Very high-dose methotrexate (33.6 g/m(2)) as central nervous system preventive therapy for childhood acute lymphoblastic leukemia: results of National Cancer Institute/Children's Cancer Group trials CCG-191P, CCG-134P and CCG-144P.
Between 1977 and 1991, the Children's Cancer Group and the National Cancer Institute conducted three trials of very high-dose methotrexate (33.6 g/m2; VHD-MTX) in place of cranial radiation (CRT) as central nervous system (CNS) preventive therapy, and assessed efficacy, acute toxicity and long-term neurocognitive outcome. CCG-191P compared VHD-MTX to CRT plus intrathecal methotrexate (IT-MTX) in 181 patients and demonstrated equivalent survival. However, patients treated with CRT had poorer performance on neurocognitive testing over time. CCG-134P evaluated the addition of intensified systemic and intrathecal therapy to VHD-MTX in 128 patients with high-risk acute lymphoblastic leukemia (ALL) and demonstrated reduced CNS relapse compared to the CCG-191P trial, but equivalent survival. CCG-144P compared VHD-MTX to IT-MTX alone in 175 patients with average-risk ALL and demonstrated equivalent survival. VHD-MTX was associated with significant toxicities, particularly neutropenia, transient hepatic dysfunction and sepsis. VHD-MTX achieved similar survival to other CNS-directed therapies without the long-term impact on intelligence, but with substantial acute toxicities.
Nathan
Paul C
PC
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Whitcomb
Trish
T
Wolters
Pamela L
PL
Steinberg
Seth M
SM
Balis
Frank M
FM
Brouwers
Pim
P
Hunsberger
Sally
S
Feusner
James
J
Sather
Harland
H
Miser
James
J
Odom
Lorrie F
LF
Poplack
David
D
Reaman
Gregory
G
Bleyer
W Archie
WA
D000293:Adolescent; D000328:Adult; D016543:Central Nervous System Neoplasms / Q000517:prevention & control*; D002648:Child; D002675:Child, Preschool; D003071:Cognition / Q000187:drug effects; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D010865:Pilot Projects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D012306:Risk; D016896:Treatment Outcome
D008727:Methotrexate