High-dose methotrexate: a critical reappraisal.

Area of Science:

• Oncology
• Pharmacology
• Clinical Therapeutics

Background:

• High-dose methotrexate (HDMTX) with leucovorin (LV) rescue is a widely used cancer treatment.
• Its administration aims for tumoricidal drug concentrations while minimizing host toxicity through careful monitoring and LV support.
• The mechanism of LV rescue, intended to protect normal cells by bypassing methotrexate's metabolic block, remains incompletely understood.

Purpose of the Study:

• To evaluate the established efficacy and clinical understanding of HDMTX with LV rescue.
• To determine if HDMTX offers unequivocal advantages over conventional methotrexate doses.
• To assess the clinical applicability of HDMTX in overcoming methotrexate resistance.

Main Methods:

• Review of existing clinical data and pharmacologic rationale for HDMTX with LV rescue.
• Comparison of HDMTX efficacy against conventional methotrexate doses in various oncologic settings.
• Analysis of the theoretical and practical ability of HDMTX to overcome methotrexate resistance mechanisms.

Main Results:

• HDMTX with LV rescue has not demonstrated clear superiority to conventional methotrexate in most cancers, with potential exceptions in osteosarcoma and childhood leukemia.
• While HDMTX is part of successful treatment regimens for specific diseases, its exact contribution is undefined.
• Clinical data supporting HDMTX's ability to overcome known methotrexate resistance mechanisms are lacking.

Conclusions:

• HDMTX with LV rescue, despite its long history, is not fully understood and requires further clinical research.
• Its role in routine oncologic practice remains questionable outside of specific indications like osteosarcoma and childhood leukemia.
• Continued investigation is crucial to define the precise clinical utility and mechanisms of HDMTX with LV rescue.