Review
Cerebral radiation necrosis: A review of the pathobiology, diagnosis and management considerations

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Abstract

Radiation therapy forms one of the building blocks of the multi-disciplinary management of patients with brain tumors. Improved survival following radiation therapy may come with a cost, including the potential complication of radiation necrosis. Radiation necrosis impacts the quality of life in cancer survivors, and it is essential to detect and effectively treat this entity as early as possible.

Significant progress in neuro-radiology and molecular pathology facilitate more straightforward diagnosis and characterization of cerebral radiation necrosis. Several therapeutic interventions, both medical and surgical, may halt the progression of radiation necrosis and diminish or abrogate its clinical manifestations, but there are still no definitive guidelines to follow explicitly that guide treatment of radiation necrosis. We discuss the pathobiology, clinical features, diagnosis, available treatment modalities, and outcomes in the management of patients with intracranial radiation necrosis that follows radiation used to treat brain tumors.

Introduction

Conventional radiation therapy (CRT) and stereotactic radiation therapy (SRT) represent important components of comprehensive strategies to treat patients with brain tumors. Three time-limited forms of radiation toxicity have been described: acute, early delayed and delayed long-term radiation-induced neurotoxicity. Acute toxicity occurs during or immediately after radiation treatment; early delayed neurotoxicity occurs up to 12 weeks following treatment; and delayed neurotoxicity develops and evolves from 3 months to a few years following treatment (Fig. 1).1 The various manifestations of delayed radiation neurotoxicity include radiation necrosis (RN), radiation leukoencephalopathy, radiation myelopathy, and, in the peripheral nervous system, plexus or nerve root lesions.2, 3 In 1930, Fischer and Holfelder described the first case of delayed RN following radiation therapy of a basal cell carcinoma of the scalp.4 In 1950, Lowenberg-Scharenberg described the pathological occurrence of amyloid degeneration in cerebral parenchyma following X-ray irradiation.5 These initial descriptions were followed by numerous additional reports, series and reviews that have since documented RN as a major complication of therapeutic central nervous system (CNS) irradiation.6, 7, 8, 9, 10, 11 Similar effects have also been observed as a complication of radiation therapy to tumors of the paranasal sinuses, nasopharynx, middle ear, parotid and lacrimal glands, in which cases the CNS is incidentally involved in the treatment field(s).12, 13

The exact incidence of intracranial RN remains undetermined, although it ranges from 5–50%, depending on the modality of treatment, the dose delivered, the duration a patient is followed clinically and with neuroimaging, the neuroimaging criteria used, and whether clinical signs and symptoms are present.14 Kramer et al. initially attempted to determine the incidence of RN by reviewing the literature, but could not come to a conclusion because of a lack of data regarding the total treated population.15 Several factors continue to complicate a detailed analysis of the actual rates of RN, including alternate modalities of radiation therapy, the fact that the published literature comprising mostly class III evidence, that not all reported studies have histopathological confirmation of their findings, and that variable treatment parameters have been used for radiation delivery (including dose, fractionation schedules, treatment times, radiation field arrangements and volume).9 Additionally, most of the studies took place prior to the availability of modern neuro-imaging, making it difficult to calculate radiation parameters.9, 16, 17 The use of adjuvant chemotherapy has further confounded the analysis of data. In addition, the exact population being diagnosed and treated has also been variably reported in the literature as the number of patients treated rather than those at risk (survivors), which may underestimate risk, thus making it difficult to ascertain a precise incidence for RN.

In this review we present a comprehensive review of intracranial RN after therapeutic brain irradiation, with a focus on RN developing in patients after radiation therapy of a brain tumor. We discuss the pathobiology of RN, its clinical features, its diagnosis, and potential strategies for its management, including the benefit and toxicity profiles of these therapies.

Section snippets

Pathobiology of radiation necrosis

Radiation-induced damage can occur with radiation doses as low as 50 Gy, however the radiation dose is directly proportional to the risk of brain injury.18 In cases where fractionated therapy is used, larger fractional doses correspond to a greater risk of subsequent RN.19 Chemotherapy may potentiate the risk of brain injury, and was first reported in children who survived treatment for leukemia.20 Lai et al. reported a series of five patients, treated with whole brain radiotherapy and high-dose

Determinants of radiation necrosis

Patients vary in their individual responses to radiation therapy. Some may develop severe adverse reactions, while others treated for similar pathologies in similar locations with comparable radiation doses and administration protocols do not. The extent of these adverse reactions are a limiting factor in the total radiation dose delivered, modulating the success of radiation therapy, both with respect to tumor response and toxicity. The precise cause of this variability in response remains

Conventional radiation therapy (CRT)

The reported incidence of cerebral RN has fluctuated over the years. In 1975, Marsa et al.76 reported an incidence of 15%, while in 1986, Hohweiler et al.77 noted a rate of 14% following CRT protocols. In addition to focal patterns of RN, both groups observed more diffuse changes, such as periventricular white matter changes, consistent with patterns of diffuse radiation induced injury. These changes increased with age, cerebral volume irradiated, dose and interval between imaging and

Diagnosis

The dilemma in the diagnosis of RN lies in the fact that tumor recurrence and necrosis may have similar manifestations, both in clinical presentation and radiological appearance. However, management of these two entities may be diametrically opposed, with recurrent tumors requiring intervention to stop growth whereas RN may follow a more benign management path.

Management considerations

Spontaneous resolution of cerebral RN may occur, but in many patients symptoms develop and can be progressive, necessitating treatment to provide symptomatic relief.157 In a few patients, the relentless nature of the pathology may necessitate surgical resection of the necrotic mass.9, 158 It is paramount that the patient understands the nature of the pathology being treated, and the consequences and sequelae of the condition – as well as the various treatments that may be used and their

Considerations for patient evaluation and management

We have classified considerations for patient management into four ascending categories based on clinical and radiological findings (Fig. 5). Recommendations for clinical and imaging follow-up are detailed above, in the section entitled “Observation and steroids.” One common strategies to initially perform clinical and imaging follow-up at short intervals (for example, every 6–12 weeks for 2–4 cycles), slowly increasing over time (every 4–6 months for 2–4 cycles until the imaging lesion is

Conclusion

Radiation therapy is an important treatment modality in patients with brain tumors, but local toxicities complicate this treatment. A subset of patients receiving radiotherapy as adjuvant brain tumor therapy will ultimately develop RN. Significant risk factors for developing RN are the total dose of radiotherapy delivered, the fractionated dose, and the addition of concurrent chemotherapy.190 Although modern imaging techniques have improved the specificity and sensitivity of radiographic

Conflict of Interest

There are no conflicts of interest to report for any of the authors.

Role in the Study

Conception and Design: Rahmathulla, Marko, Weil

Acquisition of Data: Rahmathulla, Marko

Analysis and Interpretation of the Data: Rahmathulla, Marko, Weil

Drafting the article: Rahmathulla, Weil

Critically revising the article: Rahmathulla, Marko, Weil

Final manuscript review and approval: Rahmathulla, Marko, Weil

Study supervisor: Weil

Acknowledgements

We wish to thank the Melvin Burkhardt chair in Neurosurgical Oncology and the Karen Colina Wilson Research Endowment within the Burkhardt Brain Tumor and Neuro-oncology Center at the Cleveland Clinic Foundation for additional support and funding.

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