Topical Imiquimod vs. LEEP for Women With Carcinoma In-situ of the Cervix
Topical Imiquimod vs. LEEP for Women With Carcinoma In-situ of the Cervix
OBJECTIVE: The standard of care for high grade cervical intraepithelial neoplasia grade 2 to
 3 (CIN 2-3) has been the excision of the cervical transformation zone by way of a loop
 electrosurgical excision procedure (LEEP) or cold knife conization (CKC). However, it has
 been recognized that these procedures can increase the risks for pre-term labor in women who
 still desire to conceive. Recent studies have shown that medical treatment with Imiquimod, a
 topical immune response modulator, has significant effects on histological regression of CIN
 2-3 when compared with placebo. The investigators propose that treatment with Imiquimod may
 be preferable offering similar outcomes on histological regression when compared with
 excision or ablation while potentially avoiding or reducing the number of surgical procedure
 that places them at risk for future pregnancies.
MATERIALS AND METHODS: A randomized controlled trial of patients with CIN 2-3 to receive
 either surgical excision with LEEP or CKC versus medical therapy with Imiquimod once weekly
 inserted vaginally for 16 weeks. Inclusion criteria are women age 21 years or older with
 confirmed histological diagnosis of CIN 2-3 with a normal endocervical curettage (ECC) if
 obtained and satisfactory colposcopy (the transformation zone of the cervix was completely
 visualized.) Exclusion criteria include positive CIN2-3 on ECC, presence of cancer, pregnancy
 or lactation, immune deficiency, hepatitis, or hypersensitivity to Imiquimod. Patients will
 be randomized to receive excision with LEEP/CKC or Imiquimod 250 mg (5%) cream (12.5 mg of
 active ingredient) inserted vaginally once a week for 16 weeks.

 The primary outcome will be histological regression to CIN 1 or less. Secondary outcomes will
 be complete histological regression, high-risk Human Papilloma Virus (HPV) clearance,
 Clearance of HPV 16, 18/45, and patient tolerance of Imiquimod regimen. Follow up with repeat
 pap, HPV typing to include 16 and 18/45 subtyping, and colposcopy with directed cervical
 biopsy will be performed at 6 months post initiation of treatment. Patients unable to
 complete at least 8 treatments and miss two treatments consecutively will be considered
 failures and offered immediate LEEP. Those patients that complete 8 treatments of Imiquimod
 will be reevaluated 6 months from initiating treatment. Demographic information will be
 obtained to include age, gravidity and parity, smoking history, and contraceptive use.

 Descriptive statistics will include numbers and rates of occurrence with confidence intervals
 of regression, pre, and post-treatment HPV including HPV 16 and 18/45 typing, and adverse
 effects. The assumed regression rate for the LEEP arm varies within studies. We are choosing
 a conservative estimate of 85% regression rate from CIN2+ to CIN1 or less. More recently in a
 2014 publication in the Journal of Virology (Author Antonio Frega, Journal of Clinical
 Virology 60 (2014) 39-43) 13% of the LEEP patients out of 475 had residual disease after
 LEEP. In this study they excluded the 10% of patients that had had positive margins on their
 LEEP specimen. We are not excluding them as this is intent to treat study. For Imiquimod the
 Grimm study found a 73.3% regression rate with those treated with the active ingredient. A
 non-inferiority-type design for two proportions using differences is used in which the
 difference between treatments is defined as medical treatment being preferable if the
 regression rate is not more than 15% below that of the excisional treatment. Comparison of
 the regression rates of the two treatments will be made by a non-inferiority Fisher's exact
 test.

 Required sample size was assessed using the PASS software of the NCSS statistical package.
 Using power = 0.80 and alpha = 0.05, a power analysis predicts the need for 68 patients per
 arm for 136. Post-treatment HPV rates will be compared similarly. We will recruit 75 patients
 to each arm to buffer for a dropout rate.
Inclusion Criteria:

 -  Healthy women older than age 21, military or civilian

 -  Negative pregnancy test results

 -  Confirmed CIN 2-3 on cervical biopsy with a negative endocervical curettage (ECC) and
 satisfactory colposcopy visualizing the complete transformation zone of the cervix.

 -  The patient will be available and in the San Diego area for 6 months after enrollment
 to complete the clinic visits and follow up.

 Exclusion Criteria:

 -  Positive CIN 2-3 on ECC

 -  Presence of cancer

 -  Pregnancy or lactation

 -  Immuno-compromised (systemic lupus erythematosus, kidney transplant)

 -  Hepatitis

 -  Hypersensitivity to Imiquimod

 -  Ulcerative colitis

 -  Crohn's disease

 -  Human Immunodeficiency virus