Effective presymptomatic central nervous system therapy, pioneered by Pinkel and coworkers at St. Jude Children's Research Hospital, is prerequisite to all subsequent advances in the treatment of childhood ALL.^125,126 Nesbit and coworkers showed that 24 Gy craniospinal irradiation might be replaced with 24 Gy cranial radiation and 6 doses of intrathecal methotrexate¹²⁷ and that 24 Gy cranial irradiation might be safely replaced with 18 Gy.¹²⁸ Bleyer and coworkers devised a widely adopted age-based dosage schedule for intrathecal methotrexate.¹²⁹

Elimination of cranial irradiation has been a priority for more than two decades. Cranial irradiation has been linked to second malignancies^130,131 and neurocognitive damage.^132–134 Lesser problems are seen in patients who received no cranial irradiation.¹³⁵ However, other elements of therapy may also be neurotoxic. 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.

Improved systemic therapy has allowed elimination of cranial irradiation for most patients. Freeman and coworkers showed that cranial irradiation might be replaced safely with IDM with no extended maintenance intrathecal therapy.^106–108 CCG showed that cranial irradiation might be replaced with maintenance intrathecal methotrexate in the lowest risk patients by age and WBC.¹¹ Then CCG showed that cranial irradiation might be replaced with maintenance intrathecal methotrexate in average risk patients, providing that patients received either intensive induction/ consolidation (Protocol I) or DI (Protocol II).¹³⁶ Finally, CCG showed that cranial irradiation might be replaced with additional intrathecal methotrexate in HR patients with a rapid initial response to therapy in the context of BFM-based systemic therapy.¹³⁷ CCG now limits cranial irradiation to HR patients with a poor initial response to therapy and to patients with overt CNS leukemia at diagnosis, about 15% of patients. Contrary to the experience of some,¹³⁸ CCG studies find that neither overt nor occult CNS disease at diagnosis adversely impacts on prognosis.^139–141

Current intrathecal therapy on some United States regimens may be excessive for some subsets of patients in the context of today's effective systemic therapy. Children on CCG trials receive more than 20 doses of intrathecal therapy over the course of treatment. Children on BFM trials receive only 11 doses of intrathecal therapy over the first 6 months of treatment and no subsequent maintenance intrathecal treatment.¹⁰⁵