Incidence of, and risk factors for, mandibular osteoradionecrosis in patients with oral cavity and oropharynx cancers

Oral Oncology 72 (2017) 98–103

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Incidence of, and risk factors for, mandibular osteoradionecrosis in patients with oral cavity and oropharynx cancers Dominic H. Moon a, Sung Ho Moon b, Kyle Wang a, Mark C. Weissler c, Trevor G. Hackman c, Adam M. Zanation c, Brian D. Thorp c, Samip N. Patel c, Jose P. Zevallos c, Lawrence B. Marks a, Bhishamjit S. Chera a,⇑ a b c

Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States Department of Radiation Oncology, Research Institute and Hospital, National Cancer Center, Goyang, South Korea Department of Otolaryngology/Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

a r t i c l e

i n f o

Article history: Received 24 May 2017 Accepted 9 July 2017

Keywords: Osteoradionecrosis Oral cavity cancer Oropharynx cancer Radiation therapy Intensity-modulated radiation therapy (IMRT) 3D-Conformal radiation therapy (3D-CRT) Tooth extraction Smoking

a b s t r a c t Objectives: To evaluate the incidence of, and risk factors associated with, mandibular osteoradionecrosis (MORN) following radiation therapy (RT) for oral cavity and oropharyngeal cancers. Materials and Methods: Patient and treatment records of 252 consecutive patients with oral cavity or oropharynx cancers treated with RT by a single radiation oncologist at a high volume academic institution from August 2009 to December 2015 were retrospectively reviewed. A Cox regression model was used to assess factors associated with the development of MORN. RT dosimetry was compared between patients with MORN and a matched cohort of patients without MORN. Results: MORN developed in 14 patients (5.5%), occurring 3–40 (median 8) months post-RT. Factors associated with MORN on univariable analysis included primary diagnosis of oral cavity vs oropharynx cancer (hazard ratio [HR]: 3.0, p = 0.04), smoking at the time of RT (HR: 3.1, p = 0.04), mandibular invasion of the primary (HR: 3.7, p = 0.04), pre-RT tooth extraction (HR: 4.52, p = 0.01), and treatment with 3Dconformal RT vs intensity-modulated RT (HR: 5.1, p = 0.003). On multivariable analysis, pre-RT tooth extractions and RT technique remained significant. A dosimetric comparison between patients with and without MORN showed no significant differences. Conclusions and Relevance: The incidence of MORN is low in the modern era at a high volume academic center. Modifiable risk factors including pre-RT tooth extractions, smoking, and RT technique are associated with MORN, and the risk should be minimized with appropriate dental evaluation and treatment, smoking cessation efforts, and the use of intensity-modulated RT. Ó 2017 Elsevier Ltd. All rights reserved.

Introduction Mandibular osteoradionecrosis (MORN) is a cause of significant morbidity in patients with head and neck cancers treated with radiation therapy (RT). Osteoradionecrosis is defined as an area of exposed bone secondary to necrosis following RT with failure to heal after a period of 3–6 months [1]. The mandible is the most commonly affected bone due to the distribution of head and neck primaries and the relative hypovascular nature of the mandible. The pathogenesis of MORN is thought to be secondary to bone tissue and vascular damage causing a hypoxic, hypocellular, and ⇑ Corresponding author at: Department of Radiation Oncology, University of North Carolina Hospitals, 101 Manning Drive, CB #7512, Chapel Hill, NC 275997512, United States. E-mail address: [email protected] (B.S. Chera). http://dx.doi.org/10.1016/j.oraloncology.2017.07.014 1368-8375/Ó 2017 Elsevier Ltd. All rights reserved.

hypovascular environment [2] and a radiation-induced fibroatrophic process [3]. The reported incidence of MORN has decreased in recent years. The rate of MORN has declined from approximately 20% several decades ago [4,5] to 4–8% in modern series [6–9] with one series reporting no cases in a cohort of 176 patients at a median follow-up of 34 months [10]. This consistent decline in the incidence of MORN is attributed to the advances in RT technique and possible improvement in recognizing and mitigating risk factors. Multiple risk factors have been associated with the development of MORN. These include tumor-related factors (tumor location, size, stage, presence of bone invasion), treatment-related factors (total RT dose, RT technique, volume of mandible irradiated), and patient-related factors (tobacco/alcohol use, oral hygiene, dental extractions, comorbidities) [6–9,11–14]. The variability in results

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from different series likely reflects a diverse patient population and RT techniques studied. The primary objective of this study was to evaluate the incidence of MORN in patients with oral cavity cancers (OCC) and oropharyngeal cancers (OPC) treated by a single radiation oncologist at a high volume tertiary institution with a multidisciplinary head and neck oncology program. We also sought to examine and verify the potential risk factors associated with MORN.

Whitney test with two tails. P-values of < 0.05 were considered statistically significant. All statistical analyses were conducted using SPSS (IBM SPSS Statistics, version 21.0, New York, United States).

Materials and methods

Of the 282 eligible patients, 30 were excluded based on the exclusion criteria, leaving 252 patients for analysis with a median follow-up of 25 months (range: 6–81 months). Patient and treatment characteristics are summarized in Table 1. In this cohort, most patients had OPC (73%), were treated with IMRT (89%), and received concurrent chemotherapy with RT (85%). Mandibular surgery including mandibulotomy, partial, segmental, and hemimandibulectomy were performed in 31% of the OCC patients. Median, mean, and range of RT doses delivered were 70 Gy, 66.3 Gy, and 60 Gy–74.4 Gy, respectively.

Patients All patients with OCC and OPC treated with RT by a single radiation oncologist at a high volume tertiary academic institution between August 2009 and December 2015 were retrospectively reviewed. Patients receiving RT dose less than 60 Gy in 2-Gy fractions (or its equivalent using biological effective dose calculation for late effect) or re-irradiation, and those with less than 6 months of follow-up were excluded (except if MORN occurred prior to 6 months). Patient’s demographics, social history including smoking and alcohol use, tumor characteristics, and treatment information were analyzed. Patients with MORN were identified based on the definition of clinically exposed mandibular bone secondary to necrosis following RT not related to progression of disease with failure to heal after a period of 3 months. Schwartz and Kagan classification system was used to stage the MORN [15]. Treatment OPC patients received 60–70 Gy, depending on enrollment on a de-intensification protocol, which mandated a definitive dose of 60 Gy, with elective nodal RT dose to 50–54 Gy. OCC patients receiving post-operative RT received 60–66 Gy with elective nodal RT dose to 50–54 Gy. All patients received RT in 2-Gy fractions with the exception of 3 patients receiving 2.2 Gy/fraction and 4 patients receiving 1.2 Gy/fraction twice daily. Patients were predominantly treated with intensity-modulated radiation therapy (IMRT) with a subset receiving 3-dimensional conformal RT (3DCRT), and received concurrent chemotherapy as appropriate. Patients underwent a pre-RT dental evaluation and management including tooth extractions as deemed appropriate by the radiation oncologist and/or dentist based on risk assessment. Statistical analysis Chi-squared test was used to compare patient and treatment characteristics of patients with and without MORN. A univariable Cox regression model was used to assess patient and treatment factors associated with the development of MORN. In addition, a multivariable Cox regression was performed with two covariates per analysis. A matched, nested case-control analysis was done to evaluate the dosimetry to the mandible. One patient without MORN was matched to each of the 14 patients with MORN (i.e. 1:1 matching) by RT type (3D-CRT vs IMRT), status of pre-RT tooth extraction, primary site (OCC vs OPC), smoking status, and the presence of mandibular invasion (all potential risk factors for MORN). When feasible, the patient’s age, sex, and treatment period were also matched. Dosimetric data for the mandible analyzed included maximum dose to the mandible (Dmax), mean mandibular dose (Dmean), and the percent volume of mandible receiving 40 Gy (V40), 50 Gy (V50), 60 Gy (V60), and 70 Gy (V70). Dosimetry of patients between those with and without MORN and those who received 3D-CRT vs IMRT were compared using the Mann-

Results Patient and treatment characteristics

Incidence of mandibular osteoradionecrosis MORN developed in 14 patients (5.5%) with a median time to developing MORN of 8 months (range: 3–40 months). Patient and treatment characteristics of those with and without MORN are summarized in Table 1. The rate of MORN was higher in current smokers vs non-smokers (11% vs 3.4%, p = 0.032), patients receiving pre-RT tooth extraction vs those who did not (11% vs 2.4%), and patients treated with 3D-CRT vs IMRT (19% vs 4.0%, p = 0.01). Details of 14 patients who developed MORN are summarized in Table 2. MORN developed spontaneously without an associated procedure or trauma in 11 of 14 patients (79%). The majority had stage 1–2 MORN by Schwartz and Kagan classification with stage 3 MORN developing in 5 patients (overall incidence of 2.0%). Three patients (21%) required surgical management, 3 additional patients (21%) received hyperbaric oxygen therapy, and the rest were managed conservatively. At the time of analysis, 11 of 14 patients (79%) had either a resolution or stabilization of their MORN. Risk factors associated with the development of mandibular osteoradionecrosis Factors associated with MORN on univariable analysis included primary diagnosis of OCC vs OPC (Hazard ratio [HR]: 3.0, p = 0.04), smoking at the time of RT (HR: 3.1, p = 0.04), mandibular invasion of the primary (HR: 3.7, p = 0.04), pre-RT tooth extraction (HR: 4.52, p = 0.01), and treatment with 3D-CRT vs IMRT (HR: 5.1, p = 0.003) (Table 3). On multivariable analysis of two covariates per analysis, RT technique remained significant when accounting for pre-RT tooth extraction and smoking status. Pre-RT tooth extraction was also significant when accounting for all other covariates in pairs. The site of the primary, mandibular invasion, and smoking status fell out of statistical significance on multivariable analysis. Dosimetry of patients with and without mandibular osteoradionecrosis Among the 14 patients with MORN, the mean Dmean, Dmax, V40, V50, V60, and V70 were 49.0 Gy, 71.7 Gy, 69%, 61%, 45%, and 17%, respectively (Table 4). There was no significant difference in the dosimetry when compared to a nested cohort of patients without MORN matched for the factors associated with MORN on univariable analysis (primary diagnosis, smoking status, mandibular invasion, pre-RT tooth extraction, and RT treatment modality). Among

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Table 1 Patient and treatment characteristics. Characteristic

All patients (Column%)

Patients without MORN (Row%)

Patients with MORN (Row%)

N Age (mean) Gender Male Female Smoking Not currently smoking Currently smoking Alcohol Use None or Mild Moderate or Heavy Hypertension No Yes Diabetes Mellitus No Yes Site Oral Cavity Oropharynx T-Stage T0-2 T3-4 Nodal status Node negative Node positive Mandibular invasion No Yes Pre-RT surgery No Yes Pre-RT mandible surgery No Yes Pre-RT tooth extraction No Yes RT technique IMRT 3D-CRT Neoadjuvant chemotherapy No Yes Concurrent chemotherapy No Yes

252 57

238 (94) 57

14 (5.9) 54

198 (79) 54 (21)

188 (95) 50 (93)

10 (5.1) 4 (7.4)

177 (70) 75 (30)

171 (97) 67 (89)

6 (3.4) 8 (11)

174 (69) 78 (31)

163 (94) 75 (96)

11 (6.3) 3 (3.8)

154 (61) 98 (39)

143 (93) 95 (97)

11 (7.1) 3 (3.1)

226 (90) 26 (10)

213 (94) 25 (96)

13 (5.8) 1 (3.8)

68 (27) 184 (73)

61 (90) 177 (96)

7 (10) 7 (3.8)

161 (64) 91 (36)

154 (96) 84 (92)

7 (4.3) 7 (7.7)

91 (36) 161 (64)

85 (83) 153 (95)

6 (6.6) 8 (5.0)

233 (92) 19 (7.5)

222 (95) 16 (98)

11 (4.7) 3 (1.6)

182 (72) 70 (28)

174 (96) 64 (93)

8 (4.4) 6 (8.6)

231 (92) 21 (8.3)

219 (94) 19 (90)

12 (5.7) 2 (9.5)

164 (65) 88 (35)

160 (98) 78 (89)

4 (2.4) 10 (11)

225 (89) 27 (11)

216 (96) 22 (81)

9 (4.0) 5 (19)

230 (91) 22 (8.7)

218 (95) 20 (91)

12 (5.2) 2 (9.1)

38 (15) 214 (85)

37 (97) 201 (94)

1 (2.6) 13 (6.1)

Pa 0.25 0.51

0.032

0.56

0.26

1.0

0.062

0.27

0.58

0.078

0.22

0.33

0.007

0.010

0.35

0.70

Abbreviations: MORN, mandibular osteoradionecrosis; RT, radiotherapy; 3D-CRT, 3-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy. a Chi-squared test p-value shown for all covariates with the exception of age (t-test).

the MORN patients, mean Dmax (74.5 Gy vs 70.2 Gy, p = 0.046), V60 (65% vs 33%, p = 0.033) and V70 (36% vs 7%, p = 0.011) were significantly higher in patients receiving 3D-CRT vs IMRT.

Discussion In our cohort of 252 patients, the incidence of MORN was 5.5%, consistent with other recent series [6–9], with most patients achieving resolution or stabilization of MORN after appropriate management. Factors associated with developing MORN on univariable analysis consisted of non-modifiable factors including primary diagnosis of OCC vs OPC and mandibular invasion of the primary, but also comprised of modifiable factors including smoking at the time of RT, pre-RT tooth extraction, and treatment with 3D-CRT vs IMRT. The requirement for pre-RT tooth extraction and the use of 3D-CRT remained significant factors on multivariable analysis. MORN can be difficult to treat with no established evidencebased standard for its management. As such, it is important to min-

imize potential risk factors to help prevent the development of MORN. Dental hygiene and tooth extractions have historically been considered one of the most importance risk factors. At our institution, patient’s dental health is assessed as part of the pre-RT evaluation with referral to the dental clinic for cleaning, restoration, and/or extraction as appropriate. For patients with nonrestorable teeth and/or teeth in the high dose regions (>50 Gy) with high likelihood of requiring post-RT extractions, prophylactic extractions are generally recommended. A thorough evaluation and a thoughtful discussion is required prior to prophylactic extractions, as they significantly affect the patient’s quality of life and may delay definitive cancer treatment. The rationale for prophylactic extractions is the compromised wound healing of irradiated tissue that predisposes the patient to developing MORN. Studies done decades ago confirmed higher rates of MORN with post-RT extractions, and recommended prophylactic extractions when necessary [16,17]. A recent review of the literature showed no evidence of an advantage for prophylactic extraction of restorable or healthy teeth; thus, prophylactic extractions should be limited to teeth with significant decay beyond restoration [18].

care care

care care

care care care

Resolved Resolved Resolved Stable Resolved Resolved Resolved Resolved Aggravated Aggravated Stable Aggravated Resolved Stable care

Abbreviations: MORN, mandibular osteoradionecrosis; 3D-CRT, 3-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; HBO, hyperbaric oxygen therapy. a Schwartz and Kagan classification. b Partial/segmental mandibulectomy with a free fibular tissue flap.

Conservative Surgery Surgery Conservative Conservative Conservative Surgery HBO Conservative Conservative HBO Conservative Conservative HBO None None None Tooth extraction None Tooth extraction None None Tooth extraction None None None None None 1 3 3 1 1 1 3 2 3 3 2 2 1 2 4 4 8 40 8 3 7 6 27 9 6 20 10 3 Concurrent Concurrent Concurrent Concurrent No Concurrent Neoadjuvant/ Concurrent Neoadjuvant/Concurrent Concurrent Concurrent Concurrent Concurrent Concurrent Concurrent 70 70 66 70 60 70 70 70 70 66 60 70 66 70 3D-CRT 3D-CRT 3D-CRT IMRT IMRT 3D-CRT IMRT IMRT IMRT IMRT IMRT IMRT IMRT 3D-CRT Yes Yes Yes Yes No No Yes Yes No Yes No Yes Yes Yes No Yesb No No No No No No No No No No Yesb No Oral tongue Floor of mouth Lip Tonsil Oral tongue Retromolar Tonsil Soft palate Oropharynx Oral tongue Tonsil Base of tongue Floor of mouth Oropharynx 27/Female 37/Male 62/Male 54/Male 50/Male 53/Male 55/Male 63/Female 72/Male 57/Female 69/Female 48/Male 50/Male 61/Male

No Yes No No No Yes No No No No No No Yes No

Primary site Age/Sex

Table 2 Details of 14 patients with MORN.

Mandibular involvement of primary

Mandibular surgery

Pre-RT extraction

RT technique

RT dose (Gy)

Chemotherapy

Onset after RT (months)

MORN stagea

Related trauma

Management of MORN

Outcome of MORN

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Interestingly, our study showed that pre-RT extraction is an independent risk factor for the development of MORN. Ten of the 14 patients who developed MORN had a pre-RT extraction. This corroborates the results of a study by Chang et al., which found preRT extraction as a risk factor for MORN and prophylactic extraction did not reduce the risk regardless of the condition of the patient’s teeth [19]. These results may reflect an inherent risk of wound healing issues from tooth extractions even prior to RT, but it is also possible that the need for a pre-RT extraction is a surrogate for the patient’s overall poor dental health, predisposing them to MORN. Nonetheless, in carefully selected patients as discussed above, we do perform pre-RT extractions at our institution. The lower rates of MORN in the last decade have been attributed, in part, to the advancement in RT techniques, namely the use of IMRT, which potentially allows for better sparing of normal tissues with a sharper dose falloff [20]. Multiple studies support this idea. In a Surveillance, Epidemiology, and End Results (SEER)Medicare study of 1848 patients, Beadle et al. reported a trend towards lower rate of jaw complications in those receiving IMRT vs 3D-CRT (14.0% vs 17.3%, p = 0.064) [21]. Similarly, an MD Anderson study of 402 T1-T2 oropharynx cancer patients suggested lower rates of MORN with IMRT (6.3% vs 13%, p = 0.07) [9], while a VA hospital study of 158 of head and neck cancer patients showed a statistically significant improvement in the MORN rate with IMRT (0% vs 10.1%, p = 0.014). However, a recent study by Maesschalck et al. of 89 patients treated with IMRT and 145 patients treated with 3D-CRT showed no difference in MORN rates (10% vs 11%) with, in fact, a higher 3-year cumulative incidence risk in those receiving IMRT (8.9% vs 4.8%, p = 0.03) [22]. On the contrary, our results showed significantly lower rates of MORN in those receiving IMRT vs 3D-CRT (19% vs 4.0%, p = 0.01), adding to the growing evidence suggesting improved mandible toxicity outcomes with advances in RT technique. Numerous studies have reported a relationship between maximum RT doses >60–75 Gy with the development of MORN [6,7,10,11]. However, specific dosimetric parameters to help guide RT planning is limited. Tsai et al. showed an association between V50-V60 and MORN in a nested, matched case-control analysis of dosimetry between patients with and without MORN [9], but our data did not demonstrate any significant differences in dosimetry between these groups. The currently accepted dose constraint is Dmax<70 Gy. At out institution, we limit Dmax to <105% of the prescription dose and otherwise minimize low to moderate dose spillage to the mandible and oral cavity using an avoidance structure during treatment planning. A selected cohort of modern series reporting the incidence of osteoradionecrosis is summarized in Table 5. Overall, the rate of osteoradionecrosis is low across various patient populations and treatment centers, despite a common misconception among patients and even physicians of a high risk of MORN following RT to the head and neck. In reality, at a high volume center with a multidisciplinary team, a close relationship with the dentists, and regular follow-up, the risk of MORN is low. Even among those who develop MORN, early recognition often allows for conservative management, with a minority of patients developing severe MORN requiring surgical intervention, as evident in our series. MORN, however, can be associated with significant morbidity, and potential risk factors need to be minimized. We emphasize with patients the importance of smoking cessation and maintaining regular follow-up with his/her dentist to maximize post-RT dental hygiene. This includes a visit with the dentist at least twice a year with appropriate cleaning, fluoride trays, and mouth rinses to avoid the need for tooth extractions or procedures that may cause trauma to the mandible, especially posteriorly where the doses are frequency approaching or exceeding 60–70 Gy. We also communicate with the patient’s dentist on a regular basis to dis-

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Table 3 Cox proportional hazards regression for MORN. Univariable Analysis

Multivariable Analysis (2 covariates per analysis)

Characteristic

P

HR (95% CI)

Characteristic

P

HR (95% CI)

Age Gender (female vs male) Currently smoking Moderate / heavy alcohol Hypertension Diabetes mellitus Site (oral cavity vs oropharynx) T3-4 Node-positive Mandibular invasion Pre-RT surgery Mandibular surgery Pre-RT tooth extraction RT technique (3D-CRT vs IMRT) Neoadjuvant chemotherapy Concurrent chemotherapy

0.24 0.52 0.037 0.43 0.22 0.76 0.039 0.22 0.64 0.044 0.21 0.35 0.011 0.003 0.42 0.41

0.97 1.46 3.09 0.60 0.45 0.73 3.02 1.94 0.78 3.72 1.96 2.06 4.52 5.12 1.86 0.42

RT technique (3D-CRT vs IMRT) Pre-RT tooth extraction RT technique (3D-CRT vs IMRT) Currently smoking RT technique (3D-CRT vs IMRT) Site (oral cavity vs. oropharynx) RT technique (3D-CRT vs IMRT) Mandibular invasion Pre-RT tooth extraction Currently smoking Pre-RT tooth extraction Site (oral cavity vs oropharynx) Pre-RT tooth extraction Mandibular invasion

0.009 0.019 0.015 0.11 0.066 0.45 0.013 0.20 0.031 0.14 0.018 0.080 0.020 0.14

4.34 4.02 4.04 2.42 3.65 0.60 4.27 2.42 3.72 2.27 4.08 0.39 4.05 2.63

(0.93: 1.02)/yr (0.46: 4.66) (1.07: 8.93) (0.17: 2.14) (0.13: 1.63) (0.10: 5.60) (1.06: 8.61) (0.68: 5.53) (0.27: 2.24) (1.04: 13.35) (0.68: 5.66) (0.46: 9.22) (1.42: 14.43) (1.71: 15.30) (0.42: 8.29) (0.31: 18.14)

(1.44: 13.03) (1.25: 12.92) (1.31: 12.50) (0.81: 7.22) (0.92: 14.54) (0.45: 6.27) (1.35: 13.48) (0.63: 9.26) (1.13: 12.26) (0.76: 6.74) (1.27: 13.10) (0.89: 7.35) (1.25: 13.15) (0.72: 9.63)

Abbreviations: HR, hazard ratio; CI, confidence interval, RT, radiotherapy; 3D-CRT, 3-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy.

Table 4 Dosimetric analysis of patients with MORN vs matched cohort of patients without MORN. Dosimetry

Dmean (Gy) Dmax (Gy) V40 (%) V50 (%) V60 (%) V70 (%)

All patients

Patients with MORN

Patients without MORN

Patients with MORN

P

3D-CRT

IMRT

P

52.3 71.5 72.5 60.9 45.9 21.9

49.0 71.7 68.6 60.6 44.7 17.4

0.42 0.87 0.32 0.73 0.98 0.66

52.0 74.5 73.4 71.7 65.3 35.6

47.3 70.2 66.0 54.5 33.3 7.3

0.42 0.046 0.50 0.18 0.033 0.011

Abbreviations: MORN, mandibular osteoradionecrosis; 3D-CRT, 3-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy, Dmean, mean mandibular dose; Dmax, maximum dose to mandible; Vx, percent volume of mandible receiving x Gy.

Table 5 Selected modern series reporting rates of osteoradionecrosis. Study

N

Primary

RT technique

Median follow-up (months)

ORN incidence (%)

Risk factors/Comments

Tsai (2013)[9]

402

T1-2 Oropharynx

31

7.5

Higher V50 and V60 associated with ORN

Gevorgyan (2013)[23]

1575

Head and neck

26

0.84

Duarte (2014)[24]

158

Head and neck

NR

6.3

3D-CRT (vs IMRT) predictive of severity of ORN 3D-CRT (10.1%) vs IMRT (0%) ORN rate

Chen (2016)[6]

1692

Oral

3D-CRT (17%) IMRT (83%) 3D-CRT IMRT 3D-CRT (63%) IMRT (37%) IMRT

36.8 (mean)

6.2

Maesschalck (2016)[22]

234

Oropharynx

653

Head and neck

3D-CRT: 4.9 yrs IMRT: 3.2 yrs NR

11

De Felice (2016)[25]

5.5

Raguse (2016)[26]

149

Head and neck

3D-CRT (62%) IMRT (38%) 3D-CRT (11%) IMRT (89%) 3D-CRT (70%) IMRT (30%)

41

25.5

Studer (2016)[8]

531

IMRT

38

7

Owosho (2017)[7]

1023

Oral cavity, salivary gland, mesopharynx Oral cavity, oropharynx

IMRT

52.5

4.3

Primary site (floor of mouth, buccal mucosa, retromolar trigone, or gum), segmental mandibulectomy, total dose > 75 Gy associated with ORN No difference in ORN rate between 3DCRT and IMRT Smoking associated with ORN persistence, no dosimetric factors associated with ORN Any comorbidity, pre-RT mandibular surgery, poor oral hygiene, and insufficient dentoalveolar surgery associated with ORN Marginal or periosteal bone resection associated with ORN Poor periodontal status, history of alcohol use and radiation dose associated with ORN

Abbreviations: ORN, osteoradionecrosis; 3D-CRT, 3-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; NR, not reported.

cuss specific teeth at risk of MORN and isodose distributions of the patient’s RT plan in the era of IMRT. Our study has several limitations. Due to the retrospective nature of the study, unmeasured confounding variables and potential

selection biases could not be accounted for in our analysis. The precise location of MORN was not always apparent in reviewing the medical records, and therefore, individual analysis of the dosimetry in relation to the location of the MORN was not conducted.

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Rather, an aggregate dosimetric comparison was done for those with MORN and a nested, matched cohort of non-MORN patients. The use of a matched cohort in this setting may have contributed additional confounders in comparing dosimetry, which may explain why no dosimetric correlates with MORN were identified. Last, the patients reviewed were all treated by a single radiation oncologist at a high volume academic institution, thus minimizing variability in the treatment approach and treatment volumes, but may also limit generalization of the results to other settings. Conclusions The incidence of MORN is low in the modern era using IMRT techniques at a high volume academic center. Oral cavity primary, mandibular bone invasion, pre-RT tooth extraction, continued smoking, and the use of 3D-CRT vs IMRT may increase the risk of MORN. The risk should be minimized with appropriate dental evaluation, education, and treatment, smoking cessation efforts, and the use of IMRT technique.

[8]

[9] [10]

[11]

[12]

[13]

[14]

[15] [16]

Conflict of interest [17]

None declared [18]

Acknowledgments [19]

All authors have no conflicts of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

[20]

[21]

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