Head and neck radiotherapy-induced changes in dentomaxillofacial structures detected on panoramic radiographs: A systematic review.

PURPOSE: This study aimed to summarize the impact of neck and head radiation treatment on maxillofacial structures detected on panoramic radiographs.
MATERIALS AND METHODS: In this systematic review, the authors searched PubMed Central, Embase, Scopus, Cochrane Central Register of Controlled Trials, Web of Science, and Google Scholar for original research studies up to February 2020 that included the following Medical Subject Headings keywords: words related to "radiotherapy" and synonyms combined with keywords related to "panoramic radiography" and "oral diagnosis" and synonyms. Only original studies in English that investigated the maxillofacial effects of radiotherapy via panoramic radiographs were included. The quality of the selected manuscripts was evaluated by assessing the risk of bias using Cochrane's ROBINS-I tool for non-randomized studies.
RESULTS: Thirty-three studies were eligible and included in this review. The main objectives pertained to the assessment of the effects of radiation on maxillofacial structures, including bone architecture alterations, periodontal space widening, teeth development abnormalities, osteoradionecrosis, and implant bone loss. The number of participants evaluated ranged from 8 to 176.
CONCLUSION: The interaction between ionizing radiation and maxillofacial structures results in hazard to the tissues involved, particularly the bone tissue, periosteum, connective tissue of the mucosa, and endothelium. Hard tissue changes due to radiation therapy can be detected on panoramic radiographs.

Introduction

Essential treatment approaches for head and neck malignant neoplasms include radiotherapy, chemotherapy, and surgery, which may be performed independently or combined depending on the type of neoplasm and the extent of disease progression. Radiotherapy is usually the first-line approach for patients with head and neck cancer and is frequently applied as a complement to surgical tumor resection. There are three distinct types of radiotherapy: external beam radiation, brachytherapy, and radioisotope therapy.1 Radiotherapy protocols vary according to the histological type, location, and stage of the tumor,1 and frequently consist of 50–70 Gy for a period of 4 to 7 weeks.2 The aim of radiotherapy is to eliminate or ablate the neoplasm while minimizing damage to the surrounding healthy tissue; however, healthy tissue injury is an unavoidable consequence of radiotherapy.1

Tissue changes induced by radiotherapy result from decreased tissue perfusion and tissue fibrosis, as well as capillary obstruction.3 Capillary obliteration leads to decreased osteoblastic and osteoclastic activity, which affects bone repair and remodeling.3 Hence, post-radiotherapy alterations in maxillary bones, as well as in other mineralized tissues such as tooth structures, are observed in patients undergoing radiation treatment. These include widening of the periodontal ligament space4 and aggressive tooth decay.5 Furthermore, the destruction of acinar cells in salivary glands decreases the production of saliva and leads to other changes in the oral cavity.5

The deleterious effects of radiation on mineralized tissues have been studied by many investigators, mainly using panoramic radiographs, which is the most requested imaging examination in dentistry. Panoramic radiographs have a number of advantages, including the ability to provide a range of essential information about the status of the oral cavity and related bones.6 Hence, knowledge of the effects of radiotherapy in the maxilla and mandible, as detected using panoramic radiographs, is necessary for the treatment of patients who have undergone this oncologic treatment.

Thus, the objective of this study was to review the literature regarding radiotherapy-induced changes in dentomaxillofacial structures, as detected on panoramic radiographs, in patients undergoing head and neck radiotherapy. Specifically, this review addressed the following questions: 1) “What have researchers investigated regarding changes in dentomaxillofacial structures due to radiotherapy treatment for head and neck cancer based on panoramic radiographs?” and 2) “What results have researchers obtained?”

Materials and Methods

The present systematic review was registered with the National Institute for Health Research International Prospective Register of Systematic Reviews (registration number: CRD4201913058). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was adopted.7

Studies published up to February 2020 were screened for inclusion in this review by searching PubMed Central (United States National Institutes of Health's National Library of Medicine), Embase (Excerpta Medica Database), Scopus (Elsevier), the Cochrane Central Register of Controlled Trials, Web of Science (Institute of Scientific Information - Clarivate Analytics), and Google Scholar (Google) databases. The Boolean operator “AND” was used to combine search keywords. Itemized search strategies for each database were organized on the basis of the following search keywords: radiotherapy AND panoramic radiograph, radiotherapy AND oral manifestations, radiotherapy AND jaw; radiotherapy AND jaw diseases, radiotherapy AND mandible, radiotherapy AND maxilla, radiotherapy AND oral diagnosis, radiotherapy AND oral diseases, radiation effects AND panoramic radiograph, radiation effects AND oral manifestations, radiation effects AND jaw, radiation effects AND jaw diseases, radiation effects AND mandible, radiation effects AND maxilla, radiation effects AND oral diagnosis, radiation effects AND oral diseases, radiation effects AND panoramic radiograph, radiation effects AND oral manifestations, radiation treatment AND jaw, radiation treatment AND jaw diseases, radiation treatment AND mandible, radiation treatment AND maxilla, radiation treatment AND oral diagnosis, radiation treatment AND oral diseases, targeted radiation therapy AND panoramic radiograph, targeted radiation therapy AND oral manifestations, targeted radiation therapy AND jaw, targeted radiation therapy AND jaw diseases, targeted radiation therapy AND mandible, targeted radiation therapy AND maxilla, targeted radiation therapy AND oral diagnosis, targeted radiation therapy AND oral diseases. A summary of the keyword combinations is presented in Figure 1.

Fig. 1

A summarized representation of the keywords selected in this review.

Only original studies were considered suitable for inclusion. Abstracts, case reports, oral presentations, technical notes, abstracts, and literature reviews were excluded. Research articles that investigated the maxillofacial effects of radiotherapy, but not via panoramic radiographs, were not eligible. Moreover, studies in which the main objective was to test protocols, techniques, treatment for osteoradionecrosis, software, and assessment tools were excluded. If the use of panoramic radiographs was not clearly described in a given study, the study was not considered eligible. Additionally, non-English-language articles and non-human studies were not included. All studies with publication dates until February 2020 were included.

Research groups of patients who underwent radiotherapy as adjuvant treatment for head and neck cancer were included. Any patients in a given study's sample who had not received radiotherapy in the head and neck region were excluded.

Data extraction was performed by 2 independent reviewers who evaluated the full text of each investigation to select potentially eligible investigations after screening the titles and abstracts. A third reviewer verified each investigation before conclusively considering it as eligible. Disagreements among reviewers were solved by discussion, and when agreement could not be achieved, another collaborator was consulted. The authors or coauthors of the selected investigation were contacted when the full text was not available.

The following data were extracted and recorded: author information, the number of participants evaluated, radiation dose, and type of radiotherapy (Table 1). Details including the timing of the radiographic assessment, main results, and conclusions (Table 2) were also summarized and presented in tables.

Table 1

Research results: authors, objective pertaining to radiotherapy assessment using panoramic radiographs, size of the sample studied, radiation dose applied in each study, and type of radiotherapy applied

RT: radiotherapy, HNC: head and neck cancer, SCC: squamous cell carcinoma, ORN: osteoradionecrosis, 3-DCR: 3-dimensional conformational radiotherapy, IMRT: 3-dimensional conformational radiotherapy and intensity-modulated radiation therapy, 2-DPRT: conventional 2-dimensional plan radiotherapy, 3-DPRT: 3-dimensional plan radiotherapy, SI3FT: single-isocenter 3-field technique

Table 2

Main results and conclusions pertaining to the effects of head and neck radiotherapy and the timing of the panoramic assessment performed in the studies

Gy: Gray, RT: radiotherapy, HNC: head and neck cancer, SCC: squamous cell carcinoma, ORN: osteoradionecrosis

The quality of the selected manuscripts was evaluated using the Cochrane ROBINS-I tool for assessing the risk of bias in non-randomized intervention studies.8 ROBINS-I evaluates bias in studies according to 7 distinct domains (organized using “signaling questions,” described as: confounding selection of participants; classification of the interventions, biases due to deviations from intended interventions, missing data, measurement of outcomes, selection of the reported missing data, measurement of outcomes, and selection of the reported result).8 The bias assessment results are demonstrated in Table 3.

Table 3

Risk of bias assessment according to the Cochrane ROBINS-I tool for assessing the risk of bias in non-randomized intervention studies8

D1: bias due to confounding, D2: bias due to selection of participants, D3: bias in classification of interventions, D4: bias due to deviations from intended interventions, D5: bias due to missing data, D6: bias in measurement of outcomes, D7: bias in selection of the reported result

Results

A total of 13,261 research articles were initially found in the databases after searching for all keywords. After applying the eligibility criteria and removing overlapping studies, 13,228 investigations were excluded, and a total of 33 studies5,910111213141516171819202122232425262728293031323334353637383940 on the oral and maxillofacial effects of radiotherapy, as assessed by panoramic radiographs, were included. Table 1 summarizes the details of the selected studies.

The oldest study was published in 1980,40 while the most recent ones were published in 2020.910 The number of participants evaluated in the sample studied ranged from 837 to 176,31 and the samples included were highly heterogeneous. Patients with head and neck cancer were often included in the investigated samples,5171922242829303132333435363740 as were patients with hematopoietic neoplasms (such as leukemia),1218232833 although those with neck cancer were also studied independently.3839 Some studies were exclusively dedicated to patients with oral squamous cell carcinomas,212532 rhabdomyosarcoma survivors,101422 patients with osteoradionecrosis,173640 and patients in whom the outcomes of surgical procedures such as mandibulotomy111934 or the use of mandible reconstruction methods were investigated.13152627

Regarding the objectives of investigations pertaining to head and neck radiotherapy, 4 studies focused on determining whether radiotherapy may induce calcified carotid artery atheroma in patients with head and neck cancer,16353839 and 2 studies exclusively examined patients with osteoradionecrosis by imaging.1731 The effects on oral structures such as teeth in children survivors of head and neck rhabdomyosarcoma was the subject of 4 investigations.10142233 Surgical outcomes or complications in patients who received radiotherapy were evaluated in 10 studies,9111315192526273437 while changes in marginal bone levels or survival rates of implants were investigated in 2 studies.2124 Lastly, the appearance of the mandible,2029 apical periodontitis,5 and dental abnormalities or dental status alterations due to radiotherapy182328303233 were also assessed using panoramic radiographs.

The main results and conclusions pertaining to the effects of head and neck radiotherapy and the timing of panoramic assessments in each study are presented in Table 2. In 11 studies, panoramic radiographs were performed before and after radiotherapy,910161719203031333435 particularly when the primary objective of the study was to investigate the effects of radiotherapy that could be evaluated by panoramic radiographs. Distinct results and conclusions were obtained by the researchers, reflecting the aim of each investigation (Table 2).

The radiation type and dose applied in radiotherapy treatment are also summarized in Table 1. The radiation dose varied from 41.4 Gy14 to 74 Gy.3839

Four studies included patients with benign lesions in their samples;15242627 in these studies, evaluating the effects of radiotherapy was a secondary objective, and the studies focused on post-surgical calcification of the pedicle in cases of mandibulotomy26 and a broad range of surgical outcomes,1327 as well as on implant placement or survival.1524

Regarding the quality assessment, we found that most missing data in the manuscripts involved a lack of information about the type of radiotherapy and radiation dose used (Table 3). We considered that research articles without such information entailed a “critical” or “serious” risk of bias.121823273340 Regarding studies where the type of radiotherapy was missing, we assumed that conventional radiotherapy had been used.10121316181923242526272829333537383940 Nevertheless, the radiation dose was essential information that could not be deduced. The assessment results of the risk of bias are presented in Table 3.

Discussion

Head and neck neoplasms are usually treated with radiotherapy, which applies ionizing radiation. Radiotherapy primarily targets malignant cells through the production of free radicals that damage the genetic material of vulnerable malignant cells.41 However, it also damages healthy cells, particularly those that are fast-dividing, resulting in radiation-induced adverse effects.42

Bone architecture alterations,1429 periodontal space widening,20 tooth development abnormalities,101218222833 osteoradionecrosis,131736 and peri-implant bone loss152124 are examples of the interactions of ionizing radiation with maxillofacial hard structures, which can be detected by panoramic radiographs. Moreover, radiotherapy for head and neck neoplasms has an unfavorable impact on patients' quality of life, especially as it negatively affects oral health and oral function commitment. Hyposalivation,30 reduced mouth opening, mucositis, oral pain, dental caries, and osteoradionecrosis are examples of the deleterious oral effects of radiotherapy, even when using modern radiotherapy techniques.43

Regarding alveolar bone changes, patients who receive irradiation show crestal bone changes,21 which increase the peri-implant bone resorption.15 Periodontal space widening is a finding often reported in the literature when describing maxillomandibular imaging changes in these patients. Although its pathophysiological process is unknown, it is postulated that the inflammatory changes that lead to the enlargement of the periodontal ligament space are associated with resorption of the adjacent bone and subsequent filling with fibrotic tissue.20 When the inflammation is resolved, the periodontal ligament maintains its width.20

Other local complications of radiotherapy include changes in the shape, number, and developmental abnormalities in the teeth of children who receive radiotherapy and chemotherapy for head and neck cancer,101214182223283233 such as rhabdomyosarcoma.101422 The multimodal approach for childhood head and neck cancer includes systemic multi-agent chemotherapy, local surgery, and/or radiotherapy.22 This treatment results in significant alterations in the developing teeth and maxilofacial bones, which persist during the patient's life, especially when the treatment is administered at a young age (less than 5 years old).101444 This is because immature teeth are at higher risk for developmental disturbances.33 The most common reported alterations are root shortening, anodontia, microdontia, and taurodontia.14 The frequency and intensity of these alterations seem to be proportional to the treatment's intensity and duration (i.e., a higher amount of ionizing radiation used and a longer duration of the radiation treatment lead to worse alterations) and the child's age at diagnosis (i.e., a younger age is associated with worse alterations), while chemotherapy without head and neck radiotherapy has been shown to result in the least severe abnormalities.2844

Osteoradionecrosis was mentioned by the analyzed studies,13173240 which showed it to be associated with alcohol and tobacco use, high radiation doses, poor oral hygiene, and dental disease.131732 Osteoradionecrosis has also been investigated as a complication of radical and reconstructive maxillofacial surgery.111319252634 A study proposed that the pathophysiological mechanism of bone tissue breakdown in osteoradionecrosis is associated to hypoxia, hypovascularity, and hypocellularity in bone tissue due to radiation exposure.45 This negative effect was also reflected in the study of Palma et al.,9 who, by using panoramic radiographs and pixel analysis, verified that mandibular bone microarchitecture is affected by radiotherapy. In addition to evaluating the effects of radiotherapy as assessed by panoramic radiographs, some of the analyzed studies' primary objective was to investigate whether radiotherapy induces or increases the risk of developing calcified carotid artery atheroma in patients without16353839 or with osteoradionecrosis.31 The formation of atheromatous plaques and their further calcification result from chronic vascular inflammation, which may be induced by low-density lipoprotein cholesterol, free radicals from chronic smoking, and deleterious metabolic effects from diseases such as diabetes or hypertension.16

Lastly, implant survival and success after radiotherapy have also been assessed.1524 Overall, radiotherapy negatively impacts the implant's osseointegration and stability.24 It also leads to progressive vessel and soft-tissue fibrosis, reducing the healing capacity of the bone tissue.24 The time of loading is associated with implant success; thus, delayed loading is desirable to achieve adequate osteointegration.24

Regarding the radiotherapy techniques used in the analyzed studies, most studies did not specify the type of radiotherapy applied in their investigations;10121316181923242526272829333537383940 thus, we assumed that these studies used conventional radiotherapy. Other studies mentioned the use of intensity-modulated radiotherapy (IMRT),91415172021223031 and 1 study included a mixed sample of patients treated with IMRT by conventional radiotherapy.14 The objective of these previous investigations and of the present review was not to compare different radiotherapy techniques, their effects, or the radiation-induced changes observed in panoramic radiographs; nonetheless, certain differences among these techniques can be appreciated. IMRT delivers a minimal, homogeneous radiation dose into the neoplasm with maximum protection of tissues at risk,46 thereby improving the outcome when compared to that of conventional radiotherapy.47 If the studies' samples and objectives were more homogeneous, direct comparisons could have been performed to evaluate the effects of radiotherapy detected on panoramic radiographs.

The interaction between ionizing radiation and maxillofacial structures results in hazard to the tissues involved, particularly the bone tissue, periosteum, connective tissue of the mucosa, and endothelium. Radiation-induced effects that can be detected on panoramic radiographs include tooth development abnormalities, mandibular or maxillary bone architecture alterations, peri-implant bone loss, hyposalivation, reduced mouth opening, and osteoradionecrosis. Tooth development abnormalities and mandibular or maxillary bone architecture alterations induced by radiotherapy occur when the radiation treatment is performed during craniofacial development. Dentists should be aware of these side effects in order to provide proper oral treatment to patients with a history of radiotherapy treatment.