Introduction
Osteoradionecrosis is one of the most severe late side effects of head and neck tumour treatment, in which irradiated bone becomes devitalised and exposed through overlying skin or mucosa. There are two main hypotheses that describe the underlying pathophysiology. The long-standing Marx hypothesis proposes osteoradionecrosis to be akin to a non-healing wound secondary to metabolic and homeostasis disturbance.Reference Madrid, Abarca and Bouferrache 1 , Reference Marx 2 More recently, Delanian and Lefaix proposed that osteoradionecrosis occurs via a fibro-atrophic mechanism that involves a complex interaction between tissue ischaemia, free radical formation, endothelial dysfunction, vascular thrombosis, inflammation, fibrosis and finally tissue necrosis.Reference Madrid, Abarca and Bouferrache 1 , Reference Delanian and Lefaix 3
Treatment for osteoradionecrosis remains variable, but, in general, resection and reconstruction with vascularised tissue is recommended for refractory cases.Reference Pitak-Arnnop, Sader, Dhanuthai, Masaratana, Bertolus and Chaine 4 Despite limited evidence to support its use, hyperbaric oxygen therapy has been widely used to treat osteoradionecrosis since the 1970s, but, in the modern era of widespread use of free-flap reconstruction, hyperbaric oxygen therapy has become increasingly unneccesary.Reference Madrid, Abarca and Bouferrache 1 , Reference Pitak-Arnnop, Sader, Dhanuthai, Masaratana, Bertolus and Chaine 4 It has been shown that hyperbaric oxygen therapy without aggressive surgical therapy is ineffective.Reference Annane 1 The only randomised, placebo-controlled and blinded study of hyperbaric oxygen therapy for treating osteoradionecrosis failed to show any benefit.Reference Annane 5 Recent studies have shown the benefits of pentoxifylline and tocopherol use in all stages of osteoradionecrosis, this effect having been attributed to their anti-fibrotic effects.Reference Dion, Hussey, Doornbos, Vigliotti, Wen and Anderson 6 – Reference Delanian, Chatel, Porcher, Depondt and Lefaix 8 Other therapeutic strategies including ultrasound, distraction osteogenesis, and biological agents such as BMP-1 and bFGF are not supported by clinical evidence.Reference Madrid, Abarca and Bouferrache 1
Currently, surgical treatment to extricate devitalised bone and free-flap reconstruction is the only useful therapy for grade III osteoradionecrosis. However, this therapy is costly and it is associated with a high morbidity.Reference Cannady, Dean, Kroeker, Albert, Rosenthal and Wax 9 , Reference Kelishadi, St-Hilaire and Rodriquez 10 A study from two large centres in the USA estimated the total cost of osteoradionecrosis treated by free-flap surgery, including hyperbaric oxygen therapy, surgical management, conservative management and hospital stay, to be $55 040 USD per patient.Reference Kelishadi, St-Hilaire and Rodriquez 10 This study aimed to compare the cost of surgical management of grade III osteoradionecrosis in an Australasian setting with similar surgical management in non-osteoradionecrosis patients.
Materials and methods
Osteoradionecrosis patients
All patients who underwent free-flap reconstructive surgery for osteoradionecrosis between July 2004 and July 2010 at Auckland City Hospital were identified using the Auckland City Hospital database, and relevant data were collected. Following collection of the initial data, the administration and finance department at the Auckland District Health Board calculated the in-patient and out-patient costs (NZD). The main components of interest for an in-patient admission were: number of days in the intensive care unit; number of days on the ward; surgery, including operating theatre and implant costs; and laboratory and radiology assessments, including blood test and imaging costs. The out-patient osteoradionecrosis treatment costs included those associated with out-patient surgical and dental clinics, such as length of appointment time, staffing and hyperbaric oxygen therapy.
Non-osteoradionecrosis patients
All patients who underwent free-flap reconstructive surgery for reasons other than osteoradionecrosis between July 2004 and July 2010 at Auckland City Hospital were identified using the Auckland City Hospital database. Patients were included in the study if data regarding treatment were complete and single free-flap reconstructive surgery was performed. Age and gender matching was then performed to match these patients to the osteoradionecrosis patient cohort, and the same data points and costs were calculated.
Results
Patient data
A total of 19 patients who underwent free-flap reconstructive surgery for osteoradionecrosis were identified. Patients’ ages ranged from 36 to 72 years (median, 58 years). Other patient data are presented in Table I.
Table I Osteoradionecrosis patient information and conservative management details
Pt no. = patient number; y = years; TNM = tumour–node–metastasis; RT = radiotherapy; F = female; L = left; N/A = not applicable; ? = unknown or missing data; R = right; SCC = squamous cell carcinoma; M = male; NPC = nasopharyngeal carcinoma
Age- and gender-matched patients were found for all 19 osteoradionecrosis patients. The non-osteoradionecrosis patients’ ages ranged from 35 to 75 years (median, 57 years). Other patient data are presented in Table II.
Table II Non-osteoradionecrosis patient information and conservative management details
Pt no. = patient number; y = years; TNM = tumour–node–metastasis; RT = radiotherapy; F = female; SCC = squamous cell carcinoma; M = male; N/A = not applicable; BCC = basal cell carcinoma
Cost
Total costs included in-patient, out-patient and hyperbaric oxygen therapy costs. A breakdown of costs and total costs for the osteoradionecrosis and non-osteoradionecrosis patients are shown in Tables III and IV. The median total costs were $123 900 NZD (£70 283 GBP) for the osteoradionecrosis patients and $86 000 NZD (£48 784 GBP) for the non-osteoradionecrosis patients (Table V).
Table III Breakdown of costs and total costs for osteoradionecrosis patients*
* Rounded to nearest NZD$100. Pt no. = patient number
Table IV Breakdown of costs and total costs for non-osteoradionecrosis patients*
* Rounded to nearest NZD$100. Pt no. = patient number
The median cost of hyperbaric oxygen treatment in osteoradionecrosis patients was $16 500 NZD (£9360 GBP). When the hyperbaric oxygen treatment costs for osteoradionecrosis patients were excluded (total hospital cost), the median costs were $105 100 NZD (£59 619 GBP) for the osteoradionecrosis group and $86 000 NZD (£48 784 GBP) for the non-osteoradionecrosis group.
Analysis
We carried out the statistical analysis using the JMP program (SAS Institute, Cary, North Carolina, USA), and statistical significance was calculated using the Wilcoxon signed rank test.
The treatment cost for osteoradionecrosis patients (total cost) was 44 per cent higher when compared to the cost for non-osteoradionecrosis patients. This finding was statistically significant, with a p-value of 0.027 (Figure 1).
Fig. 1 Total treatment costs for osteoradionecrosis (ORN) versus non-osteoradionecrosis (non-ORN) patients.
We also calculated the total hospital cost, which excluded the cost for hyperbaric oxygen treatment. This was carried out to assess the difference in the costs of surgical management between these two groups. The total hospital cost was 22 per cent higher in the osteoradionecrosis group compared to the non-osteoradionecrosis group. However, this finding was not statistically significant, with a p-value of 0.4221 (Figure 2).
Fig. 2 Total hospital costs for osteoradionecrosis (ORN) versus non-osteoradionecrosis (non-ORN) patients, excluding the costs for hyperbaric oxygen treatment.
Discussion
Our study reveals a substantial difference in treatment costs between the osteoradionecrosis and non-osteoradionecrosis patients, when free-flap reconstruction was utilised with or without hyperbaric oxygen.
The study also investigated cost differences when hyperbaric oxygen treatment costs were excluded. Although not statistically significant, the difference in cost is still economically significant. The insignificant p-value is likely to be because of our small study population size.
Although we did not formally analyse the reasons for increased costs in the osteoradionecrosis patients, this is likely to be a result of the higher rates of post-operative complications. More complications are expected because of poorer tissue quality associated with radiation therapy and chronic inflammation.
Surgical management, including free-flap reconstruction, is the ‘gold standard’ for stage III osteoradionecrosis. However, the cost of free-flap surgery for the treatment of stage III osteoradionecrosis patients is substantial and poses a significant cost burden to the New Zealand healthcare system.
A recent phase II trial by Delanian et al., which used a combination of pentoxifylline, tocopherol and clodronate (‘PENTOCLO’), showed this therapy to be effective in treating osteoradionecrosis.Reference Delanian, Chatel, Porcher, Depondt and Lefaix 8 That study enrolled patients with osteoradionecrosis for whom mainly hyperbaric oxygen therapy and local surgery had been ineffective. All study participants experienced complete recovery in a median of nine months, with very few reported side effects.
A randomised, placebo-controlled trial is needed to confirm the efficacy of the pentoxifylline, tocopherol and clodronate protocol; nevertheless, given the high cost and relatively poor outcomes of other available therapies, this protocol presents an alternative therapeutic option. However, given the lack of confirmatory trials showing the efficacy of this treatment and the associated costs, Pharmac, New Zealand's pharmaceutical management agency, has not funded its use. This poses a parachute-like dilemma.Reference Smith and Pell 11 , Reference Potts, Prata, Walsh and Grossman 12 The existing treatment options for grade III osteoradionecrosis are poor, and pentoxifylline, tocopherol and clodronate therapy has considerable anecdotal and now scientific evidenceReference Dion, Hussey, Doornbos, Vigliotti, Wen and Anderson 6 – Reference Delanian, Chatel, Porcher, Depondt and Lefaix 8 regarding its efficacy, despite no randomised controlled trial. This leaves patients suffering from osteoradionecrosis and in a situation where they face major surgery with considerable side effects, until there is good evidence confirming the efficacy of pentoxifylline, tocopherol and clodronate.
Interestingly, despite evidence demonstrating the inefficacy of hyperbaric oxygen therapy,Reference Annane 5 it is still funded by hospitals as therapy for osteoradionecrosis. This study has shown hyperbaric oxygen therapy to represent a significant cost, at a median of $16 500 NZD (£9360 GBP) per patient.
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• Treatment for osteoradionecrosis remains variable, but resection and reconstruction with vascularised tissue is generally recommended for refractory cases
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• Despite limited supporting evidence, hyperbaric oxygen therapy is widely used to treat osteoradionecrosis
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• Pentoxifylline, tocopherol and clodronate is a potentially effective treatment for osteoradionecrosis
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• There is a substantial difference in treatment costs for osteoradionecrosis and non-osteoradionecrosis patients
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• There is evidence that pentoxifylline, tocopherol and clodronate may be effective in treating this condition
In conclusion, surgical free-flap techniques and hyperbaric oxygen for the treatment of grade III osteoradionecrosis pose a significant cost burden to the healthcare system. With this burden, and the growing evidence that the alternative possible therapy (pentoxifylline, tocopherol and clodronate) may be effective in treating this condition, we should aim to further explore the possibility of pentoxifylline, tocopherol and clodronate use.
Acknowledgements
We would like to formally acknowledge the Otolaryngology Head and Neck Surgery Department at Auckland City Hospital, and consultants Mr Mark Izzard, Mr Nick McIvor and Mr John Chaplin for making the necessary data available. We would also like to acknowledge the Financial Department at Auckland City Hospital and statistician Peter Reed for their assistance with the study.
