Journal of Clinical Oncology, Vol 5, 2017-2031, Copyright © 1987 by American Society of Clinical Oncology
High-dose methotrexate: a critical reappraisal
SP Ackland and RL Schilsky
Joint Section of Hematology/Oncology, University of Chicago, IL.
High-dose methotrexate (HDMTX) with leucovorin (LV) rescue has been used as
a therapeutic strategy in oncology for more than a decade. Administration
of HDMTX results in tumoricidal plasma concentrations of the drug without
significant host toxicity, provided that plasma MTX levels are monitored
and LV rescue is properly administered. The original premise of LV rescue
was that the provision of reduced folate to normal cells would circumvent
the metabolic block produced by MTX and allow resumption of DNA synthesis,
although the presumed therapeutic selectivity of leucovorin has not yet
been adequately explained. Despite a strong pharmacologic rationale and a
vast clinical experience, HDMTX with leucovorin rescue has not been shown
to be unequivocally superior to conventional doses of MTX in any clinical
situation except, perhaps, for treatment of osteogenic sarcoma and
childhood acute leukemia. While HDMTX is an important component of
effective treatment regimens for these diseases, its precise contribution
to the success of these regimens remains undefined. Although HDMTX can
theoretically overcome all known mechanisms of MTX resistance, no data
exist to suggest that this can be accomplished in the clinic. Thus, this
well-known but poorly understood treatment regimen must remain a subject of
clinical investigation rather than a part of routine clinical practice.
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