Post-radiotherapy osteomyelitis of the cervical spine in head and neck cancer patients

Objective To evaluate patient characteristics, risk factors, disease course, and management of cervical vertebral osteomyelitis in patients who had radiation for head and neck cancers. Methods A retrospective cohort study (case series) of patients diagnosed with post-radiation osteomyelitis of the cervical spine between 2012 and 2021. Data were collected from the patient’s medical files. Results Seven patients (71% male) with post-radiation cervical osteomyelitis were reviewed. The median patient age was 64 years. The mean interval between diagnosis of osteomyelitis and the first and last radiotherapy course was 8.3 and 4.0 years, respectively. A medical or surgical event preceded the diagnosis in four patients (57%) by a mean of 46.25 days. Common imaging findings were free air within the cervical structures and fluid collection. Four patients recovered from osteomyelitis during the follow-up within an average of 65 days. Conclusion: Post-radiation osteomyelitis is characterized by a subtle presentation, challenging diagnosis, prolonged treatment, and poor outcome. Clinicians should maintain a high index of suspicion for the long-term after radiotherapy. Multidisciplinary evaluation and management are warranted. Advances in knowledge: The study describes post-radiotherapy osteomyelitis of the cervical spine, a rare and devastating complication. Literature data regarding this complication are sparse.


INTRODUCTION
Head and neck cancer (HNC) is the seventh most common malignancy worldwide, with approximately 900,000 new cases and half a million deaths annually. 1,2Squamous cell carcinoma is the most common histological type of HNC, accounting for about 90% of patients.Radiotherapy is the mainstay of treatment, with or without chemotherapy or surgery. 3,4Variations in the combination and order of treatments depend on tumor site, histology, stage, patient's medical history, and preference.[7] Radiotherapy to the head and neck often causes immunological and vascular changes to the upper aerodigestive mucosa.As a result, it may induce mucosal ulceration, tissue breakdown, and the formation of non-healing wounds and fistulas, through which microorganisms colonizing the irradiated mucosa can penetrate and infect the soft tissue and bone. 8Furthermore, substantially adverse effects may be on cellular physiology, including inhibition of osteoblast and osteoclast activity, vascular injury, cellular metabolic imbalance leading to osteolysis, increased susceptibility to infection, and tissue necrosis. 9][12] ORN affects 2% of irradiated patients with HNC, commonly presenting in the mandible and maxillary bones. 13ORN of the mandible was described in up to 5% of patients after head and neck irradiation and was attributed to the bone density that absorbs a more considerable amount of radiation and less vascular supply than other bones. 11Conversely, ORN of the cervical spine and skull base is a rare condition. 14,15s opposed to the mandible and maxilla, the cervical spine and skull base are deeper beyond anatomical barriers and https://doi.org/10.1259/bjro.20230001

Published online: 28 September 2023
Objective To evaluate patient characteristics, risk factors, disease course, and management of cervical vertebral osteomyelitis in patients who had radiation for head and neck cancers.Methods A retrospective cohort study (case series) of patients diagnosed with post-radiation osteomyelitis of the cervical spine between 2012 and 2021.Data were collected from the patient's medical files.Results Seven patients (71% male) with post-radiation cervical osteomyelitis were reviewed.The median patient age was 64 years.The mean interval between diagnosis of osteomyelitis and the first and last radiotherapy course was 8.3 and 4.0 years, respectively.A medical or surgical event preceded the diagnosis in four patients (57%) by a mean of 46.25 days.Common imaging findings were free air within the cervical structures and fluid collection.Four patients recovered from osteomyelitis during the follow-up within an average of 65 days.

Conclusion:
Post-radiation osteomyelitis is characterized by a subtle presentation, challenging diagnosis, prolonged treatment, and poor outcome.Clinicians should maintain a high index of suspicion for the longterm after radiotherapy.Multidisciplinary evaluation and management are warranted.

Advances in knowledge:
The study describes postradiotherapy osteomyelitis of the cervical spine, a rare and devastating complication.Literature data regarding this complication are sparse.

BJR|Open
Tsur et al not in close contact with the contaminated biofilm of the oral cavity mucosa; also, the cervical spine and skull base are rarely positioned within the maximal radiation field, as in the case of oral cavity cancer and the jaws.
Cervical vertebrae osteomyelitis refers to the infection and inflammation of the bone and bone marrow in the cervical spine (neck region).It is typically caused by bacteria, such as Staphylococcus aureus, which can enter the vertebrae through various routes, including direct trauma, surgery, or bloodstream infections.Osteomyelitis can affect any bone in the body, including the cervical vertebrae.Compared to osteomyelitis, radionecrosis refers to tissue death or damage due to exposure to radiation therapy.It most commonly affects tissues that have been irradiated as part of cancer treatment.Radionecrosis can occur in various body regions, including the head and neck, where the cervical vertebrae are located. 16,17To summarize, cervical vertebrae osteomyelitis is an infection and inflammatory condition of the cervical spine bones, usually caused by bacteria.Radionecrosis, conversely, is tissue death or damage resulting from prior radiation therapy, commonly seen in the cervical vertebrae following treatment for HNC.
The treatment of head and neck osteomyelitis may require specific expertise.Besides the tendency for polymicrobial infections, important anatomic considerations are owing to the challenging drainage approach and the proximity of essential major blood vessels and the skull base.9][20][21] In addition, radiation may damage the cervical vertebrae and the adjacent ligamentous structures, which are close to the radiation field, resulting in cervical spine deformity and instability and, ultimately, spinal cord compression, neurological deficit, and myelopathy. 22,23though ORN and osteomyelitis of the cervical spine and skull base are devastating complications of HNC radiation, they have not been thoroughly described in the medical literature.Therefore, this study aims to present a series of those patients and analyze their characteristics, identify potential risk factors, and describe disease course and management.

MATERIAL AND METHODS
A retrospective case series study was conducted in the tertiary radiation oncology center, Davidoff Cancer Center for the Treatment and Research of Cancer of Rabin Medical Center.The institutional ethics committee approved the study protocol (IRB-XXX 0731-2020).The cohort consisted of patients previously treated with radiation, with or without chemotherapy and surgery, for HNC who presented to the institute's multidisciplinary head and neck boards (either tumor boards or radiology rounds) between 2012 and 2020 with a diagnosis of osteomyelitis of the cervical spine or skull base region based on a combination of clinical findings, radiological features and a culture positive finding from the infection site without another infectious site.Clinical data for the study were collected from the patient's medical files: demographics, past medical and surgical history, detailed radiation therapy protocols, clinical presentation, imaging characteristics, clinical course, and management of osteomyelitis.The duration of follow-up was calculated in months from diagnosis to the last follow-up visit.Recovery time was calculated in days from diagnosis to resolution of osteomyelitis, as noted in the discharge form or follow-up report.
Categorical variables are presented as absolute values and percentages; continuous variables are presented as median and range.

RESULTS
Seven patients were enrolled in the study: five males (71%) and two females of median age of 64 years (range 54-85) at diagnosis.The characteristics and medical history of the patients are detailed in Table 1.The average interval between initiation of steroid treatment and diagnosis of osteomyelitis was 139.5 days (range 28-426 days); Table 2 summarizes the malignant disease and treatment characteristics.Four patients (57%) had squamous cell carcinoma of the head and neck, two had nasopharyngeal carcinoma (29%), and one (14%) had papillary thyroid carcinoma.Most patients were treated with radiochemotherapy (five patients, 71%), and two of them also had surgery.Of the remainder, one patient was treated with radiation alone, and one patient with radiation and surgery.Four patients (57%) were  1 shows treatment plans using absolute dose color wash for three patients.
Imaging and infectious-related data All patients had imaging studies, as detailed in Table 3. Imaging included CT-non-contrast (NCCT) and contrast enhancement (CECT), MRI, and positron emission tomography-CT (PET-CT).Contrast material enhancement was noted in seven patients (100%): vertebral enhancement in five and meningeal and epidural enhancement in four.Figures 2-5 were carefully collected and described key features of the patients in our series.
A microbial culture was held in six patients (85%); results are detailed in Table 4.

Preceding events and possible triggers
In four patients (57%), a surgical or medical event preceded the diagnosis of osteomyelitis, as detailed in Table 4.These included an invasive intervention in three patients (43%), namely surgical alternative enteral feeding and biopsy, and pneumonia in one patient (14%).The mean interval from the precedent event to the diagnosis of osteomyelitis was 46.25 days (range 6-125 days).For these four patients, the mean interval from completion of the first radiotherapy to the diagnosis of osteomyelitis was 5.30 years (range 1.69-11.9).Three patients had tracheostomies while diagnosed with osteomyelitis.The mean interval between tracheostomy insertion and osteomyelitis diagnosis was 5.30 years (range 0.75-11.18)

Treatment and outcome
Table 4 shows infectious-related data.Four patients (57%) required surgical intervention and antibiotic treatment for osteomyelitis, and in three (43%), long-term broad-spectrum intravenous antibiotics alone were sufficient.Overall, 86% of patients received broad-spectrum antibiotics.Of the four patients (57%) with cervical spinal instability, three underwent cervical fusion surgery, and one was treated with a cervical collar alone.One  Five patients (71%) died during follow-up; three related to osteomyelitis-two died from septic shock, and one from cervical hemorrhage.Those patients died within 35 days of diagnosis of osteomyelitis (range 11-52 days).The remaining two patients died due to sepsis, unrelated to osteomyelitis: one due to pneumonia and the other urosepsis.Post-radiation osteomyelitis has a variable presentation. 24The mean time in our cohort between the first radiation treatment and diagnosis of osteomyelitis was long and had a wide range, similar to the experience of other centers. 24Thus, clinicians should maintain a high index of suspicion even decades after radiotherapy, alongside regular evaluation for recurrent or persistent squamous cell carcinoma. 22When post-radiation osteomyelitis is suspected, a thorough evaluation should be conducted, including flexible nasal endoscopy to assess discharge, local swelling, edema, and pharyngeal wall defect, in conjunction with a complete radiological assessment.The radiological assessment may be complex because of significant scar tissue from prior radiotherapy, limiting soft tissue swelling on lateral cervical spine X-rays.MRI is the modality of choice.and hypointensity on T1 images indicates loss of marrow fat signal. 8,25,26Contrast enhancement on T1 may be present with a soft-tissue inflammatory mass or a low-grade infection.However, MRI cannot differentiate infection superimposed on ORN from pure osteomyelitis.

Hyperintense signals on T 2 weighted images indicate infection
In our study, patients were evaluated using MRI, CT, PET-CT, or a combination of those studies, which yielded findings that might indicate active inflammation, which include contrast material enhancement of the vertebral body epidural and meningeal enhancement, fluid collection, free air caused by gasforming bacteria, and reactive lymphadenopathy.Thus, several imaging modalities may help diagnose active chronic infection, which would require an aggressive treatment approach.Table 5 addresses the imaging-based differences between osteomyelitis and the most relevant differential diagnosis-osteoradionecrosis based on different modalities of imaging.
In equivocal cases, bone biopsies can help identify ORN.All patients should undergo biopsies since tumor recurrence is an important differential diagnosis. 22Samples should include the suspected bone and surrounding soft tissue.Some authors advocated transoral instead of CT-guided biopsy via an anterior or transverse approach because CT-guided biopsy poses a risk to vital structures like the carotid triangle. 22This is especially true in necks that have been irradiated in which the extensive scarring distorts the anatomy.
The treatment of osteomyelitis is complex, let alone osteomyelitis of the head and neck central compartment owing to the complicated anatomy and the proximity to critical vascular, parenchymal structures and skull base.It usually includes surgery in addition to long-term broad-spectrum antibiotics. 27In our study, most patients required debridement and cervical fusion.In addition, surgical decompression would likely be necessary in the event of spinal cord compression by an epidural abscess.Furthermore, a few case reports have suggested the possible advantages of hyperbaric oxygen, including abscess reduction and improvement in mucosal defect. 28Thus, due to the potential benefits and relatively minor side-effects, hyperbaric oxygen should be considered in those dreadful complications.Further prospective research should better evaluate the advantages of hyperbaric oxygen.A critical finding in the present study was that a precedent event in most patients may have triggered osteomyelitis.Invasive procedures and localized infections in irradiated patients might cause temporary bacteremia, leading to infection in the damaged tissue.In addition, prior case reports have described anaerobic bacteremia after tracheostomy that might further complicate osteoradionecrotic tissue causing osteomyelitis in the head and neck central tissues. 29Nevertheless, we believe routine prophylactic antibiotics are not advised because of the complications of prolonged antibiotic use.
Cervical spine osteomyelitis is a dreadful complication with devastating short-and long-term outcomes causing high degrees of morbidity, debilitation, and mortality. 30In our research, the majority of patients who died during follow-up had an osteomyelitis-related death, and others died of severe inflammatory response syndrome due to infection.Cervical spine osteomyelitis is a complication that may cause mortality and indicates a poor patient prognosis since all those patients were malnourished, active, or cured of advanced-stage HNSCC after one or more highdose radiation treatments with possible concurrent chemotherapy.In recent decades, substantial advances have been made in radiotherapy, such as the transition from a two-dimensional to a three-dimensional technique.Additionally, the introduction of stereotactic radiotherapy allows for accurate delivery of high-dose radiation in multiple directions, thereby causing fewer side-effects. 31[34] This study was limited, first and foremost, by aa small cohort, single-institution experience, and a comparable control group.
In addition, due to the retrospective design, the reported data might be incomplete.

CONCLUSION
Midline structure osteomyelitis is a devastating complication of head and neck radiotherapy.Data in the literature remain sparse.
Diagnosis may be difficult because symptoms are often delayed and may be subtle.A thorough evaluation, including endoscopic examination, MRI, and possibly biopsy, must be performed in all cases to rule out tumor recurrence or metastasis, and infections should be treated aggressively with antibiotics.Internal stabilization and fusion should be performed in cases of instability and deformity.The present case series highlights the multidisciplinary protocol used in our institute, Rabin Medical Center, to evaluate patients with radiation-induced osteomyelitis to narrow the differential diagnosis, optimize work-up, and initiate prompt appropriate integrative treatment.Its application in various oncology centers worldwide is an attainable goal.We conclude that our initial results merit a continued effort in this direction.
patient was treated with hyperbaric oxygen therapy, which comprised 30 decompressions due to anaerobic drug-resistant bacteria.The average duration of follow-up was 1.90 months (range 11 days-3.97months).Four patients recovered from osteomyelitis; the average time to recovery in the four patients for whom data were available was 65 days (range 18-118 days).

Figure 1 .
Figure 1.An example of comparative treatment plans using relative dose color wash of axial slices from a 3D conformal portion plan for a patient with nasopharyngeal carcinoma (a) and Glottic SCC (b).

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birpublications.org/bjroBJR Open;5:20230001 BJR|Open Original research: Radiation-induced cervical osteomyelitis DISCUSSION Osteomyelitis of the cervical spine and skull base is an infrequent but dangerous head and neck radiation complication.Sparse data are available in the literature.The present case series describes the characteristics and clinical course of seven affected patients treated in a tertiary medical center over 8 years.Notably, in most patients, a medical or surgical event occurred in the months preceding the diagnosis of osteomyelitis.Multidisciplinary treatment was required, including broad-spectrum antibiotics and surgery.Recovery time was long, and outcomes were poor.

Figure 2 .
Figure 2. A SAGITAL NCCT of the cervical spine in bone window shows cortical irregularity in the anterior vertebral body of C5 and C6, prevertebral soft tissue swelling with air in the soft tissue and in the spinal canal.

Figure 3 .
Figure 3. C PET CT show high FDG intake in prevertebral soft tissue and C5-C6 vertebral bodies.

Table 2 .
Malignant disease and treatment characteristics

Table 5 .
Clinical features15 History of prior radiation therapy 16 Delayed onset (months to years after radiation) 17 Progressive symptoms 18 History of malignancy or radiation treatment 19 Infection-related symptoms (fever, chills, elevated WBC) 20 Acute or subacute presentation 21 Pain, tenderness, restricted neck movement PET, positron emission tomography.