Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: a Childrens Cancer Group report.
OBJECTIVE
This study (Childrens Cancer Group [CCG]-105) was designed in part to determine in a prospective randomized trial whether intrathecal methotrexate (IT MTX) administered during induction, consolidation, and maintenance could provide protection from CNS relapse equivalent to that provided by cranial radiation (CXRT) in children with acute lymphoblastic leukemia (ALL) and intermediate-risk features.


METHODS
We randomized 1,388 children with intermediate-risk ALL to the two CNS regimens. They received either IT MTX at intervals throughout their course of therapy or CXRT (18 Gy) during consolidation with IT MTX during induction, consolidation, and delayed intensification. Systemic therapy was randomized to one of four treatment regimens derived from a regimen used by CCG in recent studies for this patient population and three more intensive regimens based on the Berlin-Frankfurt-Munster trials.


RESULTS
Life-table estimates at 7 years show a 93% and 91% CNS relapse-free survival rate for the CXRT and IT MTX groups, respectively. The corresponding event-free survival (EFS) rates are 68% and 64%. The differences are not significant. Patients who received more intensive systemic therapy had a 94% CNS relapse-free survival rate on either CXRT or IT MTX, while patients who received standard systemic therapy had 90% and 80% rates for CXRT and IT MTX, respectively (P < .0001). Patients less than 10 years of age who received CXRT or IT MTX had 72% and 71% EFS rates if they received more intensive systemic therapy. Patients 10 years or older who received CXRT had an improved EFS (61% v 53%) with a more intensive systemic program. This was primarily due to fewer bone marrow relapses (P = .04).


CONCLUSIONS
IT MTX during induction, consolidation, and maintenance provides protection from CNS relapse in patients with intermediate-risk ALL equivalent to that provided by CXRT if more intensive systemic therapy is given. The CNS relapse rate with either CXRT or IT MTX is in part dependent on the associated systemic therapy. For intermediate-risk patients less than 10 years of age, IT MTX with an intensified systemic regimen provided CNS prophylaxis comparable to that provided by CXRT, whereas older patients had fewer systemic relapses if they received CXRT.
Tubergen
D G
DG
Children's Hospital, Denver, CO.
Gilchrist
G S
GS
O'Brien
R T
RT
Coccia
P F
PF
Sather
H N
HN
Waskerwitz
M J
MJ
Hammond
G D
GD
D000293:Adolescent; D000328:Adult; D016543:Central Nervous System Neoplasms / Q000517:prevention & control* / Q000556:secondary; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D005260:Female; D006801:Humans; D007223:Infant; D007278:Injections, Spinal; D015993:Life Tables; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy*; D011446:Prospective Studies; D016019:Survival Analysis
D008727:Methotrexate