Cognitive Late effects in Leukemia Survivors

By Nancy Keene and Kevin Oeffinger MD
Source: Summer 2001 CCCF Newsletter

Changes in the way survivors of childhood cancer think, remember, and learn are called cognitive late effects. These problems with brain function are common in survivors of brain tumors and leukemia. To cover the topic in depth, we will write a two part series of articles. The first will be on the cognitive late effects in leukemia survivors. The second will talk about ways to address school and social issues that result from late effects to the brain. As with other late effects that we have addressed in previous articles, it is important to remember that each child is unique and many will not have the late effects discussed below.

Treatment and late effects in children treated in the 1970s

In the past, the most common site of recurrence of leukemia (return of the cancer after treatment) was the central nervous system (CNS), which includes the brain and the spinal cord. In the 1960s, more than half of children with ALL developed leukemia in the CNS. In most patients, CNS relapse was quickly a return of cancer cells in the blood stream. From this it was learned that in addition to treating the blood stream it was also important to treat the brain and spinal cord.

In the early 1970s both brain and spinal column radiation, referred to as craniospinal radiation, were used to prevent CNS relapse in children with leukemia. Doctors quickly learned that the spinal part of the radiation slowed or stopped growth of the spine, so only the brain was treated with radiation. This type of radiation, referred to as whole brain or cranial irradiation therapy, was given at a dose of 24 Gy. Gy is a measure of radiation. 24 Gy is the same dose as 2400 cGy.

This use of whole brain radiation revolutionized the treatment of childhood leukemia, as the rate of return of the cancer in the CNS went from 50% to less than 10%. However, it was soon recognized that this marked increase in cure rates often came at a cost. Many survivors developed cognitive dysfunction (cognitive = thinking process; dysfunction = abnormal function). This occurred because tissues of the brain are very sensitive to radiation. The dose and location of radiation, age, sex, and individual vulnerability all play a role in how much the radiation affects brain function. Those at highest risk to develop problems are children under the age of two. Children under the age of five are at high risk, with girls showing a greater sensitivity to radiation than boys. However, any child whose brain is irradiated may develop long-term changes in brain function.

Damage from radiation to the young brain typically does not appear until two to five years after the radiation. In the early 1980s, a number of studies on children who were treated with brain radiation in the 1970s showed that 24 Gy could significantly affect the thinking process of survivors. The IQ of the average survivor decreased by about 10 points, with the verbal scores being most affected. Although more than half of survivors had mild to moderate learning problems, there was a lot of variation among survivors. Some patients experienced 20 to 30 point losses while many others had no changes at all. Problems were noted in measures of visual-spatial abilities, attention, concentration, nonverbal memory, and mathematics.

A study by the Children's Cancer Group looked at the impact of 24 Gy brain radiation on school performance of survivors in comparison with their brothers and sisters. Survivors were 4 times as likely to enter special education and 5 times as likely to enter learning disabled programs as the siblings. On the bright side, survivors were just as likely to enter gifted and talented programs as their brothers or sisters. In general, survivors were as likely to finish high school. There were no differences between males and females in educational achievements.

Treatment in the 1980s and 1990s

Because of the problems that developed after 24 Gy, other treatment plans that could prevent return of the cancer to the central nervous system were studied. The three main treatment options used were: (1) lower dose of radiation (18 Gy) with intrathecal methotrexate (chemo medication given in the fluid that surrounds the spinal cord and brain), (2) more intense chemotherapy with high doses methotrexate to the whole body (systemic) and in the spinal fluid, or (3) use of three medications, including methotrexate, given in the spinal fluid (called triple intrathecals). The last of these three options, using the three medications in the spinal fluid, was found to sometimes cause seizures and other similar problems during treatment, and so most treatment plans now use one of the first two approaches.

Because of the location of the leukemia or the genetic makeup of the cancer cells, some leukemia patients have less of a chance to be cured of their cancer. There has been a great deal of research to find out who these patients are soon after diagnosis so that they can receive more intense treatments (brain radiation and chemotherapy) in hopes of curing the cancer and preventing it from coming back. Needless to say, these intense treatments can often cure the cancer but also may also cause problems in survivors. Conversely, better identification of those at high risk, allows all of the others to receive milder treatments with less likelihood of long-term side effects.

Though it will take several years and more studies to better understand the late effects of these newer treatment plans, the damage from these treatments will be much less than some survivors experienced from 24 Gy brain radiation. Small studies following survivors who were treated with 18 Gy brain radiation have shown that fewer survivors have problems with thinking and learning skills and those who do have problems usually have milder ones than survivors who were treated with 24 Gy brain radiation. Even more encouraging, recent studies suggest that leukemia survivors treated with chemotherapy alone generally have fewer cognitive late effects than those who received radiation.

Identifying the late effects

It is important for parents and educators to remain vigilant for potential learn-ing problems so that if they are found help at school can be started. The signs of possible learning disabilities are problems with:

  • Handwriting.
  • Spelling.
  • Reading or reading comprehension.
  • Understanding math concepts, remembering math facts, comprehend-ing math symbols, sequencing, and working with columns and graphs.
  • Difficulty in using calculators or computers.
  • Auditory or visual language processing. These children have trouble with vocabulary, blending sounds, and syntax.
  • Attention deficits. Some children become either inattentive or hyperac-tive or both. These behaviors are indicative of neurologically-based def-icits in attention, which can cause children to be more impulsive and distractible than their peers.
  • Short-term memory and information retrieval.
  • Planning and organizational skills.
  • Social maturity and social skills.

You should also suspect learning difficulties if:

  • Your child was an A student prior to cancer, and she is working just as hard and getting Cs.
  • Your child takes three hours to do homework that used to take one hour.
  • Your child reads a story and then has trouble explaining the plot.
  • Your child frequently comes home frustrated from school, saying he just doesn't understand things as well as the other kids.
  • Your child's teacher complains that she "just doesn't pay attention" or "just needs to work harder."

If any of the above situations are occurring, take action to begin the evalua-tion process before your child's self-esteem plummets. It is sometimes hard to take this first step because children affected by radiation and/or chemother-apy can reason well and think clearly and may be above average academi-cally in several areas. They may fall behind their classmates, however, on tasks that require fast processing skills, short-term memory, sequential oper-ations, and organizational ability (especially visual). Once identified, these differences can be addressed by strategies such as resource services in memory enhancement, eliminating timed tests, improving organizational skills, and providing extra help in mathematics, spelling, reading, and organization.

Whatever your child's treatment, awareness of the potential for learning problems will help you identify any late effects early. The next article will focus on testing and interventions to address cognitive changes in survivors of childhood cancer. Many children with learning problems do extremely well in school with appropriate accommodations.