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 Table of Contents  
Year : 2021  |  Volume : 33  |  Issue : 1  |  Page : 27-31

To evaluate the efficacy and tolerability of topical 5% imiquimod in cases of oral leukoplakia: A pilot study

1 Department of Pharmacology, LTMMC Medical College and Hospital, Sion, Mumbai, Maharashtra, India
2 Department of Oral Medicine and Radiology, Dr. G D Pol Foundations YMT Dental College and Hospital, Kharghar, Mumbai, Maharashtra, India
3 Department of Public Health Dentistry, Dr. G D Pol Foundations YMT Dental College and Hospital, Kharghar, Mumbai, Maharashtra, India

Date of Submission16-Jul-2020
Date of Decision14-Jan-2021
Date of Acceptance18-Jan-2021
Date of Web Publication26-Mar-2021

Correspondence Address:
Dr. Bhakti Patilsoman
B 1502, The Orien, Opposite Navi Mumbai Police Headquarters, Roadpali - 410218, Navi Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jiaomr.jiaomr_147_20

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Background: Oral leukoplakia is a condition commonly associated with tobacco use. The literature also has documentation pertaining to likely cancerous transformation of leukoplakia. It is always a challenge to discover a therapeutic modality to prevent this transformation. Imiquimod is an immune response modifier possessing antiviral and anti-tumor activity which is being explored as an off label use in many cancerous conditions. Aim: To show any regression in oral leukoplakia and to test its safety and tolerability. Setting and Design: This is a randomized, open-label, single-centered clinical pilot study carried out with Imiquimod. Material and Methods: Two groups OPD of dental college with topical 5% Imiquimod and Topical Vitamin A (50,000 IU) were compared for their efficacy in the management of oral leukoplakia, pre- and post-treatment clinically and regression of oral dysplasia was observed histopathologically. Unit of improvement was noted for assessing the effectiveness of treatment. Statistical Analysis: Quantitative data were analyzed by Wilcoxon signed test. Results: Topical 5% Imiquimod application resulted in good clinical response +1, +2 unit of improvement with more regression of lesion noted in non-homogeneous leukoplakia and areas with less salivary contamination. Topical Imiquimod 5% is the best alternative to conservative management of moderate to severe dysplasia cases where we can offer more to the patient than just observation, and it is also better than a surgical option where surgery leads to more morbidity, in recurrent cases.

Keywords: Imiquimod, nonsurgical management, oral dysplasia

How to cite this article:
Mane S, Patilsoman B, Bhate P, Das D, Malusare P, Tomar N. To evaluate the efficacy and tolerability of topical 5% imiquimod in cases of oral leukoplakia: A pilot study. J Indian Acad Oral Med Radiol 2021;33:27-31

How to cite this URL:
Mane S, Patilsoman B, Bhate P, Das D, Malusare P, Tomar N. To evaluate the efficacy and tolerability of topical 5% imiquimod in cases of oral leukoplakia: A pilot study. J Indian Acad Oral Med Radiol [serial online] 2021 [cited 2021 Apr 18];33:27-31. Available from: https://www.jiaomr.in/text.asp?2021/33/1/27/312195

   Introduction Top

Potentially malignant disorders in recent years comprise a group of diseases, which should be diagnosed in the early stage. Oral leukoplakia, oral submucous fibrosis, oral erythroplakia, and lichenoid dysplasia are the most common oral mucosal diseases that have a very high malignant transformation rate.[1]

Literature reports that the malignant transformation of these lesions depends on the severity of epithelial dysplasia. The higher the dysplasia, the more are the chances of malignant transformation. Oral leukoplakia is a predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion. The treatment of oral leukoplakia comprises the elimination of the causative factor, which is usually the use of tobacco which may lead to regression of the lesion. When no cause can be found, or when the lesion does not disappear, it is necessary to proceed to other therapeutic procedures like surgical excision, cryosurgery, CO2-laser ablation, and non-surgical treatment modalities like carotenoids (β-carotene, lycopene), vitamins [L-ascorbic acid (vitamin C), α-tocoferol (vitamin E), retinoic acid (vitamin A), and fenretinide], and bleomycin have been tried.[1]

It is always a challenge to discover new therapeutic agents that can prevent the transformation of precancerous lesions into cancer, or even cause their regression. Imiquimod belongs to the family of synthetic small nucleotide-like molecules of imidazoquinolinamines. Each gram of the 5% cream contains 50 mg of imiquimod in an off-white oil-in-water vanishing cream base. It is an immune response modifier with potent antiviral and antitumor effects, which are mediated by Toll-like receptors (TLR7 and TLR8).[2]

Topical imiquimod cream 5% is effective to treat actinic keratoses, superficial basal cell carcinoma, and anogenital warts. Topical imiquimod is especially recommended to treat large clinically asymptomatic fields containing tumor cells “field cancerization,” which is prevalent in oral potentially malignant lesions.[3]

The dosing schedule and treatment duration are not standardized. The recommended schedule for superficial basal cell carcinoma in the USA and Europe is 5 times a week for 6 weeks with a success rate of 73–77%.[4] Whereas a case report in giant basal cell carcinoma treated with topical imiquimod 5% cream, 2–3 days/week for 12 weeks resulted in a complete clinical and pathological cure.[5],[6]

In our institute, a case of oral leukoplakia is administered topical vitamin A as a treatment modality, so we used the same as an active control. The present pilot study was conducted to test any regression of oral leukoplakia after application of topical 5% imiquimod cream three times a week for 6 weeks. The study also assessed the tolerability of topical imiquimod in these patients.

   Subjects and Methods Top

This is a randomized, open-label, single-centered clinical pilot study. The institutional review board of dental college and hospital, Navi Mumbai YMTDC SH/IEC Navi Mumbai (YMTDC SH/IEC/2018/34) approved the study.

All procedures followed were by the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1964. The inclusion criteria were all patients above 18 years of age, of either sex who were diagnosed to have oral leukoplakia after biopsy were enrolled. Patients with other comorbid conditions or major illness, pregnant, and lactating females, and refusing to give informed consent were excluded from the study. After screening 40 patients, finally, 30 patients fulfilling the study criteria were randomly allocated into two groups, having 15 patients in each. The cases of oral leukoplakia were confirmed by history, clinical examination, and histopathological examination performed by incisional biopsy of the lesion at the baseline visit. Being a pilot study we did not aim for a large sample size and a sample size of 30 was selected to make the randomized control trial pilot study, statistically sound. The patients were randomly allocated by picking up chits to two groups viz. Group I, Imiquimod 5% topical, and group II, Tablet Vitamin A (Aquasol) (50,000 IU) topical. The group I received topical 5% Imiquimod (Glenmark Pharmaceuticals India Pvt Ltd.) mixed with benzocaine jelly three times per week (in office) for 6 weeks. Group II received tablet Aquasol (50,000 IU) twice daily for 6 weeks topically at lesion and then swallow, which is a routine practice at our institute. The treatment was given for 6 weeks and followed up for 6 months. [Figure 1], [Figure 2], [Figure 3] The lesions which did not subside clinically were given three times application for over 3 weeks. Subjects were tested every week post initiation of treatment for 6 weeks and then once every month during follow-up for 6 months. Both the groups were counseled for tobacco and alcohol consumption cessation. The outcome was assessed clinically and histologically at the end of 6 weeks. The clinical aim response was tested by bi-dimensional measurement of the lesions and color photography and Van der Waals (OLEP)[7] staging of oral leukoplakia was used for quantifying clinical and histological change pre- and post-treatment. The assessments were recorded at every visit and follow-up. All the variables computed from the study, for example, the measurement of the size of the lesion before the treatment and after the treatment were recorded. The response was assessed as a unit of improvement. The patients were monitored for adverse effects by direct questioning and clinical examination at each visit. The tolerability was assessed based on the number of patients requiring discontinuation of imiquimod permanently or temporary discontinuation with successful reinstitution of the therapy. At the end of 6 weeks, the patient was asked to rate the overall experience of the treatment as excellent, good, and bad. After 6 weeks, patients were followed up every month for any evidence of recurrence till 6 months after completion of treatment.
Figure 1: Multiple areas of non homogenous leukoplakia

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Figure 2: Post treatment results after 3 weeks of Topical 5% Imiquimod application for 3 times/week

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Figure 3: Pretreatment & post treatment histopathology

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The efficacy parameters were analyzed for any statistically significant change from baseline to end of 6 weeks. Quantitative data were analyzed using Wilcoxon signed- rank test. P- value < 0.05 was considered as statistically significant.

   Results Top

The study enrolled 30 patients with 15 in each group, a group I: Topical imiquimod and group II: Topical Aquasol (vitamin A 50,000 IU) [Table 1]. All the patients were treated for 6 weeks with follow-up for a further six months. The unit of improvement + 1 was for 73.33% cases in group I and 53.33% in group II. + 2 units of improvement was seen in group I 6.66% cases. In Group I, there was no -1 unit of improvement which was noted in group II [Table 2] and [Table 3]. After statistical analysis, the P- value was 0.001 and significant for Group I and the P- value was 5.889 insignificant for group II [Table 4]. 6 patients in Group I reported burning sensation at the site of application and 1 patient developed flu- like symptoms with fever for whom the application was stopped for a week and continued later with no side effect. The burning sensation was moderate and is considered a sign of the effectiveness of the cream. 5 patients in Group II complained of stomach upset [Table 5].
Table 1: Distribution of age, gender, habits and leukoplakia according to site in each group

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Table 2: Staging of oral leukoplakia lesions in both groups before and after treatment

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Table 3: Overall improvement

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Table 4: Pre and post treatment comparison among two treatment groups

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Table 5: Adverse effects

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The tolerability for Group I, Topical Imiquimod was reported as excellent by 5 and good as 10 patients. Group II 14 patients reported tolerability of treatment as good and 1 as bad [Table 6]. It was observed that cases of non-homogenous leukoplakia with erythematous component showed a good response in the first two applications, mostly because of increased absorption of the cream from the site. Lesions at the site where salivary contact was less also showed faster recovery. It was observed that more contact time with the lesion is desired for the imiquimod cream action.
Table 6: Tolerability of treatment

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   Discussion Top

Most of the oral cancers are preceded by potentially malignant lesions, which may appear as white or red patches on the oral mucosa. Histological grading of oral epithelial dysplasia remains the only determinant for confirmation of the potential malignant change.[8] Oral dysplasia grading ranges from mild which shows few cytological abnormalities involving only the lower third of the epithelium to severe, which shows significant cytological atypia extending into the involved upper third of the epithelium, which may later involve the full thickness of the epithelium designated as carcinoma in situ. treatment at an early stage is the key to a better prognosis.[9] Surgical excision though is being a gold standard treatment modality for premalignant lesions,[10] it is an invasive procedure and is followed by disabilities, recurrence up to 35%[11] and does not eliminate the risk.[7],[12],[13]

An experimental study testing 5% imiquimod cream application to dysplastic lesions in wistar rats for 16 weeks demonstrated the regression of mild dysplasia to hyperplasia for all the samples. In one case, a well-differentiated squamous cell carcinoma was converted to a papilloma-like squamous neoplasm with a benign morphology. These findings were indicative that imiquimod may be effective in the treatment of precancerous lesions of the oral mucosa and thus inhibit the progress of carcinogenesis.[2] Imiquimod's small size (Mr = 240.3) and hydrophobicity allow it to penetrate the epidermal barrier and its use as a topical agent.

Mullin et al. reported treatment of oral dysplasia on the soft palate with 5% imiquimod cream for 6 weeks with a cover plate and observed the disappearance of dysplasia post treatment. They emphasized the need for the development of preparation suitable for the oral mucosa.[14]

Wester A et al.[15] reported robust clinical improvement with the use of 5% topical imiquimod in the management of recurrent oral squamous cell carcinoma.

A study by Martinez et al. showed that proliferative verrucous leukoplakia can be successfully treated with 5% topical imiquimod which is well tolerated by the patient with mild side-effects, with no mutilating consequences, and with probably fewer recurrences than surgery.[16]

Another study also found topical Imiquimod 5% cream an effective option to treat primary small (<2 cm) superficial basal cell carcinoma (sBCC).[6]

As with all drugs, side effects may occur when using imiquimod and the severity of the effect is dose-dependent. The most common side effect is application site reaction, such as itching, burning, bleeding, stinging, pain, induration, tenderness, and irritation. Other side effects include upper respiratory tract infection, sinusitis, and headache.[17]

There is no published pharmacokinetic data on the mucosal application of imiquimod. But concerns with the direct application of drugs in the oral cavity are saliva in association with swallowing, chewing, and phonation washes away most of the drug from the site of application, resulting in a short retention time of the dosage forms and, low therapeutic efficacy.[18] Also, the unpleasant taste and texture of the drug in the mouth reduces patient compliance, and saliva and swallowing washes away most of the drug from the site of application resulting in low therapeutic effects. The development of a new formulation for topical imiquimod drug delivery within the oral cavity would help use this drug to its maximum therapeutic potential.

A high proportion of participants with good response rates to topical treatment (58–92%) experienced local side effects such as itching and burning, less commonly erosion and ulceration, but the proportion of participants ceasing treatment has not been high. To date, one long-term study shows a treatment success rate of 78–81% and that initial response is a predictor of long-term outcome. Recurrences occur within the first year after treatment.[19] The most common adverse effects of imiquimod encountered when used to treat basal cell carcinoma included tumor site reactions (erythema, scaling, ulceration) and flu-like symptoms.[20] In our study, only one patient developed flulike symptoms on Imiquimod application which subsided on stoppage of drug and showed maximum changes in the lesion in first two application supporting hypothesis that greater imiquimod penetration and changes in body cytokine level higher therapeutic effect is obtained. Imiquimod has the added benefit of a self-application topical therapy which tends to be preferred by the patients, thus reducing the number of hospital visits. Also in patients, who have failed to respond to other therapeutic modalities or who have had a recurrence following standard therapy, or who are medically unfit for surgery, imiquimod may be beneficial. However, a close follow-up is mandatory.[21]

Limitations and future prospects

The limitation of our study is that it did not explore more sophisticated cellular markers of dysplasia.

Further studies for the optimal dosing and long- term outcomes of imiquimod treatment for dysplasia management and efforts to develop a mucoadhesive agent with Imiquimod should be tried to take advantage of its high therapeutic effect.

   Conclusion Top

Our study concludes that 5% topical Imiquimod holds a promise in the management of oral potentially malignant disorders. It is the best alternative to conservative management of moderate to severe dysplasia cases where we can offer more to the patient than just observation, and it's also better than a surgical option where surgery leads to more morbidity.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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Yardimci G, Kutlubay Z, Engin B, Tuzun Y. Precancerous lesions of oral mucosa. World J Clin Cases 2014;2:866-72.  Back to cited text no. 1
Gkoulioni V, Eleftheriadou A, Yiotakis I, Ferekidou E, Chrisovergis A, Lazaris ACh, et al. The efficacy of imiquimod on dysplastic lesions of the oral mucosa: An experimental model. Anticancer Res 2010;30:2891-6.  Back to cited text no. 2
Kemény L, Nagy N. New perspective in immunotherapy: Local imquimodtreatment. Orv Hetil 2010;151:774-83.  Back to cited text no. 3
Schulze HJ, Cribier B, Requena L, Reifenberger J, Ferrándiz C, Garcia Diez A, et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: Results from a randomized vehicle-controlled phase III study in Europe. Br J Dermatol 2005;152:939-47.  Back to cited text no. 4
Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: Results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 2004;50:722-33.  Back to cited text no. 5
Chun-Guang M, Qi-Man L, Yu-Yun ZH, Li-Hua Ch, Cheng T, Jian-De H. Successful treatment of giant basal cell carcinoma with topical imiquimod 5% cream with long term follow-up. Indian J Dermatol 2014;59:575-8.  Back to cited text no. 6
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Wester A, Eyler J, swan J.Topical Imiquimod for the pallaitive traetment of recurrent oral sqaumous cell carcinoma. JAAD Case Reports 2017;3:329-31.  Back to cited text no. 15
Martinez-Lopez A, Blasco-Morente G, Perez-Lopez I, Naranjo-Diaz MJ, Aneiros-Fernandez J, Ruiz-Villaverde R, Tercedor-Sanchez J. Successful treatment of proliferative verrucous leukoplakia with 5% topical imiquimod. Dermatologic therapy. 2016 Sep 20;30 (2).  Back to cited text no. 16
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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