Volume 41, Issue 1 , Pages 2-4, January 2012
Platelet rich plasma for the prevention of osteoradionecrosis. A double blinded randomized cross over controlled trial☆
Article Outline
- Abstract
- Introduction
- Materials and methods
- Results
- Discussion
- Funding
- Competing interests
- Ethical approval
- Acknowledgement
- References
- Copyright
Abstract
Osteoradionecrosis of the jaws is a complication of radiotherapy and controversy remains about the management of teeth in the field of radiotherapy. Platelet rich plasma has been advocated in multiple surgical sites, both bone and soft tissue, to promote healing and reduce complications. A randomized double blinded controlled trial was performed on patients receiving bilateral radiotherapy that affected the mandible who required pre treatment dental extractions. One side received platelet rich plasma and the other acted as a control. Twenty-two patients were recruited over 12 months and over a 5-year period following treatment three developed osteoradionecrosis (14%). Platelet rich plasma failed to show any benefit in the prevention of osteoradionecrosis. Nor was there any benefit in pain scores or mucosal healing on sides that were treated with platelet rich plasma. Platelet rich plasma fails to show a benefit in the prevention of osteoradionecrosis. The rate of osteoradionecrosis is high compared to other published series and the prophylactic removal of molar teeth should be questioned as a preventative measure.
Key words: platelet rich plasma, osteoradionecrosis, dental extraction, radiotherapy
Introduction
Radiotherapy is an integral component of the management of head and neck cancer. Although recent advances in delivery techniques have minimized damage to surrounding tissues, the side effects of treatment remain significant. The mandible, in particular, is sensitive to radiotherapy and osteoradionecrosis (ORN) remains one of the most feared complications of treatment. Its incidence ranges from 5 to 15% depending on the series1 and considerable controversy remains with regards to the management of the dentition in the mandible prior to radiotherapy10. The rate of ORN is lower in patients who are edentulous at the time of presentation1 and the practice of dental extraction of even pathologically normal ‘in field’ teeth is widespread prior to radiotherapy in an attempt to minimize the risk. Recent studies have called into question this practice1, 13.
The exact pathogenesis of radiotherapy in ORN is unknown, though an evolution from Marx's7 ‘hypoxic, hypocellular and hypovascular’ theory towards the fibroatrophic theory of Delanian & Lefaix2 is underway. Irrespective of the pathogenesis of ORN, there is little argument that an adequate healing time is required between dental extractions and the commencement of radiotherapy. Primary mucosal coverage of extraction sockets is thought to be important, though the importance of the underlying bone remodelling, which can go on for months, is unknown.
Platelet rich plasma (PRP) is an autologous blood product created by spinning whole blood in a centrifuge to isolate a platelet rich ‘buffy coat’. Platelets contain growth factors including platelet derived growth factor (PDGF), transforming growth factor beta (TGFβ) and vascular endothelial growth factor (VEGF). The use of PRP has been extensively promoted for improving the survival of bone grafts, in dental implantology, cosmetic surgery and orthopaedic procedures8, 9. Despite good theoretical reasons for efficacy, there is still controversy surrounding its use4, 5 and the majority of published studies are case series or unblinded trial. Systematic reviews have failed to show the benefit of PRP in bone grafting of the maxillary sinus3, face lift surgery11, and fracture healing6.
The principal aim of this study was to determine whether PRP in dental extraction sockets prior to radiotherapy could help to prevent ORN of the mandible. The secondary aim of the study was to determine its effects on wound pain.
Materials and methods
The study design was a double blinded randomized cross over controlled trial. Ethical approval was granted by the Royal Brisbane Hospital Human Research and Ethics Committee.
Patients were recruited from the Hospital's head and neck clinic in 2003 over a 12-month period. At the time of recruitment, prophylactic dental extractions were performed for posterior mandibular teeth in the field of radiotherapy. All patients had a diagnosis of head and neck cancer that required bilateral external beam radiotherapy and affected the posterior mandible.
Patients were offered participation in the study if they met the following inclusion criteria: the ability to comprehend the study and give informed consent; bilateral posterior mandibular teeth in the field of radiotherapy; and were aged over 18 years at the time of diagnosis. Patients were excluded from the study if they had: overtly pathologic teeth with either periodontal or periapical infection; a history of radiotherapy to the head and neck.
Following recruitment, patients were randomized at the time of surgery to receive PRP to either the right or left side. The surgical technique consisted of atraumatic extraction, limited alveoloplasty and primary closure. The treatment side received PRP harvested using the 3i PCCS system according to the manufacturer's instructions, placed in the sockets with cellulose foam, and activated with the patient's whole blood and calcium chloride. The control side received cellulose foam only. The patient was blinded as to the side and all surgical procedures were carried out by the senior author (CA).
Assessment was undertaken by either of two experienced surgical trainees who were blinded as to the side receiving PRP. Patients were reviewed at 2 weeks, then 2, 6, 9 and 12 months. A 5-year review of all patient notes was undertaken to determine survival and late development of ORN. Data were collected on bone exposure and pain (self reported via a Likert scale ranging from 1 to 10).
ORN was defined as exposed bone in a field of radiotherapy persisting for more than 3 months. Additional data were collected on demographic details, tumour, nodes, metastases (TNM) status, duration between dental extraction and commencement of radiotherapy and dose/fields of radiotherapy.
Fisher's exact test was used to determine whether there were any differences between the treatment side and the presence of ORN. To determine whether there were any differences in the pain scores of the treatment sides, a paired-samples t test was used to assess the differences over the five time-points. Independent sample t tests were used to assess differences in the time of dental extraction and dose radiation to ORN and no ORN patients. All statistical analyses were performed in SPSS Statistics Version 17.0.
Results
During the study period 22 patients met the study criteria and consented to participate. There were 5 women (23%) and 17 men (77%). Their age, demographic details, and radiotherapy characteristics are summarized in Table 1. Tumour site was unknown in five patients, it was oropharyngeal in nine patients, nasopharyngeal in three patients, and the larynx/hypopharynx in five patients.
Table 1. Age, dose of radiotherapy and time from extraction to commencement of radiotherapy.
| Mean | Range | |
|---|---|---|
| Age (years) | 54.5 | 30–68 |
| Radiotherapy dose (gray) | 65.7 | 60–72.5 |
| Time from extraction to radiotherapy (days) | 34 | 11–72 |
Three patients developed ORN during the 5-year follow-up period (one patient had bilateral ORN) giving an overall rate of 14%. ORN developed on three sides treated with PRP and one control side. This difference was not statistically significant (P value
=0.61, Fisher's exact test).
The mean pain scores at each of the five time periods are shown in Table 2. Missing assessments are identified by a sample size (n) less than 22 patients. Hence some calculations are based on sample sizes smaller than 22 patients. At all the follow-up periods, there were no significant differences in the recorded pain scores between the control or PRP sides. The difference in the pain scores between the treatment side was marginally different after 2 weeks (P value=0.09, paired-samples t test).
Table 2. Mean pain scores (1–10 Likert scale) at five time points.
| Time period | PRP side | Control side | Difference (PRP−control) | ||||
|---|---|---|---|---|---|---|---|
| n | Mean (SD) | n | Mean (SD) | Mean (SD) | t-test | P-value | |
| 2 weeks | 21 | 2.5 (1.99) | 21 | 2.0 (1.41) | 0.5 (1.36) | 1.759 | 0.09 |
| 2 months | 22 | 1.2 (2.49) | 22 | 1.0 (2.24) | 0.2 (1.40) | 0.608 | 0.55 |
| 6 months | 22 | 0.3 (1.29) | 22 | 0.0 (0.21) | 0.3 (1.28) | 1.000 | 0.33 |
| 9 months | 21 | 0.1 (0.48) | 21 | 0.2 (0.51) | −0.0 (0.22) | −1.000 | 0.33 |
| 12 months | 21 | 0.2 (0.60) | 21 | 0.0 (0.00) | 0.2 (0.60) | 1.451 | 0.16 |
There was no association between the development of ORN and the site of the tumour. Nor was there any association between the dose of radiotherapy or time from dental extraction to radiotherapy in the development of ORN (Table 3).
Table 3. Comparison of time of extraction to radiotherapy, and dose of radiotherapy between patients who developed ORN and those who did not.
| ORN (n=3) | No ORN (n=19) | Mean difference | P-value (two-sided) | |
|---|---|---|---|---|
| Time of dental extraction to radiotherapy in days (SD) | 22.3 (4.62) | 36.1 (18.35) | −13.8 | 0.22 |
| Dose of radiation in gray (SD) | 67.5 (6.61) | 65.7 (3.05) | 1.8 | 0.42 |
Discussion
The use of PRP to assist healing is based on the premise that enhanced levels of the growth factors present within platelets and released on their activation are beneficial. Its use has also been promoted by the fact that it is an autologous blood product thus removing the risk of viral transmission. The literature surrounding PRP is made up of case series and unblinded trials and good level 1 evidence of its efficacy is difficult to find12. The hardware required to separate the PRP from whole blood cost approximately $400AUD at the time of this study, which is cheaper than manufactured growth factors such as bone morphogenetic protein 7 (BMP7).
The authors undertook this study because of the significant clinical problem of ORN of the mandible and the promising early results of PRP in assisting bony healing8. The fact that the sides that received PRP did worse in terms of ORN (albeit without achieving statistical significance) allows the authors to draw some conclusions. Firstly, it is possible that PRP is not effective in preventing ORN of the mandible and has no benefit in wound healing following dental extractions prior to radiotherapy. Secondly, it is possible that that this study was underpowered to determine a positive effect from PRP. Given the cost of the treatment and the number of patients in this study, it is reasonable to conclude that it is not a cost effective method of prevention. Thirdly, it is possible that the authors’ method of application was flawed thus preventing the benefit of PRP from being realized, although all manufacturers’ guidelines were followed and the device used was one of the most effective at concentrating platelets8.
There was no statistically significant difference in pain scores although the 2-week score approached significance (P value=0.09). This might be expected due to the theoretically increased levels of pro-inflammatory growth factors present in PRP.
The only teeth removed in this study were pathologically normal (effectively prophylactic removal) and the overall rate of ORN was 14%. This rate is high compared with the literature and must add to the growing body of evidence that removal of healthy teeth prior to radiotherapy does not prevent ORN and may increase its incidence1. The focus has previously been on primary mucosal healing which led to the delay between extraction and commencement of radiotherapy of 2–3 weeks. The present study showed no association between ORN and time from dental extraction to radiotherapy and it is possible that the underlying bony remodelling which goes on for many months following dental extraction is more important than primary mucosal healing.
Funding
3i Australia generously donated the equipment for the harvest of PRP in this study. 3i Australia played no role in study design, collection or analysis of data, writing of the manuscript or decision on publication.
Competing interests
None declared.
Ethical approval
Ethical approval was granted by the Royal Brisbane and Women's Hospital Research and Ethics Committee.
Acknowledgement
The authors would like to acknowledge the generous donation of the equipment used to harvest platelet rich plasma from 3i Australia.
References
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☆ This study was presented at the Australian and New Zealand Head and Neck Cancer Society Meeting in Sydney, September 2010.
PII: S0901-5027(11)00255-4
doi:10.1016/j.ijom.2011.06.018
© 2011 International Association of Oral and Maxillofacial Surgeons. All rights reserved.
Volume 41, Issue 1 , Pages 2-4, January 2012
