Abstract
Objective:
To examine effects of Radiation therapy (RT) for Head and Neck Cancer (HNC) on periodontal disease and relationships to caries.
Methods:
Multicenter prospective observational cohort study conducted in patients undergoing RT for HNC. Assessments conducted by calibrated examiners at the pre-RT (baseline) visit (n=533), the 12-month visit (n=414), and the 24-month visit (n=365).
Results:
Average whole mouth mean(SE) distance from the cemento-enamel junction to the gingival margin (CEJ-GM) decreased significantly from 0.43(0.04) mm at baseline to 0.24(0.04) mm at 12 months, and 0.11(0.04) mm at 24 months (p-values ≤0.001). Whole mouth mean(SE) percentage of sites with CEJ-GM distance of less than 0 mm increased significantly from 23.3%(1.0%) at baseline, to 28.5%(1.0%) at 12 months, and 30.5%(1.1%) at 24 months (p-values ≤0.02).
Higher mean radiation dose to the mandible was associated with greater increase in percentage of mandibular sites with CEJ-GM distance of less than 0 mm (p=0.003).
Both mean CEJ-GM distance and percentage of sites with CEJ-GM distance less than 0 mm were strongly associated with whole mouth mean proportion of decayed, missing, and filled surfaces, as well as proportion of decayed or filled facial/buccal surfaces specifically, (p-values<0.001), with greater gingival recession associated with increased caries.
Conclusion:
RT for HNC leads to mandibular gingival recession, in a dose-dependent manner. This gingival recession may contribute to increased risk for cervical caries seen in these patients.
Keywords: Head and Neck Cancer, Radiation Therapy, Gingival Recession, Dental Caries, Periodontal Disease
Introduction
Most patients with head and neck cancer (HNC) are treated with high-dose (5000-7000 cGy) radiation therapy (RT), typically delivered in daily fractions (~200 cGy), 5 days per week, over a period of 5-7 weeks. This treatment results in several side-effects in the oral and maxillofacial tissues, including a marked increase in the risk for dental caries after RT. This has mainly been attributed to reduced salivary flow resulting from the effects of RT on the salivary glands, although some evidence also supports additional mechanisms including changes in the oral microflora and in the hard dental tissues [1].
In comparison to dental caries, relatively little is known about the impact of RT for HNC on periodontal disease. Three small studies have shown worsening of periodontal disease after older conventional modalities of RT [2-4]. A retrospective study found a lower rate of periodontitis one month after the end of intensity modulated radiation therapy (IMRT) compared to conventional RT, though the difference was not statistically significant [5].
The objective of this study was to prospectively determine the impact of contemporary H&N RT on periodontal disease in a large multicenter cohort and to assess the relationship of periodontal disease to dental caries in this population.
Methods
Study Design
OraRad is a prospective observational cohort study of oral complications after high-dose RT for HNC. Study participants were enrolled prior to the start of RT and assessed every 6 months for up to 2 years after RT. A total of 572 participants were enrolled across the following 6 clinical sites in the United States: Brigham and Women’s Hospital, University of Pennsylvania, Atrium Health Carolinas Medical Center, New York University, University of North Carolina (UNC), and University of Connecticut (with sub-sites at Hartford Hospital and Yale New Haven Hospital). Institutional Review Board (IRB) approval was obtained at each site. All participants provided written informed consent.
Inclusion/Exclusion Criteria
Inclusion criteria for OraRad included: age 18 or older; diagnosed with H&N squamous cell carcinoma (SCC) or a salivary gland cancer (SGC) and intending to receive external beam RT with curative intent, or diagnosed with a non-SCC, non-SGC H&N malignancy, and expected to receive at least 4500 cGy RT to the H&N region; and having at least 1 natural tooth remaining after pre-RT dental extractions. Exclusion criteria included: receiving palliative RT and/or a history of prior curative RT for H&N cancer. For a detailed listing of study inclusion/exclusion criteria, please see the study details at clinicaltrials.gov (NCT02057510) and our prior publication [6].
Study Procedures
Study visits were conducted at the following time-points: Baseline (pre-RT), 6, 12, 18 and 24 months after start of RT. Clinical assessments included tooth loss, caries, periodontal measures (described below), and other assessments. Subject-reported data was recorded on relevant parameters including demographics and use of tobacco and alcohol. Mean radiation dose to the mandible was collected from medical records. A detailed description of study procedures has been published [6].
Caries assessment (Decayed, Missing and Filled Surfaces - DMFS) was recorded at baseline, 6, 12, 18, and 24 month visits. The entire dentition was examined for active decay, restorations, and missing teeth because of extraction and/or spontaneous exfoliation. A No. 23 explorer or a No. 2A explorer was used to detect decay. Five tooth surfaces on the posterior teeth and four tooth surfaces on the anterior teeth were scored for DMFS.
Periodontal measures were collected on all teeth except for third molars at the baseline, 12, and 24 month visits. Individuals who did not complete their periodontal exam at the 12 month visit were allowed to make up the exam at the month 18 visit. Pocket depths and the distance from the cemento-enamel junction (CEJ) to the gingival margin (GM) was measured using a UNC 15 probe at six sites on each tooth. The clinical attachment loss (CAL) was calculated as the difference between measured pocket depth and CEJ-GM distance. The presence of bleeding upon probing was documented at the six periodontal probing sites on each tooth. The invasive periodontal measures were not performed on participants who required antibiotic prophylaxis prior to invasive dental procedures.
Training and Calibration
All study personnel received detailed training on the activities they conducted in the study. This includes training on carrying out clinical assessments as well as training on completing study forms, data entry, and all non-clinical procedures. In addition, annual in-person calibration on healthy volunteers was conducted for all clinical examiners for DMFS and periodontal measurements. Clinical examiners were required to meet minimum standards for intra- and inter-rater consistency annually for these measurements. For periodontal measures, examiners achieved at least 95% intra-examiner reproducibility within ± 2 mm for both CAL and pocket depth; at least 75% inter-examiner agreement for pocket depth within ± 1 mm; and at least 60% inter-examiner agreement for CAL within ± 1 mm. Examiners also received hands-on training on measuring furcation involvement and tooth mobility.
Data Management and Monitoring
Study data was entered into a secure database using web-based data-entry screens created for this study. The database is hosted at the Data Coordinating Center (DCC), located at the University of Minnesota. DCC staff monitored study data to identify missing data or forms and communicated with the clinical sites to resolve these issues. Formal monitoring of study records was conducted by an independent contract research organization. An independent Data and Safety Monitoring Board (DSMB) met annually during the clinical phase of the study.
Statistical Methods
Seven periodontal outcomes were evaluated: percent of sites with bleeding on probing, whole mouth average probing depths, percent of sites with probing depths ≥ 4 mm, whole mouth average CAL, percent of sites with CAL ≥ 2 mm, whole mouth average distance from CEJ to GM, and percent of sites with distance from CEJ to GM of less than 0 (indicating that the GM is apical to the CEJ). Linear mixed-effects models with patient specific random intercepts were used to evaluate change in periodontal measurements across study time points (baseline, visit 12, and visit 24; treated as a categorical variable).
Linear mixed effect models with interaction terms between study visit and mean radiation dose to the mandible (scaled by 1000 cGy) were used to evaluate the relationship between radiation dose and two measures of gingival recession: average distance from the CEJ to GM for mandibular sites and percent of mandibular sites with distance from the CEJ to GM of less than 0. Tooth decay was evaluated using two measures: the proportion of evaluable surfaces which were decayed, filled, or missing; and the proportion of non-missing facial/buccal surfaces which were decayed or filled. Linear mixed effect models with interaction terms between study visit and recession measures were used to test the association between recession measures and tooth decay measures over time.
As a sensitivity analysis, models with outcomes transformed based on the Box-Cox procedure were evaluated. The models with transformed outcomes gave similar findings as the model with untransformed outcomes, so only the results from models with untransformed outcomes are presented. All analyses were conducted using R version 3.6.0. P-values have not been adjusted for multiple comparisons.
Results
Of the 572 participants enrolled in the OraRad study, periodontal measurements were able to be collected for 533 participants at the pre-RT (baseline) visit, 414 participants at the 12 month visit (24 of these participants actually completed their mid-study periodontal measurements at the 18 month visit), and 365 participants at the 24 month visit. Data on a total of 538 participants was used for the periodontal analyses, including five participants for whom we had periodontal data at the 12 month and 24 month visits but not at the baseline visit. Of these 538 participants, 77.7% were male, 82.7% were white, and mean age was 57.9 years at the baseline visit (Table 1). Squamous cell carcinoma accounted for 82% of cases, with oropharynx and oral cavity being the most common primary sites of RT (Table 2). Figure 1 provides a flow diagram which includes the numbers of participants recruited, screened, and seen at each study visit, along with reasons for periodontal data not being collected.
Table 1:
Demographics of the Study Cohort
| Characteristic | Number of Subjects (%) |
|---|---|
| Total Number | 538 |
| Sex | |
| Male | 418 (77.7%) |
| Female | 120 (22.3%) |
| Age (at baseline visit, in years) | 57.9 ± 10.9 |
| Highest grade of education | |
| ≤ High school | 149 (27.7%) |
| > High school | 388 (72.1%) |
| Marital status | |
| Married | 378 (70.3%) |
| Not Married | 159 (29.6%) |
| Race | |
| White Only | 445 (82.7%) |
| Black Only | 40 (7.4%) |
| Other | 51 (9.5%) |
| Ethnicity | |
| Not Hispanic | 512 (95.2%) |
| Hispanic | 26 (4.8%) |
Table 2:
Clinical Characteristics of the Study Cohort
| Characteristic | Number of Subjects (%) |
|---|---|
| Total Number | 538 |
| Tobacco use | |
| Ever Used | 300 (55.8%) |
| Never used | 237 (44.1%) |
| Alcohol use in past 12 months | |
| Yes | 362 (67.3%) |
| No | 174 (32.3%) |
| Don't know | 2 (0.4%) |
| Type of cancer | |
| Squamous Cell Carcinoma | 441 (82.0%) |
| Salivary Gland Cancer | 63 (11.7%) |
| Other | 34 (6.3%) |
| Primary site of Radiation Therapy | |
| Oropharynx | 246 (45.7%) |
| Oral Cavity | 76 (14.1%) |
| Salivary Gland | 52 (9.7%) |
| Larynx/Hypopharynx | 37 (6.9%) |
| Other | 127 (23.6%) |
| Cancer classification | |
| Tumor (T): | |
| T1 or T2 | 324 (60.2%) |
| T3 or T4 | 169 (31.4%) |
| Metastases (M): | |
| M0 | 505 (93.9%) |
| M1 | 9 (1.7%) |
| MX | 24 (4.5%) |
| Nodes (N): | |
| N00 | 130 (24.2%) |
| N01/02/2a/2b/2c/03 | 402 (74.7%) |
Figure 1:
Flow Diagram of Study Participants
Bleeding on Probing
The estimated average whole mouth mean percentage of sites with bleeding on probing was 12.4% (SE 0.7%) at baseline, 12.3% (SE 0.7%) at 12 months, and 12.2% (SE 0.7%) at 24 months (Table 3). There was no significant difference between time-points (p-value=0.94).
Table 3:
Periodontal Measures at each Time-point and Comparison between Time-points.
| % of Sites with Bleeding on Probing |
Whole Mouth Average Pocket Depth in mm |
% of Sites with Pocket Depth ≥4 mm |
Whole Mouth Average CAL in mm |
% of Sites with CAL ≥2 mm |
Whole Mouth Average Distance from CEJ to GM in mm |
% of Sites with CEJ to GM distance of less than 0 mm |
|
|---|---|---|---|---|---|---|---|
| Mean (Standard Error) | |||||||
| Baseline visit (BL) | 12.4% (0.7%) | 2.35 (0.02) | 11.1% (0.5%) | 1.92 (0.04) | 53.1% (1.2%) | 0.43 (0.04) | 23.3% (1.0%) |
| 12 month visit (V12) | 12.3% (0.7%) | 2.24 (0.02) | 8.9% (0.6%) | 2.00 (0.04) | 54.3% (1.2%) | 0.24 (0.04) | 28.5% (1.0%) |
| 24 month visit (V24) | 12.2% (0.7%) | 2.23 (0.02) | 8.8% (0.6%) | 2.11 (0.05) | 57.5% (1.2%) | 0.11 (0.04) | 30.5% (1.1%) |
| P-values | |||||||
| Overall | 0.942 | ≤0.001 | ≤0.001 | ≤0.001 | ≤0.001 | ≤0.001 | ≤0.001 |
| BL vs. V12 | 0.816 | ≤0.001 | ≤0.001 | 0.004 | 0.173 | ≤0.001 | ≤0.001 |
| BL vs. V24 | 0.739 | ≤0.001 | ≤0.001 | ≤0.001 | ≤0.001 | ≤0.001 | ≤0.001 |
| V12 vs. V24 | 0.915 | 0.476 | 0.889 | ≤0.001 | ≤0.001 | ≤0.001 | 0.014 |
CAL= Clinical Attachment Loss
CEJ = Cemento-Enamel Junction
GM = Gingival Margin
Periodontal Pocket Depth
Estimated average whole mouth mean periodontal pocket depth was 2.35 mm (SE 0.02) at baseline; 2.24 mm (SE 0.02) at 12 months, and 2.23 mm (SE 0.02) at 24 months. The baseline mean pocket depth differed significantly from the 12 month (p-value ≤0.001) and 24 month (p-value ≤0.001) means, which did not differ significantly from each other (p-value=0.48).
The mean percentage of all sites with pocket depth ≥4 mm decreased from 11.1% at baseline (SE 0.5%), to 8.9% (SE 0.6%) at 12 months and 8.8% (SE 0.6%) at 24 months. The baseline mean percentage differed significantly from the 12 month (p-value ≤0.001) and 24 month (p-value≤0.001) means, which did not differ significantly from each other (p value=0.89).
Clinical Attachment Loss
Estimated average whole mouth mean CAL was 1.92 mm (SE 0.04) at baseline, 2.00 mm (SE 0.04) at 12 months, and 2.11 mm (SE 0.05) at 24 months. The mean CAL at each time-point differed significantly from the other time-points with all p-values ≤0.005.
The mean percentage of sites with CAL ≥2 mm increased from 53.1% (SE 1.2%) at baseline, to 54.3% (SE 1.2%) at 12 months, and 57.5% (SE 1.3%) at 24 months. The mean percentage at 24 months differed significantly from baseline and 12 months (p-values ≤0.001), while the baseline and 12 month percentages did not differ significantly from each other (p-value=0.17).
Gingival Recession
Average whole mouth mean distance from the cementoenamel junction to the gingival margin (CEJ-GM) reduced from 0.43 mm (SE 0.04) at baseline, to 0.24 mm (SE 0.04) at 12 months, and 0.11 mm (SE 0.04) at 24 months. The CEJ-GM mean distance differed significantly between all time-points, with all p-values ≤0.001.
The whole mouth mean percentage of sites with CEJ-GM distance of less than 0 mm (i.e. sites with the GM apical to the CEJ) increased from 23.3% (SE 1.0%) at baseline, to 28.5% (SE 1.0%) at 12 months, and 30.5% (SE 1.1%) at 24 months. The mean percentage of sites with CEJ-GM distance of less than 0 mm differed significantly between all time-points, with all p-values ≤0.02.
Relationship between Gingival Recession and Radiation Dose
A higher mean radiation dose to the mandible was associated with a greater increase in percentage of mandibular sites with CEJ-GM distance of less than 0 mm (p=0.003). For every additional 1,000 cGy of radiation, the percentage of mandibular sites with recession increased by an additional 2.0% (SE 0.7%) from baseline to visit 12 (p-value=0.006) and an additional 2.3% (SE 0.8%) from baseline to visit 24. No association was found between mean radiation dose to the mandible and change in average mandibular CEJ-GM distance (p-value=0.25).
Relationship between Gingival Recession and Dental Caries
The proportion of whole mouth decayed, missing or filled (DMF) surfaces was associated with both the mean CEJ-GM distance and with mean percentage of sites with CEJ-GM distance of less than 0 mm (p-values<0.001; Table 4). Greater gingival recession was associated with a higher overall proportion of DMF surfaces at all time-points examined. This relationship became more pronounced over time (p-values<0.001). At baseline, a 1 mm smaller CEJ-GM distance was associated with 0.88% (SE 0.41%) more DMF surfaces (p-value=0.032). At the 24 month visit, a similar 1 mm smaller CEJ-GM distance was associated with 2.83% (SE 0.44%) more DMF surfaces (p-value<0.001).
Table 4:
Relationship between Gingival Recession and Dental Caries at each Time-point.
| Measure | Visit | % change in all Decayed, Missing, or Filled Surfaces |
% change in Facial/Buccal Decayed or Filled Surfaces |
||
|---|---|---|---|---|---|
| Estimate (Standard Error) |
p-value | Estimate (Standard Error) |
p-value | ||
| 1 mm decrease in CEJ-GM distance | Change in relationship over time | ≤0.0001* | ≤0.0001 | ||
| Baseline Visit | 0.88% (0.41%) | 0.0321 | 1.25% (0.63%) | 0.0476 | |
| 12 month visit | 1.39% (0.43%) | 0.0013 | 2.47% (0.68%) | 0.0003 | |
| 24 month visit | 2.83% (0.44%) | ≤0.0001 | 4.36% (0.69%) | ≤0.0001 | |
| Increase of 10% of sites with CEJ-GM distance <0 | Change in relationship over time | ≤0.0001* | ≤0.0001 | ||
| Baseline visit | 0.48% (0.16%) | 0.0022 | 0.63% (0.25%) | 0.0111 | |
| 12 month visit | 0.70% (0.16%) | ≤0.0001 | 1.19% (0.26%) | ≤0.0001 | |
| 24 month visit | 1.25% (0.16%) | ≤0.0001 | 1.91% (0.26%) | ≤0.0001 | |
Estimate = The values presented represent the relationship between a 1 unit change in recession measure and change in proportion of all decayed, filled, or missing surfaces and the proportion of facial/buccal surfaces which were decayed or filled.
Represents the omnibus p-value for the interaction between visit and the measure of gingival recession.
Furthermore, the whole mouth proportion of decayed or filled facial/buccal surfaces was also associated with both the mean CEJ-GM distance and the mean percentage of sites with CEJ-GM distance of less than 0 mm (p-values<0.001; Table 4). Greater gingival recession was associated with a higher proportion of decayed or filled facial/ buccal surfaces. This relationship also became more pronounced over time. At baseline, a 1 mm smaller CEJ-GM distance was associated with 1.25% (SE 0.63) more decayed or filled facial/buccal surfaces (p-value= 0.048). At the 24 month visit, a similar 1 mm smaller CEJ-GM distance was associated with 4.36% (SE 0.69%) more decayed or filled facial/buccal surfaces (p value <0.001).
Discussion
This large prospective multicenter study provided a valuable opportunity to document changes in periodontal status after modern era high-dose RT for HNC. At first glance, changes in pocket depth and CAL appear relatively modest and somewhat contradictory. Mean whole mouth pocket depths slightly decreased (by less than 5%) from baseline (pre-RT) to 12 months after RT. Mean whole mouth CAL slightly increased, by about 4% from baseline to 12 months, and then by another 6% from 12 months to 24 months after RT. However, these findings are much more interesting when considered in the context of the striking increases in gingival recession. The mean whole mouth CEJ-GM distance decreased by 44% from baseline to 12 months and then by an additional 54% from 12 months to 24 months after RT. Over the entire 2-year study period, the mean CEJ-GM distance decreased by an impressive 74%, from 0.43 mm at baseline to 0.11 mm at 24 months. These findings demonstrate a highly significant increase in gingival recession after RT (p-values ≤0.001). The large apical movement of the gingival margin also helps to explain the small reductions in pocket depth, in the context of the modest increase in CAL.
In order to determine the role of RT in gingival recession, we examined the relationship between RT dose and gingival recession in the mandible. We found a strong relationship between higher mean RT dose to the mandible and increased percentage of mandibular sites with gingival recession (p=0.003). We did not collect data on mean radiation dose to the maxilla as this was not consistently available in the medical records. The biological plausibility of RT leading to gingival recession is strongly supported by the scientific literature. In multiple model systems and human studies, RT has been shown to increase local levels of matrix metalloproteinase (MMP) enzymes in soft tissues, including the collagenase enzymes [7,8]. In HNC patients, local levels of IL-6 and MMP-8 in mouthrinse samples were significantly increased after RT [9]. Both IL-6 and MMP-8 have been implicated in the progression of periodontal disease. IL-6 is a pro-inflammatory cytokine, which also upregulates cell signaling leading to tissue damage and loss [10-12]. MMP-8, also known as collagenase-2, is significantly upregulated in periodontal disease and is a major contributor to the tissue breakdown which leads to gingival recession [13-15].
Patients who have received high-dose RT for HNC often develop an aggressive pattern of tooth decay, sometimes referred to as radiation-related caries. It is characterized by not only a greater incidence and faster progression of caries but also by the development of carious lesions in typically less caries-susceptible locations such as cusp tips and cervical areas of teeth. Radiation-related caries is also a major contributor to the development of osteoradionecrosis due to the need for extractions [16]. A number of factors may contribute to radiation-related caries including hyposalivation, changes in salivary pH and composition, changes in the oral microflora, changes in diet and oral hygiene, as well as potential direct effects of RT on dental tissues [1,17]. Since radiation-related caries often present on the cervical area of the facial/buccal surface of teeth, we examined the relationship of gingival recession to facial/buccal caries in our study sample. Interestingly, we found a highly significant relationship between greater gingival recession and increases in decayed or filled facial/buccal surfaces (p-value<0.001). Furthermore, this relationship was more pronounced at 24 months, supporting a role for gingival recession in contributing to the progression of cervical caries over time. These results indicate that the large increases in gingival recession seen after RT likely contribute to the development of cervical caries by exposing the cervical areas of teeth to the oral environment.
The previous literature on periodontal changes after RT is relatively sparse and involves patients receiving older modalities of RT. Epstein et al examined 10 patients at a mean follow-up time of 6 years after RT for HNC. They reported statistically significant greater degree of gingival recession for teeth in the radiated area as compared to teeth in non-radiated regions [2]. Mean total attachment loss was also significantly higher for teeth in radiated areas. Marques et al examined 27 patients at baseline and 6-8 months after RT for HNC [3]. They found a decrease in pocket depths, increase in CAL, and increase in gingival recession; however these findings were not statistically significant. Ammajan et al examined 29 patients at baseline and 6 months after RT for HNC. They found statistically significant increases in CAL and gingival recession after RT, but no significant changes in pocket depth [4]. Thus, the previous literature supports our findings of increases in gingival recession and CAL, as well as a small reduction in pocket depths after RT for HNC.
This study is the first large multicenter study to provide data on periodontal changes after modern modalities of RT for HNC. The study has several strengths including the prospective data collection, large sample size, annual calibration and training of clinical examiners, state of the art systems and processes for data entry and management using a dedicated DCC, and robust study monitoring by multiple entities including the DCC, an external monitoring company, as well as an independent DSMB. A potential limitation is that this was an observational cohort study without a control group and therefore not as strong as a randomized controlled trial in determining causation. Nevertheless, several independent factors support the conclusion that the large increase in gingival recession seen was a result of the RT for HNC. First, as described above, prior studies have reported similar increases in gingival recession following RT for HNC, although in much smaller samples. Second, there is a clear and well-accepted biological mechanism whereby RT can lead to the tissue damage and loss that causes gingival recession. Third, we demonstrated a dose-response relationship wherein higher dose of RT was related to increased proportion of sites with gingival recession. Fourth, the dramatic increase in gingival recession we found after RT far exceeds the rate of gingival recession that is typically found in the general population [18]. Finally, such longitudinal cohort studies with assessment time points before and after therapeutic interventions are a well-accepted design to measure risk factors associated with positive and negative outcomes of various treatments.
In conclusion, high dose RT for HNC leads to significant increases in mandibular gingival recession. This gingival recession may contribute to the risk for radiation-related caries in cervical areas of teeth.
Statement of Clinical Relevance.
This large prospective study provides data on periodontal changes after radiation therapy for head and neck cancer, and relationships to dental caries. These findings are directly applicable in the dental management of these patients, before and after radiation therapy.
Acknowledgements
The authors gratefully acknowledge the contributions of the study participants, the Data and Safety Monitoring Board, NIDCR staff, and of the study staff at each clinical site and at the Data Coordinating Center at the University of Minnesota.
Funding
This study was funded by the National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), USA (grant number U01DE022939).
Footnotes
Conflict of Interest Statement
No conflicts declared.
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