Low Dose 5-Fluorouracil Intravaginal Therapy for the Treatment of Cervical Intraepithelial Neoplasia 2/3: A Case Series

Introduction

Guidelines from the United States recommend surgical treatment—a loop electrosurgical excision procedure (LEEP), cryotherapy, or cold-knife conization—for cervical intraepithelial neoplasia (CIN) 2/3. ¹ A 6-month observation timeperiod is preferentially recommended for young women (defined as women in whom the risks of adverse pregnancy outcomes outweigh the risk of cancer) with CIN 2 and are “acceptable” for management of CIN 3. ¹ Despite the success of excisional treatments and low risk of complications, women undergoing excisional procedures carry a two- threefold increased risk of preterm delivery, compared with women without excision histories. ² Women can experience psychologic distress and bleeding associated with invasive procedures. ³ There also are significant individual and infrastructure costs associated with treatment of high risk human papilloma virus (hrHPV)–related disease.^4,5

There are no recommendations for medical management of CIN 2/3. 5-Fluorouracil (5-FU), which prevents DNA replication, is used widely to treat a variety of malignancies, including HPV-associated head and neck cancers.^6,7 Topical 5-FU is used off-label for treatment of preinvasive vulvar and vaginal cancer.^8–10 Data from observational studies and clinical trials have demonstrated efficacy and tolerability for treatment of vulvar, vaginal, and cervical precancers, as well for as genital warts.^8–12 Previously, treatment with intravaginal 5-FU was limited by side-effects, including burning, erythema, erosion, and pain, because treatment regimens required frequent applications. ¹³ Limiting applications to once every 2 weeks dosing or decreasing the concentration has produced improved tolerance.^11,12,14

Materials and Methods

This retrospective case series included 25 women who received 5% 5-FU (Efudex, Valeant Pharmaceuticals) intravaginal treatment at a U.S. academic medical center between January 1, 2014, and July 30, 2018. Women with histologically confirmed CIN 2/3 were counseled regarding guideline-based recommendations, including repeat colposcopy at 6 months or surgical treatment. Women who declined these options, requested medical therapies, or had delays before surgical treatment were offered off-label medical management with 5-FU.

The women were instructed on how to self-apply 8-doses of intravaginal 5-FU every 2 weeks over 16 weeks. ¹¹ The women were also counseled regarding the risks of 5-FU therapy, including genitourinary side-effects and teratogenic potential. These patients were also required to use dual contraception (condoms plus another method) and were scheduled for a visit after 3–4 doses to assess tolerance. Follow-up for each patient included a Papanicolaou smear and colposcopy with biopsy at 6 and 12 months after the initial diagnosis. Demographic information and medical outcomes were reported, based on a retrospective chart review that was approved by the institutional review board of the University of North Carolina at Chapel Hill, NC.

Results

Twenty-five women with histologically confirmed CIN 2/3 were included in the case series. The median age was 28 (range: 24–44), and 64% of these women were nulliparous (Table 1). Two (8%) of the women had a known human immunodeficiency virus/acquired immunodeficiency syndrome diagnosis. The women's reasons for pursuing medical management are summarized in Table 1; most (80%) sought an alternative to surgical treatment. Often, these women wanted to avoid an excisional procedure (56%). while others had previous loop electrosurgical excision procedures (LEEPs) and did not want another (24%; primary therapy). Three women (12%) had residual disease detected at their LEEP surgical margins and opted for medical management to reduce their risk of persistent or recurrent disease (adjuvant therapy). Two women (8%) started 5-FU intravaginal therapy while awaiting immune-status improvement to undergo surgical excision (neoadjuvant therapy) safely.

Within the 12-month follow-up timeperiod, 16 of the women(64%) avoided initial or further surgical therapy by having regression to CIN 1 or normal histology status. Seven of the participants underwent a LEEP within this 12-month timeperiod, while 1 woman opted for cryoablation. Among the 7/8 women who required surgical intervention for CIN 2/3, all reported completing 4 or fewer of the 8 recommended doses of 5-FU. Notably, both of the women in whom surgical treatment was contraindicated due to immunosuppression experienced regression of their cervical dysplasia after initiation of antiretroviral therapy.

Most women tolerated intravaginal 5-FU therapy. Two women had severe allergic reactions (swelling in the hands and extremities) after the first dose. One of these women continued 5-FU therapy against medical advice and developed hives after 4 doses. Three women reported local genital side-effects (all of which resolved within 1 week) and discontinued their treatment course, based on the recommendation of the provider. In sum, a total of 6 women discontinued 5-FU treatment: 2 due to allergy; 3 due to self-resolving local side-effects; and 1 due to a desire to stop contraception (Table 1).

Discussion

This case series represents a clinical setting in which 5-FU was offered to women in the course of their routine care for CIN 2/3 and provides encouraging data to support further study of 5-FU or other medical therapies for treatment of CIN 2/3. The series highlights patient ability for self-treatment and patient interest in nonsurgical alternatives for management of CIN 2/3. Approximately two-thirds of the women in this case series were able avoid LEEP, which was their desired outcome. Adverse events were limited and without long-term morbidity. There were also women who used this regimen as neoadjuvant therapy in order to delay a primary surgical procedure. Rather than no or delayed treatment, it was possible to initiate immediate medical therapy to these high-risk patients.

Intravaginal therapy with 5-FU has been limited due to concerns about side-effects and comparisons with the efficacy of surgical therapy. ¹⁵ This treatment regimen was based on 2 prior randomized clinical trials in women with CIN. Maiman et al., studied the use of intravaginal 5-FU after surgical treatment for CIN 2/3 in HIV-infected women (adjuvant therapy). ¹² Women treated with 5-FU were less likely to develop a CIN 2/3 recurrence than women in the observation arm, p = 0.014). ¹² Rahangdale et al used a similar dose schedule over 16 weeks in women with CIN 2 (primary therapy). The composite outcome of histology, Papanicolaou smear, and hrHPV results was more likely to be normal in the 5-FU group than in the observation group (relative risk: 2.25; 95% confidence interval: 1.05–5.09). ¹¹ Most women in this setting tolerated this regimen.

As a case-series, this study was limited by its sample size and retrospective design. Adherence to the regimen was based on patient recall and was subject to desirability bias, although it is notable that most of the treatment failures involved patients who utilized less than half of the recommend doses of 5-FU. This study might also be limited by selection bias in that a limited number of women could access intravaginal 5-FU, as the users were cared for by a single provider or were motivated women who sought out medical therapy.

Conclusions

Although excisional procedures are “gold standard,” further research into medical options for management of CIN is needed. The cost, infrastructure requirements, and need for skilled providers limits access to excisional therapy, particularly in low-resource and rural settings. A single LEEP is associated with an increased risk of preterm birth.^16,17 The current study shows that there is patient interest in alternatives to conventional management of CIN. Neoadjuvant topical therapy (prior to surgical therapy) could be useful for immediate self-treatment for CIN 2/3 to decrease lesion size or while awaiting surgical procedures in settings of treatment delay. Adjuvant therapy (after surgical therapy) could potentially treat residual disease associated with positive margin status or decrease risk of recurrent CIN 2/3. Given these implications, the use of intravaginal therapies for treatment of CIN 2/3 merits further study as a patient-centered approach to enhance cervical cancer prevention in larger prospective studies.