Providing Primary Care for Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia
Primary care physicians will be providing longitudinal health care for long-term survivors of childhood acute lymphoblastic leukemia (ALL) with increasing frequency. Late effects (sequelae) secondary to treatment with radiation or chemotherapeutic agents are frequent and may be serious. Depending on treatment exposures, this at-risk population may experience life-threatening late effects, such as cirrhosis secondary to hepatitis C or late-onset anthracycline-induced cardiomyopathy, or life-changing late effects, such as cognitive dysfunction. Many survivors of childhood ALL will develop problems such as obesity and osteopenia at a young age, which will significantly affect their risk for serious health outcomes as they grow older.
The goal of our review is to assist primary care physicians in providing longitudinal health care for long-term survivors of childhood ALL. We also highlight areas needing further investigation, including the prevalence of different late effects, determination of risk factors associated with a late effect, a better understanding of the potential impact of late effects on the premature development of common adult health problems, and the value and timing of different tests for screening asymptomatic survivors.
Because bone marrow transplantation (BMT) is a relatively new therapy affecting a much smaller number of ALL survivors, our review does not include the late effects related to total body irradiation and BMT.
Cognitive dysfunction and performance at school and work
As described in the section on the evolution of treatment, 24 Gy CRT is associated with cognitive dysfunction. A meta-analysis of more than 30 retrospective and prospective studies established that 24 Gy CRT in combination with MTX resulted in a mean decrease of 10 points in full-scale intelligence quotient (IQ).9 Verbal scores were affected more than performance IQ, and changes were noted to be progressive. Although more than half the patients had mild to moderate learning problems, the outcomes were highly variable, and some patients experienced 20- to 30-point losses, while others had no discernable changes.9,14 Deficits have been noted in measures of visual-spatial abilities, attention-concentration, nonverbal memory, and somatosensory functioning.8-10,15-20 Studies have also shown that girls and patients treated with CRT before the age of 4 years are at significantly higher risk. Neuropathologic changes resulting from 24 Gy CRT include leukoencephalopathy, mineralizing microangiopathy, subacute necrotizing leukomyelopathy, and intracerebral calcifications, commonly with subsequent cerebral atrophy and microcephally.21,22
Treatment with 18 Gy CRT in combination with chemotherapy also affects cognition, though not as profoundly as with 24 Gy CRT. In a retrospective study of children with ALL, randomized by risk group to receive either 18 Gy CRT with chemotherapy or chemotherapy alone, 66 survivors were subsequently tested using several cognitive measures.23 Girls who were treated with CRT/chemotherapy had a mean IQ 9 points lower than those treated with chemotherapy alone. All patients had impairments in verbal coding and short-term memory regardless of CRT use or MTX dose, suggesting that another agent such as glucocorticoids may be responsible. Other small prospective and retrospective studies have found a mild decrease in full-scale IQ in patients treated with 18 Gy CRT/chemotherapy, although subanalysis generally showed that changes were only significant for girls and patients treated at a younger age.24-27
Recent studies suggest that neurodevelopmental outcomes for survivors treated with chemotherapy alone are generally positive.28 An analysis of 30 survivors whose condition was diagnosed before the age of 12 months showed no decrease in 6 cognitive and motor indices and no sex differences.29 Though full-scale IQ was normal, Brown and colleagues30 reported that girls had significantly decreased nonverbal scores in a study of 47 ALL survivors. Fine motor disturbances and manual dexterity difficulties, which may compound learning difficulties, have been seen in 25% to 33% of ALL survivors evaluated in 2 small cross-sectional studies.31,32 Changes in cerebellar-frontal subsystems that correlate with neuropsychological deficits have also been seen in ALL patients treated with chemotherapy alone.33
The Children’s Cancer Group investigated the impact of treatment on scholastic performance of 593 adult survivors, compared with 409 sibling controls.34 Patients treated with 24 Gy CRT were more likely to enter special education or learning-disabled programs, with relative risks of 4.1 and 5.3, respectively. Previous treatment with 18 Gy CRT had less impact, with a relative risk of 4.0 to enter a special education program but no increased risk of entering a learning-disabled program. Patients treated with CRT (18 or 24 Gy) were just as likely to enter gifted and talented programs as their sibling controls. In general, survivors were as likely to finish high school and enter college as controls, but those treated with 24 Gy or treated before the age of 6 years were less likely to enter college. There were no sex differences in educational achievements.
There are no studies that explore problems in job acquisition, promotion, and retention for ALL survivors with evidence of cognitive dysfunction. Abstract thinking abilities in higher-level decision making may be problematic for some ALL survivors, particularly those treated with 24 Gy CRT. Further study is warranted, particularly in evaluating methods to assist at-risk survivors in developing job skills and applying for a job.
Obesity, physical inactivity, and risk of premature cardiovascular disease
Several retrospective cohort and cross-sectional studies have shown an increased incidence and prevalence of obesity in ALL survivors. Early studies suggested that the resulting obesity was secondary to CRT, with 38% to 57% of the survivors having a body mass index (BMI) >2 standard deviations (SDs) above the norm at the time of attainment of final height.35-38 Two recent cross-sectional studies suggest that the increased prevalence of obesity may be due to other factors. Van Dongen-Melman and coworkers39 compared the weight gain and BMI of 113 ALL survivors who had received CRT/chemotherapy or chemotherapy alone and found that children treated with a combination of prednisone and dexamethasone had the highest prevalence of obesity (44%).39 Talvensaari and colleagues40 evaluated 50 childhood cancer survivors with a median age of 18 years (including 28 ALL patients) and found an increased prevalence of obesity in survivors that was not associated with CRT.
