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Dental implants in irradiated versus non-irradiated patients: a meta-analysis
Running Title: Dental implants and irradiation
Bruno Ramos Chrcanovic, DDS, MSc 1*
Tomas Albrektsson, MD, PhD 1,2
Ann Wennerberg, DDS, PhD 1
1 Department of Prosthodontics, Faculty of Odontology, Malmö University, Malmö, Sweden
2 Department of Biomaterials, Göteborg University, Göteborg, Sweden
* Corresponding author:
Dr. Bruno Ramos Chrcanovic, Department of Prosthodontics, Faculty of Odontology, Malmö
University, Carl Gustafs väg 34, SE-205 06, Malmö, Sweden. bruno.chrcanovic@mah.se;
brunochrcanovic@hotmail.com Mobile: +46 725 541 545 Fax: +46 40 6658503
ACKNOWLEDGEMENTS
This work was supported by CNPq, Conselho Nacional de Desenvolvimento Científico e
Tecnológico – Brazil. The authors would like to thank Dr. Christian Walter, Dr. Véronique
Brogniez, and Dr. Jean-Louis Blanc for having sent us their articles, and Dr. Sabine Linsen,
Dr. Regina Mericske-Stern, and Dr. María Mancha de la Plata, who provided us some missing
information about their studies.
KEYWORDS
Dental implants; radiotherapy; infection; marginal bone loss; meta-analysis
This article has been accepted for publication and undergone full peer review but has not beenthrough the copyediting, typesetting, pagination and proofreading process which may lead todifferences between this version and the Version of Record. Please cite this article as an‘Accepted Article’, doi: 10.1002/hed.23875
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ABSTRACT
Background/Methods. The purpose of the present meta-analysis was to test the null
hypothesis of no difference in dental implant failure rates, postoperative infection, and
marginal bone loss for patients being rehabilitated by dental implants and being previously
irradiated in the head and neck region versus non-irradiated patients, against the alternative
hypothesis of a difference.
Results/Conclusion. The study suggests that irradiation negatively affects the survival of
implants, as well as the difference in implant location (maxilla vs. mandible), but there is no
statistically significant difference in survival when implants are inserted before or after 12
months after radiotherapy. The study failed to support the effectiveness of hyperbaric oxygen
therapy in irradiated patients. It was observed a tendency to lower survival rates of implants
inserted in the patients submitted to higher irradiation doses. The results should be interpreted
with caution due to the presence of uncontrolled confounding factors in the included studies.
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INTRODUCTION
In an attempt to decrease implant failure rates, more attention is being placed on
understanding the etiologic and risk factors that lead to the failure of dental implants.1 The
question of whether or not irradiated patients in the head and neck region are more at risk of
losing dental implants has been receiving increasing attention in the last years, as implants
have been increasingly used in oral cancer patients.
Radiotherapy is largely used for treatment of head and neck cancer, as primary
therapy, adjuvant to surgery as well as in conjunction with concurrent chemotherapy or as
palliative treatment for late stage and untreatable head and neck malignancies. Although the
radiotherapy can increase cure rates, the irradiated patient is susceptible to secondary effects
and a series of potential orofacial complications. Radiotherapy may result in progressive
fibrosis of blood vessels and soft tissues, in xerostomia, in osteoradionecrosis, and in
reduction of bone-healing capacity, among others.2-4
Because of the cumulative effects of
radiation on bone vascularity, the regenerative capacity of these tissues is limited, and this
may have a deleterious impact on subsequent implant osseointegration.5
The ability to anticipate outcomes is an essential part of risk management in an
implant practice. Recognizing conditions that place the patient at a higher risk of failure will
allow the surgeon to make informed decisions and refine the treatment plan to optimize the
outcomes.1 The use of implant therapy in special populations requires consideration of
potential benefits to be gained from the therapy. To better appreciate this potential, we
conducted a systematic review and meta-analysis to compare the survival rate of dental
implants, postoperative infection, and marginal bone loss of dental implants inserted in
irradiated and non-irradiated patients.
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MATERIALS AND METHODS
This study followed the PRISMA Statement guidelines.6 A review protocol does not
exist.
Objective
The purpose of the present review was to test the null hypothesis of no difference in
the implant failure rates, postoperative infection, and marginal bone loss for patients being
rehabilitated by dental implants and being irradiated or previously irradiated in the head and
neck region versus non-irradiated patients, against the alternative hypothesis of a difference.
Search strategies
An electronic search without time or language restrictions was undertaken in April
2014 in the following databases: PubMed, Web of Science, and the Cochrane Oral Health
Group Trials Register. The following terms were used in the search strategy on PubMed:
((dental implant[Text word]) AND irradiated[Text word])
((dental implant[Text word]) AND radiotherapy[Text word])
((dental implant[Text word]) AND radiation[Text word])
((dental implant[Text word]) AND radiation therapy[Text word])
The following terms were used in the search strategy on Web of Science, in all
databases:
((dental implant[Topic]) AND irradiated[Topic])
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((dental implant[Topic]) AND radiotherapy[Topic])
((dental implant[Topic]) AND radiation[Topic])
((dental implant[Topic]) AND radiation therapy[Topic])
The following terms were used in the search strategy on the Cochrane Oral Health
Group Trials Register:
(dental implant OR dental implant failure OR dental implant survival OR dental
implant success AND (irradiated OR radiotherapy OR radiation OR radiation
therapy))
A manual search of dental implants-related journals, including British Journal of Oral
and Maxillofacial Surgery, Clinical Implant Dentistry and Related Research, Clinical Oral
Implants Research, European Journal of Oral Implantology, Head and Neck, Implant
Dentistry, International Journal of Oral and Maxillofacial Implants, International Journal of
Oral and Maxillofacial Surgery, International Journal of Periodontics and Restorative
Dentistry, International Journal of Prosthodontics, Journal of Clinical Periodontology,
Journal of Dental Research, Journal of Oral Implantology, Journal of Oral Rehabilitation,
Journal of Craniofacial Surgery, Journal of Cranio-Maxillofacial Surgery, Journal of
Maxillofacial and Oral Surgery, Journal of Oral and Maxillofacial Surgery, Journal of Oral
Rehabilitation, Journal of Periodontology, Oral Oncology, and Oral Surgery Oral Medicine
Oral Pathology Oral Radiology and Endodontology, was also performed.
The reference list of the identified studies and the relevant reviews on the subject were
also scanned for possible additional studies. Moreover, online databases providing
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information about clinical trials in progress were checked (clinicaltrials.gov;
www.centerwatch.com/clinicaltrials; www.clinicalconnection.com).
Inclusion and Exclusion Criteria
Eligibility criteria included clinical human studies, either randomized or not,
comparing implant failure, postoperative infection, and/or marginal bone loss in patients
irradiated for head and neck cancers versus non-irradiated patients. For this review, implant
failure represents the complete loss of the implant. Implants that were placed and could not be
used because of positional problems (the so-called ‘sleepers’) were here not considered as
failures. Exclusion criteria were case reports, technical reports, animal studies, in vitro
studies, and reviews papers.
Study selection
The titles and abstracts of all reports identified through the electronic searches were
read independently by the three authors. For studies appearing to meet the inclusion criteria,
or for which there were insufficient data in the title and abstract to make a clear decision, the
full report was obtained. Disagreements were resolved by discussion between the authors.
Quality assessment
The quality assessment was performed by using the recommended approach for
assessing risk of bias in studies included in Cochrane reviews.7 The classification of the risk
of bias potential for each study was based on the four following criteria: sequence generation
(random selection in the population), allocation concealment (steps must be taken to secure
strict implementation of the schedule of random assignments by preventing foreknowledge of
the forthcoming allocations), incomplete outcome data (clear explanation of withdrawals and
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exclusions), and blinding (measures to blind study participants and personnel from knowledge
of which intervention a participant received). The incomplete outcome data will also be
considered addressed when there are no withdrawals and/or exclusions. A study that included
all the criteria mentioned above was classified as having a low risk of bias, a study that did
not include one of these criteria was classified as having a moderate risk of bias. When two or
more criteria were missing, the study was considered to have a high risk of bias.
Data extraction and meta-analysis
From the studies included in the final analysis, the following data was extracted (when
available): year of publication, study design, unicenter or multicenter study, number of
patients, patients’ age, follow-up, days of antibiotic prophylaxis, mouth rinse, implant healing
period, failed and placed implants, postoperative infection, marginal bone loss, implant
surface modification, radiotherapy, timespan between irradiation and implant surgery,
hyperbaric oxygen therapy (HBO), type of prosthetic rehabilitation, jaws receiving implants
(maxilla and/or mandible), grafting procedures, observed occurrences of death during the
follow-up period, presence of smokers and/or alcohol drinkers among the patients, and
adjunctive chemotherapy. Contact with authors for possible missing data was performed.
Implant failure and postoperative infection were the dichotomous outcomes measures
evaluated. Weighted mean differences were used to construct forest plots of marginal bone
loss, a continuous outcome. The statistical unit for ‘implant failure’ and ‘marginal bone loss’
was the implant, and for ‘postoperative infection’ was the patient. Whenever outcomes of
interest were not clearly stated, the data were not used for analysis. The I2 statistic was used to
express the percentage of the total variation across studies due to heterogeneity, with 25%
corresponding to low heterogeneity, 50% to moderate and 75% to high. The inverse variance
method was used for random-effects or fixed-effects model. Where statistically significant (P
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< .10) heterogeneity is detected, a random-effects model was used to assess the significance
of treatment effects. Where no statistically significant heterogeneity is found, analysis was
performed using a fixed-effects model.8 The estimates of relative effect for dichotomous
outcomes were expressed in risk ratio (RR) and in mean difference (MD) in millimeters for
continuous outcomes, both with a 95% confidence interval (CI). Only if there were studies
with similar comparisons reporting the same outcome measures was meta-analysis to be
attempted. In the case where no events (or all events) are observed in both groups the study
provides no information about relative probability of the event and is automatically omitted
from the meta-analysis. In this (these) case(s), the term ‘not estimable’ is shown under the
column of RR of the forest plot table. The software used here automatically checks for
problematic zero counts, and adds a fixed value of 0.5 to all cells of study results tables where
the problems occur.
A funnel plot (plot of effect size versus standard error) will be drawn. Asymmetry of
the funnel plot may indicate publication bias and other biases related to sample size, although
the asymmetry may also represent a true relationship between trial size and effect size.
The data were analyzed using the statistical software Review Manager (version 5.2.11,
The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark, 2014).
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RESULTS
Literature search
The study selection process is summarized in Figure 1. The search strategy resulted in
1683 papers. Four combinations of terms were used for PubMed and Web of Science, which
resulted in a number of 686 duplicates. The three reviewers independently screened the
abstracts for those articles related to the focus question. The initial screening of titles and
abstracts resulted in 78 full-text papers; 919 were excluded for not being related to the topic.
The full-text reports of the remaining 78 articles led to the exclusion of 24 because they did
not meet the inclusion criteria (9 did not inform of the number of implants per group, 6
evaluated implants only in irradiated mandibles, 3 evaluated implants for craniofacial
prostheses, 2 were earlier follow-ups of the same study, 2 were the same study published in
another journal, 1 did not insert implants in irradiated bone, and 1 paper was not evaluating
implant failures). Additional hand-searching of the reference lists of selected studies did not
yield additional papers. Thus, a total of 54 publications were included in the review.
Description of the Studies
Detailed data of the 54 included studies are listed in Tables 1 and 2. Ten controlled
clinical trials9-18
and forty-four retrospective studies5,19-61
were included in the meta-analysis.
When the e-mail of one or more authors of the articles was found, questions were sent to
request information about missing data. Authors of three studies59-61
replied with the
requested information.
Seventeen studies5,10,11,16,19,21,25,26,30,32,33,39,42,53,58,60,61
had a maximum follow-up from 5
to 9 years, whereas eighteen studies13,23,24,27,36-38,41,43-46,50,51,54-56,59
had a maximum follow-up
of at least 10 years. From the studies with available data of patients’ range age, ten12,25,36,38,44-
46,50,53,59 included non-adults patients. Eight studies
5,19,21,23,29,43,52,57 did not inform of the
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patients’ age. Only six studies22,24,28,47,48,59
provided information about postoperative infection,
with 35 occurrences in a total of 158 patients receiving 543 implants. Three22,24,47
of the six
studies compared postoperative infection between implants inserted in irradiated maxillae and
irradiated mandibles, and the other three28,48,59
between implants inserted in irradiated and
non-irradiated patients. Only four studies14,15,17,48
provided information about marginal bone
loss. Thirteen studies19,23,28,36,37,40,41,43,44,52,55,56,61
did not inform of the healing period of the
implants before loading.
Twenty-seven studies10,11,13-16,20,25-28,31-33,35,37,44-46,48-51,55,58,59,61
informed of the death
occurrences among the patients during the follow-up. Eighteen studies5,9,12,17,21,22,32,34,42,44,46-
48,50,51,59-61 had patients who were also submitted to adjunctive chemotherapy. In two
studies,17,50
all patients were submitted to chemotherapy. Part of the patients in nine
studies5,11,21,35,44,52,58,60,61
were smokers, and two studies excluded smokers.17,18
It was
informed in five studies5,11,58,60,61
that part of the patients was frequent consumers of alcoholic
beverages.
Patients were submitted to bone grafting procedures in twenty-nine studies.5,9,11,20,22,26-
29,31,33,36,38-43,45,50,51,53,55-61 Four studies
18,37,48,49 evaluated implants in native bone only.
Eighteen studies5,9,14-16,20,21,29,31,35,36,38,40,48-50,54,58
evaluated implants inserted in the mandible
only, of which four studies14,15,48,49
assessed the implants in the interforaminal region only,
and three34,38,42
only in maxilla. HBO was performed in patients of fourteen
studies.5,10,11,14,30,34,37,43-46,55,56,60
The most commonly used implants used was the turned Brånemark (Nobel Biocare
AB, Göteborg, Sweden), in thirty-five studies,5,9,10,12,14-16,19-22,24-27,30-32,34,35,37-39,42,44-
47,49,51,52,55,57-59 but not exclusively in twelve studies.
9,10,20,25,26,39,42,45-47,51,52 Eight
studies23,36,40,41,43,54,56,61
did not inform of what kind of implants was used. Sixteen
studies5,12,13,16,18,34,35,39,40,42,45,46,50-52,60
informed whether there was a statistically significant
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difference or not between the implant failure rates between the procedures, whereas one
study28
showed no implant failures. Thirteen studies9,10,13,14,17,21,24,28,32,47,48,51,58
provided
information about the use of prophylactic antibiotics, and only three13,28,48
about mouth rinse
by the patients.
The comparisons concerning the outcome ‘implant failure’ are summarized in Table 3.
Quality Assessment
Each trial was assessed for risk of bias, and the scores are summarized in Table 4. All
studies were judged to be at high risk of bias.
Meta-analysis
A summary of the meta-analyses comparisons concerning implant failures is presented
in Table 3. The forest plots are presented in Figures 2 to 11.
Six studies22,24,28,47,48,59
provided information about postoperative infection. A fixed-
effects model was used, due to lack of statistically significant heterogeneity either when
comparing implants inserted in irradiated versus in non-irradiated patients (P = 0.52; I2 = 0%;
Figure 12) or when comparing implants inserted in irradiated maxilla versus in irradiated
mandible (P = 0.86; I2 = 0%; Figure 13). The results showed that there was no statistically
significant difference in the two comparisons (RR 1.40, 95% CI 0.73-2.68, P = 0.31 and RR
0.81, 95% CI 0.09-7.27, P = 0.85, respectively).
Only two studies15,48
provided information about the marginal bone loss with standard
deviation, necessary for the calculation of comparisons in continuous outcomes, comparing
implants inserted in irradiated versus in non-irradiated patients. There was statistically
significant difference (MD 0.62, 95% CI 0.21-1.03, P = 0.003; heterogeneity: I2 = 92%, P <
0.00001, random-effects model; Figure 14) between the groups concerning the marginal bone
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loss, favoring non-irradiated patients. One study14
provided information comparing marginal
bone loss in implants inserted in irradiated patients being submitted versus not submitted to
HBO. A meta-analysis for this comparison was not performed.
Publication bias
The funnel plot did not show asymmetry when the studies reporting the outcome
‘implant failure’ in the comparison between irradiated and non-irradiated patients was
analyzed, indicating possible absence of publication bias (Figure 15).
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DISCUSSION
One relevant question in the present study is whether the lack of a difference between
irradiated and non-irradiated patients in some studies concerning implant failure rates is a real
finding or is due to the lack of statistical power, given the small number of patients and/or
implants per group. However, a statistically and clinically significant difference favoring the
non-irradiated patients was found after the meta-analyses, stressing the importance of meta-
analyses to increase sample size of individual trials to reach more precise estimates of the
effects of interventions. The significantly higher failure rates in irradiated compared to non-
irradiated patients might be caused by the long-term effects of reduced vascularization
compromising the implantation site.50
In general, radiation therapy has two antagonistic
effects with regard to recovery of irradiated tissue: a short-term positive cellular effect
resulting in the improvement of reduced bone-healing capacity,62
and a long-term negative
effect resulting in permanent damage of osteoprogenitor cells63
and a gradual, progressive
endarteritis obliterans, with thrombosis of small blood vessels, fibrosis of the periosteum and
mucosa and damage to osteocytes, osteoblasts and fibroblasts.64
Moreover, irradiation of
tissues that contain integrated implants increases the risk of soft tissue dehiscences around the
implants, and osteoradionecrosis may lead to loss of the implants.65
This failure difference
after radiation therapy was observed in several studies here included, although the radiation
dosage and observation period varied in the majority of these cases.
Another aspect to consider is the use of HBO. There is no strict consensus about the
use of adjunctive HBO therapy but many studies stressed the advantages of HBO treatment
for wound healing in the irradiated soft and hard tissue.50
As a result, some authors use HBO
as an additive therapy when implant therapy in irradiated bone is planned. It is stated in the
literature that HBO results in an increased oxygen tension in the irradiated ischemic bone and
provokes capillary neoangiogenesis63
and bone formation.66
The exact correlation between
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HBO dose and duration of antifibrotic response is not yet settled. It has been convincingly
demonstrated that such treatment dramatically decreases the risk of trauma-induced
osteoradionecrosis by promoting vascular proliferation, collagen synthesis, bone remodeling
activities, and healing of bone wounds in irradiated tissues.67
Moreover, HBO therapy
increases the amount of force necessary to unscrew integrated titanium implants in irradiated
bone68
which suggests that promoted integration has occurred. Larsen et al66
showed a
difference of 13.9% in mean percent of integration after 4 months in irradiated versus non-
irradiated animals. This difference dropped to 6.38% when animals received HBO before and
after implantation. The difference was shown to be significant, though without establishing
whether this reduction is of significance in relation to implant support. As long as the direct
bone-implant interface is sufficiently large to support the suprastructure, it can be argued that
additional support to the implant surface is unnecessary, particularly in light of patient
inconvenience and the cost of HBO treatment.32
Moreover, results from animal experiments
may only partly be extrapolated to clinically relevant conditions for endosseous implants in
irradiated bone. Apart from considerable methodological limitations in the simulation of the
therapeutic reality and temporal restrictions, events during the follow-up (induction of
neoplasms, loss of implants, osteoradionecrosis, etc), differences related to cell cycles,
structural peculiarities of the bone matrix, the periosteal situation, and the enzyme system of
the species have to be taken into account.69
It is no less important to mention that several
studies here included9,10,14,15,17,19,21,23,26-28,30-33,35,47-49,51,59,60
demonstrated a high survival rate
for the implants placed in irradiated jaws without the use of adjunctive HBO therapy. It might
have been expected a significantly higher failure for patients submitted to HBO, since most of
the patients selected for HBO could have been at a higher risk for osteoradionecrosis due to a
higher irradiation dose, and consequently at a higher risk of implant loss. For example, the
difference in implant survival between the HBO and non-HBO treated patients observed in
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the study of Schoen et al14
was remarkable, but was mainly caused by one HBO treated
patient who developed osteoradionecrosis and subsequently lost all four implants. However,
the present meta-analysis found no statistically significant difference when comparing implant
failures in irradiated patients receiving or not HBO, which is most likely the result of the
small sample size in many studies and selection bias. There are still no randomized,
controlled, double-blind studies conducted to prove that HBO really has a significant
osseointegration stimulating effect in irradiated patients. However, there are certain technical
difficulties related to designing such a study, such as blinding a chamber treatment and the
design of the placebo treatment.37
The timespan between the irradiation and the implant surgery may influence the
survival of the dental implants, but recommendations for an optimal time interval are
inconsistent. Dental implants can be inserted during the ablative surgery or after completed
radiotherapy. When the implants are inserted during the ablative surgical session, a large part
of the integration will occur in the period between surgery and radiotherapy, i.e. within 4-6
weeks70
However, a clear majority of studies here reviewed report on implants installed after
radiotherapy. The advantage of placement after radiotherapy is that the anatomical situation,
residual function and prognosis can be taken into account in the decision of whether to use
implants. Moreover, tumor recurrence has been reported to occur most often between 8 and
12 months after surgery according to one study,71
or within 2 years according to another
one,21
thus oral rehabilitation may be delayed until this period of highest risk has passed. The
disadvantage is that patients are often psychologically and physically weakened by the
therapy, resulting in postponement or even cancellation of prosthetic rehabilitation.72
Moreover, after radiotherapy the vascularization and regenerative ability of the irradiated
tissues can be decreased, which may lessen the prospect of successful osseointegration of the
dental implants.11
The subject is controversial. King et al73
indicated that blood vessels that
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were destroyed radiologically show partial recovery after 3 to 6 months. Wächter and Stoll74
conducted histomorphometric studies, the results of which state that implantation can be
performed, at the earliest, 12 to 18 months after the conclusion of irradiation. Jacobsson62
reported an improvement in the bone healing capacity by a factor of almost 2.5 during a 12-
month period following irradiation. According to the author, functional self-regeneration of
the damaged tissue would provide sufficient implant healing and osseointegration capacities
of the bone 1 year after radiation therapy. On the other side, Marx and Johnson63
stated that
after 6 months, fibrosis is expected to start in the irradiated tissues as a result of reduced cell
reproducibility and progressive ischemia. This process will increase with time, especially
when curative doses of radiotherapy have been given. The present meta-analysis found no
statistically significant difference when failure of implants was compared for the implants
installed before and after a period of 12 months from the radiotherapy, and this is most likely
the fact that only three studies13,18,50
performed this comparison. Two other studies did not
report defined time point to make the comparison, but did not find any influence of time of
implantation on the implant failure rates.10,48
Concerning the radiation dose, the implants inserted into locations irradiated with ≥ 50
Gray in four studies13,18,21,54
had a lower survival rate than implants in locations that are
irradiated with < 50 Gray. The same happened in another study,40
but comparing different
dose thresholds (> 54 versus < 54 Gray). Generally, high radiation doses > 50 Gy have been
reported to result in chronic complications like radioxerostomia and impaired wound
healing.75
Also, irradiation doses above 65 Gy may significantly increase the risk of
development of osteoradionecrosis,76
which may also be a reason for implant failures.
Moreover, it was showed that there is a distinct dose-dependent relationship between the
duration and extent of irradiation and the resulting reduced osteogenesis.77
Bone healing was
delayed at lower doses of radiation with the formation of more impaired fibrous tissue and
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non-lamellar bone, and bone healing was severely disturbed at radiation doses used to treat
head and neck cancer.78
However, the present meta-analysis was not able to find a
significantly higher risk of losing an implant in patients receiving higher doses of
radiotherapy. Once again, this result may have been influenced by the limited number of
studies performing this comparison. The comparable survival rates of both groups in the study
of Niimi et al30
and even a higher survival rate of implants inserted into locations of higher
doses in the study of Shaw et al45
might be caused by the effects of reduced vascularization
that compromises both irradiated and non-irradiated locations.63
Another circumstance that may increase implant failure is the anatomy of the
implantation site. Oral anatomy may change after ablative surgery and eventually following
reconstruction by grafts and flaps, and the resulting defects and bulky areas or the presence of
insufficient soft tissues for coverage may compromise prosthetic rehabilitation41,79
One could
speculate that the bony section of the graft may have been non-vital from the time of
placement or that placement of implants in the grafted block of bone may have compromised
the vitality of the block.57
Some studies on this topic address the increased implant loss in
augmented bone to the reduced primary stability of dental implants due to impaired
mechanical bone quality as well as to increased bone resorption kinetics.80-82
The lower
survival of implants in the grafted bone may be the result of differences in bone quality, bone
volume and revascularization compared with the original residual bone. There is also a
difference when it comes to the graft type. Vascularized bone flaps maintain their viability
even following prolonged periods of ischemia provided that the medullary nutrient blood
supply is later restored.83
This is unlike nonvascularized bone grafts, where implant placement
must await a lengthy delay to allow for ‘creeping substitution’84
to occur. Even with all these
disadvantages, the present study found no statistically significant difference concerning
failures of dental implants when inserted in irradiated grafted bone or in irradiated native
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bone. This could be related to the assumption that the clinical courses of implants may not be
affected by the presence of grafted bone once the graft has succeeded,41
even if this is difficult
to ascertain, as not every study included in the present review provided detailed information
about grafting procedures. On the other side, when the failure rates were compared in
irradiated versus non-irradiated patients, there was a statistically significant difference for
implants inserted in grafted bone and in native bone. Once again, when the term ‘irradiation’
is inserted into the equation, there are significant differences.
Concerning the different jaws, it was observed in one study13
that the most dominant
variable influencing implant survival in irradiated bone is the implant's location in the maxilla
or mandible. The side effects of radiotherapy appear to be more serious in the mandible than
in the maxilla because of the inferior blood supply of the former bone.10
However, according
to the results of the present meta-analysis, it appears that implant failure in the maxilla
follows a similar course in irradiated and non-irradiated patients. The results comparing
implant failures in irradiated and non-irradiated maxilla19,59
and in irradiated and non-
irradiated mandible19,26,45,59
must be interpreted with caution, due to the limited number of
studies reporting this information (2 and 4, respectively). It is also important to consider
whether all implants had been inserted in the field of irradiation, even though this information
was rarely provided by the included studies. In the case of the mandible, for example, the
external beam radiation therapy for oral malignancies does not always include the whole
mandible and, hence, implants inserted anterior to the mental foramina might be inserted in a
field of lower radiation dose. This will naturally affect the outcome for the implants.37
When it comes to postoperative infection, soft tissue may be affected by irradiation,
and the causes might be the post-operative and post-irradiation xerostomia, different saliva
quantity and quality and altered microflora as well as the presence of scar tissues after
reconstruction and the loss of attached and keratinized gingiva adjacent to the implants.48,50
It
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may be suggested that stable soft tissue conditions are crucial for the possibility to perform
oral hygiene and can influence the clinical performance of the implants in irradiated
patients.17
This could influence the incidence of peri-implantitis and consequently the
marginal bone loss. The present meta-analysis showed that there was a statistically significant
difference between the irradiated versus non-irradiated patients concerning the marginal bone
loss, favoring non-irradiated patients. However, this result must be interpreted with caution,
due to the limited number of studies that evaluated the condition. The same can be said about
the meta-analysis results for the outcome postoperative infection.
The studies included here have a considerable number of confounding factors, and
most of the studies, if not all, did not inform how many implant were inserted and
survived/lost in several different conditions.
First, bone resections may result in unfavorable prosthetic circumstances by producing
bulky and soft areas. In these situations, (removable) prosthetic appliances are often
complicated and may cause overloading of the implants.79
This negative influence may be
responsible for lower survival rate of implants inserted into jaws treated with bone resections,
compared with that of implants inserted into jaws that did not undergo bone surgery.13
Second, the percentage of patients who had received postoperative radiotherapy may
have decreased over time among the survivors, as it was observed in many studies, which
could have contributed to the relatively low failure rate of implants in irradiated bone. Those
patients selected to be submitted to radiotherapy may be the patients with cancers of the worst
prognosis.
Third, in the analysis of implant survival, it is important to ascertain whether the
implants that were placed and considered osseointegrated were, in fact, used for the final
implant-supported prosthesis.85
A longer follow-up period can lead to an increase in the
failure rate, especially if it extended beyond functional loading, may lead to an increase in the
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failure rate, because other prosthetic factors can influence implant failure from that point
onward. This might have led to an underestimation of actual failures in some studies.
However, it is hard to define what would be considered a short follow-up period to evaluate
implant failures when comparing these techniques.
Fourth, most oral cancer patients have a history of poor oral hygiene, smoking and
drinking.29
The local environment is less favorable to dental implants than in healthy subjects.
Saliva quantity and quality as well as oral microflora change considerably after salivary gland
resection. Landes and Kovács48
observed that plaque and peri-implant bleeding index
remained typically high compared with non-cancer patients. Oral hygiene and compliance
were limited although patients received individual oral hygiene instruction. On the other hand,
a rapid plaque accumulation and bleeding tendency was concomitant with post-operative and
post-irradiation xerostomia, altered microflora, saliva quantity and quality, smoking and
drinking. Irradiation leaves a less-viable bone that is prone to infection; furthermore, oral
xerostomia post-radiotherapy complicates the situation.40
Fifth, as oral cancer represents around 3% of the total cancer incidence,86
most of the
studies were not able to create a homogenous collective for more than factors such as oral
squamous cell carcinoma, edentulousness or severely reduced tooth number. By breaking
down the study by each variable, the authors of the studies may have had serious doubts
regarding the clinical value in a study that is not totally homogenous in tumor staging, precise
dose of irradiation, etc. It can be said that in order to have sufficient group sizes and a
clinically relevant conclusion, groups in the studies were therefore not supposedly broken
down further. Homogenous or matched collectives somewhat have a higher significance but
they tend to be inhibited by small case numbers.48
Sixth, it is known that the surface properties of dental implants such as topography and
chemistry are relevant for the osseointegration process influencing ionic interaction, protein
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adsorption and cellular activity at the surface.87
The studies here included made use of
implants with different brands and surface treatments. Titanium with different surface
modifications shows a wide range of chemical, physical properties, and surface topographies
or morphologies, depending on how they are prepared and handled,88-90
and it is not clear
whether, in general, one surface modification is better than another.87
Seventh, there was a great variation of the implant healing time before the prosthetic
loading. In irradiated tissue, the local healing ability is impaired30,40
and the vulnerable time
period following insertion becomes jeopardized with early loading. Possible overloading of
the implants, induced by altered oral anatomy following ablative surgery or reconstruction by
grafts and flaps may also increase implant failure in malignant cancer patients compared with
healthy patients.78
The optimal head and neck oncology treatment-related healing time of
implants before loading is still in need of further research and probably can be shortened
significantly.15
Eighth, patients in some studies were subject to adjunctive chemotherapy. The effect
of chemotherapy on the osseointegration and survival of endosteal implants is not well
established, even though it was shown that the risk of irradiation-induced bone damage is
increased by chemotherapy.91
It is suggestive by animal model studies that chemotherapeutic
agents have an adverse effect on normal physiological bone turnover, especially osteoblastic
activity, and would also be expected to alter fracture-healing and bone-allograft incorporation
by these same mechanisms.92,93
However, chemotherapy did not have a detrimental effect on
the survival and success of dental implants in some studies,17,46,94
even though implant
insertion in these studies was performed after at least 6 months after chemotherapy. Thus, it is
unknown whether the time point of chemotherapy might be decisive.
Ninth, it is important that the patients are followed-up long enough before reporting
implant success in irradiated bone.37
However, since the life-span prognosis for most patients
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with oral malignant tumors is rather poor and the 5-year survival rate is reached by only
approximately 50% of the patients, it is difficult to collect long-term data on implants placed
in these patients.11
Moreover, one study61
showed that the early dropout after the final
prosthetic treatment is high and that some patients were hindered to attend the regular recall
sessions due to serious health conditions, which makes even more difficult to collect
substantial data on the long-term. It is also important to stress that the patients with better oral
and general health conditions are usually the ones who are more willing to pay a recall visit.
Tenth, reports of implants in tumor patients included all types of restorations. Data on
the rehabilitation of a well-defined patient collective are rare. This does not allow identifying
common characteristic traits and comparing various types of prostheses with regard to
function and esthetics.61
Thus, the results of the present study have to be interpreted with caution because of its
limitations. First of all, all confounding factors may have affected the long-term outcomes and
not just the fact that implants were placed in patients who were submitted to radiation therapy
or not, and the impact of these variables on the implant survival rate, postoperative infection
and marginal bone loss is difficult to estimate if these factors are not identified separately
between the two different procedures in order to perform a meta-regression analysis. The lack
of control of the confounding factors limited the potential to draw robust conclusions. Second,
most of the included studies had a retrospective design, and the nature of a retrospective study
inherently results in flaws. These problems were manifested by the gaps in information and
incomplete records. Furthermore, all data rely on the accuracy of the original examination and
documentation. Items may have been excluded in the initial examination or not recorded in
the medical chart.95-97
Third, much of the research in the field is limited by small cohort size
and short follow-up periods.
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The failure of dental implants in irradiated patients is therefore subjected to many
considerations and predictability is dependent upon issues like the use of HBO and
chemotherapy, the timing of the implant placement in relation to radiation therapy, the
radiation dosage, the insertion of implants in native of grafted bone, selection of anatomic
site, the patients’ oral hygiene conditions and habits (smoking, drinking), the implant surface
treatment, the prosthetic loading conditions, the type of prosthetic restoration, the period of
follow-up, and risk of osteoradionecrosis.
CONCLUSION
The results of the present review should be interpreted with caution due to the
presence of uncontrolled confounding factors in the included studies, none of them
randomized. Within the limitations of the existing investigations, the present study suggests
that irradiation negatively affects the survival rates of dental implants, as well as the
difference in the implant location, i.e. maxilla or mandible. The study has failed to support the
effectiveness of HBO therapy in irradiated patients requiring dental implants. It also suggests
that there is no statistically significant difference in survival when implants are inserted before
or after 12 months after the radiotherapy. It was observed a tendency to a lower survival rate
of implants inserted in the patients submitted to higher irradiation doses.
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FIGURE LEGENDS
Figure 1. Study screening process.
Figure 2. Forest plot for the event ‘implant failure’ in the comparison between irradiated vs.
non-irradiated patients.
Figure 3. Forest plot for the event ‘implant failure’ in the comparison between irradiated
patients receiving vs. not receiving HBO.
Figure 4. Forest plot for the event ‘implant failure’ in the comparison between irradiated
maxilla vs. irradiated mandible.
Figure 5. Forest plot for the event ‘implant failure’ in the comparison between irradiated vs.
non-irradiated maxilla.
Figure 6. Forest plot for the event ‘implant failure’ in the comparison between irradiated vs.
non-irradiated mandible.
Figure 7. Forest plot for the event ‘implant failure’ in the comparison between irradiated
grafted bone vs. irradiated native bone.
Figure 8. Forest plot for the event ‘implant failure’ in the comparison between irradiated vs.
non-irradiated grafted bone.
Figure 9. Forest plot for the event ‘implant failure’ in the comparison between irradiated vs.
non-irradiated native bone.
Figure 10. Forest plot for the event ‘implant failure’ in the comparison between higher vs.
lower irradiation dose.
Figure 11. Forest plot for the event ‘implant failure’ in the comparison between insertion of
implants within 12 months after radiotherapy vs. after 12 months after radiotherapy.
Figure 12. Forest plot for the event ‘postoperative infection’ in the comparison between
irradiated vs. non-irradiated patients.
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Figure 13. Forest plot for the event ‘postoperative infection’ in the comparison between
irradiated maxilla vs. irradiated mandible.
Figure 14. Forest plot for the event ‘marginal bone loss’ in the comparison between irradiated
vs. non-irradiated patients.
Figure 15. Funnel plot for the studies reporting the outcome event ‘implant failure’.
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Study screening process
118x121mm (300 x 300 DPI)
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Forest plot for the event ‘implant failure’ in the comparison between irradiated vs. non-irradiated patients
412x359mm (300 x 300 DPI)
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Forest plot for the event ‘implant failure’ in the comparison between irradiated patients receiving vs. not receiving HBO
399x124mm (300 x 300 DPI)
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Forest plot for the event ‘implant failure’ in the comparison between irradiated maxilla vs. irradiated
mandible
379x198mm (300 x 300 DPI)
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Forest plot for the event ‘implant failure’ in the comparison between irradiated vs. non-irradiated maxilla
375x76mm (300 x 300 DPI)
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Forest plot for the event ‘implant failure’ in the comparison between irradiated vs. non-irradiated mandible
379x91mm (300 x 300 DPI)
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Forest plot for the event ‘implant failure’ in the comparison between irradiated grafted bone vs. irradiated native bone
355x130mm (300 x 300 DPI)
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Forest plot for the event ‘implant failure’ in the comparison between irradiated vs. non-irradiated grafted bone
374x106mm (300 x 300 DPI)
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Forest plot for the event ‘implant failure’ in the comparison between irradiated vs. non-irradiated native
bone
360x106mm (300 x 300 DPI)
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Forest plot for the event ‘implant failure’ in the comparison between higher vs. lower irradiation dose 363x260mm (300 x 300 DPI)
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Forest plot for the event ‘implant failure’ in the comparison between insertion of implants within 12 months
after radiotherapy vs. after 12 months after radiotherapy
363x83mm (300 x 300 DPI)
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Forest plot for the event ‘postoperative infection’ in the comparison between irradiated vs. non-irradiated
patients
357x83mm (300 x 300 DPI)
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Forest plot for the event ‘postoperative infection’ in the comparison between irradiated maxilla vs. irradiated
mandible
351x83mm (300 x 300 DPI)
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Forest plot for the event ‘marginal bone loss’ in the comparison between irradiated vs. non-irradiated patients
409x76mm (300 x 300 DPI)
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Funnel plot for the studies reporting the outcome event ‘implant failure’ 224x140mm (300 x 300 DPI)
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