Revisão Sistemática de Doenças Dentárias em Pacientes com Câncer

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REVIEW ARTICLE
A systematic review of dental disease in patients undergoing
cancer therapy
Catherine H. L. Hong & Joel J. Napeñas &
Brian D. Hodgson & Monique A. Stokman &
Vickie Mathers-Stauffer & Linda S. Elting &
Fred K. L. Spijkervet & Michael T. Brennan &
Dental Disease Section, Oral Care Study Group,
Multi-national Association of Supportive Care
in Cancer (MASCC)/International Society
of Oral Oncology (ISOO)
Received: 8 October 2009 /Accepted: 29 March 2010 /Published online: 7 May 2010
# The Author(s) 2010. This article is published with open access at Springerlink.com
Abstract
Introduction This purpose of this systematic review was to
evaluate the literature and update our current understanding
of the impact of present cancer therapies on the dental
apparatus (teeth and periodontium) since the 1989 NIH
Development Consensus Conference on the Oral Compli-
cations of Cancer Therapies.
Review method A systematic literature search was con-
ducted with assistance from a research librarian in the
databases MEDLINE/PubMed and EMBASE for articles
published between 1 January 1990 and 31 December
2008. Each study was independently assessed by two
reviewers. Taking into account predetermined quality
measures, a weighted prevalence was calculated for the
prevalence of dental caries, severe gingival disease, and
dental infection. Data on DMFT/dmft, DMFS/dmfs,
plaque, and gingival indexes were also gathered. The level
of evidence, recommendation, and guideline (if possible)
were given for published preventive and management
strategies.
Results Sixty-four published papers between 1990 and 2008
were reviewed. The weighted overall prevalence of dental
caries was 28.1%. The overall DMFT for patients who were
post-antineoplastic therapy was 9.19 (SD, 7.98; n=457).
The overall plaque index for patients who were post-
antineoplastic therapy was 1.38 (SD, 0.25; n=189). The GI
C. H. L. Hong (*) : J. J. Napeñas :M. T. Brennan
Department of Oral Medicine, Carolinas Medical Center,
1000 Blythe Blvd, P.O. Box 32861, Charlotte, NC 28232, USA
e-mail: catherine.hong@carolinashealthcare.org
J. J. Napeñas
e-mail: joel.napenas@carolinashealthcare.org
M. T. Brennan
e-mail: mike.brennan@carolinas.org
B. D. Hodgson
Program in Pediatric Dentistry, Department of Developmental
Sciences, Marquette University School of Dentistry,
1801 W. Wisconsin Ave,
Milwaukee, WI 53233, USA
e-mail: brian.hodgson@marquette.edu
M. A. Stokman
Department of Oral & Maxillofacial Surgery,
University Medical Center Groningen, University of Groningen,
P.O. Box 30.001, 9700 RB Groningen, The Netherlands
e-mail: m.a.stokman@kchir.umcg.nl
V. Mathers-Stauffer
Penrose Cancer Center,
2222 North Nevada Avenue,
Colorado Springs, CO 80907, USA
e-mail: vickimathers@centura.org
L. S. Elting
The University of Texas M.D. Anderson Cancer Centre,
P.O. Box 301402, Houston, TX 77230-1402, USA
e-mail: lelting@mdanderson.org
F. K. L. Spijkervet
Department of Oral & Maxillofacial Surgery,
University Medical Center Groningen,
University of Groningen,
Hanzeplein 1,
9700 RG Groningen, The Netherlands
Support Care Cancer (2010) 18:1007–1021
DOI 10.1007/s00520-010-0873-2
for patients who were post-chemotherapy was 1.02 (SD,
0.15; n=162). The weighted prevalence of dental infections/
abscess during chemotherapy was reported in three studies
and was 5.8%.
Conclusions Patients who were post-radiotherapy had the
highest DMFT. The use of fluoride products and chlorhex-
idine rinses are beneficial in patients who are post-
radiotherapy. There continues to be lack of clinical studies
on the extent and severity of dental disease that are
associated with infectious complications during cancer
therapy.
Keywords Cancer therapy . Dental caries .
Periodontal disease
Introduction
Surgical resection, radio-, and chemotherapy, either used
singly or in combination, are the three most common
modalities used in head and neck cancer treatment.
Although these modalities are effective in eradicating the
tumor, they also negatively impact the normal head and
neck structures surrounding the tumor. Direct damage to the
oral structures (soft and hard tissue) frequently occurs from
radio- and chemotherapy, and indirect damage may also
arise from systemic toxicity. These oral complications may
occur during and following cancer therapy and are
generally grouped into two broad categories: acute and
chronic. This review will focus on the acute and chronic
effects of cancer therapy on the dental apparatus (i.e., teeth
and periodontium). Because of the known long-term impact
of cancer therapy on the dental apparatus, in particular, the
increased risk of dental caries, this article will also examine
the evidence for various preventive and treatment
approaches of dental disease in such patients.
Another important issue covered by this review was the
evidence for pre-cancer therapy dental clearance. The
rationale for dental examination and treatment prior to
cancer therapy is based on reports in the literature linking
increased incidence of intra-therapy complications and
viridans streptococcal bacteremia in patients with poor
dental health [1–3]. One of the concerns is the occurrence
of acute dental infections while patients are undergoing
cancer therapy. Even though this has not been extensively
reported in patients who are immunosuppressed from
chemotherapy, from theoretical reasoning, it is possible
for a minor odontogenic infection to develop into a
systemic infection and result in a life-threatening event.
Another frequently cited reason for pre-cancer therapy
dental clearance is the risk of post-radiation jaw osteor-
adionecrosis in patients who receive radiation doses above
6,000 cGy in the head and neck region. The estimated
incidence of osteoradionecrosis in radiated (conventional
radiation) jaw bone is approximately 7% and occurs more
frequently in the mandible than in the maxilla [4]. The
process may occur spontaneously, may be caused by trauma
(e.g., accidental injury to oral mucosa from masticatory
activity or iatrogenically from dental extractions) or oral
infections (e.g., periapical and periodontal infections). Due
to the concern of oral and systemic sequelae from dental
infection, the dentist is often part of the pre-cancer therapy
work up in many treatment centers.
The purpose of this systematic review was to evaluate
the literature and update our current understanding of the
impact of present cancer therapies on the dental apparatus
(teeth and periodontium) and the role of pre-cancer
treatment dental protocols since the 1989 NIH Develop-
ment Consensus Conference on the Oral Complications of
Cancer Therapies [5].
Historical perspective (prior to 1990)
The historical perspective was summarized from the 1989
National Institute of Health (NIH) Development Consensus
Conference on the oral complications of cancer therapies.
Dental disease and the necessity of pre-cancer therapy
dental clearance
Patients with chronic dental disease and poor oral hygiene
were thought to be at increased risk for the development of
acute odontogenic infections and potentially life-
threatening systemic infections during periods of immuno-
suppression, though this appeared to occur less frequently
than other acute mucosal oral infections [6, 7]. Oncology
centers employed empiric guidelines to prevent these
odontogenic infections, which often entailed the implemen-
tation of pre-cancer treatment dental protocols. These
protocols typically included restoration of carious teeth,
root canal therapy (if time permits), extraction of hopeless
teeth, and dental prophylaxis with or without scaling and
root planning. The guidelines for endodontic care and
extractions proposed during the consensus in 1990 are
illustrated in Tables 1 and 2, respectively.
These guidelines varied greatly amongst centers due to
the lack of outcome-oriented trials to assess efficacy of a
specific pre-cancer therapy dental protocol. Ultimately, the
decision on the type of dental treatment rendered was based
on the clinician'sassessment of the clinical and radiographic
condition of the pulpal and periodontal status of the tooth
involved, the time available prior to cancer treatment
initiation, and patient's immune status at the time of dental
treatment.
Experts concluded that larger scale prospective studies
were needed to examine the risk-benefit ratio of dental
1008 Support Care Cancer (2010) 18:1007–1021
procedures prior to myelosuppressive chemotherapy. In
addition, studies should also focus on the extent of
periodontal, pericoronal, and dental disease that were likely
to cause serious complications during chemotherapy.
Long-term effect of cancer therapies on teeth
and periodontium
Prior to 1990, data on the caries profile in patients who
have undergone chemotherapy were limited and conflicting
[8]. Some studies reported increase caries incidence, while
others did not find any changes in caries activity. Similar
findings were found regarding the periodontium of these
patients. In patients who had received head and neck
radiotherapy, the ensuing xerostomia caused by damage to
the salivary glands predisposed these patients to post-
radiation caries. Fluoride therapy was considered to be the
best option for prevention of post-radiation caries. The role
of long-term use of chlorhexidine rinses and saliva
substitutes was uncertain.
Aims
The aim of the present review was to expand on the 1989
NIH Development Consensus Conference on the Oral
Complications of Cancer Therapies [5]. The specific goals
of this systematic review of dental disease as an oral
complication of cancer therapies were as follows:
1. Determine the prevalence of dental caries in cancer
survivors.
2. Determine prevalence of periodontal disease in cancer
survivors.
3. Determine the prevalence of local and systemic infections
caused by dental disease during cancer therapy.
4. Determine the efficacy of preventive and treatment
approaches in managing dental disease in cancer survivors.
5. Determine the efficacy of pre-cancer therapy dental
clearance in preventing oral complications during and
after cancer therapy.
Systematic review methodology
Search strategy and criteria for selecting studies
A systematic literature search was conducted with assistance
from a research librarian in the databases MEDLINE/PubMed
and EMBASE for articles published between 1 January 1990
and 31 December 2008. The primary outcome was to retrieve
all literature containing original data on dental caries and
periodontal disease and pre-cancer dental clearance protocols
in cancer patients undergoing head and neck radiotherapy,
chemotherapy, or combined treatment modalities.
The following publication types were eliminated from this
systematic review: systematic and non-systematic reviews;
microbiology studies; growth and development studies; organ
transplant studies; studies eliciting dental complications
through questionnaires, studies reporting data from previous
publications; phase I and II studies, opinion papers, and case
reports; articles published before 1990; and publications from
the 1990 NCI Monographs [9] based on the 1989 NIH
Development Consensus Conference on the Oral Complica-
tions of Cancer Therapies [5]. The search was limited to the
English language. Gender and age were not limited.
Review methodology
Each article was independently evaluated by two reviewers
(BH, CH, JJN, MS, and VM) with pilot-tested collection
forms customized for reviewing dental disease data. Dental
caries was assessed by the presence (Y/N), DMFT/dmft
(decayed, missing, and filled teeth: DMFT for permanent,
adult teeth and dmft signifying deciduous teeth), and
DMFS/dmfs indexes (decayed, missing, and filled surfaces:
DMFS for permanent, adult teeth and dmfs signifying
deciduous teeth) if available. Periodontal health was
assessed using the plaque and gingival indexes. Further
Table 1 Empiric guidelines for endodontic care in patients scheduled to receive myelosuppressive chemotherapy [7]
Diagnosis Management
Reversible pulpitis Caries control
Irreversible pulpitis Initial biomechanical preparation of canal(s); temporary double closure
Necrotic pulp with chronic periapical pathosis No endodontic treatment unless patient has 7 days from completion of
endodontic therapy to onset of myelosuppression (<1,000 granulocytes/mm3)
Necrotic pulp with acute periapical infection Endodontic therapy or extraction depending on systemic status of patient and
scheduling of chemotherapy
Table 2 Guidelines for dental extractions [7]
Primary wound closure with multiple interrupted sutures
Ten days between extraction date and granulocyte count <500/mm3
Avoidance of intra-alveolar hemostatic packing agents
Platelet transfusion if platelet count <40,000/mm3
Prophylactic antibiotics if granulocyte count <2,000/mm3
Support Care Cancer (2010) 18:1007–1021 1009
data collected for each article such as type of study, blinding,
presence of control group, scale validity, and sample size
were used to determine quality outcomes utilized to
determine the weighted prevalence of caries and dental
infection. Further details of this methodology can be
reviewed in the publication by Brennan MT et al. [10].
The following assumptions were made regarding cancer
diagnosis and treatment modality in this review:
1. There were several articles that only described the
treatment modality but did not include the cancer
diagnosis. If the treatment modality involved head and
neck radiation, the assumption was made that this
treatment was for head and neck cancer. No assump-
tions were made regarding the type of head and neck
malignancy.
2. Although, the modality of cancer treatment (i.e.,
radiotherapy and chemotherapy) was described in detail
in the majority of the studies, many did not specify or
clarify whether this was the only treatment approach.
Therefore, if only one mode of antineoplastic therapy
(e.g., chemotherapy, radiotherapy, and surgery) was
described in the manuscript, we made the assumption
that this particular treatment was the only therapy
rendered, unless otherwise stated by the authors.
Results
The electronic searches identified over a thousand titles and
abstracts. After examination of the abstracts and full-text
articles by the review group, 64 articles satisfied the inclusion
criteria. Forty-six studies were observational, and 18 were
interventional studies. Of the 64 studies included, 31 studies
recruited adult patients, 24 recruited pediatric patients, 4
included both pediatric and adult patients, and 5 did not
provide the age of the population sampled. The two most
common malignancies were head and neck cancer and
hematological malignancies (Table 3). The majority of studies
reported the type of cancer treatment rendered (Table 4).
Observational studies
Of the 46 observational studies, 24 were cohort, 8 were
case control, and 14 were cross-sectional studies. The
majority of studies were conducted in single institution
settings. Only one observational study did not report the
type of antineoplastic therapy rendered.
(A) Teeth
1. Dental infection/abscess
Dental infections/abscess during chemotherapy was
reported in three studies, and the weighted prevalence was
5.8% [11–13] (standard of error, 0.009; 95% confidence
interval, 1.8–9.7).
1. Dental caries (Table 5)
The weighted overall prevalence of dental caries was
28.1% and was determined from 19 studies [14–32]. The
weighted prevalence of dental caries in patients who
received only chemotherapy was 37.3%. The weighted
prevalence of dental caries in patients who were post-
radiotherapy and those who were post-chemo- and radio-
therapy were 24% and 21.4%, respectively.
2. DMFT
The overall DMFT for patients whowere post-antineoplastic
therapy was 9.19 (SD, 7.98; n=457) [14, 17, 25, 29, 30, 33–
36]. The DMFT for patients who were post-chemotherapy
[17, 25, 33] and post-radiotherapy [14, 30, 36] was 4.5 (SD,
2.88; n=132) and 17.01 (SD, 9.14; n=157), respectively. The
mean DMFT value in patients prior to treatment was 8.2 (SD,0.71; n=80) [14, 35]. The mean DMFT for healthy controls
was 4.4 (SD, 4.07; N=275) [14, 17, 25, 29, 34].
3. dmft
The overall dmft for patients who were post-cancer
therapy (all modalities) was 3.23 (SD, 2.42; n=128) [29,
33, 34]. The mean dmft for healthy controls was 2.15 (SD,
1.77; n=103) [29, 34].
4. DMFT/dmft
The overall DMFT/dmft for patients who were post-
chemotherapy was 5.63 (SD, 0.88; n=66) [37, 38]. The mean
DMFT/dmft for healthy controls was 4.7 (SD, 0.14; n=56)
[37, 38].
5. DMFS
The overall DMFS for patients who were post-cancer
therapy (all modalities) was 11.8 (SD, 9.01; n=128) [17,
34, 35]. The mean DMFS for healthy controls was 4.1 (SD,
0.28; n=86) [17, 34].
6. DMFS/dmfs
The overall DMFS/dmfs for patients who were post-
chemotherapy was 8.01 (SD, 2.14; n=66) [37, 38]. The
mean DMFS/dmfs for healthy controls was 1.08 (SD, 0.04;
n=56) [37, 38].
(B) Periodontium
1. Severe gingivitis
The weighted prevalence of severe gingivitis from three
studies was 20.3% (standard of error, 0.49; 95% confidence
interval, 0–41.4) [12, 13, 39]. All three studies were
conducted on patients undergoing chemotherapy.
2. Plaque index (PI)
1010 Support Care Cancer (2010) 18:1007–1021
The overall PI for patients who were post-antineoplastic
therapy was 1.38 (SD, 0.25; n=189) [25, 37, 38, 40]. The
PI for patients who were post-chemotherapy was 1.46 (SD,
0.23; n=162) [25, 37, 38]. The mean PI for healthy controls
was 0.91 (SD, 0.12; n=152) [25, 37, 38].
3. Gingival index (GI)
The GI for patients who were post-chemotherapy was
1.02 (SD, 0.15; n=162) [25, 37, 38]. The mean GI for
healthy controls was 0.76 (SD, 0.10; n=152) [25, 37, 38].
(C) Febrile episodes from oral source
One study reported the incidence of patients with febrile
episode originating from a dental problem was 4% [41].
Another study found that an oral source was the only
identifiable foci of infection in 42% of recorded febrile
episodes [42]. The same study also reported that patients
with febrile episodes had more severe dental infection
(57.6%) than those without (23.3%) [42].
Interventional studies
Fluoride therapy
The anticariogenic benefits of fluoride therapy are well
documented in the literature. Water fluoridation has been
touted to be responsible for the dramatic decrease in dental
caries in the twentieth century. There are several studies
Table 3 Cancer diagnosis (n=64)
Cancer diagnosis Number of studies (references) Number
of patientsa
Cancers in the head and neck region
Squamous cell carcinoma 9 [18, 56, 63–69] 385
Head and neck cancer 12 [22, 26, 36, 40, 43, 44, 46, 49, 51, 53, 57, 58] 550
Head and neck cancer (assumptions made by reviewers) 3 [45, 52, 54] 77
Nasopharyngeal cancer 8 [14, 27–30, 70–72] 272
Cancer requiring radiation to the ENT/H&N region 2 [21, 50] 2,507
Tumors in the salivary gland areas 3 [48, 63, 67] 17
Hematologic malignancies
Hematologic malignancies/diseases (exclude lymphoma if possible) 16 [12, 13, 17, 19, 24, 29, 33, 39, 41, 55, 73–78] 2,008
Lymphoma (Hodgkin's, non-Hodgkin's disease, NOS) 15 [12, 25, 29, 35, 37, 38, 41, 42, 47, 55, 67, 69, 70, 74, 78] 325
Other diagnosis
Rhabdomyosarcoma 7 [12, 15, 20, 25, 29, 32, 74] 264
Osteosarcoma/Ewing sarcoma 2 [12, 25] 15
Wilms tumor/nephroblastoma 5 [12, 23, 25, 29, 74] 64
Neuroblastoma 4 [12, 16, 29, 69] 59
Small cell cancer 1 [11] 21
Breast cancer 1 [41] 1
Childhood cancer 1 [34] 52
Thyroid cancer 1 [31] 121
Diagnosis not specified 5 [12, 25, 29, 69, 74] 25
a Healthy controls were excluded
Table 4 Breakdown of studies and patients with reference to treatment modality (n=64)
Treatment modality Number of studies (references) Number
of patientsa
Chemotherapy only±surgery 22 [11, 13, 15–17, 19, 23, 25, 29, 32, 33, 37–39, 41, 42, 47, 73–76, 78] 710
Radiation only±surgery 30 [14, 21, 22, 26, 30, 36, 40, 43–46, 48–54, 56, 57, 63–72] 3,477
Radiation and chemotherapy±surgery 19 [15–18, 20, 26–29, 32, 33, 40, 41, 64, 72, 75–78] 696
No breakdown or vague description of cancer
therapy or other type of therapy
7 [6, 12, 24, 31, 35, 55, 58] 1,812
a Healthy controls and patients who have not yet underwent treatment were excluded
Support Care Cancer (2010) 18:1007–1021 1011
that have extrapolated and investigated the benefits of
fluoride use in the general population for management of
dental caries in patients have undergone head and neck
radiation. Because of the damage to the salivary glands
during radiation and the ensuing xerostomia that follows,
these patients are at higher risk that the average person for
the development of dental caries. We retrieved five
randomized control trials on fluoride therapy in patients
who have undergone antineoplastic therapy [43–47]; four
studies were on patients who were post-radiation, and one
was on patients who were undergoing chemotherapy
(Table 6). Two studies compared different types and
methods of fluoride application on the caries activity [43,
44]. In both studies, they found no difference in caries
activity between the treatment groups. Al Joburi et al. noted
that patients who were noncompliant with their fluoride
therapy had a significantly higher caries increment com-
pared to the fluoride treatment groups [43]. Two articles
investigated the use of an intraoral fluoride releasing system,
and in both studies, there were no significant differences in
dental caries between groups that used the system and those
that used regular fluoride gels in custom fabricated trays [45,
46]. Meurman et al. compared the use of chlorhexidine 0.12%
to amine-stannous fluoride mouth rinses in patients undergo-
ing chemotherapy [47]. They found that both rinses reduced
the gingival bleeding scores and plaque scores as well as the
levels of streptococcus mutans in the saliva.
Toothpaste
There were three studies that investigated the use of various
toothpastes [48–50] (Table 7). Two studies examined the
benefits of toothpaste containing lactoperoxidase in patients
who have undergone radiotherapy for head and neck cancer
[48, 49]. Toljanic et al. found that the toothpaste containing
salivary lactoperoxidase provided slight improvement in
plaque and gingival index scores compared to placebo
toothpaste, but this was not significant [49]. In the other
study by Van Steenberghe et al., authors found that patients
using toothpaste containing lactoperoxidase (Biotene) sig-
nificantly reduced sulcular bleeding index after 10 days of
use [48]. In addition, when only interdental spaces were
considered, there was significantly lower plaque seen in the
Biotene group compared to patients who were using
Sensodyne toothpaste. The third article retrieved in this
category compared a dual phase remineralizing toothpaste
to conventional toothpaste [50]. The authors found signif-
icantly (p=0.03) lower net root surface caries increment/
year in patients using Enamelon toothpaste compared to
those using conventional toothpaste.
Chlorhexidine
Chlorhexidine is a bisguanide with bactericidal activity
against gram-positive and -negative bacteria. Its mechanism
of action is through disruption of bacterial membranes and
enzyme systems. There were three studies that evaluated
the effect of chlorhexidine mouth rinse on oral hygiene
indexes in patients who have undergone antineoplastic
therapy [39, 47, 51] (Table 8). Two studies found that
chlorhexidine rinse reduced plaque scores as well as the
levels of salivary streptococcus mutans count [47, 51].
However, in both studies, the lactobacillus counts was
either higher or did not change with the use of chlorhex-
idine. One study compared the use of chlorhexidine with
and without mechanical removal of plaque and calculus on
day 1 of chemotherapy and found that the plaque scores
and bleeding scores were significantly lower in the group
that had mechanical removal of plaque and calculus [39].
Dental restorations
There were three studies that investigated the use of various
dental restorative materials in patients who have undergone
head and neck radiation [52–54] (Table 9).In studies by
McComb et al. [52] and Wood et al. [53], conventional glass
ionomer cements performed more poorly than the compara-
tive materials, specifically amalgam, resin-modified glass
ionomer, and composite resin restorations. Hu et al.
compared Ketac molar (KM) to Fuji IX (FIX) restorations
and found that there was statistically (p=0.01) higher number
of KM restorations (30%) lost compared to FIX (12.5%)
restorations at the 12- and 24-month follow up [54].
Others
There were two articles on oral care protocols, one [41]
examined the benefits of a minimal intervention pre-cancer
therapy dental protocol, and the other [55] examined the
impact of an intensive preventive protocol on patients
Table 5 Weighted prevalence of dental caries following cancer therapy (n=19)
Treatment modality Number of studies Mean prevalence (%) STD error 95% confidence interval
Chemotherapy only 5 37.3 0.17 0–85.7
Radiotherapy only 4 24.1 0.13 0–66.2
Chemoradiotherapy 9 21.4 0.06 6.9–35.8
1012 Support Care Cancer (2010) 18:1007–1021
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em
(I
R
F
S
)
re
ta
in
er
s,
at
4,
8,
12
,
24
,
36
,
an
d
48
w
ee
ks
S
us
ta
in
ed
re
le
as
e
fl
uo
ri
de
ta
bl
et
re
pl
ac
ed
ev
er
y
3
m
on
th
s
0.
4%
S
ta
nn
ou
s
fl
uo
ri
de
ge
l
in
cu
st
om
tr
ay
s
da
ily
fo
r
10
m
in
S
od
iu
m
fl
uo
ri
de
/h
yd
ro
xy
et
hy
l
m
et
ha
cr
yl
at
e/
m
et
hy
ly
m
et
ha
cr
yl
at
e
(5
0:
50
ra
tio
of
H
E
M
A
/M
M
A
)
M
eu
rm
an
et
al
.
19
91
[4
7]
H
od
gk
in
's
an
d
no
n-
H
od
gk
in
's
di
se
as
e
C
T
d
R
C
T
c
D
ur
in
g
co
m
bi
na
tio
n
C
T
d
A
ll
pa
tie
nt
s
w
en
t
th
ro
ug
h
a
ri
ns
e
pe
ri
od
w
ith
0.
05
%
so
di
um
fl
uo
ri
de
so
lu
tio
n
fr
om
w
ee
ks
2
to
4
D
ou
bl
e-
bl
in
d
cr
os
s-
ov
er
st
ud
y
A
ss
es
se
d
pr
io
r
to
an
tic
an
ce
r
tr
ea
tm
en
t,
an
d
be
fo
re
an
d
af
te
r
ea
ch
pe
ri
od
of
ri
ns
in
g
w
ith
di
ff
er
en
t
ty
pe
of
m
ou
th
w
as
h
In
ad
di
tio
n,
pa
tie
nt
s
in
th
e
am
in
e-
st
an
no
us
fl
uo
ri
de
gr
ou
p
al
so
ha
d
0.
05
%
so
di
um
fl
uo
ri
de
so
lu
tio
n
fr
om
w
ee
ks
6
to
8
N
=
51
(s
el
f
co
nt
ro
l)
N
=
51
(s
el
f
co
nt
ro
l)
0.
12
%
C
hl
or
he
xi
di
ne
(C
H
L
X
)
ri
ns
e
0.
02
5%
A
m
in
e-
st
an
no
us
fl
uo
ri
de
m
ou
th
ri
ns
e
M
ey
er
ow
itz
et
al
.
19
98
[4
5]
N
ot
sp
ec
if
ie
d
(a
ss
um
ed
H
&
N
a )
H
&
N
a
R
T
R
C
T
c
P
os
t-
R
T
b
(c
om
pl
et
ed
>
3
m
on
th
s
be
fo
re
st
ud
y)
N
=
13
N
=
10
S
in
gl
e
bl
in
d
(o
pe
ra
to
r)
A
ss
es
sm
en
ts
at
ba
se
lin
e
(b
ef
or
e
pl
ac
em
en
t
of
IF
R
S
),
1,
2,
3,
4,
5,
an
d
6
(e
nd
of
st
ud
y)
m
on
th
s
In
tr
ao
ra
l
fl
uo
ri
de
re
le
as
in
g
sy
st
em
(I
F
R
S
),
fl
uo
ri
de
pe
lle
t:
so
di
um
fl
uo
ri
de
/h
yd
ro
xy
et
hy
l
m
et
ha
cr
yl
at
e/
m
et
hy
ly
m
et
ha
cr
yl
at
e
(5
0:
50
ra
tio
of
H
E
M
A
/M
M
A
)
1.
1%
N
eu
tr
al
so
di
um
fl
uo
ri
de
in
cu
st
om
tr
ay
s,
5
m
in
da
ily
S
pa
k
et
al
.
19
94
[4
4]
H
&
N
a
R
T
b
R
C
T
c
A
ss
es
se
d
im
m
ed
ia
te
pr
io
r
to
R
T
b
,
6
an
d
at
12
m
on
th
s
af
te
r
R
T
b
N
=
19
N
=
18
D
ou
bl
e
bl
in
d
0.
42
%
F
lu
or
id
e
ge
l
da
ily
fr
om
st
ar
t
of
ra
di
at
io
n
un
til
2
w
ee
ks
af
te
r
en
d
of
ra
di
at
io
n,
th
en
da
ily
us
e
of
1.
23
%
fl
uo
ri
de
ge
l
fo
r
4
w
ee
ks
.
T
he
re
af
te
r,
sw
itc
he
d
to
0.
42
%
fl
uo
ri
de
ge
l
an
d
us
e
un
til
1
ye
ar
af
te
r
ba
se
lin
e
ex
am
0.
42
%
F
lu
or
id
e
ge
l
da
ily
fr
om
st
ar
t
of
ra
di
at
io
n
un
til
1
ye
ar
af
te
r
ba
se
lin
e
ex
am
a
H
ea
d
an
d
ne
ck
b
R
ad
ia
tio
n
c
R
an
do
m
iz
ed
co
nt
ro
l
tr
ia
l
d
C
he
m
ot
he
ra
py
Support Care Cancer (2010) 18:1007–1021 1013
T
ab
le
7
S
um
m
ar
y
of
to
ot
hp
as
te
st
ud
ie
s
(3
)
A
ut
ho
r
C
an
ce
r
D
x
C
an
ce
r
T
x
S
tu
dy
ty
pe
T
im
e
of
as
se
ss
m
en
t
F
in
al
N
/in
te
rv
en
tio
n
1
F
in
al
N
/in
te
rv
en
tio
n
2
P
ap
as
et
al
.
20
08
[5
0]
N
ot
sp
ec
if
ie
d
(a
ss
um
ed
H
&
N
a )
H
&
N
a
R
T
b
R
C
T
c
S
om
e
po
st
-R
T
b
(0
–1
5
ye
ar
s)
,
so
m
e
st
ill
ac
tiv
el
y
tr
ea
te
d
w
ith
R
T
b
N
=
23
N
=
19
D
ou
bl
e
bl
in
d
A
ss
es
se
d
at
ba
se
lin
e,
th
en
1,
2,
4,
6,
8,
10
,
an
d
12
m
on
th
s
E
na
m
el
on
(d
ua
l
ph
as
e
re
m
in
er
al
iz
in
g
to
ot
hp
as
te
)
C
on
ve
nt
io
na
l
to
ot
hp
as
te
To
lja
ni
c
et
al
.
19
96
[4
9]
H
&
N
a
R
T
b
R
C
T
c
P
os
t-
R
T
b
A
ll
w
er
e
gi
ve
n
a
to
ot
hb
ru
sh
an
d
1.
1%
ne
ut
ra
l
so
di
um
fl
uo
ri
de
ge
l
ev
er
y
ni
gh
t
fo
r
5
m
in
,
cr
os
s-
ov
er
at
3
m
on
th
s
D
ou
bl
e
bl
in
d
A
ss
es
sm
en
ts
do
ne
at
st
ar
t
of
st
ud
y,
1,
2,
3,
4,
5,
an
d
6
m
on
th
s
N
=
19
(s
el
f
co
nt
ro
l)
N
=
19
(s
el
f
co
nt
ro
l)
G
ro
up
1
(1
0)
,
gr
ou
p
2
(9
)
G
ro
up
1
(1
0)
,
gr
ou
p
2
(9
)
G
ro
up
1:
to
ot
hp
as
te
w
ith
la
ct
op
er
ox
id
as
e
an
d
gl
uc
os
e
ox
id
as
e
th
en
pl
ac
eb
o
to
ot
hp
as
te
G
ro
up
2:
pl
ac
eb
o
to
ot
hp
as
te
th
en
to
ot
hp
as
te
w
ith
la
ct
op
er
ox
id
as
e
an
d
gl
uc
os
e
ox
id
as
e
va
n
S
te
en
be
rg
he
et
al
.
19
94
[4
8]
T
um
or
s
in
th
e
m
aj
or
sa
liv
ar
y
gl
an
d
ar
ea
R
T
b
R
C
T
c
M
in
im
um
3
m
on
th
s
po
st
-R
T
b
P
ri
or
to
st
ud
y,
al
l
pa
tie
nt
s
re
ce
iv
ed
2
se
ss
io
ns
of
or
al
hy
gi
en
e
in
st
ru
ct
io
ns
(O
H
I)
w
hi
ch
in
cl
ud
ed
su
pe
rv
is
ed
to
ot
hb
ru
sh
in
g
an
d
in
te
rp
ro
xi
m
al
pl
aq
ue
co
nt
ro
l.
A
t
ba
se
lin
e,
al
l
pa
tie
nt
s
re
ce
iv
ed
a
pr
of
es
si
on
al
cl
ea
ni
ng
.
C
ro
ss
-o
ve
r
on
da
y
42
S
in
gl
e
bl
in
d
(p
at
ie
nt
)
A
ss
es
sm
en
ts
do
ne
at
da
ys
0,
10
,
42
,
an
d
52
N
=
12
(s
el
f
co
nt
ro
l)
N
=
12
(s
el
f
co
nt
ro
l)
6
O
n
ea
ch
gr
ou
p
6
O
n
ea
ch
gr
ou
p
B
io
te
ne
to
ot
hp
as
te
th
en
S
en
so
dy
ne
to
ot
hp
as
te
on
da
y
42
S
en
so
dy
ne
to
ot
hp
as
te
th
en
B
io
te
ne
to
ot
hp
as
te
on
da
y
42
a
H
ea
d
an
d
ne
ck
b
R
ad
ia
tio
n
c
R
an
do
m
iz
ed
co
nt
ro
l
tr
ia
l
d
C
he
m
ot
he
ra
py
1014 Support Care Cancer (2010) 18:1007–1021
T
ab
le
8
S
um
m
ar
y
of
ch
lo
rh
ex
id
in
e
st
ud
ie
s
(3
)
A
ut
ho
r
C
an
ce
r
D
x
C
an
ce
r
T
x
S
tu
dy
ty
pe
T
im
e
of
as
se
ss
m
en
t
F
in
al
N
/in
te
rv
en
tio
n
1
F
in
al
N
/in
te
rv
en
tio
n
2
B
er
gm
an
n
et
al
.
19
92
[3
9]
A
cu
te
m
ye
lo
ge
no
us
le
uk
em
ia
C
T
d
R
C
T
c
D
ur
in
g
an
tin
eo
pl
as
tic
tr
ea
tm
en
t
N
=
10
N
=
10
B
lin
di
ng
un
kn
ow
n
A
ss
es
se
d
on
da
ys
1,
14
,
an
d
28
of
C
T
d
0.
1%
C
hl
or
he
xi
di
ne
ri
ns
e
w
ith
m
ec
ha
ni
ca
l
re
m
ov
al
of
pl
aq
ue
an
d
ca
lc
ul
us
on
da
y
1
0.
1%
C
hl
or
he
xi
di
ne
ri
ns
e
Jo
ys
to
n-
B
ec
ha
l
et
al
.
19
92
[5
1]
H
&
N
a
R
T
b
B
ef
or
e
an
d
af
te
r
A
ss
es
se
d
1
w
ee
k
be
fo
re
R
T
b
,
on
cew
ee
kl
y
du
ri
ng
4
w
ee
ks
of
tr
ea
tm
en
t,
an
d
at
ap
pr
ox
im
at
el
y
6,
8,
10
,
12
,
26
,
40
,
an
d
52
w
ee
ks
af
te
r
st
ar
t
of
R
T
b
N
=
25
N
A
0.
2%
C
hl
or
he
xi
di
ne
,
di
lu
te
d
1:
1
w
ith
w
at
er
tw
ic
e
a
da
y
fo
r
1
w
ee
k
be
fo
re
R
T,
du
ri
ng
R
T,
an
d
4
w
ee
ks
af
te
r
ra
di
at
io
n
M
eu
rm
an
et
al
.
19
91
[4
7]
H
od
gk
in
's
an
d
no
n-
H
od
gk
in
's
di
se
as
e
C
T
d
R
C
T
c
D
ur
in
g
co
m
bi
na
tio
n
C
T
d
A
ll
pa
tie
nt
s
w
en
t
th
ro
ug
h
a
ri
ns
e
pe
ri
od
w
ith
0.
05
%
so
di
um
fl
uo
ri
de
so
lu
tio
n
fr
om
w
ee
ks
2
to
4
D
ou
bl
e-
bl
in
d
cr
os
s-
ov
er
st
ud
y
A
ss
es
se
d
be
fo
re
an
tic
an
ce
r
tr
ea
tm
en
t
be
ga
n
an
d
be
fo
re
an
d
af
te
r
ea
ch
pe
ri
od
of
ri
ns
in
g
w
ith
di
ff
er
en
t
ty
pe
of
m
ou
th
w
as
h
In
ad
di
tio
n,
pa
tie
nt
s
in
th
e
am
in
e-
st
an
no
us
fl
uo
ri
de
gr
ou
p
al
so
ha
d
0.
05
%
so
di
um
fl
uo
ri
de
so
lu
tio
n
fr
om
w
ee
ks
6
to
8
N
=
51
(s
el
f
co
nt
ro
l)
N
=
51
(s
el
f
co
nt
ro
l)
0.
12
%
C
hl
or
he
xi
di
ne
ri
ns
e
0.
02
5%
A
m
in
e-
st
an
no
us
fl
uo
ri
de
m
ou
th
ri
ns
e
a
H
ea
d
an
d
ne
ck
b
R
ad
ia
tio
n
c
R
an
do
m
iz
ed
co
nt
ro
l
tr
ia
l
d
C
he
m
ot
he
ra
py
Support Care Cancer (2010) 18:1007–1021 1015
undergoing chemotherapy (Table 10). Both studies had
several flaws in them, including small sample size or lack
of comparison groups. There was one article each on the
benefits of amifostine [56], cheese [57], and honey on
dental health [58]. Results from these studies should be
interpreted with caution because of the lack of additional
randomized control trials.
Summary and recommendations
1. The use of fluoride products reduces caries activity in
patients who are post-radiotherapy. However, the type of
fluoride gel or fluoride delivery system used did not
significantly influence caries activity (Level of Evidence:
II, Grade of Recommendation: B, Recommend the use of
fluoride to prevent dental caries in patients who are
post-radiotherapy).
2. The use of chlorhexidine rinse reduces plaque scores and
oral streptococcus mutans scores. This reduction was not
seen with lactobacillus counts (Level of Evidence: II,
Grade of Recommendation: B, Recommend the use of
chlorhexidine to improve oral hygiene, although poten-
tial side effect of tooth staining, increased calculus, and
taste changes need to be taken into account)
3. There is evidence suggesting that conventional glass
ionomer restorations performed more poorly that resin-
modified glass ionomer, composite resin, and amalgam
restorations in patients who had been treated with
radiotherapy (Level of Evidence: III, Grade of Recom-
mendation: B, Suggest the use of resin-modified glass
ionomer, composite resin or amalgam restoration, and
not a conventional glass ionomer restoration in
patients who have been treated with radiotherapy).
4. More studies are needed to determine the benefits of
various types of toothpaste, pre-cancer therapy dental
intervention, honey, and cheese on dental health (Level
of Evidence: III, Grade of recommendation: C, No
guideline possible can be made at this juncture due to
the lack of well designed studies).
Discussion
In this systematic review, the weighted prevalence of dental
caries amongst cancer survivors were surprisingly highest
in patients who only received chemotherapy compared to
those who received radiotherapy or chemoradiotherapy.
This discrepancy may be attributed to the distinct differ-
ences in the dental management of patients prior to
radiotherapy versus those being prepared for chemotherapy.
Patients undergoing head and neck radiotherapy are at life-
long risk of developing osteoradionecrosis; subsequently,T
ab
le
9
S
um
m
ar
y
of
st
ud
ie
s
on
de
nt
al
re
st
or
at
io
ns
(3
)
A
ut
ho
r
C
an
ce
r
D
x
C
an
ce
r
T
x
S
tu
dy
ty
pe
T
im
e
of
as
se
ss
m
en
t
F
in
al
N
/in
te
rv
en
tio
n
1
F
in
al
N
/in
te
rv
en
tio
n
2
F
in
al
N
/in
te
rv
en
tio
n
3
H
u
et
al
.
20
02
[5
4]
M
al
ig
na
nt
tu
m
or
s
(a
ss
um
ed
H
&
N
a )
C
er
vi
co
fa
ci
al
R
T
b
C
oh
or
t
P
os
t-
R
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Support Care Cancer (2010) 18:1007–1021 1017
dental management protocols prior to radiation oftenentail
aggressive approaches such as extractions. Another expla-
nation for the unanticipated caries prevalence may be
because the majority of the studies were carried out on
children (12/19 studies) [14–17, 20, 23–25, 27–29, 32], and
a high proportion of the diagnoses in children was
hematologic malignancies that were treated largely with
curative chemotherapy. These children are ill for a long
period of time and could have higher caries activity because
of the need to frequently consume highly cariogenic dietary
supplements for weight maintenance or are taking sucrose-
rich medications. In addition, caregivers are often over-
whelmed by their child's medical diagnosis and often
neglect the oral health component. In contrast to the caries
prevalence, the DMFT index is expectedly highest in
patients who were post-radiation therapy compared to
patients who were post-chemotherapy and healthy controls.
The DMFT/S index is a means to obtain an estimation of
dental disease in a population and is recommended by the
World Health Organization (WHO) for the measurement of
caries experience, thereby allowing for easy comparison
among international studies [59]. Despite the shortcomings
of the DMFT/S index (e.g., failure to detect dental decay
between posterior teeth surfaces due to the lack of dental
radiographs, failure to distinguish the various reasons for
missing teeth) and the suggestions by several authors to
switch to alternative indices, the DMFT/S index is still the
most widely utilized caries assessment tool presently [60,
61]. It would have been helpful to look at the caries activity
trends longitudinally in this systematic review; however, it
was not possible to compile this information due to the lack
of specification, standardization, and/or wide ranges of time
periods of DMFT data collection.
Similarly, attempts to describe periodontal health and
periodontal disease beyond that of plaque and gingival
indexes in cancer patients were difficult in this review. PI is
a measure of oral hygiene that synthesizes both number of
surfaces covered and the amount of hard and soft deposits
on the teeth, and gingival index is a measurement of the
amount of inflammation present in the gingival tissues.
Although, there were other measurements of periodontal
health such as oral health index-simplified (OHI-S),
probing depth, clinical attachment loss, gingival recession,
and bleeding index, each of these parameters were only
reported in a single study and therefore could not be
combined or compared with other studies to have any
meaningful results. Other difficulties encountered include
the various reports of outcome variables (raw data versus
percentages) and the categorization of periodontal health
without clear definition. The measurements of DMFT/S, PI,
and GI are important clinical considerations for dental
practitioners because they are predictive indicators for the
determination of future disease [62].
The majority of the intervention studies were carried out on
patients who were post-head and neck radiotherapy, likely
because these individuals are thought to be at a much higher
risk for the development of dental caries compared to their
post-chemotherapy counterparts. Expectedly, the use of
fluoride products and chlorhexidine rinses are beneficial in
reducing caries activity and levels of streptococcus mutans,
respectively.
There continues to be a lack of clinical trials to evaluate the
extent of dental disease associated with complications during
cancer therapy, despite recommendations from the 1989 NIH
consensus for more studies in this area [5]. In this review, the
weighted prevalence of an odontogenic infection during
chemotherapy is approximately 6%. However, these studies
had small sample sizes, did not report pre-existing oral
conditions, and had varied styles of reporting results, making
it tricky to draw conclusions. In addition, the pre-existing oral
conditions in these patients were unknown. Despite the low
prevalence of dental infections, there is some evidence in the
literature that these infections may cause bloodstream
bacteremia and become potentially life-threatening in immu-
nosuppressed individuals. Based on this theoretical reasoning
and indirect evidence, it appears reasonable to propose that
all acute and potential sources of oral infections should be
eradicated. Although, large prospective studies are required to
definitively address this theoretical concern for oral infection.
Another area with poor evidence is the necessity for pre-
cancer therapy dental clearance, and if required, the extent of
disease that needs to be eradicated. However, conducting a
prospective randomized controlled trial to evaluate eradicating
all oral infections prior to patients undergoing cancer therapy
versus no dental treatment may likely pose ethical concerns,
especially if there is sufficient time for dental clearance.
Eradicating acute dental problems versus eradicating both
acute and chronic dental issues may be a more practical
research design. At the time of this review, there was one
cohort study that examined the viability of a minimal dental
intervention clearance protocol in patients prior to chemo-
therapy. They found a 4% conversion rate of previously
diagnosed chronic dental disease to acute inter-therapy
pathology and a relative incidence of 10% conversion rate of
acute conversion of previously diagnosed severe chronic
periodontal disease [41]. Based on their findings, the authors
felt that patients with chronic dental pathology could proceed
safely with chemotherapy, as the conversion rate to an acute
condition was infrequent. Due to the distinct differences in
the implications of the presence of dental disease in patients
who are pre-chemotherapy versus those who are pre-
radiotherapy, the results of this study cannot be extrapolated
to patients undergoing radiotherapy. There are presently no
studies that have investigated or assessed which dental
treatment protocol may be the most superior and appropriate
in patients undergoing radiotherapy.
1018 Support Care Cancer (2010) 18:1007–1021
Conclusions
1. Patients who were post-radiotherapy had the highest
DMFT compared to those who were post-chemotherapy
and healthy controls.
2. Patients who were post-antineoplastic therapy had
higher PI and GI than healthy patients.
3. The use of fluoride products and chlorhexidine rinses
are beneficial in patients who are post-radiotherapy.
4. Conventional glass ionomer restorations performed
more poorly than resin-modified glass ionomer, com-
posite resin, and amalgam restorations in patients who
were post-radiotherapy.
5. There continues to be lack of clinical studies on the
extent and severity of dental disease that is associated
with infectious complications during cancer therapy.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
Conflict of interest statement None to declare.
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Support Care Cancer (2010) 18:1007–1021 1021
	A systematic review of dental disease in patients undergoing cancer therapy
	Abstract
	Abstract
	Abstract
	Abstract
	Abstract
	Introduction
	Historical perspective (prior to 1990)
	Dental disease and the necessity of pre-cancer therapy dental clearance
	Long-term effect of cancer therapies on teeth and periodontium
	Aims
	Systematic review methodology
	Search strategyand criteria for selecting studies
	Review methodology
	Results
	Observational studies
	Interventional studies
	Fluoride therapy
	Toothpaste
	Chlorhexidine
	Dental restorations
	Others
	Summary and recommendations
	Discussion
	Conclusions
	References
<<
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 /ENU (Use these settings to create Adobe PDF documents best suited for on-screen display, e-mail, and the Internet. Created PDF documents can be opened with Acrobat and Adobe Reader 5.0 and later.)
 /DEU <FEFF004a006f0062006f007000740069006f006e007300200066006f00720020004100630072006f006200610074002000440069007300740069006c006c0065007200200037000d00500072006f006400750063006500730020005000440046002000660069006c0065007300200077006800690063006800200061007200650020007500730065006400200066006f00720020006f006e006c0069006e0065002e000d0028006300290020003200300031003000200053007000720069006e006700650072002d005600650072006c0061006700200047006d006200480020>
 >>
 /Namespace [
 (Adobe)
 (Common)
 (1.0)
 ]
 /OtherNamespaces [
 <<
 /AsReaderSpreads false
 /CropImagesToFrames true
 /ErrorControl /WarnAndContinue
 /FlattenerIgnoreSpreadOverrides false
 /IncludeGuidesGrids false
 /IncludeNonPrinting false
 /IncludeSlug false
 /Namespace [
 (Adobe)
 (InDesign)
 (4.0)
 ]
 /OmitPlacedBitmaps false
 /OmitPlacedEPS false
 /OmitPlacedPDF false
 /SimulateOverprint /Legacy
 >>
 <<
 /AddBleedMarks false
 /AddColorBars false
 /AddCropMarks false
 /AddPageInfo false
 /AddRegMarks false
 /ConvertColors /ConvertToRGB
 /DestinationProfileName (sRGB IEC61966-2.1)
 /DestinationProfileSelector /UseName
 /Downsample16BitImages true
 /FlattenerPreset <<
 /PresetSelector /MediumResolution
 >>
 /FormElements false
 /GenerateStructure false
 /IncludeBookmarks false
 /IncludeHyperlinks false
 /IncludeInteractive false
 /IncludeLayers false
 /IncludeProfiles true
 /MultimediaHandling /UseObjectSettings
 /Namespace [
 (Adobe)
 (CreativeSuite)
 (2.0)
 ]
 /PDFXOutputIntentProfileSelector /NA
 /PreserveEditing false
 /UntaggedCMYKHandling /UseDocumentProfile
 /UntaggedRGBHandling /UseDocumentProfile
 /UseDocumentBleed false
 >>
 ]
>> setdistillerparams
<<
 /HWResolution [2400 2400]
 /PageSize [595.276 841.890]
>> setpagedevice