Viability of dental implants in head and neck irradiated patients: A systematic review

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1 CLINICAL REVIEW David W. Eisele, MD, Section Editor Viability of dental implants in head and neck irradiated patients: A systematic review Edson Virgılio Zen Filho, DDS, MSc, 1 Elen de Souza Tolentino, DDS, PhD, 2 * Paulo Sergio Silva Santos, DDS, PhD 1 1 Department of Stomatology, Bauru School of Dentistry, University of S~ao Paulo, Bauru, S~ao Paulo, Brazil, 2 Department of Dentistry, Maringa State University, Maringa, Parana, Brazil. Accepted 16 April 2015 Published online 15 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this systematic review was to evaluate the safety of dental implants placed in irradiated bone and to discuss their viability when placed post-radiotherapy (RT). Methods. A systematic review was performed to answer the questions: Are dental implants in irradiated bone viable? and What are the main factors that influence the loss of implants in irradiated patients? Results. The search strategy resulted in 8 publications. A total of 331 patients received 1237 implants, with an overall failure rate of 9.53%. The osseointegration success rates ranged between 62.5% and 100%. The optimal time interval between irradiation and dental implantation varied from 6 to 15 months. Conclusion. The interval time between RT and implant placement and the radiation doses are not associated with significant implant failure rates. The placement of implants in irradiated bone is viable, and head and neck RT should not be considered as a contraindication for dental rehabilitation with implants. VC 2015 Wiley Periodicals, Inc. Head Neck 38: E2229 E2240, 2016 KEY WORDS: dental implant, osseointegration, radiotherapy, endosseous implant, radiation therapy INTRODUCTION Radiotherapy (RT) is an established treatment modality in the management of malignant diseases of the head and neck. It is often applied before or after oral cancer surgery to improve the therapeutic outcome. Patients who undergo RT may require implant-supported oral rehabilitation and, in some cases, these implants are placed after the antineoplastic therapy. However, tissue damage invariably follows the course of RT, and this may interfere with the success of the implants osseointegration. 1 Irradiation causes endarteritis, leading to tissue hypoxia, hypocellularity, hypovascularity, and reduces the proliferation of bone marrow, collagen, and periosteal and endothelial cells. 2 The reduced viability of irradiated bone may not be capable of promoting osseointegration, compromising implant survival. Furthermore, there is an increased risk of osteoradionecrosis in the irradiated bone. 2 Despite the high quantity of studies, several questions persist regarding the osseointegration and functional stability of dental implants in patients who under head and neck irradiation. The purpose of this systematic review was to evaluate the safety of dental implants placed in irradiated bone and to discuss if these implants are viable when placed post-rt. *Corresponding author: E. de Souza Tolentino, Department of Dentistry, Maringa State University, Av. Mandacaru, Bloco S08, Maringa, PR, Brazil, C.E.P: elen_tolentino@hotmail.com MATERIALS AND METHODS Focused question A systematic review of the best evidence available in the literature was performed to answer the following clinical questions: Are osseointegrated dental implants in irradiated bone viable? and What are the main factors that influence the loss of implants in irradiated patients? Search strategy An initial electronic search was performed using PubMed (all years to October 2014). Further search was performed through Embase, Web of Science, Scopus, and The Cochrane Library database. A broad search strategy was undertaken using the following keywords: ( oral OR dental OR endosseous OR osseointegrated ) AND ( implant[s] ) AND ( radiotherapy OR irradiation OR radiation therapy OR radiated bone ). The search was conducted using the separate terms, and then the results were merged with AND. Two independent observers made a quality assessment of the studies according to fixed eligibility criteria. The title and abstract (when available) of each result of the search were examined separately. For studies that seemed to be relevant, and for those with insufficient data in the title and abstract, in order to make a clear decision, the full article was obtained. Both reviewers evaluated the full text of all articles independently. Articles selected after the full-text assessment were submitted to final eligibility assessment for inclusion in the review. If both readers considered the article relevant, it was included in the HEAD & NECK DOI /HED APRIL 2016 E2229

2 ZEN FILHO ET AL. FIGURE 1. PRISMA flowchart of the selection process of studies for the systematic review. study. When there was no agreement between the 2 reviewers, a third reviewer read the article and made the decision. Eligibility criteria The following criteria were used to determine eligibility: (1) they had to be original clinical studies based on humans (randomized controlled clinical trials, cohort, prospective, retrospective, case series, and case-control studies); (2) intervention: patients having undergone dental implant placement after head and neck RT (RT affecting the mandible, maxilla, or both); (3) implants placed in irradiated native bone (maxilla and mandible) and not in bone grafts; (4) minimum sample size of 10 irradiated patients; (5) patients must not have been submitted to hyperbaric oxygen adjuvant therapy; and (6) articles had to have been published in English. The exclusion criteria were lack of information about the number of patients, number of placed implants, radiation dose, irradiated region, interval between the RT and implant placement, number of implants lost, and followup period. Case reports, reviews, systematic reviews, letters to editor, annals, and presentations in congresses were also excluded. Quality assessment The quality assessment of the included studies was undertaken independently and in duplicate by the 2 reviewers as part of the data extraction process. It was performed by taking into account factors that could introduce bias to the results. The following variables were evaluated (adapted from Papadopoulos et al 3 ): (1) study design (randomized and/or controlled clinical trials 5 3 points; prospective study 5 2 points; retrospective study- 5 1 point; and case series 5 0 points); (2) sample size (adequate 5 2 points [31 patients or more]; partly adequate 5 1 point [21 30 patients]; and acceptable 5 0 points [10 20 patients]); (3) selection description and inclusion/exclusion criteria (adequate 5 2 points; partly adequate 5 1 point; and acceptable 5 0 points); (4) follow-up (adequate 5 3 points [48 months or more]; partly adequate 5 2 points [23 47 months]; acceptable 5 1 point [11 23 months]; and inadequate 5 0 points [1 11 months]); (5) measurement methods (clear 5 2 points; acceptable 5 1 point; and unclear 5 0 points); (6) use of E2230 HEAD & NECK DOI /HED APRIL 2016

3 DENTAL IMPLANTS IN HEAD AND NECK IRRADIATED PATIENTS TABLE 1. Quality assessment of the included studies. Quality level Confounding factors Score* Adequate statistics provided Blinding in measurements Method error analysis Measurement methods Selection description Follow-up Sample size Study design Study Andersson et al (1998) Medium Niimi et al (1998) Medium Wagner et al (1998) Medium Visch et al (2002) High Landes and Kovacs (2006) Medium Schoen et al (2007) Medium Heberer et al (2011) Medium Sammartino et al (2011) Medium * 0 5 points: low quality; 6 11: medium quality; or 12 16: high quality. method error analysis (yes 5 1 point; no 5 0 points); (7) blinding measurements (yes 5 1 point; no 5 0 points); (8) adequate statistics provided (yes 5 1 point; no 5 0 points); and (9) confounding factors estimated in analysis (yes 5 1 point; no 5 0 points). In summary, the studies could maximally score 16 points and were classified as low (0 5 points), medium (6 11 points), or high (12 16 points) quality. Articles classified as high or medium quality were included in the systematic review. Evaluated parameters The following variables were assessed: number of patients, sex, age, type of implant, number of placed implants, number of lost implants, site of implant placement (mandible/maxilla), site of implant failure, survival rate, success rate, radiation dose, type of radiation, irradiated region, implant length and surface, adjuvant therapy (ie, antibiotics, chemotherapy) delay from RT to implant placement, and follow-up time. The main outcome considered was implant failure, defined as implant mobility, and implant removal needed by progressive marginal bone loss or infection (biologic failure implying failure to establish or to maintain osseointegration). 4 The presence of peri-implantitis or a buried implant was not considered as a negative outcome. RESULTS The database search identified 4487 studies: 1272 duplicates were removed and 3215 records were screened by title and abstract. Fifty full-text articles were selected on the basis of the title and abstract review. Forty-two were excluded, as they did not completely meet the eligibility criteria (Appendix 1). The eligibility process (Figure 1) and the quality assessment resulted in 8 studies (Table 1). Authors, study design, number of patients, number of implants inserted, implant failure, follow-up duration, and study conclusion are summarized in Table 2. Two studies were randomized controlled trials, 5,6 2 were retrospective (1 multicenter), 7,8 and 4 were prospective Four papers did not mention the sex and the age of the irradiated patients. 7,8,11,12 The other studies included a total of 113 men and 64 women, with ages ranging from 34 to 87 years. All patients received radiation in the head and neck region to treat malignances in the jaws, oral soft tissues, or oropharynx. Three studies 6,9,11 mentioned the use of adjuvant chemotherapy. The follow-up period ranged from 1 month 7 to 14 years 10 (Table 2). A total of 331 patients received 1237 implants, with an overall failure rate of 9.53% (118 implants; Table 2). The exact times of the implant failures were not specified. Only Landes and Kovacs 11 and Andersson et al 9 have reported that the implants that failed were lost early. 11 In the study by Landes and Kovacs, 11 1 irradiated patient had early loss of 1 implant at the time of loading. The causes of implant loss were not always reported. Andersson et al 9 reported that both patients who lost implants were heavy smokers. Moreover, 1 lost implant was in the only patient who received chemotherapy during RT. In HEAD & NECK DOI /HED APRIL 2016 E2231

4 ZEN FILHO ET AL. TABLE 2. Reviewed studies. Authors (year) Study design No. of patients Implant failures No. of implants No. % Follow-up, mo Conclusion Andersson et al (1998) 9 Prospective Implant treatment for oral rehabilitation can be carried out as a safe procedure in patients irradiated for cancer in the head and neck region without adjunctive HBO. Niimi et al (1998) 7 Retrospective/ multicenter Dental implants can osseointegrate and remain functionally stable in patients having undergone therapy for oral malignancy. Wagner et al (1998) 8 Retrospective Because of the high osseointegration rate and the low incidence of side effects, dental implantation has a tremendous impact on the quality of life in such patients. Visch et al (2002) 10 Prospective Implant survival is significantly influenced by location, extent of surgery, and by the irradiation dose at the implant site. Landes and Kovacs (2006) 11 Prospective (25 46) Nonsubmerged healing and early loading have been shown to be reliable in irradiated and nonirradiated cases in a 2-y follow-up. Schoen et al (2007) 5 Heberer et al (2011) 6 Randomized controlled trial Randomized controlled trial RT should not be considered an absolute contraindication for implant therapy in the mandible (12 26) Sandblasted, acid-etched implants with or without a chemically modified surface can be loaded early in irradiated patients with a high predictability of success within 1 y after loading. Sammartino et al (2011) 12 Prospective There is a higher implant success rate in the mandible and in irradiated implant site with a dosage no more than 40 to 50 Gy. Abbreviations: HBO, hypobaric oxygen; RT, radiotherapy. the study by Wagner et al, 8 osteoradionecrosis occurred in 1 patient, with a loss of 5 implants. Table 3 summarizes the osseointegration success rates regarding the site of placement, time delay from RT to implant placement, and radiation dose. The osseointegration success rates ranged between 62.5% 7 and 100%. 6 In 1 study, this value was not specified. 8 From 1237 implants, 259 (21%) were placed in the maxilla and 978 (79%) in the mandible. In 3 studies 5,8,11 implants were placed only in the mandible. The reported rate of implant failure in the maxilla was 25% (65 of 259) and 5.4% in the mandible (53 of 978; Table 3). The time delay from RT to implant placement ranged from 1 month to 20 years 7 (Table 3). The direct association between this variable and implant failures has been reported in 7 studies. 5,7 12 The optimal time interval between irradiation and dental implantation varied from 6 to 15 months. 8,10 The radiation doses varied from <25 Gy 7 to 72 Gy 6 (Table 3). Data on radiation dose and implant failure were reported in 4 studies. 7,9,10,12 In the study by Andersson et al, 9 the 2 lost implants were placed in patients irradiated with 50 and 68 Gy. Visch et al 10 showed that implants inserted into locations irradiated with >50 Gy have a significantly lower survival rate (73%) than implants in locations that were irradiated with <50 Gy (84%). The same occurred in the study by Sammartino et al, 12 who found an overall success rate of 78.6% in E2232 HEAD & NECK DOI /HED APRIL 2016

5 DENTAL IMPLANTS IN HEAD AND NECK IRRADIATED PATIENTS TABLE 3. Osseointegration success rates regarding site of placement, time delay from radiotherapy to implant placement and radiation dose. No. of implants No. of failures Authors Maxilla Mandible Maxilla Mandible Time from RT, mo* Radiation dose Success, % Andersson et al (8 65) Gy 97.8 (654.3 Gy) Niimi et al <25 66 Gy Wagner et al (4 107) 60 Gy Not specified Visch et al Gy 78 >50 Gy Landes and Kovacs (4 55) 57 Gy 98 Schoen et al Gy 93.9 Heberer et al Gy 96 (SLA )/100 (modsla ) Sammartino et al Gy 88.3 >50 Gy TOTAL Abbreviation: RT, radiotherapy. * Time delay from RT to implant placement. Conventional sandblasted acid-etched surface titanium implants. Chemically modified sandblasted acid-etched surface titanium implants. >50 Gy dosage-treated patients and 93.6% with <50 Gy. However, Niimi et al 7 reported no implant failures in patients who were irradiated with a dose >66 Gy. Conversely, there was 1 implant failure at a dosage of <25 Gy. Data regarding the implant system, length, and surface of the implants were variable. The systems mainly included the Straumann (Institut Straumann AG, Waldenburg, Switzerland) 6,11 and Branemark (Nobel Biocare, G oteborg, Sweden) 5,7 9 implants. The length of the implants varied from 8 to 20 mm, but many studies did not specify these data. 5,7,8,10 Only Heberer et al 6 compared 2 types of surfaces: modified and conventional sandblasted acid-etched implants, with success rates of 100% and 96%, respectively. DISCUSSION There are some published systematic reviews regarding this topic 2,4,13 17 (Appendix 2). However, the search strategies and eligibility criteria vary widely. This variation is reflected in the results of the number of records identified through database searches, which ranged from to 842, The number of included studies also varied, ranging from 8 17 (and this present work) to No study found similar results as the present review. Claudy et al 15 evaluated the association between the time interval after RT and dental implant failure. On the other hand, Colella et al 4 and Nooh 16 investigated the effects of preimplantaiton and postimplantation RT on dental implant failure. The most investigated topic was the difference between implant survival in irradiated and nonirradiated jaws. 2,14,17 Ihde et al 2 considered both human and animal studies. Javed et al 13 assessed the implant survival rate after RT and chemotherapy. Only 1 study 17 considered a minimum sample size of 10 irradiated patients, and 2 studies also included case reports. 4,16 Six reviews included studies in which hyperbaric oxygen adjuvant therapy was used. 2,13 17 Colella et al 4 did not mention the therapy. Furthermore, 4 studies also assessed bone grafts. 4,15 17 One study excluded implants placed in bone grafts 14 and 2 studies did not even mention the use of grafts. 2,13 The present review did not include patients who had undergone hyperbaric oxygen adjuvant therapy or implants placed in bone grafts in an attempt to standardize the sample. When the articles were confused or did not describe the results of each group separately (ie, irradiated and nonirradiated, grafted and nongrafted bone, with and without hyperbaric oxygen adjuvant therapy), they were excluded. Thus, we believe that our data are quite specific and true to what we proposed: verify viability of implants placed in irradiated native jaws without the use of hyperbaric oxygen adjuvant therapy. The question of whether osseointegrated dental implants in irradiated bones are viable is very important. It is still controversial whether patients who previously had head and neck RT are suitable candidates for dental implants. Exposure of the jaws to high-dose irradiation has already been considered an essential contraindication for dental implantation 18 because of the risk of osteoradionecrosis. However, the improvement of surgical techniques and clinical protocols allows predictable clinical results currently. In general, all revised studies reported that dental implants can osseointegrate and remain functionally stable in patients having undergone RT. The impact that the oral rehabilitation exerts on quality of life of patients undergoing RT seems to outweigh the risks of the surgical procedure. In general, the quality of the included studies was medium quality (Table 1). Unfortunately, only 2 randomized clinical trials were found. 5,6 It was not possible to perform a meta-analysis because the data were widely dispersed and studies were very heterogeneous. It is known that this kind of study offers stronger evidence, and randomization, when done properly, reduces the risk of bias that could influence the clinical course of the participants. Some limitations appeared with respect to the review process of this work. It was hard to compare studies HEAD & NECK DOI /HED APRIL 2016 E2233

6 ZEN FILHO ET AL. because of differences regarding the follow-up period, implant systems, radiation dose, exact implant location, and interval between RT and implant placement. Moreover, some risk factors, such as advanced age, systemic diseases, poor oral hygiene, alcoholism, smoking, and parafunctional habits could not be evaluated in this review. Three studies 6,9,11 have mentioned the adjuvant use of cisplatin chemotherapy. In 1 study, 9 the only patient who received chemotherapy during RT had an implant that failed. Twenty-two patients studied by Landes and Kovacs 11 received chemotherapy and, although they were not significant, complications appeared in these patients. All patients studied by Heberer et al 6 (n 5 20) received radiochemotherapy. For these authors, chemotherapy does not inhibit the osseointegration of implants, but the timepoint of chemotherapy might be decisive. For Andersson et al, 9 the combination of RT and chemotherapy could increase the biological effects of the RT, possibly contributing to the implant failure. An overall implant failure rate of 9.53% was found (Table 2), and the exact time of the failure was not specified. The lack of this information makes it impossible to discuss the survival of implants, despite the fact that the follow-up time was presented in all articles. Only 2 studies 9,11 have reported that the implants that failed were lost early. For Andersson et al, 9 this contrasted with the findings of Granstr om, 1 who found that loss of implants increases with time. According to Landes and Kovacs, 11 the early failure may indicate irradiation as a risk factor of implant failure after early loading. However, the reasons for implant failure were not specified in the majority of studies. Andersson et al 9 speculated that smoking and chemotherapy were possible contributors for implant loss. Moreover, for the authors, traumatic occlusion might have been an alternative reason or a contributory cause to the implant failure. Surprisingly, the osteoradionecrosis was mentioned in only 1 patient. 8 The osseointegration success rates ranged from 62.5% to 100%. The lowest rate was reported in a multicenter study by Niimi et al 7 in a Japanese sample for the implants placed in maxilla. The success rate of 100% was reported in the same study for the implants placed in the mandible for the United States sample and by Heberer et al 6 for chemically modified, sandblasted, acid-etched surface titanium implants inserted both into the maxilla and mandible. For the other studies, the success rates varied from 78% 10 to 98%. 11 From the reviewed literature, the functional stability of dental implants is higher in the mandible as compared to the maxilla. According to Visch et al, 10 the most dominant variable influencing implant survival in irradiated bone is the implant s location in the maxilla or mandible, whereas the implants inserted into the maxilla presented a significantly lower survival rate. Niimi et al 7 speculated that poor bone quality of the maxilla could be related to a high failure rate. However, for Niimi et al 7 and Andersson et al, 9 the reported small number of implants placed in the maxilla does not allow any firm conclusions. The difference in survival percentages between anterior and posterior locations in the mandible or maxilla was only reported by Visch et al, 10 and this difference was not significant. The higher success rate in the mandible compared to the maxillary bone brings doubt regarding the action mechanism of RT causing osteoradionecrosis in the maxillofacial bones. Considering that RT induces hypoxic, hypocellular and hypovascular deterioration of bone, maxillary implants were expected to have a higher success rate than the mandibular implants 2 because of the poor blood supply of the mandible that would be more compromised by the RT. It is known that osteoradionecrosis more frequently affects the mandible, and that complications in the maxilla are more suitable to be treated. 2 One possible reason for the maxilla lower success rate is that the poor bone architecture of the maxilla allows a poor initial stabilization of the implants. However, the initial stabilization of the implants is only the beginning of the osseointegration. The most important phases of osseointegration are done by vessels and cells, which orchestrate the bone turnover. Therefore, either the maxilla has more cellularity and vascularity and is more prone to RT effects, or the whole principle of RT effects in bone metabolism causing osteoradionecrosis may be mistaken. The time delay from RT to implant placement is considered a responsible factor for a successful osseointegration. 1 However, an ideal time lapse has not yet been defined. 12 According to Visch et al, 10 after a postirradiation interval of 6 months, the influence of time on implant survival is not significant. The data from Andersson et al 9 suggest that implant surgery should be performed about 12 months after cancer therapy. However, a time >12 months as an interval between the last irradiation and implant placement seems not to promote better clinical results. 9 For Landes and Kovacs, 11 a longer time interval after irradiation did not lead to less complications. These data agree with those of Schoen et al, 5 in which the loss of implants was not related to the time interval between RT and placement of implants. According to these studies, the time interval from RT to implant surgery is not an important factor for implant failure. Similarly, a significant link between implant failure and the radiation dose could not been established. Some implants were removed even in patients who received low-dose irradiation, which suggests that implant loss is likely related to other risk factors, 7 such as smoking and advanced age. Andersson et al 9 considered the radiation dose used in their study to be low (654.3 Gy), and presumed that it did not cause the failure. Some studies 10,12 agree that lower radiation doses (<50 Gy) are associated with a significantly improved implant survival. However, according to Heberer et al, 6 the success rates achieved in their study could not confirm these statements, as all patients received RT >50 Gy. Based on the reviewed studies, the time interval between RT and implant placement as well as the radiation doses are not associated with significant implant failure rates. However, significantly better outcomes were observed in the mandible than in the maxilla. Considering the results, we believe that the placement of osseointegrated dental implants in irradiated bone is viable, and head and neck RT should not be considered as a contraindication for dental rehabilitation with implants. Furthermore, the most important factor related to the implant loss is the site of placement. E2234 HEAD & NECK DOI /HED APRIL 2016

7 DENTAL IMPLANTS IN HEAD AND NECK IRRADIATED PATIENTS APPENDIX 1. Articles excluded on basis of full-text from this study and reason for exclusion. No. Study* Reason for exclusion 1 Ali A, Patton DW, el-sharkawi AM, Davies J. Implant rehabilitation of irradiated jaws: a preliminary report. Int J Oral Maxillofac Implants 1997;12: Arcuri MR, Fridrich KL, Funk GF, Tabor MW, LaVelle WE. Titanium osseointegrated implants combined with hyperbaric oxygen therapy in previously irradiated mandibles. J Prosthet Dent 1997;77: August M, Bast B, Jackson M, Perrott D. Use of the fixed mandibular implant in oral cancer patients: a retrospective study. J Oral Maxillofac Surg 1998;56: Barrowman RA, Wilson PR, Wiesenfeld D. Oral rehabilitation with dental implants after cancer treatment. Aust Dent J 2011;56: Bolind P, Johansson CB, Johansson P, Granstr om G, Albrektsson T. Retrieved implants from irradiated sites in humans: a histologic/histomorphometric investigation of oral and craniofacial implants. Clin Implant Dent Relat Res 2006;8: Brogniez V, Lejuste P, Pecheur A, Reychler H. Dental prosthetic reconstruction of osseointegrated implants placed in irradiated bone. Int J Oral Maxillofac Implants 1998;13: Buddula A, Assad DA, Salinas TJ, Garces YI, Volz JE, Weaver AL. Survival of turned and roughened dental implants in irradiated head and neck cancer patients: a retrospective analysis. J Prosthet Dent 2011;106: Buddula A, Assad DA, Salinas TJ, Garces YI, Volz JE, Weaver AL. Survival of dental implants in irradiated head and neck cancer patients: a retrospective analysis. Clin Implant Dent Relat Res 2012;14: Cao Y, Weischer T. Comparison of maxillary implant-supported prosthesis in irradiated and non-irradiated patients. J Huazhong Univ Sci Technolog Med Sci 2003;23: Donoff RB. Treatment of the irradiated patient with dental implants: the case against hyperbaric oxygen treatment. J Oral Maxillofac Surg 2006;64: Eckert SE, Desjardins RP, Keller EE, Tolman DE. Endosseous implants in an irradiated tissue bed. J Prosthet Dent 1996;76: Esser E, Wagner W. Dental implants following radical oral cancer surgery and adjuvant radiotherapy. Int J Oral Maxillofac Implants 1997;12: Granstr om G, Tjellstr om A, Brånemark PI. Osseointegrated implants in irradiated bone: a case-controlled study using adjunctive hyperbaric oxygen therapy. J Oral Maxillofac Surg 1999;57: Granstr om G. Radiotherapy, osseointegration and hyperbaric oxygen therapy. Periodontol ;33: Granstr om G. Osseointegration in irradiated cancer patients: an analysis with respect to implant failures. J Oral Maxillofac Surg 2005;63: Granstr om G. Placement of dental implants in irradiated bone: the case for using hyperbaric oxygen. J Oral Maxillofac Surg 2006;64: Goto M, Jin Nouchi S, Ihara K, Katsuki T. Longitudinal follow-up of osseointegrated implants in patients with resected jaws. Int J Oral Maxillofac Implants 2002;17: Jisander S, Grenthe B, Alberius P. Dental implant survival in the irradiated jaw: a preliminary report. Int J Oral Maxillofac Implants 1997;12: Keller EE. Placement of dental implants in the irradiated mandible: a protocol without adjunctive hyperbaric oxygen. J Oral Maxillofac Surg 1997;55: Keller EE, Tolman DE, Zuck SL, Eckert SE. Mandibular endosseous implants and autogenous bone grafting in irradiated tissue: a 10-year retrospective study. Int J Oral Maxillofac Implants 1997;12: Klein MO, Gr otz KA, Walter C, Wegener J, Wagner W, Al-Nawas B. Functional rehabilitation of mandibular continuity defects using autologous bone and dental implants prognostic value of bone origin, radiation therapy and implant dimensions. Eur Surg Res 2009;43: Kwakman JM, Freihofer HP, van Waas MA. Osseointegrated oral implants in head and neck cancer patients. Laryngoscope 1997;107: Larsen PE. Placement of dental implants in the irradiated mandible: a protocol involving adjunctive hyperbaric oxygen. J Oral Maxillofac Surg. 1997;55: Linsen SS, Martini M, Stark H. Long-term results of endosteal implants following radical oral cancer surgery with and without adjuvant radiation therapy. Clin Implant Dent Relat Res 2012;14: Missing data: interval between RT and implant placement No. of irradiated patients <10 Implants placed in bone grafts HBO therapy used Evaluation of implants removed from cadavers native bone are not specified native bone are not specified native bone are not specified Missing data: site of implants placement, no. of implants lost Review Missing data: no. of patients and implants, irradiated region native bone are not specified Missing data: interval between RT and implant placement, site of implants placement Review Missing data: interval between RT and implant placement, follow-up, site of implant placement Review Missing data: site of implants placement, no. of implants Data from patients with or without HBO are not separated Review Unclear data Implants placed in bone grafts Missing data: no. of patients and implants, irradiated region Review native bone are not specified HEAD & NECK DOI /HED APRIL 2016 E2235

8 ZEN FILHO ET AL. APPENDIX 1. Continued No. Study* Reason for exclusion 25 Lorant JA, Roumanas E, Nishimura R, Beumer J III, Wagman LD. Restoration of oral function after maxillectomy with osseous integrated implant retained maxillary obturators. Am J Surg 1994;168: Mancha de la Plata M, Gıas LN, Dıez PM, Mu~noz Guerra M, Gonzalez Garcıa R, Lee GY, Castrejon Castrejon S, Rodrıguez Campo FJ. Osseointegrated implant rehabilitation of irradiated oral cancer patients. J Oral Maxillofac Surg 2012;70: Marker P, Siemssen SJ, Bastholt L. Osseointegrated implants for prosthetic rehabilitation after treatment of cancer of the oral cavity. Acta Oncol 1997;36: Marx RE, Morales MJ. The use of implants in the reconstruction of oral cancer patients. Dent Clin North Am 1998;42: Mericske Stern R, Perren R, Raveh J. Life table analysis and clinical evaluation of oral implants supporting prostheses after resection of malignant tumors. Int J Oral Maxillofac Implants 1999;14: Mirza FD, Dikshit JV. Use of implant prosthesis following radiation therapy. J Prosthet Dent 1978;40: Mizbah K, Dings JP, Kaanders JH, van den Hoogen FJ, Koole R, Meijer GJ, Merkx MA. Interforaminal implant placement in oral cancer patients: during ablative surgery or delayed? A 5-year retrospective study. Int J Oral Maxillofac Surg 2013;42: Nelson K, Heberer S, Glatzer C. Survival analysis and clinical evaluation of implantretained prostheses in oral cancer resection patients over a mean follow-up period of 10 years. J Prosthet Dent 2007;98: Niimi A, Ueda M, Kaneda T. Maxillary obturator supported by osseointegrated implants placed in irradiated bone: report of cases. J Oral Maxillofac Surg 1993;51: Niimi A, Fujimoto T, Nosaka Y, Ueda M. A Japanese multicenter study of osseointegrated implants placed in irradiated tissues: a preliminary report. Int J Oral Maxillofac Implants 1997;12: Schoen PJ, Raghoebar GM, Bouma J, Reintsema H, Burlage FR, Roodenburg JL, Vissink A. Prosthodontic rehabilitation of oral function in head-neck cancer patients with dental implants placed simultaneously during ablative tumour surgery: an assessment of treatment outcomes and quality of life. Int J Oral Maxillofac Surg 2008;37: Shaw RJ, Sutton AF, Cawood JI, Howell RA, Lowe D, Brown JS, Rogers SN, Vaughan ED. Oral rehabilitation after treatment for head and neck malignancy. Head Neck 2005;27: Taylor TD, Worthington P. Osseointegrated implant rehabilitation of the previously irradiated mandible: results of a limited trial at 3 to 7 years. J Prosthet Dent 1993;69: Watzinger F, Ewers R, Henninger A, Sudasch G, Babka A, Woelfl G. Endosteal implants in the irradiated lower jaw. J Craniomaxillofac Surg 1996;24: Weischer T, Schettler D, Mohr C. Concept of surgical and implant-supported prostheses in the rehabilitation of patients with oral cancer. Int J Oral Maxillofac Implants 1996;11: Weischer T, Mohr C. Ten-year experience in oral implant rehabilitation of cancer patients: treatment concept and proposed criteria for success. Int J Oral Maxillofac Implants 1999;14: Werkmeister R, Szulczewski D, Walteros Benz P, Joos U. Rehabilitation with dental implants of oral cancer patients. J Craniomaxillofac Surg 1999;27: Yerit KC, Posch M, Seemann M, Hainich S, D ortbudak O, Turhani D. Implant survival in mandibles of irradiated oral cancer patients. Clin Oral Implants Res 2006;17: Missing data: interval between RT and implant placement, follow-up, site of implant placement Implants placed in bone grafts No. of irradiated patients <10 Review No. of irradiated patients <10 Case report HBO therapy used native bone are not specified. Missing data: site of implant placement Case report The same data were used in a later and more complete study (Niimi et al 7 ) Article based on questionnaires Missing data: no. of implants, no. of implants lost No. of irradiated patients <10 No. of irradiated patients <10 Data from pre-rt and post-rt are not separated native bone are not specified Implants placed in bone grafts Missing data: interval between RT and implant placement, site of implants placement Abbreviations: RT, radiotherapy; HBO, hyperbaric oxygen. * Authors are listed in alphabetical order. E2236 HEAD & NECK DOI /HED APRIL 2016

9 DENTAL IMPLANTS IN HEAD AND NECK IRRADIATED PATIENTS APPENDIX 2. Published systematic reviews regarding this topic. Authors, y Journal Focused question/aim Database Search terms Eligibility criteria Colella et al Ihde et al Javed et al Int J Oral Maxillofac Implants Oral Surg Oral Med Oral Pathol Oral Radiol Endod To examine the effects of preimplantation and postimplantation RT on dental implant failure. Are patients with irradiated bone at greater risk of implant failure? Do greater doses lead to higher failure rates? Is implant survival dependent on when a patient receives radiation? Are some anatomic areas at greater risk of failure due to radiation? Are some implants more effective in treating patients with irradiated bone? Adjunctive therapies may improve the outcome after RT and implant placement? Oral Oncol Can dental implants osseointegrate and remain functionally stable in patients having undergone oral cancer treatment? PubMed, SCI- RUS, CENTRAL* PubMed, Cochrane database Oral cancer AND dental implants, dental implants AND radiation therapy, dental implants AND radiated bone, dental implants AND vascularized free flaps Irradiation AND ( orthopedics OR device OR prosthesis OR implant OR nail OR plate ), irradiation AND orthopedics AND ( device OR prosthesis OR implant ), radiation, Ionizing AND prostheses AND implants, bone AND fixation AND radiotherapy, radiation, ionizing AND prostheses AND implants AND comparative study, hyperbaric oxygenation AND radiotherapy AND comparative study, osseointegration/radiation effects, dental implants AND radiotherapy, dental implants AND radiation AND systematic PubMed Cancer, chemotherapy, dental implant, oral, osseointegration, radiotherapy, surgery, and treatment in various combinations. Original studies based on humans (randomized and nonrandomized clinical trials, cohort, case-control studies, and case reports); RT before or after implant placement; minimum follow-up of 6 mo from abutment placement. Human studies or metaanalyses comparing the success/failure of craniofacial and dental implants in irradiated and nonirradiated bone; studies describing success/ failure of implants in irradiated bone; animal studies of biomechanical, histomorphometric, and histologic measures of craniofacial and dental implants in irradiated and nonirradiated bone; studies of high methodological quality (systematic reviews, randomized controlled trials, and cohort studies). Original clinical studies; reference list of pertinent original and review studies; patients having undergone RT and chemotherapy; articles published in English. Initial no. of records Final no. of records Conclusion There is a similar failure rate for implants placed post-rt and pre-rt. 842, Studies from both animal subjects and human patients indicate that irradiated bone has a greater risk of implant failure than nonirradiated bone. This increase in risk may be up to 12 times greater; however, studies making these comparisons are of poor to moderate quality, so the magnitude of this difference should be accepted with caution Dental implants can osseointegrate and remain functionally stable in patients having undergone oral cancer therapy. HEAD & NECK DOI /HED APRIL 2016 E2237

10 ZEN FILHO ET AL. APPENDIX 2. Continued Authors, y Journal Focused question/aim Database Search terms Eligibility criteria Chambrone et al Schiegnitz et al Claudy et al J Dental Res Does RT to the head decrease the survival rate of titanium dental implants placed in nongrafted jaws? Clin Oral Investig Clin Implant Dent Relat Res Is implant survival in irradiated jaw different to the nonirradiated jaw? To compare the risk of failure of dental implants placed within 6 and 12 mo after the end of RT with the risk of those implants placed after 12 mo from the end of RT. PubMed, EMBASE, CENTRAL*, OpenGRAY and hand searching/ reference lists Electronic databases of the National Library of Medicine and manual search Database searches (including of the CENTRAL*) MeSH terms, key words, and other free terms with the Boolean operators AND/ OR Dental implants, radiation, quality of life, implant survival, risk factors MESH terms: dental implants or dental prosthesis, implant-supported, or dental implantation or oral implants and head and neck neoplasms or head and neck neoplasms/ radiotherapy or oral squamous cell carcinomas or irradiated jaw and survival rate or implant survival Osteonecrosis OR necrosis AND mandible OR maxilla OR bone OR necrosis AND bone and bones OR mandible OR maxilla OR periimplantitis OR tooth mobility dental implant OR osseointegration OR dental implants OR dental implantation OR osseointegration radiotherapy OR radiation, ionizing AND neoplasms Observational studies reporting outcomes from irradiated and nonirradiated patients (randomized controlled trials and controlled clinical trials); titanium implants placed in patients who had undergone head and neck RT; outcomes from irradiated and nonirradiated patients/implants reported separately; implants placed in nongrafted areas. >10 subjects; published in English or German; prospective studies: randomized controlled, nonrandomized controlled, cohort studies; retrospective studies: controlled, case-control, single cohort. Any type of observational study (cross-sectional, case-control, or cohort) and case series conducted in humans; any patient rehabilitated with dental implants who received irradiation in head and/or neck; Exposed group: individuals who received dental implants between 6 and 12 mo after the end of RT; Control group: individuals who received dental implants at least 12 mo after the end of RT; follow-up period >6 mo. Initial no. of records Final no. of records Conclusion Overall, implant therapy seems to be a viable treatment option for reestablishing adequate occlusion and masticatory conditions in irradiated patients This study describes for the first time a comparable implant survival in nonirradiated and irradiated native bone. Grafted bone combined with RT was identified as a negative prognostic factor on implant survival Placing implants in bone within a period shorter than 12 mo after RT may result in a higher risk of failure; however, additional evidence from clinical trials is needed to verify this risk. E2238 HEAD & NECK DOI /HED APRIL 2016

11 DENTAL IMPLANTS IN HEAD AND NECK IRRADIATED PATIENTS APPENDIX 2. Continued Authors, y Journal Focused question/aim Database Search terms Eligibility criteria Nooh Present work Int J Oral Maxillofac Implants Can dental implants osseointegrate and survive when placed in patients treated with RT for oral cancer? Are osseointegrated dental implants in irradiated bone feasible? What are the main factors that influence the loss of implants in irradiated patients? PubMed SCI- RUS, and Google Scholar PubMed, Embase, Web of Science, Scopus, The Cochrane Library database Dental implant, implant survival, osseointegration, oral cancer, radiation therapy, radiotherapy, surgery, and treatment in combination with the Boolean operators AND/OR. ( oral OR dental OR endosseous OR osseointegrated ) AND ( implant[s] ) AND ( radiotherapy OR irradiation OR radiation therapy OR radiated bone ) Original research articles published in English, based on clinical trials, case-control studies, cohort studies, case series, and case reports related to patients who underwent RT and rehabilitation with dental implants; published details pertaining to surgery, RT, radiation dosage, no. of implants, site of implant placement, whether HBO therapy was administered had to be available; follow-up period >6 mo. Original clinical studies based on humans (randomized controlled clinical trials, cohort, prospective, retrospective, case series, and case-control studies); patients having undergone dental implant placement after head and neck RT; implants placed in irradiated native bone; sample size 10 patients; patients without HBO therapy; articles published in English. Abbreviations: RT, radiotherapy; HBO, hyperbaric oxygen. * Cochrane Central Register of Controlled Trial. Initial no. of records Final no. of records Conclusion There was no significant difference in dental implant survival rates between preimplantation and postimplantation RT. The anatomic site of implant placement in preimplantation RT was the most pertinent variable affecting implant survival, with a better survival rate in the mandible compared to the maxilla and grafted bone The placement of osseointegrated dental implants in irradiated bone is feasible and head and neck RT should not be considered as a contraindication for dental rehabilitation with implants and the most important factor related to the implant loss is the site of placement. HEAD & NECK DOI /HED APRIL 2016 E2239

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