to differentiate between persistent and new infections. The goal is to evaluate sensitivity of VIA, cytology, and HPV testing post-treatment. Women diagnosed with recurrent/untreated CIN2+ on biopsy will be asked to return to undergo LEEP. Women with suspected cancer on biopsy will be referred to the local cancer hospital for standard of care.

Eligibility Criteria:
Inclusion Criteria:

* Women aged 18 and older
* Biopsy results of CIN2, CIN2-3, CIN3, or high-grade CIN not otherwise specified
* Willing and able to provide informed consent
* Willing and able to provide permanent or reliable address

Exclusion Criteria:

* Pregnant or plans to become pregnant during study
* History of total hysterectomy (verified by medical record or pelvic evaluation)
* Previous surgery destructive to the cervix within the last 5 years
* Patient not eligible for cryotherapy (lesion \>75% of cervix, lesion extends into canal or there is suspicion for invasive cancer)
* Cervix shape disfigured or hard to reach