Objectives
Human papillomavirus (HPV) infection is a major risk factor for cervical cancer. Imiquimod is a topical medication that enhances the immune response to HPV-induced genital warts. This study evaluated cervical application of imiquimod as an adjunct to standard treatment for cervical dysplasia.
Study Design
Fifty-six patients were randomized to standard excisional/ablative treatment vs applications of imiquimod followed by standard treatment. The primary endpoint was dysplasia recurrence within 2 years.
Results
There were no differences in dysplasia recurrence between the 2 groups. Treatment was well tolerated, with side effects being mild but significantly worse in women receiving imiquimod for, chills, fatigue, fever, headache, myalgias, and vaginal discharge.
Conclusion
This trial does not support the hypothesis that imiquimod, as used in this trial, has an impact on recurrence of cervical dysplasia, but the adequacy of findings are limited by sample size. The trial does support the feasibility and acceptability of the use of imiquimod on the cervix.
Cervical cancer is the second most common cancer in women worldwide, with more than 270,000 deaths annually. Cervical dysplasia and invasive cervix cancer are caused by human papillomavirus (HPV). The association between infection and development of cervical cancer is strongest with HPV types 16 and 18. Persistent infection with a high-risk HPV type is the strongest predictor of cervical dysplasia and cancer. Pursuant to the notation of this association, HPV testing has begun to be incorporated into cervical cancer screening. In addition, the HPV vaccines were designed to protect against the oncogenic HPV types 16 and 18.
Current treatments for cervical dysplasia involve the use of freezing, laser, electrosurgery, or a surgical scalpel to remove or destroy the cells that have become abnormal or precancerous as a consequence of HPV infection. Although these approaches are effective, they can lead to complications, including cervical stenosis, bleeding, and pelvic infection. Therefore, there is increasing interest in HPV immunotherapies for the treatment-of HPV associated neoplasia.
Imiquimod is an immune response modifier with antiviral and antitumor activity. It induces the expression of cytokines, such as interferon, tumor necrosis factor, and interleukins 1, 6, and 8. Imiquimod also activates T cells, resulting in a tumor directed immune response, which has been associated with clearance of HPV. Imiquimod was approved in 1997 for the treatment of genital warts, most of which are caused by HPV types 6 and 11. Recently imiquimod has also been found to be effective for treatment of vulvar intraepithelial neoplasia (VIN), which is also associated with HPV infection.
The purpose of this clinical trial was to evaluate the efficacy and safety of imiquimod for women with cervical dysplasia. The primary goal was to determine whether topical treatment with imiquimod could decrease recurrence of cervical dysplasia. A secondary goal was to determine patient acceptability and toxicity of topical imiquimod to the cervix. The current communication presents the results of this study as it relates to these goals.
Materials and Methods
This clinical trial was supported by the National Institutes of Health and approved by the Mayo Foundation Institutional Review Board. All participants received and signed informed consent forms per federal regulations ( NCT00031759 ).
Women aged 18 years or older, with biopsy-proven cervical intraepithelial neoplasia (CIN) II or III, or recurrent or persistent CIN I, were randomized to experimental or standard treatment. Other eligibility criteria included an exclusively ectocervical lesion (determined by colposcopy and/or normal endocervical brushing or endocervical curettage) and a negative pregnancy and human immunodeficiency virus test. In addition, all participants were to use adequate contraception for 3 months following enrollment. All biopsies and Papanicolaou smears were reviewed by a qualified single pathologist, who was blinded to treatment assignment. At the time of entry into this study, patients were stratified, using dynamic allocation, according to severity of dysplasia, primary vs recurrent dysplasia, and tobacco use.
Patients randomized to standard treatment received the excisional or ablative treatment recommended by their provider. Options included a loop electrosurgical excision procedure (LEEP), laser, cryotherapy, or conization, as dictated by the size, location, and severity of the lesion and according to the usual treatment practice of the attending physician.
Patients randomized to the experimental treatment received 5 applications of the immune response modifier, imiquimod. One single-use packet, containing 50 mg of 5% imiquimod in an oil-in-water cream base, was used for each treatment. After insertion of a vaginal speculum, the cream was applied directly to the ectocervix using a cotton-tipped applicator. The speculum was withdrawn and a contraceptive diaphragm was placed as a medication barrier. The patient was instructed to leave the diaphragm in place for at least 6, but no more than 10, hours. The diaphragm was then removed by the research nurse, a vaginal speculum was reinserted, and the cervical region was gently flushed with saline. Treatment was repeated every 3-4 days (about twice a week) but was suspended during menses. Side effects were graded following each of the 5 applications of imiquimod by a single research nurse. Toxicities were graded per National Cancer Institute Common Terminology Criteria version 2.0. Two to 4 weeks following the fifth topical treatment, ablative or excisional therapy was carried out as described for the standard treatment group mentioned in earlier text.
Patients were to return for repeat evaluation 3-4 months following definitive treatment. In addition to a Papanicolaou smear, a cervicovaginal swab was obtained to test for HPV. Colposcopy was performed at the discretion of the physician, with abnormal appearing areas on the cervix being biopsied per usual clinical practice. Subsequent evaluations were scheduled at 3- to 4-month intervals until patients had 2 consecutive normal Papanicolaou smears and then at least twice yearly for 2 years.
The primary endpoints were the rates of persistent and recurrent CIN and progression to cervical cancer within 2 years. Recurrent or persistent dysplasia was defined as those participants who were diagnosed with CIN after treatment who exhibited at least 1 of the same HPV type(s) as they had at study entry. If CIN was diagnosed with a new HPV type, or there was no detectable HPV type, this was coded as new disease.
In a previous trial involving a similar population of women with cervical dysplasia, the rate of recurrent or persistent disease following standard treatment was 26-29%, depending on the treatment used. Power was based on a 25% recurrence rate within 2 years following treatment. A sample size of 152 patients would provide a 90% chance of detecting a 50% decrease (12% recurrent or persistent disease) in treatment failures. The study was closed because of slow accrual prior to reaching the planned number of protocol subjects.
HPV detection was accomplished using 2 complementary methods. The first method was a polymerase chain reaction (PCR) amplification and automated deoxyribonucleic acid (DNA) sequencing strategy, developed in a Mayo Clinic research laboratory. This strategy combines the use of broad range primers for detection of multiple HPV types and type-specific primers to insure the most sensitive detection of HPV types 16 and 18.
The second method was the Roche HPV linear array genotyping system (Roche Molecular Systems, Inc, Alameda, CA). This noncommercial Roche product is a reverse line blot containing 27 different HPV probes. For both HPV detection methods, DNA was extracted from samples using a modified Isoquick procedure. The extracted DNA was amplified by PCR. Reactions showing agarose gel bands of the appropriate size were subjected to purification and then submitted to a core laboratory for automated DNA sequencing (PE ABI 377 DNA sequencer; PE Applied Biosystems, Foster City, CA).
Sequences were compared with HPV sequences in the Gene Bank database using commercial software (Wisconsin Package version 9.1; Genetics Computer Group, Madison, WI). An HPV type was assigned if the sequence of the amplified region showed at least 90% homology to a known HPV type. Negative control samples were interspersed with test specimens to monitor the possible development of contamination problems during preparation, amplification, or detection. Samples with negative or equivocal results using the standard primer set were retested using different primers and/or using nested PCR techniques.
Results
Between September 1999 and January 2003, 56 women were enrolled and randomized to experimental treatment (n = 28) or standard treatment (n = 28). One woman was seen for a single visit at which time she consented to participate in the study but did not return for study treatment. Another patient received her first treatment with imiquimod but withdrew after experiencing chills and headaches. Both patients remain in the analysis according to their assigned treatment group. Patient flow is described in the CONSORT diagram ( Figure ).
Patient characteristics are listed in Table 1 . They were well balanced between groups except for tobacco use, which was higher in the experimental group. The mean and median follow-up times were 3.1 years (SD 1.36 years) and 3.3 years, respectively. There was no difference in follow-up time by study arm ( P = .67).
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