Click here to load reader
Upload
moni-abraham-kuriakose
View
7
Download
3
Embed Size (px)
DESCRIPTION
Review article
Citation preview
Squamous cell carcinoma andprecursor lesions: prevention
SA M A N WA R N A K U L A S U R I Y A
Introduction
Major risk factors for oral squamous cell carcinoma
and precursor lesions of the oral cavity are smoking,
use of smokeless tobacco and alcohol misuse. In
specific regions of the world, particularly in some
Asian-Pacific countries, the chewing of betel quid is
an additional risk factor. Human papillomavirus
(HPV) infection is an emerging risk factor for oro-
pharyngeal carcinomas. These risk factors and etio-
pathogenesis are considered in detail by Johnson
et al. (40) in this volume, and in an earlier review
(107). The purpose of this review is to inform oral
healthcare professionals about effective methods for
reducing harm from these etiological agents, and
about care pathways to reduce the burden of oral
cancer by engaging in public health programs or
clinical interventions. These interventions should
mostly be targeted at the high-risk groups who
present in primary care settings with oral potentially
malignant disorders (110). The objective of this
article is to stimulate a debate on effective preventive
measures in clinical practice. This review includes an
overview of both public health measures and targeted
measures that could be undertaken in dental offices
by oral healthcare professionals and that may lead to
control of oral cancer by effectively managing
patients with established risk factors and potentially
malignant disorders (precursor lesions). The current
evidence available on treatment of precursor
lesions in the hope of eliminating future develop-
ment of a carcinoma in the precursor lesion is also
reviewed.
The methods of prevention or interventions dis-
cussed include cessation of tobacco use, moderation
of alcohol use, stopping betel quid use, vaccination
against viruses, dietary intervention, and chemopre-
vention, as well as tertiary prevention measures e.g.
surgery to prevent malignant transformation.
Cessation of tobacco use
The risk for oral cancer in former smokers almost
matches that of never smokers 10 years after cessa-
tion (106), clearly indicating the benefits of stopping
tobacco use. Smoking cessation has been shown to
reduce both the relative risk (20) and lifetime risk (6)
of developing oral and other aerodigestive tract can-
cers. For cancers of the oral cavity and pharynx
together, the cumulative risk for Italian men who
continued to smoke any type of tobacco was 3.3% by
75 years of age, but the risk dropped to 1.4% and
0.5% for men who stopped smoking at approximately
50 and 30 years old, respectively (6). Pooled data
from the Head and Neck Epidemiology Consortium,
based on 17 studies reporting smoking cessation,
confirmed these observations (61). It has been esti-
mated that tobacco cessation, alone could contribute
to the prevention of a substantial proportion of can-
cers at this site.
Smoking cessation is also associated with reversal
of epithelial dysplasia in pre-cancer (64). In India, a
primary prevention trial of oral cancer was under-
taken in Kerala state. A high proportion of subjects
were smokeless tobacco users. When tobacco use was
stopped or reduced substantially, the regression rates
of pre-cancer increased significantly (27).
Community interventions
There is evidence that comprehensive tobacco con-
trol programs including media campaigns, higher
taxes and smoke-free environments can be effective
in changing smoking behavior in adults, but the evi-
dence comes from a heterogeneous group of studies
of variable methodological quality. Bala et al. (2)
performed a systematic review of media campaigns
and reported significant decreases in smoking
prevalence after the Massachusetts and California
38
Periodontology 2000, Vol. 57, 2011, 3850
Printed in Singapore. All rights reserved
2011 John Wiley & Sons A/S
PERIODONTOLOGY 2000
statewide tobacco control campaigns compared with
the rest of the USA. Community interventions as
outlined in the World Health Organization Frame-
work Convention on Tobacco Control represent a
key component of current anti-smoking strategies.
Population-level tobacco control interventions also
have the potential to benefit more disadvantaged
groups (98). Oral health professionals should be
ardent supporters of such public health measures.
They need to engage in debates about important
developments in tobacco control and assume a
leading role in inter-professional activities on control
of oral cancer.
Preventive measures for smokingcessation undertaken in dental practices
There is good evidence that brief interventions by
health professionals can increase rates of smoking
cessation (75). Attempts at encouraging tobacco ces-
sation in dental pratices by have been previously re-
viewed (114). Trials that examined the feasibility of
involvement of dental practices in smoking cessation
confirmed a pivotal role of the team approach in better
outcomes (92). Dentists who implement an effective
smoking cessation program can expect to achieve
cessation rates of up to 1015% each year among
patients who smoke or use smokeless tobacco. The
recommended care pathway is to provide brief
interventions in the dental practice, while utilizing
specialist smoking cessation services to provide addi-
tional benefits, (75). Such schemes should provide
information exchange between the specialist smoking
cessation services and the dental team that could be
valuable for patient follow up.
Ebbert et al. (13) performed a meta-analysis of
randomized trials on interventions for smokeless
tobacco cessation, mostly in US dental offices. The
majority of these behavioral interventions were
undertaken by oral hygienists dentists who hadreceived training in tobacco intervention skills. The
odds ratio for giving up smokeless tobacco use fol-
lowing behavioral interventions that mostly included
an oral examination and feedback, was 1.66 (95%
confidence interval; 1.481.88). Varenicline was also
effective in Swedish users of snus (odds ratio 1.6; 95%
confidence interval; 1.082.36).
Preventive measures in hospital clinics
A number of studies have examined the effectiveness
of tobacco cessation interventions in oral medicine
practices for patients diagnosed with precursor
lesions. For example, Roed-Petersen (78) reported
resolution of leukoplakia following smoking cessa-
tion. Another interventional study in a dysplasia
clinic in London provided brief cessation advice and
utilized a specialist smoking cessation clinic for
intensive interventions and pharmacotherapy. They
achieved a cessation rate of 30% (74).
Methodological issues
For both tobacco smoking and the use of oral
smokeless tobacco, nicotine remains the main
determinant of addiction. For smokers who wish to
quit, effective smoking cessation treatments are
available (112), and every patient diagnosed with oral
pre-cancer or cancer who uses tobacco should be
offered one or more of these treatments.
There are many intervention strategies and poli-
cies for smoking cessation among adults. Data from
many sources confirm that a wide array of effective
smoking cessation intervention approaches and
policies can have a significant impact on improving
smoking cessation rates.
Treatment methods that have been researched and
found to be effective are set out in Table 1. These
summary results are extracted from data published in
Table 1. Evidence-based treatment methods for suc-cessful smoking cessation published in the CochraneDatabase of Systematic Reviews based on publishedmeta-analyses (7, 24, 36, 48, 77, 93, 94, 115)
Type of therapy Number
of trials
Estimated odds ratios
(OR) and 95%
confidence
intervals (CI)
OR CI
Nursing intervention 42 1.28 1.181.38
Physicians advice
Brief advice 17 1.66 1.421.94
Intensive advice 11 1.84 1.602.13
Dentists advice 6 1.44 1.161.78
Counselling 21 1.56 1.321.84
Nicotine replacement
therapy
132 1.58 1.50 1.66
Clonidine 6 1.89 1.302.74
Bupropion 31 1.94 1.722.19
Varenicline 7 2.33 1.952.80
Nortriptyline 4 2.34 1.613.41
Acupuncture 24 1.36 1.071.72
39
Prevention of cancer and precursor lesions
the Cochrane Database of Systematic Reviews (http://
www2.cochrane.org/reviews/), including a number
of meta-analyses. Advice and support from health
professionals (nurses, dentists and physicians) could
increase peoples success in giving up smoking.Intensive group treatment is better than brief advice.
Nicotine replacement therapy aims to reduce
withdrawal symptoms associated with cessation of
smoking by replacing cigarettes with medicinal nic-
otine. The chances of stopping smoking increase by
5070% with use of nicotine replacement therapy.
Nicotine replacement therapy is available as skin
patches that deliver nicotine slowly, and as chewing
gum, lozenges tablets, inhalers and nasal spray, allof which deliver nicotine to the brain via the blood-
stream. Those that deliver nicotine rapidly, (e.g. nasal
sprays), may be used in combination with prepara-
tions that deliver nicotine more slowly. Smokers
attending UK National Health Service Stop Smokingservices are four times more likely to succeed in
giving up and remain as ex-smokers than those who
attempt to quit unaided, on the basis that medication
approximately doubles the chances of quitting, and
behavioral support further doubles the outcome.
Medications prescribed under physicians guidanceas adjuncts to smoking cessation include bupropion
and varenicline, and both have shown promising
long-term results (Table 1). These medications ap-
pear to attenuate the urge to smoke, the negative
effect of withdrawal symptoms, and people find it
easy to quit because smoking loses its appeal. They
have a high affinity for nicotine receptors. In trials
comparing these two therapies, varenicline was
superior to bupropion (odds ratio 2.18, 95% confi-
dence interval; 1.094.08) (14).
Most adult smokers would like to quit, and effec-
tive therapies are now available. The adverse health
consequences of smoking and smokeless tobacco use
could be avoided by improving awareness and by
providing services that are accessible to those at risk.
Tobacco dependency requires targeted therapies
(112), and those with oral precursor lesions constitute
a special group who need assistance in giving up
tobacco use. Providing support for tobacco cessation
through oral healthcare providers could contribute to
saving lives. Why then, is smoking cessation over-
looked when there are opportunities to intervene, as
tobacco use is quite apparent in the oral cavity as
either melanosis, gum disease, or precursor lesions?
Some dentists may view smoking as a lifestyle choice
rather than an addiction that requires treatment.
Others cite a lack of time, training or proper com-
pensation for smoking cessation programs. There are
now excellent online resources on tobacco cessation
interventions for European dentists, and one such
is managed by the Oral Health Network of Tobacco
Use Prevention and Cessation (http://www.tobacco-
oralhealth.net).
Alcohol
Alcohol use is the second most important risk factor
for the development of oral cancer. Ethanol is clas-
sified by the International Agency for Research on
Cancer as a human carcinogen (37). A large number
of cohort and casecontrol studies provide strong
evidence that consumption of alcohol is an inde-
pendent risk factor for oral and pharyngeal cancers
(37). Daily consumption of approximately 100 g of
ethanol above recommended levels increases the risk
for oral and oropharyngeal cancers two- to threefold
compared with the risk for non-drinkers. The risk of
oral cancer increases with the number of alcoholic
drinks consumed per day in a dose-dependent fash-
ion (5). Pooled data from the Head and Neck Epide-
miology Consortium based on 13 studies on alcohol
cessation confirmed the benefits of abstaining or
reducing alcohol consumption (61). The risk is mul-
tiplicative for combined use of alcohol and tobacco.
Some population groups with inherited defects in
metabolism of alcohol may have an inability to break
down acetaldehyde (the carcinogenic metabolite of
alcohol) and may be at increased risk. Oral biofilms
(bacteria) assist in the metabolism of alcohol to
acetaldehyde, and improving oral sepsis and hygiene
among alcoholics may help to reduce local acetal-
dehyde formation and thereby reduce the potential
risk of oral cancer.
Alcohol use has also been shown to be associated
with oral leukoplakia (30), and moreover with malig-
nant transformation from leukoplakia to cancer (86).
There is a controversy as to which types of alco-
holic drinks mostly cause mouth cancer. It is not clear
whether its the alcohol concentration in beverages or
the quantity drunk that contributes to excess risk.
There is no clear evidence that specific alcoholic
drinks, i.e. spirits, wine or beer, have different effects
on oral cancer. Substitution of the type of drink is
therefore not advisable. The most frequently con-
sumed alcoholic beverage in a population is likely to
be associated with the highest risk for that given
population.
If followed, the guidelines in the European Code
Against Cancer (2008), i.e. daily consumption of less
than two drinks for men and one drink for women,
40
Warnakulasuriya
would lead to a significant reduction of cancer risk in
the population (www.cancercode.org/code.htm).
Combating binge drinking would also contribute to
control the reported rising incidence of tongue
cancer noted in young people.
Most people who misuse alcohol require support-
ive care, and those who are dependent require
pharmacotherapy to manage alcohol withdrawal and
medical treatment to prevent relapse. The drugs used
to prevent relapse include disulfiram, acamprosate,
baclofen and naltrexone. The mechanisms of action
of these agents in relapse prevention were discussed
in a recent review by Lingford-Hughes et al. (53).
These drugs should be used as adjuncts to psycho-
social programs. Abstinence is the goal of treatment.
Brief advice and motivational enhancement against
alcohol misuse (Table 2) (70, 84) are effective
healthcare interventions, and the oral healthcare
team is ideally placed to provide these with some
additional training.
Betel quid
In parts of South and South East Asia and in Mela-
nesia, there is a high incidence of oral cancer, and
betel quid use is recognized as a risk factor for the
disease burden in these populations (28). A recent
evaluation by the International Agency for Research
on Cancer concluded that areca nut, the main
ingredient used in betel quid or commercially pack-
aged pan masala, is carcinogenic to humans (38).
Cancers of the oral cavity arise in locations in the
mouth where betel quid and areca nut are kept for
long periods (113). Furthermore, chewing betel quid
without tobacco has recently been shown to increase
the risks of cancer and various oral precursor
conditions (39). A recent meta-analysis of five studies
that controlled for smoking reported an increased
risk among betel quid users for oral leukoplakia (odds
ratio 7.9, 95% confidence interval; 4.314.6) (99). Oral
sub-mucous fibrosis caused by areca nut use is a
debilitating disorder with a significant potential for
malignant transformation. Medical interventions to
manage oral sub-mucous fibrosis in the hope of
preventing oral cancer have been recently reviewed
(42).
Some individuals develop a dependency syndrome
to areca nut (116), and development of an appro-
priate care pathway is required, as for tobacco
intervention, with facilities for treatment and pro-
grams to reduce harm. Only a few studies have been
performed. In a 10-year follow up study in India,
cessation of chewing habits (areca nut and tobacco
use) was reported in 8.7% men and 13.6% women
(26). In a community pilot investigation, Croucher
et al. (12) confirmed that methods identified as
helping tobacco smokers to successfully stop smok-
ing, such as nicotine replacement therapy, can also
be used for Bangladeshi women who chew paan with
tobacco. The neuropharmacology of addiction to
areca nut has not been studied in detail to suggest
suitable pharmacotherapy. The dopaminergic meso-
limbic system is likely to play a central role, as
described in other addictions (53). Further research is
required to characterize which neurotransmitters
modulate the dopaminergic pathway in areca nut
abusers so that medications available to treat addic-
tions or new therapies can be tried. Substitution with
gums that taste of areca may help to reduce craving
in people who experience withdrawal.
Human papillomavirus
Human papillomavirus (HPV), the causal agent for
cervical cancer, is now implicated in causation of
cancers of the oral cavity and particularly the oro-
pharynx (23). Finding HPV DNA in oral and oropha-
ryngeal cancers provides one explanation as to why
people who have no major lifestyle risk factors (to-
bacco and alcohol use) may develop cancer at this
site. The presence of HPV DNA in oral and oropha-
ryngeal cancers adds weight to the hypothesis that
sexual transmission of the virus may be implicated
in the development of oropharyngeal cancer. We
previously reported on the involvement of HPV in
precursor lesions and during progression from pre-
cancer to cancer (15).
Table 2. Brief advice and motivational enhancementagainst alcohol use (70, 84)
Brief advice (delivered by generalists)
Simple structured advice to reduce to sensible or less
risky levels
Motivational enhancement (2030 min)
Structured feedback on personal risk and harm
Emphasis on personal responsibility to change
Clear advice to cut down or abstain
Discussion of options for changing patterns of use
Reinforcement of the patients self-efficacy
*Should be non-judgmental*Express empathy when interviewing and giving advice
41
Prevention of cancer and precursor lesions
These findings suggest a strategy to prevent or
reduce the incidence of oropharyngeal cancer by the
introduction of vaccination programs. Two pre-
ventive vaccines [Gardasil (Merck) and Cervarix
(GlaxoSmithKline)], which target high-risk HPV types
16 and 18, are now available. In the UK, human
papillomavirus vaccines are licensed for girls aged
915 years. There is an optimistic outlook for HPV
vaccination, and the research community needs to
provide confirmation on its effect on oral cancer
whether it is as promising as initially demonstrated
in reducing the incidence of cervical cancer. The
effect is expected to be greatest in women who have
not yet been exposed to HPV. Vaccination before
adolescence makes it more likely that the recipient
has not been exposed to HPV. Large prospective ran-
domized trials are required to document the clinical
effectiveness of HPV vaccination to control oral and
oropharyngeal cancer. It has been suggested that HPV
immunization be offered to boys to counter the
increased incidence of HPV related oral cancer
(The Guardian, 20 February 2011; http://www.
guardian.co.uk/science/2011/feb/20/boys-human-
papilloma-virus-jabs?INTCMP=SRCH).
Diet and nutrition
Most foods that are protective against cancer of the
mouth and pharynx are of plant origin. Based on a
recent evaluation by the World Cancer Research
Fund (118), there is convincing evidence that
higher consumption of non-starchy raw vegetables
including cruciferous and green leafy vegetables
and non-starchy tubers (e.g. carrots) may protect
against cancers of the upper aerodigestive tract,
including the mouth and pharynx (summary odds
ratio 0.72, 95% confidence interval: 0.630.82).
There is evidence that fruits (particularly citrus
fruits) may also provide protection (summary odds
ratio per 100 g per day 0.72, 95% confidence
interval: 0.590.87. Carotene-rich vegetables such as
broccoli, carrots and peppers (capsicums) or green
leafy vegetables appear to provide greater protec-
tion than vegetables lacking b-carotene. Thus, it isclear that cancers of the mouth and pharynx and
probably also the wider range of malignant neo-
plasms that affect the aerodigestive tract can be
prevented by consuming a diet rich in antioxidants,
notably fresh vegetables and fruits (71, 108). This
should be coupled with a reduction in the levels of
consumption of processed, preserved and smoked
foodstuffs, as well as roasted and grilled foods. The
message at the heart of the UK 5 A DAY program to eat at least five portions of a variety of fruit and
vegetables each day (total 400 g day) is consis-tent with dietary recommendations around the
world, including those from the WHO (120), and
will contribute to a reduction of oral cancers in the
community.
Chemoprevention
Chemoprevention attempts to reduce cancer inci-
dence by prescribing pharmacological agents or by
dietary supplementation using vitamins, minerals,
trace elements and other bioactive substances.
Long-term supplementation for a median period of
6 years with either a-tocopherol (50 mg day) orb-carotene (20 mg day), or both supplements in 409subjects who smoked did not prevent oral leuko-
plakia (50). The prevalence of leukoplakia (5.9%) in
those receiving either supplement was similar to
population estimates.
Trials on the use of chemopreventive agents for
non-surgical treatment of oral leukoplakia have been
previously reviewed (57, 58, 76), and summary out-
comes are given in Table 3 (4, 9, 10, 17, 21, 22, 34, 41,
43, 44, 54, 56, 60, 66, 73, 80, 85, 89, 91, 95, 96, 100, 101,
121). Primary outcomes of interest are clinical reso-
lution of precursors and preventing malignant
transformation. Dietary supplements that have been
investigated for the treatment of oral leukoplakia
include vitamin A and retinoids (e.g. 13-cis-retinoic
acid, isotretinoin, fenretinide) and their analyses,
used either topically or systemically, as well as
b-carotene and a-tocopherol. Follow-up periods havenot been long enough to estimate the possibility of
malignant transformation, and recurrence of pre-
cancer after discontinuation of supplements appears
to be a common finding in these trial results. Fur-
thermore, toxicity is reported with many agents
used in chemoprevention. A critical review of pub-
lished chemoprevention studies on oral leukoplakia
noted number of inadequacies in the trial designs
(68, 82). Based on one small randomized controlled
trial, the use of oral lycopene over a period of
5 months appears to be effective (91). Even aggres-
sive antioxidant treatment combinations have so far
not been found to be effective in reversing advanced
pre-malignant lesions of the oral cavity and oro-
pharynx, suggesting an urgent need for innovative
approaches (108).
More recently, non-steroidal anti-inflammatory
drugs (NSAIDs) have received attention as potential
42
Warnakulasuriya
Table 3. Chemopreventive trials for oral leukoplakia
Study Therapy Dose Number of
patients
Clinical
resolution (%)
Follow-up
(months)
Recurrence progression
(%)
Sankaranarayanan
et al. (80)
Systemic
retinyl acetate
300,000 IU 42 52 12 67
Stich et al. (95) Systemic
retinol
200,000300,000 IU 21 57 12
Silverman et al. (89) Topical retinol 600 000 IU 16 44 218 0
Shah et al. (85) Topical
isotretinoin
310 mg day 11 28 6 18
Koch (43) Analogues of
retinoic acid
70 mg 75 43 264 3
Koch (44) Etretinate 45 71
Toma et al. (101) Isotretinoin 0.21.0 mg kg 14 36
Chiesa et al. (9) Fenretinate 200 mg day 80 95 9 years 5
Lippman et al. (55) Fenretinide 200 mg day 35 34 3 22
Hong et al. (34) Isotretinoin 12 mg kg 24 67 6
Epstein et al. (17) Topical
tretinoin
0.05% gel 26 27 23 40
Piatelli et al. (73) Topical
isotretinoin
1% 10 10 48
Garewal et al. (22) b-carotene 60 mg day 24 52 6 18
Toma et al. (100) b-carotene 90 mg day 23 26 7 5
Sankaranarayanan
et al. (80)
b-carotene 360 mg 46 54 12 5
Garewal et al. (21) b-carotene 60 mg day 50 4 18 17
Singh et al. (91) Lycopene 48 mg 58 2555 5 0
Benner et al. (4) a-tocopherol 400 IU x2 day 43 23 6 7
Malaker et al. (60) b-carotene orretinoic acid
30 mg x4 day10 mg x3 day
18 33 24 16
Stitch et al. (96) b-caroteneb-carotene +
vitamin A
30 mg x2 week90 mg x2 week
50,000 IU
27
51
15
28
6
Kaugars et al. (41) b-carotene +a-tocopherol +
vitamin C
30 mg day800 IU
1,000 mg
79 56 9 9
Lippman et al. (56) b-carotene +isotretinoin
30 mg day0.51.5 mg kg
33
26
45
92
28 8.5
Zoller (121) b-carotene +a-tocopherol +
vitamin C
75 mg
100 mg
1,000 mg
24 98 3
Nagao et al. (66) b-carotene +vitamin C
10 mg
500 mg
46 25 24 6
43
Prevention of cancer and precursor lesions
chemopreventive agents. Sulindac and celecoxib are
effective in promoting regression in high-risk indi-
viduals with adenomas in the large bowel, but
important concerns exist regarding cardiovascular
toxicity associated with selective COX-2 inhibitors. A
few years ago, a cyclooxygenase inhibitor in the form
of an oral rinse (ketorolac) was used in a randomized,
double-blind, placebo-controlled trial (65). Fifty-
seven subjects were enrolled, and complete or partial
response was observed in 30% of subjects for
ketorolac and 32% for the placebo, leading to the
conclusion that ketorolac rinse as tested had no sig-
nificant effect. The authors argued that it may be
necessary to reformulate the agent to enhance pen-
etration of the molecule through the keratin layers
(65). In a phase II randomized controlled trial, cel-
ecoxib at 100 or 200 mg twice daily was ineffective at
controlling oral pre-malignant lesions (69). In an-
other pilot study on 22 subjects, the effectiveness of
celecoxib on oral pre-malignant lesions after being
on the drug over a period of 12 months was reported.
Among compliant subjects, eight of 11 biopsies (73%;
P = 0.0703) showed an improvement in the degree of
dysplasia after 12 months of theraphy (117). These
landmark studies, although their results are contra-
dictory, are very important as they provide proof-
of-concept for experimentation on the use of active
chemopreventive agents in high-risk pre-cancers to
prevent the development of oral cancer. However, a
range of difficulties encountered in clinical trials
suggest that the evidence of the use of chemopre-
vention is not yet strong for oral cancer. Further
clinical trials on inhibition of COX-2 using ketorolac
as an oral rinse, and oral pioglitazone, a drug that is
commonly used to treat type II diabetes, are under
way or have been completed (http://www.cancer.
gov/clinicaltrials).
Topically applied bleomycin (0.51% dissolved in
dimethyl sulfoxide), a cytotoxic agent used in can-
cer therapy, has been used in two trials for treat-
ment of oral leukoplakia (16, 29). Resolution of
leukoplakia and reversal of dysplasia were reported.
In one of the studies, two of the 19 treated cases
transformed to cancer. A number of adverse reac-
tions may occur with bleomycin, including stoma-
titis, erythema, vesiculation and hyperpigmentation
of the skin.
Photodynamic therapy
Photodynamic therapy uses light to activate a
photosensitizing agent in the presence of oxygen to
cause localized photodamage and cell death. At
present, portable diode laser systems are predomi-
nantly used. A number of photosensitizers have
been advocated, including porphyrin derivatives,
5-aminolevulinic acid and temoporfin. Technical
aspects of this treatment have been discussed in
reviews by Konopka & Goslinski (45) and Kubler
(46). Photodynamic therapy with orally or topically
administered 5-aminolevulinic acid has been used
for the treatment of oral leukoplakia. The regression
of leukoplakia or clinical improvement to less
dysplastic states in partially responsive cases has
been reported (8, 18, 47, 87, 102). Significant
side-effects are prolonged photosensitivity,
particularly after the use of intravenous photosen-
tisizers, mucosal burns, and scarring and hyper-
pigmentation.
Surgical intervention
Some experts in the UK routinely advise excision of
any white patch with a diagnosis of leukoplakia (C.
Scully, Eastman Dental Hospital, London, personal
communication) on the basis that some already
contain or will transform to cancer, and one cannot
reliably estimate which ones do or will, not least as
biopsies often only sample a small part of many
lesions. A recent systematic review (62) examined
14 non-randomized studies (1, 3, 11, 25, 31, 32, 35,
49, 51, 59, 63, 79, 83, 88, 90, 97, 103, 104) that
compared surgical excision of oral leukopla-
kia epithelial dysplasia vs. no treatment. Theyfound a considerably higher malignant transforma-
tion rate among the lesions that were not excised
than for those that were excised (14.6% vs. 5.4%;
P = 0.003). The authors concluded that excision of
dysplastic lesions significantly decreased the risks of
transformation but did not completely eliminate
that risk. The results of this meta-analysis should be
viewed with caution due to the heterogeneity of the
studies: Of the 14 studies included, only five of the
publications specified surgical excision, periods of
follow-up were variable, and the rates of malignant
transformation in the various studies ranged from
0% to 37%. Some of the studies included by the
authors we believe do not appear to satisfy the
criteria for selection as the method of treatment
was not specified in few of the original publications
(11, 35), and in one of them was limited to a
medical intervention (49). The authors commented
on the distinct lack of randomized controlled trials
examining different surgical techniques or a con-
44
Warnakulasuriya
siderable lack of follow-up studies. Table 4 lists
some of the relevant studies (1, 3, 25, 32, 59, 63, 79,
83, 97) undertaken, showing the range of outcomes
following surgery or no treatment. The study by
Coredero et al. (10) that included only three sub-
jects was excluded. A group from the Netherlands
reported benefits of laser surgery in oral leukoplakia
in that recurrences following treatment were far
fewer compared with knife excision (103). Whether
we can prevent malignancy by treating precursor
lesions remains an open question. This is one of the
most important problems in oral medicine (33) and
requires further research.
The natural history of oral leukoplakia the most
common precursor lesion encountered in the oral
cavity remains unclear (67). At present, the ab-
sence or presence (and the grade) of oral epithelial
dysplasia remains the most useful guide to our
management of leukoplakia (109). The presence of
oral dysplasia significantly increases the rate of
transformation to cancer, and this may increase
with the grade (62). It is therefore argued that
treatment of dysplastic lesions may prevent cancer
development in high-risk patients with oral leuko-
plakia. Currently, there is debate as to how we
should manage oral leukoplakia or other precursor
lesions as none of the available treatments (medical
or surgical) have sufficiently being researched to be
evidence-based.
Screening
Population screening provides a means of reducing
cancer incidence (prevention). Benefits have not
been widely evaluated for oral cancer. The concept
underpinning screening is based on the premise that
earlier detection of the asymptomatic phases of oral
precursor will allow modification of risky behaviors
and use of other clinical interventions in an attempt
to prevent cancer (111). Screening high-risk groups
and opportunistic screening where people have good
access to dental care will allow earlier case detection
(105). In addition to visual screening, a number of
adjunctive tests are available (19), but these have
limitations in predicting which suspicious lesions
may progress to cancer. However, new technology is
encouraging dentists to perform thorough systematic
oral cavity examinations (52).
Strong evidence to support any national screening
program is still lacking, but one randomized trial in
users of tobacco and alcohol has shown a significant
reduction in mortality from oral cancer in a screened
population compared to deaths in the control group
(mortality rate ratio 0.66, 95% confidence interval;
0.450.95) (81). Screening for precursor lesions and
their effective management could lead to a reduction
in the incidence of cancer in the screened popula-
tion, and thereby contribute to the control of oral
Table 4. Selected follow-up studies showing outcome of surgical excision or no intervention for cases of oral leu-koplakia or epithelial dysplasia
Study Country Mean
follow-up
(years)
Total cases Percentage with malignant
transformation
Excised Followed-up Excised Followed-up
Holmstrup et al. (32) Denmark 6.8 89 147 12 4
Vedtofe et al. (104) Denmark 3.9 61* 5
Arduino et al. (1) Italy 4.6 128 74 9 4
Schepman et al. (83) The
Netherlands
2.5 39 79 20 15
Lumerman et al. (59) USA 1.5 44, 16
Mincer et al. (63) USA 8.0 20 22 15 9
Saito et al. (79) Japan 4.0 75 51 1 8
Gupta et al. (25) India 8.5 0 426 2
Sugar & Bancozy (97) Hungary 23 18 306 0 6
Bancozy & Csiba (3) Hungary 3.6 45 23 2 34
*Includes five cases of oral lichen planus.Includes only oral dysplasia cases.Follow up date based on a pathology database: authors unclear whether completely excised or not.
45
Prevention of cancer and precursor lesions
cancer (119). Community-oriented screening pro-
grams and communication on signs and symptoms
and risk factors also increase public awareness and
knowledge of oral cancer (72).
Conclusions
The findings of this review suggest that interventions
to change the health behavior of people at risk of oral
cancer require an educational as well as a personal-
ized approach. Those at risk should be identified by
oral health professionals during regular dental visits
and continued support should be provided after the
initial intervention. The most important steps of
interventions are discouraging young people from
taking up tobacco use, and support for cessation of
tobacco use for those who cannot do so without
professional support. Given the strength of the evi-
dence that ex smokers significantly reduce their
cancer risks, oral health professionals must include
tobacco cessation services as part of routine care,
particularly for those with oral precursor lesions.
Several other preventive measures, e.g. reducing
harm from betel quid use, moderating alcohol habits
and improving oral hygiene health, are also impor-tant in appropriate settings. An ideal chemopreven-
tive agent remains to be discovered. Future research
is required to evaluate surveillance of precursor le-
sions, and less invasive and more effective treatment
protocols are required to prevent cancer development
in subjects with precursor lesions.
References
1. Arduino PG, Surace A, Carbone M, Elia A, Massolini G,
Gandolfo S, Broccoletti R. Outcome of oral dysplasia: a
retrospective hospital-based study of 207 patients with a
long follow-up. J Oral Pathol Med 2009: 38: 540544.
2. Bala M, Strzeszynski L, Cahill K. Mass media interventions
for smoking cessation in adults. Cochrane Database
Syst Rev 2008: http://www2.cochrane.org/reviews/en/
ab004704.html (e-publication only).
3. Banoczy J, Csiba A. Occurrence of epithelial dysplasia in
oral dysplasia. Oral Surg Oral Med Oral Pathol 1976: 42:
766773.
4. Benner SE, Winn RJ, Lippman SM, Poland J, Hansen KS,
Luna MA, Hong WK. Regression of oral leukoplakia with
a-tocopherol: a community Clinical Oncology Program(CCOP) chemoprevention study. J Natl Cancer Inst 1993:
85: 4447.
5. Boffetta P, Hashibe M. Alcohol and cancer. Lancet Oncol
2006: 7: 149156.
6. Bosetti C, Gallus S, Peto R, Negri E, Talamini R, Tavani A,
Franceschi S, La Vecchia C. Tobacco smoking, smoking
cessation, and cumulative risk of upper aerodigestive tract
cancers. Am J Epidemiol 2008: 167: 468473.
7. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial
agonists for smoking cessation. Cochrane Database Syst Rev
2007: http://www2.cochrane.org/reviews/en/ab006103.
html (e-publication only).
8. Chen HM, Yu CH, Tu PC, Yeh CY, Tsai T, Chiang CP.
Successful treatment of oral verrucous hyperplasia and
oral leukoplakia with topical 5-aminolevulinic acid-med-
iated photodynamic therapy. Lasers Surg Med 2005: 37:
114122.
9. Chiesa F, Tradati N, Grigolato R, Boracchi P, Biganzoli E,
Crose N, Cavadini E, Formelli F, Costa L, Giardini R,
Zurrida S, Costa A, De Palo G, Veronesi U. Randomized
trial of fenretinide (4-HPR) to prevent recurrences, new
localizations and carcinomas in patients operated on for
oral leukoplakia: long-term results. Int J Cancer 2005: 115:
625629.
10. Coredero AA, Allevato MAJ, Barclay CA. Treatment of
lichen planus and leukoplakia with oral retinoid Ro
10-0359. In: Orfanos CE, Braun-Falco O, Farber EM,
Grupper C, Polano MK, Schuppli R, editors. Retinoids:
advances in basic research and therapy. Berlin: Springer,
1981: 273278.
11. Cowan CG, Gregg TA, Napier SS, Mckenna SM, Kee F.
Potentially malignant oral lesions in Northern Ireland: a
20-year population-based perspective of malignant
transformation. Oral Dis 2001: 7: 1824.
12. Croucher R, Islam S, Jarvis MJ, Garrett M, Rahman R,
Shajahan S, Howells G. Oral tobacco cessation with UK
resident Bangladeshi women: a community pilot investi-
gation. Health Educ Res 2003: 18: 216223.
13. Ebbert JO, Montori V, Erwin PC, Stead LF. Interventions
for smokeless tobacco use cessation. Cochrane Database
Syst Rev 2011: http://www2.cochrane.org/reviews/en/
ab004306.html (e-publication only).
14. Eisenberg MJ, Filion KB, Yavin D, Belisle P, Mottillo S,
Joseph L, Gervais A, OLoughlin J, Paradis G, Rinfret S,Pilote L. Pharmacotherapies for smoking cessation: a
meta-analysis of randomized controlled trials. Can Med
Assoc J 2008: 179: 135144.
15. Elamin F, Steingrimsdottir H, Warnakulasuriya S, Johnson
N, Tavassoli M. Prevalence of human papillomavirus
infection in premalignant and malignant lesions of the
oral cavity in UK subjects. A novel method of detection.
Oral Oncol 1998: 34: 191197.
16. Epstein JB, Gorosky M, Wong FLW, Millner A. Topical
bleomycin for the treatment of dysplastic oral leukoplakia.
Cancer 1998: 83: 628634.
17. Epstein JB, Gorsky M. Topical application of vitamin A to
oral leukoplakia. Cancer 1999: 86: 921927.
18. Fan KF, Hopper C, Speight PM, Buonaccorsi G, MacRob-
ert AJ, Brown SG. Photodynamic therapy using 5-amino-
levulinic acid for premalignant and malignant lesions of
the oral cavity. Cancer 1996: 78: 13741383.
19. Fedele S. Diagnostic aids in screening of oral cancer. Head
Neck Oncol 2009: 1: 511.
20. Gandini S, Botteri E, Iodice S, Boniol M, Lowenfels AB,
Maisonneuve P, Boyle P. Tobacco smoking and cancer: a
meta-analysis. Int J Cancer 2008: 122: 155164.
21. Garewal HS, Katz RV, Meyskens F, Pitcock J, Morse D,
Friedman S, Peng Y, Pendrys DG, Mayne S, Alberts D,
46
Warnakulasuriya
Kiersch T, Graver E. b-carotene produces sustainedremissions in patients with oral leukoplakia: results of a
multicentre prospective trial. Arch Otolaryngol Head Neck
Surg 1999: 125: 13051310.
22. Garewal HS, Mayskens FL, Killen D, Reeves D, Kiersch TA,
Elletson H, Strosberg A, King D, Steinbronn K. Response of
oral leukoplakia to beta-carotene. J Clin Oncol 1990: 8:
17151720.
23. Gillison ML. Current topics in the epidemiology of oral
cavity and oropharyngeal cancers. Head Neck 2007: 29:
779792.
24. Gourlay SG, Stead LF, Benowitz NL. Clonidine for smok-
ing cessation. Cochrane Database Syst Rev 2004: http://
www2.cochrane.org/reviews/en/ab000058.html (e-publi-
cation only).
25. Gupta PC, Mehta FS, Daftary DK, Pindborg JJ, Bhonsle RB,
Jalnawalla PN, Sinor PN, Pitkar VK, Murti PR, Irani RR, Shah
HT, Kadam PM, Iyer KS, Iyer HM, Hegde AK, Chandra-
shekar GK, Shiroff BC, Sahiar BE, Mehta MN. Incidence
rates of oral cancer and natural history of oral precancerous
lesions in a 10-year follow-up study of Indian villagers.
Community Dent Oral Epidemiol 1980: 8: 287333.
26. Gupta PC, Mehta FS, Pindborg JJ, Bhonsle RB, Murti PR,
Daftary DK, Aghi MB. Primary prevention trial of oral
cancer in India: a 10-year follow- up study. J Oral Pathol
Med 1992: 21: 433439.
27. Gupta PC, Murti PR, Bhonsle RB, Mehta FS, Pindborg JJ.
Effect of cessation of tobacco use on the incidence of oral
mucosal lesions in a 10-yr follow-up study of 12,212 users.
Oral Dis 1995: 1: 5458.
28. Gupta PC, Warnakulasuriya S. Global epidemiology of
areca nut use. Addict Biol 2002: 7: 7783.
29. Hammersley N, Ferguson MM, Rennie JS. Topical bleo-
mycin in the treatment of oral leukoplakia: a pilot study.
Br J Oral Maxillofac Surg 1985: 23: 251258.
30. Hashibe M, Sankaranarayanan R, Thomas G, Kuruvilla B,
Mathew B, Somanathan T, Parkin DM, Zhang ZF. Alcohol
drinking, body mass index and the risk of oral leuko-
plakia in an Indian population. Int J Cancer 2000: 88:
129134.
31. Hogewind WFC, van der Kwast WAM, van der Waal I. Oral
leukoplakia, with emphasis on malignant transformation.
J Craniomaxillofac Surg 1989: 17: 128133.
32. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term
treatment outcome of oral premalignant lesions. Oral
Oncol 2006: 42: 461474.
33. Holmstrup P. Can we prevent malignancy by treating
premalignant lesions? Oral Oncol 2009: 45: 549550.
34. Hong WK, Endicott J, Itri LM, Doos W, Batsakis JG, Bell R,
Fofonoff S, Byers R, Atkinson EN, Vaughan C, Toth BB,
Kramer A, Dimery IW, Skipper P, Strong S. 13-cis-retinoic
acid in the treatment of oral leukoplakia. N Engl J Med
1986: 315: 15011505.
35. Hsue SS, Wang WC, Chen CH, Lin CC, Chen YK, Lin LM.
Malignant transformation in 1458 patients with poten-
tially malignant oral mucosal disorders: a follow-up study
based in a Taiwanese hospital. J Oral Pathol Med 2007: 36:
2529.
36. Hughes JR, Stead LF, Lancaster T. Antidepressants for
smoking cessation. Cochrane Database Syst Rev 2006:
http://www2.cochrane.org/reviews/en/ab000031.html (e-
publication only).
37. International Agency on Research for Cancer. IARC
monographs on the evaluation of carcinogenic risks to
humans, Volume 96: alcohol consumption and ethyl car-
bamate. Lyon, France: IARC Press, 2010.
38. International Agency on Research for Cancer. IARC
monographs on the evaluation of carcinogenic risks to
humans, Volume 85: betel-quid and areca-nut chewing
and some areca-nut-derived nitrosamines. Lyon, France:
IARC Press, 2004.
39. Jacob BJ, Straif K, Thomas G, Ramadas K, Mathew B,
Zhang ZF, Sankaranarayanan R, Hashibe M. Betel quid
without tobacco as a risk factor for oral precancers. Oral
Oncol 2004: 40: 697704.
40. Johnson NW, Jayasekara P, Amarasinghe AAHK. Squa-
mous cell carcinoma and precursor lesions of the oral
cavity: epidemiology and aetiology. Periodontol 2000
2011: 57: 1937.
41. Kaugars GE, Silverman S, Lovas JGL, Brandt RB, Riley
WT, Dao Q, Singh VN, Gallo J. A clinical trial of
antioxidant supplements in the treatment of oral leu-
koplakia. Oral Surg Oral Med Oral Pathol 1994: 78:
462468.
42. Kerr AR, Warnakulasuriya S, Mighell A, Dietrich T, Nasser
M, Rimal J, Jalil A, Bornstein MM, Nagao T, Fortune F,
Hazarey VH, Reichart PA, Silverman S, Johnson NW.
Management issues in oral submucous fibrosis: a sys-
tematic review of medical interventions and recommen-
dations for future research. Oral Dis 2011: 17(Suppl. 1):
4257.
43. Koch HF. Effects of retinoids on precancerous lesions of
oral mucosa. In: Orfanos CE, Braun-Falco O, Farber EM,
Grupper C, Polano MK, Schuppli R editors. Retinoids:
advances in basic research and therapy. Berlin: Springer,
1981: 307312.
44. Koch HF. Biochemical treatment of precancerous oral
lesions; the effectiveness of various analogues of retinoic
acid. J Maxillofac Surg 1978: 6: 5963.
45. Konopka K, Goslinski T. Photodynamic therapy in den-
tistry. J Dent Res 2007: 86: 694707.
46. Kubler AC. Photodynamic therapy. Med Laser Appl 2005:
20: 3745.
47. Kubler A, Haase T, Rheinwald M, Barth T, Muhling J.
Treatment of oral leukoplakia by topical application of
5-aminolevulinic acid. Int J Oral Maxillofac Surg 1998: 27:
466469.
48. Lancaster T, Stead LF. Individual behavioural counselling
for smoking cessation. Cochrane Database Syst Rev 2005:
http://www2.cochrane.org/reviews/en/ab001292.html (e-
publication only).
49. Lee JJ, Hong WK, Hittelman WN, Mao L, Lotan R, Shin
DM, Benner SE, Xu XC, Lee JS, Papadimitrakopoulou VM,
Geyer C, Perez C, Martin JW, El-Naggar AK, Lippman SM.
Predicting cancer development in oral leukoplakia: ten
years of translational research. Clin Cancer Res 2000: 6:
17021710.
50. Liede K, Hietanen J, Saxen L, Haukka J, Timonen T,
Hayrinen-Immonen R, Heinonen OP. Long-term supple-
mentation with alpha-tocopherol and beta-carotene and
prevalence of oral mucosal lesions in smokers. Oral Dis
1998: 4: 7883.
51. Lind PO. Malignant transformation in oral leukoplakia.
Scand J Dent Res 1987: 95: 449455.
47
Prevention of cancer and precursor lesions
52. Lingen MW, Kalmar JR, Karrison T, Speight PM. Critical
evaluation of diagnostic aids for the detection of oral
cancer. Oral Oncol 2008: 44: 1022.
53. Lingford-Hughes A, Watson B, Kalk N, Reid A. Neuro-
pharmacology of addiction and how it informs treatment.
Br Med Bull 2010: 96: 93110.
54. Lippman SM, Lee JS, Lotan R, Hittleman WN, Wargovich
MJ, Hong WK. Biomarkers as intermediate endpoints in
chemoprevention trials. J Natl Cancer Inst 1990: 82: 555
560.
55. Lippman SM, Lee JS, Martin JW, El-Naggar AK, Xu X, Shin
DM, Thomas M, Mao L, Fritsche HA, Zhou X, Papadi-
mitrakopoulou V, Khuri FR, Tran H, Clayman GL, Hittleman
WN, Hong WK, Lotan R. Fenretinide activity in retinoid-
resistant oral leukoplakia. Clin Cancer Res 2006: 12: 3109
3114.
56. Lippmann SM, Batsakis JG, Toth BB, Weber RS, Lee JJ,
Martin JW, Hays GL, Goepfret H, Hong WK. Comparison
of low-dose isoretinoin with beta-carotene to prevent oral
carcinogenesis. N Engl J Med 1993: 328: 1520.
57. Lodi G, Porter S. Management of potentially malignant
disorders; evidence and critique. J Oral Pathol Med 2008:
37: 6369.
58. Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A. Inter-
ventions for treating oral leukoplakia. Cochrane Database
Syst Rev 2004: http://www2.cochrane.org/reviews/en/
ab001829.html (e-publication only).
59. Lumerman H, Freedman P, Kerpel S. Oral epithelial dys-
plasia and the development of invasive squamous cell
carcinoma. Oral Surg Oral Med Oral Pathol Radiol Endod
1995: 79: 321329.
60. Malaker K, Anderson BJ, Beecroft WA, Hodson DI. Man-
agement of oral mucosa dysplasia with beta-carotene or
retinoic acid: a pilot cross-over study. Cancer Detect Prev
1991: 15: 335340.
61. Marron M, Boffetta P, Zhang ZF, Zaridze D, Wunsch-Filho
V, Winn DM, Wei Q, Talamini R, Szeszenia-Dabrowska N,
Sturgis EM, Smith E, Schwartz SM, Rudnai P, Purdue MP,
Olshan AF, Eluf-Neto J, Muscat J, Morgenstern H, Mene-
zes A, McClean M, Matos E, Mates IN, Lissowska J, Levi F,
Lazarus P, La Vecchia C, Koifman S, Kelsey K, Herrero R,
Hayes RB, Franceschi S, Fernandez L, Fabianova E, Daudt
AW, Dal Maso L, Curado MP, Cadoni G, Chen C, Cas-
tellsague X, Boccia S, Benhamou S, Ferro G, Berthiller J,
Brennan P, Mller H, Hashibe M. Cessation of alcohol
drinking, tobacco smoking and reversal of head and neck
cancer risk. Int J Epidemiol 2010: 39: 182196.
62. Mehanna HM, Rattay T, Smith J, McConkey CC. Treat-
ment and follow-up of oral dysplasia a systematic review
and meta-analysis. Head Neck 2009: 31: 16001609.
63. Mincer HH, Coleman SA, Hopkins KP. Observations on
the clinical characteristics of oral lesions showing histo-
logic epithelial dysplasia. Oral Surg Oral Med Oral Pathol
1972: 33: 389399.
64. Morse DE, Katz RV, Pendrys DG, Holford TR, Krutchkoff
DJ, Eisenberg E, Kosis D, Mayne ST. Smoking and drinking
in relation to oral epithelial dysplasia. Cancer Epidemiol
Biomarkers Prev 1996: 5: 769777.
65. Mulshine JL, Atkinson JC, Greer RO, Papadimitrakopoulou
VA, Van Waes C, Rudy S, Martin JW, Steinberg SM, Lie-
wehr DJ, Avis I, Linnoila RI, Hewitt S, Lippman SM, Frye R,
Cavanaugh PF Jr. Randomized, double-blind, placebo
controlled phase IIb trial of the cyclooxygenase inhibitor
ketorolac as an oral rinse in oropharyngeal leukoplakia.
Clin Cancer Res 2004: 10: 15651573.
66. Nagao T, Warnakulasuriya S, Ito Y, Fukano H, Yuassa H,
Nakamura T, Yamamoto K, Uchida K, Kato S, Shimozato
K. Beta-carotene and vitamin C supplements for oral
leukoplakia. In: Mouth and Medicine 7th Biennial Con-
gress of the European Association of Oral Medicine. Berlin:
European Association of Oral Medicine, 2004: Abst. 33.
67. Napier SS, Speight PM. Natural history of potentially
malignant oral lesions and conditions: an overview of the
literature. J Oral Pathol Med 2008: 37: 110.
68. OShaughnessy JA, Kelloff GJ, Gordon GB, Dannenberg AJ,Hong WK, Fabian CJ, Sigman CC, Bertagnolli MM, Strat-
ton SP, Lam S, Nelson WG, Meyskens FL, Alberts DS,
Follen M, Rustgi AK, Papadimitrakopoulou V, Scardino
PT, Gazdar AF, Wattenberg LW, Sporn MB, Sakr WA,
Lippman SM, Von Hoff DD. Treatment and prevention of
intraepithelial neoplasia: an important target for acceler-
ated new agent development. Clin Cancer Res 2002: 8:
314346.
69. Papadimitrakopoulou VA, William WN, Dannenberg AJ,
Lippman SM, Lee JJ, Ondrey FG, Peterson DE, Feng L,
Atwell A, El-Naggar AK, Nathan CA, Helman JI, Du B, Yueh
B, Boyle JO. Pilot randomized phase II study of celecoxib
in oral premalignant lesions. Clin Cancer Res 2008: 14:
20952101.
70. Parker AJR, Marshall EJ, Ball DM. Diagnosis and manage-
ment of alcohol use disorders. Br Med J 2008: 336: 496501.
71. Pavia M, Pileggi C, Nobile CG, Angelilo F. Association
between fruit and vegetable consumption and oral cancer;
a meta-analysis of observational studies. Am J Clin Nutr
2006: 83: 11261134.
72. Petersen PE. Strengthening the prevention of oral cancer;
the WHO perspective. Community Dent Oral Epidemiol
2005: 33: 397399.
73. Piattelli A, Fioroni M, Santinelli A, Rubini C. bcl-2
expression and apoptotic bodies in 13-cis-retinoic acid
(isotretinoin)-topically treated oral leukoplakia: a pilot
study. Oral Oncol 1999: 35: 314320.
74. Poate TWJ, Warnakulasuriya KAAS. Effective management
of smoking in an oral dysplastic clinic in London. Oral Dis
2006: 12: 2226.
75. Ramseier CA, Warnakulasuriya S, Needleman IG, Galla-
gher JE, Lahtinen A, Ainamo A, Alajbeg I, Albert D,
Al-Hazmi N, Antohe ME, Beck-Mannagetta J, Benzian H,
Bergstrom J, Binnie V, Bornstein M, Buchler S, Carr A,
Carrassi A, Casals Peidro E, Chapple I, Compton S, Crail J,
Crews K, Davis JM, Dietrich T, Enmark B, Fine J, Gallagher
J, Jenner T, Forna D, Fundak A, Gyenes M, Hovius M,
Jacobs A, Kinnunen T, Knevel R, Koerber A, Labella R,
Lulic M, Mattheos N, McEwen A, Ohrn K, Polychronop-
oulou A, Preshaw P, Radley N, Rosseel J, Schoonheim-
Klein M, Suvan J, Ulbricht S, Verstappen P, Walter C,
Warnakulasuriya S, Wennstrom J, Wickholm S, Zoito-
poulos L. Consensus report: 2nd European Workshop on
Tobacco Use Prevention and Cessation for Oral Health
Professionals. Int Dent J 2010: 60: 36.
76. Ribeiro AS, Salles PR, da Silva TA, Mesquita RA. A review
of the nonsurgical treatment of oral leukoplakia. Int J Dent
2010: 2010: 186018 published online doi:10.1155/2010/
186018.
48
Warnakulasuriya
77. Rice VH, Stead LF. Nursing interventions for smoking
cessation. Cochrane Database Syst Rev 2007: http://
www2.cochrane.org/reviews/en/ab001188.html (e-publi-
cation only).
78. Roed-Petersen B. Effect on oral leukoplakia of reducing or
ceasing tobacco smoking. Acta Derm Venereol 1982: 62:
164167.
79. Saito T, Sugiura C, Hirai A, Notani K, Totsuka Y, Shindoh
M, Fukuda H. Development of squamous cell carcinoma
from pre-existent oral leukoplakia: with respect to
treatment modality. Int J Oral Maxillofac Surg 2001: 30:
4953.
80. Sankaranarayanan R, Mathew B, Varghese C, Sudhakaran
PR, Menon V, Jayadeep A, Nair MK, Mathews C, Maha-
lingam TR, Balaram P, Nair PP. Chemoprevention of oral
leukoplakia with vitamin A and beta carotene: an assess-
ment. Oral Oncol 1997: 33: 231236.
81. Sankaranarayanan R, Ramadas K, Thomas G, Muwonge R,
Thara S, Mathew B, Rajan B, Trivandrum Oral Cancer
Screening Study Group. Effect of screening on oral cancer
mortality in Kerala, India: a cluster-randomised controlled
trial. Lancet 2005: 365: 19271933.
82. Scheer M, Kuebler AC, Zoller JE. Chemoprevention of oral
squamous cell carcinomas. Onkologie 2004: 27: 187193.
83. Schepman KP, van der Meij EH, Smeele LE, van der Waal
I. Malignant transformation of oral leukoplakia: a follow-
up study of a hospital-based population of 166 patients
with oral leukoplakia from the Netherlands. Oral Oncol
1998: 34: 270275.
84. Sellman JD, Sullivan PF, Dore GM, Adamson SJ, MacEwan
I. A randomized controlled trial of motivational
enhancement therapy (MET) for mild to moderate alcohol
dependence. J Stud Alcohol 2001: 62: 389396.
85. Shah JP, Strong EW, DeCosse J, Itri L, Sellers P. Effect of
retinoids on oral leukoplakia. Am J Surg 1983: 146: 466
470.
86. Shiu MN, Chen TH. Impact of betel quid, tobacco and
alcohol on three-stage disease natural history of oral
leukoplakia and cancer: implications for prevention of
cancer. Eur J Cancer Prev 2004: 13: 3945.
87. Sieron A, Adamek M, Kawczyk-Krupka A, Mazur S, Ilewicz
L. Photodynamic therapy (PDT) using topically applied
d-aminolevulinic acid (ALA) for the treatment of oralleukoplakia. J Oral Pathol Med 2003: 32: 330336.
88. Silverman S, Bhargava K, Mani NJ, Smith LW, Malaowalla
AM. Malignant transformation and natural history of oral
leukoplakia in 57,518 industrial workers of Gujarat, India.
Cancer 1976: 38: 17901795.
89. Silverman S, Renstrup G, Pindborg JJ. Studies in oral
leukoplakias: III. Effects of vitamin A comparing clinical,
histopathological, cytologic, and haematologic responses.
Acta Odontol Scand 1963: 21: 271292.
90. Silverman S, Gorsky M, Lozada F. Oral leukoplakia and
malignant transformation. A follow-up study of 257
patients. Cancer 1984: 53: 563568.
91. Singh M, Krishanappa R, Bagewadi A, Keluskar V. Efficacy
of oral lycopene in the treatment of oral leukoplakia. Oral
Oncol 2004: 40: 591596.
92. Smith SE, Warnakulasuriya KA, Feyerabend C, Belcher M,
Cooper DJ, Johnson NW. A smoking cessation programme
conducted through dental practices in the UK. Br Dent J
1998: 185: 299303.
93. Stead LF, Bergson G, Lancaster T. Physician advice for
smoking cessation. Cochrane Database Syst Rev 2008:
http://www2.cochrane.org/reviews/en/ab000165.html (e-
publication only).
94. Stead lF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine
replacement therapy for smoking cessation. Cochrane
Database Syst Rev 2007: http://www2.cochrane.org/
reviews/en/ab000146.html (e-publication only).
95. Stich HF, Hornby AP, Mathew B, Sankaranarayanan R,
Nair MK. Response of oral leukoplakia with vitamin A.
Cancer Lett 1988: 40: 93100.
96. Stich HF, Rosin MP, Hornby AP, Mathew B, Sankara-
narayanan R, Nair MK. Remission of oral leukoplakia and
micronuclei in tobacco betel quid chewers treated withbeta-carotene and with beta-carotene plus vitamin A. Int J
Cancer 1988: 42: 195199.
97. Sugar L, Banoczy J. Follow-up studies in oral leukoplakia.
Bull World Health Organ 1969: 41: 289293.
98. Thomas S, Fayter D, Misso K, Ogilvie D, Petticrew M,
Sowden A, Whitehead M, Worthy G. Population tobacco
control interventions and their effects on social inequali-
ties in smoking: systematic review. Tob Control 2008: 17:
230237.
99. Thomas SJ, Harris R, Ness AR, Taulo J, Maclennan R,
Howes N, Bain CJ. Betel quid not containing tobacco and
oral leukoplakia; a report on a cross-sectional study in
Papua New Guinea and a meta-analysis of current evi-
dence. Int J Cancer 2008: 123: 18711876.
100. Toma S, Benso S, Albanese E, Palumbo R, Cantoni E,
Nicolo G, Mangiante P. Treatment of oral leukoplakia with
beta-carotene. Oncology 1992: 49: 7781.
101. Toma S, Mangiante PE, Margarino G, Nicolo G, Palumbo
R. Progressive 13-cis-retinoid acid dosage in the treatment
of oral leukoplakia. Oral Oncol 1992: 28: 121123.
102. Tsai JC, Chiang CP, Chen HM, Huang SB, Wang CW, Lee
MI, Hsu YC, Chen CT, Tsai T. Photodynamic therapy of
oral dysplasia with topical 5-aminolevulinic acid and
light-emitting diode array. Lasers Surg Med 2004: 34: 18
24.
103. Van der Herm PS, Nauta JM, van der wal JE, Roodenburg
JLN. The results of CO2 laser surgery in patients with oral
leukoplakia: a 25 year follow up. Oral Oncol 2005: 41: 31
37.
104. Vedtofte P, Holmstrup P, Hjorting-Hansen E, Pindborg JJ.
Surgical treatment of premalignant lesions of the oral
mucosa. Int J Oral Maxillofac Surg 1987: 16: 656664.
105. Warnakulasuriya S, Cain N. Screening for oral cancer:
contributing to the debate. J Invest Clin Dent 2011: 2: 29.
106. Warnakulasuriya S, Dietrich T, Bornstein MM, Casals
Peidro E, Preshaw PM, Walter C, Wennstrom JL, Bergs-
trom J. Oral health risks of tobacco use and effects of
cessation. Int Dent J 2010: 60: 730.
107. Warnakulasuriya S. Causes of oral cancer an appraisal of
controversies. Br Dent J 2009: 207: 471475.
108. Warnakulasuriya S. Food, nutrition and oral cancer. In:
Wilson M editor. Food constituents and oral health.
Cambridge: Woodhead Publishing Ltd, 2009: 273295.
109. Warnakulasuriya S, Reibel J, Bouquot J, Dabelsteen E.
Oral epithelial dysplasia. J Oral Pathol Med 2008: 37:
127133.
110. Warnakulasuriya S, Johnson NW, Van der Waal I.
Nomenclature and classification of potentially malignant
49
Prevention of cancer and precursor lesions
disorders of the oral mucosa. J Oral Pathol Med 2007: 36:
575580.
111. Warnakulasuriya S, Nagao T. Oral cancer and precancer
screening: from research to policy and practice. Globel
Forum Health Res 2005: 2: 188191.
112. Warnakulasuriya S, Sutherland G, Scully C. Tobacco, oral
cancer and treatment of dependence. Oral Oncol 2005: 41:
244260.
113. Warnakulasuriya S, Trivedy C, Peters TJ. Areca nut use: an
independent risk factor for oral cancer. Br Med J 2002:
324: 799800.
114. Warnakulasuriya S. Effectiveness of tobacco counseling in
the dental office. J Dent Educ 2002: 66: 10791087.
115. White AR, Rampes H, Campbell JL. Acupuncture and
related interventions for smoking cessation. Cochrane
Database Syst Rev 2005: http://www2.cochrane.org/
reviews/en/ab000009.html (e-publication only).
116. Winstock A. Areca nut-abuse liability, dependence and
public health. Addict Biol 2002: 7: 133138.
117. Wirth LJ, Krane JF, Li Y, Othus M, Moran AE, Dorfman
DM, Norris CM, Goguen L, Posner MR, Haddard RI, Ber-
tagnolli MM. A pilot surrogate endpoint biomarker study
of celecoxib in oral premalignant lesions. Cancer Prev Res
2008: 1: 312315.
118. World Cancer Research Fund American Institute forCancer Research. Food, Nutrition and Physical Activity
and Prevention of Cancer: a Global Perspective. Washing-
ton, DC: American Institute for Cancer Research, 2007.
119. World Health Organization. Control of oral cancer in
developing countries. Bull World Health Organ 1984: 62:
817830.
120. World Health Organization. Diet, nutrition, and the pre-
vention of chronic diseases: WHO technical report series
916. Geneva: World Health Organization, 2003.
121. Zoller JE. Zur Malignen Transformation des Epithels der
Mundschleimhaut unter Chemotherapie under Chemo-
pravention Untersuchungen zur multitrischen Karzino-
genese. Berlin: Quintessenz, 1995.
50
Warnakulasuriya
Copyright of Periodontology 2000 is the property of Wiley-Blackwell and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.