Cerebral radiation necrosis: Incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy

Purpose: To investigate radiation necrosis in patients treated for glioma in terms of incidence, outcomes, predictive and prognostic factors.

Methods and Materials: Records were reviewed for 426 patients followed up until death or for at least 3 years. Logistic regression analysis was performed to identify predictive and prognostic factors. Multivariate survival analysis was conducted using Cox proportional hazards regression. Separate analyses were performed for the subset of 352 patients who received a biologically effective dose (BED) ≥85.5 Gy₂ (≥45 Gy/25 fractions) who were at highest risk for radionecrosis.

Results: Twenty-one patients developed radionecrosis (4.9%). Actuarial incidence plateaued at 13.3% after 3 years. In the high-risk subset, radiation parameters confirmed as risk factors included total dose (p < 0.001), BED (p < 0.005), neuret (p < 0.001), fraction size (p = 0.028), and the product of total dose and fraction size (p = 0.001). No patient receiving a BED <96 Gy₂ developed radionecrosis. Subsequent chemotherapy significantly increased the risk of cerebral necrosis (p = 0.001) even when adjusted for BED (odds ratio [OR], 5.8; 95% confidence interval [CI], 1.6–20.3) or length of follow-up (OR, 5.4; 95% CI, 1.5–19.3). Concurrent use of valproate appeared to delay the onset of necrosis (p = 0.013). The development of radionecrosis did not affect survival (p = 0.09).

Conclusions: Cerebral necrosis is unlikely at doses below 50 Gy in 25 fractions. The risk increases significantly with increasing radiation dose, fraction size, and the subsequent administration of chemotherapy.

Introduction

Malignant gliomas are the most common primary brain tumors (1, 2), and glioblastoma multiforme (GBM) comprises over half of these tumors (3). Treatment for fit patients comprises maximal safe resection followed by radiotherapy (RT) ± concurrent and adjuvant chemotherapy. Studies by the Brain Tumor Study Group and the Scandinavian Glioblastoma Study Group in the late 1970s and 1980s demonstrated a 6-month gain in survival with the addition of radiotherapy to management protocols (4, 5, 6, 7, 8); however, even with treatment, outcomes are poor. The median survival for patients with GBM is 10–12 months (9), whereas 2-year survival rates for GBM and anaplastic astrocytoma are only 9% and 44%, respectively (2).

Radiation doses in the region of 46–50 Gy are as efficacious as higher doses in the treatment of low-grade glioma (10, 11), but doses of 60 Gy provide better outcomes for high-grade gliomas and are commonly prescribed for these tumors (12, 13, 14). The subsequent development of radionecrosis in some glioma patients is therefore not surprising.

Cerebral radionecrosis is a potentially devastating complication of radiotherapy to the brain. It was first described by Fischer and Holfelder in 1930 following radiotherapy administered for a basal cell carcinoma of the scalp (15). Since then, numerous case reports (16, 17, 18), case series (19, 20, 21, 22), and reviews (23, 24) have documented its occurrence after radiation therapy for a variety of intra-axial and extra-axial diseases over a range of doses and fractionation schedules. While thresholds of 54 Gy (21) and 57.6 Gy (25) have been reported for fraction sizes of 1.8–2.0 Gy delivered once daily, it is apparent that radionecrosis may occur below these limits (10, 23).

The incidence of radionecrosis after conventional radiotherapy for primary brain tumors in modern radiation oncology practice is largely unknown. Moreover, data are lacking on the actuarial risk of radiation necrosis in the general glioma population. This is mainly due to a lack of knowledge of the populations from which patients were accrued to various series, as well as a lack of data regarding the radiation doses and schedules employed (23). Additional difficulties relate to differentiating necrosis from tumor recurrence radiologically and to the low rates of reoperation and autopsy in these patients (26). Few authors have reported on this, and almost all these studies took place before the routine availability of modern anatomic and functional neuroimaging (10, 21, 26, 27, 28). Incidences ranging from 3% up to 24% for patients treated on an aggressive experimental protocol have been reported (26, 29).

Known risk factors for the development of radiation necrosis include total radiation dose; fraction size; treatment duration; and, at least in patients who receive radiosurgery, the irradiated volume (21, 23, 30, 31). These risks are difficult to quantify owing to deficiencies in their reporting in the literature, which is usually retrospective and often anecdotal. Furthermore, many studies date from an era when magnetic resonance imaging (MRI) and even computed tomographic scans were not widely available (19, 21, 23, 32), whereas others rely predominantly on abnormal radiology findings for diagnosis (33). The risks of radiosurgical or interstitial radiation boosts are, however, well appreciated (34, 35, 36, 37). Clinical experience also suggests that chemotherapy increases the risk of subsequent necrosis, but this has not been definitively demonstrated (23, 38, 39).

The deleterious clinical consequences of radiation necrosis are well appreciated. It is a condition that is associated with considerable morbidity and mortality despite therapy (23, 40). However, findings of some studies provocatively suggest that outcomes in patients with glioblastoma who survive after the development of radionecrosis may actually be more favorable than in those who do not develop this complication (36, 41, 42).

The purpose of this study was to investigate cerebral radiation necrosis in patients with glioma treated at our center in terms of incidence, outcomes, predictive and prognostic factors.