Dental extractions related to head and neck radiotherapy: tenyear experience of a single institution

Daniel Henrique Koga, DDS, MSc,a Joo Victor Salvajoli, MD, PhD,b Luiz Paulo Kowalski, MD, PhD,c Ines N. Nishimoto, PhD,c and Fabio Abreu Alves, DDS, PhD,a So Paulo, Brazil
A. C. CAMARGO HOSPITAL

Objective. This study evaluates the frequency of osteoradionecrosis associated with dental extractions. Study design. A total of 405 patients submitted to radiotherapy and had dental extractions were evaluated. The patients were divided into 3 groups. Results. In group 1, 316 patients were submitted to 1.647 dental extractions (mean 5.2 teeth per patient) and in another 47 patients the number of teeth removed was not clearly reported. Group 2 comprised 5 patients who had 33 teeth extracted (mean 6.6 each). In group 3, 55 patients had 290 teeth removed (mean 5.3 each) and in another 2 patients the number of dental extractions could not be established. In general, only 3 cases of osteoradionecrosis related to dental extractions were observed: 2 related to exodontias performed before and 1 after radiotherapy. Conclusions. The low prevalence of osteoradionecrosis found in this work suggests the possibility of performing exodontias after radiotherapy by experienced dentists in the management of head and neck cancer. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:e1-e6)

Radiotherapy is largely used in head and neck cancer as single primary therapy, adjuvant to surgery, or concomitant with chemotherapy, as well as in palliation practice for advanced tumors. Despite technologic advances and new techniques of radiotherapy, the management of irradiated patients represents a challenge for the multidisciplinary team, because the secondary effects include mucositis, xerostomia, loss of taste, trismus, progressive periodontal attachment loss, dental caries, microvascular alteration, soft tissue necrosis, and osteoradionecrosis (ORN). The prevention and management of these side effects is still a challenge for the multidisciplinary team. The ORN treatment cannot achieve good control, resulting in progression of bone or soft tissue losses, and its main causative factors are previous or postradiotherapy dental extractions.1-9 Dental extractions of unrestorable teeth or those with advanced periodontal disease before radiotherapy could minimize the ORN rates. However, few studies have shown lower risk for ORN development when exodontias are executed after radiotherapy,1,2 and others show
Supported by Sao Paulo Research FoundationFAPESP. a Stomatology Department, A.C. Camargo Hospital. b Radiotherapy Department, A.C. Camargo Hospital. c Head and Neck Surgery and Otorhinolaryngology Departments, A.C. Camargo Hospital. Received for publication Sep 20, 2007; returned for revision Dec 20, 2007; accepted for publication Jan 7, 2008. 1079-2104/$ - see front matter 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2008.01.007

similar results between dental extractions before and after radiotherapy.8,10 In general, the decision to extract teeth before or after irradiation treatment has traditionally not been based on evidence from studies.1,4,11,12 The present study evaluates the frequency of ORN associated with dental extractions performed before, during, and after radiotherapy, consequently identifying the best time to perform the dental extractions in relation to radiotherapy. PATIENTS AND METHODS A retrospective evaluation of the medical charts of 2,677 head and neck cancer patients that received radiotherapy at A. C. Camargo Hospital between 1992 and 2002 was performed. Of these patients, a total of 405 (15.1%) were submitted to dental extractions by the stomatology department. Patients demographic data, pathologic type, clinical staging, tumor site, and oncologic treatment were reviewed. Adjuvant therapies consisting of antibiotics and hyperbaric oxygenation were also evaluated. All patients received radiation doses of 4,000 cGy. To analyze the dental extractions, the 405 patients were divided into 3 groups according to the extraction time in relation to radiotherapy. Moreover, 20 patients were classied in both groups 1 and 3, because they had their teeth extracted before and after radiotherapy. Group 1: Dental extractions performed before radiotherapy; 363 patients. Group 2: Dental extractions performed during radiotherapy; 5 patients. e1

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Table I. Tumor sites in 405 patients submitted to radiotherapy

Site Oral cavity Oropharynx Larynx Hypopharynx Nasopharynx/maxillary sinus Neck. Parotid Lower lip Face n 116 103 58 56 50 16 3 2 1 % 28.5 25.4 14.3 13.8 12.3 3.9 0.7 0.5 0.2

Table II. External radiotherapy doses in the head and neck region of 405 patients
Dose (cGy) 4,000 5,000 5,001 6,000 6,001 7,000 7,001 n 30 71 226 78 % 7.4 17.5 55.8 19.3

Group 3: Dental extractions performed after radiotherapy; 57 patients. Numeric variables were described by measures of central tendency and variability, categoric variables were represented by distribution of frequencies, and time of occurrence of ORN was described individually. The study was carried out with approval of the Human Research Ethics Committee of the hospital (no. 633/04). RESULTS General data The majority of the patients were male (356 male, 87.9%; 49 female, 12.1%), with a mean age of 53 years (range 7-91 years, median 54.0). Squamous cell carcinoma was the most common histologic type, affecting 348 patients (86.1%), followed by undifferentiated carcinomas in 22 cases (5.4%), minor salivary gland tumors in 13 patients (3.2%), sarcomas (7 cases, 1.5%), and other tumors (14 cases, 3.5%). The main site affected was the oral cavity in 113 cases (28.5%), followed by the oropharynx in 103 (25.4%; Table I). Regarding the clinical stage, 52 patients presented tumors at stages I and II, representing 3.2% and 9.6%, respectively. Most of the patients, 321 out of 405, had advanced-stage disease, stages III (23.7%) and IV (55.5%). Thirty-one patients (7.6%) presented metastasis of unknown primary sites or tumors without complete description of extension (TxNxM0), and 1 patient (0.2%) was irradiated owing to a multiple myeloma affecting the mandible. The main oncologic treatment modality was surgery with adjuvant radiotherapy (201 patients, 49.6%), followed by radiotherapy alone (74 patients, 18.3%) and concomitant radiochemotherapy (72 patients, 17.8%). For the remaining 58 patients (14.3%), a combination of surgery, radiotherapy, and chemotherapy was used. Regarding the patients treated surgically, 233 (57.5%) were submitted to neck dissection, 78 to mandible

resections, and 120 received soft tissue or bone reconstructions. Regarding radiotherapy, external irradiation was used in 385 patients (95.1%) and external radiotherapy and brachytherapy in 20 patients (4.9%). Conventional fractionated radiotherapy was applied in 398 individuals (98.3%) and hyperfrationated regimen in 7 (1.7%). Linear accelerator was used in all 405 patients, and the mean dose of radiation delivered to the cervicofacial elds was 6,304 cGy (rang 4,000-7,520 cGy, median 6,480; Table II). In 20 patients (4.9%), brachytherapy with doses ranging from 800 to 4,500 cGy was associated with external radiotherapy. Dental extractions Group 1: exodontias performed before radiotherapy. In 316 patients, 1.647 teeth (Table III) were removed before radiotherapy (range 1 to 32 teeth per patient, mean 5.2, median 4.0). The other 47 patients were submitted to multiple dental extractions and it was not possible to determine the number of extracted teeth. Mean time between dental extraction and the start of radiotherapy was 30.7 days (median 24.0 days). Most of the patients, 292 out of 316 (80.4%), did not receive antibiotics. In 15 patients (4.2%), antibiotics were prescribed before dental extractions, in 46 (12.7%) after, and 10 individuals (2.7%) used antibiotics before and after the exodontias. The follow-up ranged from 1 to 160 months, with a mean of 44.8 months (median 29.8 months). This group presented only 2 cases of ORN (0.5%) associated to dental extractions. Group 2: dental extractions performed during radiotherapy. In 5 patients, 33 teeth were removed during the radiotherapy (Table III), ranging from 1 to 16 teeth per patient (mean 6.6, median 5.0). The procedures were executed at a mean of 7.2 days from the beginning of irradiation (median 3.0 days). In 4 patients (80.0%), the radiotherapy was interrupted owing to dental extractions, and the median time of interruption was 10.5 days. Hyperbaric oxygenation (HBO) was not used and the medical charts of these patients did not present information about antibiotics. In this group, there was no case of ORN and the

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Table III. Evaluation of 1,970 teeth removed in 405 patients submitted to radiotherapy
Teeth Maxilla Incisors Canines Premolars Molars Mandible Incisors Canines Premolars Molars Total RT, Radiotherapy. Before RT (n) 61 61 136 304 274 187 298 326 1,647 During RT (n) 6 2 1 6 3 2 9 4 33 After RT (n) 14 11 23 70 55 27 47 43 290 Total (n) 81 74 160 380 332 216 354 373 1,970

Table IV. Causative factors of ORN (17 cases) in 405 irradiated patients
Causative factor Spontaneous Primary oncologic surgery Dental extraction Salvage surgery Trauma by prosthesis Plates and screws infection Root infection n 5 4 3 2 1 1 1 % 29.4 23.5 17.6 11.8 5.9 5.9 5.9

patients were followed for a mean of 53.7 months (range 4.2-129.5, median 38.6). Group 3: dental extractions performed after radiotherapy. This group was composed of 57 patients. In 55 patients, 290 teeth were removed (Table III), ranging from 1 to 19 per patient (mean 5.3, median 4.0), and in the other 2 patients the number of teeth could not be established. The dental extractions were performed at a mean 42.6 months after radiotherapy treatment (median 31.1 months). In relation to adjuvant therapies, 49 out of 57 patients (86.0%) used antibiotics, 26 of them before and 23 both before and after the dental extraction. HBO was used in 10 patients (17.5%), with 20 sessions before and 10 after the extraction. The median follow-up was 42.8 monthsn and only 1 case of ORN (1.7%) associated with dental extractions was observed in this group. Osteoradionecrosis analysis The osteoradionecrosis diagnosis was performed through clinical examination that revealed the exposed bone of mandible or maxilla with concomitant soft tissue ulceration or necrosis and all patients had received more than 60 Gy radiation therapy. Regarding the 405 patients evaluated, we found 17 cases of ORN: 16 (94.1%) in the mandible (14 in the premolars and molars regions and two in the incisors region) and 1 (5.9%) affecting the maxilla. Of these, 5 (29.4%) occurred spontaneously, 4 (23.5%) due to primary oncologic surgery, 3 (17.7%) related to dental extractions, 2 (11.8%) secondary to salvage surgery, 1 (5.9%) associated with trauma by prosthesis, 1 (5.9%) associated with infection of plates and screws, and 1 (5.9%) due to root infection (Table IV). Of the 3 cases associated with dental extractions, 2 were associated with exodontias performed before radiotherapy and 1 with exodontias after irradiation.

In 13 patients (76.4%) the management of the ORN was conservative and consisted of local irrigation with 0.12% chlorohexidine and debridement (minor surgical procedure with removal of the affected bone). In 4 patients (23.6%) large surgical interventions (partial resection of the mandible) were performed and antibiotics were given. In 14 episodes (82.3%) cure was achieved, and 3 patients (17.7%) died without ORN resolution. DISCUSSION The relationship between dental extractions and radiotherapy must be seriously considered, because exodontia is pointed to as the main causative factor of ORN. Radiation promotes decrease of cellularity, blood vessels, and oxygen levels, consequently compromising tissue repair.6,8,13-19 The surgical wound after dental extraction requires activity of cellular elements involved in protein synthesis and the vascular network. However, ionizing radiation promotes irreversible cellular and vascular damage, resulting in hypoxic, hypocellular, and hypovascular tissue.6,8,13-21 Complications are expected to be more frequent in irradiated elds, especially after surgical procedures like dental extractions. In this context, most papers have demonstrated high rates of ORN associated with postirradiation dental extractions.1,2,5-8 However, some authors demonstrated ORN cases related to teeth removed before radiotherapy.2,4,9,22 In the present study, 2.677 patients were evaluated who were submitted to radiotherapy owing to head and neck cancer at A. C. Camargo Hospital between 1992 and 2002. Of these, 405 patients had dental extractions: 363 before starting, 5 during, and 57 after irradiation. It is important to relate that 20 patients had exodontias performed both before and after the radiotherapy. The general incidence of ORN in the 405 patients was 4.2% (17 cases), but only 3 cases (0.7%) were associated with the dental extractions. Regarding the ORN cases related to extractions performed before radiotherapy, most studies have shown low incidence: Bedwinek et al.23 found 6.3% ORN

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cases, Regezi et al.2 2% after 311 dental extractions (49 patients), Epstein et al.5 5.4% in 454 exodontias (92 patients), Sulaiman et al.1 2.6% in 300 teeth removed in 77 patients, and Oh et al.9 1.8% in 55 patients submitted to 99 extractions of third molars. In the present study, we performed 1,647 extractions in 363 patients and found 2 ORN cases (0.5%). Interesting, Starcke and Shannon11 and Makkonen et al.15 evaluated 515 exodontias (62 patients) and 45 exodontias (10 patients), respectively, and there were no ORN cases related to dental extractions executed before irradiation. On the other hand, Chang et al.22 observed higher risk of ORN in dental extractions performed before radiotherapy compared with preservation of teeth. Although there is a consensus that exodontia should not be performed during radiotherapy owing to higher ORN risk and interruption of oncologic treatment, in 5 patients (1.2%) of the present study, 33 teeth were removed during irradiation. All of these patients presented advanced tumors and needed urgent oncologic treatment. During the course of radiotherapy, the patients complained of pain related to teeth and consequently some exodontias were performed. There was no ORN cases in this group, and the mean interruption time of radiotherapy was 10 days. In this regard, Epstein et al.5 evaluated 36 dental extractions performed in 12 patients during irradiation and did not nd ORN. Even though there were no ORN cases, exodontia should not be performed during this time. Considering the exodontias performed after radiotherapy (57 patients), only 1 patient developed ORN (1.7%). This rate is lower than the 9.1% encountered by Horiot et al.,24 7.1% found in 42 patients submitted to 137 dental extractions by Epstein et al.,5 and 20.0% noted after 7 third molars extracted in 5 patients by Oh et al.9 Similarly to our data, Sulaiman et al.1 observed 1.8% ORN rates in 330 exodontias (107 patients). However, Regezi et al.,2 Makkonen et al.,15 and Maxymiw et al.21 evaluated 10, 25, and 72 patients submitted to 23, 88, and 126 dental extractions, respectively, and there was no case of ORN related to dental extractions after head and neck irradiation. In this context, there is a consensus that previous evaluation is determinate in the prevention of ORN and that during and after irradiation all patients must be followed by a dental team.3,5,6,8,10,15,17,22-26 Brown et al.25 emphasized the importance of adequate oral evaluation before radiotherapy. Those authors evaluated 92 head and neck cancer patients and observed that there was at least 1 tooth to extract in 48 patients and that all patients needed oral care. Factors that predispose to decay and loss of teeth must be considered in the oral evaluation and dental planning before radiotherapy. Patients presenting bad oral care,

unrestorable teeth, or periodontal disease in special advanced bone loss and mobility are indicated for dental extractions before irradiation.1-5,7,9,10,12,15,23-25 If dental extractions are indicated, radiotherapy elds, doses, and oncologic prognosis must be evaluated. Considering the prognosis, the study performed in our institution by Carvalho et al.27 evaluated patients with advanced tumors admitted in the 1990s, it was observed that 32.2% of the patients survived over 5 years. In our sample, 79.2% of patients presented tumors in stages III and IV. Previous oral evaluation also permits execution of exodontias with a sufcient time for alveolar healing. This examination must not delay the commencement of irradiation.6,8,11,12,16,21,24 The median time found in the present study was 24 days. This time was higher than the 10-14 days reported by Regezi et al.2 and Beumer et al.4 but similar to other studies1,5,6,9,17 that ranged of 21 to 32 days. In general, we use 14 days between exodontia and the beginning of radiotherapy. The longer time found in the present study can be justied by the dental extractions being executed at the same time of oncologic surgery, after which postoperative radiotherapy usually starts in 4-6 weeks. Antibiotics can be indicated as auxiliary therapy to prevent ORN in exodontia performed after irradiation. Although the literature is not clear, antibiotics are routinely used but antibiotic type and doses are not usually mentioned.21,24 In the present study, 86% of the patients who had teeth removed after radiotherapy received antibiotics, and the other 14% probably also used antibiotics although it was not mentioned in the patient charts. Maxymiw et al.21 used 2 g penicillin V potassium 1 h before procedures and 600 mg 4 times a day for 1 week 72 patients (196 dental extractions in irradiated elds), there were no ORN cases. Hyperbaric oxygen therapy raises levels and diffusion of oxygen in the tissues, increasing angiogenesis, collagen synthesis, bone metabolism, and consequently the capacity for repair. The guideline used for dental extractions after radiotherapy usually consists of 20-30 sessions before the procedure and 10 after.20 Marx et al.20 conducted the main study using adjuvant HBO in irradiated eld exodontia. The HBO group had 37 patients submitted to 156 dental extractions, and an antibiotic (penicillin) group had 37 patients submitted to 136 exodontias. Osteoradionecrosis was observed in 5.4% of the patients in the HBO group and in 29.9% of the patients that received antibiotics. Kraut14 used the same protocol of HBO20 in 49 exodontias performed in 3 patients, and there was no ORN. In contrast, some reports have questioned HBO use for ORN treatment. Recently, in a randomized, sequential, double-bind,

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7. Thorn JJ, Hansen HS, Specht L, Bastholt L. Osteoradionecrosis of the jaws clinical characteristics and relation to the eld of irradiation. J Oral Maxillofac Surg 2000;58:1088-93. 8. Reuther T, Schuster T, Mende U, Kbler A. Osteoradionecrosis of the jaws as a side effect of radiotherapy of head and neck tumor patientsa report of a thirty year retrospective review. Int J Oral Maxillofac Surg 2003;32:289-95. 9. Oh HK, Chambers MS, Garden AS, Wong PF, Martin JW. Risk of osteoradionecrosis after extraction of impacted third molars in irradiated head and neck cancer patients. J Oral Maxillofac Surg 2004;62:139-44. 10. Epstein JB, Wong FLW, Stevenson-Moore P. Osteoradionecrosis clinical experience and a proposal for classication. J Oral Maxillofac Surg 1987;45:104-10. 11. Starcke EN, Shannon IL. How critical is the interval between extractions and irradiation in patients with head and neck malignancy? Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1977;43:333-7. 12. Beumer J III, Seto B. Dental extractions in the irradiated patient. Spec Care Dent 1981;1:166-73. 13. Murray CG, Herson J, Daly TE, Zimmerman S. Radiation necrosis of the mandiblea 10 year study. Part I. Factors inuencing the onset of necrosis. Int J Radiat Oncol Biol Phys 1980;6:543-8. 14. Kraut RA. Prophylatic hyperbaric oxygen to avoid osteoradionecrosis when extractions follow radiation therapy. Clin Prev Dent 1985;7:17-20. 15. Makkonen TA, Kiminki A, Makkonen TK, Nordman E. Dental extractions in relation to radiation therapy of 224 patients. Int J Oral Maxillofac Surg 1987;16:56-64. 16. Costantino PD, Friedman CD, Steinberg MJ. Irradiated bone and its management. Otolaryngol Clin North Am 1995;5:1021-38. 17. Lambert PM, Intriere N, Eichstaedt R. Management of dental extractions in irradiated jawsa protocol with oxygen therapy. J Oral Maxillofac Surg 1997;55:268-74. 18. Al-Nawas B, Duschner H, Grtz KA. Early cellular alterations in bone after radiation therapy and its relation with osteoradionecrosis. J Oral Maxillofac Surg 2004;62:1045. 19. Assael LA. New fundations in understanding osteoradionecrosis of the jaws. J Oral Maxillofac Surg 2004;62:125-6. 20. Marx RE, Johnson RP, Kline SN. Prevention of osteoradionecrosisa randomized prospective clinical trial of hyperbaric oxygen versus penicillin. J Am Dent Assoc 1985;111:49. 21. Maxymiw WG, Wood RE, Liu FF. Postradiation dental extractions without hyperbaric oxygen. Oral Surg Oral Med Oral Med Oral Pathol Oral Radiol Endod 1991;72:270-4. 22. Chang DT, Sandow PR, Morris CG, Hollander R, Scarborough L, Amdur RJ, Mendenhall WM. Do pre-irradiation dental extractions reduce the risk of osteoradionecrosis of the mandible? Head Neck 2007;29:528-36. 23. Bedwinek JM, Shukowsky LJ, Fletcher GH, Daley TE. Osteonecrosis in patients treated with denitive radiotherapy for squamous cell carcinomas of the oral cavity and naso- and oropharynx. Radiology, 1976;119:665-7. 24. Horiot JC, Bone MC, Ibrahim E, Cstro JR. Systematic dental management in head and neck irradiation. Int J Radiat Oncol Biol Phys 1981;7:1025-9. 25. Brown RS, Miller JH, Bottomley WK. A retrospective oral/ dental eveluation of 92 head and neck oncology patients, before, during and after irradiation therapy. Gerodontol 1990;9:35-9. 26. Ben-David MA, Diamante M, Radawski JD, Vineberg KA, Stroup C, Murdoch-Kinch CA, et al. A. Lack of osteoradionecrosis of the mandible after intensity-modulated radiotherapy for head-and-neck cancer: likely contributions of both dental care

placebo-controlled study, Annane et al.28 did not observe any benets of HBO in the treatment of ORN. In general, for all patients that will be submitted to head and neck radiotherapy we accomplish a rigorous clinical evaluation plus panoramic radiograph, and if necessary periapical images are taken. Furthermore, knowledge of radiation dose, volume, modality, urgency, general state, and prognosis play an important role in the decision of teeth removal. Unreparable teeth, owing to caries or periodontal disease, and partially erupted teeth are submitted to exodontias a minimum of 15 days before radiation therapy. During radiotherapy, exodontias must be avoided, owing to interruption of the oncologic treatment. In 10 years of evaluation (the present work), we performed exodontias in only 5 patients because of tooth pain, and all of those patients needed to stop radiotherapy. If exodontias are unavoidable, we recommend performing them with the minimal trauma and under antibiotic prophylaxis (amoxicillin metronidazole or clindamycin). However, there is no scientic evidence for this statement. In irradiated areas, we have frequently performed exodontias, and they must be as nontraumatic as possible: Alveolectomy with careful bone trimming, primary closure without tension, and removal of few teeth per session contribute to minimizing postoperative complications and ORN. In conclusion, the present study showed a low prevalence of ORN related to exodontia: only 2 ORN (0.5%) cases associated with 1.647 exodontia performed before radiotherapy and 1 ORN case (1.7%) in 290 exodontia after irradiation. These results point to the possibility of performing exodontias in irradiated patients. However, these specic dental extractions should be performed by dentists experienced in management of head and neck cancer.
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1. Sulaiman F, Huryn JM, Zlotolow IM. Dental extractions in irradiated head and neck patienta retrospective analysis of Memorial Sloan-Kettering Cancer Center protocols, criteria and end results. J Oral Maxillofac Surg 2003;61:1123-31. 2. Regezi JA, Courtney RM, Kerr DA. Dental management of patients irradiated for oral cancer. Cancer 1976;38:994-1000. 3. Morrish RB, Chan E, Silverman S, Meyer J, Fu KK, Greenspan D. Osteonecrosis in patients irradiated for head and neck carcinoma. Cancer, 1981;47:1980-3. 4. Beumer J III, Harrison R, Sanders B, Kurrasch M. Preradiation dental extractions and the incidence of bone necrosis. Head Neck Surg 1983;5:514-21. 5. Epstein JB, Rea G, Wong FL, Spinelli J, Stevenson-Moore P. Osteonecrosisstudy of the relationship of dental extractions in patients receiving radiotherapy. Head Neck Surg 1987;10:48-54. 6. Marx RE, Johnson RP. Studies in the radiobiology of osteoradionecrosis and their clinical signicance. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1987;64:379-90.

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Reprint requests: Fabio Abreu Alves, DDS, PhD Stomatology Department A. C. Camargo Hospital R: Prof. Antnio Prudente, 211 CEP: 01509-900 So Paulo Brazil falves@hcancer.org.br

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and improved dose distributions. Int J Radiat Oncol Biol Phys 2007;68:396-402. 27. Carvalho AL, Ikeda MK, Magrin J, Kowalski LP. Trends of oral and oropharyngeal cancer survival over ve decades in 3267 patients treated in a single institution. Oral Oncol 2004;40:71-6. 28. Annane D, Depondt J, Aubert P, Villart M, Ghanno P, Gajdos P, et al. Hyperbaric oxygen therapy for radionecrosis of the jawa randomized, placebo-controled, double-blind trial from the ORN96 study group. J Clin Oncol 2004;24:4893-900.