Risk of Late or Recurrent Radiation Necrosis beyond 5 Years from Stereotactic Radiosurgery

Abstract

<h3>Purpose/Objective(s)</h3> Radiation necrosis (RN) is a well-recognized complication most commonly occurring within 1-3 years of stereotactic radiosurgery (SRS). However, the incidence of late RN after this period is poorly described. This study characterizes the incidence of and risk factors for late or recurrent RN occurring five years after SRS. <h3>Materials/Methods</h3> This single-institution, retrospective analysis included patients treated with LINAC-based SRS (any indication) who were followed for over five years clinically and with serial MRI imaging. Late or recurrent RN was defined as any imaging changes with corresponding neurologic symptoms or deficits occurring after five years from treatment not attributable to disease recurrence. Associations with late RN were analyzed using Pearson coefficients, Mann-Whitney U tests, and Fisher's exact test. Univariate and multivariate analyses were performed using Cox proportional hazards model. <h3>Results</h3> We identified 219 patients who were treated to a cumulative 297 lesions over 246 SRS courses to a median dose of 17.0 Gy (range: 12-35 Gy). 290 (97.3%) were treated in a single fraction with 64 (21.5%) of the lesions having been adjuvantly following resection. The median follow-up time was 7.4 years (range: 5.1-16.1 years), and late or recurrent RN occurred in 19 (12.9%) patients and in 23 (7.7%) lesions at a median 6.1 years (range: 5.1-13.9 years) from SRS. 15 of the 23 (65.2%) lesions with late RN were managed successfully with steroids, bevacizumab, and/or anti-epileptic drugs. The remaining 8 (34.8%) were refractory to medical therapy and required resection, and histopathology confirmed necrosis without disease recurrence in each. Late or recurrent RN was more common among brain metastases and arterial-venous malformations or fistulas (Table 1). The mean dose in lesions that developed late RN was higher than for lesions that did not (18.5 ±1.5 Gy vs. 16.5± 4.1 Gy; p<0.001). Gross tumor volume >1.5cc (HR: 4.6, 95% CI: 1.8-11.6; p=0.001), PTV margins >1mm (HR: 3.1; 95%CI: 1.1-9.0, p=0.040), brain V12 Gy >5cc (HR: 18.7, 95% CI: 5.5-63.2; p<0.001), and a history or early, resolved RN (HR: 13.7, 95% CI: 5.1-36.8; p<0.001) were all associated with late or recurrent RN. On multivariate analysis, only brain V12 Gy >5cc (HR: 4.6 95% CI: 1.0-20.5; p=0.046) and a history of early, resolved RN (HR: 4.0; 95% CI: 1.2-12.7; p=0.021) remained significantly associated with late or recurrent RN. <h3>Conclusion</h3> This is the first study, to our knowledge, describing the risk of late or recurrent RN beyond five years from SRS. While uncommon, late or recurrent RN was associated with brain V12 Gy >5 cc a history of early RN, suggesting that closer long-term follow-up may be warranted for these select patients.