DEGRO practical guideline for central nervous system radiation necrosis part 2: treatment

Corticosteroids, such as dexamethasone, have long been the gold standard of RN treatment. For symptomatic patients, corticosteroids are the first-line treatment due to their anti-inflammatory potential and reduction of BBB leakage [9]. Improvement can often be seen rapidly due to the reduction of edema in RN patients with symptoms associated with the edema. Corticosteroids are potent, but offer only symptomatic relief from RN. Corticosteroids can be a double-edged sword, with a significant benefit and a low incidence of adverse effects for a limited treatment duration, but unmindful withdrawal or prolonged administration can have serious side effects [10]. Adverse effects of corticosteroids are both dose and time dependent, whereas other adverse effects follow a linear dose response, with an incidence increase with higher dose. Other adverse effects may follow a threshold dose–response pattern [11]. Benefits of corticosteroid use include their general and fast availability in most countries and the relative inexpensiveness compared to bevacizumab use or surgery. Since there are no studies regarding dose, we prefer to use dexamethasone with an initially high starting dose of 20–40 mg intravenous dexamethasone or 8 mg (1-0‑0 up to 1‑1-1) in symptomatic patients for 3 to 5 days, followed by a gradual reduction. We recommend a short-course maintenance dose of 1.5–2 mg, until the first follow-up (FU) MRI (6–8 weeks after initial diagnosis of blood–brain barrier disruptions [BBD]/RN) is performed to prevent a rebound effect. For immediate symptom relief, an attempt with high-dose dexamethasone (e.g., 20 mg i.v.) can be reasonable. In general, the lowest possible dose for the shortest possible duration is recommended. Patient education is vital in recognizing the adverse effects early. Furthermore, communication with other health professionals, especially in post-hospital treatment, is necessary to ensure that the patient is adequately monitored and the corticosteroid dose is reduced. With multimodal oncological treatments, it is often necessary to combine dexamethasone with other ongoing systemic therapies. In the era of immunotherapy, this becomes challenging, posing the question of whether the immunosuppressive effects of corticosteroids may lower the efficacy of immune- or targeted therapies [12].

Bevacizumab is a potent mediator in inhibiting the vicious cycle of RN development, and the efficacy of bevacizumab is supported by class IIb evidence. A double-blind, placebo-controlled phase II study evaluated bevacizumab for the treatment of symptomatic and progressive CNS radiation necrosis [13]. Eligible bevacizumab-naïve patients had undergone cranial radiation for grade 2–3 primary brain neoplasm, meningioma, or head and neck carcinoma and had progressive neurological symptoms with radiographic evidence of radiation necrosis. Patients were randomized to receive bevacizumab 7.5 mg/kg every 3 weeks (n = 5) or placebo (n = 7). At week 6, a median increase of 14% in T2-weighted FLAIR volume was observed in placebo-treated patients vs. a median decline of 59% for bevacizumab-treated patients (p = 0.0149). In addition, a median increase of 17% in T1-weighted contrast-enhanced volume was observed in placebo-treated patients vs. a median decrease of 63% in bevacizumab-treated patients (p = 0.0058). Xu et al. investigated, in a multicenter open-label study, patients with RN who were randomly assigned to a bevacizumab group (5 mg/kg intravenously every 2 weeks, 4 cycles) or a corticosteroid group: 38 patients in the bevacizumab group showed a response, which was significantly higher proportion than in the corticosteroid group (65.5% vs. 31.5%, p < 0.001). Furthermore, radiographic response was improved in the bevacizumab group [14]. Several additional studies reported excellent response rates for the treatment of RN with bevacizumab. The recurrence rate for RN after bevacizumab treatment is unclear and studies have reported recurrence rates between 10 and 39%, mainly independent of the primary disease [15]. Li et al. indicated that the duration from RN diagnosis to start of bevacizumab is a predictive factor for RN recurrence [16]. In general, RN diagnosis is difficult, even more so in the recurrent setting. Therefore, accurate recurrence rates are rare because physicians are often unable to distinguish between RN and tumor progression. In addition to diagnostic response, bevacizumab offers clinical improvement in the majority of patients suffering from RN with minimal toxicity [15]. The dose in the literature varies, but lower doses of 5.0–7.5 mg/kg every 2 weeks seem sufficient under regular control of blood pressure or thrombotic events to prevent typical side effects. The obvious broad therapeutic range shows that studies are needed to establish a minimum dose requirement for achieving the maximum clinical benefit and to make the bevacizumab treatment more cost effective. In a prospective clinical trial, patients were even treated with ultra-low doses of 1 mg/kg and radiographic responses were observed in 20 of the 21 patients [17], suggesting that efficacy is associated with its anti-angiogenic effects rather than dose [14, 18]. Several studies reported that side effects were mild and reported mostly low-grade adverse events [13, 17, 19]. Side effects included vascular events, hypertension, fatigue, proteinuria, anemia, leukopenia, neutropenia, and lymphocytopenia. In a prospective trial, Levin et al. reported that 6 (55%) patients experienced serious adverse events, including aspiration pneumonia, pulmonary embolism, and superior sagittal sinus thrombosis [13]. Another prospective trial by Xu et al. reported 40 grade 1 or 2 adverse events experienced by 58 patients but only one grade 3 adverse event of ischemic stroke. Interestingly, comparable side effects were seen in the corticosteroid-treated group, indicating that bevacizumab may not increase toxicity in the treatment of RN compared to dexamethasone [14]. The results of a randomized phase II study, which aims to investigate whether the addition of bevacizumab to standard corticosteroid therapy results in greater improvement in symptoms and less treatment-induced symptoms compared to standard corticosteroid therapy for patients with symptomatic RN following SRS are pending (NCT02490878) [20].

Laser interstitial thermal therapy (LITT) is a potential treatment option, but direct comparative data are scarce, with only a few patients being treated with LITT, and the technique is not generally available [21, 22]. The advantage of LITT is its minimal invasiveness and ability to provide same-procedure pathologic confirmation of RN. Palmisciano summarized the available evidence in a recent review. Among the 18 studies included, 143 patients received bevacizumab and 148 underwent LITT. Both strategies were effective in providing post-treatment symptomatic improvement (p = 0.187), weaning off steroids (p = 0.614), and local lesion control (p = 0.5) [23].

Hyperbaric oxygen therapy (HBOT) demonstrated the ability to reduce edema and prospective studies report radiographic and symptomatic improvement of RN with HBOT [24‐27]. Approximately 90% of the patients improved and 60% responded clinically during the course of HBOT after a median of 30 treatments. It has to be highlighted that in many reported cases, HBOT was administered with concomitant dexamethasone or bevacizumab, and studies evaluating hyperbaric oxygen therapy alone are rare and the available evidence is low. Common side effects of HBOT are usually low grade and can include ear barotrauma, dyspnea, ear pain requiring myringotomy, and sinusitis [24, 27, 28].

Standard of care for rapidly progressing, symptomatic RN is considered to be surgical removal, depending on the location and estimated morbidity of the procedure. This approach is consistent with the tumor-like growth pattern of RN and can be achieved with low rates of morbidity if patients are selected carefully and discussed within an interdisciplinary setting [29]. The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in bevacizumab-treated patients; thus, at least 28 days of bevacizumab “wash-out” before elective surgery is recommended at present [30]. Currently, data on the benefit of surgical resection of RN are sparse. However, existing evidence shows that gross total resection leads to reduced edema and use of steroids during follow-up [31]. Preoperative symptoms, such as headache or seizures, only improved in 55% after surgery but were independent of the extent of resection. However, regarding BM data, symptom relief was reported by 55% of patients undergoing RN resection independently of the extent of surgical resection (EOR), while most effects of bevacizumab were only reported 3 months after treatment or later.

GBM does not usually have extracranial disease necessitating systemic therapy but requires an evaluation of rather a purely local disease.

Surgery can potentially reduce the CNS tumor burden if RN is combined with residual tumor cells. Yet, at least for GBM, no difference was shown in overall survival for surgery or bevacizumab if RN consisted of necrosis only vs. residual tumor cells [32]. Thus, there seems to be no advantage of cytoreduction or RN resection in terms of survival. Considering the goal of maximizing quality of life (QOL) in tumor patients, the treatment of agonizing symptoms, such as seizures or headache, is a legitimate rationale for surgical treatment. The resection of RN is very similar to a glioma resection, with a continuous border between healthy tissue and necrosis. Thus, the same principles need to be applied by the neurosurgeon, including intraoperative neurophysiology via MRI to secure maximum safe resection. Since RN neighbors previous resection cavities, it can affect eloquent subcortical anatomy, necessitating the respective caution and measures, especially considering the usually closer location to eloquent tracts.