Approach to the patient with radiation necrosis

Introduction

Cerebral radiation necrosis is a challenging and potentially devastating complication of cranial irradiation. Based on the temporal relationship to radiation therapy (RT), it can be classified as pseudoprogression (a form of early subacute injury) or radiation necrosis (a form of delayed injury). Pseudoprogression typically occurs within 3 months of fractionated RT and usually reverses spontaneously after a few weeks. Delayed radiation necrosis typically develops months or years after RT and is considered more irreversible. Radiation necrosis can have a waxing and waning clinical course but may also be relentlessly progressive. ^, The pathophysiology is attributed to a combination of vascular endothelial cell damage, glial cell injury, and immune–mediated reactions. These cascading events lead to increased permeability of the blood-brain barrier, followed by coagulative necrosis and demyelination. Vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1α appear to be increased in the tumor micro-environment and may play important roles in the development of radiation necrosis. ^,

Diagnosis

Both early pseudoprogression and delayed radiation necrosis are typically characterized by increased contrast-enhancement or the appearance of ring-enhancing lesions on T1-weighed magnetic resonance imaging (MRI) sequences as well as increased vasogenic edema on T2-weighed MRI sequences. These changes may be accompanied by neurological symptoms such as headache, seizure, speech difficulty, cognitive dysfunction, or vision deficits. The clinical and imaging characteristics are indistinguishable from tumor progression or recurrence. However, they typically regress over time, and surgical resection of enhancing lesions reveals extensive necrotic tissues that may also contain minimal viable tumor cells that exhibit significant treatment-related changes. ^,

The diagnosis of radiation necrosis can be very challenging and can pose significant dilemma for treating physicians. Prolonged follow-up of the clinical course with imaging is often preferred; surgery with histopathologic confirmation is the gold standard for confirming the diagnosis. ^, However, surgery is not always possible or preferable, and observation may risk delaying salvage treatment for recurrent tumor. Advanced imaging techniques, such as MR perfusion, MR spectroscopy, and positron emission tomography (PET), have been reported by different institutional studies as effective at distinguishing radiation necrosis from tumor recurrence with mixed results. ^{, ,}

MR perfusion . In one of the largest studies on MR perfusion, Barajas et al. retrospectively analyzed 57 glioblastoma (GBM) patients who developed progressively enlarging lesions within the RT fields after chemoradiotherapy and were evaluated using MR perfusion. Their study cohort consisted of 40 patients who had histologic confirmation of recurrent tumor, 15 with histologically confirmed radiation necrosis, and 2 with clinically diagnosed radiation necrosis. Although relative cerebral blood volume (rCBV), the common parameter used to analyze MR perfusion, was statistically higher among the recurrent tumor cohort than the radiation necrosis cohort, there was significant overlap between the two groups. Overall, rCBV did not reliably distinguish recurrent GBM from radiation necrosis (sensitivity: 79%; specificity: 72%). This study showed that relative peak height (rPH), a less common parameter to analyze MR perfusion, was more accurate (sensitivity: 89%; specificity: 81%). However, these findings have not been consistently replicated in other retrospective studies.

MR spectroscopy . MR spectroscopy measures metabolic composition of tissue such as lipid and choline to distinguish tumor and necrosis. However, it suffers from poor spatial resolution and low reproducibility, and its accuracy has been mixed in the literature. ^{, ,}

Positron emission tomography (PET) . Fluorodeoxyglucose (FDG)-based PET has generally shown modest predictive accuracy for distinguishing radiation necrosis from recurrent tumor in small retrospective studies, with sensitivity ranging from 65–81% and specificity ranging from 40–94%. Normal brain unfortunately exhibits variable FDG update and can obscure the uptake of a tumor. Radiation necrosis can also trigger repair mechanisms to increase glucose uptake, leading to a false-positive interpretation. Novel amino acid tracers, such as 3,4-dihydroxy-6-(18F)-fluoro-phenylalanine (FDOPA) or (18F)-fluciclovine, may be superior to FDG for PET evaluation of suspected radiation necrosis but are not widely available in most clinics. To date, none of these advanced imaging techniques have been validated in large prospective studies to reliably diagnose radiation necrosis from recurrent tumor. Thus, findings should be interpreted with caution and evaluated as part of the larger context of the patient’s clinical course and other risk factors for radiation necrosis or recurrent tumor. Suspected radiation necrosis cases should ideally be managed by an experienced multidisciplinary team of neurosurgeons, radiation oncologists, and neuro-oncologists.