Treatment of oral leukoplakia with a low‐dose of beta‐carotene and vitamin C supplements: A randomized controlled trial

Abstract

Management of oral leukoplakia-a potentially malignant disorder-is currently not evidence-based. Of the few randomized trials that have been reported, most have negative data. Therefore, a multi-centre, randomized, double-blind controlled trial (RCT) was undertaken to evaluate the use of low-dose beta-carotene combined with vitamin C supplements for the treatment and to prevent malignant transformation of oral leukoplakia. 46 Japanese participants with oral leukoplakia were allocated randomly either to an experimental arm (10 mg day 21 of beta-carotene and 500 mg day 21 of vitamin C) or placebo arm (50 mg day 21 of vitamin C). Current or ex-smokers within 3 months of cessation were excluded. The supplements were continued over a period of 1 year. The primary endpoint was clinical remission at 1-year and the likelihood of malignant transformation during a 5-year follow-up period as a secondary endpoint. The overall clinical response rate in the experimental arm was 17.4% (4/23) and 4.3% (1/23) in the placebo arm (p 5 0.346). During the median 60-month follow-up period, two subjects in the experimental arm and three in the control arm developed oral cancer. Under the intention-to-treat principle, relative risk by supplementing with beta-carotene and vitamin C was 0.77 (95%CI: 0.28-1.89) (p 5 0.580) by the Cox proportional hazards model. No unfavorable side-effects were noted. Beta-carotene (10 mg day 21 ) and vitamin C were neither effective for clinical remission, nor for protection against the development of cancer. Data from this RCT does not support the hypothesis that chemoprevention with this treatment is effective for oral leukoplakia.Oral leukoplakia-a potentially malignant disorder of the oral cavity-is associated with an increased risk of oral cancer. 1 Although a number of options for treatment of oral leukoplakia are available, 2 there is a lack of consensus on the most appropriate method of management and ways to minimize malignant transformation. 3 Tobacco and alcohol misuse are significant risk factors for the development of oral leukoplakia. 4 While it is possible to treat tobacco dependence, 5 the compliance of users and resources offered by healthcare delivery systems have been disappointing. Surgical and laser treatment of oral leukoplakia, although reducing the risk of malignant transformation, is at times associated with recurrences. 6 In this context, a medical treatment for leukoplakia is attractive, particularly if a chemopreventive agent that is effective and safe, and produces lasting benefit, can be found. 7,8 In 1981, Peto et al. hypothesized that high dietary intake of carotenoids may reduce cancer among humans. 9 Observational studies on diet suggest that its role in cancer prevention is mainly related to antioxidants in foods and/or beverages. 10,11 The incidence of a number of cancer types (i.e. lung, oral, pharyngeal and stomach) are inversely related to beta-carotene intake or blood concentrations. 12,13 A Japanese population study reported that high serum beta-carotene levels wer...

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“…Previous studies have also demonstrated that combined treatment with vitamin C and conventional anticancer agents can enhance anticancer activities (15,30,31). Currently, vitamin C supplements are being applied for clinical cancer therapy (32)(33)(34). However, vitamin C…”

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“…It could potentially prevent the development of second malignancies in patients healed of a primary oral cancer as well. However, β-carotene was inefficient in the chemoprevention of oral leukoplakia, which was confirmed by Nagao et al [314].…”

p53 and ki67 as biomarkers in determining response to chemoprevention for oral leukoplakia

“…Forty‐six patients with oral leukoplakia who were never or ex‐smokers of 3‐month duration or more were randomly allocated to the experimental and the placebo group. The target disease was a predominantly white lesion of oral mucosa clinically diagnosed as leukoplakia as described by us elsewhere . Any white patch caused by friction or other known clinical entities were excluded.…”

“…Chemoprevention has been proposed and evaluated for the management of oral potentially malignant disorders to prevent or delay the development of cancer (1). We performed a randomized controlled trial for the chemoprevention of oral leukoplakia by administrating low dose of beta-carotene (10 mg/day) and vitamin C (500 mg/day) supplements (experimental arm) or vitamin C (50 mg/day) alone (placebo arm) given orally for 1 year (2). Our results did not support the use of these agents to achieve either clinical remission (17.4% vs. 4.3%; P = 0.346) or for cancer prevention (RR: 0.77, 95%CI, 0.28-1.89).…”