Table 1.
Summary of Topical Therapies for the treatment of Cervical Intraepithelial Neoplasia (CIN) 2/3.
| Study | Study Type | Dysplasia | Regimen | Sample Size | Diagnostic Testing | Findings |
|---|---|---|---|---|---|---|
| IMMUNE MODULATORS | ||||||
| Imiquimod | ||||||
| Lin 2012 | Prospective Cohort | CIN or VAIN | Twice weekly for 12 doses | 72 | Histology 6 months post-treatment | 51.4% with histological regression while 8.3% had progressive histology |
| Grimm 2012 | RCT | CIN 2/3 | Titrating 1–3 vaginal suppositories over 16 weeks | 24(per group) | 4 quadrant colposcopic-guided biopsies at 20 weeks | 73% regression to low grade or normal vs. 39% in the placebo group |
| Diaz-Arrastia 2001 | Prospective Case series | HSIL of vulvar, vagina or cervix | Application three times weekly for 6–16 weeks | 8(2 cervical dysplasia) | Histology by 1 month | 50% with complete resolution, 25% with regression to low grade |
| (Chen, 2013) | Retrospective case series | CIN or VAIN already treated with surgery | Twice weekly for 8 weeks | 76 | Repeat cytology/HPV 3 mos. after treatment | 76.3% with normal pap smear. No histology performed. |
| Pachman 2012 | RCT | CIN 2/3, recur or pers CIN I | 1 packet every 4 days for 5 application then ablative vs. excisional therapy | 56 | Cytology +/- histology at 4 mos then q4-6 mos. Endpoint: persis/recur CIN by 2 years | No difference dysplasia (CIN2/3 or recurrent CIN with same HPV type) between 2 groups (25% vs. 21% in control) |
| Trans retinoic Acid | ||||||
| Weiner 1986 | Prospective cohort | Mild, mod, sev dysplasia | Daily for 4 days; 2 different concentration cohorts | 42 | Histology at 5 – 18 months | 14% (2/14) and 45% (10/22) with resolution in the low and high concentration |
| Meyskens 1983 | Phase I prospective cohort | Mild or mod CIN | Escalating doses of TRA for 4 consecutive days | 35 | Clinical and colposcopic examination of side effects | No systemic effects, mild cervical inflammation at higher doses, high vaginal toxicity at 0.484% |
| Graham 1986 | Phase II prospective cohort | Mild, mod, sev dysplasia | Cervical cap for 4 days then 2-days every 3 months for one year | 25 | Cytology and Histology | 50% (10/20) histologic and cytologic repression regression of disease |
| DiSilvestro 2001 | Prospective cohort | CIN 2/3 | Gel on sponge inside cervical cap for 4, 8 or 14 days | 52 | Colposcopic directed histology 90 days after treatment | 46.9% regression. 53.1% with no change. |
| ªChen 1994 | RCT | NR | Once daily for 50 days | NR | 74.3% regression after two-courses of treatment | |
| Surwit 1982 | Prospective Cohort | CIN 2/3 | Daily applications for 4 days | 18 | Conization of cervix 4 weeks post- treatment | Reduced lesion size in 33% and complete regression in 11% |
| Meyskens 1994 | Phase III RCT | CIN 2/3 | Cervical sponge daily for 4 days then 2 days at 3 and 6 mos. | 301 | Cytology and colposcopic guided histology at 15 months | Histologic resolution in 43% vs. 27% in CIN 2 placebo group. No difference in the CIN3 group. |
| Ruffin 2004 | Prospective cohort | CIN 2/3 | 4 doses daily at different dosages | 175 | Histology at 12 weeks | Response to therapy not statistically significant in all 4 dose groups |
| Interferon | ||||||
| Krause 1987 | Prospective Cohort | CIN 3 | Interferon gel in vaginal cup for 4 consecutive weeks | 9 | Conization after 4 weeks | 22% (2/9) with complete resolution |
| Moller 1983 | Prospective Cohort | CIN 2/3, CIS | Interferon gel via cervical cap2 times per week for 6 weeks | 6 | Histology at 6 and 12 wks | 50% (3/6) with “light dysplasia” |
| Schneider 1995 | Phase II RCT | CIN 2/3 | 3 concentrations of interferon gel for 28 days via diaphragm | 33(24 therapy vs 9 laser) | Cytology and histology with HPV typing after 6 months | 42% (10/24) vs 89% (8/9) with resolution and 42% (10/24) vs 11% (1/9) with regression |
| Yliskoski 1990 | RCT | CIN or VAIN | Vaginal gelnightly for 2 weeks, multiple courses over 1 year | 19(9 interferon vs 10 placebo) | HPV genotyping at 16 months | 67% (6/9) HPV negative |
| Choo 1985 | Prospective cohort | Mod, sev dysplasia, CIS | Twice daily application of gel via vaginal applicator | 7 patients | Colposcopy – no histology | 28% (2/7) resolution, 43% (3/7) regression and 28% (2/7) with no response on colposcopy |
| Granulocyte-macrophage colony stimulation factor (GM-CSF) | ||||||
| Hubert 2010 | RCT | CIN 1 | Gel applied every 3 days for 4 doses with applicator | 26 (15 CIN 1 and 11 controls) | Plasma HPV viral load and histology at 26–30 months | Decreased HPV viral load; no clinical response based on histology. |
| ANTIPROLIVERATIVE | ||||||
| 5-Fluorouracil (5FU) | ||||||
| Maiman 1999 | RCT | CIN 2/3 | Cream applied once every 2 weeks for 6 months after excision | 101 (50 therapy and 51 controls) | Histology at up to 18 mos | 28% (14/50) vs. 47% (24/51) with recurrent CIN 2/3 |
| (Barten, 1987) | Prospective Cohort | CIN 1,3 | Cervical cap daily for 7 days | 10 | Histology at 6–12 mos | 20% (2/10) resolution, 40% (4/10) with regression to CIN1, and 40% (4/10) with persistent CIN1/CIS |
| Sillman 1981 | Prospective cohort | Vulvar, vaginal,cervical mod, sev dysplasia | Cream applied nightly for 2 weeks then once monthly | 16 | Histology | 100% (16/16) with resolution |
| Rahangdale 2014 | RCT | CIN 2 | Cream every 2 weeks for 16 weeks | 60 (31 treatment vs 29 placeb0) | Histology at 6 months | 93% (26/28) vs. 56% (15/27) with regression |
| Pride 1982 | Prospective Cohort | Vaginal/Cervical dysplasia | Nightly for 10 nights via diaphragm | 11 | Conization or hysterectomy | 55% (6/11) with resolution |
| Sidhu 1997 | RCT | CIN 1/2 | Bio-adhesive film using applicator | 104 (51 with therapy vs 53 with placebo | Histology at 6 months | 67% (32/48) and 72% (33/46) regression or resolution in the treatment and placebo group. |
| Cisplatin | ||||||
| ªNakayama 1992 | Prospective cohort | mild/mod/sev and “microinvasive ca” | Daily placement via gauze tampon for 10 days. | 12 | Histology at day 10 | 100% with resolution in CIN group (10/10) and 50% (1/2) regression in microinvasive ca group |
| Iodosteric Acid | ||||||
| †Gleeson 1992 | RCT | CIN 2/3 | Application with pessary vs. placebo for 30 nights | NR | Histology at 30 days | No clinically significant difference in the 2 groups |
| ANTIVIRALS | ||||||
| Cidofovir | ||||||
| VanPachterbeke 2009 | RCT | CIN 2,3 | Gel via cervical cap once 6 weeks prior to conization | 48 (23 treatment vs 25 placebo) | Conization | 61% (14/23) cidofovir vs 20% (5/25) placebo with resolution |
| Snoeck 2000 | Prospective Cohort | CIN 3 | Gel applied every other day for 3 applications | 15 | Histology within 1 month | 47% 7/15 with resolution, 7% (1/15) with regression to CIN I, 33% (5/15) with persistent CIN 2/3 |
| Bossens 2018 | Prospective cohort | CIN 2,3 | Gel applied once per week for 3 weeks for 5 or 10 h | 9 | N/A | No clinically significant adverse events |
| Lopinavir and Ritonavir | ||||||
| Hampson 2016 | Prospective Cohort study | HSIL | Vaginal pessary twice daily for 2 weeks | 23 | Cytology at 12 weeks | 63.6% with no dysplasia, 18.2% with low grade |
| Vidarabine | ||||||
| †Okamoto 1999 | Cohort study | CIN I and 2 | Vidarabine ointment and/or podophyllin | 21 | Cytology and Histology | 81% (17/21) with regression |
| Niwa 2003 | Cohort study | CIN and Stage IA1 cervical cancer | Regimen not described | 30 | HPV typing by PCR | 10% (1/10) with resolution of HPV infection |
| Terameprocol | ||||||
| Khanna 2007 | Phase I/II clinical trial | CIN 1 and 2/3 | Direct cervical application once weekly for 3 weeks | 7 | N/A | No serious adverse events noted |
| HORMONALS | ||||||
| Progesterone | ||||||
| Hefler 2010 | Phase II clinical trial | CIN 1 | 10 days month for 6 months | 40 | Cytology and histology | 30% regression vs 38.3% in the placebo |
| Dehydroepiandrosterone (DHEA) | ||||||
| Suh-Burgmann 2003 | Prospective Cohort study | LSIL | Daily for up to 6 months | 12 | Histology | 83% (10/13) with no dysplasia |
| HERBAL AND ALTERNATIVE REMEDIES | ||||||
| Alternative Remedies | ||||||
| Joshi 2011 | Prospective cohort | LSIL | Capsules twice daily for 12 weeks | 21 | Histology | 76% (16/21) with resolution to normal and 19% (3/21) unchanged. |
| Ahn 2003 | RCT | Cervicitis, CIN 1, 2 and 3 | 4 groups (1 topical). Ointment twice weekly for 12 weeks | 27 (topical group) | Histology | 74% (20/27) topical vs. 10% (4/39) control with regression |
| Ashrafian 2015 | RCT | CIN 1 and 2 | 3 groups (high dose, low dose, placebo) daily application for 180 days | 25 high dose vs 24 low dose vs 23 placebo | Histology | 100%, 90.5% and 61% regression in high dose, low dose and placebo |
| Shukla 2009 | RCT | HPV 16 infection +/- LSIL | Praneem tablet vaginally daily for 30 days | 20 (10 treatment vs 10 placebo) | HPV 16 PCR | Elimination of HPV 16 in 60% (6/10) |
| Swanick 2009 | Case Report | CIN 2/3 | Escharotic treatment 2x/weekly for 5 weeks | 1 | Cytology and colposcopy | NILM pap smear at 4 and 10 mos and satisfactory colposcopy at 10 mos |
| Valencia 2011 | Prospective Cohort | LSIL cytology | Oral or topical spray for 8 weeks minimum. | 62 | Treatment until improvement per cytology and colposcopy | Improvement in colposcopic appearance in 74% at 12 weeks |
| Laccetta 2015 | Prospective Cohort | ASCUS or LSIL cytology | Two cycles of daily application for 20 days | 356 (176 treatment vs 180 placebo) | Cytology and Colposcopic evaluation at 6 and 12 mos. | 83.5% vs. 60% of controls with negative pap smear. 55.4% vs. 24.7% of controls with no colpo lesions |
| Stentella 2017 | Retrospective case-control | CIN 1/2 | Carbodymethyl beta-glucan gel | 999 | Cytology, histology, colposcopic changes | Nonsignificant regression of CIN 2 |
| Stefani 2014 | Prospective Cohort | CIN 1 | Bovine colostrum containing vaginal tablets | 256 | Histology at 6 months | 75.5% regression |
| †Bottino 1991 | RCT | NR | Cream applied vaginally | 40 in dysplasia group | NR | 70% (28/40) efficacy in dysplasia patients |
ªIn these studies, only an abstract was available in English.
†In these studies, only an abstract was available for review.
RCT = randomized controlled trial; CIN = Cervical Intraepithelial Neoplasia, VAIN = Vaginal intraepithelial neoplasia, HSIL = High grade intraepithelial lesion, LSIL = Low grade intraepithelial lesion, CIS = carcinoma in situ, ASCUS = atypical squamous cells or unknown significance, mos = months, ca = carcinoma, NR = not reported.