Irradiation therapy for the brain cancer medulloblastoma is more likely to impair IQ and reading skills of younger children than older children even if the dose of radiation is reduced, according to the results of the largest study of its kind, conducted by investigators at St. Jude Children's Research Hospital, Texas Children's Cancer Center (Houston) and Royal Children's Hospital (Melbourne, Australia).
The researchers found that the greatest rates of decline in IQ and reading skills occurred in patients who were younger than 7 years old at diagnosis. Patients who were at either high or average risk of treatment failure suffered significant loss of reading skills over time following treatment.
The study used "risk-adapted" radiation therapy in which the dose of radiation was adjusted according to whether the patient's cancer had already spread and how much tumor was left following initial surgery to remove the cancer. Patients in the study were classified as high risk (HR, 37 patients) or average risk (AR, 74 patients) depending on whether they had those risk factors. HR patients were considered more likely to experience treatment failure and therefore received higher doses of radiation.
The loss of reading and spelling skills among both AR and HR children apparently is caused by impairments of the fundamental cognitive processes that are critical to the early development of these skills in a child, according to Amar Gajjar, M.D., a member of the Hematology-Oncology department and director of Neuro-Oncology at St. Jude. Gajjar is the senior author of a report on this study that appears in the August 20 issue of Journal of Clinical Oncology.
In addition to confirming that younger age increases the risk of neurocognitive deficits, the current study also allowed the researchers to develop a way to predict the number of IQ points that would be lost by both HR and AR patients depending on whether they were older (at least 7 years of age) or younger (less than 7 years) at time of diagnosis and treatment.
The investigators are now using results of this study to identify and help children in need of special training to enhance their cognitive functioning following treatment for medulloblastoma.
The study, which included 111 children (age 3-20 at time of diagnosis), was unprecedented because it followed a larger number of patients than any previous such investigation, Gajjar said. In addition, the investigators conducted neurocognitive testing of children for up to six years after diagnosis--that is, both before and after treatment, he added. Moreover, no other such previous prospective study (a study following patients over the course of time) has compared the outcome of children receiving risk-adapted radiation therapy doses.
Risk-adapted treatment included surgery to remove as much of the tumor as possible, followed within 28 days by initial post-operative craniospinal irradiation therapy (CSI) plus a radiation therapy "boost" to the primary (original) tumor site delivered by 3-D conformal radiation therapy (CRT). Six weeks after completion of radiation therapy, children underwent four rounds of chemotherapy with cyclophosphamide, cisplatin and vincristine. The investigators observed the patients every three months for two years and every six months thereafter for a total of five years.
CRT combines CAT scans and MRI to create pictures of the cancer that a computer then turns into three-dimensional images of the tumor. These images are combined with computer-controlled radiation beams and meticulous positioning of the treatment table on which the patient lies. Radiation hits the tumor at precisely calculated angles and depths matching the 3-D image of the tumor, obliterating the cancer and sparing healthy tissue.
All children underwent neurocognitive testing after surgery and at approximately one, two and five years after diagnosis. The IQ of the 104 patients who were at least 3 years old was evaluated using the age-appropriate Wechsler Intelligence Scale; and academic achievement was measured in patients at least 5 years of age using a variety of tests that measured reading, math and spelling skills.
"This study significantly adds to our understanding of the long-term neurocognitive development of these children. It also helps us develop and test intervention programs that aim at reducing the deficits these children experience," said Shawna Palmer, Ph.D., one of two lead neuropsychologists on the study.
Other authors of the study include Raymond K. Mulhern, Thomas E. Merchant, Dana Wallace, Mehmet Kocak, Vida L. Tyc, Larry Kun and James Boyett (St. Jude); Murali Chintagumpala, Pim Brouwers, Kevin Krull (Texas Children's Cancer Center); David Ashley and Robyn Stargatt (Royal Children's Hospital, Melbourne, Australia).