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Meta-Analysis
. 2016 Jul 29;7(7):CD001829.
doi: 10.1002/14651858.CD001829.pub4.

Interventions for treating oral leukoplakia to prevent oral cancer

Giovanni Lodi  1 , Roberto Franchini, Saman Warnakulasuriya, Elena Maria Varoni, Andrea Sardella, Alexander R Kerr, Antonio Carrassi, L C I MacDonald, Helen V Worthington
Affiliations
Meta-Analysis

Interventions for treating oral leukoplakia to prevent oral cancer

Giovanni Lodi et al. Cochrane Database Syst Rev. .

Abstract

Background: Oral leukoplakia is a relatively common oral lesion that, in a small proportion of people, precedes the development of oral cancer. Most leukoplakias are asymptomatic; therefore, the primary objective of treatment should be to prevent onset of cancer. This review updates our previous review, published in 2006.

Objectives: To assess the effectiveness, safety and acceptability of treatments for leukoplakia in preventing oral cancer.

Search methods: We searched the following electronic databases: Cochrane Oral Health's Trials Register (to 16 May 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 4), MEDLINE Ovid (1946 to 16 May 2016), Embase Ovid (1980 to 16 May 2016) and CancerLit via PubMed (1950 to 16 May 2016). We searched the metaRegister of Controlled Trials (to 10 February 2015), ClinicalTrials.gov (to 16 May 2016) and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials (to 16 May 2016). We placed no restrictions on the language or date of publication when searching electronic databases.

Selection criteria: We included randomised controlled trials (RCTs) that enrolled people with a diagnosis of oral leukoplakia and compared any treatment versus placebo or no treatment.

Data collection and analysis: We collected data using a data extraction form. Oral cancer development, demonstrated by histopathological examination, was our primary outcome. Secondary outcomes were clinical resolution of the lesion, improvement of histological features and adverse events. We contacted trial authors for further details when information was unclear. When valid and relevant data were available, we conducted a meta-analysis of the data using a fixed-effect model when we identified fewer than four studies with no heterogeneity. For dichotomous outcomes, we calculated risk ratios (RRs) and 95% confidence intervals (CIs). We assessed risk of bias in studies by using the Cochrane tool. We assessed the overall quality of the evidence by using standardised criteria (Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE)).

Main results: We included 14 studies (909 participants) in this review. Surgical interventions, including laser therapy and cryotherapy, have never been studied by means of an RCT that included a no treatment or placebo arm. The included trials tested a range of medical and complementary treatments, in particular, vitamin A and retinoids (four studies); beta carotene or carotenoids (three studies); non-steroidal anti-inflammatory drugs (NSAIDs), specifically ketorolac and celecoxib (two studies); herbal extracts (four studies), including tea components, a Chinese herbal mixture and freeze-dried black raspberry gel; bleomycin (one study); and Bowman-Birk inhibitor (one study).We judged one study to be at low risk of bias, seven at unclear risk and six at high risk. In general, we judged the overall quality of the evidence to be low or very low, so findings are uncertain and further research is needed.Five studies recorded cancer incidence, only three of which provided useable data. None of the studies provided evidence that active treatment reduced the risk of oral cancer more than placebo: systemic vitamin A (RR 0.11, 95% CI 0.01 to 2.05; 85 participants, one study); systemic beta carotene (RR 0.71, 95% CI 0.24 to 2.09; 132 participants, two studies); and topical bleomycin (RR 3.00, 95% CI 0.32 to 27.83; 20 participants, one study). Follow-up ranged between two and seven years.Some individual studies suggested effectiveness of some proposed treatments, namely, systemic vitamin A, beta carotene and lycopene, for achieving clinical resolution of lesions more often than placebo. Similarly, single studies found that systemic retinoic acid and lycopene may provide some benefit in terms of improvement in histological features. Some studies also reported a high rate of relapse.Side effects of varying severity were often described; however, it seems likely that interventions were well accepted by participants because drop-out rates were similar between treatment and control groups.

Authors' conclusions: Surgical treatment for oral leukoplakia has not been assessed in an RCT that included a no treatment or placebo comparison. Nor has cessation of risk factors such as smoking been assessed. The available evidence on medical and complementary interventions for treating people with leukoplakia is very limited. We do not currently have evidence of a treatment that is effective for preventing the development of oral cancer. Treatments such as vitamin A and beta carotene may be effective in healing oral lesions, but relapses and adverse effects are common. Larger trials of longer duration are required to properly evaluate the effects of leukoplakia treatments on the risk of developing oral cancer. High-quality research is particularly needed to assess surgical treatment and to assess the effects of risk factor cessation in people with leukoplakia.

PubMed Disclaimer

Conflict of interest statement

Giovanni Lodi: none known Roberto Franchini: none known Saman Warnakulasuriya: none known Elena Maria Varoni: none known Andrea Sardella: none known Alexander R Kerr: none known Antonio Carrassi: none known LCI MacDonald: none known. LM is a salaried member of staff with Cochrane Oral Health Helen V Worthington: none known. HW is a Co‐ordinating Editor with Cochrane Oral Health

Figures

1
1
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
3
3
Study flow diagram
4
4
Forest plot of comparison: 1 Vitamin A or retinoids vs placebo, outcome: 1.1 Cancer development
5
5
Forest plot of comparison: 1 Vitamin A or retinoids vs placebo, outcome: 1.2 Oral lesion not completely resolved
6
6
Forest plot of comparison: 2 Beta carotene or carotenoids vs placebo, outcome: 2.1 Cancer development
7
7
Forest plot of comparison: 2 Beta carotene or carotenoids vs placebo, outcome: 2.2 Oral lesion not completely resolved
1.1
1.1. Analysis
Comparison 1 Vitamin A or retinoids versus placebo, Outcome 1 Oral cancer development.
1.2
1.2. Analysis
Comparison 1 Vitamin A or retinoids versus placebo, Outcome 2 Clinical resolution.
1.3
1.3. Analysis
Comparison 1 Vitamin A or retinoids versus placebo, Outcome 3 Improvement of histological features.
2.1
2.1. Analysis
Comparison 2 Beta carotene or carotenoids versus placebo, Outcome 1 Oral cancer development.
2.2
2.2. Analysis
Comparison 2 Beta carotene or carotenoids versus placebo, Outcome 2 Clinical resolution.
2.3
2.3. Analysis
Comparison 2 Beta carotene or carotenoids versus placebo, Outcome 3 Improvement of histological features.
3.1
3.1. Analysis
Comparison 3 NSAIDs versus placebo, Outcome 1 Clinical resolution.
4.1
4.1. Analysis
Comparison 4 Herbal extracts versus placebo, Outcome 1 Clinical resolution.
4.2
4.2. Analysis
Comparison 4 Herbal extracts versus placebo, Outcome 2 Improvement of histological features.
5.1
5.1. Analysis
Comparison 5 Topical bleomycin versus placebo, Outcome 1 Oral cancer development.
5.2
5.2. Analysis
Comparison 5 Topical bleomycin versus placebo, Outcome 2 Clinical resolution.
5.3
5.3. Analysis
Comparison 5 Topical bleomycin versus placebo, Outcome 3 Improvement of histological features.
6.1
6.1. Analysis
Comparison 6 Bowman‐Birk inhibitor versus placebo, Outcome 1 Clinical resolution.
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References

References to studies included in this review

Armstrong 2013 {published data only}
    1. Armstrong WB, Taylor TH, Kennedy AR, Melrose RJ, Messadi DV, Gu M, et al. Bowman Birk inhibitor concentrate and oral leukoplakia: a randomized phase IIb trial. Cancer Prevention Research (Philadelphia, Pa.) 2013;6:410‐8. - PMC - PubMed
Epstein 1994 {published and unpublished data}
    1. Epstein JB, Wong FL, Millner A, Le ND. Topical bleomycin treatment of oral leukoplakia: a randomized double‐blind clinical trial. Head & Neck 1994;16(6):539‐44. - PubMed
Hong 1986 {published data only}
    1. Hong WK, Endicott J, Itri LM, Doos W, Batsakis JG, Bell R, et al. 13‐cis‐retinoic acid in the treatment of oral leukoplakia. New England Journal of Medicine 1986;315(24):1501‐5. - PubMed
Li 1999 {published and unpublished data}
    1. Li N, Sun Z, Han C, Chen J. The chemopreventive effects of tea on human oral precancerous mucosa lesions. Proceedings of the Society for Experimental Biology and Medicine 1999;220(4):218‐24. - PubMed
Mallery 2014 {published data only}
    1. Mallery SR, Tong M, Shumway BS, Curran AE, Larsen PE, Ness GM, et al. Topical application of a mucoadhesive freeze‐dried black raspberry gel induces clinical and histologic regression and reduces loss of heterozygosity events in premalignant oral intraepithelial lesions: results from a multicentered, placebo‐controlled clinical trial. Clinical Cancer Research 2014;20(7):1910‐24. - PMC - PubMed
Mulshine 2004 {published data only}
    1. Mulshine JL, Atkinson JC, Greer RO, Papadimitrakopoulou VA, Waes C, Rudy S, et al. Randomized, double‐blind, placebo‐controlled phase IIb trial of the cyclooxygenase inhibitor ketorolac as an oral rinse in oropharyngeal leukoplakia. Clinical Cancer Research 2004;10(5):1565‐73. - PubMed
Nagao 2015 {published and unpublished data}
    1. Nagao T, Warnakulasuriya S, Fukano H, Nakamura T, Kato S, Yamamoto K, et al. A randomized controlled trial for the treatment of oral leukoplakia with the aid of chemopreventive agents. Journal of Oral and Maxillofacial Surgery 2007;65(9 Suppl):41.e6.
    1. Nagao T, Warnakulasuriya S, Fukano H, Suzuki K, Shimozato K, Hashimoto S. A randomised trial for preventing malignant transformation of oral leukoplakia. Oral Surgery 2010;3:103–14.
    1. Nagao T, Warnakulasuriya S, Nakamura T, Kato S, Yamamoto K, Fukano H, et al. Treatment of oral leukoplakia with a low‐dose of beta‐carotene and vitamin C supplements: a randomized controlled trial. International Journal of Cancer 2015;136:1708‐17. - PubMed
    1. Nagao T, Warnakulasuriya S, Sakuma H, Suzuki K, Hashimoto S. Is response to chemoprevention in oral leukoplakia determined by p53 expression?. Oral Diseases 2010;16:518.
Papadimitrakopoulou 2008 {published data only}
    1. Papadimitrakopoulou VA, William WN Jr, Dannenberg AJ, Lippman SM, Lee JJ, Ondrey FG, et al. Pilot randomized phase II study of celecoxib in oral premalignant lesions. Clinical Cancer Research 2008;14:2095‐101. - PubMed
Piattelli 1999 {published and unpublished data}
    1. Piattelli A, Fioroni M, Santinelli A, Rubini C. bcl‐2 expression and apoptotic bodies in 13‐cis‐retinoic acid (isotretinoin)‐topically treated oral leukoplakia: a pilot study. Oral Oncology 1999;35(3):314‐20. - PubMed
Sankaranarayan 1997 {published data only}
    1. Sankaranarayanan R, Mathew B, Varghese C, Sudhakaran PR, Menon V, Jayadeep A, et al. Chemoprevention of oral leukoplakia with vitamin A and beta carotene: an assessment. Oral Oncology 1997;33(4):231‐6. - PubMed
Singh 2004 {published data only}
    1. Singh M, Krishanappa R, Bagewadi A, Keluskar V. Efficacy of oral lycopene in the treatment of oral leukoplakia. Oral Oncology 2004;40(6):591‐6. - PubMed
Stich 1988 {published data only}
    1. Stich HF, Hornby AP, Mathew B, Sankaranarayanan R, Nair MK. Response of oral leukoplakias to the administration of vitamin A. Cancer Letters 1988;40(1):93‐101. - PubMed
Sun 2009 {published data only}
    1. Sun Z, Guan X, Li N, Liu X, Chen X. Chemoprevention of oral cancer in animal models, and effect on leukoplakias in human patients with ZengShengPing, a mixture of medicinal herbs. Oral Oncology 2010;46:105‐10. - PubMed
Tsao 2009 {published data only}
    1. Tsao AS, Liu D, Martin J, Tang XM, Lee JJ, El‐Naggar AK, et al. Phase II randomized, placebo‐controlled trial of green tea extract in patients with high‐risk oral premalignant lesions. Cancer Prevention Research (Philadelphia, Pa.) 2009;2:931‐41. - PMC - PubMed

References to studies excluded from this review

Bocharova 2004 {published data only}
    1. Bocharova OA, Pozharitskaya MM, Chekalina TL, Lyzhenkova MA, Karpova RV, Mezentseva MV, et al. Leukoplakia of oral mucosa: pathogenesis and possible correction with phytoadaptogen. Bulletin of Experimental Biology and Medicine 2004;138(6):578‐83. - PubMed
Boisnic 1994 {published data only}
    1. Boisnic S, Branchet MC, Pascal F, Ben Slama L, Rostin M, Szpirglas H. Topical tretinoin in the treatment of lichen planus and leukoplakia of the mouth mucosa. A clinical evaluation [Trétinoine topique dans le traitement des lichens plans et des leucoplasies de la muqueuse buccale. Evaluation clinique]. [French]. Annals of Dermatology and Venereology 1994;121(6‐7):459‐63. - PubMed
Chee 2013 {published data only}
    1. Chee M, Sasaki C. Carbon dioxide laser fiber for the excision of oral leukoplakia. Annals of Otology, Rhinology, and Laryngology 2013;122:547‐9. - PubMed
Chiesa 2005 {published data only}
    1. Chiesa F, Tradati N, Grigolato R, Boracchi P, Biganzoli E, Crose N, et al. Randomized trial of fenretinide (4‐HPR) to prevent recurrences, new localizations and carcinomas in patients operated on for oral leukoplakia: long‐term results. International Journal of Cancer 2005;115(4):625‐9. - PubMed
    1. Chiesa F, Tradati N, Marazza M, Rossi N, Boracchi P, Mariani L, et al. Fenretinide (4‐HPR) in chemoprevention of oral leukoplakia. Journal of Cellular Biochemistry Supplement 1993;17F:255‐61. - PubMed
    1. Chiesa F, Tradati N, Marazza M, Rossi N, Boracchi P, Mariani L, et al. Prevention of local relapses and new localisations of oral leukoplakias with the synthetic retinoid fenretinide (4‐HPR). Preliminary results. European Journal of Cancer. Part B, Oral Oncology 1992;28B(2):97‐102. - PubMed
    1. Costa A, Formelli F, Chiesa F, Decensi A, Palo G, Veronesi U. Prospects of chemoprevention of human cancers with the synthetic retinoid fenretinide. Cancer Research 1994;54(7 Suppl):2032s‐7s. - PubMed
    1. Palo G, Veronesi U, Marubini E, Camerini T, Chiesa F, Nava M, et al. Controlled clinical trials with fenretinide in breast cancer, basal cell carcinoma and oral leukoplakia. Journal of Cellular Biochemistry Supplement 1995;22:11‐7. - PubMed
Femiano 2001 {published data only}
    1. Femiano F, Gombos F, Scully C, Battista C, Belnome G, Esposito V. Oral leukoplakia: open trial of topical therapy with calcipotriol compared with tretinoin. International Journal of Oral and Maxillofacial Surgery 2001;30(5):402‐6. - PubMed
Gaeta 2000 {published and unpublished data}
    1. Gaeta GM, Gombos F, Femiano F, Battista C, Minghetti P, Montanari L, et al. Acitretin and treatment of the oral leucoplakias. A model to have an active molecules release. Journal of the European Academy of Dermatology and Venereology 2000;14(6):473‐8. - PubMed
Garewal 1999 {published data only}
    1. Garewal H, Pitcock J, Friedman S, Alberts D, Meyskens F, Ramsey L, et al. Beta‐carotene in oral leukoplakia. Proceedings, Annual Meeting of the American Society of Clinical Oncology 1992;11:141.
    1. Garewal HS, Katz RV, Meyskens F, Pitcock J, Morse D, Friedman S, et al. Beta‐carotene produces sustained remissions in patients with oral leukoplakia: results of a multicenter prospective trial. Archives of Otolaryngology ‐ Head and Neck Surgery 1999;125(12):1305‐10. - PubMed
Krishnaswamy 1995 {published data only}
    1. Krishnaswamy K, Prasad MP, Krishna TP, Annapurna VV, Reddy GA. A case study of nutrient intervention of oral precancerous lesions in India. European Journal of Cancer. Part B: Oral Oncology 1995;31B(1):41‐8. - PubMed
Lippman 1993 {published data only}
    1. Lippman SM, Batsakis JG, Toth BB, Weber RS, Lee JJ, Martin JW, et al. Comparison of low‐dose isotretinoin with beta carotene to prevent oral carcinogenesis. New England Journal of Medicine 1993;328(1):15‐20. - PubMed
    1. Papadimitrakopoulou VA, Lippman SM, Lee JS, Toth BB, Martin JW, Lee JJ, et al. Long term follow‐up of low‐dose isotretinoin (13‐cRA) versus beta carotene to prevent oral carcinogenesis. Proceedings, Annual Meeting of the American Society of Clinical Oncology 1996;15:A340.
López‐Jornet 2013 {published data only}
    1. López‐Jornet P, Camacho‐Alonso F. Comparison of pain and swelling after removal of oral leukoplakia with CO₂ laser and cold knife: a randomized clinical trial. Medicina Oral, Patologia Oral y Cirugia Bucal 2013;18:38e‐44e. - PMC - PubMed
Mathew 1995 {published data only}
    1. Mathew B, Sankaranarayanan R, Nair PP, Varghese C, Somanathan T, Amma BP, et al. Evaluation of chemoprevention of oral cancer with Spirulina fusiformis. Nutrition and Cancer 1995;24(2):197‐202. - PubMed
Schwarz 2005 {published data only}
    1. Schwarz F, Maraki D, Yalcinkaya S, Bieling K, Bocking A, Becker J. Cytologic and DNA‐cytometric follow‐up of oral leukoplakia after CO2‐ and Er:YAG‐laser assisted ablation: a pilot study. Lasers in Surgery and Medicine 2005;37(1):29‐36. - PubMed
Zaridze 1993 {published data only}
    1. Zaridze D, Evstifeeva T, Boyle P. Chemoprevention of oral leukoplakia and chronic esophagitis in an area of high incidence of oral and esophageal cancer. Annals of Epidemiology 1993;3(3):225‐34. - PubMed

References to studies awaiting assessment

Califano 2012 {published data only}
    1. Califano JA, Ferris RL, Epstein JB, Gillespie MB, Feldman LE, Gibson MK, et al. A phase II trial of cetuximab in high‐risk premalignant lesions of the upper aerodigestive tract. Journal of Clinical Oncology 2012;30(No 15_suppl (May 20 Suppl)):5528.
Chiba 2012 {published data only}
    1. Chiba I, Takeshima M, Abiko Y, Kobayashi H, Muthumala M, Sugiura C, et al. Curcumin is an effective chemopreventive substance for betel quid chewer's oral precancer in Sri Lanka. Cancer Prevention Research 2012;5(11 Suppl 1):PR‐04. [DOI: 10.1158/1940-6207.PREV-12-PR-04] - DOI

References to ongoing studies

NCT00004161 {published data only}
    1. NCT00004161. Fenretinide in treating patients with leukoplakia of the mouth. https://clinicaltrials.gov/ct2/show/NCT00004161 (accessed 16 May 2016).
NCT00014404 {published data only}
    1. NCT00014404. Celecoxib in treating patients with precancerous lesions of the mouth. https://clinicaltrials.gov/ct2/show/NCT00014404 (accessed 16 May 2016).
NCT00101335 {published data only}
    1. NCT00101335. Celecoxib in preventing head and neck cancer in patients with oral leukoplakia. https://clinicaltrials.gov/ct2/show/NCT00101335 (accessed 16 May 2016).
NCT00155337 {published data only}
    1. NCT00155337. Photodynamic therapy for oral leukoplakia and erythroleukoplakia. https://clinicaltrials.gov/ct2/show/NCT00155337 (accessed 16 May 2016).
NCT00176566 {published data only}
    1. NCT00176566. A phase II trial to assess the effects of green tea in oral leukoplakia. https://clinicaltrials.gov/ct2/show/NCT00176566 (accessed 16 May 2016).
NCT00299195 {published data only}
    1. NCT00299195. A randomized study of sulindac in oral premalignant lesions. https://clinicaltrials.gov/ct2/show/NCT00299195 (accessed 16 May 2016).
NCT00402779 {published data only}
    1. NCT00402779. Erlotinib prevention of oral cancer (EPOC). https://clinicaltrials.gov/ct2/show/NCT00402779 (accessed 16 May 2016).
NCT00951379 {published data only}
    1. NCT00951379. Pioglitazone for oral premalignant lesions. https://clinicaltrials.gov/ct2/show/NCT00951379 (accessed 16 May 2016).
NCT01497951 {published data only}
    1. NCT01497951. Photodynamic therapy for oral precursor lesions (PDT). https://clinicaltrials.gov/ct2/show/NCT01497951 (accessed May 2016).

Additional references

Abbey 1995
    1. Abbey LM, Kaugars GE, Gunsolley JC, Burns JC, Page DG, Svirsky JA, et al. Intraexaminer and interexaminer reliability in the diagnosis of oral epithelial dysplasia. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontics 1995;80(2):188‐91. - PubMed
Arduino 2013
    1. Arduino PG, Bagan J, El‐Naggar AK, Carrozzo M. Urban legends series: oral leukoplakia. Oral Diseases 2013;19:642‐59. [DOI: 10.1111/odi.12065] - DOI - PubMed
Axell 1984
    1. Axell T, Holmstrup P, Kramer IRH, Pindborg JJ. International seminar on oral leukoplakia and associated lesions related to tobacco habits. Community Dentistry and Oral Epidemiology 1984;12:145‐54.
Axell 1987
    1. Axell T. Occurrence of leukoplakia and some other oral white lesions among 20,333 adult Swedish people. Community Dentistry and Oral Epidemiology 1987;15(1):46‐51. - PubMed
Axell 1996
    1. Axell T, Pindborg JJ, Smith CJ, Waal I. Oral white lesions with special reference to precancerous and tobacco‐related lesions: conclusions of an international symposium held in Uppsala, Sweden, May 18‐21, 1994. International Collaborative Group on Oral White Lesions. Journal of Oral Pathology & Medicine 1996;25(2):49‐54. [MEDLINE: ] - PubMed
Bouquot 1986
    1. Bouquot JE, Gorlin RJ. Leukoplakia, lichen planus, and other oral keratoses in 23,616 white Americans over the age of 35 years. Oral Surgery, Oral Medicine and Oral Pathology 1986;61(4):373‐81. - PubMed
Dietrich 2004
    1. Dietrich T, Reichart PA, Scheifele C. Clinical risk factors of oral leukoplakia in a representative sample of the US population. Oral Oncology 2004;40(2):158‐63. - PubMed
Epstein 2012
    1. Epstein JB, Thariat J, Bensadoun RJ, Barasch A, Murphy BA, Kolnick L, et al. Oral complications of cancer and cancer therapy: from cancer treatment to survivorship. CA: A Cancer Journal for Clinicians 2012;62:400‐22. - PubMed
Gupta 1980
    1. Gupta PC, Mehta FS, Daftary DK, Pindborg JJ, Bhonsle RB, Jalnawalla PN, et al. Incidence rates of oral cancer and natural history of oral precancerous lesions in a 10‐year follow‐up study of Indian villagers. Community Dentistry and Oral Epidemiology 1980;8(6):283‐33. - PubMed
Higgins 2011
    1. Higgins JPT, Deeks JJ, Altman DG, on behalf of the Cochrane Statistical Methods Group. Chapter 16: Special topics in statistics. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. Chichester, UK: John Wiley & Sons, Ltd, 2011.
Higgins 2011a
    1. Higgins JPT, Deeks JJ, Altman DG, on behalf of the Cochrane Statistical Methods Group. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. Chichester, UK: John Wiley & Sons, Ltd, 2011.
Holmstrup 2006
    1. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long‐term treatment outcome of oral premalignant lesions. Oral Oncology 2006;42(5):461‐74. - PubMed
Holmstrup 2009
    1. Holmstrup P. Can we prevent malignancy by treating premalignant lesions?. Oral Oncology 2009;45:549‐50. - PubMed
Ikeda 1991
    1. Ikeda N, Ishii T, Iida S, Kawai T. Epidemiological study of oral leukoplakia based on mass screening for oral mucosal diseases in a selected Japanese population. Community Dentistry and Oral Epidemiology 1991;19(3):160‐3. - PubMed
Karabulut 1995
    1. Karabulut A, Reibel J, Therkildsen MH, Praetorius F, Nielesen HW, Dabelsteen E. Observer variability in the histologic assessment of oral premalignant lesions. Journal of Oral Pathology Medicine 1995;24(5):198‐200. - PubMed
Kramer 1978
    1. Kramer IR, Lucas RB, Pindborg JJ, Sobin LH. Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surgery, Oral Medicine and Oral Pathology 1978;46(4):518‐39. [MEDLINE: ] - PubMed
Lind 1987
    1. Lind PO. Malignant transformation in oral leukoplakia. Scandinavian Journal of Dental Research 1987;95(6):449‐55. - PubMed
Lodi 2008
    1. Lodi G, Porter S. Management of potentially malignant disorders: evidence and critique. Journal of Oral Pathology & Medicine 2008;37:63‐9. - PubMed
Lumerman 1995
    1. Lumerman H, Freedman P, Kerpel S. Oral epithelial dysplasia and the development of invasive squamous cell carcinoma. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontics 1995;79(3):321‐9. - PubMed
Marley 1998
    1. Marley JJ, Cowan CG, Lamey PJ, Linden GJ, Johnson NW, Warnakulasuriya KA. Management of potentially malignant oral mucosal lesions by consultant UK oral and maxillofacial surgeons. British Journal of Oral and Maxillofacial Surgery 1998;34(1):28‐36. - PubMed
Nagao 2005
    1. Nagao T, Ikeda N, Fukano H, Hashimoto S, Shimozato K, Warnakulasuriya S. Incidence rates for oral leukoplakia and lichen planus in a Japanese population. Journal of Oral Pathology and Medicine 2005;34(9):532‐9. - PubMed
Petti 2003
    1. Petti S. Pooled estimate of world leukoplakia prevalence: a systematic review. Oral Oncology 2003;39:770‐80. - PubMed
Pitiyage 2009
    1. Pitiyage G, Tilakaratne WM, Tavassoli M, Warnakulasuriya S. Molecular markers in oral epithelial dysplasia: review. Journal of Oral Pathology & Medicine 2009;38:737‐52. - PubMed
Reichart 2000
    1. Reichart PA. Oral mucosal lesions in a representative cross‐sectional study of aging Germans. Community Dentistry and Oral Epidemiology 2000;28(5):390‐8. - PubMed
Saito 2001
    1. Saito T, Sugiura C, Hirai A, Notani K, Totsuka Y, Shindoh M, et al. Development of squamous cell carcinoma from pre‐existent oral leukoplakia: with respect to treatment modality. International Journal of Oral and Maxillofacial Surgery 2001;30(1):49‐53. - PubMed
Scheifele 2003
    1. Scheifele C, Reichart PA. Is there a natural limit of the transformation rate of oral leukoplakia?. Oral Oncology 2003;39(5):470‐5. - PubMed
Schepman 1998
    1. Schepman KP, Meij EH, Smeele LE, Waal I. Malignant transformation of oral leukoplakia: a follow‐up study of a hospital‐based population of 166 patients with oral leukoplakia from The Netherlands. Oral Oncology 1998;34(4):270‐5. - PubMed
Scully 2009
    1. Scully C, Bagan J. Oral squamous cell carcinoma overview. Oral Oncology 2009;45:301‐8. - PubMed
Shiu 2000
    1. Shiu MN, Chen TH, Chang SH, Hahn LJ. Risk factors for leukoplakia and malignant transformation to oral carcinoma: a leukoplakia cohort in Taiwan. British Journal of Cancer 2000;82(11):1871‐4. - PMC - PubMed
Silverman 1984
    1. Silverman S Jr, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. A follow‐up study of 257 patients. Cancer 1984;53(3):563‐8. - PubMed
Smith 2009
    1. Smith J, Rattay T, McConkey C, Helliwell T, Mehanna H. Biomarkers in dysplasia of the oral cavity: a systematic review. Oral Oncology 2009;45:647‐53. - PubMed
Sperandio 2013
    1. Sperandio M, Brown AL, Lock C, Morgan PR, Coupland VH, Madden PB, et al. Predictive value of dysplasia grading and DNA ploidy in malignant transformation of oral potentially malignant disorders. Cancer Prevention Research (Philadelphia, Pa.) 2013;6:822‐31. - PubMed
Syrjänen 2011
    1. Syrjänen S, Lodi G, Bültzingslöwen I, Aliko A, Arduino P, Campisi G, et al. Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: a systematic review. Oral Diseases 2011;17 Suppl 1:58‐72. - PubMed
Torres‐Rendon 2009
    1. Torres‐Rendon A, Stewart R, Craig GT, Wells M, Speight PM. DNA ploidy analysis by image cytometry helps to identify oral epithelial dysplasias with a high risk of malignant progression. Oral Oncology 2009;45:468‐73. - PubMed
Van der Waal 2009
    1. Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral Oncology 2009;45:317‐23. - PubMed
Warnakulasuriya 2007
    1. Warnakulasuriya S, Johnson NW, Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. Journal of Oral Pathology & Medicine 2007;36:575‐80. - PubMed
Warnakulasuriya 2011
    1. Warnakulasuriya S, Kovacevic T, Madden P, Coupland VH, Sperandio M, Odell E, et al. Factors predicting malignant transformation in oral potentially malignant disorders among patients accrued over a 10‐year period in South East England. Journal of Oral Pathology & Medicine 2011;40:677‐83. - PubMed
Worthington 2015
    1. Worthington H, Clarkson J, Weldon J. Priority oral health research identification for clinical decision‐making. Evidence‐based Dentistry 2015;16(3):69‐71. - PubMed

References to other published versions of this review

Lodi 2002
    1. Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A. Systematic review of randomized trials for the treatment of oral leukoplakia. Journal of Dental Education 2002;66(8):896‐902. - PubMed
Lodi 2004
    1. Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A. Interventions for treating oral leukoplakia. Cochrane Database of Systematic Reviews 2004, Issue 3. [DOI: 10.1002/14651858.CD001829.pub2] - DOI - PubMed
Lodi 2006
    1. Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A. Interventions for treating oral leukoplakia. Cochrane Database of Systematic Reviews 2006, Issue 4. [DOI: 10.1002/14651858.CD001829.pub3] - DOI - PubMed

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