Prevention of central nervous system leukemia by irradiation

Abstract

During the past 10 years, 1962 to 1972, we have administered irradiation to the central nervous system (CNS) during the first few weeks of remission of acute lymphocytic leukemia (ALL) as an integral part of a treatment plan aimed at cure of ALL. Its purpose has been to eradicate residual leukemia in the CNS and thus prevent CNS relapse. The results indicate that craniospinal irradiation alone, 2400 rads, or cranial irradiation, 2400 rads, with simultaneous intrathecal methotrexate is effective in ‐preventing CNS relapse. This results in marked improvement in complete remission duration and a 50% frequency of long‐term leukemia‐free survival and possible cure. Although intermittent intrathecal methotrexate during remission is said to reduce the incidence of CNS relapse by one half, a 15‐fold reduction results from adequate preventive CNS irradiation. Until a better method is found, all children with ALL should receive adequate CNS irradiation early during remission in order to prevent CNS relapse and to prolong complete remission.

Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000

“…1,2 The study was based on the results from research on drug resistance and on the first observations that long-term remissions of ALL can be achieved by using drug combinations and central nervous system (CNS) irradiation. 3 The probability of event-free survival (EFS) at 5 years was 55% (±6%) in this trial, which was achieved by an 8-week remission induction regimen ('Protocol I') combining the eight most effective antileukemic agents known at that time. The regimen also comprised cranial or craniospinal irradiation followed by antimetabolite-based maintenance therapy.…”

“…A randomized study question was asked in the large intermediate-risk group: (1) Can the outcome of intermediate-risk patients be improved by an additional late re-intensification element ('Protocol S')? Other treatment modifications were implemented in a non-randomized manner for a historical comparison with the results of the previous trials: (2) ID-MTX was substituted by high-dose MTX (HD-MTX, 5 g/m 2 /24 h  4) combined with IT MTX ('Protocol M') for all patients to improve extramedullary disease control, but also to allow further elimination/reduction of pCRT; (3) pCRT was omitted in all SR patients (BFM-RFo0.8) and irradiation dose was reduced to 12 Gy for intermediate-risk patients with BFM-RFo1.2; (4) The anthracycline dose and dose intensity was increased in induction and (5) For HR patients, now mainly identified by PPR and/or induction failure, an experimental, intensive consolidation treatment was initiated ('Protocol E'). 15 Trial ALL-BFM 90 aimed at further reduction of treatment burden for the majority of patients while selectively targeting subgroups with increased risk for treatment failure.…”

Long-term follow-up of childhood acute lymphoblastic leukemia in Tokyo Children's Cancer Study Group 1981–1995

“…The development of prophylactic cranial irradiation greatly contributed to the improvement of outcome of childhood ALL. 1,2 Trials to reduce the utilization of cranial irradiation had already been initiated in the 1970s and the results were reported in 1980. 3,4 From the 1980s to 1990s, fundamental prognostic factors such as age, leukocyte count, cell lineage and chromosomal abnormalities were elucidated and applied to the risk-adopted strategy.…”

CNS minimal disease therapy in childhood leukaemia: the place for irradiation

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In the 1960s, when the initial trials of combination chemotherapy began to prolong remission duration in childhood acute lymphoblastic leukaemia, an increasing incidence of central nervous system relapse was noted with rates between 50 and 70% (Hardisty & Norman, 1967;Evans et al, 1970;Hustu et al, 1973). Overt CNS leukaemia appeared difficult to control, but its major significance was that it was almost invariably followed by bone marrow relapse, whilst deaths from neurological dysfunction were quite rare, even in the presence of multiple CNS recurrences (Ortega et al, 1987).

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“…As cell numbers increase the arachnoid trabeculae are destroyed with subsequent penetration of cerebrospinal fluid channels over the surface of the brain. (Aur et al, 1971;Hustu et al, 1973). Whether such treatment prevents subsequent haematological relapse is more controversial.…”