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PERIODONTOLOGY 2000
Introduction
38
Community interventions
There is evidence that comprehensive tobacco control programs including media campaigns, higher
taxes and smoke-free environments can be effective
in changing smoking behavior in adults, but the evidence 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
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 policies 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 successful smoking cessation published in the Cochrane
Database of Systematic Reviews based on published
meta-analyses (7, 24, 36, 48, 77, 93, 94, 115)
Type of therapy
Nursing intervention
CI
42
1.28
1.181.38
Brief advice
17
1.66
1.421.94
Intensive advice
11
1.84
1.602.13
Dentists advice
1.44
1.161.78
Counselling
21
1.56
1.321.84
Nicotine replacement
therapy
132
1.58
1.50 1.66
Clonidine
1.89
1.302.74
Bupropion
31
1.94
1.722.19
Varenicline
2.33
1.952.80
Nortriptyline
2.34
1.613.41
Acupuncture
24
1.36
1.071.72
Physicians advice
39
Warnakulasuriya
40
Alcohol
Alcohol use is the second most important risk factor
for the development of oral cancer. Ethanol is classified 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 independent 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 fashion (5). Pooled data from the Head and Neck Epidemiology Consortium based on 13 studies on alcohol
cessation confirmed the benefits of abstaining or
reducing alcohol consumption (61). The risk is multiplicative 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 acetaldehyde 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 malignant transformation from leukoplakia to cancer (86).
There is a controversy as to which types of alcoholic 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 consumed 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,
Betel quid
In parts of South and South East Asia and in Melanesia, 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 packaged 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
Human papillomavirus
Table 2. Brief advice and motivational enhancement
against 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
Warnakulasuriya
42
Chemoprevention
Chemoprevention attempts to reduce cancer incidence 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) or
b-carotene (20 mg day), or both supplements in 409
subjects who smoked did not prevent oral leukoplakia (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 outcomes 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 resolution 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 have
not been long enough to estimate the possibility of
malignant transformation, and recurrence of precancer after discontinuation of supplements appears
to be a common finding in these trial results. Furthermore, toxicity is reported with many agents
used in chemoprevention. A critical review of published 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 aggressive antioxidant treatment combinations have so far
not been found to be effective in reversing advanced
pre-malignant lesions of the oral cavity and oropharynx, suggesting an urgent need for innovative
approaches (108).
More recently, non-steroidal anti-inflammatory
drugs (NSAIDs) have received attention as potential
Dose
Number of
patients
Clinical
resolution (%)
Follow-up
(months)
Recurrence
progression
(%)
Systemic
retinyl acetate
300,000 IU
42
52
12
67
Systemic
retinol
200,000300,000 IU
21
57
12
Topical retinol
600 000 IU
16
44
218
Topical
isotretinoin
310 mg day
11
28
18
Koch (43)
Analogues of
retinoic acid
70 mg
75
43
264
Koch (44)
Etretinate
45
71
Isotretinoin
0.21.0 mg kg
14
36
Fenretinate
200 mg day
80
95
9 years
Fenretinide
200 mg day
35
34
22
Isotretinoin
12 mg kg
24
67
Topical
tretinoin
0.05% gel
26
27
23
40
Topical
isotretinoin
1%
10
10
48
b-carotene
60 mg day
24
52
18
b-carotene
90 mg day
23
26
Sankaranarayanan
et al. (80)
b-carotene
360 mg
46
54
12
b-carotene
60 mg day
50
18
17
Lycopene
48 mg
58
2555
a-tocopherol
400 IU x2 day
43
23
b-carotene or
retinoic acid
30 mg x4 day
10 mg x3 day
18
33
24
16
b-carotene
b-carotene +
vitamin A
30 mg x2 week
90 mg x2 week
50,000 IU
27
51
15
28
b-carotene +
a-tocopherol +
vitamin C
30 mg day
800 IU
1,000 mg
79
56
b-carotene +
isotretinoin
30 mg day
0.51.5 mg kg
33
26
45
92
28
8.5
b-carotene +
a-tocopherol +
vitamin C
75 mg
100 mg
1,000 mg
24
98
b-carotene +
vitamin C
10 mg
500 mg
46
25
24
Study
Sankaranarayanan
et al. (80)
Stich et al. (95)
Silverman et al. (89)
Shah et al. (85)
Zoller (121)
43
Warnakulasuriya
Photodynamic therapy
Photodynamic therapy uses light to activate a
photosensitizing agent in the presence of oxygen to
44
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 leukoplakia epithelial dysplasia vs. no treatment. They
found a considerably higher malignant transformation 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-
Table 4. Selected follow-up studies showing outcome of surgical excision or no intervention for cases of oral leukoplakia or epithelial dysplasia
Study
Country
Mean
follow-up
(years)
Total cases
Followed-up
Excised
Followed-up
Denmark
6.8
89
147
12
Denmark
3.9
61*
Italy
4.6
128
74
The
Netherlands
2.5
39
79
20
15
USA
1.5
44,
16
USA
8.0
20
22
15
Japan
4.0
75
51
India
8.5
426
Hungary
23
18
306
Hungary
3.6
45
23
34
Excised
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 population, and thereby contribute to the control of oral
45
Warnakulasuriya
cancer (119). Community-oriented screening programs and communication on signs and symptoms
and risk factors also increase public awareness and
knowledge of oral cancer (72).
7.
8.
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 personalized 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 evidence 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 important in appropriate settings. An ideal chemopreventive agent remains to be discovered. Future research
is required to evaluate surveillance of precursor lesions, and less invasive and more effective treatment
protocols are required to prevent cancer development
in subjects with precursor lesions.
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