Late radiation toxicity after whole-brain radiotherapy - The influence of antiepileptic drugs

This retrospective study had the following aims: (a) calculation of actuari al 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 re gard to concomitant treatment with antiepileptic drugs. We analyzed 49 adul t 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-rel ated parameters as possible predictive factors for clinical symptoms of lat e 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 prophylac tic intention (n = 3). Carbamazepine was given to 15 patients, phenytoin to 12, and barbiturate to 7, respectively; 42 patients also received corticos teroids. The median dose of WBRT was 30 Gy (range 27-66 Gy). Median fractio n 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). Medi an 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% afte r 1 year, 49% after 2 years, and 83% after 5 years. Actuarial rates of cere bral atrophy were 50% after I year and 84% after 2 years (white matter abno rmalities: 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 barbitu rate use, and preexisting cerebral atrophy. Clinical symptoms usually were dependent on BED too, but treatment with carbamazepine was more important i n 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 f ollow-up. Actuarial rates of grade I-III symptoms were 18% versus 50% after 1 year with or without carbamazepine. Even after exclusion of carbamazepin e-treated patients, CT changes and clinical symptoms did not correlate. In conclusion, a BED <120 Gy was associated with a lower rate of late radiatio n toxicity after WBRT. The anticonvulsant drug carbamazepine showed a surpr isingly clear influence on clinical symptoms of late radiation toxicity; th at might be explained by the fact that the side effects of long-term drug t reatment are indistinguishable from mild or moderate true radiation sequela e, rather than that it has a role in the pathogenesis of radiation-induced changes.