Pediatric Oncology
Education Materials

Both cranial radiation therapy (CRT) and methotrexate (MTX) can cause damage to the white matter of the brain (leukoencephalopathy) and cognitive dysfunction⁴.

Radiation therapy (RT) is the most important risk factor for treatment induced cognitive decline in ALL patients as a late effect.

CNS prophylaxis with CRT in ALL patients can be associated with⁵:

Mild to moderate problems:

• Cognitive dysfunction
  • Increased distractibility
  • Memory deficits
• Poor academic performance (especially in arithmetic/math)

Severe problems:

• Severe developmental delay
• Seizures

 

An early study showed that survivors of ALL given cranial RT had significantly lower IQ scores than patients given chemotherapy (IV and IT MTX).

In an attempt to give less cranial RT (CRT), the dose of whole brain RT was reduced from 24 to 18 Gy.  Declines in IQ persisted despite the lower RT doses.  For both 24 Gy and 18 Gy progressive intellectual deterioration occurred with IQs still continuing to fall 4–5 years later.  The problem was that as the RT dose was decreased, the dose and frequency of administration of MTX was increased. In a study from St. Jude, patients were randomized to no CRT, 18 Gy, or 24 Gy to the whole brain and no significant differences were noted among the groups. But, those receiving no CRT received 10.7 times more MTX than the 18 Gy group. Leukemia studies are difficult to interpret because of  the use of adjuvant chemotherapy^2,3,6.

 

Chemotherapy: Methotrexate (MTX) is associated with damage to white matter and leukoencephalopathy⁷

Children given cranial RT plus MTX did significantly worse on IQ tests than either those who received MTX alone or sibling controls. RT increased the risk of MTX neurotoxicity,

Patients treated for a CNS relapse of ALL and given intraventricular MTX had significantly delayed clearance of MTX from the CSF.

Toxicity of MTX is related not only to peak levels but to duration of exposure. Patients with meningeal disease who had delayed MTX clearance from the CSF had a high incidence of developing leukoencephalopathy even if no CRT given.

For many years it was thought that children with ALL treated with intrathecal/intravenous MTX who did not have CRT or CNS leukemia, would not develop MTX induced neurotoxicity. By the late 1990s however, reports began to surface documenting that children treated for ALL without CRT developed progressive declines in intelligence 3–4 years following completion of therapy

Pediatric Oncology Group study: Children with ALL who had no CNS disease and had not been given CRT and were treated on 3 different regimens:

• Group A: IV MTX 1000 mg/m² and IV 6 mercaptopurine (6MP) leukovorin
  • Acute neurotoxicity including seizures, transient ischemic attacks and mental status changes in 8.3% of patients in this group.
  • leukoencephalopathy on neuroimaging identified in 75%
• Group B: po MTX IV 6 MP
  • Similar neurotoxicity in 3.7% of patients
  • leukoencephalopathy on neuroimaging identified in 15.4%
• Group C: IV MTX 1000 mg/ m² leukovorin.
  • Similar neurotoxicity in 11.2% of patients
  • leukoencephalopathy on neuroimaging identified in 77%

40% of all patients had significantly reduces IQs.  The intermediate dose intravenous MTX appeared to be the cause of the neurotoxicity.  Other studies have shown that as the dose and frequency of administration of MTX has increased, so does the risk of neurotoxicity².

Most of the chemotherapy-only studies in ALL have found deficiencies in:

• attention
• verbal and visual memory
• executive functioning
• processing speed

IQ tests have varied widely, with some reports finding no differences and others finding significant deficits compared to normal controls.

The cumulative dose of intravenous MTX in one study was a significant risk factor when children receiving intensified chemotherapy were compared with those receiving standard chemotherapy. The high intensity group fared worse on attention and information processing.

Other important risk factors are:

• young age
• female gender

A meta-analysis of 13 studies was performed⁸. The authors found that intellectual functioning was affected in chemotherapy-only treated children with leukemia, especially
in the realms of perceptual reasoning, working memory and processing speeds. In addition both reading and math achievement may be affected in long term survivors. Full
scale, verbal and performance IQ scores were also significantly below controls.

In another literature review of studies published from 1997, chemotherapy only treated patients with ALL were found to have deficiencies in attention, information processing, visuomotor functioning, visuospatial skills, verbal comprehension and memory. Executive function was characteristically affected adversely but unlike the Peterson review, global intelligence was preserved.

Thus, although there are discrepancies in the literature, there is good evidence that although chemotherapy-only protocols for children with ALL are less neurotoxic than those protocols involving radiation therapy, these patients are still at risk for neurocognitive decline².