Cognitive Outcomes Following Contemporary Treatment Without Cranial Irradiation for Childhood Acute Lymphoblastic Leukemia

H. M. Conklin; K. R. Krull; W. E. Reddick; D. Pei; C. Cheng; C. H. Pui


J Natl Cancer Inst. 2012;104(18):1386-1395. 

In This Article

Abstract and Introduction


Background Treatment of acute lymphoblastic leukemia (ALL) has included the use of prophylactic cranial irradiation in up to 20% of children with high-risk disease despite known cognitive risks of this treatment modality.
Methods Patients enrolled on the St Jude ALL Total Therapy Study XV, which omitted prophylactic cranial irradiation in all patients, were assessed 120 weeks after completion of consolidation therapy (n = 243) using a comprehensive cognitive battery. χ2 analysis was used to compare the percentage of below-average performers among the entire ALL patient group to the expected rate based on the normative sample. Univariate logistic regression was used to estimate the effect of intensity of chemotherapy (treatment arm), age at diagnosis, and sex on the probability of below-average performance. All statistical tests were two-sided.
Results Overall, the ALL group had a statistically significantly higher risk for below-average performance on a measure of sustained attention (67.31% more than 1 SD below the normative mean for omission errors, P < .001) but not on measures of intellectual functioning, academic skills, or memory. Patients given higher intensity chemotherapy were at greater risk for below-average performance compared with those given lower intensity therapy on measures of processing speed (27.14% vs 6.25%, P = .009) and academic abilities (Math Reasoning: 18.60% vs 3.90%, P = .008; Word Reading: 20.00% vs 2.60%, P = .007; Spelling: 27.91% vs 3.90%, P = .001) and had higher parent-reported hyperactivity (23.00% vs 9.84%, P = .018) and learning problems (35.00% vs 16.39%, P = .005). Neither age at diagnosis nor sex was associated with risk for below-average cognitive performance.
Conclusions Omitting cranial irradiation may help preserve global cognitive abilities, but treatment with chemotherapy alone is not without risks. Caregiver education and development of interventions should address both early attention deficits and cognitive late effects.


The prognosis for children diagnosed with acute lymphoblastic leukemia (ALL) has improved dramatically, with 5-year event-free survival rates as high as 79% to 82% among patients treated in the 1990s.[1–3] Higher survival rates have resulted in heightened focus on improving quality of life of survivors by reducing treatment-related late effects, including cognitive deficits.

Historically, treatment of childhood ALL with cranial irradiation has been associated with substantial cognitive morbidity;[4,5] however, these findings are based on doses generally exceeding those used in modern therapy. When directly compared, treatment with lower dose cranial irradiation (eg, ≤18 Grey [Gy]) used in contemporary clinical trials typically,[6–9] but not always,[10] results in worse cognitive outcomes than chemotherapy alone on measures of intellectual function as well as more specific cognitive abilities. There is also some evidence[11] to suggest that different chemotherapy regimens carry greater cognitive risk than others based on drugs used (eg, triple intrathecal methotrexate, hydrocortisone and cytarabine [ITMHA] vs intrathecal methotrexate alone; dexamethasone vs prednisone) as well as drug dosage and mode of administration (eg, lower dose oral methotrexate vs high-dose intravenous methotrexate [HDMTX]). Partly because of inconsistent reports of cognitive difference between treatment with lower dose cranial irradiation and intensive chemotherapy, and partly because of concern about increased central nervous system relapse, most pediatric collaborative study groups continue to use prophylactic cranial irradiation in their clinical trials in up to 20% of ALL patients.[12]

The St Jude Total Therapy XV study evaluated whether intensification of systemic drugs that affect control of ALL in the central nervous system, together with optimal intrathecal treatment, would allow for complete omission of prophylactic cranial irradiation without compromising overall survival. The clinical trial resulted in 5-year event-free survival of 85.6% and overall survival of 93.5%.[13] With additional follow-up, the treatment results remain excellent with a 10-year overall survival rate of 91.0% for all patients, 96.1% for low-risk patients, and 86.0% for standard/high-risk patients. Cognitive outcomes have not been systematically investigated or reported.

Demographic and clinical factors are associated with cognitive late effects in childhood ALL. Intensive treatment has been the most reliable predictor of increased risk.[6–9,14–16] Younger age at treatment has been associated with worse cognitive outcomes, most likely resulting from greater vulnerability of the developing brain to neurotoxic agents.[[6,16–18] However, it is unclear whether this relationship is specific to children receiving cranial irradiation or also holds true for those receiving chemotherapy alone.[16] Sex may also be associated with cognitive changes following ALL therapy, with girls more likely to experience deleterious effects.[19,20] The mechanism for sex-specific risk is not fully understood but may result from differences in cerebral myelination.[21,22] Furthermore, the literature is divided as to whether increased risk in girls is limited to children receiving cranial irradiation,[23,24] and sex differences may vary depending on cognitive ability assessed.[25] Few studies have been able to examine these demographic and clinical risk factors in a large cohort of prospectively studied patients who received homogeneous treatment and had comprehensive cognitive evaluations.

The first objective of this study was to systematically evaluate cognitive outcomes in a radiation-naive sample treated with contemporary risk-adapted therapy. The second objective was to investigate the predictive value of treatment intensity, age at treatment, and sex with respect to cognitive outcomes. Based on the existing literature, our primary hypothesis was that patients would perform well on global measures of cognitive ability, such as intellectual functioning; however, a subset of them would show evidence of difficulties on measures of attention, particularly on performance-based measures of sustained attention including indices of processing efficiency, which may be more sensitive to central nervous system–directed therapy.[14,18,25,26] Secondarily, we predicted that higher treatment intensity and younger age at diagnosis would be risk factors for cognitive problems, whereas female sex would not reliably predict risk when looking across a range of cognitive skills.