TITLE: Immediate Osseointegrated Implants for Cancer Patients: A Review of Clinical and Cost-Effectiveness DATE: 13 January 2015 CONTEXT AND POLICY ISSUES According to the World health Organization, the incidence of oral cancer ranges from one to 10 cases per 100,000 people in most countries. 1 The prevalence of oral cancer is relatively higher in males (almost double the estimate for females), in older people, and among people of low education and low income. 1,2 In Canada, 4,300 new cases of oral cancer were reported in 2014, which is equivalent to an 8.8 per 100,000 age-adjusted incidence rate. 2 Oral cancers can develop in any part of the mouth, but most oral cancers start within the tongue or the floor of the mouth. They can also spread or originate from the bony structures of the mandibles. Oral cancers are commonly treated with ablative surgery alone or in combination with radiation and/or chemotherapy. 3 Ablative surgeries may range from minor soft tissue trimming to a major resection of the tongue and jaw and face bones. Ablative surgeries of the face and mouth can introduce significant defects in the orofacial region. 4 If not restored, these defects can compromise essential functions such as mastication, speech, and even breathing. Therefore, prosthetic rehabilitation is planned along with the ablative surgery. Oral prosthetics are usually constructed for edentulous patients, and they are stabilized and retained over the jaw bones. However, their stability and retention can be compromised due to the ablative surgery conducted on oral soft tissues and bone. The use of osseointegrated implants is suggested to improve the stability and retention of oral prosthetics in oral cancer patients. 5 Osseointegrated implants are metallic, or even ceramic, structures which can be fixed within the jaw bones. They are connected to external structures which can be used to anchor oral prostheses. Classically, oral prostheses are put directly on the defective area and rely on the remaining oral structure for retention and stability. The purpose of this report is to review the evidence of the clinical effectiveness and cost-effectiveness of immediate osseointegrated implants for cancer patients. Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by email or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.
RESEARCH QUESTIONS 1. What is the clinical effectiveness of immediate osseointegrated implants for cancer patients following ablative surgery of the face or mouth? 2. What is the cost-effectiveness of immediate osseointegrated implants for cancer patients following ablative surgery of the face or mouth? KEY FINDINGS One study was included in this review. It was a retrospective controlled study which evaluated the effectiveness of immediate osseointegrated implants compared with delayed implants in patients with oral squamous cell carcinoma. The study provided very limited evidence that delayed and immediate osseointegrated implant protocols have similar implant survival rate at 5 years. However, there was no information about other outcomes of interest such as the impact of treatment on quality of life, oral function, and complications. METHODS Literature Search Methods A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2014, Issue 12), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2009 and December 5, 2014. Selection Criteria and Methods One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1. Population Intervention Comparator Outcomes Study Designs Table 1: Selection Criteria Cancer patients requiring oncologic rehabilitation of the face, mouth, and oral function after ablative surgery has compromised jaw integrity Immediate osseointegrated implants in bone for reconstruction of the jaw Any Quality of life, oral functions, adverse events and complications, and cost effectiveness Health technology assessments, systematic reviews, meta-analyses, randomized and non-randomized controlled studies, and economic evaluations Immediate Osseointegrated Implants for Cancer Patients 2
Exclusion Criteria Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published prior to 2009. Critical Appraisal of Individual Studies The included non-randomized study was critically appraised using Downs and Black checklist. 6 Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described narratively. SUMMARY OF EVIDENCE Details of study characteristics, critical appraisal, and study findings are located in Appendices 2, 3, and 4, respectively. Quantity of Research Available A total of 222 citations were identified in the literature search. Following screening of titles and abstracts, 201 citations were excluded and 21 potentially relevant reports from the electronic search were retrieved for full-text review. Eleven potentially relevant publications were retrieved from the grey literature search. Of these potentially relevant articles, 31 publications were excluded for various reasons, while one publication met the inclusion criteria and was included in this report. Appendix 1 describes the PRISMA flowchart of the study selection. Summary of Study Characteristics Mizbah et al. conducted a retrospective controlled study to evaluate the effectiveness of immediate osseointegrated implants compared with delayed implants in patients with oral squamous cell carcinoma. 7 The study was conducted in Netherlands, and it was based on the medical registries of two oncology centres for patients treated between 2000 and 2005. Each centre adopted one implant protocol, either immediate or delayed. Another difference between the two centres was the implant system used; one centre used Brenmark implants and the other used Frialit implants. The included patients had a regional (levels I-III) or modified radical (levels I-V) neck dissection, and they were edentulous at the time of diagnosis or became edentulous because of therapy. The study excluded patients if they had mandibular reconstruction using micro revascularized bone graft or homologous bone transplants. A total of 99 patients had dental implants during the ablative surgery, and 29 patients received their implants 6 to 12 months after the ablative surgery. In both groups, implants were inserted in native mandibular bone. The study compared the two groups in terms of implant survival and time between ablative surgery and implant loading. Summary of Critical Appraisal The study screened all patients treated in the two centres for inclusion. However, the article did not provide sufficient details explaining the difference between the screened population and the analysed patients. Immediate Osseointegrated Implants for Cancer Patients 3
The included study had limitations related to its non-randomized and unblinded design. Nonrandomized studies should provide convincing evidence that intervention groups are comparable at baseline. It was reported in the study that both groups were comparable relative to tumor classification, characteristics, and pathological features. However, Mizbah s study included patients from two different medical centres without any obvious adjustment to baseline demographics or differences in the skills or experience of the treating teams. 7 That would render the comparison of outcomes impossible. 8 It was not clear if immediate or delayed implants were provided because of the expertise of the medical team in each centre or because of patient related indications. 8 The main outcome of the study was time between ablative surgeries and implant loading. This outcome is irrelevant because the study interventions were centered on implant timing. It is inappropriate to conclude efficacy based on implant loading timing, simply because one of the included interventions was to delay implant insertion until bone healing, which was 6 to 12 months after implants were inserted in the immediate implant group. The study did not evaluate other outcomes that could be of interest such as differences in functional outcomes, quality of life, or complications between the two treatment protocols. Summary of Findings What is the clinical effectiveness of immediate osseointegrated implants for cancer patients following ablative surgery of the face or mouth? The study reported that the time to implant loading was 7.4 months in the immediate implant group, and it was 27.4 months in the delayed implant group. The percentage of lost implants was similar between groups (9.6% and 9.2% for the immediate and delayed implants groups respectively). What is the cost-effectiveness of immediate osseointegrated implants for cancer patients following ablative surgery of the face or mouth? No relevant cost-effectiveness studies on immediate osseointegrated implants for cancer patients following ablative surgery of the face or mouth were identified. Limitations The searched literature did not provide evidence on the effectiveness or cost-effectiveness of osseointegrated implants in reconstructed bone. The included study evaluated the effectiveness of these implants in native jaw bones; frequently, cancer patients would require extensive jaw bone reconstruction. Furthermore, the comparative efficacy of prosthetic rehabilitation using osseointegrated implants versus classical prosthetic rehabilitation (without implants) was not identified. Immediate Osseointegrated Implants for Cancer Patients 4
CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING This review evaluated the evidence about the clinical effectiveness of immediate osseointegrated implants for cancer patients following ablative surgery of the face or mouth. One study was included in the review. There was no relevant literature to answer the costeffectiveness question. With respect to the efficacy of immediate osseointegrated implants, the data was limited to one retrospective study that compared immediate versus delayed osseointegrated implants in terms of time to implant loading and implant survival. The available evidence suggests that both protocols have similar implant survival rate at 5 years. However, there was no information about other outcomes of interest such as the impact of treatment on quality of life, oral functions and complications. Insights from uncontrolled studies indicated that oral cancer patients who received immediate osseointegrated implants had good oral functions and high quality of life up to five and fourteen years after ablative surgery. 5,9 However, these studies do not answer the question of the comparative efficacy of implant-based prostheses relative to classic (not implantbased) prosthesis. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca Immediate Osseointegrated Implants for Cancer Patients 5
REFERENCES 1. World Health Organization [Internet]. Geneva: World Health Organization. Oral health; 2012 Apr [cited 2015 Jan 7]. Available from: http://www.who.int/mediacentre/factsheets/fs318/en/ 2. Canadian Cancer Society's Advisory Committee on Cancer Statistics, Statistics Canada, Public Health Agency of Canada, Provincial/Territorial Cancer Registries. Canadian Cancer Statistics 2014. Special topic: skin cancers [Internet]. Toronto: Canadian Cancer Society; 2014 May. Available from: http://www.cancer.ca/~/media/cancer.ca/cw/cancer%20information/cancer%20101/cana dian%20cancer%20statistics/canadian-cancer-statistics-2014-en.pdf 3. Buddula A, Assad DA, Salinas TJ, Garces YI. Survival of dental implants in native and grafted bone in irradiated head and neck cancer patients: a retrospective analysis. Indian J Dent Res. 2011 Sep;22(5):644-8. 4. Carbiner R, Jerjes W, Shakib K, Giannoudis PV, Hopper C. Analysis of the compatibility of dental implant systems in fibula free flap reconstruction. Head Neck Oncol [Internet]. 2012 [cited 2014 Dec 16];4:37. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3448503 5. Korfage A, Schoen PJ, Raghoebar GM, Bouma J, Burlage FR, Roodenburg JL, et al. Fiveyear follow-up of oral functioning and quality of life in patients with oral cancer with implant-retained mandibular overdentures. Head Neck. 2011 Jun;33(6):831-9. 6. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health [Internet]. 1998 Jun [cited 2015 Jan 12];52(6):377-84. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc1756728/pdf/v052p00377.pdf 7. Mizbah K. Interforaminal implant placement in oral cancer patients: during ablative surgery or delayed? A 5-year retrospective study. Int J Oral Maxillofac Surg. 2013 Aug;42(8):1039. 8. Korfage A, Raghoebar GM, Roodenburg JL, Vissink A, Reintsema H. Mandibular implants placed during ablative tumour surgery--which patients can benefit? Int J Oral Maxillofac Surg. 2013 Aug;42(8):1037-9. 9. Korfage A, Raghoebar GM, Slater JJ, Roodenburg JL, Witjes MJ, Vissink A, et al. Overdentures on primary mandibular implants in patients with oral cancer: a follow-up study over 14 years. Br J Oral Maxillofac Surg. 2014 Nov;52(9):798-805. Immediate Osseointegrated Implants for Cancer Patients 6
APPENDIX 1: SELECTION OF INCLUDED STUDIES 222 citations identified from electronic literature search and screened 201 citations excluded 21 potentially relevant articles retrieved for scrutiny (full text, if available) 11 potentially relevant reports retrieved from other sources (grey literature, hand search) 32 potentially relevant reports 31 reports excluded: -uncontrolled studies (16) -delayed Implant rehabilitation (5) -timing of implant rehabilitation was not specified (6) -intervention not of interest (2) -editorial (2) 1 article reporting on 1 unique study was included in the review Immediate Osseointegrated Implants for Cancer Patients 7
APPENDIX 2: CHARACTERISTICS OF INCLUDED PUBLICATIONS Table A: Characteristics of Included Clinical Studies Study Design Patient Characteristics Intervention(s) Comparator(s) Clinical Outcomes Mizbah et al. 2013, 7 Netherlands Retrospective controlled study. Data were retrieved for from the medical files of two oncology centres. All consecutive patients treated in the two centres from 2000 to 2005 were screened for inclusion in the study 5 years of follow-up 510 patients were edentulous; of which, 128 patients received dental implants. Patients had a regional (levels I-III) or modified radical (levels I-V) neck dissection. Patients were edentulous at the time of diagnosis or became edentulous because of therapy. Patients were excluded if they had mandibular reconstruction using micro revascularized bone graft or homologous bone transplants Immediate implant: 99 patients received dental implants; of which 82 patients had implant supported overdentures Implants were inserted in the native bone of the mandible during the ablative surgery Postponed implants: 29 patients received dental implants; of which, 27 patients had implant supported overdentures Implants were inserted in the native bone of the mandible 6-12 months after the ablative surgery. Patients received hyperbaric oxygen therapy before implant insertion Mandibular overdenture retained by dental implants Implants were inserted in the interforaminal region Each patient received two to four implants Osseointegration (time before loading the implant) was: 3 months if no radiotherapy was required At least 6 months if radiotherapy was required Implant survival Time to implant loading (counted from the time of ablative surgery) Immediate Osseointegrated Implants for Cancer Patients 8
APPENDIX 3: CRITICAL APPRAISAL OF INCLUDED PUBLICATIONS Table A: Strengths and Limitations of Non-Randomized Controlled Trials Strengths Limitations Mizbah et al. 2013, 7 Netherlands The study screened the files of all patients treated in the two study centres. However, it was not clear in the report how the total number of the eligible patients (N=510) was reduced to 128 in the analysis. The study design might have introduced classification bias because of the unblinded analysis of outcomes. Patients were recruited from two different centres, each centre used one treatment protocol (intervention). Therefore, confounding factors such as disease severity or patients background and environment could not be excluded. The study was relatively small and did not have sufficient power to detect differences between treatment groups in outcomes of interest such as: o Differences in functional outcomes between the two protocols o Differences in quality of life for patients receiving either protocol o Differences in rate of complications between the two protocols, such as lost implants and patients who received implants but could not benefit from the overdentures due to varies reasons. Immediate Osseointegrated Implants for Cancer Patients 9
APPENDIX 4: MAIN STUDY FINDINGS AND AUTHOR S CONCLUSIONS Table A: Summary of Findings of Included Studies Main Study Findings Author s Conclusions Mizbah et al. 2013, 7 Netherlands Implant survival (Number of implant lost) o Immediate implant group: 24 out of 249 (9.6%) o Postponed implant group: 6 out of 65 (9.2%) Time to implant loading (from ablative surgery): o Immediate implant group: 7.4 months (SD = 4.2) o Postponed implant group: 27.4 months (SD = 18.8) o Difference between group was 20 months (P-value < 0.001) Authors concluded that using immediate implant rehabilitation resulted in earlier overdenture delivery for more patients than the postponed implant group. Reviewer s comments: The difference in time to implant loading was expected because of the two protocols compared in the study. Other outcomes of interest were neglected in this study: 1. Differences in functional outcomes between the two protocols 2. Differences in quality of life for patients receiving either protocol 3. Differences in rate of complications between the two protocols, such as lost implants and patients who received implants but could not benefit from the overdentures due to varies reasons. These differences would have a substantial economic impact. Immediate Osseointegrated Implants for Cancer Patients 10