Late radiation toxicity after whole brain radiotherapy: the influence of antiepileptic drugs.

Abstract

This retrospective study had the following aims: (a) calculation of actuarial rate of late radiation toxicity after whole-brain radiotherapy (WBRT), (b) correlation of clinical symptoms with changes of computed tomography (CT) scans, and (c) analysis of potentially predictive factors with special regard to concomitant treatment with antiepileptic drugs. We analyzed 49 adult patients, selected from a preexisting data base. Inclusion criteria were as follows: no previous brain irradiation; WBRT without boost; CT, clinical, and neurologic examination before and more than 3 months after completion of WBRT. Uni- and multivariate tests of various patient- and treatment-related parameters as possible predictive factors for clinical symptoms of late radiation toxicity (scored according to the RTOG/EORTC system) as well as cerebral atrophy and white matter abnormalities were performed. Median age was 54 years. Patients were treated for brain metastases (n = 37), primary cerebral lymphoma (n = 2), primary brain tumors (n = 7), or with prophylactic intention (n = 3). Carbamazepine was given to 15 patients, phenytoin to 12, and barbiturate to 7, respectively; 42 patients also received corticosteroids. The median dose of WBRT was 30 Gy (range 27-66 Gy). Median fraction size was 3 Gy (1-3 Gy). Nine patients received two fractions per day. The biologically effective dose (BED) according to the linear-quadratic model ranged between 90 and 141 Gy (median, 120 Gy; alpha/beta value, 1 Gy). Median follow-up was 10 months (range, 4-130 months). In 16 cases, symptoms of late radiation toxicity grade I-III appeared. Actuarial rates were 32% after 1 year, 49% after 2 years, and 83% after 5 years. Actuarial rates of cerebral atrophy were 50% after 1 year and 84% after 2 years (white matter abnormalities: 25% and 85%, respectively). There was a significant correlation between atrophy and white matter abnormalities, but not between CT changes and clinical symptoms. CT changes were dependent on BED, absence of barbiturate use, and preexisting cerebral atrophy. Clinical symptoms usually were dependent on BED too, but treatment with carbamazepine was more important in the multivariate model. Neither other drugs nor other factors influenced late radiation toxicity. A detailed analysis showed that most carbamazepine-treated symptomatic patients took the drug during WBRT as well as during follow-up. Actuarial rates of grade I-III symptoms were 18% versus 50% after 1 year with or without carbamazepine. Even after exclusion of carbamazepine-treated patients, CT changes and clinical symptoms did not correlate. In conclusion, a BED <120 Gy was associated with a lower rate of late radiation toxicity after WBRT. The anticonvulsant drug carbamazepine showed a surprisingly clear influence on clinical symptoms of late radiation toxicity; that might be explained by the fact that the side effects of long-term drug treatment are indistinguishable from mild or moderate true radiation sequelae, rather than that it has a role in the pathogenesis of radiation-induced changes.