Interventions for treating oral leukoplakia to prevent oral cancer

  • Review
  • Intervention

Authors


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.

摘要

治疗口腔白斑病预防口腔癌的干预措施

研究背景

口腔白斑病是一种相对常见的口腔病变,在少数人的口腔癌发生前。大多数黏膜白斑病是无症状的;因此,治疗的首要目标应该是预防癌症的发生。这篇综述更新了我们2006年发表的一篇综述。

研究目的

本篇综述旨在评价黏膜白斑病在预防口腔癌中的有效性、安全性和可接受度。

检索策略

我们检索了以下电子数据库:Cochrane口腔健康试验注册库(Cochrane Oral Health's Trials Register,2016年5月16日为止),Cochrane对照试验中心注册库(CENTRAL)(Cochrane图书馆,2016年第4期),MEDLINE Ovid(1946年至2016年5月16日),Embase Ovid(1980年至2016年5月16日)和PubMed癌症数据库(1950年至2016年5月16日)。我们检索了metaRegister的对照试验(截至2015年2月10日),ClinicalTrials.gov(截至2016年5月16日)和世界卫生组织(WHO)国际临床试验注册平台(截至2016年5月16日)。在检索电子数据库时,我们没有对发表的语言或出版日期加以限制。

标准/纳入排除标准

我们纳入诊断为口腔白斑病患者的随机对照试验(RCTs),为任何治疗与安慰剂或不治疗相比较。

数据收集与分析

我们使用数据提取表提取数据。口腔癌的发生,是由组织病理学检查所证实的,是我们的主要结局。次要结局是对病变的临床治疗,改善组织学特征和不良事件。当信息不清楚的时候,我们联系了试验作者以获取更多的细节。当我们得到有效的和相关的数据时,且发现没有异质性的研究少于4项时,用固定效应模型进行meta分析。对于二分类的结果,我们计算风险比(RRs)和95%置信区间(CIs)。我们使用Cochrane工具评价研究中存在偏倚风险。我们通过使用标准化标准(推荐等级、评估、开发和评估工作组(GRADE))的标准来评估证据的整体质量。

主要结果

本综述中纳入了14项研究(909名研究对象)。外科干预手段包括激光疗法和冷冻疗法,从未被以包含无治疗或安慰剂组的RCT的方式所研究。纳入的试验测试了一系列的药物和补充治疗,特别是维生素A和类维生素A(四项研究);β胡萝卜素或类胡萝卜素(三种研究);非甾体消炎药(NSAIDs),特别是酮咯酸和塞来浦西(两项研究);草药提取物(四项研究),包括茶成分,一种中药混合物和冻干黑树莓凝胶;博来霉素(一项研究);Bowman-Birk的抑制剂(一项研究)。

我们认为一项研究是低偏倚风险的,七项风险不清楚,六项高风险。总的来说,我们认为证据的总体质量低或者极低,所以研究发现是不确定的,需要进一步的研究。

5项研究记录了癌症发病率,其中只有3项提供了可用的数据。没有研究提供证据表明,阳性治疗比安慰剂更能降低口腔癌的风险:全身性维生素A(RR=0.11,95%CI=0.01 - 2.05;85名研究对象,一项研究);全身性β胡萝卜素(RR=0.71,95%CI=0.24 - 2.09;132名研究对象,两项研究);局部性博莱霉素(RR=3.00,95%CI=0.32 - 27.83;20名研究对象,一项研究)。随访时间为2至7年。

一些单个的研究表明了一些推荐的治疗方法的有效性,即全身性维生素A、β胡萝卜素和番茄素,比安慰剂更能达到临床治疗的效果。同样的,单个的研究发现,全身性的维甲酸和番茄素在组织学特征改善上有益。一些研究也报告了高复发率。

不同严重程度的副作用经常被描述;然而,这些干预措施似乎很有可能被研究对象接受,因为在治疗组合对照组之间的退出率是相似的。

作者结论

对口腔白斑病的外科治疗还进行过RCT评价,包括无治疗对照或安慰剂对照。也没有停止像吸烟这样的危险因素的评价。关于治疗黏膜白斑病的药物和补充治疗干预措施的证据是非常有限的。我们目前还没有证据表明治疗口腔白斑病可以有效预防口腔癌的发生。像维生素A和β胡萝卜素这样的治疗方法在治疗口腔损伤方面可能有效,但是复发和副作用是很常见的。需要更大的更长疗程的试验来正确评价治疗口腔白斑病对患口腔癌风险的影响。尤其需要高质量的研究来评价外科治疗和评价停止危险因素对白斑病患者的影响。

Plain language summary

Interventions for treating oral leukoplakia to prevent oral cancer

Review question

People with oral leukoplakia are at higher risk of developing oral cancer than those with normal oral mucosa. This review, produced through Cochrane Oral Health, seeks to evaluate whether people affected by leukoplakia can benefit from surgical, medical or complementary treatments, either local or systemic. In particular, we conducted this review to find out which, if any, treatment is able to prevent people with leukoplakia of the mouth from getting oral cancer. This review updates our previous review published in 2006.

Background

Oral leukoplakia is a white patch formed in the mouth lining that cannot be rubbed off. It often does not hurt and may go unnoticed for years. People with leukoplakia develop oral cancer more often than people without it. Preventing this is critical because rates of oral cancer survival longer than five years after diagnosis are low. Drugs, surgery and other therapies have been tried for treatment of oral leukoplakia.

Objectives

This review aimed to evaluate whether treatments for oral leukoplakia are effective in preventing oral cancer, and safe and acceptable to patients.

Study characteristics

The evidence on which this review is based is up-to-date as of May 2016. We found 14 randomised controlled trials (RCTs) of medical and complementary treatments, which involved 909 participants in total. Treatments included herbal extracts, anti-inflammatory drugs, vitamin A, beta carotene supplements and others. Surgical treatment has not been compared with placebo or no treatment in an RCT.

Key results

Cancer development was measured in studies of three treatments: systemic vitamin A, systemic beta carotene and topical bleomycin. None of these treatments showed effectiveness in preventing cancer development, as measured up to two years for vitamin A and beta carotene, and seven years for bleomycin.

Some individual studies of vitamin A and beta carotene suggested that these treatments may be effective for improving or healing oral lesions. However, some studies observed a high rate of relapse in participants whose lesions were initially resolved by treatment.

Most treatments caused side effects of differing severity in a high proportion of participants.

It seems likely that interventions were well accepted by participants because drop-out rates were similar between treatment and control groups.

Quality of the evidence

The available evidence is very limited. Most interventions were assessed by only one small study. Most studies had problems in the way they were conducted, making their results unreliable. We judged the quality of evidence for the outcome of cancer development to be very low.

Author conclusions

Larger, better studies of longer duration are required. As well as further studies of drug treatment and alternative treatments like vitamins, studies are needed to evaluate the effectiveness and safety of surgery, and of stopping risk factor habits such as smoking.

Laički sažetak

Mjere liječenja oralne leukoplakije za sprječavanje oralnog karcinoma

Istraživačko pitanje

Oralna leukoplakija je čimbenik rizika za nastanak oralnog karcinoma. Ovaj pregled literature izrađen je u okviru Cochrane uredničke skupine za oralno zdravlje i u njemu su istražene mogućnosti liječenja leukoplakije raznim metodama: kirurški, lijekovima i pomoćnim sredstvima putem sistemske ili lokalne primjene. Važno je ustanoviti mjere liječenja leukoplakija i sprječavanja nastanka oralnog karcinoma (karcinoma usne šupljine). Ovaj Cochrane sustavni pregled je obnovljena verzija pregleda koji je ranije objavljen 2006. godine.

Dosadašnje spoznaje

Oralna leukoplakija je bjelkasta promjena sluznice u ustima koju nije moguće ukloniti. Najčešće je bezbolna i može dugo proći neopaženo. U osoba s leukoplakijom je pojava oralnog karcinoma češća. Važno je sprječavanje budući da je petogodišnje preživljenje nisko u bolesnika s oralnim karcinomom. Mogućnosti liječenja leukoplakije uključuju kirurški zahvat, lijekove i druge postupke.

Cilj istraživanja

Ispitali smo učinkovitost pristupa liječenju oralne leukoplakije u sprječavanju oralnog karcinoma, te sigurnost i prihvatljivost ovih metoda za bolesnike.

Obilježja studija

Dokazi na kojima se temelji ovaj pregled dolaze iz kliničkih studija objavljenih do svibnja 2016. Nađeno je 14 randomiziranim kontroliranih pokusa u kojima su ispitane različite medicinske terapije i komplementarna liječenja. U tim je istraživanjima sudjelovalo ukupno 909 ispitanika. Lijekovi su uključili biljne pripravke, protuupalne lijekove, vitamin A, beta karoten i ostalo. Kirurški zahvat nije uspoređen s placebom ili nikakvim liječenjem u kliničkoj studiji.

Ključni rezultati

Pojava karcinoma je ispitana u studijama s tri vrste liječenja: sistemska primjena A vitamina, sistemska primjena beta karotena i lokalno bleomicin. Niti jedno od ovih pristupa nisu bili učinkoviti u sprječavanju karcinoma u praćenju do 2 godine za A vitamin i beta karoten i 7 godina za bleomicin.

Pojedinačne studije su pokazale da bi A vitamin i beta karoten mogli biti učinkoviti u poboljšanju ili liječenju oralnih promjena. U nekim studijama je nađena visoka pojavnost ponavljanja promjena oralne sluznice, a koje su prvobitno izliječene.

Većina liječenja je imalo nuspojave različite težine u većem broju ispitanika.

Bolesnici su dobro podnosili liječenje te je udio odustajanja bio podjednak u liječenih i kontrolnoj skupini.

Kvaliteta dokaza

Postojeći dokazi su ograničeni. Većina terapija ispitana je samo u jednoj maloj studiji. U većine studija je provedba bila upitna, a onda i rezultati nepouzdani. Kvaliteta dokaza je vrlo niska za ishode nastanka karcinoma.

Zaključak

Potrebne su veće i bolje studije koje dulje traju. Osim ispitivanja lijekova i pomoćnih sredstava, primjerice vitamina, potrebno je ispitati učinkovitost kirurškog zahvata, te ispravljanja navika koje pogoduju nastanku karcinoma tj. pušenje.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Vesna Kušec
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Ringkasan bahasa mudah

Intervensi untuk merawat leukoplakia oral bagi mencegah kanser oral

Soalan sorotan

Penghidap leukoplakia berisiko lebih tinggi untuk kanser oral berbanding orang yang mempunyai mukosa oral yang normal. Sorotan yang dihasilkan melaluiKumpulan Kesihatan Oral Cochraneini bertujuan menilai sama ada penghidap leukoplakia boleh mendapat manfaat daripada rawatan surgikal, perubatan atau rawatan komplemen secara setempat atau sistemik.Secara khusus, kami menjalankan sorotan ini untuk mengenalpasti rawatan yang boleh mencegah kejadian kanser oral dalam kalangan orang yang ada leukoplakia, jika ada.Sorotan ini mengemaskini sorotan terdahulu terbitan 2006.

Latarbelakang

Leukoplakia oral adalah tompok putih yang terbentuk pada lapisan dalam mulut yang tidak dapat dihilangkan. Seringkali ia tidak sakit dan mungkin tidak disedari selama beberapa tahun. Penghidap leukoplakia lebih kerap mendapat kanser oral berbanding orang yang tiada leukoplakia. Pencegahan ini adalah kritikal memandangkan kadar kemandirian kanser oral melebihi lima tahun selepas diagnosis adalah rendah.Ubat-ubatan, surgeri dan pelbagai terapi telah dijalankan untuk merawat leukoplakia oral.

Objektif

Sorotan ini bertujuan menilai sama ada rawatan untuk leukoplakia oral berkesan bagi mencegah kanser oral, selamat dan boleh diterima pesakit.

Ciri kajian

Bukti sorotan ini adalah terkini sehingga Mei 2016. Kami mendapati 14 kajian rawak terkawal (RCT) perubatan atau rawatan komplemen melibatkan sejumlah 909 peserta. Rawatan termasuklah ekstrak herba, ubat anti-keradangan, vitamin A, suplemen beta karotina dan lain-lain lagi. Tiada kajian rawak terkawal yang membandingkan rawatan surgikal dengan plasebo atau tanpa rawatan.

Keputusan utama

Perkembangan kanser diukur dalam kajian yang melibatkan tiga rawatan: vitamin A sistemik, beta karotina sistemik dan bleomisin topikal. Rawatan-rawatan tersebut tidak menunjukkan keberkesanan dalam pencegahan perkembangan kanser apabila dinilai sehingga dua tahun bagi vitamin A dan beta karotina, dan sehingga tujuh tahun bagi bleomisin.

Beberapa kajian individu vitamin A dan beta karotina mengusulkan rawatan tersebut mungkin berkesan untuk penyembuhan lesi oral.Namun, beberapa kajian mendapati kadar relaps yang tinggi dalam kalangan peserta yang mana lesi awal telah sembuh dengan rawatan.

Kebanyakan rawatan menyebabkan pelbagai tahap keterukan akibat kesan sampingan dalam sebahagian besar peserta.

Ia mungkin menunjukkan intervensi diterima baik oleh peserta kerana kadar keciciran adalah sama antara kelompok rawatan dan kelompok kawalan.

Kualiti bukti

Bukti sedia ada sangat terhad.Kebanyakan intervensi dinilai oleh satu kajian kecil. Kebanyakan kajian mempunyai masalah dalam cara perlaksanaan dan menimbulkan keraguan pada keputusan.Penilaian kami tentang kualiti bukti bagi hasil perkembangan kanser adalah rendah.

Kesimpulan penulis

Lebih banyak kajian jangka panjang yang bermutu diperlukan.Sebagaimana kajian lanjutan terhadap rawatan ubat dan rawatan alternatif seperti vitamin, kajian yang menilai keberkesanan dan keselamatan surgeri dan pemberhentian faktor risiko merokok juga diperlukan.

Catatan terjemahan

Diterjemahkan oleh Noorliza Mastura Ismail (Kolej Perubatan Melaka-Manipal). Untuk sebarang pertanyaan berkaitan terjemahan ini sila hubungi noorliza.mastura@manipal.edu.my. Disunting oleh Norhayati Mohd Noor (Universiti Sains Malaysia).

Laienverständliche Zusammenfassung

Interventionen zur Behandlung von oraler Leukoplakie zur Vorbeugung von oralem Krebs

Fragestellung

Menschen mit oraler Leukoplakie stehen unter größerem Risiko Mundkrebs zu entwickeln, verglichen mit denen mit normaler Mundschleimhaut. Dieser Review, erstellt von der Cochrane Oral Health Groupversucht zu bewerten, ob Personen, die von Leukoplakie betroffen sind, einen Nutzen von entweder lokalen oder systematischen chirurgischen, medizinischen oder ergänzenden Behandlungen haben. Das bedeutet, wir erstellten diesen Review, um herauszufinden, ob eine Behandlung Mundkrebs bei Personen mit Leukoplakie im Mund vorbeugen kann und wenn ja welche Behandlung dies kann. Dieser Review ist die Aktualisierung eines Reviews, der 2006 veröffentlicht wurde.

Hintergrund

Eine orale Leukoplakie ist ein weißer Belag auf der Mundschleimhaut, der nicht entfernt werden kann. Es verursacht oft keine Schmerzen und kann unbemerkt über Jahre hinweg vorliegen. Personen mit Leukoplakie entwickeln häufiger Mundkrebs, als Personen ohne Leukoplakie. Dessen Vorbeugung ist wichtig, da die fünf-Jahres-Überlebensrate nach der Diagnose von Mundkrebs, gering ist. Medikamente, Operationen und andere Therapien sind als Behandlung von oraler Leukoplakie versucht worden.

Zielsetzungen

Dieser Review soll bewerten, ob die Behandlungen von oraler Leukoplakie wirksam für die Vorbeugung von Mundkrebs sind und ob sie sicher und annehmbar für die Patienten sind.

Studienmerkmale

Die Evidenz auf der dieser Review basiert, ist auf dem Stand von Mai 2016. Wir fanden 14 randomisierte kontrollierte Studien (RCTs) zu medizinischen und ergänzenden Behandlungen, welche insgesamt 909 Teilnehmende einschlossen. Behandlungen umfassten Kräuterextrakte, entzündungshemmende Medikamente, Vitamin A, Beta-Carotin-Supplementierungen und andere. Operative Behandlungen wurden in keiner RCT mit Placebo oder keiner Behandlung verglichen.

Hauptergebnisse

Die Krebsentwicklung wurde in Studien zu drei Behandlungen erfasst: systemisches Vitamin A, systemisches beta-Carotin und topisches Bleomycin. Keine dieser Behandlungen zeigte eine Wirksamkeit bezüglich der Vorbeugung einer Krebs-Entwicklung, gemessen bis zu zwei Jahre bei Vitamin A und beta-Carotin und bis zu sieben Jahren bei Bleomycin.

Einige einzelne Studien von Vitamin A und beta-Carotin legen nahe, dass diese Behandlungen bei der Verbesserung oder Heilung von oralen Verletzungen wirksam sein könnten. Einige Studien beobachteten jedoch eine hohe Rückfallrate bei Patienten, deren Verletzungen anfänglich durch die Behandlung geheilt wurden.

Die meisten Behandlungen verursachten bei einem hohen Anteil der Teilnehmer Nebenwirkungen von unterschiedlicher Schwere.

Es scheint wahrscheinlich, dass die Maßnahmen von den Teilnehmern gut akzeptiert wurden, da die Rate der Studienabbrecher in der Behandlungs- und der Kontrollgruppe ähnlich war.

Qualität der Evidenz

Die verfügbare Evidenz ist sehr begrenzt. Die meisten Behandlungen wurden lediglich in einer kleinen Studie erhoben. Die meisten Studien wiesen Probleme in ihrer Durchführung auf, was ihre Ergebnisse unzuverlässig macht. Wir bewerteten die Qualität der Evidenz für den Endpunkt Krebsentwicklung als sehr niedrig.

Schlussfolgerung der Autoren

Größere, bessere und längerfristige Studien sind nötig. Neben weiteren Studien bezüglich der Behandlung mit Medikamenten und alternativen Behandlungen, wie Vitamine, werden auch Studien zur Bewertung der Wirksamkeit und Sicherheit von Operationen und von Verhaltensänderungen bezüglich Risikofaktoren, wie Rauchen, benötigt.

Anmerkungen zur Übersetzung

I. Nolle, freigegeben durch Cochrane Deutschland.

概要

治疗口腔白斑病预防口腔癌的干预措施

系统综述问题

患有口腔白斑病的人比正常口腔黏膜的人患口腔癌的风险更高。这项由Cochrane口腔健康组所完成的综述,旨在评估受白斑病影响的人是否能从手术、医疗或补充治疗中获益,无论是局部的还是全身的。特别地,我们进行了这项研究,以找出是否存在可能的治疗能够预防口腔癌的白斑病患者患口腔癌。这篇综述是对我们2006年发表的综述的更新。

背景

口腔白斑是在口腔粘膜上形成的白色斑块,不能被擦掉。它通常不会造成伤害,可能会被忽视很多年。患有白斑病的人比不患的人更容易患口腔癌。预防这一点是至关重要的,因为在确诊后五年内,口腔癌的存活率很低。药物、手术和其他治疗方法治疗口腔白斑病已进行过相关临床试验。

目的

本综述旨在评估口服白斑病的治疗方法是否能有效地预防口腔癌,以及对患者的安全和可接受度。

研究特征

这篇更新综述的证据是基于2016年5月的文献。我们发现了14项药物和补充疗法的随机对照试验(RCTs),共涉及909名研究对象。治疗方法包括草药提取物、抗炎药、维生素A、胡萝卜素补充剂等。在RCT中,外科治疗没有与安慰剂或没有治疗相比较。

主要结果

三种治疗方法的研究测量了癌症的发生:系统性的维生素A,全身性的胡萝卜素和局部的布利霉素。这些疗法中没有一个能有效地预防癌症的发生,如测定长达两年的维生素A和β胡萝卜素,七年博莱霉素。

一些维生素A和β胡萝卜素的单个研究表明,这些治疗可能对改善或治愈口腔损伤有效果。然而,一些研究发现,在最初通过治疗来解决病变的患者中,复发率很高。

大多数治疗方法在很大比例的研究对象中造成了不同程度的副作用。

似乎干预措施很可能被研究对象接受,因为在治疗组和对照组之间的退出率是相似的。

证据的质量

现有的证据是非常有限的。大多数的干预措施都是通过一项小规模的研究来评价的。大多数的研究在实施过程中都有问题,致使他们的研究结果不可靠。我们认为癌症发生结果的证据质量很低。

作者结论

更大、更好的研究疗程更长的研究第必需的。除了进一步药物治疗和维生素等替代疗法外的研究,评估手术的效果和安全性以及停止吸烟等危险因素习惯的研究也是需要的。

翻译注解

译者:杨小英,审校:鲁春丽,北京中医药大学循证医学中心,2017年12月6日。

Резюме на простом языке

Вмешательства по лечению лейкоплакии для предупреждения рака полости рта

Вопрос обзора

Люди с лейкоплакией полости рта имеют более высокий риск развития рака полости рта, чем люди со нормальной слизистой оболочкой. Этот обзор, подготовленный в группе Кокрейновских обзоров по здоровью полости рта , стремится оценить, может ли хирургическое, лекарственное или какое-либо дополнительное лечение, будь то местное или системное, помочь людям, страдающим лейкоплакией. В частности, мы разработали этот обзор, чтобы выяснить какой из видов лечения, если таковой существует, может предотвратить появление рака у людей с лейкоплакией полости рта. Это обновление Кокрейновского обзора, опубликованного в 2006.

Актуальность

Лейкоплакия полости рта представляет собой образующийся в ней беловатый налет, который невозможно удалить. Часто симптомы лейкоплакии протекают безболезненно и незаметно в течение многих лет. Люди с лейкоплакией больше подвержены риску возникновения рака, чем люди без неё. Профилактика болезни крайне необходима, так как пятилетняя и более длительная выживаемость при раке полости рта с момента диагностирования очень низкая. Для лечения лейкоплакии полости рта используют лекарственные средства, хирургические и другие виды лечения.

Цели обзора

Этот обзор направлен на выяснение, является ли лечение лейкоплакии эффективным способом профилактики рака полости рта, безопасным и приемлемым способом для пациентов.

Характеристика исследований

Доказательства, на которых основан этот обзор, актуальны на май 2016. Мы обнаружили 14 рандомизированных контролируемых испытаний (РКИ) медицинских и дополнительных видов лечения, в которые было включено в целом 909 человек. Лечение включало в себя растительные экстракты, противовоспалительные лекарственные средства, витамин А, добавки бета каротина и другие. Хирургическое лечение не было сравнено с плацебо или отсутствием лечения в РКИ.

Основные результаты

Развитие рака измеряли в исследованиях трех видов лечения: системного витамина А, системного бета каротина и местного (топического) блеомицина. Ни один из этих видов лечения не показал эффективности в предотвращении развития рака, ни применение витамина А, ни бета-каротина в течение двух лет, ни блеомицина в течение семи лет.

Некоторые отдельные исследования витамина А и бета-каротина позволили предположить, что эти виды лечения могут быть эффективны для улучшения или заживления повреждений полости рта. Однако, в некоторых исследованиях наблюдали высокий уровень рецидивов у участников, у которых поражения полости рта первоначально разрешались с помощью лечения.

Большинство видов лечения вызвало побочные эффекты различной степени тяжести у значительной доли участников.

Вполне вероятно, что вмешательства хорошо переносились участниками, поскольку частота выбывания участников была сходной в группах лечения и контроля.

Качество доказательств

Доступные доказательства очень ограничены. Большинство вмешательств были оценены лишь одним небольшим исследованием. В большинстве исследований были проблемы с тем, как их проводили, что сделало их результаты ненадежными. Мы оценили качество доказательств в отношении исхода - развитие рака, как очень низкое.

Выводы авторов

Необходимы более крупные и качественные исследования с длительной продолжительностью наблюдения. Помимо дальнейших исследований лекарственного и альтернативного лечения, как в случае с витаминами, необходимы исследования по оценке эффективности и безопасности хирургических вмешательств, а также прекращения воздействия таких факторов риска, вредных привычек, как курение.

Заметки по переводу

Перевод: Гумерова Эльвина Эльмеровна. Редактирование: Мулланурова Алия Фаритовна и Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: cochrane.russia.kpfu@gmail.com; cochranerussia@kpfu.ru

Summary of findings(Explanation)

Summary of findings for the main comparison. Vitamin A or retinoids versus placebo for treating oral leukoplakia
  1. *From event rate in control group
    aDowngraded 3 levels as single small study at unclear risk of bias with very imprecise result
    bDowngraded as single small study

Systemic or topical vitamin A vs placebo for treating leukoplakia
Patient or population: people with oral leukoplakia
Intervention: vitamin A or retinoids
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
Number of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Risk with placeboRisk with vitamin A or retinoids
Cancer development at 24 months from start of treatment (treatment lasted 12 months)93 per 100010 per 1000
(1 to 191)
RR 0.11
(0.01 to 2.05)
85
(1 RCT)
⊕⊝⊝⊝
very low a
This study evaluated systemic treatment
Clinical resolution (not completely resolved) at 4 to 12 months

Studies could not be combined in meta-analysis

One study evaluated topical treatment and did not find evidence of benefit

3 studies of systemic vitamin A - 2 showed benefit in terms of clinical resolution, and 1 did not

Histological changes (not improved) at 3 months889 per 1000382 per 1000 (213 to 676)RR 0.43 (0.24 to 0.76)

41

(1 RCT)

⊕⊕⊕⊝
moderate b
This study evaluated systemic treatment
Safety of the intervention at 4 to 12 months3 studies (1 each evaluating topical acitretin, topical 13-cis-retinoic acid, 200,000 IU per week of vitamin A) found no adverse effects. Systemic 13-cis-retinoic acid (1 to 2 mg/kg/d) caused adverse effects of varying severity in 79% of participants
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI = confidence interval; RR = risk ratio; vs = versus; d = day
GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect but may be substantially different
Low quality: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect

Summary of findings 2 Systemic beta carotene or carotenoids vs placebo for treating oral leukoplakia

Summary of findings 2. Systemic beta carotene or carotenoids vs placebo for treating oral leukoplakia
  1. * From event rate in control group
    aDowngraded 3 levels for unclear or high risk of bias and serious imprecision
    bDowngraded 2 levels as single small study at unclear risk of bias

Systemic beta carotene or carotenoids vs placebo for treating oral leukoplakia
Patient or population: people with oral leukoplakia
Intervention: systemic beta carotene
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
Number of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Risk with placeboRisk with beta carotene or carotenoids

Cancer development at

24 months from start of treatment (treatment lasted 12 months)

108 per 100079 per 1000
(26 to 238)
RR 0.73
(0.24 to 2.20)
132
(2 RCTs)
⊕⊕⊝⊝
very low 1
 

Clinical resolution (not completely resolved) at

5 to 12 months

The 3 studies could not be combined in meta-analysis. 2 found benefit for systemic beta carotene, and 1 did not

Histological changes (not improved)

at 5 months (treatment lasted 3 months)

833 per 1000

200 per 1000

(100 to 383)

RR 0.24 (0.12 to 0.46)

58

(1 RCT)

⊕⊕⊝⊝
low 2
 
Safety of the intervention at 5 to 12 months

Systemic beta carotene did not cause any adverse effects in 1 study supplementing 10 mg/d, and caused adverse effects of varying severity in 9% of participants in another study supplementing 360 mg/wk

No adverse effects were reported by participants treated with systemic lycopene in one study

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI = confidence interval; RR = risk ratio; vs = versus; d = day; wk = week
GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but may be substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Summary of findings 3 Non-steroidal anti-inflammatory drugs (NSAIDs) vs placebo for treating oral leukoplakia

Summary of findings 3. Non-steroidal anti-inflammatory drugs (NSAIDs) vs placebo for treating oral leukoplakia
NSAIDs vs placebo for treating oral leukoplakia

Patient or population: people with oral leukoplakia

Intervention: NSAIDs

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
Number of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Risk with placeboRisk with NSAIDs
Cancer developmentNot measured
Clinical resolution (not completely resolved) at 3 months1 study evaluated systemic treatment and 1 evaluated topical treatment. Neither found benefit for NSAIDs
Histological changes (not improved)Not measured

Safety of the intervention

over 3 months

Systemic celecoxib (1 study) - 32 intervention participants reported 56 adverse effects and 20 placebo participants in the placebo group reported 20 adverse effects. Minor adverse events included dizziness, diarrheoa and abdominal pain. 4 participants (2 from the placebo group and 2 from an intervention group) had grade 3 adverse events. 2 participants permanently discontinued treatment owing to an adverse event (grade 2 vision abnormality and hypertension in a participant receiving 400 mg twice daily of celecoxib and a grade 3 ischaemic cerebrovascular accident in a participant receiving 200 mg twice daily of celecoxib)

Ketorolac oral rinse (1 study) caused adverse effects of varying severity in 29% of participants

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI = confidence interval; RR = risk ratio; vs = versus
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

Summary of findings 4 Herbal extracts vs placebo for treating oral leukoplakia

Summary of findings 4. Herbal extracts vs placebo for treating oral leukoplakia
Herbal extracts vs placebo for treating oral leukoplakia

Patient or population: people with oral leukoplakia

Intervention: herbal extracts - tea components; a Chinese herbal mixture; curcumin chewing gum; freeze-dried black raspberry gel

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
Number of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Risk with placeboRisk with herbal extracts
Cancer developmentNot measured
Clinical resolution (not completely resolved) at 3 to 6 months3 studies (1 of freeze-dried black raspberry gel, 1 of green tea extract capsules and 1 of mixed tea treatment) did not find evidence of benefit for the intervention
Histological changes (not improved) at 3 months2 studies (1 of green tea extract capsules and 1 of freeze-dried raspberry gel) did not find evidence of benefit from these interventions
Safety of the intervention up to 3 months3 studies measured adverse effects: green tea extract capsules caused high frequency (93%) of adverse effects of varying severity in 1 study; the mixed tea treatment study did not mention adverse effects; freeze-dried black raspberry gel did not cause any adverse effects
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI = confidence interval; RR = risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

Summary of findings 5 Topical bleomycin vs placebo for treating oral leukoplakia

Summary of findings 5. Topical bleomycin vs placebo for treating oral leukoplakia
  1. * From event rate in control group
    aDowngraded 3 levels as a single small study at unclear risk of bias with imprecise result

Topical bleomycin vs placebo for treating oral leukoplakia
Patient or population: people with oral leukoplakia
Intervention: topical bleomycin
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
Number of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Risk with placeboRisk with topical bleomycin
Cancer development up to 7 years83 per 1000

250 per 1000

(27 to 1000)

RR 3.00
(0.32 to 27.83)
20
(1 RCT)
⊕⊝⊝⊝
very low a
 

Clinical resolution (not completely resolved)

at 3 months

917 per 1000504 per 1000 (266 to 954)RR 0.55 (0.29 to 1.04)

22

(1 RCT)

⊕⊝⊝⊝
very low a
 
Histological changes (not improved) at 3 months818 per 1000401 per 1000 (180 to 900)RR 0.49 (0.22 to 1.10)

21

(1 RCT)

⊕⊝⊝⊝
very low a
 
Safety of the intervention up to 3 months"All patients in the bleomycin group developed erythema with erosion by the end of the applications, whereas erythema developed in the placebo group. Discomfort was reported by 60% of the bleomycin group, but analgesics were not required. Taste of the topical application as well-tolerated. There was no observed systemic toxicity in the patient groups"
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI = confidence interval; RR = risk ratio; vs = versus
GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but may be substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Summary of findings 6 Bowman-Birk inhibitor versus placebo for oral leukoplakia

Summary of findings 6. Bowman-Birk inhibitor versus placebo for oral leukoplakia
  1. * From event rate in control group
    aDowngraded 2 levels as a single small study at high risk of bias

Bowman-Birk inhibitor vs placebo for treating oral leukoplakia

Patient or population: people with oral leukoplakia

Intervention: Bowman-Birk inhibitor

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
Number of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Risk with placeboRisk with Bowman-Birk inhibitor
Cancer developmentNot measured
Clinical resolution (not completely resolved) at 6 months957 per 1000

957 per 1000

(871 to 1000)

RR 1.00 (0.91 to 1.09)

21

(1 RCT)

⊕⊕⊝⊝
low a
 
Histological changes (not improved) at 6 monthsNot measured
Safety of the intervention up to 6 monthsTrial authors reported that there were no significant adverse effects. 33 participants in the intervention group reported 75 adverse effects. 25 participants in the placebo group reported 63 adverse effects
*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI = confidence interval; RR = risk ratio; vs = versus
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

Background

Description of the condition

"The term leukoplakia should be used to recognize white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer" (Warnakulasuriya 2007). Such a definition is the result of the efforts of an international working group comprising specialists in the fields of epidemiology, oral medicine, pathology and molecular biology with a special interest in cancer and precancer, who met in London in 2005. This meeting was co-ordinated by the World Health Organization (WHO) Collaborating Centre for Oral Cancer and Precancer in the UK, to review definitions, classifications, natural history and management of potentially malignant disorders on the basis of previously published work (Axell 1984; Axell 1996; Kramer 1978) and new scientific acquisitions. Thus, 'leukoplakia' is a clinical term that is used when the clinician has excluded any other condition of the oral mucosa that can present as a white lesion (e.g. frictional keratosis, lichen planus, white sponge nevus, hairy leukoplakia). Such lesions warrant biopsy and histopathological examination to assess the possible presence of epithelial dysplasia or carcinoma. Leukoplakia is often associated with tobacco smoking or chewing, although idiopathic forms are not rare (Axell 1987). The role of alcohol, viruses and systemic conditions needs further investigation (Dietrich 2004; Syrjänen 2011).

Clinical variants of leukoplakia are often classified into two groups: (1) homogeneous leukoplakia, a lesion of uniform flat appearance that may exhibit superficial irregularities, but with consistent texture throughout; and (2) non-homogeneous leukoplakia, a predominantly white or white and red lesion (erythroleukoplakia) with an irregular texture that may include ulceration and may be characterised by a speckled, nodular or verrucous topography. Histological features of both forms of leukoplakia are variable and may include ortho-keratosis or para-keratosis of various degrees, acanthosis or atrophy of the squamous epithelium, mild inflammation in the corium, dysplastic changes of various grades (i.e. mild, moderate or severe), carcinoma in situ or carcinoma. Some cases of predominantly white lesions that are difficult to diagnose, in spite of the availability of a biopsy.

Leukoplakia is not uncommon, and although it is highly variable among geographical areas and demographic groups, the prevalence of leukoplakia in the general population varies from less than 1% to more than 5% (Axell 1984; Axell 1987; Bouquot 1986; Ikeda 1991; Reichart 2000). In a systematic review that included studies with more than 1000 individuals, the pooled prevalence was estimated to be between 1.49% and 4.27% (Petti 2003). Incidence data are very scarce. A study from Japan reported an age-adjusted incidence rate per 100,000 person-years of 409.2 among males and 70 among females (Nagao 2005), and an Indian study, conducted in a population with distinctive risk factors for oral cancer, reported lower figures: 240 among males and 3 among females (Gupta 1980).

Leukoplakia is one of a group of conditions defined as potentially malignant disorders (i.e. "morphological alterations amongst which some may have an increased potential for malignant transformation, [they] are also indicators of risk of likely future malignancies elsewhere in (clinically normal appearing) oral mucosa and not only site specific predictors") (Warnakulasuriya 2007). The rate of malignant transformation into squamous cell carcinoma varies from almost 0% to 36.4% (Arduino 2013), and a study investigating the natural limit of malignant transformation on the basis of European epidemiological data concluded that the upper limit of the annual transformation rate of oral leukoplakia is unlikely to exceed 1% (Scheifele 2003).

Non-homogeneous leukoplakias carry a higher degree of risk of transformation when compared with homogeneous variants. Among patients with a histopathological diagnosis of dysplasia, about 1/10 of the total may be at higher risk. Other reported risk factors of statistical significance for cancer development in people with leukoplakia include female gender, long duration of leukoplakia, non-smoking status, location on the lateral tongue and/or floor of the mouth, size > 200 mm2 (Holmstrup 2006) and the presence of Candida albicans (Van der Waal 2009). Studies investigating biomarkers and histological features have suggested methods that can be used to identify which patients with leukoplakia will develop oral cancer, and which will not (Pitiyage 2009; Smith 2009); however, a definitive, evidence-based and clinically useful predictor of malignant transformation for dysplastic and non-dysplastic leukoplakias is not available at the moment. Aneuploid lesions (i.e. with abnormal DNA content) are more likely to transform to cancer compared with diploid lesions (i.e. with normal DNA content) (Sperandio 2013; Torres-Rendon 2009).

Description of the intervention

Most leukoplakias are asymptomatic; therefore, the need for treatment is based primarily on the precancerous nature of the lesion, and the primary aim of management should be to avoid development of cancer. This is particularly important in view of the poor prognosis associated with oral squamous cell carcinoma, in which only about 50% of patients are still alive five years after diagnosis (Scully 2009), and of the morbidity associated with oral cancer and complications of oral cancer therapy (Epstein 2012).

Many approaches to the treatment of leukoplakia have been proposed in an attempt to prevent cancer development and to evaluate clinical/histological resolution of oral leukoplakias (Lodi 2008). These approaches include surgical excision with different techniques (scalpel, cryosurgery, photodynamic therapy, laser surgery and vaporisation), medical treatment (topical or systemic), cessation of risk activities (smoking and alcohol) and no intervention but strict surveillance.

How the intervention might work

The rationale of surgical excision is that removing the clinically altered tissue could prevent the onset of oral cancer. For medical treatments, the rationale depends on the mechanism of action of the agent employed: retinoids, vitamin A and carotenoids might influence epithelial turnover; non-steroidal anti-inflammatory drugs (NSAIDs) block cyclo-oxygenase activity, thereby modulating specific prostaglandins possibly involved in carcinogenesis; and chemotherapeutic agents act directly on early neoplastic cells. As many of these treatments have potentially serious adverse effects, the “wait and see” approach, based on strict clinical and histological surveillance, is generally employed to identify early cancer onset and to initiate cancer treatment to render the best possible prognosis. Although surgery and medical treatments aim to remove or reduce the lesion, it must be stressed that no evidence has shown a relationship between changes in size or resolution and decreased risk of oral cancer.

Why it is important to do this review

Cochrane Oral Health undertook an extensive prioritisation exercise in 2014 to identify a core portfolio of titles that were the most clinically important reviews to maintain in The Cochrane Library (Worthington 2015). This review was identified as a priority title by the oral medicine expert panel (Cochrane OHG priority review portfolio). Treatment of leukoplakia continues to be based on expert opinion, and more research is needed. This review aims to provide evidence-based support for clinicians and patients and a clinical research agenda for planning future studies.

Objectives

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

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) comparing effects of surgery, medical or complementary treatments (local or systemic) or risk factor cessation versus placebo.

Types of participants

Anyone with a diagnosis of oral leukoplakia (without histopathological evidence of carcinoma) as defined, at the time of the studies, by consensus conferences held in 1978, 1983, 1994 and 2005 (Axell 1984; Axell 1996; Kramer 1978, Warnakulasuriya 2007).

Types of interventions

Active
  • Surgical removal of the lesion, including surgical excision, laser surgery, cryotherapy

  • Systemic medical treatment

  • Topical medical treatment, including anti-inflammatory agents, antimycotic agents, carotenoids and retinoids, cytotoxic agents, etc.

  • Removal of predisposing habits (e.g. tobacco, alcohol)

  • Other treatment (e.g. photodynamic therapy)

  • Combined treatment

Control
  • Placebo

  • No treatment

Types of outcome measures

In light of the pre-cancerous nature of leukoplakia, the primary objective of treatment is to prevent cancer development.

Primary outcomes
  • Oral cancer development, demonstrated by histopathological examination

Secondary outcomes
  • Clinical resolution, in terms of the proportion of lesions that did not resolve (with relapse data when provided)

  • Improvement of histological features, in terms of the proportion of lesions that did not show improvement in histological features

  • Safety of the intervention, as measured by the incidence of adverse effects

Search methods for identification of studies

To identify studies included in or considered for this review, we developed detailed search strategies for each database searched. These were based on the search strategy developed for MEDLINE Ovid but revised appropriately for each database. The search strategy used a combination of controlled vocabulary and free text terms and was linked with the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomised controlled trials (RCTs) in MEDLINE: sensitivity-maximising version (2008 revision) as referenced in Chapter 6.4.11.1 and detailed in Box 6.4.c of the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011) (Higgins 2011). We have provided details of the MEDLINE search in Appendix 1.

Electronic searches

We searched the following databases.

  • Cochrane Oral Health's Trials Register (to 16 May 2016) (see Appendix 2);

  • The Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 4) (see Appendix 3);

  • MEDLINE Ovid (1946 to 16 May 2016) (see Appendix 1);

  • Embase Ovid (1980 to 16 May 2016) (see Appendix 4);

  • CancerLit via PubMed (1950 to 16 May 2016) (see Appendix 5).

We placed no restrictions on the language or date of publication when searching the electronic databases.

Searching other resources

We searched the following databases for ongoing trials (see Appendix 6 for details of the search strategy).

We manually checked the reference lists of included studies and existing reviews. The metaRegister of Controlled Trials is no longer available and so was not searched in May 2016.

Data collection and analysis

Selection of studies

Two review authors (GL and RF) separately examined the title and abstract of each article identified by the different search strategies. When at least one review author considered the article relevant, it progressed in the review process and was included in a digital archive prepared by using dedicated software. We obtained full reports for all relevant studies.

Data extraction and management

All studies meeting the inclusion criteria underwent data extraction performed by at least two review authors, using a specially designed form. We present the characteristics of trial participants, interventions and outcomes for the included trials in the Characteristics of included studies tables.

Assessment of risk of bias in included studies

Two review authors independently assessed the risk of bias of included trials and resolved disagreements through discussion and consensus. We used the recommended approach for assessing risk of bias in studies included in Cochrane reviews (Higgins 2011a). This approach addresses the following seven specific domains.

  • Random sequence generation (selection bias)

  • Allocation concealment (selection bias)

  • Blinding of participants and personnel (performance bias)

  • Blinding of outcome assessment (detection bias)

  • Incomplete outcome data (attrition bias)

  • Selective reporting (reporting bias)

  • Other bias

Each domain in the tool includes one or more specific entries in a ‘Risk of bias’ table. Within each entry, the first part of the tool describes what was reported to have happened in the study, in sufficient detail to support a judgement about risk of bias. The second part of the tool assigns a judgement related to the risk of bias for that entry - ‘low risk’, ‘high risk’ or ‘unclear risk’. After taking into account the additional information provided by trial authors, we summarised the risk of bias in included studies as follows.

  • Low risk of bias: low risk of bias for all key domains

  • Unclear risk of bias: unclear risk of bias for one or more key domains

  • High risk of bias: high risk of bias for one or more key domains

We completed a 'Risk of bias' table for each included study (see Characteristics of included studies) and presented results graphically by study (Figure 1) and by domain over all studies (Figure 2).

Figure 1.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Measures of treatment effect

The primary measure of intervention effect was onset of oral cancer. Dichotomous data were reported for this outcome measure: cancer development versus absence of cancer development.

Secondary outcomes, clinical resolution, histological changes and adverse effects were usually reported as ordinal measures. We dichotomised data: clinical resolution vs partial or no clinical response; decreased severity vs worsening of histology or no change in histological features.

For each intervention, we sought and summarised data on the number of participants from both intervention and control groups who experienced the event (outcome) and the total number of participants. We analysed dichotomous data by calculating risk ratios. As we anticipated pooling data from studies in which true treatment effects were likely to differ, we planned to use a random-effects model in statistical analyses; however, we used a fixed-effect model because of the very small number of studies combined.

Unit of analysis issues

The individual participant was the unit of analysis.

Dealing with missing data

Whenever possible, we obtained missing data from tables and graphs or through personal contact with study authors. When this was not possible, and we found no evidence that data were missing because of a specific bias, we analysed only available data (Higgins 2011). This represents a change from the previous version of the review, in which missing data were imputed with the assumption that all were poor outcomes.

Assessment of heterogeneity

We assessed the significance of discrepancies in the estimates of treatment effects provided by different trials by using Cochran’s test for heterogeneity and the I² statistic; the latter describes the percentage total variation across studies that is due to heterogeneity rather than to chance. Heterogeneity was considered statistically significant if the P value was less than 0.1. A rough guide to the interpretation of I² given in the Cochrane Handbook for Systematic Reviews of Interventions is as follows: 0 to 40% might not be important, 30% to 60% may represent moderate heterogeneity, 50% to 90% may represent substantial heterogeneity, 75% to 100% represents very substantial ('considerable') heterogeneity (Higgins 2011).

Assessment of reporting biases

We attempted to minimise reporting biases by conducting a thorough search of multiple sources including trial registries, and by making efforts to identify unpublished trials and non-English language publications.

Data synthesis

When valid and relevant data were collected, we undertook a meta-analysis of the data. We grouped and analysed studies on the basis of intervention category. We conducted meta-analyses in Review Manager software, using the Mantel-Haenszel method with a fixed-effect model. We had planned to use a random-effects model, but this would not have been appropriate because of the small number of studies included. We did not pool data when substantial heterogeneity was identified.

Subgroup analysis and investigation of heterogeneity

We had planned to conduct subgroup analyses for smoking and non-smoking participants, and for lesions with or without dysplasia. Unfortunately, as such data were not available, we did not perform subgroup analyses.

Sensitivity analysis

We had planned to undertake sensitivity analysis excluding studies at high risk and at unclear risk of bias.

Summarising findings and assessing the quality of the evidence

We constructed 'Summary of findings' tables for each comparison to present the results for our review outcomes. We assessed the quality of the evidence using GRADE (Grades of Recommendation, Assessment, Development and Evaluation Working Group) criteria.

Results

Description of studies

See Characteristics of included studies, Characteristics of excluded studies and Characteristics of ongoing studies.

Results of the search

This review was originally published in 2001, and updates were published in 2004 and 2006. Since its first publication up until May 2016, we have identified a total of 3438 articles through the search strategy. We have examined titles and abstracts for eligibility and have eliminated those not matching the inclusion criteria. We identified 68 apparently eligible studies and rejected 30 because they were not pertinent. Nine of the studies are ongoing (see Characteristics of ongoing studies for details). After we obtained the full-text version of the remaining 29 studies, we excluded 13 additional studies (Characteristics of excluded studies) - one because it was quasi-randomised, four because of inadequate allocation, four for problems in selection of participants and four for lack of an adequate control group. We categorised two studies as awaiting classification (Califano 2012; Chiba 2012; Characteristics of studies awaiting classification). Thus we included 14 studies in this review. See Figure 3.

Figure 3.

Study flow diagram

Included studies

Characteristics of trial setting and design
Location

Of the 15 studies included, six were conducted in the USA (Armstrong 2013; Hong 1986; Mallery 2014; Mulshine 2004; Papadimitrakopoulou 2008; Tsao 2009), three in India (Sankaranarayan 1997; Singh 2004; Stich 1988), one in Italy (Piattelli 1999), two in China (Li 1999; Sun 2009), one in Canada (Epstein 1994) and one in Japan (Nagao 2015). The setting for all studies was a university hospital.

Design

Ten trials had a two-arm parallel design (Armstrong 2013; Epstein 1994; Hong 1986; Li 1999; Mallery 2014; Mulshine 2004; Nagao 2015; Piattelli 1999; Stich 1988; Sun 2009); three, a three-arm parallel design (Papadimitrakopoulou 2008; Sankaranarayan 1997; Singh 2004); and one, a four-arm parallel design (Tsao 2009). In three of the four studies with more than two arms, we pooled together data from the active arms: interventions differed in dosage in Papadimitrakopoulou 2008; Singh 2004; and Tsao 2009.

Duration

The trials varied in length. Three studies used an open follow-up (Epstein 1994; Nagao 2015; Tsao 2009); one study lasted two years (Sankaranarayan 1997); and all other studies lasted less than one year.

Funding

Two trials did not specify any funding source (Epstein 1994; Sankaranarayan 1997). In two trials, some study authors worked for the company that supplied the study drug (Mulshine 2004; Tsao 2009); in another, the first study author had ownership interest in the patent of the drug tested (Mallery 2014). One study was supported by Central Soya Company and NIH (National Institutes of Health) (Armstrong 2013), one by Hoffmann-La Roche and the National Cancer Institute (Hong 1986), one by the Chinese National Natural Science Foundation (Li 1999), one by NIH (Mallery 2014), one by the National Cancer Institute Specialized Programs of Reasearch Excellence (SPORE) Program (Mulshine 2004), one by the Butterfield Award of the Sasakawa Foundation GB and DSM Nutrition Japan (Nagao 2015), one by Pfizer (Papadimitrakopoulou 2008), one by the Italian National Research Council (CNR) and the Italian Ministry of University, Research, Science and Technology (MURST) (Piattelli 1999), one by Jagsonpal Pharmaceuticals Ltd., New Delhi, India (Singh 2004), one by the National Cancer Institute of Canada (Stich 1988), one by the Beijing Natural Science Foundation, the National Natural Science Foundation of China and the Tenth 5-Year Plan of National Key Technologies R&D Program in China and NIH (Sun 2009) and one by Ito En Ltd. (Tsao 2009).

Characteristics of participants

The total number of participants randomised in the trials was 909, with a mean of 64.9 participants per study (ranged from 10 to 131 participants).

The reported proportion of smoking and drinking participants (the two main risk factors for oral cancer) varied from 8% (Papadimitrakopoulou 2008) to 86% (Mulshine 2004), and from 9% (Sun 2009) to 71% (Mulshine 2004), respectively. Use of tobacco products (Mallery 2014) and smoking (Nagao 2015) were exclusion criteria in two studies. None of the study authors reported significant changes in these habits during the course of the trial. In two studies, all participants recruited were chewers of tobacco-containing betel quid (another well-known risk factor for oral cancer) from the same Indian village (Trivandrum, Kerala) (Sankaranarayan 1997; Stich 1988). All participants enrolled in the studies underwent a confirmatory biopsy; however, only four studies reported the histological criteria employed (Epstein 1994; Papadimitrakopoulou 2008; Stich 1988; Sun 2009). Seven studies reported the percentage of dysplastic lesions, which ranged from 18.75% (Sun 2009) to 73.2% (Tsao 2009) (see Table 1). One study excluded lesions with severe dysplasia (Li 1999), and another study included cases with at least one of the following features: at least mild dysplasia, high-risk location, significant extent of tissue involvement and presence of symptoms (Tsao 2009).

Table 1. Participants with dysplastic leukoplakia
Study Participants with dysplastic leukoplakia (any grade)
Armstrong 2013Not reported
Epstein 199422%
Hong 198627%
Li 199920%
Mallery 201472.5%
Mulshine 2004Not reported
Nagao 2015Not reported
Papadimitrakopoulou 2008Not reported
Piattelli 1999Not reported
Sankaranarayan 1997Not reported
Singh 200459%
Stich 1988Not reported
Sun 200918.75%
Tsao 200973.2%
Characteristics of interventions

We did not identify any RCTs that compared surgical treatments with placebo or no treatment, nor did we identify any RCTs of risk factor cessation. All included trials compared medical or complementary treatment versus placebo, usually a preparation similar to the treatment, without the active ingredient; in one case, the placebo contained vitamin C, which we considered an inactive ingredient (Nagao 2015).

Four RCTs compared topical treatment versus placebo (129 participants) (Epstein 1994; Mallery 2014; Mulshine 2004; Piattelli 1999), and nine RCTs compared systemic treatment versus placebo (716 participants) (Armstrong 2013; Hong 1986; Nagao 2015; Papadimitrakopoulou 2008; Sankaranarayan 1997; Singh 2004; Stich 1988; Sun 2009; Tsao 2009). One RCT compared a combination of topical and systemic treatments versus placebo (64 participants) (Li 1999).

Four studies tested vitamin A or retinoids (Hong 1986; Piattelli 1999; Sankaranarayan 1997; Stich 1988); three studies tested beta carotene or carotenoids (Nagao 2015; Sankaranarayan 1997; Singh 2004); two studies tested NSAIDs: ketorolac (Mulshine 2004) and celecoxib (Papadimitrakopoulou 2008); and four studies tested herbal extracts, in particular, tea components (Li 1999 - mixed; Tsao 2009 - green tea extract capsules), a Chinese herbal mixture (Sun 2009) and gel containing freeze-dried black raspberries (Mallery 2014). The other interventions tested were bleomycin (Epstein 1994) and Bowman-Birk inhibitor (Armstrong 2013).

Characteristics of outcomes

Five studies reported data on oral cancer development (Epstein 1994; Nagao 2015; Papadimitrakopoulou 2008; Sankaranarayan 1997; Tsao 2009). In Epstein's trial, although seven out of 12 participants in the control group received the active treatment at the end of the study period, we conducted an intention-to-treat (ITT) analysis for this review.

All studies used lesion measurement as the clinical parameter to assess change; five studies also used pictures of the lesions for clinical evaluation (Armstrong 2013; Epstein 1994; Hong 1986; Mallery 2014; Piattelli 1999). In 11 RCTs, a complete response was defined as complete disappearance of the lesion (Armstrong 2013; Epstein 1994; Hong 1986; Li 1999; Mulshine 2004; Nagao 2015; Papadimitrakopoulou 2008; Piattelli 1999; Sankaranarayan 1997; Singh 2004; Tsao 2009), lasting at least four weeks in four of them (Hong 1986; Mulshine 2004; Sankaranarayan 1997; Singh 2004). For partial response, nine studies used the definition 'greater than 50% reduction', and one used a slightly different criterion - 'greater than 30% reduction' (Li 1999). Three studies defined “stable disease” as a reduction of less than 50% of the lesion (Hong 1986; Mulshine 2004; Singh 2004); three studies adopted an otherwise non-specified "unchanged clinical aspect" (Li 1999; Stich 1988; Sun 2009); and two studies defined "stable disease" as lesions not satisfying any other category (Papadimitrakopoulou 2008; Tsao 2009). Eight studies gave similar definitions of "disease progression" as an increase in the size of the lesion or the appearance of new lesions (Armstrong 2013; Hong 1986; Li 1999; Mulshine 2004; Papadimitrakopoulou 2008; Singh 2004; Sun 2009; Tsao 2009). One study included the "no response" category, indicating stable and progressive lesions (Sankaranarayan 1997). Three studies adopted different categories for clinical evaluation. Stich 1988 used the following: remission, no change, new leukoplakia. Sun 2009 used positive response (including complete and partial response), stable disease and progressive disease. One study reported the change in lesion measurement, expressed in mm2 (Mallery 2014). Clinical response was recorded immediately at the end of treatment in 10 studies (Armstrong 2013; Li 1999; Mallery 2014; Nagao 2015; Papadimitrakopoulou 2008; Piattelli 1999; Sankaranarayan 1997; Singh 2004; Stich 1988; Tsao 2009), two weeks after the end of treatment in Epstein 1994 and three months after the end of treatment in Sun 2009. In two studies, it was not clear when the reported clinical assessment was recorded (Hong 1986; Mulshine 2004).

Six studies reported assessment of histological changes (Armstrong 2013; Epstein 1994; Hong 1986; Papadimitrakopoulou 2008; Singh 2004; Tsao 2009). These studies did not use a unique histological classification, and the comparison between pre-treatment and post-treatment histological features was highly variable. One study defined histological response as an otherwise non-specified "reversal" or "improvement" of dysplastic features (Papadimitrakopoulou 2008); another adopted a graphical method for evaluating histological changes (Armstrong 2013). Stich 1988 reported histological changes in the treatment group only. In one study, a control biopsy was taken only if development of cancer was suspected (Sankaranarayan 1997).

Biomarkers evaluated included bcl-2 immunostaining (Piattelli 1999), AgNOR (silver-stained nucleolar organizer region) and PCNA (proliferation cell nuclear antigen) labelling indexes (Li 1999; Sun 2009), biomarkers of DNA damage in exfoliated cells and peripheral blood lymphocytes (Li 1999), Neu protein of exfoliated cells and serum (Armstrong 2013), epidermal growth factor receptors (EGFRs) (Li 1999) and p53 and Ki67 (protein; cellular marker of neoplasia) (Nagao 2015).

Most trials monitored safety of the intervention. Only Li 1999 and Sun 2009 did not appear to measure adverse effects.

Excluded studies

The primary reason for exclusion of each study is given in the Characteristics of excluded studies table. Many trials were ineligible for more than one reason; however, the more common reasons for exclusion were inappropriate selection of participants, lack of random allocation and absence of a proper control arm. In particular, although we found three randomised controlled trials evaluating surgical interventions (Chee 2013; López-Jornet 2013; Schwarz 2005), we were unable to include them in the review as they did not include a no treatment or placebo group.

Risk of bias in included studies

On the basis of criteria used in the critical appraisal of studies, one study had an overall low risk of bias (Hong 1986). We judged seven studies as having unclear risk of bias (Epstein 1994; Mallery 2014; Papadimitrakopoulou 2008; Piattelli 1999; Sankaranarayan 1997; Singh 2004; Tsao 2009). We considered the remaining studies to be at high risk of bias (Armstrong 2013; Li 1999; Mulshine 2004; Nagao 2015; Stich 1988; Sun 2009). See Figure 1 and Figure 2.

Allocation

We assessed the generation of the randomisation sequence as having low risk of bias for six trials and unclear risk for eight trials.

We assessed the concealment of allocation as having low risk of bias for three trials, at unclear risk for 10 trials and at high risk for one trial (Armstrong 2013). In Armstrong 2013, the block size was two.

Blinding

We assessed blinding of participants and personnel, as well as blinding of outcome assessment, as low risk of bias for 11 trials and unclear risk for four studies in which not enough information was provided.

Incomplete outcome data

The reported drop-out rate ranged from 0% (Epstein 1994; Mallery 2014; Singh 2004) to 32.5% (Armstrong 2013). We assessed 11 trials as having low risk of bias with regard to attrition bias because they reported there were no drop-outs, or because drop-out was not likely to influence findings. We assessed three studies with high drop-out rates as having high risk of bias (Armstrong 2013; Nagao 2015; Stich 1988).

Selective reporting

Most trials reported important outcomes and were assessed as having low risk of bias. Five studies failed to report histological results (Li 1999; Mulshine 2004; Nagao 2015; Stich 1988; Sun 2009); we assessed these trials as having high risk of bias for this domain.

Other potential sources of bias

We assessed Epstein 1994, which had discrepant published and unpublished data, along with baseline imbalance, as having unclear risk of bias for this domain. See Figure 2.

Effects of interventions

See: Summary of findings for the main comparison Vitamin A or retinoids versus placebo for treating oral leukoplakia; Summary of findings 2 Systemic beta carotene or carotenoids vs placebo for treating oral leukoplakia; Summary of findings 3 Non-steroidal anti-inflammatory drugs (NSAIDs) vs placebo for treating oral leukoplakia; Summary of findings 4 Herbal extracts vs placebo for treating oral leukoplakia; Summary of findings 5 Topical bleomycin vs placebo for treating oral leukoplakia; Summary of findings 6 Bowman-Birk inhibitor versus placebo for oral leukoplakia

Vitamin A and retinoids versus placebo

Four studies (one at high, two at unclear and one at low risk of bias) compared vitamin A and retinoids versus placebo. Three of these studies evaluated systemic treatment (Hong 1986; Sankaranarayan 1997; Stich 1988), and one evaluated topical treatment (Piattelli 1999).

Oral cancer development

One study reported effects of systemic vitamin A on cancer incidence (Sankaranarayan 1997). Investigators found no evidence of benefit compared with placebo (risk ratio (RR) 0.11, 95% confidence interval (CI) 0.01 to 2.05; 85 participants) (Analysis 1.1; Figure 4).

Figure 4.

Forest plot of comparison: 1 Vitamin A or retinoids vs placebo, outcome: 1.1 Cancer development

Clinical resolution

Five studies reported effects of vitamin A or retinoids on clinical features of leukoplakia, in particular, on its resolution (Analysis 1.2; Figure 5). In particular, three studies tested systemic treatment (Hong 1986; Sankaranarayan 1997; Stich 1988), but because heterogeneity was high (I2 = 94%), it was inappropriate to combine findings in a meta-analysis. Two of the three studies at high or unclear risk of bias showed some benefit (Sankaranarayan 1997: RR 0.51, 95% 0.37 to 0.71; 85 participants; Stich 1988: RR 0.44, 95% CI 0.27 to 0.73; 54 participants), but Hong 1986, which was at low risk of bias, showed no clear evidence of benefit (RR 0.92, 95% CI 0.78 to 1.08; 40 participants).

Figure 5.

Forest plot of comparison: 1 Vitamin A or retinoids vs placebo, outcome: 1.2 Oral lesion not completely resolved

Hong 1986 provided relapse data: nine out of 16 (56%) participants who responded to treatment (partially or completely) subsequently relapsed (no information was available regarding the two partial responders from the placebo group). Sankaranarayan 1997 reported that 14 out of 22 (64%) complete responders developed recurrent lesions (no information was available regarding the three complete responders in the placebo group).

One study at unclear risk of bias tested topical treatment (nine participants) and found treatment was not more likely to completely resolve the lesion than placebo: RR 0.83, 95% CI 0.48 to 1.44 (Piattelli 1999).

In Piattelli 1999, one out of five (20%) participants responding completely or partially to the experimental treatment relapsed, and one out of four (25%) participants responding to placebo relapsed.

Improvement of histological features

A single study recorded histological improvement and showed that improvement in histological features of lesions was more likely in participants treated with systemic retinoic acid than in those treated with placebo (RR 0.43, 95% CI 0.24 to 0.76; 39 participants; Analysis 1.3) (Hong 1986).

Safety

Topical 13-cis-retinoic acid (Piattelli 1999) and 200,000 IU per week of vitamin A (Stich 1988) produced no adverse effects. Systemic 13-cis-retinoic acid (1 to 2 mg/kg/d) (Hong 1986) caused adverse effects of varying severity in 79% of participants (see Table 2). Two participants withdrew from Hong 1986 because of severe conjunctivitis and hypertriglyceridaemia.

Table 2. Participants reporting adverse effects
  1. vs = versus

StudyArmsActive treatmentPlaceboAdverse effects
Armstrong 2013Bowman Birk inhibitor concentrate vs placebo75 reported from 33 of 67 participants63 reported from 25 of 65 participantsMinor adverse effects
Epstein 1994Topical bleomycin vs placebo10/100/12

Bleomycin group - erythema and erosion (100%), discomfort (60%)

Placebo group - erythema only

Hong 1986Systemic 13-cis-retinoic acid (from 1 to 2 mg/kg per day) vs placebo19/244/20Cheilitis, facial erythema, dryness and peeling of skin, conjunctivitis, hypertriglyceridaemia
Li 1999Systemic and topical tea vs placebo  Not measured or reported
Mallery 2014Freeze-dried black raspberry gel vs placebo gel0/220/18"No participant experienced any treatment-associated complications"
Mulshine 2004Ketorolac oral rinse vs placebo11/383/19Pain, toxicity grade 1 and 2
Nagao 2015Beta carotene and vitamin C vs placebo0/230/23No untoward side effects were noted
Papadimitrakopoulou 2008Celecoxib vs placebo56 reported from 32 participants20 reported from 18 participants4 participants presented grade 3 adverse events: 2 in placebo arm and 2 in active treatment arm. 2 participants from intervention groups discontinued treatment owing to adverse effects (1 grade 2 and 1 grade 3).
Piattelli 1999Topical 13-cis-retinoic acid vs placebo0/50/5"No side effects from the use of the gel
were ever observed"
Sankaranarayan 1997Vitamin A (300,000 IU per week) vs placebo13/501/55Headache, muscular pain, dry mouth
Sankaranarayan 1997Beta carotene (360 mg per week) vs placebo5/551/55Headache, muscular pain
Singh 2004Lycopene (8 mg or 4 mg) vs placebo0/400/18"No side effects, toxicity of any sort were encountered in the complete duration of the therapy"
Stich 1988Vitamin A (200,000 IU per week) vs placebo0/300/35"The administered doses of vitamin A did not produce any detectable adverse
effects during the trial period"
Sun 2009Chinese herbal mixture vs placebo  Not measured or reported
Tsao 2009Green tea extract at different doses (500, 750 or 1000 mg/m2 daily) vs placebo28/308/11Grade 1 to 2 adverse events including insomnia, headache, nausea and nervousness

Beta carotene or carotenoids versus placebo

Three studies compared systemic beta carotene or carotenoids versus placebo (Nagao 2015; Sankaranarayan 1997; Singh 2004).

Oral cancer development

Two studies reported the effects of systemic beta carotene on cancer incidence (Nagao 2015; Sankaranarayan 1997). Investigators found no evidence of benefit when compared with placebo (RR 0.71, 95% CI 0.24 to 2.09; 132 participants; I2 = 0%; Analysis 2.1; Figure 6).

Figure 6.

Forest plot of comparison: 2 Beta carotene or carotenoids vs placebo, outcome: 2.1 Cancer development

Clinical resolution

Three studies tested effects of systemic beta carotene and carotenoids on clinical resolution (Nagao 2015; Sankaranarayan 1997; Singh 2004) (Analysis 2.2; Figure 7). Owing to high heterogeneity (I2 = 87%), it was not appropriate to combine findings in a meta-analysis. Two of the individual studies, which were at unclear risk of bias, found that systemic beta carotene was more effective than placebo for complete resolution of the lesion (Sankaranarayan 1997: RR 0.72, 95% CI 0.58 to 0.90; 89 participants; Singh 2004: RR 0.61, 95% CI 0.47 to 0.80; 58 participants). The other study, at high risk of bias, failed to show evidence of benefit (Nagao 2015: RR 0.95, 95% CI 0.84 to 1.08; 43 participants).

Figure 7.

Forest plot of comparison: 2 Beta carotene or carotenoids vs placebo, outcome: 2.2 Oral lesion not completely resolved

Sankaranarayan 1997 reported that eight out of 15 (54%) complete responders developed recurrent lesions (no information was available regarding the three complete responders in the placebo group).

Improvement of histological features

Evidence of histological improvement was recorded when lycopene (a carotenoid) was compared with placebo (RR 0.24, 95% CI 0.12 to 0.46; one study; 58 participants; Analysis 2.3) (Singh 2004).

Safety

Systemic treatment with beta-carotene produced no adverse effects in one study supplementing 10 mg/d (Nagao 2015). It caused adverse effects of varying severity in 9% of participants in another study supplementing 360 mg/wk (Sankaranarayan 1997). Researchers reported no adverse effects among participants treated with systemic lycopene (Singh 2004). See Table 2.

Non-steroidal anti-inflammatory drugs (NSAIDs) versus placebo

Two studies at unclear risk of bias compared NSAIDs - ketorolac in Mulshine 2004 and celecoxib in Papadimitrakopoulou 2008 - versus placebo.

Oral cancer development

Cancer development was among the outcomes reported in Papadimitrakopoulou 2008. This did not occur in either arm, probably because of the extremely short duration of the study (12 weeks).

Clinical resolution

Investigators found no evidence of benefit for systemic celecoxib (Papadimitrakopoulou 2008: RR 0.94, 95% CI 0.83 to 1.08; 46 participants) nor topical ketorolac (Mulshine 2004: RR 0.94, 95% CI 0.81 to 1.10; 56 participants) compared with placebo in terms of clinical resolution of lesions (Analysis 3.1).

Improvement of histological features

Histological changes were not among the outcomes in the studies testing NSAIDs.

Safety

In Papadimitrakopoulou 2008, which tested systemic celecoxib, trialists reported that the treatment was "safe and well tolerated". Thirty-two intervention participants reported 56 adverse effects, and 20 placebo participants reported 20 adverse effects. Minor adverse events included dizziness, diarrheoa and abdominal pain. No participants had grade 4 adverse events. Four participants (two from the placebo group and two from an intervention group) had grade 3 adverse events. Two people discontinued treatment due to an adverse event (grade 2 vision abnormality and hypertension in a participant receiving 400 mgtwice daily of celecoxib and a grade 3 ischemic cerebrovascular accident in a participant receiving 200 mg twice daily of celecoxib.

Ketorolac oral rinse caused adverse effects of varying severity in 29% of participants (see Table 2). One person withdrew from the trial after the first dose because of mouth pain.

Herbal extracts versus placebo

Four studies compared herbal extracts, in particular, tea components (Li 1999; Tsao 2009), a Chinese herbal mixture (Sun 2009) and freeze-dried black raspberry gel (Mallery 2014), versus placebo.

Oral cancer development

Cancer development was among the outcomes in Tsao 2009; however, it was not possible to analyse data because trial authors reported the cumulative number of cases, without specifying the allocation arm.

Clinical resolution

The four studies testing herbal extracts included clinical resolution among outcomes (Analysis 4.1).

Systemic treatment with green tea extract showed no evidence of benefit in terms of clinical resolution of leukoplakia when compared with the control in one study at unclear risk of bias (Tsao 2009: RR 0.99, 95% CI 0.86 to 1.14; 39 participants). Li 1999, which was at high risk of bias, investigated a treatment integrating systemic (capsules containing 0.38 g of dried mixture of the whole water extract of green tea, green tea polyphenols and tea pigments) and topical preparations of mixed tea extract (mixed tea in glycerin at the concentration of 10%), but was not able to demonstrate benefit when compared with placebo in terms of clinical resolution (RR 1.00, 95% CI 0.94 to 1.07; 59 participants).

In one study investigating effects of a Chinese herbal mixture, it was not possible to extract data on clinical resolution (Sun 2009).

One topical herbal treatment (freeze-dried black raspberries) showed no evidence of benefit when compared with placebo in a study that was at unclear risk of bias (Mallery 2014: RR 4.13, 95% CI 0.21 to 80.91; 40 participants). Among participants who did respond to such treatment, six of 22 (32%) in the treatment arm and seven of 17 (41%) in the placebo arm had visible evidence of lesion recurrence at former treatment sites at three months post trial follow-up (Mallery 2014).

Improvement of histological features

In two studies reporting histological changes, neither active treatment (topical freeze-dried black raspberries and systemic green tea extract) showed benefit when compared with placebo (Mallery 2014: RR 0.97, 95% CI 0.58 to 1.60; Tsao 2009: RR 0.86, 95% CI 0.66 to 1.13; Analysis 4.2).

Safety

People undergoing treatment with green tea reported very high frequency (93%) of adverse effects of varying severity in one study (Tsao 2009). Adverse effects were not mentioned in Li 1999. Freeze-dried black raspberry gel caused no adverse effects (Mallery 2014). Sun 2009 stated, "drug toxicity was not monitored in the clinical trial". See Table 2.

Topical bleomycin versus placebo

Topical bleomycin was tested against placebo in a single small study at unclear risk of bias that included 22 participants (Epstein 1994). Following post-treatment biopsy, seven participants in the placebo group were crossed over to receive the active intervention. An ITT analysis was conducted for outcomes measured after post-treatment biopsy.

Mean follow-up from the end of the study was 15 months for group A and 22 months for group B.

Oral cancer development

The trial found no evidence of benefit of topical bleomycin compared with placebo in reducing cancer development among participants affected by leukoplakia (RR 3.00, 95% CI 0.32 to 27.83; 20 participants; Analysis 5.1).

Clinical resolution

Topical bleomycin showed no benefit for clinical resolution when compared with placebo: RR 0.55, 95% CI 0.29 to 1.04. In addition, among participants for whom follow-up information was available, two out of four (50%) participants with a complete response relapsed and one out of two (50%) participants with a partial response relapsed (Analysis 5.2).

Improvement of histological features

Epstein 1994 reported histological changes, showing no benefit of topical bleomycin when compared with placebo: RR 0.49, 95% CI 0.22 to 1.10 (Analysis 5.3).

Safety

Topical bleomycin caused adverse effects of varying severity in 100% of participants (see Table 2). Participants in the bleomycin group developed erythema with erosion. Erythema developed in the placebo group; 60% of the bleomycin group reported discomfort but did not require analgesics. The trial found no evidence of systemic toxicity.

Bowman-Birk Inhibitor versus placebo

A single study tested the Bowman-Birk inhibitor against placebo (Armstrong 2013).

Oral cancer development

Cancer development was not among the outcomes of the study testing the Bowman-Birk inhibitor.

Clinical resolution

The topical Bowman-Birk inhibitor showed no benefit for clinical resolution when compared with placebo: RR 1.00, 95% CI 0.91 to 1.09 (Analysis 6.1).

Improvement of histological features

Data on histological changes from Armstrong 2013 were not available for analysis, but study authors reported no statistically significant differences in histological changes between study arms.

Safety

The Bowman-Birk inhibitor caused adverse effects of varying severity in 49% of participants (see Table 2).

Sensitivity analysis

We did not undertake sensitivity analysis excluding studies at high or unclear risk of bias, as the only study at low risk of bias was not included in a meta-analysis (Hong 1986).

Discussion

Leukoplakia is the most common potentially malignant oral disorder. Although rates of oral ccancer development may vary among studies, probably as the result of differences in diagnostic criteria for leukoplakia and follow-up intervals, the morbidity and mortality associated with oral cancer suggest that leukoplakia is a relevant health issue for affected individuals. Yet, of the 14 studies included in the present review, none evaluated a surgical intervention nor the effect of habit cessation, and only three studies provided data on the effects of a medical or complementary treatment on cancer incidence.

Summary of main results

At present, there is no evidence that any of the medical or complementary treatments studied for people with leukoplakia can reduce the likelihood of oral cancer development. It should be noted that this conclusion is based on only three studies, namely, those testing systemic vitamin A, systemic beta carotene and topical bleomycin. These studies, which were at high or unclear risk of bias, included relatively few participants and had limited follow-up. Overall, the quality of the evidence was very low.

Clinical change, in terms of variation in lesion size, was an outcome reported by all studies, although esearchers used different methods of measurement. Some single studies suggested effectiveness of some proposed treatments, namely, vitamin A, beta carotene and lycopene, in achieving complete clinical resolution of lesions more often than placebo (Sankaranarayan 1997; Singh 2004; Stich 1988). Similarly, single studies showed that vitamin A and lycopene provided some benefit in terms of improvement in histological features (Hong 1986; Singh 2004).

Leukoplakias generally are not associated with significant signs and symptoms, and the risk of developing cancer is relatively low (i.e. many patients with leukoplakia receive treatment that is not necessary). Therefore, proposed treatments should have minimal propensity for adverse effects. The proportion of participants reporting adverse effects varied between 0 and 100% in the active arms of the included trials, and between 0 and 90% in the placebo arms; however adverse effects were always more common in the study group than in the control group (see Table 2). It seems likely that interventions were well accepted by participants because drop-out rates were similar between treatment and control groups (see Table 3); however, follow-up may not have been long enough to permit this assessment. Adverse effects caused participants to withdraw in three studies: when systemic 13-cis-retinoic acid induced severe conjunctivitis and hypertriglyceridaemia (Hong 1986); when intolerable mouth pain followed the initial ketorolac mouthrinse (Mulshine 2004); and in two participants treated with celecoxib, because of vision abnormality and hypertension in one, and ischaemic cerebrovascular accident in another (Papadimitrakopoulou 2008).

Table 3. Participants leaving the studies
  1. vs = versus

StudyArmsActive treatmentPlacebo
Armstrong 2013Bowman Birk inhibitor concentrate vs placebo24/6719/65
Epstein 1994Topical bleomycin vs placebo0/101/12
Hong 1986Systemic 13-cis-retinoic acid (from 1 to 2 mg/kg per day) vs placebo2/242/20
Li 1999Systemic and topical tea vs placebo3/322/32
Mallery 2014Freeze-dried black raspberry gel vs placebo gel0/220/18
Mulshine 2004Ketorolac oral rinse vs placebo1/380/19
Nagao 2015Beta carotene and vitamin C vs placebo5/235/23
Papadimitrakopoulou 2008Celecoxib vs placebo3/321/18
Piattelli 1999Topical 13-cis-retinoic acid vs placebo0/51/5
Sankaranarayan 1997Vitamin A (300,000 IU per week) vs placebo8/5012/55
Sankaranarayan 1997Beta carotene (360 mg per week) vs placebo9/5512/55
Singh 2004Lycopene (8 mg or 4 mg) vs placebo0/400/18
Stich 1988Vitamin A (200,000 IU per week) vs placebo9/302/35
Sun 2009Chinese herbal mixture vs placebo1/607/60

Overall completeness and applicability of evidence

Less than half (33% to 42%) of people with leukoplakia who develop oral cancer do so within two years of diagnosis (Lind 1987; Silverman 1984), and the incidence of oral cancer increases with the duration of follow-up (Shiu 2000). Therefore, to properly test the effects of treatments on cancer incidence, it would be necessary to plan studies with large groups of participants and a long follow-up period - ideally, multi-centre randomised controlled trials (RCTs) assessing outcomes at 10 years. As the duration of the studies included in this review was less than 12 months in all but four studies (Epstein 1994; Nagao 2015; Sankaranarayan 1997; Tsao 2009), cancer incidence rates are likely to be underestimated. Indeed, most of the studies did not include cancer incidence as an endpoint, but rather employed outcomes that assessed clinical or histological markers or both. Although easier to perform, studies using such outcomes pose a double problem: first, there is little evidence of the predictive value of many of those outcomes; second, they are difficult to compare. In addition, widespread outcomes, such as dysplasia grade, may be affected by high inter-observer and even intra-observer variation (Abbey 1995; Karabulut 1995).

It is noteworthy that, although surgery is the first choice in leukoplakia management for many clinicians, there is an absence of RCTs comparing the effects of surgical excision versus no treatment or placebo (Marley 1998). The only data available are from observational studies comparing rates of cancer incidence in people who did or did not undergo surgical treatment for oral leukoplakias. Such studies have differences in diagnostic and inclusion criteria, follow-up interval, participant characteristics and surgical techniques employed (scalpel, laser, cryotherapy). They show highly variable results and sometimes are conflicting in their conclusions (Saito 2001; Schepman 1998). In addition, on the basis of animal and clinical studies, it has been speculated that surgery itself might act to promote carcinogenesis in pre-malignant oral lesions (Holmstrup 2009). Trials evaluating interventions directed against risk factors (e.g. smoking) are also missing.

The applicability of results of two of the included studies (Sankaranarayan 1997; Stich 1988) should be considered in the context of their different risk factor profile as the participants were all betel quid chewers, a risk factor uncommon in individuals from geographical areas outside South Asia.

Leukoplakias with different histological or molecular characteristics may have different risks of transforming into cancer. However, the value of predictive factors proposed so far in the literature requires sound confirmatory data. The presence of epithelial dysplasia may be predictive of a transformation to oral cancer and the risk of cancer may increase with the severity of dysplastic changes (Lumerman 1995; Schepman 1998; Warnakulasuriya 2011), although this hypothesis has been recently challenged (Holmstrup 2006). Unfortunately, the available data did not allow us to perform a subgroup analysis of lesions with and without dysplasia, thus it is not possible to establish whether any particular treatment may be more indicated in the presence of dysplasia of different severity. Many different molecular biomarkers have been proposed, but no single marker or battery of markers seems predictive enough to be implemented during clinical care.

Quality of the evidence

Of the studies included in the present review, we judged one as having low risk of bias, six asunclear risk of bias and seven ashigh risk of bias. Although these studies were randomised trials, information about randomisation methods was missing or incomplete in most studies. In particular, methods used for random sequence generation were unclear in eight out of 15 studies, and details on allocation concealment were missing in 10 out of 15 studies. The body of evidence for cancer incidence comprises three studies investigating three different treatments: vitamin A, beta carotene and topical bleomycin. We assessed these studies as having very low quality according to GRADE (Grades of Recommendation, Assessment, Development and Evaluation) assessment criteria (see Summary of findings for the main comparison; Summary of findings 2; Summary of findings 5). Thus, the quality and the number of included trials, often with short follow-up times, suggest cautious interpretation of results.

Authors' conclusions

Implications for practice

No randomised controlled trials (RCTs) on surgical treatment for people who have oral leukoplakia have included placebo and active treatment arms. Nor have RCTs examined risk factor cessation (e.g. smoking). Therefore, the effectiveness of these interventions cannot be reliably assessed. None of the medical and complementary treatments studied (vitamin A, beta carotene, bleomycin) has been shown to be effective in preventing cancer onset in people with leukoplakia, and, despite the findings of some studies that vitamin A or beta carotene may be effective in reducing or even resolving oral leukoplakia in the short term, the risk of subsequent relapse seems high.

Implications for research

Although surgery remains the treatment option favoured by most clinicians, the effectiveness of surgery compared with no treatment ("wait and see") has not been assessed in RCTs for prevention of cancer development in people with leukoplakia. Research is needed to assess surgical treatment of patients with leukoplakia and to evaluate effects of risk factor cessation in people with leukoplakia. Larger, better conducted trials of longer duration are required to properly evaluate the effects of any treatment on malignant transformation rates, which should be considered the primary outcome when effectiveness of treatments for leukoplakia is tested.

Acknowledgements

The review authors wish to thank all researchers in cited studies who have provided some of the data used in the review. We also thank members of the Cochrane Oral Health editorial team (Anne Littlewood, Marco Esposito), who assisted with this update, and external referees Isaac van der Waal and Andrew Ness, who provided clinical feedback.

Data and analyses

Download statistical data

Comparison 1. Vitamin A or retinoids versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Oral cancer development1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
1.1 Systemic treatment1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Clinical resolution4 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2.1 Systemic treatment3 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 Topical treatment1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Improvement of histological features1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 Systemic treatment1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 1.1.

Comparison 1 Vitamin A or retinoids versus placebo, Outcome 1 Oral cancer development.

Analysis 1.2.

Comparison 1 Vitamin A or retinoids versus placebo, Outcome 2 Clinical resolution.

Analysis 1.3.

Comparison 1 Vitamin A or retinoids versus placebo, Outcome 3 Improvement of histological features.

Comparison 2. Beta carotene or carotenoids versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Oral cancer development2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Systemic treatment2132Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.24, 2.09]
2 Clinical resolution3 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2.1 Systemic treatment3 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Improvement of histological features1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 Systemic treatment1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 Beta carotene or carotenoids versus placebo, Outcome 1 Oral cancer development.

Analysis 2.2.

Comparison 2 Beta carotene or carotenoids versus placebo, Outcome 2 Clinical resolution.

Analysis 2.3.

Comparison 2 Beta carotene or carotenoids versus placebo, Outcome 3 Improvement of histological features.

Comparison 3. NSAIDs versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Clinical resolution2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Systemic treatment146Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.83, 1.08]
1.2 Topical treatment156Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.81, 1.10]
Analysis 3.1.

Comparison 3 NSAIDs versus placebo, Outcome 1 Clinical resolution.

Comparison 4. Herbal extracts versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Clinical resolution3 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
1.1 Systemic treatment1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 Topical treatment1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.3 Systemic plus topical treatment1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Improvement of histological features2 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2.1 Systemic treatment1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 Topical treatment1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 4.1.

Comparison 4 Herbal extracts versus placebo, Outcome 1 Clinical resolution.

Analysis 4.2.

Comparison 4 Herbal extracts versus placebo, Outcome 2 Improvement of histological features.

Comparison 5. Topical bleomycin versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Oral cancer development1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Clinical resolution1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3 Improvement of histological features1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
Analysis 5.1.

Comparison 5 Topical bleomycin versus placebo, Outcome 1 Oral cancer development.

Analysis 5.2.

Comparison 5 Topical bleomycin versus placebo, Outcome 2 Clinical resolution.

Analysis 5.3.

Comparison 5 Topical bleomycin versus placebo, Outcome 3 Improvement of histological features.

Comparison 6. Bowman-Birk inhibitor versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Clinical resolution1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
Analysis 6.1.

Comparison 6 Bowman-Birk inhibitor versus placebo, Outcome 1 Clinical resolution.

Appendices

Appendix 1. MEDLINE Ovid search strategy

1. exp Leukoplakia, Oral/
2. (erythroplak$ or erythroleukoplak$).ti,ab.
3. (leukoplak$ adj (oral or mucosa$ or mouth$)).ti,ab.
4. (keratosis adj (oral or mucosa$ or mouth$)).ti,ab.
5. (leukokeratosis adj (oral or mucosa$ or mouth$)).ti,ab.
6. ((precancer$ or pre-cancer$ or preneoplas$ or pre-neoplas$) adj6 (oral or mouth$ or mucosa$)).ti,ab.
7. ((white adj (spot$ or lesion$ or patch$)) and (mouth$ or oral or mucosa$)).ti,ab.
8. "oral dysplasia".ti,ab.
9. or/1-8

The above subject search was linked to the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomized trials in MEDLINE: sensitivity maximising version (2008 revision) as referenced in Chapter 6.4.11.1 and detailed in box 6.4.c of The Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 [updated March 2011] (Higgins 2011).

1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized.ab.
4. placebo.ab.
5. drug therapy.fs.
6. randomly.ab.
7. trial.ab.
8. groups.ab.
9. or/1-8
10. exp animals/ not humans.sh.
11. 9 not 10

Appendix 2. Cochrane Oral Health's Trials Register search strategy

(leukoplak* or erthroplak* or erythroleukoplak* or keratosis or leukokeratosis or precancer or pre-cancer or preneoplas* or pre-neoplas* or "white spot*" or "white lesion*" or "white patch*" or "oral dysplasia")

Appendix 3. The Cochrane Central Register of Controlled Trials (CENTRAL) search strategy

#1 MeSH descriptor Leukoplakia, Oral this term only
#2 (erythroplak* in All Text or erythroleukoplak* in All Text)
#3 (oral next leukoplak* in All Text or mucosa* next leukoplak* in All Text or mouth* next leukoplak* in All Text)
#4 (oral next keratosis in All Text or muscoa* next keratosis in All Text or mouth* next keratosis in All Text)
#5 (oral next leukokeratosis in All Text or muscoa* next leukokeratosis in All Text or mouth* next leukokeratosis in All Text)
#6 ( (precancer* in All Text near/6 oral in All Text) or (pre-cancer in All Text near/6 oral in All Text) or (preneoplas* in All Text near/6 oral in All Text) or (pre-neoplas* in All Text near/6 oral in All Text) )
#7 ( (precancer* in All Text near/6 mouth* in All Text) or (pre-cancer in All Text near/6 mouth* in All Text) or (preneoplas* in All Text near/6 mouth* in All Text) or (pre-neoplas* in All Text near/6 mouth* in All Text) )
#8 ( (precancer* in All Text near/6 mucosa* in All Text) or (pre-cancer in All Text near/6 mucosa* in All Text) or (preneoplas* in All Text near/6 mucosa* in All Text) or (pre-neoplas* in All Text near/6 mucosa* in All Text) )
#9 ( ("white spot*" in All Text near/6 mouth* in All Text) or ("white lesion*" in All Text near/6 mouth* in All Text) or ("white patch*" in All Text near/6 mouth* in All Text) )
#10 ( ("white spot*" in All Text near/6 oral in All Text) or ("white lesion*" in All Text near/6 oral in All Text) or ("white patch*" in All Text near/6 oral in All Text) )
#11 ( ("white spot*" in All Text near/6 mucosa* in All Text) or ("white lesion*" in All Text near/6 mucosa* in All Text) or ("white patch*" in All Text near/6 mucosa* in All Text) )
#12 "oral dysplasia" in All Text
#13 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12)

Appendix 4. Embase Ovid search strategy

1. Leukoplakia/
2. (erythroplak$ or erythroleukoplak$).ti,ab.
3. (leukoplak$ adj (oral or mucosa$ or mouth$)).ti,ab.
4. (keratosis adj (oral or mucosa$ or mouth$)).ti,ab.
5. (leukokeratosis adj (oral or mucosa$ or mouth$)).ti,ab.
6. ((precancer$ or pre-cancer$ or preneoplas$ or pre-neoplas$) adj6 (oral or mouth$ or mucosa$)).ti,ab.
7. ((white adj (spot$ or lesion$ or patch$)) and (mouth$ or oral or mucosa$)).ti,ab.
8. "oral dysplasia".ti,ab.
9. or/1-8

The above subject search was linked to the Cochrane Oral Health Group filter for identifying RCTs in EMBASE via OVID:

1. random$.ti,ab.
2. factorial$.ti,ab.
3. (crossover$ or cross over$ or cross-over$).ti,ab.
4. placebo$.ti,ab.
5. (doubl$ adj blind$).ti,ab.
6. (singl$ adj blind$).ti,ab.
7. assign$.ti,ab.
8. allocat$.ti,ab.
9. volunteer$.ti,ab.
10. CROSSOVER PROCEDURE.sh.
11. DOUBLE-BLIND PROCEDURE.sh.
12. RANDOMIZED CONTROLLED TRIAL.sh.
13. SINGLE BLIND PROCEDURE.sh.
14. or/1-13
15. (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.)
16. 14 NOT 15

Appendix 5. CancerLit (PubMed) search strategy

#1 Oral leukoplakia [mh:exp]
#2 oral AND leukoplak*[Title/Abstract]
#3 mucosa* AND leukoplak*[Title/Abstract]
#4 mouth* AND leukoplak*[Title/Abstract]
#5 erthroplak* or erythroleukoplak*[Title/Abstract]
#6 oral AND keratosis[Title/Abstract]
#7 mouth* AND keratosis [tiab]
#8 oral AND leukokeratosis [tiab]
#9 mucosa* AND leukokeratosis [tiab]
#10 mouth* AND leukokeratosis [tiab]
#11 precancer* AND oral [tiab]
#12 pre-cancer* AND oral [tiab]
#13 preneoplas* AND oral [tiab]
#14 pre-neoplas* AND oral [tiab]
#15 precancer* AND mouth*
#16 pre-cancer* AND mouth* [tiab]
#17 preneoplas* AND mouth* [tiab]
#18 pre-neoplas* AND mouth* [tiab]
#19 precancer* AND mucosa* [tiab]
#20 pre-cancer* AND mucosa* [tiab]
#21 preneoplas* AND mucosa* [tiab]
#22 pre-neoplas* AND mucosa* [tiab]
#23 "white spot*" AND mouth* [tiab]
#24 "white spot*" AND oral [tiab]
#25 "white spot*" AND mucosa* [tiab]
#26 "white lesion*" AND mouth* [tiab]
#27 "white lesion*" AND oral [tiab]
#28 "white lesion*" AND mucosa* [tiab]
#29 "white patch*" AND mouth* [tiab]
#30 "white patch*" AND oral [tiab]
#31 "white patch*" AND mucosa* [tiab]
#32 oral AND dysplasia [tiab]
#33 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32

The above subject search was linked to the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomised trials in MEDLINE: sensitivity maximising version (2008 revision) as referenced in Chapter 6.4.11.1 and detailed in box 6.4.a of The Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 [updated March 2011] (Higgins 2011).

#1 randomized controlled trial [pt]
#2 controlled clinical trial [pt]
#3 randomized [tiab]
#4 placebo [tiab]
#5 drug therapy [sh]
#6 randomly [tiab]
#7 trial [tiab]
#8 groups [tiab]
#9 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8
#10 animals [mh] not humans [mh]
#11 #9 NOT #10

[limits: Cancer]

Appendix 6. Trials registries search strategies

metaRegister of Controlled Trials search strategy

leukoplakia

ClinicalTrials.gov search strategy

"oral leukoplakia"

WHO International Clinical Trials Registry Platform search strategy

"oral leukoplakia"

What's new

DateEventDescription
30 June 2016New citation required but conclusions have not changed6 new studies included. 1 previously included study has been excluded, as it was quasi-randomised (Gaeta 2000)
16 May 2016New search has been performedSearch updated

History

Protocol first published: Issue 3, 1999
Review first published: Issue 4, 2001

DateEventDescription
5 August 2008AmendedConverted to new review format
4 July 2006New citation required but conclusions have not changedReview updated. 2 new included studies (Mulshine 2004; Singh 2004), 3 new ongoing studies, 3 newly excluded studies. Conclusions remained essentially the same
25 May 2004New citation required but conclusions have not changedReview updated. 1 new study (Gaeta 2000) has been included, but summary estimates did not change significantly, and conclusions remained essentially the same

Contributions of authors

Giovanni Lodi: main review author, participation in all phases of review preparation
Roberto Franchini: selection of articles, data extraction, text preparation
Elena Varoni: data extraction, interpretation of studies
Saman Warnakulasuriya: interpretation of results, text preparation
Andrea Sardella: selection of articles, interpretation of results
Alexander R Kerr: interpretation of results, text preparation
Antonio Carrassi: group co-ordinator, interpretation of results
LCI MacDonald: updated text, data extraction and analysis, quality assessment
Helen V Worthington: data extraction and analysis, quality assessment

Declarations of interest

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

Sources of support

Internal sources

  • Università degli Studi di Milano, Italy.

External sources

  • School of Dentistry, The University of Manchester, UK.

  • Cochrane Oral Health Group Global Alliance, Other.

    Through our Global Alliance (http://ohg.cochrane.org/partnerships-alliances), the Cochrane Oral Health Group has received support from British Association for the Study of Community Dentistry, UK; British Association of Oral Surgeons, UK; British Orthodontic Society, UK; British Society of Paediatric Dentistry, UK; British Society of Periodontology, UK; Canadian Dental Hygienists Association, Canada; Mayo Clinic, USA; National Center for Dental Hygiene Research & Practice, USA; New York University College of Dentistry, USA; NHS Education for Scotland (NES); and Royal College of Surgeons of Edinburgh, UK

  • National Institute for Health Research (NIHR), UK.

    This project was supported by the NIHR, via Cochrane Infrastructure funding to the Cochrane Oral Health Group. The views and opinions expressed therein are those of the review authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service (NHS) or the Department of Health

Differences between protocol and review

We changed the title to specify that oral leukoplakia is treated to prevent oral cancer.

When it was not possible to obtain missing data from trial authors, and we found no evidence that data were missing because of a specific bias, we analysed only available data (Higgins 2011). This represents a change from the previous version of the review, wherein missing data were imputed with the assumption that all were poor outcomes.

We used fixed-effect rather than random-effects meta-analysis because of the small number of included studies.

In accordance with the methodological recommendations of Cochrane Oral Health, we now include only randomised controlled trials to reduce risk of bias from quasi-randomised studies. Therefore, we have excluded the small, quasi-randomised study (Gaeta 2000) from this version of the review.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Armstrong 2013

Methods

Study design: RCT, parallel-group, 2 arms

Conducted in USA

Number of centres: 8

Recruitment period: May 1999 to September 2009

Funding source: Central Soya Company, NIH

Study duration: 6 months

Participants

Inclusion criteria

At least 18 years old, with histologically proven oral leukoplakia and/or erythroplakia, capable of being measured bi-dimensionally; pre-menopausal and perimenopausal women were required to agree to use adequate birth control methods and to have a negative pregnancy test. At completion of the 4-week run-in phase of the study, during which participants self administered the placebo compound, 75% compliance with administration of drug measured by counting unused drug packets was required for continuation in the study

If recent (within 3 months) histological analysis had not been documented with review of biopsy, 3-mm punch biopsy of representative lesions was conducted after measurement and photodocumentation of the lesion

Exclusion criteria

Use of systemic or topical oral steroids within 3 months, currently pregnant or lactating, presence of head and neck cancer (including in situ disease), history of such within 2 years, retinoid or beta carotene therapy for any reason within 2 years or beta carotene capsules of any size within 6 months (participants were allowed up to 2 multi-vitamins per day), participation in another randomised clinical trial within 6 months

Histological criteria for leukoplakia

Not reported

132 people randomised: 48/132 (36%) reported use of beer, wine or liquor, whereas 56/132 (42%) did not answer questions on alcohol consumption; 28/132 (21%) reported using tobacco (viz., cigarettes, cigars, pipe, oral use), whereas 66/132 (50%) did not answer questions on tobacco use. Percentage of dysplastic lesions was not reported

89 people completed the study: 32/89 females, mean age 60.7 (range 29 to 82), ethnic group 69/89 white, tobacco users 20/89 (but 40/89 unknown), alcohol users 35/89 (but 34/89 unknown)

Group A: randomised 67; 43 completed the study. 41 available for histological analysis

Group B: randomised 65; 46 completed the study. 46 available for histological analysis

Interventions

Group A: 3 grams Bowman-Birk Inhibitor concentrate twice a day for 6 months

Group B: 3 grams placebo (corn tortilla mix) twice a day for 6 months

Compliance control: not reported

Outcomes

Clinical response

The primary end point was relative per cent change in total lesion area after 6 months in the study, and the percentage of participants showing a clinical response on that measure. A complete response was declared if the relative per cent change in total lesion area was minus 100%. A partial response was a relative per cent decrease in total lesion area of 50% or more, without a complete response. Disease progression was a relative per cent increase in total lesion area of at least 50%. Remaining cases were declared to be stable disease

A secondary clinical response measure was change in clinical impression from photographs of lesions based on blinded, comparative judgements of pairs of photographs of the same lesion at baseline and at 6 months on the study using a 7-point scale

Histological response

A single, experienced pathologist compared pre-treatment and post-treatment pairs of tissue specimens. The pathologist was blinded to study arm assignment (drug or placebo), but not to time point of the specimen. For each specimen, the pathologist marked a continuum to indicate the degree of tissue abnormality. The continuum was 140 mm long, and was anchored by the word ‘normal’ on the left and ‘malignant’ on the right. The distance from the left edge of the continuum to the pathologist’s mark, in millimetres, was determined. For analyses, a score was determined by subtracting the pre-treatment value from the 6-month value. The central pathologist also made a direct comparison of pre-treatment and post-treatment specimens, marking a 170-mm continuum anchored on the left by "posttreatment shows no dysplasia in comparison with pretreatment," and on the right by "posttreatment shows greater dysplasia than pretreatment". The centre of the continuum was labelled, "pretreatment and posttreatment show no difference." The reviewer’s mark was coded as the distance from the left edge, in millimetres. On this measure, low scores denote improvement over time, a score of 85 denotes no change and a value greater than 85 indicates histological worsening

Other outcomes included changes in buccal cell and serum Neu protein, buccal cell protease activity, adverse events

Notes

Initially it was required that the total lesion area estimated at baseline be at least 100 mm2, but later this requirement was relaxed to facilitate accrual

Early in the study, participants on the drug arm who showed a partial or complete response at 6 months were allowed to continue treatment for an additional 12 months (total 18 months) with final follow-up at 21 months. However, because of the limited supply of drugs, the protocol was soon modified to limit treatment to 6 months

Bowman-Birk inhibitor concentrate was initially produced and supplied by Central Soya Company, but was later supplied by the NIH/National Cancer Institute/Division of Cancer Prevention pharmacy

Both treatment and placebo groups showed a statistically significant decrease in total lesion area

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Independent randomisation schedules were created for each performance centre (so study-arm assignment would not be confounded with geography). For those centres expected to accrue at a faster rate, the randomisation schedule incorporated a block size of 4. A block size of 2 was used for centres with lighter accrual goals"
Allocation concealment (selection bias)High riskComment: block size 2
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "double blind"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "double blind"
Incomplete outcome data (attrition bias)
All outcomes
High riskComment: high number of lost participants: 43/132 (32.5%)
Selective reporting (reporting bias)Low riskComment: important outcomes and adverse effects reported
Other biasLow riskComment: no other sources of bias identified

Epstein 1994

Methods

Study design: RCT, parallel-group, 2 arms

Conducted in Canada

Number of centres: 1

Recruitment period: unspecified

Funding source: unspecified

Study duration: 2 weeks for treatment plus open follow-up

Participants

Inclusion criteria

Patients older than 18 years with clinically visible leukoplakia and pathological diagnosis of the lesion

Exclusion criteria

Pregnant women, women of childbearing age in whom contraception was not confirmed, cases of carcinoma in situ, invasive SCC and lesions identified as inflammatory in nature

Histological criteria for leukoplakia

Histological diagnosis of hyperkeratosis or acanthosis with or without dysplasia. 22% of the lesions were dysplastic

22 participants randomised: 12/22 females, mean age 56.6 (range 25 to 79), ethnic group not reported, 14 (63%) tobacco users, 10 (45%) alcohol users. Leukoplakia was significantly larger in the placebo group (320 mm2) compared with the test group (76 mm2) at randomisation

Group A: randomised 10; 10 completed the study

Group B: randomised 12; 12 completed the study (12 analysed clinically, 11 analysed histologically)

Interventions

Group A: 1 daily topical application of 1% w/v bleomycin in dimethylsulphoxide for 14 days

Group B: 1 daily topical application of placebo (dimethylsulphoxide only) for 14 days

Compliance control: yes

Outcomes

Cancer incidence

Clinical response

Measurement of the lesion before the start of treatment and weekly during treatment: (1) complete response was defined as no clinical and histological evidence of leukoplakia, (2) partial response was defined as a greater than 50% reduction in the size of the lesion or elimination of dysplasia. Data from the first follow-up visit (2 weeks from the end of treatment) are included in the meta-analysis

Histological response

Histological grading before the start of treatment and 4 weeks after treatment

Other outcomes: assessment of oral burning and pain during application, between applications and with eating. Adverse effects

Notes

After the post-treatment biopsy (4 weeks after treatment), 7 participants in the placebo group were crossed over to receive 1% w/v bleomycin in dimethylsulphoxide. We received unpublished data on malignant transformation and based our ITT analysis on those data

Mean follow-up from the end of the study: 15 months (group A) and 22 months (group B)

Based our analyses on raw data supplied by trial authors

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: “patients were randomised to the drug or placebo arm by the department of Pharmacy, with the use of a table of random numbers”
Allocation concealment (selection bias)Low riskQuote: “patients were randomised to the drug or placebo arm by the department of Pharmacy”
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: “double blind”
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: “double blind”
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data with the exception of 1/12 (8.3%) histological outcome in the control group
Selective reporting (reporting bias)Low riskComment: important outcomes and adverse effects reported
Other biasUnclear riskSome areas of concern: discrepancies between published and raw data; baseline imbalance in lesion size; cross-over to intervention of more than half of participants in the placebo group

Hong 1986

Methods

Study design: RCT, parallel-group, 2 arms

Conducted in USA

Number of centres: unspecified

Recruitment period: unspecified

Funding source: supported by a grant from Hoffmann-La Roche and in part by a grant from the National Cancer Institute

Study duration: 9 months (3 months of treatment plus 6 months of follow-up)

Participants

Inclusion criteria

Histologically confirmed oral leukoplakia

Exclusion criteria

Women with reproductive capacity, persons taking megadoses of vitamin A (> 25,000 USP units/d), patients who had an oral cancer within the 2 years preceding the study

Histological criteria for leukoplakia

Not reported

44 participants randomised:

  • 13 females

  • 9 participants < 50 years old; 29 participants 50 to 69 years; 6 participants > 70 years

  • Ethnic group not reported

  • 9 (20%) tobacco users, 11 (25%) alcohol users, 20 (45%) tobacco + alcohol users

  • 27% of lesions were dysplastic

Group A: randomised 24; 22 completed the study (analysed 22 clinically, 21 histologically)

Group B: randomised 20; 18 completed the study

Interventions

Group A: capsules of 13-cis-retinoic acid (1 to 2 mg/kg/d) for 3 months

Group B: capsules of placebo for 3 months

Compliance control: yes, pill counts at each visit

Outcomes

Clinical response

Measurement of the lesion, colour photography performed before the start of treatment and every 2 to 3 weeks during treatment: (1) complete response was defined as no clinical evidence of leukoplakia for at least 4 weeks; (2) partial response was defined as a greater than 50% reduction in the product of the longest diameters of the lesion; (3) a response was classified as stable when the decrease in lesion size was less than 50%; (4) disease progression was defined as an unequivocal increase in the size of any lesion during treatment or as the appearance of a new lesion

Histological response

Histological grading was done before the start of treatment and upon its completion. Histological grading included (1) atypical hyperplasia; (2) mild dysplasia; (3) moderate dysplasia; (4) severe dysplasia or carcinoma in situ

Other outcomes included laboratory analysis, including fasting serum triglycerides and liver function testing

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: “the randomisation code was computer-generated”
Allocation concealment (selection bias)Low riskQuote: “randomisation was performed by the pharmacy” and “The code for treatment assignment was broken after the patients had completed the full nine months of study”
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: “neither the patient nor the physician was aware of which treatment was assigned”
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: “neither the patient nor the physician was aware of which treatment was assigned”
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups and not likely to have a clinically relevant impact on the intervention effect estimate: 4/44 (9%)
Selective reporting (reporting bias)Low riskComment: important outcomes and adverse effects reported
Other biasLow risk Comment: no other sources of bias identified

Li 1999

Methods

Study design: RCT, parallel-group, 2 arms

Conducted in China

Number of centres: 1

Recruitment period: unspecified

Funding source: supported by a grant from the Chinese National Natural Science Foundation

Study duration: 6 months

Participants

Inclusion criteria

Not specified

Exclusion criteria

Patients with severe dysplasia

Histological criteria for leukoplakia

Not reported

64 participants randomised: 24 females, mean age 54.5 (range 23 to 78), ethnic group not reported, 46 (71.9%) tobacco users. 20% of lesions were dysplastic

Group A: randomised 32, 29 completed the study

Group B: randomised 32, 30 completed the study

Interventions

Group A: systemic (capsules) and topical (paint) mixed tea (3 grams/d and 3 paintings/d) for 6 months

Group B: systemic (capsules) and topical (paint) placebo for 6 months

Compliance control: not reported

Outcomes

Clinical response

Size and number of lesions of each participant were recorded at baseline and at the end of the trial: (1) complete regression was defined as complete disappearance of the lesion; (2) partial regression was defined as a 30% or greater reduction in the size of a single lesion or in the sum of sizes of multiple lesions; (3) lesions with no change in size were recorded as no change; (4) deterioration referred to the occurrence of new lesions

Histological response

Oral biopsies were conducted at the beginning and at the end of the trial. Besides routine histopathological examination, lesional tissue investigations included also silver-stained nucleolar organizer regions (AgNOR), proliferation cell nuclear antigen (PCNA) and epidermal growth factor receptor (EGFR) analysis

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPersonal communication: random sequence based on random number table. Randomisation stratified for presence of dysplasia
Allocation concealment (selection bias)Unclear riskComment: insufficient information to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: “double blind”
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: “double blind”
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups and not likely to have a clinically relevant impact on the intervention effect estimate: 5/64 (7.8%)
Selective reporting (reporting bias)High riskComment: missing histological assessment of lesions at the end of the study
Other biasLow risk Comment: no other sources of bias identified

Mallery 2014

Methods

Study design: RCT, parallel-group, 2 arms

Conducted in US

Number of centres: 3

Recruitment period: unspecified

Funding source: supported by NIH NCI RC2 CA148099. S.R.Mallery has ownership interest (including patents) in BRB gel patent

Study duration: 6 months (12 weeks plus 3 months of follow-up)

Participants

Inclusion criteria

Microscopically confirmed pre-malignant oral epithelial lesions, no use of tobacco products for 6 weeks before and during the 3-month study, no previous history of cancer (except for basal cell carcinoma of the skin). Participants screened before entrance into and during (10 to 12 days recall intervals) the trial for no tobacco use compliance via unannounced saliva testing for nicotine (NicAlert, JANT Pharmacal Corporation)

Exclusion criteria

Previous or current history of non-basal cell cancer, use of tobacco products, and either a microscopic diagnosis of no pre-malignant change or OSCC in the pre-trial biopsy

Histological criteria for leukoplakia

Not reported

40 participants randomised: 22 females, mean age 60.15 (range 32 to 78), ethnic group not reported, 24 (60%) former smokers. 72.5% of lesions were dysplastic: 63% (14/22) in Group A and 83% (15/18) in Group B

Group A: randomised 22, 22 completed the study. 21 available for post-trial examination

Group B: randomised 18, 18 completed the study. 17 available for post-trial examination

Interventions

Group A: topical application of a bioadhesive gel that contained 10% w/w freeze-dried black raspberries (0.5 g, q.i.d. for 12 weeks)

Group B: topical application of a bioadhesive placebo gel that contained 10% w/w sucrose and food colorants (0.5 g, q.i.d. for 12 weeks)

Compliance control: yes

Outcomes

Clinical response

Clinical photographs of lesions were taken with a calibrated measuring device (Puritan) placed parallel to the long axis of the lesion. Acquired clinical images were analysed using ImagePro 6.2 software (Media Cybernetics). Lesional sizes were normalised to square millimetres (mm2) according to the following formula: lesional size mm2 = pixels of lesional area × 100/(pixels of 1 centimetre unit on the calibration device in the same image). The remaining lesional area after the initial biopsy and before gel treatment was the pre-treatment size. Post-treatment lesional size was the residual lesional area after 3 months of gel treatment and just before the final biopsy

Histological response

Histological grading was done before the start of treatment and upon its completion. A 0 to 8 grade scale (0 = normal with or without hyperkeratosis, 1 = atypia with crisply defined clinical margins, 2 = mild dysplasia, 3 = mild-moderate dysplasia, 4 = moderate dysplasia, 5 = moderate-severe dysplasia, 6 = severe dysplasia, 7 = carcinoma in situ, 8 = invasive SCC) was used to rank light microscopic diagnoses

Notes30 participants had OIN lesions (16 in BRB - 72.7% and 14 in placebo - 77.7%) that were recalcitrant to surgery and had recurred multiple times (2 to 8) at the same site before trial participation. 12 Group A and 3 Group B participants had a history of multiple lesions dispersed throughout the mouth, consistent with a diagnosis of proliferative verrucous leukoplakia
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: insufficient information to permit judgement
Allocation concealment (selection bias)Unclear riskComment: insufficient information to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "All participating oral pathologists, surgeons, and patients were blinded to the patients’ gel assignments"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "All participating oral pathologists, surgeons, and patients were blinded to the patients’ gel assignments"
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data. All randomised participants included in analysis of results
Selective reporting (reporting bias)Low riskComment: important outcomes and adverse effects reported
Other biasLow riskComment: no other sources of bias identified

Mulshine 2004

Methods

Study design: RCT, parallel-group, 2 arms

Conducted in USA

Number of centres: 3

Recruitment period: unspecified

Funding source: supported by a grant from the National Cancer Institute Specialized Programs of Reasearch Excellence (SPORE) Program

Study duration: 4 months (90 days of treatment plus 1 month of follow-up)

Participants

Inclusion criteria

Patients with bi-dimensionally measurable leukoplakia of the oral cavity or of the oropharynx. In cases of previous oral cancer diagnosis, individuals had to be free from disease for at least 3 months, excellent performance status, general good health

Exclusion criteria

Hypersensitivity to aspirin, lidocaine, NSAIDs, retinoids. Use of antibiotics, steroids, NSAIDs, aspirin, probenecid, antihistamines for > 10 consecutive days, or any immunosuppressants, anticoagulants, dilantin, lithium, methotrexate, phenothiazines or drugs that could compromise test product safety during the 30 days immediately preceding the first treatment visit, debilitating oral conditions requiring extensive dental procedures or conditions interfering with compliance. Respiratory or cardiovascular problems

Histological criteria for leukoplakia

Not reported

57 participants randomised: 19 females; age not reported; ethnic group: non-white participants: 6/57, white participants: 51/57; 48/56 (86%) smokers, 40/56 (71%) alcohol users. Percentage of dysplastic lesions not reported

Group A: randomised 38, 37 completed the study

Group B: randomised 19, 19 completed the study

Interventions

Group A: mouthwash with ketorolac 0.1%, twice a day, for 90 days

Group B: mouthwash with placebo, twice a day, for 90 days

Compliance control: yes

Outcomes

Clinical response

Measurement of the lesion. (1) Complete response was defined as no clinical evidence of leukoplakia for at least 30 days from inception of treatment. (2) Partial response was defined as a greater than 50% reduction in the product of the longest diameters of a single lesion (in the sum of these figures for all lesions, in the setting of multiple lesions) for at least 30 days. (3) A response was classified as stable when the decrease in lesion size was less than 50%. (4) Disease progression was defined as an unequivocal increase in size greater than 10%, or as the appearance of a new lesion. Clinical evaluations were made at study entry, monthly during the intervention and 1 month after cessation of study drugs

Histological response

Histological grading was done before the start of treatment and upon its completion

NotesNine of the 56 participants who completed the study had an oropharyngeal leukoplakia (6 in Group A and 3 in Group B)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: insufficient information to permit judgement
Allocation concealment (selection bias)Unclear riskComment: insufficient information to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: “double blind”
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: “double blind”
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data are balanced in numbers across intervention groups and are not likely to have a clinically relevant impact on the intervention effect estimate 1/57 (1.7%)
Selective reporting (reporting bias)High riskComment: data on histological modifications reported only partially
Other biasLow riskComment: no other sources of bias identified

Nagao 2015

Methods

Study design: RCT, parallel-group, 2 arms

Conducted in Japan

Number of centres: 3

Recruitment period: not reported

Funding source: supported by Butterfield Award of the Sasakawa Foundation GB and DSM Nutrition Japan

Study duration: 1 year plus open follow-up

Participants

Inclusion criteria

Patients with leukoplakia who had never smoked or were ex-smokers

Exclusion criteria

Current smokers or ex-smokers within 3 months of cessation

Histological criteria for leukoplakia

Not reported

46 participants randomised: 21 females; median age 65 (range 38 to 80 years); ethnic group: all Japanese; never smoked or ex-smokers; alcohol users not reported Percentage of dysplastic lesions not reported

Group A: randomised 23, 16 completed the study

Group B: randomised 23, 17 completed the study

Interventions

Group A: 10 mg/d of beta carotene and 500 mg/d of vitamin C for 1 year

Group B: 50 mg/d of vitamin C for 1 year

Compliance control: not reported

Outcomes

Cancer incidence

Study authors provided unpublished cancer incidence after a median follow-up of 86 months. Trial authors intended to exclude from the analysis any cases that progressed to oral cancer within 6 months of the start of the study, but there were no cancer cases within 6 months

Clinical response

Complete remission, partial remission, no change, disease progression

Histological response

Severity degree of epithelial dysplasia

p53 and Ki67 expression

Serum levels of antioxidant micronutrients

Notes

Follow-up since the end of treatment: 60 months for clinical response, 86 months for cancer incidence

2 participants in the experimental arm and 1 in the control arm did not receive allocated interventions. During intervention, 5 participants in the experimental arm and 5 in the control arm dropped out. Among these, 3 in the experimental arm and 4 in the control arm returned for follow-up at the close of the study

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "random allocation was performed [...] with stratification by blocking randomisation according to presence or absence of dysplasia"
Allocation concealment (selection bias)Low riskQuote: "a trial coordinator not involved in the routine care of patients generated the allocation sequence and enrolled participants. The central randomisation by numbered containers was used for allocation concealment"
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "double blind"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "double blind"
Incomplete outcome data (attrition bias)
All outcomes
High riskHigh number of drop-outs (stopping treatment) 13/46 (28.2%), although not lost to follow-up and included in ITT analysis
Selective reporting (reporting bias)High riskComment: data on histological outcomes not reported
Other biasLow riskComment: no other sources of bias identified

Papadimitrakopoulou 2008

Methods

Study design: RCT, parallel-group, 3 arms

Conducted in USA

Number of centres: 8

Recruitment period: November 2000 to January 2004

Funding source: Pfizer (grant support)

Study duration: 6 months

Participants

Inclusion criteria

Histologically confirmed early or advanced oral pre-malignant lesion; age ≥ 18 years; Zubrod performance status 0 to 1; haemoglobin level above lower limit of normal, WBC count > 3000/mm3, platelet count > 125,000/mm3, total bilirubin, aspartate aminotransferase and alanine aminotransferase levels V1.5 upper limit of normal, serum creatinine V1.5 upper limit of normal; no anticipated need for treatment with oral or i.v. corticosteroids for more than 2 consecutive weeks over any 6-month period during the study; willingness to limit aspirin use to V100 mg/d and to abstain from chronic use of all other non-steroidal anti-inflammatory drugs and COX-2 inhibitors for the duration of the study

Exclusion criteria

Diagnosis of or treatment for oesophageal, gastric, pyloric channel or duodenal ulceration within 30 days before randomisation; history of head and neck cancer in the past 18 months or of another cancer in the past 3 years (patients with a history of non-melanoma skin cancer, cervical carcinoma in situ or chronic lymphocytic leukaemia stage 0 were not excluded); chronic or acute renal or hepatic disorder or significant bleeding disorder; history of or active inflammatory bowel syndrome or pancreatic disease; current use of fluconazole or lithium 

Histological criteria for leukoplakia

Early oral pre-malignant lesion: atypical hyperplasia, atypical hyperkeratosis or mild dysplasia. Advanced oral pre-malignant lesion: moderate to severe dysplasia

50 participants randomised: 26 females; age range 34 to 84; ethnic group: 2/50 non-white participants, 48/50 white participants; 4/50 current smokers (8%), 27/50 current drinkers (54%), prior oral cancer history 10/50. Early/advanced oral pre-malignant lesion: Group A 15/2, Group B 14/1, Group C 16/2. Ten out of 32 (31%) participants in combined active arms vs 0 of 18 in the placebo arm had a history of squamous cell cancer of the oropharynx (9) or larynx (1). Percentage of participants with any degree of dysplasia not reported

Group A: randomised 17, 16 completed the study

Group B: randomised 15, 13 completed the study

Group C (placebo): randomised 18, 17 completed the study

Interventions

Group A: oral celecoxib 100 mg twice for 12 weeks

Group B: oral celecoxib 200 mg twice for 12 weeks

Group C: oral placebo twice daily for 12 weeks

Groups A and B were considered together in the present review

Compliance control: Compliance was measured by telephone queries and remaining capsule counts at weeks 8 and 12

Outcomes

Cancer incidence

Cancer development at 12 weeks

Clinical response

Clinical changes at 12 weeks: complete response (disappearance of all evidence of lesions), partial response (50% or greater decrease in the sum of products of diameters of all measured lesions); stable disease (any response that did not meet the criteria for the other categories), progressive disease (increase ≥ 25% in size of lesions or appearance of new lesions or progression to invasive cancer)

Histological response

Histological changes at 12 weeks: (1) reversal of dysplasia, (2) improvement in degree of dysplasia

Adverse events classified according to the National Cancer Institute Common Toxicity Criteria version 2.0

Notes

Follow-up from the end of treatment: 14 weeks

Quote: “After a protocol amendment in March 2003, only patients with early OPLs continued to be randomised as just described, whereas all patients with advanced OPLs received open-label oral celecoxib at 400 mg twice daily, based again on data of the familial adenomatous polyposis study showing significant efficacy of celecoxib only at 400 mg twice daily. Because this decision was made while the study was already accruing, the 400 mg twice daily open-label arm was included in an exploratory intent as an attempt to preserve the feasibility of the study while offering a possibly superior intervention for patients at higher cancer risk (i.e., advanced OPL). [….] Shortly after opening the 400 mg twice daily arm for patients with developed OPLs, the first reports potentially linking use of selective COX-2 inhibitors with serious adverse cardiovascular events emerged, leading to early closure of this arm”

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: insufficient information to permit judgement
Allocation concealment (selection bias)Unclear riskComment: insufficient information to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: “double blind”
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: “double blind”
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups and not likely to have a clinically relevant impact on the intervention effect estimate 4/50 (8%)
Selective reporting (reporting bias)Low riskComment: important outcomes and adverse effects reported
Other biasLow riskComment: no other sources of bias identified

Piattelli 1999

Methods

Study design: RCT, parallel-group, 2 arms

Conducted in Italy

Number of centres: 1

Recruitment period: unspecified

Funding source: partially supported by the National Research Council (CNR) and by the Ministry of University, Research, Science and Technology (MURST), Rome, Italy

Study duration: 4 months

Participants

Inclusion criteria

Histologically confirmed oral leukoplakia

Exclusion criteria

Women of childbearing age

Histological criteria for leukoplakia

Not reported

10 participants randomised: 4 females, mean age 61 (range 40 to 71), ethnic group: Caucasian, 4 (40%) tobacco users. Mean duration of lesions: 5.8 years (range 0.5 to 20 years). Percentage of dysplastic lesions not reported

Group A: 5 randomised, 5 completed the study

Group B: 5 randomised, 4 completed the study

Interventions

Group A: 3 times daily topical application of 0.1% isotretinoin (13-cis-retinoic acid - Roaccutane Roche) for 4 months

Group B: 3 times daily topical application of placebo (gel only), for 4 months

Compliance control: not reported

Outcomes

Clinical response

Measurement of the lesion: Photography was performed before the start of treatment and every month during treatment: Complete response was defined as complete disappearance of the lesion as assessed by visual inspection; partial response was defined as a 50% or greater reduction in the size of lesions

Histological response

Evaluation of bcl-2 immunostaining.

Laboratory studies (including serum cholesterol, triglycerides, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) were performed before the start of treatment and every month during treatment

NotesAt the end of the study period (4 months), participants who received placebo started 4-month treatment with active medication
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: insufficient information to permit judgement
Allocation concealment (selection bias)Unclear riskComment: insufficient information to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: “double blind”
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: “double blind”
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups and not likey to have a clinically relevant impact on the intervention effect estimate 1/10 (10%)
Selective reporting (reporting bias)Low riskComment: important outcomes and adverse effects reported
Other biasLow risk Comment: no other sources of bias identified

Sankaranarayan 1997

Methods

Study design: RCT, parallel-group, 3 arms

Conducted in India

Number of centres: 1

Recruitment period: unspecified

Funding source: unspecified

Study duration: 2 years (1 year of treatment + 1 year of follow-up)

Participants

Inclusion criteria

Not reported

Exclusion criteria

Not reported

Histological criteria for leukoplakia

Not reported

Participant details were available only for those who completed the trial (131 participants: 47 female; mean age 50.7; 127 (97%) chewers, 41 (31%) smokers, 72 (55%) drinkers. Percentage of dysplastic lesions not reported

Group A : randomised 50, 42 completed the study

Group B : randomised 55, 46 completed the study

Group C: randomised 55, 43 completed the study

Interventions

Group A: capsules of vitamin A (300,000 IU/wk) for 1 year

Group B: capsules of beta carotene (360 mg/wk) for 1 year

Group C: capsules of placebo for 1 year

Compliance control: yes

Outcomes

Cancer incidence

Malignant transformation: Biopsies were taken at baseline and during the study, whenever a malignant transformation was suspected. Malignant transformation was scored if malignancy was histologically established in the lesions during follow-up

Clinical response

Number, type and dimension of lesion(s) were recorded at baseline and at each review. (1) Complete response was defined as no clinical evidence of leukoplakia. (2) Partial response was defined as a greater than 50% reduction in the size of the single lesion or in the sum of sizes of multiple lesions. (3) Stable and progressive lesions were scored as no response

Notes160 participants randomised, all with tobacco chewing habits and leukoplakia, belonging to the fisherman community of Trivandrum City, Kerala, India - a population with high incidence of leukoplakia and oral cancer
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: insufficient information to permit judgement
Allocation concealment (selection bias)Unclear riskComment: insufficient information to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: “double blind” and “subjects were examined every 2 months during visits by dentists and physician, both of whom were blinded to the treatment group”
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: “double blind” and “subjects were examined every 2 months during visits by dentists and physician, both of whom were blinded to the treatment group”
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups and not likely to have a clinically relevant impact on the intervention effect estimate 29/160 (16.9%)
Selective reporting (reporting bias)Low riskComment: important outcomes and adverse effects reported
Other biasLow risk Comment: no other sources of bias identified

Singh 2004

Methods

Study design: RCT, parallel-group, 3 arms

Conducted in India

Number of centres: unspecified

Recruitment period: unspecified

Funding source: supported by Jagsonpal Pharmaceuticals Ltd., New Delhi, India

Study duration: 3 months plus 2 months of follow-up

Participants

Inclusion criteria

Not reported

Exclusion criteria

Not reported

Histological criteria for leukoplakia

Not reported

Characteristics of 58 participants who completed the study: 14 females; age: 12 participants were between 10 and 30 years, 42 were between 31 and 60 years, 4 were between 61 and 80 years; ethnic group: not reported; smoking status: not reported; alcohol status: not reported. Percentage of dysplastic lesions: 59%

Group A: randomised 20, 20 completed the study

Group B: randomised 20, 20 completed the study

Group C: randomised 18, 18 completed the study

Interventions

Group A: capsules of lycopene at high dose (8 mg/d) divided into 2 daily doses for 3 months

Group B: capsules of lycopene at low dose (4 mg/d) divided into 2 daily doses for 3 months

Group C: capsules of placebo in 2 daily doses for 3 months

Groups A and B were considered together in the present review

Compliance control: not reported

Outcomes

Clinical response

Clinical assessment was made at the third month of the study. (1) Complete response was defined as no clinical evidence of leukoplakia for at least 4 weeks. (2) Partial response was defined as a greater than 50% reduction in the product of the longest diameters of the lesion. (3) Stable response was defined to occur when the decrease in lesion size was < 50%. (4) Disease progression was defined as an unequivocal increase in the size of any lesion during treatment, or as the appearance of a new lesion

Histological response

Histological grading was done before the start of treatment and upon its completion. For histological evaluation, 5 stages were taken as normal, atypical hyperplasia, mild dysplasia, moderate dysplasia and severe dysplasia. They were ranked as 0, 1, 2, 3 and 4, respectively, so that change could be quantified in terms of these ranks. For example, a case from stage moderate dysplasia comes to stage mild dysplasia post treatment; improvement was considered as 32¼ for 1 unit

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: insufficient information to permit judgement
Allocation concealment (selection bias)Unclear riskComment: insufficient information to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: insufficient information to permit judgement
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: insufficient information to permit judgement
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data. All randomised participants included in analysis of results
Selective reporting (reporting bias)Low riskComment: important outcomes and adverse effects reported
Other biasLow riskComment: no other sources of bias identified

Stich 1988

Methods

Study design: RCT, parallel-group, 2 arms

Conducted in India

Number of centres: unspecified

Recruitment period: unspecified

Funding source: supported by a grant from National Cancer Institute of Canada

Study duration: 6 months

Participants

Inclusion criteria

Betel quid chewers

Exclusion criteria

Not reported

Histological criteria for leukoplakia

WHO 1978

The 65 participants had tobacco chewing habits and leukoplakia, belonging to the fisherman community of Trivandrum City, Kerala, India - a population with high incidence of leukoplakia and oral cancer. 2% tobacco users, 37% alcohol users, 28% tobacco + alcohol users. Percentage of dysplastic lesions not reported

Group A: randomised 30, 21 completed the study

Group B: randomised 35, 33 completed the study

Interventions

Group A: systemic capsules of vitamin A (200,000 IU/wk) for 6 months

Group B: systemic capsules of placebo for 6 months

Compliance control: yes, capsules were administered twice weekly under strict supervision of a local nurse

Outcomes

Clinical response

Leukoplakias were evaluated before the start of treatment and at the end of the study (6 months): (1) remission of leukoplakia, (2) no change, (3) development of new leukoplakia

Histological response

Biopsies were taken before the start of treatment and at the end of the study (6 months). Histological markers evaluated were (1) loss of polarity of basal cells, (2) lymphocytic infiltration, (3) nuclei with condensed chromatin

NotesQuestionnaires completed during the trial demonstrated that habits such as chewing, smoking and drinking did not change during the course of the study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: insufficient information to permit judgement
Allocation concealment (selection bias)Unclear riskComment: insufficient information to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: insufficient information to permit judgement
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: insufficient information to permit judgement
Incomplete outcome data (attrition bias)
All outcomes
High riskProportion of lost participants (11/65) with imbalance across intervention groups (30% vs 5.7%)
Selective reporting (reporting bias)High riskHistological data available for only 18 participants in the study group and for none in the control group
Other biasLow riskComment: no other sources of bias identified

Sun 2009

Methods

Study design: RCT, parallel-group, 2 arms

Conducted in China

Number of centres: 1

Recruitment period: 1998 to 2001

Funding source: Beijing Natural Science Foundation, National Natural Science Foundation of China, Tenth 5-Year Plan of National Key Technologies R&D Program in China (No. 2004BA720A28), NIH grants

Study duration: 8 to 12 months plus 3 months of follow-up

Participants

Inclusion criteria

Oral leukoplakia was defined as a white patch or plaque that cannot be characterised clinically or pathologically as any other disease. All participating patients had general good health without other uncontrolled medical conditions. Patients underwent a baseline biopsy to confirm the absence of invasive cancer 

Exclusion criteria

Those with a previous diagnosis of head and neck or oral cancer; those currently treated by other drugs or having drug hypersensitivity; those requiring extensive dental procedures; those with a history of social or psychiatric situations interfering with study compliance

Histological criteria for leukoplakia

Not reported

Characteristics of the 112 participants who completed the study: 43 females; age: Group A 52.9 ± 10.4, Group B 44.4 ±11.8; ethnic group: not reported; smokers: 53/112 (47%); alcohol drinkers: 10/112 (9%). Percentage of participants with any dysplasia: 18.75% (11.61% mild dysplasia, 3.57% moderate dysplasia, 3.57% severe dysplasia)

Group A: randomised 60, 59 completed the study

Group B: randomised 60, 53 completed the study

Interventions

Group A: ZengShengPing - a mixture of 6 medical herbs (0.3 g per tablet) - 4 tablets each time, 3 times a day, for 8 to 12 months (not better specified: length of the study)

Group B: placebo 4 tablets each time, 3 times a day, for 8 to 12 months (not better specified: length of the study)

Compliance control: self report during monthly visit

Outcomes

Clinical response

Measurement of the lesion: (1) positive response defined as disappearance or reduction in size by more than 50% at final checkup (3 months after cessation of treatment), (2) stable disease defined as insignificant change in the size of the lesion, (3) progressive disease defined as increase in size of the lesion by > 50%, or development of new lesions

Histological evaluation

AgNOR and PCNA labelling index in tissues were evaluated in tissue samples before and after treatment. Histological assessment was available for pre-treatment samples only

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: “randomly assigned to two groups”
Allocation concealment (selection bias)Unclear riskComment: insufficient information to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: insufficient information to permit judgement
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: insufficient information to permit judgement
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups and not likely to have a clinically relevant impact on the intervention effect estimate 8/120 (6.6%)
Selective reporting (reporting bias)High riskComment: information about histological features of lesions not available
Other biasLow riskComment: no other sources of bias identified

Tsao 2009

  1. a

    AgNOR = silver-stained nucleolar organizer region
    CNR = National Research Council
    COX = cyclo-oxygenase
    CR = complete response
    EGFR = epidermal growth factor receptor
    FU = follow-up
    HNSCC = head and neck squamous cell carcinoma
    ITT = intention-to-treat
    MURST = Ministry of University, Research, Science and Technology
    NIH = National Institutes of Health
    OIN = oral intraepithelial neoplasia
    OPL = oral pre-malignant lesion
    OSCC = oral squamous cell carcinoma
    PCNA = proliferation cell nuclear antigen
    PD = progressive disease
    PR = partial response
    RCT = randomised controlled trial
    SCC = squamous cell carcinoma
    WHO = World Health Organization

Methods

Study design: RCT, parallel-group, 4 arms

Conducted in Texas (USA)

Number of centres: 1

Recruitment period: August 2002 to March 2008

Funding source: supported by Ito En Ltd.

Study duration: 12 weeks and open follow-up (median 27.5 months)

Participants

Inclusion criteria

Presence of 1 or more histologically confirmed, bi-dimensionally measurable OPLs that could be sampled by biopsy and had at least 1 of the following high-risk features of malignant transformation: harbouring at least mild dysplasia, located in a high-risk area (i.e. floor of mouth, ventrolateral tongue, and soft palate), significant extent of OPL tissue involvement, and presence of symptoms (pain or substantial discomfort). Additional inclusion criteria included age between ≥ 18 and ≤ 75 years; Zubrod performance status < 2; adequate haematological, liver and renal function; adequate cardiac function (defined as no clinically significant electrocardiogram abnormality, unstable atrial or ventricular arrhythmias requiring medical control or ischaemic event experienced within the prior 6 months); negative pregnancy test in females of childbearing potential within 7 days before first dose of study medication; use of effective contraceptive method while in the trial; written informed consent for participation

Exclusion criteria

Known hypersensitivity to oral green tea extract (GTE) or its analogous, use of prior investigational agents within 30 days, any serious intercurrent illness, history of prior malignancy with less than a 1-year disease-free interval before study entry, lactating females, patients who were not able to abstain from consumption of methylxanthine-containing products (including coffee, tea, chocolate, caffeinated soft drinks and theophylline) and decaffeinated tea

Histological criteria for leukoplakia

Not reported

41 participants randomised: 22 females; mean age 57 (range 33 to 76); ethnic group: Caucasian 37/41, Hispanic 2/41, Asian 2/41; smoking status: never smoked 15/41, former smoker 22/41, current smoker 4/41; alcohol status: never 8/41, former 9/41, current 24/41. Mean duration of lesions: 5.8 years (range 0.5 to 20 years). Percentage of participants with any dysplasia: 73.2% (56.1% mild dysplasia, 17.1% moderate/carcinoma in situ). 34.1 % of participants had prior HNSCC, 12.2 % had prior radiotherapy (not specified whether head and neck radiotherapy), 90.2% had prior surgery (not specified which type of surgical therapy)

Group A: randomised 11, 11 completed the study

Group B: randomised 9, 8 completed the study

Group C: randomised 10, 9 completed the study

Group D: randomised 11, 11 completed the study

Groups A, B and C were considered together in the present review

Interventions

Group A: GTE capsules (500 mg/m2 daily), given orally thrice a day after meals for 12 weeks

Group B: GTE capsules (750 mg/m2 daily) given orally thrice a day after meals for 12 weeks

Group C: GTE capsules (1000 mg/m2 daily) given orally thrice a day after meals for 12 weeks

Group D: placebo capsules given orally thrice a day after meals for 12 weeks

Each capsule contained 350 mg of GTE. GTE dosage calculations were based on participant's body surface area according to the following formula: body surface area (m2) = weight (kg) 0.425 × height (cm) 0.725 × 0.007184. Calculated dose was adjusted downward to the closest dose that could be administered by using 1 or more 350-mg capsules

Groups A, B and C were considered together in the present review

Compliance control: yes

Outcomes

Cancer incidence

Cancer incidence was recorded during an open follow-up period

Clinical response

Bi-dimensional measurement of the lesion: (1) Disappearance of all lesions was considered a complete response. (2) 50% or greater decrease in the sum of products of diameters of all measured lesions was considered a partial response. (3) Increase of 25% or greater in size of lesions or appearance of new lesions or progression to invasive cancer was considered progressive disease. (4) Any response that did not meet criteria for CR, PR or PD was considered stable disease

Histological response

(1) Complete response was defined as a complete reversal of pre-malignancy to normal epithelium with no new lesions. (2) Partial response was defined as improvement in degree of maturation of epithelium with no new lesions and no progression of any lesion. (3) Stable disease was defined as no change in histology and no appearance of new lesions or progression of any lesion. (4) Progression of disease was defined as progression from hyperplasia and/or hyperkeratosis to dysplasia, or from a lower to a higher degree of dysplasia or invasive carcinoma, or appearance of any new lesions

NotesQuote: "With a median follow-up time of 27.5 months, 15 patients subsequently developed oral cancer with a median time to oral cancer development of 46.4 months." It is not specified how they were distributed in the 3 arms, but (quote): "There was no difference in oral cancer–free survival between the GTE and placebo arms"
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: “The randomisation was done with the Pocock-Simon dynamic allocation scheme to balance three prognostic factors in each of the four arms. The prognostic factors were tobacco use (current, stopped, never), alcohol use (current, stopped, never), and tea use (zero to four 8-oz cups daily or five or more 8-oz cups daily)
Allocation concealment (selection bias)Unclear riskComment: insufficient information to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: insufficient information to permit judgement
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: insufficient information to permit judgement
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups and not likely to have a clinically relevant impact on the intervention effect estimate 2/41 (5%)
Selective reporting (reporting bias)Low riskComment: important outcomes and adverse effects reported
Other biasLow riskComment: no other sources of bias identified

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Bocharova 2004The study was not randomised, and both arms of the study employed active treatments, i.e. no placebo (or no treatment) group was included in the study
Boisnic 1994The study included participants with traumatic lesions
Chee 2013Both arms of the study employed active treatments, i.e. no placebo (or no treatment) group was included in the study
Chiesa 2005All participants underwent active treatment. The aim of the treatment tested was to prevent recurrence of leukoplakia; all participants were randomised after surgical removal (active treatment) of the oral lesion
Femiano 2001The study was not randomised, and participants were allocated to study arms by researchers
Gaeta 2000Quasi-randomised trial
Garewal 1999Participants randomised were a selected group who responded to the drug tested in the randomised phase (beta carotene)
Krishnaswamy 1995The study used an inadequate method of allocation, and only 66% of participants had lesions, none with a histological diagnosis
Lippman 1993Participants randomised were a selected group who responded to 1 of the 2 drugs tested during the randomised phase (isotretinoin)
López-Jornet 2013Both arms of the study employed active treatments, i.e. no placebo (or no treatment) group was included in the study
Mathew 1995The study was not randomised, as controls were taken from another study control group
Schwarz 2005Both arms of the study employed active treatments, i.e. no placebo (or no treatment) group was included in the study
Zaridze 1993The oral lesions diagnosed as leukoplakia were not biopsied for histological examination. Data, as presented in the paper, do not allow analysis

Characteristics of studies awaiting assessment [ordered by study ID]

Califano 2012

Methods 
Participants

Inclusion criteria

(1) Presence of 3p, 9p21 or 17p LOH, and/or (2) surgically unresectable high-grade pre-malignant lesions and/or (3) high-grade pre-malignancy after curative therapy for HNSCC

InterventionsParticipants received cetuximab 400 mg/m2 week 1 followed by 250 mg/m2 weeks 2 to 8 or observation, with the option for cross-over to cetuximab for participants originally randomised to the observation arm
OutcomesHistological grade (1 = benign, 2 = mild dysplasia, 3 = moderate dysplasia, 4 = severe dysplasia/carcinoma in situ, 5 = invasive cancer) and change in grade of dysplasia were evaluated. Malignant transformation was evaluated
Notes 

Chiba 2012

  1. a

    HNSCC = head and neck squamous cell carcinoma
    LOH = loss of heterozygosity
    RCT = randomised controlled trial

Methods

Study design: RCT, parallel-group, 2 arms

Conducted in Sri Lanka

Number of centres: 15

Recruitment period: unspecified

Funding source: unspecified

Study duration: unspecified

Participants

Inclusion criteria

Betel quid chewers with pathological diagnosis of oral pre-cancer

Exclusion criteria

Lesion not measurable

Histological criteria for leukoplakia

Not reported

72 participants randomised: mean age 53.9, 90.2% male, ethnic 98.6% Sinhala. Percentage of dysplastic lesions not reported

Group A: unspecified

Group B: unspecified

Interventions

Group A: curcumin-coated chewing gum

Group B: placebo chewing gum

Compliance control: not reported

Outcomes

Clinical response

Lesions were measured every 6 months. Participants were followed up every month by oral and maxillofacial surgeons at each hospital

Histological response

Not reported

NotesThe only available report of this study is an abstract

Characteristics of ongoing studies [ordered by study ID]

NCT00004161

Trial name or titleFenretinide in treating patients with leukoplakia of the mouth
Methods Study design: RCT, parallel-group
Participants Inclusion criteria: histologically proven dysplastic leukoplakia > 1 cm in diameter, age 18 and older
Interventions

Group A: oral fenretinide daily (except days 1 to 3 each month) for 6 months

Group B: oral placebo daily (except days 1 to 3 each month) for 6 months, then oral fenretinide daily (except days 1 to 3 each month) for 6 months. Participants are followed up every 3 months

Outcomes

Regression of oral dysplastic leukoplakia

Intermediate endpoint markers

Surrogate endpoint biomarkers

Recurrence rate of oral dysplastic leukoplakia after administration of fenretinide, both at the same site and at new sites

Starting dateFebruary 2000
Contact informationSamuel W. Beenken; University of Alabama at Birmingham
Notes Status: completed (the study has ended normally, and participants are no longer being examined or treated)

NCT00014404

Trial name or titleCelecoxib in treating patients with precancerous lesions of the mouth
Methods Study design: RCT, parallel-group
Participants Inclusion criteria: histologically confirmed index oral pre-malignant lesion
Interventions

Group A: lower-dose oral celecoxib twice daily

Group B: higher-dose oral celecoxib twice daily

Group C: oral placebo twice daily

Treatment continues in all 3 arms for 12 weeks in the absence of disease progression or unacceptable toxicity. Participants are followed at 18, 24 and 26 weeks

Outcomes 
Starting dateOctober 2000
Contact informationJay O Boyle, Study Chair; Memorial Sloan-Kettering Cancer Center
NotesThis study is no longer recruiting participants

NCT00101335

Trial name or titleCelecoxib in preventing head and neck cancer in patients with oral leukoplakia
Methods Study design: cross-over RCT
Participants Inclusion criteria: diagnosis of oral leukoplakia with hyperplasia or dysplasia
Interventions

Group A: oral celecoxib twice daily for 3 months

Group B: oral placebo twice daily for 3 months

All participants undergo biopsy. Participants then cross over to the opposite treatment arm for 3 months

Outcomes

Primary: regression of oral leukoplakia lesions in participants with hyperplastic or dysplastic oral leukoplakia

Secondary: multiple intermediate biomarkers (e.g. COX-2, PPARγ, PPARδ) in normal and hyperplastic or dysplastic oral epithelia of participants; safety; cost-effectiveness

Starting date2005
Contact informationPaul F. Engstrom; Fox Chase Cancer Center
Notes Status: completed (the study has ended normally, and participants are no longer being examined or treated)

NCT00155337

Trial name or titlePhotodynamic therapy for oral leukoplakia and erythroleukoplakia
Methods Study design: RCT, parallel-group
Participants Inclusion criteria: patients with leukoplakia or erythroleukoplakia, age 20 to 80 years
Exclusion criteria: oral cancers
Interventions

Group A: photodynamic therapy

Group B: unclear

OutcomesRegression of lesions
Starting date2005
Contact informationChun-Pin Chiang; National Taiwan University Hospital
Notes Status: completed (the study has ended normally, and participants are no longer being examined or treated)

NCT00176566

Trial name or titleA phase II trial to assess the effects of green tea in oral leukoplakia
Methods Study design: RCT, parallel-group
Participants

Inclusion criteria: patients with oral leukoplakia without evidence of active infection

Exclusion criteria: allergy to caffeine, GI ulcers, pregnancy, previous invasive mouth cancer

Interventions

Group A: green tea lozenge

Group B: placebo

Outcomes Primary outcomes: prevalence, size, histological severity of oral leukoplakia
Starting date2005
Contact informationSusan Goodin, PharmD; University of Medicine and Dentistry New Jersey
Notes Status: terminated (the study has stopped recruiting or enrolling participants early and will not start again; participants are no longer being examined or treated)

NCT00299195

Trial name or titleA randomized study of sulindac in oral premalignant lesions
Methods Study design: RCT, parallel-group
Participants Inclusion criteria: oral pre-malignant lesion (OPL) defined as a lesion that can include atypical hyperplasia, atypical hyperkeratosis, leukoplakia and erythroplakia/erythro-leukoplakia
Interventions

Drug: sulindac 150 mg p.o. b.i.d. × 24 weeks

Drug: placebo b.i.d. × 24 weeks

OutcomesTo evaluate the efficacy of sulindac in participants with early or advanced oral pre-malignant lesion (OPL) by both clinical response (reduction in size of all lesions) and histological response (change in histological grade)
Starting date2006
Contact informationJay O. Boyle; Memorial Sloan-Kettering Cancer Center
Notes Status: This study is ongoing but is not recruiting participants

NCT00402779

Trial name or titleErlotinib prevention of oral cancer (EPOC)
Methods Study design: RCT, parallel-group
Participants

Inclusion criteria

Male or female patients with 1 of the following: (1) loss of heterozygosity (LOH) at 3p14 and/or 9p21 in the oral Intraepithelial neoplasia (IEN) of patients with a history of curatively treated oral cancer, or (2) LOH at 3p14 and/or 9p21 plus at 1 other chromosomal region in the IEN of participants with no oral cancer history; participants must have confirmed diagnosis of oral IEN lesion with LOH; age ≥ 18 years

Interventions

Group A: erlotinib 150 mg for 1 year

Group B: placebo for 1 year

Outcomes

Primary outcome: oral cancer-free survival

Secondary outcomes: Size, number and appearance of oral IEN will be assessed and correlated with cancer risk; a panel of molecular markers will be used for correlation with oral cancer development in our participants with oral IEN

Starting date2006
Contact informationVassiliki Papadimitrakopoulou; M.D. Anderson Cancer Center
Notes Status: This study is ongoing but is not recruiting participants

NCT00951379

Trial name or titlePioglitazone for oral premalignant lesions
Methods 
Participants

Inclusion criteria

STAGE I: males or females with suspected or histologically confirmed oral premalignant lesion(s)

Interventions

Group A: pioglitazone hydrochloride p.o. q.d. for 24 weeks

Group B: placebo p.o. q.d. for 24 weeks

Outcomes Primary outcome measures
Clinical and histological response defined as 50% or greater reduction in the sum of measured products of perpendicular dimensions of target lesion(s), or improvement in the degree of dysplasia or hyperplasia
Secondary outcome measures
Tissue levels of PPAR gamma, cyclin D1 and p21 as indirect measures of pharmacological effect, TUNEL for apoptosis and Ki-67 for proliferation, transglutaminase and involucrin as markers of squamous differentiation, 15-PGDH and loss of heterozygosity. Level of C-reactive protein in plasma. Tobacco and alcohol use. Adverse events and clinical laboratory toxicity assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Starting date2010
Contact informationJay Boyle; M.D. Anderson Cancer Center
Notes Status: This study is currently recruiting participants

NCT01497951

  1. a

    COX = cyclo-oxygenase
    CTCAE = Common Terminology Criteria for Adverse Events
    EPOC = excess post-exercise oxygen consumption
    IEN = intraepithelial neoplasia
    Ki-67 = protein; cellular marker of neoplasia
    NCI = National Cancer Institute
    OPL = oral pre-malignant lesion
    PDT = photodynamic therapy
    PGDH = 15-hydroxyprostaglandin dehydrogenase
    PPAR = peroxisome proliferator-activated receptor
    RCT = randomised controlled trial
    SIN = squamous intraepithelial neoplasia
    TUNEL = terminal deoxynucleotidyl transferase dUTP nick end labeling
    VAS = visual analogue scale

Trial name or titlePhotodynamic therapy for oral precursor lesions (PDT)
Methods Study design: RCT, parallel-group
Participants

Inclusion criteria

Existing leukoplakia simplex SIN III (diagnostics by biopsy); leukoplakia verrucosa without indications of malignant changes (diagnostics by biopsy); oral lichen planus SIN III (diagnostics by biopsy)

Interventions

Group A: aminolaevulinic acid

Group B: placebo

Outcomes

Primary outcome: changes in per cent (%) of initial area in mm2

Secondary outcomes: pain due to treatment, assessed by visual analogue scale (VAS)

Starting date2011
Contact informationGeorg Watzek; Medical University of Vienna
Notes Status: This study is currently recruiting participants

Ancillary