Parenteral methotrexate and rescue provides an alternative strategy for postinduction intensification. Pursuant of earlier studies in CALGB,^106–108 both Pediatric Oncology Group (POG) and St. Jude investigators employ a postinduction intensification “backbone” of intermediate dose methotrexate with rescue (IDM).^109–112 BFM family regimens include IDM in an “M” phase between Protocol I and Protocol II.¹⁰⁵

However, unambiguous demonstration of the contribution of IDM to postinduction intensification had been lacking. St. Jude Study Total X showed an advantage for a complex regimen including IDM relative to a second complex regimen excluding IDM.^109,110 Two CCG trials examined the role of IDM for SR patients. We found no advantage for either methotrexate 0.5 g/m^{2 113} or for 33.6 g/m^{2 114} over conventional oral methotrexate. More recently, UKALL XI found no advantage for methotrexate 6 to 8 g/m^{2 115} and FRALLE 93 found no advantage for methotrexate 8 g/m^{2 116} for intermediate risk patients.

CCG has achieved good outcomes with no IDM and avoided significant neurotoxicity and additional hospital stays. The dexamethasone/ oral 6-MP arm of CCG-1922 provided an 87% 5-year EFS for Rome/NCI standard risk patients with no IDM.²² Omission of IDM accounts for a 25 day/ patient advantage in median hospital stay versus a contemporary IDM regimen.¹¹⁷ IDM was implicated in a 10% to 16% incidence of CNS toxicity in three recent trials.^111,118,119 The ultimate neurocognitive consequences of these studies have not yet been reported. Neurotoxicity may be prevented with less frequent IDM and earlier or more generous rescue. However, earlier and more generous use of leucovorin may diminish any therapeutic benefit.¹²⁰

Much remains to be learned about methotrexate. Although Chessells found no advantage for intramuscular over oral methotrexate in maintenance,¹²¹ two randomized trials show an advantage for intravenous versus oral methotrexate.^122,123 Long term follow-up on a study comparing whole brain irradiation with additional intrathecal methotrexate found the early excess of CNS relapses on the methotrexate arm more than balanced by an eventual excess of marrow relapse on the radiation arm.¹²⁴ Additional vincristine, methotrexate, and asparaginase rescues standard risk patients with a slow day 15 response in the context of double Delayed Intensification.⁶⁵ Most recently, addition of five doses of IDM (5 g/m²) improved the EFS of children with T-cell leukemia in the context of Dana Farber Cancer Institute based therapy.²³