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BACKGROUND: The introduction of cranial radiotherapy (CRT) has provided efficient control of overt or subclinical meningeosis in acute lymphoblastic leukemia (ALL). Especially due to the long-term toxicity of CRT, reduction or elimination of radiotherapy appeared mandatory after cure rates of more than 70% had been achieved in ALL. The Berlin-Frankfurt-Münster (BFM) Study Group initiated several attempts in certain ALL subgroups to omit or reduce CRT while using more CNS-directed chemotherapy but without extended intrathecal treatment during maintenance therapy. This analysis summarizes the essential results that are in particular relevant because irradiation of the central nervous system (CNS) has been further reduced in the most recent trial ALL-BFM 95. PATIENTS AND METHODS: More than 4000 patients enrolled between 1981 and 1995 in one of the last four ALL-BFM trials have been analyzed to demonstrate the efficiency of intensive systemic and intrathecal chemotherapy with or without reduced CRT in the prevention of CNS relapses. RESULTS: In trial ALL-BFM81, it was shown that only in low-risk (LR) patients preventive radiotherapy can be replaced safely by intermediate dose (0.5 g/m2) methotrexate (MHD-MTX). In intermediate risk (IR) patients this attempt failed: IR pts had 8 times more CNS relapses if treated by MHD-MTX without CRT. In the subsequent trial ALL-BFM 83, all pts received MHD-MTX. IR pts were randomly treated with 12 or 18 Gy of preventive CRT which did not result in a significantly different outcome. The results from the subsequent trial ALL-BFM 86, using a more intensive consolidation with high-dose methotrexate (HD-MTX), demonstrated that the elimination of CRT in low-risk ALL, the reduced CRT of 12 Gy for IR, 18 Gy for medium (MR), and the reduced CRT with 18 Gy for high risk (HR) ALL, respectively, was justified: the incidence of relapses with CNS involvement was reduced to less than 5% (Reiter et al. 1994, Blood 84: 3122). When even less intensive preventive CRT (12 Gy for all medium and high risk patients) was used in trial ALL-BFM 90, the rate of CNS-related relapses was again below 5%. HR patients now treated with more CNS-directed chemotherapy had the lowest rate of CNS-related relapses observed so far in the BFM trials, even though CRT was also reduced to 12 Gy. Patients with T-cell ALL were shown to be protected from CNS recurrence by the combination of CRT (12 Gy) and HD-MTX more effectively than by HD-MTX in consolidation and TIT therapy during maintenance, especially if they presented with high WBC as shown in a joint AIEOP/BFM analysis (Conter et al. 1997, JCO 15: 2786). Patients with overt meningeosis which are characterized by a high leukemic cell load at diagnosis had a rate of recurrences that was comparable to that of patients with high WBC but no CNS disease. CONCLUSION: Low-risk ALL patients can be efficiently prevented from CNS relapse by intensive systemic and intrathecal chemotherapy without CRT. Patients with intermediate or medium risk ALL, including T-cell ALL, did not suffer from more CNS or systemic relapses when CRT was reduced to only 12 Gy. Patients with inadequate response to therapy are at particularly high risk for relapse with CNS involvement. Therefore, more CNS-directed systemic and intrathecal chemotherapy was applied in trial ALL-BFM 90, combined with only 12 Gy cranial irradiation, and improved the control of CNS recurrence. It seems likely that larger subsets of B-precursor ALL can be protected from CNS-related relapse by intensive chemotherapy without extended IT treatment and without CRT. This is being investigated in the ongoing trial ALL-BFM 95.