Overall, we found that 13%–21% of survivors of non-CNS cancers in this study had impairment in task efficiency, organization, memory, or emotional regulation, as determined by self-report on a standardized instrument. This rate of impairment was approximately 50% higher than that in the sibling comparison group. However, mean test scores of non-CNS cancer survivors varied only slightly (<0.5 SD) or not at all from those of the comparison group, indicating that there are vulnerable subgroups. Patient groups at highest risk were those with acute lymphoblastic leukemia and myeloid leukemia but only if they also received cranial radiation therapy. Hodgkin lymphoma, neuroblastoma, and non-Hodgkin lymphoma survivors were impaired compared with siblings, but less so. On the basis of these results, we recommend that patients in these cancer diagnosis groups should receive neuropsychological screening as part of cancer survivorship follow-up care, especially if cranial radiation therapy was given at ages younger than 6 years. Emotional distress was associated with all aspects of measured self-reported neurocognitive functioning but not with cancer diagnosis or exposure to cranial radiation therapy. This distress may stem from the impact that the neurocognitive problems have on daily living skills, employment, and educational attainment. Alternatively, depression and anxiety may manifest as cognitive disturbances or the self-perception of dysfunction, as has been found in the general population (26
). Another compelling finding from this study is that hearing difficulty was associated with an increased risk in self-reported neurocognitive dysfunction (for task efficiency, PR = 1.7, 95% CI = 1.3 to 2.0; for organization, PR = 1.6, 95% CI = 1.1 to 2.3; and for emotional regulation, PR = 1.6, 95% CI = 1.3 to 2.0). Chemotherapy exposures, including treatment with methotrexate and prednisone, were not statistically significantly associated with self-reported neurocognitive functioning after adjusting for age, sex, and cranial radiation therapy.
To gain a better understanding of the external validity of our findings, we examined the association between cognitive functioning in participants and key adult life outcomes by use of log-binomial regression in a univariate analysis. We found that impaired task efficiency, organization, memory, and behavioral regulation were associated with unemployed status, lower educational attainment, and not living independently. Similarly, we recently reported (27
) that the likelihood of never marrying was higher in CCSS survivors with impaired cognitive functioning. The cognitive, emotional, and physical factors associated with living independently will be examined more closely in the CCSS cohort in a future analysis.
We found that higher doses of cranial radiation therapy were associated with worse self-reported neurocognitive functioning but that even doses of 18 Gy or less were detrimental. This association was also apparent when the analysis was restricted to patients with acute lymphoblastic leukemia. Previous studies (28
) have, however, reported conflicting data on the role of radiation. Waber et al. (28
) concluded that children with acute lymphoblastic leukemia who were randomly assigned to receive 18 Gy of cranial radiation therapy performed similarly on neuropsychological testing to those who were randomly assigned to receive intrathecal chemotherapy. Likewise, Mulhern et al. (29
) reported no differences in Verbal, Performance, or Full-Scale IQ among patients who received cranial radiation therapy at 18 or 24 Gy or no irradiation. However, conclusions of more previous studies (30
) are consistent with that of this study, in that prophylaxis with cranial radiation therapy for patients with acute lymphoblastic leukemia was associated with greater dysfunction.
Younger age at diagnosis and female sex have been identified previously as risk factors for worse neurocognitive impairment among cancer patients who did (30
) or did not (33
) receive cranial radiation therapy. We also found this association among our study subjects. For emotional regulation, there was a statistically significant interaction between age and sex, with girls diagnosed at age younger than 6 years having the worst outcome.
Recently, there has been concern about the association between nonradiation treatments and neurocognitive impairment among cancer patients. Among prospective longitudinal studies, some investigators (9
) have found that nonirradiated patients with acute lymphoblastic leukemia are neurocognitively impaired, whereas others (37
) have found that they are within the average range. Methotrexate treatment has been implicated because the drug crosses the blood–brain barrier (40
), causes leukoencephaly on neuroimaging (10
), and has been associated with worse impairment at higher doses (41
). Treatment with corticosteroids (12
) and intrathecal chemotherapy (33
) is also potentially associated with increased risk because of their higher concentrations in the CNS. Adult survivors of breast cancer who had undergone hematopoietic stem cell transplantation have been documented to have decreased neurocognitive functioning (42
). In their recent review of non-CNS cancer and cancer therapy, Wefel et al. (42
) speculated that chemotherapy may cause neurocognitive dysfunction through metabolic changes, anemia and central hypoxia, hormonal changes from gonadotoxic therapy, and proinflammatory cytokine activation.
We did not find that treatment with methotrexate, corticosteroids, anthracyclines, or alkylators was associated with worse self-reported neurocognitive functioning, independent of cranial radiation therapy. Among non-CNS cancer survivors who received cranial radiation therapy, treatment with methotrexate and corticosteroid was not associated with increased impairment. Even without cranial radiation therapy, increased systemic methotrexate treatment was not associated with increased impairment. Although no specific chemotherapy was associated with cognitive functioning, it should be noted that Hodgkin lymphoma, neuroblastoma, non-Hodgkin lymphoma, and osteosarcoma were associated with impairment in task efficiency, even though these cancers are not treated with cranial radiation therapy. It is not clear whether it is an aspect of chemotherapy or other part of the treatment experience that is responsible for these associations.
The association between hearing and academic performance has been established in otherwise healthy children but is only starting to gain recognition among childhood cancer survivors. Gurney et al. (43
) studied 137 survivors of neuroblastoma and found that hearing loss was associated with learning problems and worse school functioning. In our study of survivors of many different cancers, hearing deficits were associated with impairment in task efficiency, organization, memory, and emotional regulation.
Our study had several limitations. The study design was retrospective, not prospective. Therefore, precancer neurocognitive status was not available. Neurocognitive functioning was assessed with a self-report instrument rather than performance testing. There is evidence in the literature that self-reported neurocognitive functioning predicts both performance-based assessments of dysfunction and neuroimaging abnormalities (44
). A study of 1049 participants by de Groot et al. (44
) found that self-reported change of neurocognitive function on rating scales preceded measured dysfunction and dementia as measured by neurocognitive performance. Mahone et al. (45
) recently concluded that report of working memory on the BRIEF is associated with frontal gray matter volume but not with temporal, parietal, or occipital gray matter volume or white matter volume; these results support the specificity of self-reported working memory ratings. Although patients in our cohort generally received the same range of chemotherapeutic agents that are currently used, some treatments may not be applicable to the experience of children treated with more modern regimens. For example, contemporary patients with acute lymphoblastic leukemia are less likely to receive cranial radiation therapy and more likely to receive dexamethasone treatment.
From this multisite study, we conclude that there is a statistically and clinically significantly higher percentage of impairment in self-reported neurocognitive functioning among survivors of non-CNS cancers than among their siblings. Self-reported neurocognitive impairment was associated with important life outcomes in adults, such as unemployment, marriage status, and lack of independent living. Thus, we recommend that parents, medical providers, and educators should monitor all non-CNS cancer survivors, particularly those with leukemia, lymphoma, and neuroblastoma, for difficulties in learning and academic performance so that the appropriate intervention and/or accommodation may be given during childhood. Focused screening is especially important for children who received any cranial radiation therapy, who are female, who are treated in the preschool age range, and who have hearing deficits. There are ongoing studies (46
) of potential interventions for affected individuals, including stimulant use and cognitive behavioral therapy. Future studies are warranted to elucidate the mechanism through which neurocognitive processing problems arise in nonirradiated patients, including investigation into possible inherited susceptibility.