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The aim of the current study was to evaluate, in an open trial, the clinical efficacy of topical calcipotriol compared with tretinoin in the therapy of hyperkeratotic oral lesions (leukoplakia). The study group consisted of 40 patients with histologically proven oral leukoplakias, 20 treated with calcipotriol, the other 20 with tretinoin. The treatment was for 5 weeks and follow-up at 4 months, with clinical assessments at 2, 4 and 5 weeks and regular laboratory assessments. The results showed a significant reduction in lesions (80%), in both calcipotriol and tretinoin groups, with no documented topical or systemic adverse reactions, results maintained at 4 months. Tretinoin however, potentially can induce erythema, angular cheilitis and xerostomia. The study suggests that topical calcipotriol is as effective in the therapy of oral leukoplakia as is topical tretinoin.

Inhibition of buccal pouch carcinogenesis induced by dimethyl-benzanthracene in hamsters with retinamide was studied. Group A received oral retinamide at a dosage of 20mg/kg, every day for eight weeks. Group B was treated by retinamide orally at the same dosage, plus topical treatment by retinamide. Group C was treated by retinamide topically for eight weeks. Experiments exhibited that under the action of retinamide the incidence of tumor was lowered significantly. All the Group A, B and C had a good response. Clinically 80 patients were randomly arranged into two groups. One group received placebo and served as controls and the other group was treated by retinamide. Results indicate that retinamide is effective against leukoplakia and the response rate is as high as 84.0%. By contrast, only 16.7% of patients receiving placebo showed some improvement.

In earlier work, we demonstrated that 0.1 p. 100 topical tretinoin is clinically effective and well tolerated compared with placebo for the treatment of oral leukoplakia and oral keratosic or erythematous lichen planus. Here we aimed to complete this clinical protocol with histological and biochemical analyses comparing the biopsy specimens collected at inclusion and those collected after 4 months of treatment. Histological results were based on changes in keratinization observed between onset of treatment and 4 months treatment. Biochemical studies included the use of antibodies (anti-cytokeratins 10-11, anti-filaggrine) for the immunohistochemical evaluation of keratinization and 2-dimensional gel electrophoresis for measuring cytokeratins. In patients with lichen planus, histological changes during treatment showed that, in the 10 patients in the tretinoin group, keratinization disappeared in 6 and decreased significantly in 3. Immunohistochemistry revealed that cytokeratins 10-11 and filaggrin disappeared in 57 p. 100 of the patients treated with tretinoin versus 25 p. 100 in the patients given placebo. Bidimensional gel electrophoresis showed that cytokeratins 1, 2, 10 and 11 disappeared only in the tretinoin group (60 p. 100 of the cases). In patients with leukoplakia, histological changes during treatment showed that, in the tretinoin group, keratinization disappeared in 5 cases and decreased in 5 others. Immunohistochemistry revealed that cytokeratins 10-11 disappeared in 30 p. 100 of the patients treated with tretinoin versus 25 p. 100 in the placebo group. Bidimensional electrophoresis demonstrated that cytokeratins 1, 2, 10 and 11 disappeared in 43 p. 100 of the patients treated with tretinoin.

A randomized study was conducted to evaluate the effect of tretinoin and patient tolerance to treatment with topical applications in series of 20 cases of smoking-related or traumatic oral keratoses leukoplakia and of 20 cases of lichen planus. In each group, patients applied the topical ointment containing tretinoin (10 patients) or placebo (10 patients) twice daily. Clinical outcome was evaluated on the basis of the surface area of the lesion, measured monthly during treatment, as compared with the area observed at treatment onset. After 4 months treatment, there was a significant decrease in the surface area of the lesion in the patients with lichen planus (p < 0.02): 94 p. 100 in the tretinoin group versus 21.4 p. 100 in the placebo group. In patients with leukoplakias, there was also a very significant reduction in the surface area of the lesion after 4 months of treatment (p < 0.001): 80 p. 100 in the tretinoin group and 16 p. 100 in the placebo group. Tolerance to treatment was generally good despite a few complaints of quite temporary burning sensation at application rapidly resolutive.

Deficiency of vitamin A and/or its precursors has been associated with increased cancer risk in animals and humans. Therapeutic trials of vitamin A and related compounds have demonstrated activity in several cancerous and precancerous conditions. The authors measured the effects of a retinoid, 13-cis-retinoic acid, and a carotenoid, beta-carotene, on the human immune system in vivo in conjunction with their use in ongoing clinical trials. Immune cell subpopulations were analyzed by quantifying the expression of markers using flow cytometric study. Both compounds produced significant effects on immune cell populations. 13-cis-Retinoic acid resulted in an increase in the percentage of peripheral blood lymphoid cells expressing surface markers for T-helper cells with only minimal effect on natural killer cell marker expression. In contrast, beta-carotene produced an increase in the percentage of cells expressing natural killer cell markers with smaller effect on T-helper markers. Modest increases in the percentage of cells expressing Ia antigen, transferrin, and interleukin-2 receptors were produced by both drugs. These results suggest that retinoids and carotenoids can produce major changes in immune cellular marker expression in vivo in humans at doses relevant to their potential clinical use.

Mucosal dysplasia in the head and neck region is recognized to be a precancerous lesion. Between January 1983 and December 1987, a pilot study was conducted at the Manitoba Cancer Treatment and Research Foundation to determine the effects of beta-carotene and cis-retinoic acid on mucosal dysplasias. Eighteen patients were treated with a "cross-over" regimen. The overall response to treatment was 61%, with 33.3% complete responses. Patients who smoked had a significantly better response than nonsmokers. The response rate for 9 of 11 smokers was 81.2%, and 2 of 7 nonsmokers or 28.6% responded to this protocol. The beneficial effect of these drugs should be established by prospective, randomized trial in high risk populations.

Vitamin A acid (VAS) has proved itself an effective local therapeutic agent for intra-oral leucoplakia. Clinical remission characterized by a decrease in horny lumps and the eosinophilic index and an increase in intermediary cells was achieved in 32 out of 50 cases. In the course of maintenance therapy development towards an exfoliocytologically healthy mucosa proceeds via increasing parakeratosis. VAS therapy is essentially thought of as symptomatic therapy.

This two phase study was designed to observe the toxicity and effectiveness of retinoids on oral leukoplakia. The study design included patients who had visible and measurable oral leukoplakia without history of synchronous oral cancer or oral cancer within the previous 2 years. Documentation of the lesion by direct measurement and photography, as well as a biopsy at the beginning and at the end of the study (for verification of the histologic appearance of the lesion), were performed in each patient. Sixteen patients with oral leukoplakia were treated with 13-cis-retinoic acid formulated in a troche in the strength of 1 mg. Three patients received 3 mg/day, 8 patients received 5 mg/day, and 5 patients received 10 mg/day. The initial visible responding event appeared to be a thinning of the leukoplakia with reduction in the whitish surface leaving a reddish, velvety epithelium. If resolution occurred, the velvety area became pink, assuming the color and texture of the normal adjacent mucosa. Toxicity of the drug appeared to be acceptable among the evaluable patients. Of the 11 patients, 3 demonstrated complete response and 6 demonstrated partial response after 6 months of treatment with the drug under study. Recurrences developed in two of the three patients with complete response, and neither of the two showed complete histologic and cytologic regression. One of the patients with partial response went on to complete response after cessation of treatment. Under the condition of our study, a treatment effect was observed with small amounts of topical 13-cis-retinoic acid and that the level of toxicity was acceptable.

The effects of the vitamin A-derived aromatic retinoid (Ro 10-9359) on 25 patients with oral hyperkeratosis were good. Compared with vitamin A, toxicity is reduced and the recurrence quota after discontinuation of the preparation is lower.

13-cis-Retinoic acid has been reported to be effective in treating oral leukoplakia. We randomly assigned 44 patients with this disease to receive 13-cis-retinoic acid (24 patients) or placebo (20), 1 to 2 mg per kilogram of body weight per day for three months, and followed them for six months. There were major decreases in the size of the lesions in 67 percent (16 patients) of those given the drug and in 10 percent (2 patients) of those given placebo (P = 0.0002); dysplasia was reversed in 54 percent (13 patients) of the drug group and in 10 percent (2 patients) of the placebo group (P = 0.01). The clinical response to the drug correlated with the histologic response in 56 percent (9 of 16) of the patients evaluated. Relapse occurred in 9 of 16 patients two to three months after treatment ended. The toxic effects of the drug were acceptable in all but two patients. Cheilitis, facial erythema, and dryness and peeling of the skin were common; conjunctivitis and hypertriglyceridemia also occurred. All adverse reactions could be reversed by reducing the dose or temporarily discontinuing the drug. We conclude that 13-cis-retinoic acid, even in short-term use, appears to be an effective treatment for oral leukoplakia and has an acceptable level of toxicity.

Leukoplakia is neither a clinical, aetiological nor histopathological entity. Therefore treatment is difficult particularly in multifocal and advanced lesions. Since 1970, we have tested the therapeutic effect of different derivatives of all-trans-retinoic acid. The study includes 75 cases with homogeneous leukoplakia without or with minimal epithelial dysplasia. Over 60% of the cases treated showed positive early results. In follow-ups from 1 to 6 years about 45% of cases showed complete or partial remission. The rest showed relapses or even progression. In cases with recurrence without changes in the morphological characteristics, positive effects were achieved with 1 to 4 repeated courses of therapy. All derivatives of retinoic acid tested so far have shown undesirable side effects with systematic manifestations or local symptoms: interruption of treatment (4) or reduction of dosage (9) were unavoidable for that reason. Regarding the side effects, retinoic acid should only be given under clinical supervision. Of the derivates tested to date, aromatic retinoid seems to have the best curative potential in homogenic leukoplakia.

Experiences in the treatment of lichen planus mucosae (including the erosive type) are reported. Good therapeutical results could be obtained in all patients. Leukoplakic patches showed a partial involution and in some cases erosive alterations healed completely. After interruption of medication a relapse was observed in most cases. Concerning side effects, some patients complained in particular of minor dryness of both labial and nasal mucosa and of diffuse hair effluvium.