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Research

General Gynecology

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Topical 5-uorouracil for treatment of cervical intraepithelial neoplasia 2: a randomized controlled trial
Lisa Rahangdale, MD, MPH; Quinn K. Lippmann, MD, MPH; Katelyn Garcia, MS; Debra Budwit, MD; Jennifer S. Smith, PhD; Linda van Le, MD
OBJECTIVE: The objective of the study was to evaluate the efcacy of

intravaginal application of 5% 5-uorouracil (5-FU) for the treatment of cervical intraepithelial neoplasia (CIN) 2 in women. STUDY DESIGN: Women aged 18-29 years with CIN 2 were recruited for this randomized controlled trial of observation vs treatment with intravaginal 5-FU. Women in the observation group returned in 6 months for a Papanicolaou smear, colposcopy, and a human papillomavirus (HPV) deoxyribonucleic acid test. Women in the 5-FU group were treated with intravaginal 5-FU once every 2 weeks for a total of 16 weeks and were similarly evaluated at 6 months. All women who had a baseline visit were included in the intention-to-treat analysis. Values of P < .05 were considered statistically signicant. RESULTS: Between August 2010 and June 2013, 60 women were randomized and had a baseline visit for intervention (n 31) vs observation (n 29). Of women who had cervical biopsy results at 6 months, regression of disease was demonstrated in 93% of women

in the 5-FU group (26 of 28) and 56% of women in the observation group (15 of 27). Under the intention-to-treat analysis, a relative risk for cervical disease regression of 1.62 (95% condence interval [CI], 1.10e2.56) was found between the 5-FU and observation arms (P .01). When the cervical biopsy, Papanicolaou smear, and HPV results were combined for the 6 month follow-up visit, 50% of the 5-FU group (14 of 28) had a documented normal biopsy, normal Papanicolaou smear, and negative HPV test compared with 22% in the observation group (6 of 27) (relative risk, 2.25; 95% condence interval, 1.05e5.09; P < .05). There were no moderate or severe side effects in the intervention group. CONCLUSION: Topical 5-FU appears to be an effective medical therapy for CIN 2 in young women. 5-FU is readily available and may be considered as an off-label treatment option for young women with CIN 2 who are interested in the treatment of disease but want to avoid excisional procedures.

Cite this article as: Rahangdale L, Lippmann QK, Garcia K, et al. Topical 5-uorouracil for treatment of cervical intraepithelial neoplasia 2: a randomized controlled trial. Am J Obstet Gynecol 2014;210:314.e1-8.

B ACKGROUND

AND

O BJECTIVE

Historically, most women with cervical intraepithelial neoplasia (CIN) 2 and 3 underwent excisional therapy or ablation of the cervical transformation zone. Excisional treatment procedures have been associated with increased risk for premature delivery as well as anxiety, pain, bleeding, and health care expenditure. Because nearly half of CIN 2 lesions regress in young women, current guidelines endorse close observation of young women as a preferable management

strategy for CIN 2 and acceptable management strategy for CIN 3. No medical therapies are recommended to promote the clearance of human papillomavirus (HPV) or cervical dysplasia. Topical 5-urouracil (5-FU) is used to treat skin cancers and lesions caused by HPV, including genital warts and vulvar and vaginal intraepithelial neoplasia. Treatment of genital disease with 5-FU is an off-label use of the medication. Studies limiting topical 5-FU to less frequent application or diluted doses

have reported favorable side effect proles. The objective of this study was to assess the efcacy, safety, and acceptability of intravaginal 5-FU as a primary treatment for CIN 2 in young women.

M ATERIALS

AND

M ETHODS

This was a prospective, nonblinded, randomized trial of intravaginal 5% 5-FU vs standard-of-care observation in young women with CIN 2 (no placebo). Primary outcome was regression of

From the Departments of Obstetrics and Gynecology (Drs Rahangdale, Lippmann, and van Le), Biostatistics (Ms Garcia), and Pathology (Dr Budwit), University of North Carolina at Chapel Hill School of Medicine; and the Department of Epidemiology, University of North Carolina Gillings School of Public Health (Dr Smith), Chapel Hill, NC. Q.K.L. is currently with the Department of Reproductive Medicine, University of California, San Diego, School of Medicine, San Diego, CA. K.G. is currently with the Department of Biostatistics, Wake Forest Baptist Medical Center, Winston-Salem, NC. This study was supported by an American College of Obstetricians and Gynecologists Hologic Research Award for the Prevention of Cervical Cancer and by a James W. Woods Junior Faculty Award from the University of North Carolina School of Medicine. QIAGEN supplied human papillomavirus testing. The authors report no conict of interest. Presented at the 40th annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology, Albuquerque, NM, Aug. 8-10, 2013, and at the 28th Annual Scientic Meeting of the International Papillomavirus Society (International Papillomavirus Conference), San Juan, Puerto Rico, Nov. 30 through Dec. 6, 2012.
0002-9378/free  2014 Mosby, Inc. All rights reserved.  http://dx.doi.org/10.1016/j.ajog.2013.12.042

314 American Journal of Obstetrics & Gynecology APRIL 2014

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disease 6 months after diagnosis of CIN 2. Women aged 18-29 years presenting to the University of North Carolinas Womens Hospital Clinics with satisfactory colposcopic examinations and a biopsy-conrmed diagnosis of CIN 2 and in whom follow-up observation with cytology and colposcopy every 6 months was planned were approached for enrollment. Dual contraception (condoms plus 1 of the following: oral, intravaginal, injectable, implantable, or intrauterine conception) was required for the 5-FU group because of its potential teratogenic effects. The 5-FU group received written and verbal instructions for the insertion of 2 g of 5-FU via a vaginal applicator every 2 weeks for a total of 8 doses. The 5-FU participants were instructed to insert 2 g of topical 5% 5-FU cream at night with a vaginal applicator. Participants placed a tampon per vagina overnight to keep the cream at the cervix. Participants were instructed to remove the tampon in the morning, shower, and frequently hand wash and change panty liners over the next 2 days to avoid irritation from the cream. Participants in the 5-FU group returned for a safety and acceptability visit at the study site after 8-16 weeks for a survey and pelvic examination. At the 6 month visit, colposcopically guided cervical biopsies were performed. A pathologist coinvestigator blinded to randomization reviewed all cytology and pathologic specimens for entry criteria and follow-up cytology and histology.

General Gynecology

Research

TABLE

Self-reported characteristics of participants


5-FU Demographics Race White African American Other
a

Observation % 77.4 19.4 3.2 n 18 7 4 % 62.1 24.1 13.8 P value .26

n 24 6 1

Ethnicity Hispanic Non-Hispanic Age, y 19-20 21-25 26-30 Median age, y Marital status Married Divorced/separated Never married Education High school or less More than high school Health insurance (public or private) Sexual history Current contraception use Ever condom use Age at rst intercourse, y 12-15 16-20 21-25 Number of sexual partners over lifetime 1-5 6-10 >10 Number of sexual partners in last year 1 2 Medical history Current tobacco use Past tobacco use HPV vaccine (1-3 doses) 7 14 10 22.6 45.2 32.3 8 10 6 27.6 34.5 20.7 .77 .44 .39 23 8 74.2 25.1 19 10 65.5 34.5 .58 10 12 9 32.3 38.7 29.0 15 9 5 51.7 31.0 17.2 .31 10 20 1 32.3 64.5 3.2 12 16 1 41.4 55.2 3.5 .79 28 18 90.3 58.1 24 13 82.8 44.8 .47 .44 8 23 18 25.8 74.2 58.1 8 21 10 27.6 72.4 34.5 .08 1.00 6 2 23 19.4 6.5 74.2 5 4 20 17.2 13.8 69.0 .65
b

3 28

9.7 90.3

4 25

13.8 86.2

.70

2 17 12 24

6.5 54.8 38.7 (19e29)

1 22 6 23

3.5 75.9 20.7 (20e29)

.28

.32

R ESULTS
From Aug. 1, 2010, through June 1, 2012, 93 women who met inclusion criteria were approached for enrollment. Of these, 60 women were randomized and underwent a baseline enrollment survey. The Table describes baseline characteristics of both groups. There were no statistically signicant differences between the 5-FU and observation groups. Of the 60 women who underwent randomization and baseline procedures, 56 women, 28 in each group, were analyzed at the 6 month visit. With the intention-to-treat analysis, the regression of disease was demonstrated in 84%

Rahangdale. 5-uorouracil for treatment of cervical intraepithelial neoplasia. Am J Obstet Gynecol 2014. (continued)

APRIL 2014 American Journal of Obstetrics & Gynecology

315

Research
TABLE

General Gynecology

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the use of the cream prior to completion because of anxiety. No woman became pregnant while using the 5-FU cream.
% 20.7 51.7 44.8 3.5 3.5 P value .74 .11 1.00 .10 .35

Self-reported characteristics of participants (continued)


5-FU Demographics Ever had an STD Nulliparous First abnormal Papanicolaou smear Prior history CIN 2 or CIN 3c Prior history cryotherapy or excision
a

Observation % 16.1 74.2 41.9 19.4 12.9 n 6 15 13 1 1

n 5 23 13 6 4

C OMMENT
In this randomized trial of clinical outcomes after the use of intravaginal 5-FU, we report a signicantly increased likelihood of histopathological regression of disease. We demonstrated that topical 5-FU dosed every 2 weeks was well tolerated by healthy women. The efcacy and acceptability of 5-FU in this dosing format has not previously been studied in this population and explores the possibility of a patient-controlled management option for CIN. Although excision and ablation are well-established standard-of-care procedures, the time has come for our eld to consider and study medical management options as alternatives for women who decline or cannot access surgical treatment.

CIN, cervical intraepithelial neoplasia; 5-FU, 5-uoruracil; HPV, human papillomavirus; STD, sexually transmitted disease. Asian (n 1), American Indian or Alaskan Native (n 1), unknown (n 3); b Age in years is represented by the median in the n column and the range in the % column; c One participant in the observation group unsure of a prior history of CIN 2 or 3.

Rahangdale. 5-uorouracil for treatment of cervical intraepithelial neoplasia. Am J Obstet Gynecol 2014.

of women (26 of 31) in the 5-FU group and 52% of women (15 of 29) in the observation group. A relative risk of 1.62 (95% condence interval [CI], 1.10e2.56) was observed, revealing that disease regressed in signicantly more women in the 5-FU group (P .01). Under the sensitivity analysis, the regression of disease was demonstrated in 93% of women (26 of 28) in the 5-FU group; 56% of women (15 of 27) were HPV negative in the 5-FU group vs 26% (7 of 27) in the observation group, a relative risk of 2.14 (95% CI, 1.07e5.37; P .05). We combined biopsy, Papanicolaou smear, and HPV data into 1 variable of normal, normal, and negative results, respectively. For the 6 month follow-up visit, 50% of the 5-FU group (14 of 28) had a documented normal biopsy, normal human papillomavirus smear, and negative HPV test vs 22% in the observation group (6 of 27) (relative risk, 2.25; 95% CI, 1.05e5.09; P < .05). Among 5-FU participants, 94% (29 of 31) completed an acceptability questionnaire and colposcopic exami-

nation after using a median of 4 doses (range, 4e8 doses) of the study drug. Most women had grossly normal examinations. Overall, 48% of women reported a side effect such as pain, bleeding, discharge, burning/itching/irritation, urinary concerns, or other concerns. The majority of women reported discharge and burning/itching/irritation as their chief concern. Despite 48% of patients reporting at least 1 side effect, 83% of participants (24 of 29) reported feeling overall satised with use of the 5-FU cream. Participants were asked whether any of the reported symptoms caused interference with any usual activities. No participant reported interference. Two women experienced vulvar irritation, which resolved within 2 weeks of stopping the cream. One of these women had a single ulceration and another had erythema on the vulva. Given the rare occurrence of such symptoms, investigators withdrew both women from further use of the cream. However, both reported that the symptoms did not interfere with daily activities. A third woman discontinued

CLINICAL IMPLICATIONS
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In this prospective randomized trial of 60 women, intravaginal 5-uoruracil was effective in promoting the regression of cervical intraepithelial neoplasia 2 in healthy women aged 18-29 years. Although caution must be taken to avoid pregnancy during use, intravaginal 5-uoruracil applied every 2 weeks was a safe and acceptable patient-controlled medical therapy. Although excision and ablation are well-established procedures, the time has come to consider and study medical management alternatives for young women.

316 American Journal of Obstetrics & Gynecology APRIL 2014