Original Research—Head and Neck Surgery
Comparison of Dental Health of Patients with Head and Neck Cancer Receiving IMRT vs Conventional Radiation
Otolaryngology– Head and Neck Surgery 2014, Vol 150(1) 81–86 Ó American Academy of Otolaryngology—Head and Neck Surgery Foundation 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599813509586 http://otojournal.org
Victor M. Duarte, MD1,2, Yuan F. Liu, MD1, Sassan Rafizadeh, PhD1, Tracey Tajima, DDS2,3, Vishad Nabili, MD1,2, and Marilene B. Wang, MD1,2
No sponsorships or competing interests have been disclosed for this article.
Abstract Objective. To analyze the dental health of patients with head and neck cancer who received comprehensive dental care after intensity-modulated radiation therapy (IMRT) compared with radiation therapy (RT). Study Design. Historical cohort study. Setting. Veteran Affairs (VA) hospital. Subjects and Methods. In total, 158 patients at a single VA hospital who were treated with RT or IMRT between 2003 and 2011 were identified. A complete dental evaluation was performed prior to radiation treatment, including periodontal probing, tooth profile, cavity check, and mobility. The dental treatment plan was formulated to eliminate current and potential dental disease. The rates of dental extractions, infections, caries, mucositis, xerostomia, and osteoradionecrosis (ORN) were analyzed, and a comparison was made between patients treated with IMRT and those treated with RT. Results. Of the 158 patients, 99 were treated with RT and 59 were treated with IMRT. Compared with those treated with IMRT, significantly more patients treated with RT exhibited xerostomia (46.5% vs 16.9%; P \ .001; odds ratio [OR], 0.24; 95% confidence interval [CI], 0.11-0.52), mucositis (46.5% vs 16.9%; P \.001; OR, 0.24; 95% CI, 0.11-0.52), and ORN (10.1% vs 0%; P = .014; OR, 0.07; 95% CI, 0.00-1.21). However, significantly more patients treated with IMRT were edentulous by the conclusion of radiation treatment (32.2% vs 11.1%; P = .002; OR, 3.8; 95% CI, 1.65-8.73). Conclusion. Patients who were treated with IMRT had fewer instances of dental disease, more salivary flow, and fewer requisite posttreatment extractions compared with those treated with RT. The number of posttreatment extractions has been reduced with the advent of IMRT and more so with a complete dental evaluation prior to treatment. Keywords dental health, radiation and dental health, IMRT and dental
Received June 7, 2013; revised August 22, 2013; accepted September 30, 2013.
E
very year, approximately 500,000 new cases of head and neck cancer are diagnosed worldwide.1 Preservation of tissue health and function is an important objective in effective cancer therapy.2 Conventional radiation therapy (RT), one the main modalities of treatment in many head and neck cancers, is associated with multiple side effects that greatly affect quality of life. The salivary glands, oral cavity, and mandible are frequently included in the radiation field.1 Consequently, 100% of patients who receive RT with fields involving the oral cavity will experience complications.3 These include, but are not limited to, xerostomia, oral infection, dental caries, mucositis, periodontal disease, osteoradionecrosis (ORN), trismus, and dysphagia. Since the consequences of radiation damage and subsequent sequelae in the treatment of head and neck cancer are difficult to manage, steps must be taken to reduce complications as much as possible. Therefore, prevention can be initiated with proper preradiation treatment planning and dental examinations.2,4 There must also be proper management of xerostomia, meticulous maintenance of oral hygiene, diet modifications, control of cariogenic flora, and prevention of dental caries with fluoride applications, as the anticariogenic effects of fluoride therapy are well documented.2,5 Perhaps the best way to reduce radiation damage is to limit the amount of tissue exposed to radiation. Intensity1
Department of Head and Neck Surgery, David E. Geffen School of Medicine at UCLA, Los Angeles, California, USA 2 Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA 3 Department of Oral Medicine, School of Dentistry at UCLA, Los Angeles, California, USA This article was presented as a poster at the 2012 AAO-HNSF Annual Meeting & OTO EXPO; September 9-12, 2012; Washington, DC. Corresponding Author: Victor M. Duarte, MD, Department of Head and Neck Surgery, David E. Geffen School of Medicine at UCLA, 62-132 Center for Health Sciences, Los Angeles, CA, 90095-1624 USA. Email: [email protected]
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modulated radiation therapy (IMRT) reduces the irradiated volume by shaping the spatial distribution of radiation to target mainly the tumor. It can assign different weights to individual rays of a beam versus one weight for the beam as a whole, making it even more optimized to prevent normal tissue damage than 3-dimensional conformal radiation techniques.2 Compared with conventional radiation, IMRT has been shown to result in significantly less pain, dry mouth, and ropey saliva.6,7 One study found the parotid flow rate to be 41% at 6 weeks and 64% at 6 months after IMRT, compared with 11% and 18%, respectively, after RT.8 Another study of 176 patients found no instances of ORN when a strict prophylactic dental care policy, along with IMRT, was implemented.9 Furthermore, IMRT was found to be better for maintaining a stable oral ecosystem than conventional radiation.10 In addition, the use of oral stents, such as tongue depressors, has been used during IMRT to minimize side effects.9 Despite these favorable findings for IMRT, however, the induction of oral radiation sequelae by IMRT remains poorly established.6 In this study, we retrospectively evaluated the oral health of patients with head and neck cancer treated with conventional RT vs those treated with IMRT to examine the progression of disease and to optimize pre- and post-RT dental and oral cavity disease treatment practices. We believe that the results should serve as a guideline for a prospective study on a dental health protocol before and during radiation.
Methods Study Design and Patient Selection A retrospective study was performed by reviewing the charts of head and neck tumor board patients with malignancy of the head and neck treated with either RT alone or combined chemoradiation (CRT) between 2003 and 2011. The study was performed at the West Los Angeles Veteran Affairs Hospital and was approved by the hospital’s institutional review board. All the patients in the study received radiation or chemoradiation as their primary form of treatment. Every patient who was referred for radiation therapy at our institution was evaluated by a dental team member prior to treatment. Patients who had any evidence of dental disease prior to treatment (eg, caries, infection, periodontitis) were excluded from the study to make a treatment comparison between IMRT and RT groups at the conclusion of the treatment. Any patient who had previous tooth extraction aside from their requisite pretreatment extraction was excluded from the study. The patient’s dental treatment plan was developed upon referral by head and neck surgeons and radiotherapists before radiotherapy. Any patient who was not compliant with dental follow-up or demonstrated missed appointment visits was also excluded from the study. The demographic data and other relevant information, including primary tumor site, stage of tumor, type of treatment (CRT or RT), radiation dose administered to the primary site, and chemotherapy, were also recorded (Table 1).
Patient Education Oral hygiene, including brushing and flossing, was reviewed with each patient. Daily use of high concentrated fluoride gel (1.1% neutral sodium fluoride) either in a fluoride carrier or by brush-on technique was also recommended and a prescription was given to the patient. Patient education was provided, including oral care during and after radiation therapy.
Before RT Prior to RT, a complete dental evaluation was performed, including periodontal probing, tooth profile, cavity check, and mobility. During this consult, complete medical, dental, social, and family histories were obtained. The dental treatment plan was formulated to eliminate current and potential dental disease, as well as to prepare for possible future dental rehabilitation. The examination included a tooth-bytooth evaluation, with particular attention to teeth in areas of the jaw expected to receive a high dose (.50 cGy). The periodontal condition was evaluated, and teeth with mobility, significant periodontal disease, furcation involvement, or attachment loss would be recommended for extraction. All patients received panoramic radiographs and intraoral periapical radiographs when indicated to evaluate for periapical abscesses, caries, periodontal condition, and other dental pathology. Teeth with nonrestorable caries or caries that extended to the gum line; teeth with large, compromised restorations with significant periodontal attachment loss (pocketing .5 mm); and those with severe erosion or abrasion were extracted if they were in areas of the mandible or maxilla expected to receive a high dose. Decisions about extraction were significantly affected by the patient’s dental competence and dental motivation in performing meticulous oral hygiene and by the past history of dental service usage. A more aggressive approach was made in patients with trismus due to the negative impact on the prognosis for the teeth. Also taken into consideration was the patient’s overall survival prognosis and quality-of-life concerns. Extractions were performed as soon as possible after examination to maximize postextraction healing time prior to the start of radiation. Postextraction healing time was 14 days prior to the start of RT. In addition, the residual alveolar ridges were prepared by performing any needed preprosthetic surgery such as alveoloplasty and torus removal. It is important to note that a noncarious tooth may have other present or past dental disease or conditions that may warrant extraction prior to radiation therapy. For example, the tooth may have significant periodontal disease or (toothbrush) abrasion that results in significant root exposure. Root surfaces lack enamel and are much more susceptible to caries especially when the patient has or will develop xerostomia. Teeth with furcation involvement are very difficult to self-clean and require meticulous self-cleaning and diligent professional cleaning. If the patient has a history of dental noncompliance, those teeth are considered for
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Table 1. Patient characteristics. IMRT (n = 59) Characteristic Sex Male Female Age, y Site
Stage
NP OC OP HP LA UP 1 2 3 4 Unknown
Dose, cGy Chemotherapy No chemotherapy
No. or Mean (SD)
59 0 63.1 (10.2) 6 10 24 3 8 8 4 4 7 30 14 6688.8 (630.8) 20 39
RT (n = 99) Range
27-91
4800-8000
No. or Mean (SD)
98 1 62.6 (10.0) 15 18 35 6 13 12 4 4 11 28 52 6404.2 (930.4) 37 62
All (N = 159) Range
24-82
3500-7700
No. or Mean (SD)
157 1 62.9 (10.1) 21 28 59 9 21 20 8 8 18 58 66 6540.5 (810.4) 57 101
Range
P Valuea
.999 24-91
.810 .959
.825
3500-8000
NA .052 .733
Abbreviations: HP, hypopharynx; IMRT, intensity-modulated radiation therapy; LA, larynx; NA, not applicable; NP, nasopharynx; OC, oral cavity; OP, oral pharynx; RT, radiation therapy; UP, unknown primary. a The P value refers to difference between IMRT and XRT groups for each characteristic.
extraction. A patient may demonstrate the inability to properly clean the tooth prior to radiation, especially if the tooth already has a history of significant dental restoration and a history of dental caries. The ability to clean teeth is strongly considered, especially with trismus and microstomia. Another example is if a tooth is supra-erupted or malpositioned as that will make future dental prostheses very difficult.
After RT At the conclusion of IMRT/RT, the incidence of Candida infection, caries, mucositis, xerostomia, periodontitis, edentulous, extractions, and ORN and the use of fluoride trays, if any, were recorded for each patient at the first dental clinic evaluation 1 month after radiation treatment. A comparison was made between patients with head and neck cancer treated with IMRT and those treated with conventional RT.
Follow-up All patients were followed every 3 to 4 months afterward in both the Radiation Oncology and Head and Neck Surgery clinics for surveillance during the first year after treatment.
Statistical Analysis Descriptive statistics were used to characterize the sample. For comparing continuous variables, 2-tailed, unequal variance, Student t tests were used. For comparing categorical and ordinal variables, Fisher exact tests were used; for
tables larger than 2 by 2, extended versions of the Fisher exact test were used. Confidence intervals for odds ratios were calculated based on z statistics, which are less exact than Fisher exact tests and may indicate a nonsignificant confidence interval when the Fisher exact test P value is significant, or vice versa. Missing values were excluded when statistical tests were performed. All statistical analyses were performed using Excel 2010 (Microsoft, Redmond, Washington), except for Fisher exact tests, which were performed using a calculator found at http://aoki2.si.gunma-u .ac.jp/exact/exact.html. For analysis, a P value of less than .05 was considered statistically significant in our study.
Results Data from these patients were gathered on a review of medical records from the RT team regarding their status during and/or immediately after RT. Of the 158 eligible patients (157 men and 1 woman), 99 were treated with conventional RT and 59 with IMRT. The patient and disease characteristics are summarized in Table 1. The mean age of the participating patients was 62.9 years (range, 24-91 years). The IMRT and RT groups had comparable distributions of sex, age, primary tumor site, stage grouping, radiation dose to the primary site, and use of chemotherapy. The chemotherapy regimens mostly included platinum drug administration (cisplatin or carboplatin) as a single agent or in combination with 5-fluorouracil or erbitux. Chemotherapy was concomitant with RT and/or neoadjuvant. Radiation dose to primary site ranged from 3500 to
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Table 2. Posttreatment findings. Characteristic Candida infection Caries Xerostomia Mucositis Fluoride trays Poor hygiene Fractures/ORN Periodontitis Edentulous Extractions No issues
IMRT (n = 59), No. (%) 4 (6.8) 12 (20.3) 10 (16.9) 10 (16.9) 8 (13.6) 1 (1.7) 0 11 (18.6) 19 (32.2) 12 (20.3) 21 (35.6)
RT (n = 99), No. (%) 12 15 46 46 14 8 10 27 11 28 21
(12.1) (15.2) (46.5) (46.5) (14.1) (8.1) (10.1) (27.3) (11.1) (28.3) (21.2)
All (N = 159), No. (%) 16 27 56 56 22 9 10 38 30 40 42
(10.1) (17) (35.2) (35.2) (13.8) (5.7) (6.3) (23.9) (18.9) (25.2) (26.4)
P Valuea
OR (95% CI)
.415 .514 \.001b \.001b .999 .155 .014b .252 .002b .345 .062
0.53 (0.16-1.72) 1.43 (0.62-3.31) 0.24 (0.11-0.52) 0.24 (0.11-0.52) 0.95 (0.37-2.43) 0.20 (0.02-1.61) 0.07 (0.00-1.21) 0.61 (0.28-1.35) 3.8 (1.65-8.73) 0.65 (0.30-1.40) 2.05 (1.00-4.21)
Abbreviations: CI, confidence interval; IMRT, intensity-modulated radiation therapy; ORN, osteoradionecrosis; OR, odds ratio; RT, radiation therapy. Note that the 95% CI of the odds ratio is calculated based on a z statistic, which is less exact than the Fisher exact test used to calculate P values. a The P value refers to difference between IMRT and RT groups for each finding. b Statistically significant.
8000 cGy. The mean total dose of patients treated with RT was 6404.2 cGy (range, 4800-8000 cGy), and the mean total dose of patients treated with IMRT was 6688.8 cGy (range, 3500-7700 cGy). After treatment with either IMRT or RT, the following were recorded for each group: no issues, ORN, extractions, edentulous, periodontitis, poor hygiene, fluoride trays, xerostomia, mucositis, caries, and Candida infection. The number of patients who were edentulous (P = .002), had ORN (P = .014), had xerostomia (P \ .001), or had mucositis (P \ .001) were significantly different between the 2 groups, with a higher proportion of edentulous patients in the IMRT groups and a higher rate of ORN, xerostomia, and mucositis present in the RT group. The number of patients having no dental issues during and after treatment in the IMRT group compared with the RT group trended toward significance (P = .062). A comparison of these measures is presented in Table 2 and shown in Figure 1. To assess any difference among the sites, patients were divided into 2 groups based on tumor location: hypopharyngeal (HP) and laryngeal (LA), and all other sites. This was done as laryngeal or hypopharynx cancers would be expected to have less dental problems, in theory. For all patients (both IMRT and RT patients grouped together), there was no significant difference between the HP/LA sites and the other sites (OC, OP, etc) in terms of any dental disease after radiation. Comparing the IMRT with the RT patients looking at the HP and LA sites, there was no significant difference in dental disease after radiation.
Discussion Radiotherapy continues to be an important mode of treatment for patients with localized head and neck cancer.11 The purported advantage of primary RT or CRT for head and neck cancer is organ preservation. However, RT is associated with multiple adverse reactions, particularly related
to oral and dental health. Previous studies have shown that between 68% and 97% of the patients examined just after the start of RT need immediate dental care.1 During the first week of RT, there is a rapid decrease in salivary flow rate, which is then followed by a gradual drop to below 10% of the initial flow rate. Xerostomia is the most common oral sequelae from RT.1 Because of both early and late responses of salivary glands to RT, damage to salivary tissue and xerostomia are likely the most common side effects of head and neck cancer radiation.2 Radiation therapy also transforms saliva composition to a more viscous white, yellow, or brown fluid with a relative immunoprotein deficiency. This supports an environment vulnerable to infections, the most common of which is candidiasis during and shortly after RT.2 One study showed an increased prevalence of positive oral Candida cultures from 43% before RT to 62% at completion to 75% during follow-up.12 In our study, more patients in the RT group (RT: 12.1% vs IMRT: 6.8%) had Candida infection during radiation, although this was not statistically significant. Xerostomia can indirectly result in other dental and oral diseases as well through disruption of normal oral cavity homeostasis, leading to increased dental caries and changes in taste, speech, eating habits, and quality of life.3 In our study, the rate of xerostomia was significantly less in the IMRT group, 16.9% vs 46.5% in the RT group. In contrast to xerostomia, mucositis is a transient adverse side effect. Although mucositis is short-lived, it is an inevitable side effect and significant contributor to the morbidity of RT.2 About 80% of patients will develop pseudomembranous mucositis during the course of curative RT. As a result, 20% to 30% of these patients will require artificial feeding. Severe mucositis may even lead to a premature cessation of therapy, thus interrupting a full treatment course and a full radiation dose. Our study demonstrated that the rate of mucositis in the patients receiving IMRT treatment was significantly less than in the RT group. Moreover,
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Figure 1. Comparison of dental conditions after intensity-modulated radiation therapy (IMRT) vs radiation therapy (RT). ORN, osteoradionecrosis. *Statistically significant differences.
every patient in our study with clinical xerostomia developed evidence of mucositis. It is thought that the adverse effects of RT on dentition are mainly due to a reduction in salivary flow rate. As a result, dental caries, with fast onset and progression, can be the result. Patients with dental disease may also be less likely to take care of their teeth. Within 1 year, dentition that was previously healthy can be lost completely in severe cases.2 In a review of 19 studies, the overall prevalence of dental caries after RT was 24%.5 In our study, the rate of radiation caries was slightly less in patients treated with RT compared with the IMRT-treated patients; however, this was not statistically significant (RT: 15.2% vs IMRT: 20.3%). Certainly, the site of primary radiation can account for oral changes at the microscopic level, and in the future, it would be interesting to see whether fractionation and boosts to the tumor site, regardless of RT or IMRT, would decrease the rate of caries development and oral sequelae. The number of dental extractions at any time after the beginning of treatment has been reduced with the advent of IMRT and significantly more so with a complete dental evaluation prior to treatment. In our study, a lower percentage of IMRT patients (20.3%-28.3%) required posttreatment extractions, although this did not display statistical significance. In our population, a higher percentage of the IMRT patients were edentulous compared with the RT group. However, we believe this to be a result of the requisite pretreatment extractions, not coincidentally leading to fewer dental issues after the start of radiation in the IMRT group (see Figure 1—categorized as ‘‘no issues’’); this category trended toward significance. Certainly less dental complications are seen with edentulous patients, but we also need to consider quality of life after radiation treatment. This is a decision that is made during the pretreatment dental evaluation.
While it may seem likely that patients with laryngeal and hypopharyngeal primary sites may have fewer problems with posttreatment dental disease compared with those with oral/oropharyngeal sites, due to the difference in the treatment beds, we did not find any significant difference between these 2 patient groups when looking at the entire cohort. In addition, there was no significant difference in dental disease following radiation between the HP and LA patients treated with IMRT vs RT. One of the most dreaded complication of RT is ORN, the incidence of which can vary from 2.6% to 22% (commonly reported to be 5%-15%) for the mandible, with a lower rate for the maxilla.2,5 Osteoradionecrosis is caused by radiation injury to vasculature of the bone, leading to endarteritis, thrombosis, and eventually obliteration of small vessels. As a result, the bone will respond poorly to trauma and becomes prone to fracture and infection.2 In our study, there was a statistically significant lower rate of ORN for the IMRT subset, with none of the IMRT patients developing ORN, compared with 10.1% in the RT group, reminiscent of results obtained in the study from Ben-David et al.9 It must be noted that a true comparison of pre- and postradiation dental status could not be made since patients with dental disease prior to the start of radiation were automatically excluded. One limitation of our study is that it is a retrospective nonrandomized study, which inevitably carries the consequence of differences in patient groups. The best assessment of comparing dental health after RT and IMRT would be a randomized prospective study, a difficult study to perform because IMRT is often adapted as standard therapy due to theoretical advantages. Another difficulty with providing comprehensive dental care is patient compliance. Reasons for noncompliance in patients may include social, medical, financial, and insurance issues. A patient with cancer may be overwhelmed with the number of
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Otolaryngology–Head and Neck Surgery 150(1)
appointments necessary during a difficult treatment period. Overcoming these obstacles through patient education and support should be one of the goals of therapy in planning for comprehensive care for patients with head and neck cancer.
Conclusion Our historical cohort study in a VA population demonstrates that patients with head and neck cancer who were treated with IMRT had fewer instances of dental disease, more salivary flow, and fewer requisite posttreatment extractions compared with those patients treated with RT. The number of posttreatment extractions has been reduced with the advent of IMRT, and significantly more so with a complete dental evaluation prior to treatment. In this subset of patients, IMRT appears to offer significant advantages to dental health compared with conventional RT in lowering dental-related side effects in the treatment of head and neck cancer via radiation, while prospective analysis of a larger population is necessary to fully support the superiority of IMRT. A multidisciplinary team approach in the management of these patients minimizes posttreatment dental complications and improves the overall quality of patient care. Author Contributions Victor M. Duarte, analysis and interpretation of data, drafting and critically revising article; Yuan F. Liu, acquisition of data, analysis and interpretation of data, critically revising article; Sassan Rafizadeh, acquisition of data, critically revising article, interpretation of data; Tracey Tajima, final approval of the version, critically revising article, conception and design; Vishad Nabili, final approval of the version, critically revising article, intellectual concept; Marilene B. Wang, final approval of the version, critically revising article, intellectual concept, conception and design.
Disclosures Competing interests: None. Sponsorships: None. Funding source: None.
References
2. Vissink A, Jansma J, Spijkervet FKL. Oral sequelae of head and neck radiotherapy. Crit Rev Oral Biol Med. 2003;14:199212. 3. Brosky ME.The role of saliva in oral health: strategies for prevention and management of xerostomia. J Support Oncol. 2007;5:215-225. 4. Epstein JB, Stevenson-Moore P.Periodontal disease and periodontal management in patients with cancer. Oral Oncol. 2001;37:613-619. 5. Hong CH, Napen˜as JJ, Hodgson BD, et al. A systematic review of dental disease in patients undergoing cancer therapy. Support Care Cancer. 2010;18:1007-1021. 6. Graff P, Lapeyre M, Desandes E, et al. Impact of intensitymodulated radiotherapy on health-related quality of life for head and neck cancer patients: matched-pair comparison with conventional radiotherapy. Int J Radiat Oncol Biol Phys. 2007;67:1309-1317. 7. Nutting CM, Morden JP, Harrington KJ, et al. Parotid-sparing Intensity Modulated versus Conventional Radiotherapy in Head and Neck Cancer (PARSPORT): a phase 3 multicenter randomized controlled trial. Lancet Oncol. 2011;12:127-136. 8. Braam PM, Terhaard CHJ, Roesink JM, et al. Intensitymodulated radiotherapy significantly reduces xerostomia compared with conventional radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66:975-980. 9. Ben-David MA, Diamante M, Radawski JD, et al. Lack of osteoradionecrosis of the mandible after IMRT for head and neck cancer: likely contributions of both dental care and improved dose distributions. Int J Radiat Oncol Biol Phys. 2007;68:396-402. 10. Shao ZY, Tang ZS, Yan C, et al. Effects of intensitymodulated radiotherapy on human oral microflora. J Radiat Res. 2011;52:834-839. 11. Jensen SB, Pederson AM, Reibel J, et al. Xerostomia and hypofunction of the salivary glands in cancer therapy. Support Care Cancer. 2003;11:207-225. 12. Ramirez-Amador V, Sol Silverman S, Mayer P, et al. Candidal colonization and oral candidiasis in patients undergoing oral and pharyngeal radiation therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84:149-153.
1. Jham BC, Reis PM, Miranda EL, et al. Oral Health status of 207 head and neck cancer patients before, during and after radiotherapy. Clin Oral Invest. 2008;12:19-24.
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Comparison of Dental Health of Patients with Head and Neck Cancer Receiving IMRT vs Conventional Radiation
Otolaryngology– Head and Neck Surgery 2014, Vol 150(1) 81–86 Ó American Academy of Otolaryngology—Head and Neck Surgery Foundation 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599813509586 http://otojournal.org
Victor M. Duarte, MD1,2, Yuan F. Liu, MD1, Sassan Rafizadeh, PhD1, Tracey Tajima, DDS2,3, Vishad Nabili, MD1,2, and Marilene B. Wang, MD1,2
No sponsorships or competing interests have been disclosed for this article.
Abstract Objective. To analyze the dental health of patients with head and neck cancer who received comprehensive dental care after intensity-modulated radiation therapy (IMRT) compared with radiation therapy (RT). Study Design. Historical cohort study. Setting. Veteran Affairs (VA) hospital. Subjects and Methods. In total, 158 patients at a single VA hospital who were treated with RT or IMRT between 2003 and 2011 were identified. A complete dental evaluation was performed prior to radiation treatment, including periodontal probing, tooth profile, cavity check, and mobility. The dental treatment plan was formulated to eliminate current and potential dental disease. The rates of dental extractions, infections, caries, mucositis, xerostomia, and osteoradionecrosis (ORN) were analyzed, and a comparison was made between patients treated with IMRT and those treated with RT. Results. Of the 158 patients, 99 were treated with RT and 59 were treated with IMRT. Compared with those treated with IMRT, significantly more patients treated with RT exhibited xerostomia (46.5% vs 16.9%; P \ .001; odds ratio [OR], 0.24; 95% confidence interval [CI], 0.11-0.52), mucositis (46.5% vs 16.9%; P \.001; OR, 0.24; 95% CI, 0.11-0.52), and ORN (10.1% vs 0%; P = .014; OR, 0.07; 95% CI, 0.00-1.21). However, significantly more patients treated with IMRT were edentulous by the conclusion of radiation treatment (32.2% vs 11.1%; P = .002; OR, 3.8; 95% CI, 1.65-8.73). Conclusion. Patients who were treated with IMRT had fewer instances of dental disease, more salivary flow, and fewer requisite posttreatment extractions compared with those treated with RT. The number of posttreatment extractions has been reduced with the advent of IMRT and more so with a complete dental evaluation prior to treatment. Keywords dental health, radiation and dental health, IMRT and dental
Received June 7, 2013; revised August 22, 2013; accepted September 30, 2013.
E
very year, approximately 500,000 new cases of head and neck cancer are diagnosed worldwide.1 Preservation of tissue health and function is an important objective in effective cancer therapy.2 Conventional radiation therapy (RT), one the main modalities of treatment in many head and neck cancers, is associated with multiple side effects that greatly affect quality of life. The salivary glands, oral cavity, and mandible are frequently included in the radiation field.1 Consequently, 100% of patients who receive RT with fields involving the oral cavity will experience complications.3 These include, but are not limited to, xerostomia, oral infection, dental caries, mucositis, periodontal disease, osteoradionecrosis (ORN), trismus, and dysphagia. Since the consequences of radiation damage and subsequent sequelae in the treatment of head and neck cancer are difficult to manage, steps must be taken to reduce complications as much as possible. Therefore, prevention can be initiated with proper preradiation treatment planning and dental examinations.2,4 There must also be proper management of xerostomia, meticulous maintenance of oral hygiene, diet modifications, control of cariogenic flora, and prevention of dental caries with fluoride applications, as the anticariogenic effects of fluoride therapy are well documented.2,5 Perhaps the best way to reduce radiation damage is to limit the amount of tissue exposed to radiation. Intensity1
Department of Head and Neck Surgery, David E. Geffen School of Medicine at UCLA, Los Angeles, California, USA 2 Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA 3 Department of Oral Medicine, School of Dentistry at UCLA, Los Angeles, California, USA This article was presented as a poster at the 2012 AAO-HNSF Annual Meeting & OTO EXPO; September 9-12, 2012; Washington, DC. Corresponding Author: Victor M. Duarte, MD, Department of Head and Neck Surgery, David E. Geffen School of Medicine at UCLA, 62-132 Center for Health Sciences, Los Angeles, CA, 90095-1624 USA. Email: [email protected]
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modulated radiation therapy (IMRT) reduces the irradiated volume by shaping the spatial distribution of radiation to target mainly the tumor. It can assign different weights to individual rays of a beam versus one weight for the beam as a whole, making it even more optimized to prevent normal tissue damage than 3-dimensional conformal radiation techniques.2 Compared with conventional radiation, IMRT has been shown to result in significantly less pain, dry mouth, and ropey saliva.6,7 One study found the parotid flow rate to be 41% at 6 weeks and 64% at 6 months after IMRT, compared with 11% and 18%, respectively, after RT.8 Another study of 176 patients found no instances of ORN when a strict prophylactic dental care policy, along with IMRT, was implemented.9 Furthermore, IMRT was found to be better for maintaining a stable oral ecosystem than conventional radiation.10 In addition, the use of oral stents, such as tongue depressors, has been used during IMRT to minimize side effects.9 Despite these favorable findings for IMRT, however, the induction of oral radiation sequelae by IMRT remains poorly established.6 In this study, we retrospectively evaluated the oral health of patients with head and neck cancer treated with conventional RT vs those treated with IMRT to examine the progression of disease and to optimize pre- and post-RT dental and oral cavity disease treatment practices. We believe that the results should serve as a guideline for a prospective study on a dental health protocol before and during radiation.
Methods Study Design and Patient Selection A retrospective study was performed by reviewing the charts of head and neck tumor board patients with malignancy of the head and neck treated with either RT alone or combined chemoradiation (CRT) between 2003 and 2011. The study was performed at the West Los Angeles Veteran Affairs Hospital and was approved by the hospital’s institutional review board. All the patients in the study received radiation or chemoradiation as their primary form of treatment. Every patient who was referred for radiation therapy at our institution was evaluated by a dental team member prior to treatment. Patients who had any evidence of dental disease prior to treatment (eg, caries, infection, periodontitis) were excluded from the study to make a treatment comparison between IMRT and RT groups at the conclusion of the treatment. Any patient who had previous tooth extraction aside from their requisite pretreatment extraction was excluded from the study. The patient’s dental treatment plan was developed upon referral by head and neck surgeons and radiotherapists before radiotherapy. Any patient who was not compliant with dental follow-up or demonstrated missed appointment visits was also excluded from the study. The demographic data and other relevant information, including primary tumor site, stage of tumor, type of treatment (CRT or RT), radiation dose administered to the primary site, and chemotherapy, were also recorded (Table 1).
Patient Education Oral hygiene, including brushing and flossing, was reviewed with each patient. Daily use of high concentrated fluoride gel (1.1% neutral sodium fluoride) either in a fluoride carrier or by brush-on technique was also recommended and a prescription was given to the patient. Patient education was provided, including oral care during and after radiation therapy.
Before RT Prior to RT, a complete dental evaluation was performed, including periodontal probing, tooth profile, cavity check, and mobility. During this consult, complete medical, dental, social, and family histories were obtained. The dental treatment plan was formulated to eliminate current and potential dental disease, as well as to prepare for possible future dental rehabilitation. The examination included a tooth-bytooth evaluation, with particular attention to teeth in areas of the jaw expected to receive a high dose (.50 cGy). The periodontal condition was evaluated, and teeth with mobility, significant periodontal disease, furcation involvement, or attachment loss would be recommended for extraction. All patients received panoramic radiographs and intraoral periapical radiographs when indicated to evaluate for periapical abscesses, caries, periodontal condition, and other dental pathology. Teeth with nonrestorable caries or caries that extended to the gum line; teeth with large, compromised restorations with significant periodontal attachment loss (pocketing .5 mm); and those with severe erosion or abrasion were extracted if they were in areas of the mandible or maxilla expected to receive a high dose. Decisions about extraction were significantly affected by the patient’s dental competence and dental motivation in performing meticulous oral hygiene and by the past history of dental service usage. A more aggressive approach was made in patients with trismus due to the negative impact on the prognosis for the teeth. Also taken into consideration was the patient’s overall survival prognosis and quality-of-life concerns. Extractions were performed as soon as possible after examination to maximize postextraction healing time prior to the start of radiation. Postextraction healing time was 14 days prior to the start of RT. In addition, the residual alveolar ridges were prepared by performing any needed preprosthetic surgery such as alveoloplasty and torus removal. It is important to note that a noncarious tooth may have other present or past dental disease or conditions that may warrant extraction prior to radiation therapy. For example, the tooth may have significant periodontal disease or (toothbrush) abrasion that results in significant root exposure. Root surfaces lack enamel and are much more susceptible to caries especially when the patient has or will develop xerostomia. Teeth with furcation involvement are very difficult to self-clean and require meticulous self-cleaning and diligent professional cleaning. If the patient has a history of dental noncompliance, those teeth are considered for
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Table 1. Patient characteristics. IMRT (n = 59) Characteristic Sex Male Female Age, y Site
Stage
NP OC OP HP LA UP 1 2 3 4 Unknown
Dose, cGy Chemotherapy No chemotherapy
No. or Mean (SD)
59 0 63.1 (10.2) 6 10 24 3 8 8 4 4 7 30 14 6688.8 (630.8) 20 39
RT (n = 99) Range
27-91
4800-8000
No. or Mean (SD)
98 1 62.6 (10.0) 15 18 35 6 13 12 4 4 11 28 52 6404.2 (930.4) 37 62
All (N = 159) Range
24-82
3500-7700
No. or Mean (SD)
157 1 62.9 (10.1) 21 28 59 9 21 20 8 8 18 58 66 6540.5 (810.4) 57 101
Range
P Valuea
.999 24-91
.810 .959
.825
3500-8000
NA .052 .733
Abbreviations: HP, hypopharynx; IMRT, intensity-modulated radiation therapy; LA, larynx; NA, not applicable; NP, nasopharynx; OC, oral cavity; OP, oral pharynx; RT, radiation therapy; UP, unknown primary. a The P value refers to difference between IMRT and XRT groups for each characteristic.
extraction. A patient may demonstrate the inability to properly clean the tooth prior to radiation, especially if the tooth already has a history of significant dental restoration and a history of dental caries. The ability to clean teeth is strongly considered, especially with trismus and microstomia. Another example is if a tooth is supra-erupted or malpositioned as that will make future dental prostheses very difficult.
After RT At the conclusion of IMRT/RT, the incidence of Candida infection, caries, mucositis, xerostomia, periodontitis, edentulous, extractions, and ORN and the use of fluoride trays, if any, were recorded for each patient at the first dental clinic evaluation 1 month after radiation treatment. A comparison was made between patients with head and neck cancer treated with IMRT and those treated with conventional RT.
Follow-up All patients were followed every 3 to 4 months afterward in both the Radiation Oncology and Head and Neck Surgery clinics for surveillance during the first year after treatment.
Statistical Analysis Descriptive statistics were used to characterize the sample. For comparing continuous variables, 2-tailed, unequal variance, Student t tests were used. For comparing categorical and ordinal variables, Fisher exact tests were used; for
tables larger than 2 by 2, extended versions of the Fisher exact test were used. Confidence intervals for odds ratios were calculated based on z statistics, which are less exact than Fisher exact tests and may indicate a nonsignificant confidence interval when the Fisher exact test P value is significant, or vice versa. Missing values were excluded when statistical tests were performed. All statistical analyses were performed using Excel 2010 (Microsoft, Redmond, Washington), except for Fisher exact tests, which were performed using a calculator found at http://aoki2.si.gunma-u .ac.jp/exact/exact.html. For analysis, a P value of less than .05 was considered statistically significant in our study.
Results Data from these patients were gathered on a review of medical records from the RT team regarding their status during and/or immediately after RT. Of the 158 eligible patients (157 men and 1 woman), 99 were treated with conventional RT and 59 with IMRT. The patient and disease characteristics are summarized in Table 1. The mean age of the participating patients was 62.9 years (range, 24-91 years). The IMRT and RT groups had comparable distributions of sex, age, primary tumor site, stage grouping, radiation dose to the primary site, and use of chemotherapy. The chemotherapy regimens mostly included platinum drug administration (cisplatin or carboplatin) as a single agent or in combination with 5-fluorouracil or erbitux. Chemotherapy was concomitant with RT and/or neoadjuvant. Radiation dose to primary site ranged from 3500 to
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Table 2. Posttreatment findings. Characteristic Candida infection Caries Xerostomia Mucositis Fluoride trays Poor hygiene Fractures/ORN Periodontitis Edentulous Extractions No issues
IMRT (n = 59), No. (%) 4 (6.8) 12 (20.3) 10 (16.9) 10 (16.9) 8 (13.6) 1 (1.7) 0 11 (18.6) 19 (32.2) 12 (20.3) 21 (35.6)
RT (n = 99), No. (%) 12 15 46 46 14 8 10 27 11 28 21
(12.1) (15.2) (46.5) (46.5) (14.1) (8.1) (10.1) (27.3) (11.1) (28.3) (21.2)
All (N = 159), No. (%) 16 27 56 56 22 9 10 38 30 40 42
(10.1) (17) (35.2) (35.2) (13.8) (5.7) (6.3) (23.9) (18.9) (25.2) (26.4)
P Valuea
OR (95% CI)
.415 .514 \.001b \.001b .999 .155 .014b .252 .002b .345 .062
0.53 (0.16-1.72) 1.43 (0.62-3.31) 0.24 (0.11-0.52) 0.24 (0.11-0.52) 0.95 (0.37-2.43) 0.20 (0.02-1.61) 0.07 (0.00-1.21) 0.61 (0.28-1.35) 3.8 (1.65-8.73) 0.65 (0.30-1.40) 2.05 (1.00-4.21)
Abbreviations: CI, confidence interval; IMRT, intensity-modulated radiation therapy; ORN, osteoradionecrosis; OR, odds ratio; RT, radiation therapy. Note that the 95% CI of the odds ratio is calculated based on a z statistic, which is less exact than the Fisher exact test used to calculate P values. a The P value refers to difference between IMRT and RT groups for each finding. b Statistically significant.
8000 cGy. The mean total dose of patients treated with RT was 6404.2 cGy (range, 4800-8000 cGy), and the mean total dose of patients treated with IMRT was 6688.8 cGy (range, 3500-7700 cGy). After treatment with either IMRT or RT, the following were recorded for each group: no issues, ORN, extractions, edentulous, periodontitis, poor hygiene, fluoride trays, xerostomia, mucositis, caries, and Candida infection. The number of patients who were edentulous (P = .002), had ORN (P = .014), had xerostomia (P \ .001), or had mucositis (P \ .001) were significantly different between the 2 groups, with a higher proportion of edentulous patients in the IMRT groups and a higher rate of ORN, xerostomia, and mucositis present in the RT group. The number of patients having no dental issues during and after treatment in the IMRT group compared with the RT group trended toward significance (P = .062). A comparison of these measures is presented in Table 2 and shown in Figure 1. To assess any difference among the sites, patients were divided into 2 groups based on tumor location: hypopharyngeal (HP) and laryngeal (LA), and all other sites. This was done as laryngeal or hypopharynx cancers would be expected to have less dental problems, in theory. For all patients (both IMRT and RT patients grouped together), there was no significant difference between the HP/LA sites and the other sites (OC, OP, etc) in terms of any dental disease after radiation. Comparing the IMRT with the RT patients looking at the HP and LA sites, there was no significant difference in dental disease after radiation.
Discussion Radiotherapy continues to be an important mode of treatment for patients with localized head and neck cancer.11 The purported advantage of primary RT or CRT for head and neck cancer is organ preservation. However, RT is associated with multiple adverse reactions, particularly related
to oral and dental health. Previous studies have shown that between 68% and 97% of the patients examined just after the start of RT need immediate dental care.1 During the first week of RT, there is a rapid decrease in salivary flow rate, which is then followed by a gradual drop to below 10% of the initial flow rate. Xerostomia is the most common oral sequelae from RT.1 Because of both early and late responses of salivary glands to RT, damage to salivary tissue and xerostomia are likely the most common side effects of head and neck cancer radiation.2 Radiation therapy also transforms saliva composition to a more viscous white, yellow, or brown fluid with a relative immunoprotein deficiency. This supports an environment vulnerable to infections, the most common of which is candidiasis during and shortly after RT.2 One study showed an increased prevalence of positive oral Candida cultures from 43% before RT to 62% at completion to 75% during follow-up.12 In our study, more patients in the RT group (RT: 12.1% vs IMRT: 6.8%) had Candida infection during radiation, although this was not statistically significant. Xerostomia can indirectly result in other dental and oral diseases as well through disruption of normal oral cavity homeostasis, leading to increased dental caries and changes in taste, speech, eating habits, and quality of life.3 In our study, the rate of xerostomia was significantly less in the IMRT group, 16.9% vs 46.5% in the RT group. In contrast to xerostomia, mucositis is a transient adverse side effect. Although mucositis is short-lived, it is an inevitable side effect and significant contributor to the morbidity of RT.2 About 80% of patients will develop pseudomembranous mucositis during the course of curative RT. As a result, 20% to 30% of these patients will require artificial feeding. Severe mucositis may even lead to a premature cessation of therapy, thus interrupting a full treatment course and a full radiation dose. Our study demonstrated that the rate of mucositis in the patients receiving IMRT treatment was significantly less than in the RT group. Moreover,
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Figure 1. Comparison of dental conditions after intensity-modulated radiation therapy (IMRT) vs radiation therapy (RT). ORN, osteoradionecrosis. *Statistically significant differences.
every patient in our study with clinical xerostomia developed evidence of mucositis. It is thought that the adverse effects of RT on dentition are mainly due to a reduction in salivary flow rate. As a result, dental caries, with fast onset and progression, can be the result. Patients with dental disease may also be less likely to take care of their teeth. Within 1 year, dentition that was previously healthy can be lost completely in severe cases.2 In a review of 19 studies, the overall prevalence of dental caries after RT was 24%.5 In our study, the rate of radiation caries was slightly less in patients treated with RT compared with the IMRT-treated patients; however, this was not statistically significant (RT: 15.2% vs IMRT: 20.3%). Certainly, the site of primary radiation can account for oral changes at the microscopic level, and in the future, it would be interesting to see whether fractionation and boosts to the tumor site, regardless of RT or IMRT, would decrease the rate of caries development and oral sequelae. The number of dental extractions at any time after the beginning of treatment has been reduced with the advent of IMRT and significantly more so with a complete dental evaluation prior to treatment. In our study, a lower percentage of IMRT patients (20.3%-28.3%) required posttreatment extractions, although this did not display statistical significance. In our population, a higher percentage of the IMRT patients were edentulous compared with the RT group. However, we believe this to be a result of the requisite pretreatment extractions, not coincidentally leading to fewer dental issues after the start of radiation in the IMRT group (see Figure 1—categorized as ‘‘no issues’’); this category trended toward significance. Certainly less dental complications are seen with edentulous patients, but we also need to consider quality of life after radiation treatment. This is a decision that is made during the pretreatment dental evaluation.
While it may seem likely that patients with laryngeal and hypopharyngeal primary sites may have fewer problems with posttreatment dental disease compared with those with oral/oropharyngeal sites, due to the difference in the treatment beds, we did not find any significant difference between these 2 patient groups when looking at the entire cohort. In addition, there was no significant difference in dental disease following radiation between the HP and LA patients treated with IMRT vs RT. One of the most dreaded complication of RT is ORN, the incidence of which can vary from 2.6% to 22% (commonly reported to be 5%-15%) for the mandible, with a lower rate for the maxilla.2,5 Osteoradionecrosis is caused by radiation injury to vasculature of the bone, leading to endarteritis, thrombosis, and eventually obliteration of small vessels. As a result, the bone will respond poorly to trauma and becomes prone to fracture and infection.2 In our study, there was a statistically significant lower rate of ORN for the IMRT subset, with none of the IMRT patients developing ORN, compared with 10.1% in the RT group, reminiscent of results obtained in the study from Ben-David et al.9 It must be noted that a true comparison of pre- and postradiation dental status could not be made since patients with dental disease prior to the start of radiation were automatically excluded. One limitation of our study is that it is a retrospective nonrandomized study, which inevitably carries the consequence of differences in patient groups. The best assessment of comparing dental health after RT and IMRT would be a randomized prospective study, a difficult study to perform because IMRT is often adapted as standard therapy due to theoretical advantages. Another difficulty with providing comprehensive dental care is patient compliance. Reasons for noncompliance in patients may include social, medical, financial, and insurance issues. A patient with cancer may be overwhelmed with the number of
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appointments necessary during a difficult treatment period. Overcoming these obstacles through patient education and support should be one of the goals of therapy in planning for comprehensive care for patients with head and neck cancer.
Conclusion Our historical cohort study in a VA population demonstrates that patients with head and neck cancer who were treated with IMRT had fewer instances of dental disease, more salivary flow, and fewer requisite posttreatment extractions compared with those patients treated with RT. The number of posttreatment extractions has been reduced with the advent of IMRT, and significantly more so with a complete dental evaluation prior to treatment. In this subset of patients, IMRT appears to offer significant advantages to dental health compared with conventional RT in lowering dental-related side effects in the treatment of head and neck cancer via radiation, while prospective analysis of a larger population is necessary to fully support the superiority of IMRT. A multidisciplinary team approach in the management of these patients minimizes posttreatment dental complications and improves the overall quality of patient care. Author Contributions Victor M. Duarte, analysis and interpretation of data, drafting and critically revising article; Yuan F. Liu, acquisition of data, analysis and interpretation of data, critically revising article; Sassan Rafizadeh, acquisition of data, critically revising article, interpretation of data; Tracey Tajima, final approval of the version, critically revising article, conception and design; Vishad Nabili, final approval of the version, critically revising article, intellectual concept; Marilene B. Wang, final approval of the version, critically revising article, intellectual concept, conception and design.
Disclosures Competing interests: None. Sponsorships: None. Funding source: None.
References
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