Long-Term Complications of Radiotherapy in a Patient with Maxillary Squamous Cell Carcinoma: a Matter of Trismus and Osteoradionecrosis

Case Report

pISSN 2288-9272 eISSN 2383-8493 J Oral Med Pain 2018;43(4):136-141 JOMP https://doi.org/10.14476/jomp.2018.43.4.136 Journal of Oral Medicine and Pain

Long-Term Complications of Radiotherapy in a Patient with Maxillary Squamous Cell Carcinoma: A Matter of Trismus and Osteoradionecrosis

Keon-Hyung Kim, Jo-Eun Park, Mee-Eun Kim, Hye-Kyoung Kim

Department of Oral Medicine, College of Dentistry, Dankook University, Cheonan, Korea

Received September 8, 2018 Oral cancer is a malignant neoplasm of the lips or oral cavity. Surgery, radiotherapy and Revised November 21, 2018 chemotherapy depending on the location and stage of the tumor can be considered as impor- Accepted November 29, 2018 tant treatment modalities of oral cancer. Unfortunately, all three treatments can have both acute and chronic complications. Among them, trismus and osteoradionecrosis (ORN), unique complications of radiotherapy in the orofacial region, are particularly difficult to treat once Correspondence to: manifested. Therefore, these two complications of radiotherapy have devastating effects on the Hye-Kyoung Kim patient’s oral health and furthermore, overall quality of life. In this study, we present a case Department of Oral Medicine, College of a patient showing trismus and ORN following radiotherapy for the treatment of maxillary of Dentistry, Dankook University, 119 Dandae-ro, Dongnam-gu, Cheonan squamous cell carcinoma and briefly discuss this matter of trismus and ORN in the perspective 31116, Korea of a dentist. Tel: +82-41-550-1913 Fax: +82-505-434-7951 E-mail: [email protected] Key Words: Mouth neoplasms; Osteoradionecrosis; Radiotherapy; Trismus

INTRODUCTION systemic manifestations including nausea, vomiting, fa- tigue, blood disorders and diarrhea are more frequent and Oral cancer is defined as malignant neoplasia of the lips dominant than radiotherapy and many side effects relat- or in the oral cavity and has higher occurrence in people ed to chemotherapy dissipate fairly quickly after the final over 50 years. Most frequent oral cancer is squamous cell treatment.5) On the other hand, radiotherapy is notorious carcinoma. Smoking and alcohol are considered as major for its complications including acute and chronic effects. risk factors, having them both can have a synergic effect.1) Acute effects occur during the early stages of radiothera- The genetic instability in keratinocytes also can contrib- py and continue into the immediate post-treatment peri- ute to tumor development.1,2) Erythroplakia and leukoplakia od (2-3 weeks). Chronic or delayed effects of radiotherapy are most common in the tongue, floor of mouth and lower can develop at any time, from weeks to years after treat- lip.1,3) ment.6,7) The acute complications include oral mucositis; Surgery, radiotherapy and chemotherapy depending on fungal, bacterial infection; taste dysfunction; and salivary the location and stage of the tumor can be considered as gland dysfunction like xerostomia. Chronic complications important treatments of oral cancer. Unfortunately, all three include mucosal fibrosis, atrophy and soft tissue necrosis; can have both acute and chronic complications. Surgical xerostomia and dental caries and infection for the result of method includes chronic complications from nerve injury salivary gland dysfunction; taste dysfunction like dysgeu- or facial deformity as well as acute ones, such as infection sia; osteoradionecrosis (ORN); muscular fibrosis or trismus.6) and bleeding.4) In case of chemotherapy, oral mucositis and Among them, trismus and ORN, unique complications of

CC This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. www.journalomp.org Keon-Hyung Kim et al. A Matter of Trismus and ORN 137 radiotherapy in the orofacial region, are particularly dif- CASE REPORT ficult to treat once manifested. Trismus caused by tonic contraction of the masticatory muscles is characterized A 69-year-old woman was referred to the Department by mandibular hypomobility which results in the limited of Orofacial Pain and Oral Medicine, Dankook University mouth opening.8,9) ORN is defined as irradiated bone expo- Dental Hospital from the Department of Prosthodontics sure that persists without healing for 3 to 6 months.10) These with a complaint of severe mouth opening limitation. Apart two complications of radiotherapy have a devastating effect from hypertension, myocardial infarction and coronary an- on the patient’s oral health and furthermore, overall quality gioplasty with stent procedure 15 years ago, her medical of life.11) history revealed that she underwent a surgical treatment to In this study, we present a case of a patient showing tris- remove squamous cell carcinoma of the oral cavity involv- mus and ORN following radiotherapy for the treatment of ing the left maxillary alveolar bone and buccal space 2.5 maxillary squamous cell carcinoma and briefly discuss a years ago at another hospital. Tumor resection, alveolecto- matter of trismus and ORN in the perspective of a dentist. my of the left maxilla and modified radical neck dissection were operated. One month later, postoperative radiotherapy was conducted. She received a dose of 2.2 Gy per fraction delivered five times per week, total 30 fraction in 6 weeks, up to a total dose of 67 Gy. Two years later, the patient was diagnosed as ORN of left maxilla in the Department of Oral and Maxillofacial Surgery due to the exposed sequestrum and bone destruction on radiograph (Fig. 1, 2) and underwent left maxillary resection (Fig. 3). After operation, she was referred to the Department of Prosthodontics for the fabrication of maxillary obturator. However, limited mouth opening, another complication of Fig. 1. Panoramic view before maxillectomy on the left side. Partial radiotherapy, was a major obstacle to the prosthetic proce- destruction and diffuse bone resorption are observed on the left posterior maxillary alveolar bone. dure. When she was referred to the Department of Orofacial Pain and Oral Medicine, we checked the medical history through chart review and took a physical examination. The patient reported that she had difficulty in opening her mouth after radiotherapy two years ago. Jaw-opening exercise subsequent to radiotherapy was strongly recommended, but she did not follow the instructions.

Fig. 2. Computerized tomography image of the patient. Partial destruction and diffuse bone resorption are observed on the left posterior maxillary alveolar bone. Fig. 3. Panoramic view after maxillary resection on the left side.

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In the extraoral examination, comfortable mouth open- depressor once or twice a day at home during the entire ing, active range of motion (AROM) and passive range of treatment period. After a month, these treatment modali- motion were 14 mm, 15 mm, and 18 mm, respectively. She ties resulted in an increase in AROM to 19 mm and the pa- expressed pain while opening her mouth with the visual tient showed some satisfaction to what she had achieved. analog scale of 3 out of 10. The amount of lateral excursion However, as treatment duration passed, her AROM de- was limited to 5 mm to the left side and 3 mm to the right. creased. Approximately 5 months later, AROM returned to A slight tenderness on the left masseter muscle was seen. the initial amount and 9 months later, even decreased to 10 Intraoral examination revealed edentulous status of the left mm (Fig. 4) and during the same time period, palpation test maxilla following surgery with missing teeth of #25, 26, 27 was negative. A 6 months later, she reported a slight pain and no lesion or abnormality, showing only dryness on the on palpation in all parts of the masseter muscle, especially oral mucosa (Fig. 3). The symptoms and signs mentioned after excessive home exercise. The patient also reported that above made it difficult for the patient to eat and talk in her home treatment was not conducted adequately because of daily life. pain, old age and underlying general illness. From the medical history and physical examination, the During physical therapy, flexible type obturator, rath- patient was diagnosed as trismus and ORN attributed to er than conventional type which was almost impossible radiotherapy. Use of nonsteroidal anti-inflammatory drug to make due to trismus, was chosen to be fabricated and for one month was satisfactory for pain control but it had was delivered to the patient. Additionally, the hopeless left no effect on the opening movement. She was instructed to lower second molar was extracted four weeks before the visit the hospital at least twice a week for physical therapy initial visit. The tooth showed high mobility and severe al- and to do exercise at home. Physical therapy included ul- veolar bone loss on the radiograph (Fig. 1, 3). After extrac- trasound and microwave treatment of masticatory muscle, tion, healing of the extraction socket area was delayed for 4 electro acupuncture stimulation therapy and spray and months with no signs of inflammation. 10 months after ex- stretch treatment. Home exercise included extra oral mas- traction, the patient complained pain and oozing sensation sage with moist heat to all affected areas and jaw-opening on the left jaws. Intraoral examination by gauze palpation exercise. The patient, however, could not afford to participate in frequent physical therapy due to her old age and the long distance from home to the hospital. Therefore, she visited the hospital for physical therapy about once a month. She practiced jaw-opening exercise using a wooden tongue

(mm)

AROM 10

Amount

0 First 123456789 ANT POST day Months Fig. 5. Whole body bone scan image. Hot spot can be seen on the Fig. 4. Progression of the amount of active range of motion (AROM). left mandible. ANT, anterior; POST, posterior.

www.journalomp.org Keon-Hyung Kim et al. A Matter of Trismus and ORN 139 revealed slight oozing pus with red color on the left man- of radiotherapy to the development of ORN ranges from dible. Additional intraoral finding was very hard to perform 22 up to 47 months.10) In this case, ORN of left maxilla oc- due to the limited opening. She was immediately referred to curred after radiotherapy and 39 months later, ORN of left the Department of Oral and Maxillofacial Surgery and ORN mandible occurred following tooth extraction. This fact on the left mandible was confirmed by whole body bone evocates caution of dentists because surgical dental treat- scan and enhanced computerized tomography. Whole body ment can cause ORN even several years after radiotherapy. bone scan showed focal hot lesion of the left mandible (Fig. The loss of function and range of motion following ra- 5) and enhanced computerized tomography exposed the se- diotherapy are directly and indirectly attributable to dam- questrum on same location. Currently, she is under the care age and fibrosis to the masticatory muscles. Abnormal of the Department of Oral and Maxillofacial Surgery for proliferation of fibroblasts is a significant initial event.16) treatment of ORN. Additionally, there may be scar tissues from radiotherapy or surgery, nerve damage or a combination of both. Studies DISCUSSION have shown that masticatory muscles begin to show signs of atrophy, while failing to move through their range of Oral cancer is a highly relevant problem on global public motion for as short as 3 days. Similarly, joints which are health. All treatment modalities for oral cancer have many immobilized early on begin to show degenerative changes complications. Among them, trismus and ORN are notably in the temporomandibular joint space, including thinning of difficult to treat. These two complications of radiotherapy cartilage and thickening of synovial fluid.9) The direct effect can do harm to the patient’s oral health and furthermore, of radiotherapy ultimately results in fibrosis and contracture the overall quality of life. with a progressive onset about 9 weeks after radiotherapy.16) Trismus caused by tonic contraction of the masticatory Mouth opening after radiotherapy decreases by an aver- muscles is characterized by mandibular hypomobility which age of 18%-32% compared with that of pre-radiotherapy. results in the limited opening ability.8,9) Dijkstra et al.12) pro- The higher the radiation dose delivered to the related struc- posed that mouth opening of 35 mm is a functional cutoff tures, the greater the decrease in amount of mouth opening. point for trismus. Studies have reported the prevalence of Most importantly, in the first 9 months after radiotherapy, trismus to be between 38% and 42% according to this stan- about two-thirds of the total reduction in mouth opening dard among patients treated for head and neck cancer.13) occurs.16) Trismus can lead to difficulties in activities, such as biting, A study for determining predictors for trismus on head chewing and speaking. It can also impair the oral hygiene, and neck cancer patients receiving radiotherapy shows that resulting in dental caries and periodontal disease.14) It may incidence of trismus is highest in six months after radio- also contribute to the decrease in quality of life.11) therapy and declines thereafter. The incidence of trismus Meanwhile, ORN is a condition in which irradiated bone was 3.6 per 10 person years at risk, calculated over the total becomes exposed and persists without healing for 3 to 6 period of 48 months after radiotherapy. The best predictors months.10) ORN is a serious complication of radiotherapy for developing trismus in the first six months are tumors for head and neck cancer, ranging from small asymptom- located in the oral cavity, oropharynx or nasopharynx, the atic bone exposure that remains stable for months to years salivary glands or ear and a longer overall treatment du- and heals with conservative treatment, to severe necrosis ration of radiotherapy. In all time points, maximal mouth with pathologic fracture that necessitates surgical interven- opening measurement in the previous time point was a sig- tion and reconstruction. Symptoms can include pain, foul nificant predictor for developing trismus at the subsequent odor, dysgeusia, dysesthesia or anesthesia fistula formation, time point.17) pathologic fracture and local or systemic infection.15) The The pathophysiology of ORN has been a controversial incidence of ORN following radiotherapy ranges from 2.6% and evolving topic since it was first described. Recently, the to 15%. Surprisingly, the average time from the completion radiation-induced fibroatrophic theory suggests that the

www.journalomp.org 140 J Oral Med Pain Vol. 43 No. 4, December 2018 key event of ORN is activation and deregulation of fibro- secondary to head and neck cancer. Furthermore, they show blastic activity that leads to atrophy. The hypothesis focuses that even with exercises, several patients still suffer from on defective radiated bone and the imbalance between tis- trismus. sue synthesis and degradation in 3 distinct phases: (1) the Dijstra et al.19) indicated that if mouth opening does not prefibrotic phase, (2) the continuative organized phase, and increase during physical therapy or decrease despite treat- (3) the late fibroatrophic phase. In the first phase, radiation- ment, recurrence of the cancer must be taken into account induced injury to endothelial cells occurs together with the and referral back to the oral and maxillofacial surgeon is acute inflammatory response. Endothelial cell injury re- recommended. In this case, AROM of the patient reduced sults in the release of cytokines that trigger acute inflam- despite treatment and recurrence of ORN was suspected on matory response and result in a further release of reactive her last visit. We referred her back to Department of Oral oxygen species (ROS). In the second phase, the ROS release and Maxillofacial Surgery and they found focal hot lesion cytokines, such as tumor necrosis factor α, resulting in ab- in left mandible by bone scan. This also thought to cause a normal fibroblastic activity causing disorganization of the failure of gaining more amount of AROM. extracellular matrix. During the third phase, attempted tis- If conservative treatment fails, it may worth considering sue remodeling occurs with the formation of fragile healed performing a surgical treatment. Coronoidectomy is an ef- tissues that are vulnerable to reactivated inflammation in fective modality for the treatment of trismus refractory to the event of local injury. The end result is hypocellular radiotherapy in patients with head and neck cancer. It can bone and reduced bone matrix formation compensated by be of benefit in selected patients but it should be used with fibrosis.10) caution as it is invasive and carries considerable risks in Early treatment has the potential to prevent or minimize previously irradiated patients.16) Our patient also needs to trismus. As the restriction becomes more severe and likely consider a coronoidectomy. Because of her old age and sev- irreversible, the need for treatment becomes more urgent.9) eral previous surgical procedures, we should weigh the pros It seems that the effect of exercise decreases with a longer and cons carefully. period of time between radiotherapy and the start of exer- In conclusion, early intervention and compliance with ex- cise. Many studies that started exercise weeks or months af- ercises would be helpful to improve trismus although there ter oncologic treatment show increase in mouth opening.13) is no established clinical guideline for treatment of trismus. Tang et al.18) started exercise 4.6 to 4.8 years after radio- Dentists also should be aware that ORN may be a persistent therapy, and found a decrease in mouth opening. But they risk factor for dental treatment and pay more attention to found a smaller decrease in mouth opening in the treatment the prevention of ORN. group than the control group (–1.9 mm vs. –6.9 mm). In this case, the patient gained temporary increase of AROM CONFLICT OF INTEREST but after the exercise period, failed to maintain the gained amount. It seems this is because she started exercise about No potential conflict of interest relevant to this article 2 years after radiotherapy and did not exercise steadily. was reported. Until now, medications are likely ineffective and Botu linum toxin injection into the masticatory muscle might REFERENCES not be a good primary treatment for trismus following radiotherapy but may have a secondary role in reducing the 1. Rivera C. Essentials of oral cancer. Int J Clin Exp Pathol 2015; 16) painful muscle spasms occurring with trismus. 8:11884-11894. Kamstra et al.13) found a large variation in stretching 2. Feller LL, Khammissa RR, Kramer BB, Lemmer JJ. Oral squamous cell carcinoma in relation to field precancerisation: pathobiology. techniques, duration, repetition of exercises and research Cancer Cell Int 2013;13:31. methods. However, no exercise technique was clearly supe- 3. van der Waal I. Potentially malignant disorders of the oral and rior to others regarding prevention or therapy of the trismus oropharyngeal mucosa; terminology, classification and present

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