The aim of this paper was to assess the nonsurgical treatment of oral leukoplakia (OL). A medline search from 1983 to 2009 was conducted. The topical or systemic nonsurgical treatments or combination of both was reviewed. The primary outcomes of interest were clinical resolution, malignant transformation, follow-up, and recurrence of OL. Studies showed a rate higher than 50% of clinical resolution with photodynamic therapy, beta-carotene, lycopene, or vitamin A. Few studies reported rates of recurrence from 5 to 67% and of malignant transformation from 8 to 23%. There is a lack of randomized clinical trials that assess the effectiveness of nonsurgical treatment of OL. At this time, randomized controlled trials for nonsurgical treatment of OL demonstrate no evidence of effective treatment in preventing malignant transformation and recurrence. It reinforces that even after clinical resolution, OL should be regularly followed.
Oral leukoplakia (OL) is a premalignant lesion described as “a predominant white lesion of the oral mucosa which cannot be defined as any other known lesion” [
OL’s etiopathogenesis encompasses two broad categories, as follows: OL of unknown etiology or idiophatic and OL associated with tobacco use [
OL located on the floor of the mouth, soft palate, and tongue are considered as high-risk lesions, while, in other areas, they may be considered as of low malignancy risk [
Gender: female patients tend to present a higher risk of developing the malignant form [
A long-time OL lesion: OL resistant to the treatments and what persist for long time may have worse prognosis than recent [
OL in sites of high risk: lesions in the floor of mouth, ventrolateral tongue and soft palate have a high risk of malignant transformation [
OL among nonsmokers (idiopathic): nonsmokers with OL have an increased rate of malignant transformation in relation to OL in smokers [
Nonhomogenous OL-type: nonhomogenous OL lesions have a mixed color of white and red alterations, and an exophytic, papillary, or verrucous aspect; regardless of treatment, they exhibit a high recurrence rate and often eventually transformation to squamous cell carcinoma [
Epithelial dysplasia: OL with moderate and severe dysplastic lesions had a significantly higher risk of developing a squamous cell carcinoma than OL without epithelial dysplasia or with mild epithelial dysplasia [
In order to conduct treatment for OL, the degree of epithelial dysplasia may be assessed. In the presence of moderate or severe epithelial dysplasia, surgical treatment is recommended [
Nonsurgical treatment may also be considered for the management of OL [
The purpose of this paper is to present the current nonsurgical treatment options for OL. A Medline from 1983 to 2009 search was conducted using the following keywords: nonsurgical treatments of OL, retinoids, carotenoids, lycopene, photodynamic therapy. We included 21 studies of patients with diagnosis of OL. The primary outcomes of interest were clinical resolution, follow-up, and when reported, malignant transformation and recurrence. The topical or systemic nonsurgical treatments or combination of both were reviewed. Furthermore, the mechanisms of action, biodisponibility, toxicity, and side effects of these treatments were analyzed. Table
Nonsurgical treatments options for oral leukoplakia.
Author | Therapy | Dose | Number of patients | Clinical resolution (%) | Follow-up (months) | Recurrence | Malignant transformation (%) |
---|---|---|---|---|---|---|---|
Benner et al. [ | Systemic Alfa tocoferol | 400 IU | 43 | 20% | 24 | NR | NR |
Garewal et al. [ | Systemic Beta-carotene | 30 mg/day | 24 | 8% | 6 | NR | 8% |
Toma et al. [ | Systemic Beta-carotene | 90 mg/day | 23 | 26% | 7 | 5% | NR |
Sankaranarayanan et al. [ | Systemic Beta-carotene | 360 mg | 46 | 54% | 12 | 5% | NR |
Liede et al. [ | Systemic Beta-carotene | 20 mg/day | 24 | NR | 60–84 | NR | NR |
Garewal et al. [ | Systemic Beta-carotene | 60 mg/day | 50 | 4% | 18 | 17% | 8% |
Sankaranarayanan et al. [ | Systemic Isotretinoin | 300.000 IU | 42 | 52% | 12 | 67% | NR |
Stich et al. [ | Systemic Vitamin A | 200.000–300.000 IU | 21 | 57% | 12 | NR | NR |
Nagao et al. [ | Systemic Lycopene | NR | 48 | NR | NR | NR | NR |
Singh et al. [ | Systemic Lycopene | 4–8 mg | 58 | 25-55% | 3 | NR | NR |
Hammersley et al. [ | Topical Bleomycin | 0,5% | 8 | NR | 12 | NR | NR |
Epstein et al. [ | Topical Bleomycin | 1% | 19 | 32% | 40 | NR | 11% |
Shah et al. [ | Topical Vitamin A | 1–5 mg | 11 | 27% | 11 | 18% | NR |
Epstein and Gorsky [ | Topical Tretinoin | 0,05% gel | 26 | 27% | 42 | 40% | NR |
Piattelli et al. [ | Topical Isotretinoin | 1% | 10 | 10% | 48 | NR | NR |
Lippman et al. [ | Systemic 4 HPR | 200 mg/day | 35 | 0 | 9 | NR | 23% |
Tradati et al. [ | Topical 4 HPR | NR | 8 | 25% | NR | NR | NR |
Kübler et al. (1998) | Topical PDT | ALA 20% | 20 | 25% | 3 | NR | NR |
Siéron et al. [ | Topical PDT | ALA 10% | 5 | 80% | 6 | 20% | NR |
Siero | Topical PDT | ALA 10% | 12 | 83% | 6 | 8% | NR |
Chen et al. [ | Systemic PDT | ALA | 24 | 33% | NR | NR | NR |
IU: International Unit; NR: not reported; 4 HPR: Fenretinide; PDT: Photodynamic therapy; ALA: Aminolevulenic acid.
The carotenoids are a group of extremely hydrophobic molecules with little or no solubility in water [
The use of beta-carotene has been recommended in order to prevent OL and possibly oral cancer [
In another study, 23 patients with OL were treated with beta-carotene, in oral doses of 90 mg/day, for three cycles of 3 months each. Of 18 patients who completed the study, 6 (33.3%) showed complete clinical response. No significant clinical signs of toxicity were detected in any of the patients [
Twenty-four patients with OL were employed in another study with beta-carotene employed at a dose of 30 mg/day for six months. Only 2 patients (8.3%) presented a complete clinical response and 15 patients (62.5%) had partial clinical response [
In the revised studies, the percentage of patients with clinical resolution ranged from 4% to 54%, with dosages regimes from 20 to 90 mg/day of beta-carotene in time periods from 3 to 12 months (Table
Lycopene is a carotenoid without provitamin A action. This is a fat-soluble red pigment found in some fruit and vegetables. The greatest known source of licopene is tomatoes, which are widely employed in cooking [
Consumed carotenoids are incorporated in lipidic micelles and are absorbed by enteric mucosa through passive diffusion and distributed to the organs by the plasmatic lipoproteins. Lycopene release from the food matrix, presence of fat in the diet, and heat-induced isomerization from trans to cis mode are some factors influencing lycopene absortion and biodisponibility [
Lycopene is better absorbed in oil resin capsules and in tomato juice than in the form of raw tomatoes [
Singh et al. [
No systemic significant toxical effect of lycopene has been observed and there is no evidence of side effects from the treatment with lycopene [
Factors influencing the uptake of lycopene in the diet, including the way it interacts with other carotenoids.
Human metabolism and the possible function of the metabolites and cis-trans isomers.
Mechanisms of the direct or indirect modulation of cancer.
Studies based on evidences of treatment in human beings.
Mechanisms of lycopene deposition in human tissues.
Lycopene effects in the immunological system.
Only one study evaluated lycopene in clinical resolution of OL. The time period was three months, the dosages regimes from 4 mg/day and 8 mg/day and patients had clinical resolution 25 and 55%, respectively (Table
L-ascorbic acid (L-AA), the so-called vitamin C, is found in citrous fruits such as kiwi, strawberries, papaya, and mango [
L-AA has antioxidizing properties and reacts with superoxide produced as a result of the cells’ normal metabolic processes; this inactivation of superoxide inhibits the formation of nitrosamines during protein digestion and helps avoid damage to DNA and cellular proteins [
The ability of L-AA to maintain oral mucosa integrity is very little documented. One study examined the presence of oral mucosal lesions in subjects with low L-AA levels in plasma, compared to controls. Subjects with low plasma L-AA levels
In another study [
There are no studies regarding the efficacy of the use of L-AA alone for OL treatment.
Benner et al. [
Seventy-nine patients with OL were enrolled in an antioxidant supplementation program that consisted of 30 mg of beta-carotene, 1000 mg of L-AA, and 800 IU of AT per day, which were taken for 9 months. No side effects were noticed during the course of the study. Although no patients showed complete resolution of the OL, 55.7% showed reduction in the size of the OL after 9 months. Clinical improvement was observed in 90% of the patients who had reduced risk factors, compared with 48.8% of improvement in those who did not. Squamous cell carcinoma developed in seven patients (8.9%) within the preexisting OL during or shortly after completion of the study [
Some studies evaluated the administration of AT, alone or combined, used the dosage of 800 IU/day from 6 to 9 months (Table
The current definition of retinoid includes all the natural and synthetic compounds with an activity similar to that of Vitamin A. Vitamin A exists in the human body as various interconvertible compounds, notably retinal (essential for vision) and retinol, which is the most potent analogue and the main form of storage and transportation [
Topic retinoids were initially tested against diseases related to keratinization. 13-cRA was used for the first time against acne, in 1969. The so-called “retinoic dermatitis” is the main side effect of tretinoin, this leads to cutaneous irritation characterized by erythema, scaling, ardency, and/or pruritus. “Retinoic dermatitis” occurs frequently, and patients ought to be previously instructed with regard to its occurrence. Furthermore, patients should also be warned to avoid the sunlight and to wear sunscreen [
The use of systemic retinoids is not indicated in cases of (
Supplementation with retinoids for OL treatment began in the 1960s. However, this treatment was not widely accepted due to its side effects—hypervitaminosis, toxicity, teratogenic effects, and alterations in various organic systems [
13-cRA is the retinoid recommended for OL treatment. The use of 13-cRA has been shown to be effective in resolving OL [
Kaugars et al. [
In another study, 13-cRA was used in 16 patients with OL for six months. Three patients were entered at a dosage of 3 mg/day, eight at 5 mg/day, and five at 10 mg/day. Eleven patients completed the study: 3 had complete clinical responses (2 at 10 mg/day and 1 at 5 mg/day). Recurrence was observed in two of these three patients [
During another study, patients with OL were distributed into two groups: one receiving 200.000 IU vitamin A per week (
In a study by Toma et al. [
One study, in two phases, was made in 70 patients with OL. In the first phase, the 67 patients were treated at a high dose of isotretinoin (1.5 mg/kg/day) for three months. Fifty-five percent of patients demonstrated complete or partial clinical responses. In the second phase of the study, 59 patients, with responses or stable lesions, were randomly assigned to maintenance therapy with either beta-carotene (30 mg/day;
Studies focusing on topical vitamin A and their derivates in the management of patients with OL have been reviewed by Gorsky and Epstein [
In an open trial, the clinical efficacy of topical calcipotriol (vitamin D3 analogue) was compared with tretinoin in the therapy of hyperkeratotic oral lesions (leukoplakia). Forty patients had histologically proven OL, 20 were treated with calcipotriol (50 mg/g), and the other 20 with tretinoin cream (0.05%). The treatment was given for 5 weeks and follow-up was at 4 months, with clinical assessments at 2, 4, and 5 weeks. Results showed complete resolution of OL in 16 patients in both calcipotriol and tretinoin groups. No documented topical or systemic adverse reactions and results were maintained at 4 months [
In a 10-year study that followed OL patients, Scardina et al. [
In the systemic use with dosage of 300.000 IU of retinoic acid (Vitamin A), a clinical resolution of the 50% has been demonstrated. In topical use with dosage range from 0.05% to 1% a clinical resolution from 10% to 27% has been obtained (Table
Fenretinide (4-HPR) or N-(4-hydroxyphenyl) retinamide is a vitamin A analogue that was synthesized in the United States during the late 1960s. This retinoid shows a preferential accumulation in breast instead of liver [
A phase II trial of 4-HPR (200 mg/day) was carried out for 3 months in OL patients who had not responded (“de novo” resistance) or who had responded and then relapsed (acquired resistance) to the previous treatment with natural retinoids. Of 35 patients with retinoid-resistant OL, no patient had complete responses and 12 (34.3%) had partial responses to 4-HPR. Nine patients had clinical responses within 9 months of stopping 4-HPR. Toxicity was minimal and compliance was excellent [
Systemic use of 4-HPR with 200 mg/day for 3 months in 35 patients demonstrated partial clinical resolution of OL of 12 patients (Table
Bleomycin, a cytotoxic antibiotic, was first used for the treatment of neoplasms of the penis and scrotum, but has also been employed for squamous cell carcinoma of the head and neck region, oesophagus, and skin [
Topical bleomycin in treatment of OL was used in dosages of 0.5%/day for 12 to 15 days or 1%/day for 14 days (Table
Photodynamic therapy (PDT) is a noninvasive method for the treatment of premalignant lesions and head and neck cancers [
Several photosensitisers have been developed during the past. Haematoporphyrin and haematoporphyrin derivatives were the first photosensitisers. Four photosensitisers have been approved so far: (
The ALA is a naturally occurring compound in the haem biosynthetic pathway, which is metabolised to a photosensitive product, protoporphyrin IX (PpIX). The major advantage of ALA when compared to synthetic photosensitisers is the rapid metabolism, which significantly reduces the period of cutaneous photosensitivity [
Zakrzewska et al. [
Siéron et al. [
Chen et al. [
From the studies using PDT-ALA in topical concentrations from 10 to 20%, it may be observed a clinical resolution of OL of the 25% to 80% (Table
Several clinical trials have investigated the treatment of OL with use of supplements. Although the administration of retinoic acid and beta-carotene has some efficacy to resolve OL, the studies were based on small samples and short periods of follow-up. Given the side effects and counter-indications of antioxidizing agents, with the exception of lycopene, the use of agents requires careful control. The small number of patients, the lack of controls, the lack of widely accepted criteria for classifying OL, the variability in nonsurgical treatment protocols, and differences in histopathologic evaluation difficult the interpretation of data of the few randomized clinical trials in nonsurgical treatment of OL. At this time, randomized controlled trials for nonsurgical treatment of OL demonstrate no evidence of effective treatment in preventing malignant transformation and recurrence. It reinforces that after clinical resolution, OL should be regularly followed.