Key Points
Question
Is the timing of dental extraction timing before radiation therapy (RT) associated with osteoradionecrosis (ORN) of the jaw in patients with head and neck cancer?
Findings
This retrospective cohort study of 879 patients with head and neck cancer found those who healed had extractions an average of 4.8 days earlier than patients who developed ORN; however, only 1.8% (16 patients) developed ORN associated with pre-RT extractions.
Meaning
These findings suggest that although the timing of dental extractions affect ORN development, most extractions performed within 14 days of the RT start date do not develop into ORN.
Abstract
Importance
Patients with head and neck cancer undergo extraction of teeth with poor prognoses to minimize post-radiation therapy (RT) extractions, which are known to cause osteoradionecrosis (ORN). However, many patients are required to start RT before the extraction sites are completely healed. The role of pre-RT extractions in the development of ORN has been disputed in literature.
Objective
To determine whether the timing of pre-RT dental extractions is associated with ORN development in patients with head and neck cancer.
Design, Setting, and Participants
This retrospective cohort study was conducted at a single institution (Princess Margaret Cancer Centre, Toronto, Canada) between January 1, 2011, and January 1, 2018, and included 879 patients with head and neck cancer who underwent pre-RT dental extractions before curative RT of 45 Gy or greater. Patient demographic information and clinical characteristics (eg, primary cancer site, nodal involvement, chemotherapy, smoking status, dental pathology) were considered. Data analyses were performed from July to December 2022.
Main outcomes and measures
Timing (number of days) from dental extractions to RT start date and pre-RT extractions categorized as healed, minor bone spicules (MBS), or ORN.
Results
The study population consisted of 879 patients with a median (range) age of 62 (20-96) years, with 685 men (78%) and 194 women (22%). Of these, 847 (96.3%) healed from pre-RT dental extractions, 16 (1.8%) developed MBS, and 16 (1.8%) developed ORN. The median (range) time in number of days from pre-RT extraction(s) to start of RT was 9 (0-98) days in the healed cohort, 6 (3-23) days in the MBS cohort, and 6 (0-12) days in the ORN cohort. There was a large difference in the timing of pre-RT extractions between the healed and the MBS cohorts (mean 11.9 vs 7.4 days to radiation; difference 4.4; 95% CI, 1.5-7.3), and the healed and the ORN cohorts (mean 11.9 vs 7.1 days; difference 4.8 days; 95% CI, 2.6-7.1).
Conclusion
The findings of this retrospective cohort study suggest that there was an important association between the timing of pre-RT dental extractions and ORN when extractions occurred within 7 days of the RT start date. Despite this, ORN after pre-RT extractions is relatively rare. These findings indicate that patients with head and neck cancer who are to undergo RT should not delay treatment for extractions when it might compromise oncologic control.
This retrospective cohort study evaluates the timing of dental extractions before radiation therapy and its association with osteoradionecrosis in patients with head and neck cancer.
Introduction
The global incidence of head and neck cancer has been on the rise, with the annual incidence rate expected to increase 30% annually by 2030.1,2,3 In particular, there has been a rapid increase in the incidence of human papillomavirus-associated oropharyngeal squamous cell carcinoma, accounting for 71% of all incidence of this cancer type in the US, and expected to continue rising during the next 20 to 30 years.4,5 Along with surgery and systemic therapy, radiation therapy (RT) is the principal treatment modality for head and neck cancer.2 Osteoradionecrosis (ORN) of the jaw is a well recognized and debilitating late complication of RT defined as exposed, necrotic irradiated bone in the absence of local cancer recurrence.6,7 As the survival rate of patients with head and neck cancer improves, the incidence of ORN is expected to increase and remains a lifelong concern for HNC survivors.8 There is no consensus or standardized guidelines for the treatment of ORN.9,10,11,12 Therefore, a thorough understanding of associated risk factors and prevention remains the best management strategy for ORN in patients with head and neck cancer who receive RT.
Dental extractions after RT are a well-established risk factor for the development of ORN.10 For this reason, patients with head and neck cancer with planned RT undergo pre-RT dental assessment and extractions of teeth with poor prognoses before initiating RT.13 This practice of pre-RT extractions of poor prognosis teeth is widely supported by the literature10,13,14,15 and by US National Comprehensive Cancer Network (NCCN) Guidelines.16 However, there have been studies that claim that pre-RT extractions do not decrease risk of developing ORN, and that pre-RT extraction itself is an independent risk factor for ORN development.17,18 There is a need for more studies on timing of pre-RT extractions and on the association with ORN.14
Traditionally, 2 to 3 weeks of healing time after pre-RT extractions has been suggested.18 In a study by Willaert et al,19 RT was delayed for 2 weeks after pre-RT extractions to allow for healing. In that study of the 214 patients who had undergone pre-RT extractions, 4 patients developed ORN after pre-RT extractions. Although it is ideal to commence RT after the dental extraction sites have healed, extended delay in RT can negatively affect the patient’s overall survival. Per the NCCN Guidelines16 worse outcomes have been shown when postoperative RT for patients with head and neck cancer is not initiated within 6 weeks of surgery. Accordingly, the objectives of the present study were to determine the incidence of ORN after pre-RT dental extractions among patients with head and neck cancer and to assess the role of timing of extractions on ORN development.
Methods
This retrospective cohort study was reviewed and approved by the institutional review board of Princess Margaret Cancer Centre. Informed consent was waived because of the retrospective design of the study and the high rate of deceased participants.
Study Population
Adult patients (age, ≥18 years) with head and neck cancer who were treated with curative intent RT of 45 Gy or greater at the Princess Margaret Cancer Centre and had undergone pre-RT dental extractions at the Department of Dental Oncology and Maxillofacial Prosthetics from January 1, 2011, to January 1, 2018, were eligible for inclusion. Edentulous patients, patients with a previous history of radiation treatment, patients not at risk of oral toxic effects (ie, diagnosed with T1-T2 and N0 carcinoma of the larynx), and patients who did not have pre-RT dental extractions or had extractions during RT were excluded.
Data Sources
The radiation oncology database and the anthology of outcomes were used to collect age, sex, smoking status, cancer characteristics, and treatment of eligible patients.20 The electronic dental records and database were used to collect data on the number of teeth extracted, location of extractions, and types of dental pathologies, including caries, alveolar bone loss, odontogenic infection presenting with periapical inflammatory disease, and partially impacted third molars. Variables related to ORN, including location and severity based on clinical and radiographic presentations, were collected from electronic health and dental records and a review of relevant imaging and reports.
Outcomes Measured
The timing (number of days) from pre-RT extractions to the start of RT was measured. When extractions occurred on multiple days, the day closest to RT was chosen. The outcomes of pre-RT extractions were categorized as healed, minor bone spicules (MBS), and ORN. Healed was defined as the absence of exposed bone with complete closure of extraction socket(s) and no symptoms; MBS, as superficial sequestrum that spontaneously exfoliated and eventually healed and was considered to be a separate entity from ORN (Figure)6; and ORN, as exposed, necrotic irradiated bone in the absence of local cancer recurrence. This study considered only ORN development directly from sites of pre-RT extractions, with the extraction sockets demonstrating exposed bone and no mucosal coverage at postoperative follow-up visits. The severity of ORN was staged based on the Princess Margaret Cancer Centre staging system.15 The outcomes of pre-RT extractions were evaluated at postextraction follow-up, midway through RT, and at subsequent post-RT dental visits—booked at 1-, 6-, and 12-month intervals after RT, with more frequent visits scheduled for patients with complications or who require dental visits.
Figure. Clinical Images of Minor Bone Spicule (MBS).
A, Exposed bone measuring less than 20 mm2 on anterior mandible. B, Exfoliated MBS next to a periodontal probe with millimeter measurements.
Statistical Analysis
Distributions of demographic and clinical characteristics were described. The magnitude of differences in clinical variables was described using η2 (for continuous variables) and Cramér V (for categorical variables). To interpret η2, 0.01 to 0.05 was considered to be a small effect; 0.06 to 0.13, a moderate effect; and 0.14 or greater, a large effect.21 For Cramér V, interpretation was based on the number of degrees of freedom; effect size interpretations (small, medium, large) are presented in Table 1 along with an interpretation guide.22
Table 1. Patient Demographic and Clinical Characteristics.
| Covariate | Overall (n = 879) | Healed (n = 847) | MBS (n = 16) | Effect sizea | ORN (n = 16) | Effect sizea | ||
|---|---|---|---|---|---|---|---|---|
| Healed vs MBS | Interpretation | Healed vs ORN | Interpretation | |||||
| Patient age, y | ||||||||
| Mean (SD) | 61.1 (12.0) | 61.2 (12.1) | 56.5 (9.8) | 0.003 | NA | 61.4 (8.3) | <0.001 | NA |
| Median (range) | 61.5 (19.9-96.2) | 61.5 (19.9-96.2) | 54.6 (42.8-77.4) | 60 (48-81) | ||||
| Patient sex | ||||||||
| Female | 194 (22) | 190 (22) | 2 (12) | 0.02 | NA | 2 (12) | 0.02 | NA |
| Male | 685 (78) | 657 (78) | 14 (88) | 14 (88) | ||||
| Primary tumor site | ||||||||
| Larynx | 89 (10) | 89 (11) | 0 | 0.09 | Small | 0 | 0.09 | Small |
| Lip and oral cavity | 169 (19) | 164 (19) | 3 (19) | 2 (12) | ||||
| Oropharynx | 298 (34) | 278 (33) | 10 (62) | 10 (62) | ||||
| Other | 323 (37) | 316 (37) | 3 (19) | 4 (25) | ||||
| T stage | ||||||||
| T0 | 57 (7) | 56 (7) | 0 | 0.08 | Small | 1 (6) | 0.08 | Small |
| T1 | 132 (15) | 124 (15) | 5 (31) | 3 (19) | ||||
| T2 | 232 (27) | 225 (27) | 6 (38) | 1 (6) | ||||
| T3 | 240 (27) | 234 (28) | 2 (12) | 4 (25) | ||||
| T4 | 214 (24) | 204 (24) | 3 (19) | 7 (44) | ||||
| Missing | 4 | 4 | 0 | 0 | ||||
| N stage | ||||||||
| N+ | 652 (75) | 628 (74) | 11 (69) | 0.008 | None | 13 (81) | 0.01 | None |
| N0 | 223 (25) | 215 (26) | 5 (31) | 3 (19) | ||||
| Missing | 4 | 4 | 0 | 0 | ||||
| Surgery | ||||||||
| No | 595 (68) | 573 (68) | 11 (69) | <0.001 | None | 11 (69) | <0.001 | None |
| Yes | 284 (32) | 274 (32) | 5 (31) | 5 (31) | ||||
| Chemotherapy | ||||||||
| No | 471 (54) | 459 (54) | 8 (50) | 0.003 | None | 4 (25) | 0.07 | None |
| Yes | 408 (46) | 388 (46) | 8 (50) | 12 (75) | ||||
| RT intent | ||||||||
| Adjuvant RT/CRT | 276 (31) | 267 (32) | 5 (31) | 0.01 | None | 4 (25) | 0.02 | None |
| Neoadjuvant RT/CRT | 9 (1) | 9 (1) | 0 | 0 | ||||
| Radical RT/CRT | 594 (68) | 571 (67) | 11 (69) | 12 (75) | ||||
| Total RT dose, Gy | ||||||||
| Mean (SD) | 67.1 (4.6) | 67.1 (4.6) | 66.9 (4.4) | <0.001 | None | 68.7 (2.7) | 0.002 | None |
| Median (range) | 70 (45-70) | 70 (45-70) | 70 (60-70) | 70 (60-70) | ||||
| Smoking status | ||||||||
| Current | 348 (40) | 335 (40) | 5 (31) | 0.07 | Small | 8 (50) | 0.04 | None |
| Former | 261 (30) | 255 (30) | 3 (19) | 3 (19) | ||||
| Nonsmoker | 252 (29) | 239 (28) | 8 (50) | 5 (31) | ||||
| Unknown | 18 (2) | 18 (2) | 0 | 0 | ||||
| Location of extraction | ||||||||
| Mandible | ||||||||
| No | 230 (26) | 229 (27) | 0 | 0.07 | None | 1 (6) | 0.05 | None |
| Yes | 649 (74) | 618 (73) | 16 (100) | 15 (94) | ||||
| Maxilla | ||||||||
| No | 379 (43) | 366 (43) | 5 (31) | 0.02 | None | 8 (50) | 0.010 | None |
| Yes | 500 (57) | 481 (57) | 11 (69) | 8 (50) | ||||
| Anterior | ||||||||
| No | 634 (72) | 606 (72) | 15 (94) | 0.06 | None | 13 (81) | 0.02 | None |
| Yes | 245 (28) | 241 (28) | 1 (6) | 3 (19) | ||||
| Posterior | ||||||||
| No | 55 (6) | 55 (6) | 0 | 0 | None | 0 | 0 | None |
| Yes | 824 (94) | 792 (94) | 16 (100) | 16 (100) | ||||
| Dental pathologies | ||||||||
| Caries | ||||||||
| No | 392 (45) | 374 (44) | 9 (56) | 0.02 | None | 9 (56) | 0.02 | None |
| Yes | 485 (55) | 471 (56) | 7 (44) | 7 (44) | ||||
| Missing | 2 | 2 | 0 | 0 | ||||
| PID | ||||||||
| No | 598 (68) | 573 (68) | 11 (69) | <0.001 | None | 14 (88) | 0.05 | None |
| Yes | 279 (32) | 272 (32) | 5 (31) | 2 (12) | ||||
| Missing | 2 | 2 | 0 | 0 | ||||
| Moderate-severe BL | ||||||||
| No | 315 (36) | 296 (35) | 11 (69) | 0.09 | None | 8 (50) | 0.03 | None |
| Yes | 562 (64) | 549 (65) | 5 (31) | 8 (50) | ||||
| Missing | 2 | 2 | 0 | 0 | ||||
| Impaction | ||||||||
| No | 845 (96) | 815 (96) | 15 (94) | <0.001 | None | 15 (94) | <0.001 | None |
| Yes | 32 (4) | 30 (4) | 1 (6) | 1 (6) | ||||
| Missing | 2 | 2 | 0 | 0 | ||||
Abbreviations: BL, bone loss; CRT, chemoradiation therapy; MBS, minor bone spicule; NA, not applicable; ORN, osteoradionecrosis; PID, periapical inflammatory disease; RT, radiation therapy.
Effect size was computed from η2 (continuous variables) or Cramér V (categorical variables), interpreted as degree of freedom (small, medium, large): 1 (0.1, 0.3, 0.5); 2 (0.07, 0.21, 0.35); 3 (0.06, 0.17, 0.29; 4 (0.05, 0.15, 0.25); and 5 (0.04, 0.13, 0.22).
Time from last extraction to RT start date was described using medians, ranges, means, and 95% CIs of the mean. Differences in time from extraction to RT among cohorts (healed, MBS, ORN) were computed as mean differences with 95% CIs. In post hoc analysis, odds ratios (ORs) and 95% CIs were computed via logistic regression to compare odds of adverse outcomes (MBS or ORN) in patients who had dental extractions 0 to 6, 7 to 14, or 15 or more days before RT.
Statistical tests were 2-tailed and P values < .05 were considered statistically significant. Data analyses were performed from July to December 2022, using R, version 4.3.0 (The R Foundation for Statistical Computing).
Results
Patient Characteristics
The study population included 879 patients with a median (range) age of 62 (20-96) years, with 685 men (78%) and 194 women (22%). Race and ethnicity data were not evaluated. We excluded 23 patients who had extractions during RT and 1834 patients who did not have pre-RT extractions.
Patients’ clinical characteristics are summarized in Table 1. The primary tumor site was the lip and oral cavity in 169 patients (19%), oropharynx in 298 (34%), and larynx in 89 (10%). Primary tumors originating in the salivary glands, nasopharynx, maxillary sinus, and skin were grouped as other; these affected 323patients (37%). Nodal metastases were commonly found, with 652 patients (75%) diagnosed with nodal involvement. In addition, 408 patients (46%) were treated with concurrent chemotherapy. A total of 609 patients (69%) were currently smoking cigarettes or had a history of smoking.
Among the 879 patients, a total of 3030 teeth were extracted, with a median (range) of 2 (1-25) teeth per patient. Most patients (94%) had posterior teeth removed, while only 245 (28%) had anterior teeth extracted. Mandibular teeth were more commonly removed, in 649 patients (74%), whereas 500 (57%) had maxillary teeth extracted. Reasons for pre-RT extraction included caries in 485 patients (55%), periapical inflammatory disease in 279 (32%), moderate to severe alveolar bone loss in 562 (64%), and partially impacted third molar(s) in 32 patients (4%). Moderate-to-severe bone loss was experienced in the healed cohort by 559 patients (65%); in the MBS cohort by 5 patients (31%); and in the ORN cohort by 8 patients (50%). However, these proportions did not reach a clinically meaningful effect size—Cramér V was 0.09 healed vs MBS (difference, 1) and 0.03 healed vs ORN (difference, 1). Although 73% of the healed, 100% of the MBS, and 94% of the ORN cohorts had mandibular extractions, these did not reach a clinically meaningful effect size (0.07 healed vs MBS; 0.05 healed vs ORN; difference, 1).
Outcomes
Of the 879 patients who had pre-RT extractions, 847 patients (96%) healed completely, 16 (2%) developed MBS, and 16 (2%) developed ORN. The median (range) time in number of days from pre-RT extraction(s) to start of RT was 9 (0-98) days in the healed cohort, 6 (0-23) days in the MBS cohort, and 6 (0-12) days in the ORN cohort. The mean time in days was 11.9 (95% CI, 11.1 to 12.7) for the healed cohort, 7.4 (95% CI, 4.8 to 10.1) for the MBS cohort, and 7.1 (95% CI, 5.0 to 9.1) for the ORN cohort. Patients who developed ORN had extractions performed an average of 4.8 days closer to the RT start date compared with those in the healed cohort (95% CI, 2.6 to 7.1 days). No meaningful difference was detected between the MBS and ORN cohorts (difference, 0.4 days; 95% CI, −3.0 to 3.8) (Table 2).
Table 2. Timing of Dental Extraction Before Radiation Therapy (RT), by Outcome Cohort.
| Cohort | Patients, No. | Time from extraction to RT start, d | |
|---|---|---|---|
| Median (range) | Mean (95% CI) | ||
| Healed | 847 | 9 (0-98) | 11.9 (11.1-12.7) |
| MBS | 16 | 6 (3-23) | 7.4 (4.8-10.1) |
| ORN | 16 | 6 (0-12) | 7.1 (5.0-9.1) |
Abbreviations: MBS, minor bone spicule; ORN, osteoradionecrosis.
Post hoc analysis assessed the timing of pre-RT extractions categorically by 0 to 6, 7 to 14, and 15 or more days before RT (Table 3). Two hundred ninety-nine patients (34%) had extractions 0 to 6 days before RT, of whom 10 (3.3%) developed MBS and 9 (3.0%) developed ORN. Three hundred eighty-six patients (44%) had extractions during the 7 to 14 days before RT, of whom 4 (1.0%) developed MBS and 7 (1.8%) developed ORN. Most patients (94% and 97%, respectively) healed completely from pre-RT extractions performed on days 0 to 6 or 7 to 14 days before RT. There were no cases of ORN associated with pre-RT extractions performed 15 days or more before RT. Odds of MBS were decreased 0.7-fold among patients with extractions 7 to 14 days before (OR, 0.30; 95% CI, 0.09-0.96) and 0.71-fold for 15 or more days (OR, 0.29; 95% CI, 0.06-1.35) compared with those with extractions during days 0 to 6 days before RT. Patients with extraction at least 7 days before RT experienced a 0.62-fold decrease in odds of ORN compared with those with extractions during days 0 to 6 (OR, 0.38; 95% CI, 0.14-1.04).
Table 3. Patients Who Underwent Dental Extractions Before RT, Categorized by Time (Days) to RT Start.
| Time to RT, d | Total patients, No. (%) |
Healed patients, No. (%) |
Patients with MBS, No. (%) |
Effect size, OR (95% CI) |
Patients with ORN, No. (%) |
Effect size, OR (95% CI) |
|---|---|---|---|---|---|---|
| Patients, No. | 879 (100) | 847 (96.4) | 16 (1.8) | NA | 16 (1.8) | NA |
| 0-6 | 299 (34) | 280 (94) | 10 (3) | 1 [Reference] | 9 (3) | 1 [Reference] |
| 7-14 | 386 (44) | 375 (97) | 4 (1) | 0.3 (0.09-0.96) | 7 (2) | 0.38 (0.14-1.04) |
| ≥15 | 194 (22) | 192 (99) | 2 (1) | 0.29 (0.06-1.35) | 0 | NA |
Abbreviations: MBS, minor bone spicule; NA, not applicable; OR, odds ratio; ORN, osteoradionecrosis; RT, radiation therapy.
Of the 16 patients in the ORN cohort, more than half of the primary tumor sites originated in the oropharynx (10 patients [62.5%]). All the cases of ORN occurred on the posterior mandible, with 1 patient also developing ORN in the posterior maxilla. No cases of ORN occurred from pre-RT extractions of anterior or premolar teeth.23 Six of the patients with ORN (37.5%) developed stage 4 ORN, per the Princess Margaret Cancer Centre staging system, and 3 (18.8%) developed pathologic jaw fractures (Table 4).
Table 4. Characteristics of the 16 Patients Who Developed Osteoradionecrosis After Pre-RT Dental Extraction.
| Patient | Primary tumor | Category | Teeth extracted23 | ORN location | Extraction to RT, d | Jaw fracture | Stagea | |
|---|---|---|---|---|---|---|---|---|
| T | N | |||||||
| 1 | Oropharynx | T4 | N2 | 38 | Posterior mandible | 0 | No | 4 |
| 2 | Lip and oral cavity | T4 | N2 | 45, 46 | Posterior mandible | 1 | No | 4 |
| 3 | Lip and oral cavity | T1 | N0 | 38 | Posterior mandible | 3 | No | 1 |
| 4 | Other (left parotid gland) | T4 | N0 | 38 | Posterior mandible | 4 | No | 3 |
| 5 | Oropharynx | T4 | N2 | 17, 16, 15, 14, 13, 12, 11, 21, 22, 23, 24, 25, 26, 27, 36, 46, 47, 48 | Posterior mandible | 4 | Yes | 4 |
| 6 | Oropharynx | T3 | N2 | 28, 38, 48 | Posterior mandible | 6 | No | 1 |
| 7 | Oropharynx | T2 | N2 | 26, 37, 35, 34, 45, 46, 47 | Posterior mandible | 6 | No | 2 |
| 8 | Other (right neck skin) | T0 | N2 | 37, 48 | Posterior mandible | 6 | No | 1 |
| 9 | Other (right maxillary sinus) | T3 | N0 | 18 | Posterior maxilla | 6 | No | 1 |
| 10 | Oropharynx | T3 | N2 | 36, 37, 38, 46 | Posterior mandible | 10 | No | 1 |
| 11 | Oropharynx | T3 | N2 | 17, 15, 14, 13, 21, 22, 23, 24, 27, 37, 36, 33, 32, 31, 42, 43, 47 | Posterior maxilla and mandible | 10 | No | 3 |
| 12 | Oropharynx | T1 | N2 | 47 | Posterior mandible | 11 | No | 4 |
| 13 | Oropharynx | T4 | N2 | 38 | Posterior mandible | 11 | No | 3 |
| 14 | Other (nasopharynx) | T1 | N2 | 27, 28, 37, 48 | Posterior mandible | 11 | No | 3 |
| 15 | Oropharynx | T4 | N2 | 17, 27, 37 | Posterior mandible | 12 | Yes | 4 |
| 16 | Oropharynx | T4 | N2 | 21, 28, 38 | Posterior mandible | 12 | Yes | 4 |
Abbreviations: RT, radiation therapy; ORN, osteoradionecrosis.
Most advanced stage, per the Princess Margaret Cancer Centre osteoradionecrosis staging system: 1, loss of mucosa with exposed bone requiring antibiotic or sequestrectomy for ≤3 months; 2, loss of mucosa with exposed bone requiring antibiotic or sequestrectomy for >3 months and ≤6 months; 3, loss of mucosa with exposed bone requiring antibiotic or sequestrectomy for >6 months, or need for hyperbaric oxygen therapy or medical management with pentoxifylline/vitamin E; 4, loss of mucosa with exposed bone requiring antibiotic or sequestrectomy for >12 m, need for surgery, or pathologic bone fracture; and 5, death.
Compared with the healed and MBS cohorts, patients who developed ORN more frequently underwent concurrent chemotherapy—12 patients (75.0%) vs 392 (45.1%) in the healed cohort and 9 (52.9%) in the MBS cohort. Eight patients (50.0%) in the ORN cohort reported being current smokers, whereas fewer reported the same status in the other 2 cohorts: 344 (39.6%) in the healed and 6 (35.3%) in the MSB cohorts. Smoking appeared to have a small effect on the development of MBS from pre-RT extractions.
Discussion
In these study findings, the average time from dental extraction to the start of RT in the healed cohort was greater than among the MBS and ORN cohorts. All 16 cases of ORN occurred from extractions performed within 14 days of the RT start date. When the timing of pre-RT extractions was categorized into 0 to 6 days vs 7 or more days before RT, there was a clinically meaningful difference in the timing of pre-RT extractions in the healed vs ORN cohorts. Similar results were found for MBS, with decreased odds for patients with extractions during days 7 to 14 days and 15 or more days before RT compared with 0 to 6 days before RT.
The findings of this study show that 3% of pre-RT extractions performed 0 to 6 days before RT were associated with ORN, whereas 97% of pre-RT extractions during this time period either healed completely or developed MBS and subsequently healed. No cases of ORN developed from extractions performed more than 14 days before RT. The small sample size of the ORN cohort compared with the healed cohort resulted in wide confidence intervals around the effect size, and thus makes it challenging to make definitive conclusions. However, the difference in timing of pre-RT extractions between the healed and ORN groups at the turning point of day 7 and day 14 is clinically meaningful. These findings are consistent with the study performed by Huang et al24 that demonstrated an increased incidence of ORN in patients with pre-RT extractions performed within 2 weeks vs patients who did not undergo extractions. In a nationwide population-based retrospective study by Liao et al,25 the incidence of ORN among 5062 patients with head and neck cancer with at least 1 tooth extraction pre-RT was 1.03%, results that are in keeping with our findings. However, the authors reported that pre-RT extractions performed 1 to 7 days before RT did not increase the risk of ORN compared with pre-RT extractions performed 7 to 21 days before RT. Presently, many institutions recommend a 2-week healing period between dental extractions and RT, a recommendation that may delay RT.
In a study by Graboyes et al,26 failure to adhere to NCCN Guidelines16 by starting adjuvant RT more than 6 weeks after surgery was associated with a 10% absolute decrease in 5-year overall survival (60.2% vs 70.8%). In our study, 3 of the 16 patients who developed ORN went on to develop jaw fractures. This means that RT would need to be delayed, for some period, in approximately 44 patients to prevent 1 case of ORN, and in 233 patients to prevent 1 jaw fracture associated with pre-RT extractions. In fact, 2 of the 3 patients with jaw fracture had extractions performed 12 days before RT, a time frame that many clinicians would consider to be safe. Were it possible for patients to simultaneously undergo recommended extractions 2 weeks before RT without delaying RT, this would be ideal. In practice, a trade-off must usually be made between these options, and the findings of this study suggest that emphasis should be placed on the initiation of RT rather than on a delay to prevent ORN.
The present study considered ORN and the added category of MBS, a well-documented condition that can occur after tooth extraction. Indeed, MBS after dental extraction has been reported in 0.2% of the general population undergoing third molar extraction, ie, patients who have not undergone RT.27 The rationale for the addition of MBS was to distinguish these spicules of bone that are not clinically important and that are a distinct entity from ORN, to avoid overestimation of ORN.28 Most recently, MBS was used by Shaw et al6 as part of the Modified Notani measurement scale for ORN in the Hyperbaric Oxygen for the Prevention of Osteoradionecrosis (HOPON) randomized clinical trial and was recommended for use in future clinical trials measuring ORN. The incidence of MBS in the present study was 1.8%, whereas it was 13% in the HOPON trial, in which extractions were performed in the post-RT setting.6 The distinction between MBS and ORN is valuable in reducing overdiagnosis of ORN, given that numerous staging systems lack this specification.29,30,31
The goal of pre-RT dental extractions is to minimize the incidence of patients with head and neck cancer requiring dental extractions after RT, a well-recognized cause of ORN. The indications for pre-RT extractions in the present study included caries, odontogenic infections, periodontal disease, and partially impacted third molars. These indications were consistent with the practice of other institutions reported in the literature.18,32,33 Muraki et al32 recommended that teeth with nonrestorable caries, periapical radiolucency greater than 5 mm on imaging, and partially erupted teeth be extracted before RT. Chang et al18 also performed pre-RT extractions for teeth with active moderate to severe periodontal disease.
All 16 cases of ORN in the present study occurred on the posterior mandible, and 1 case also involved the posterior maxilla. No cases of ORN occurred in the anterior maxilla or mandible or from the removal of an anterior or premolar tooth. This is to be expected given that many patients included in the study had a diagnosis of oropharyngeal carcinoma, where high-dose fields are limited to posterior regions. It has also been proposed that the greater susceptibility of the mandible to ORN compared with the maxilla and posterior to anterior may be due to differences in vascularity.10,34 Radiation-induced vascular fibrosis can obliterate the inferior alveolar artery, impair the revascularization by branches of the facial artery, and compromise periosteal blood supply—the main blood supply to the body of the mandible, thereby weakening the most vulnerable areas of the mandible to ORN, the buccal cortex of molar and retromolar regions.35,36
Limitations
The limitations of the study included its retrospective design and unmeasured risk factors, such as precise RT dose administered at dental extraction sites. It is not known whether some patients were recommended for dental extractions that were not performed. Another limitation was the large proportion of primary tumors from the oropharynx (33.5% of total cohort) as a source selection bias. The present study did not find an association of ORN with oropharyngeal RT. Lastly, considering that ORN cases that did not involve pre-RT extractions were excluded from the study, the results may underreport the overall total risk of ORN for patients with head and neck cancer who are undergoing RT.
Conclusions
The findings of this retrospective cohort study at a single institution found that the association of pre-RT timing of extractions was 1.8%. The location of the extraction was relevant given that no patients developed ORN from anterior or premolar tooth extractions. We reiterate that although all of the ORN cases occurred from extractions performed within 14 days of the RT start date, nearly 98% of the study patients in this group eventually healed. When faced with a trade-off between delaying RT and starting RT with incompletely healed dental extraction sites, proceeding with RT is advised.
Data Sharing Statement
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Data Sharing Statement