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To varying degrees, the adverse effects of specific anticancer therapies on long-term health and psychosocial and quality-of-life outcomes have been established. With this knowledge, new treatment approaches are being designed, tested, and implemented to prevent or minimize late effects.
To advance our knowledge, St. Jude investigators are evaluating toxicities associated with contemporary treatment strategies, while continuing to conduct research to further characterize the growing number of very long–term survivors, who are at risk for a wide-range of potential late effects such as decreased neurocognitive and psychosocial functioning, compromised physical functioning, and second malignant neoplasms.
Omitting Cranial Irradiation Improves Neurocognitive Outcomes
Historically, cranial irradiation was part of the standard care for children with acute lymphoblastic leukemia (ALL), but it was also associated with risk for impaired cognitive function. In the most recently completed St. Jude ALL trial, Total Therapy XV, investigators omitted cranial irradiation from ALL treatment while maintaining outstanding overall survival.
Heather M. Conklin, PhD (Psychology), and colleagues used a comprehensive cognitive-assessment battery to evaluate children with newly diagnosed ALL treated on Total Therapy XV, who did not receive cranial irradiation.
As reported in the Journal of the National Cancer Institute, Dr. Conklin’s team showed that at 120 weeks after completion of consolidation chemotherapy, 67% of the 243 children with ALL scored below average on a measure of sustained attention; however, they did not have impairments on measures of intellectual functioning, academic skills, and learning and memory.
When compared to patients receiving lower-intensity chemotherapy, patients receiving higher-intensity chemotherapy were at greater risk of below-average performance on measures of processing speed (27% vs. 6%), academic abilities (19% vs. 4%), parent-reported outcomes of hyperactivity (23% vs. 10%), and learning problems (35% vs. 16%).
The investigators concluded that omitting cranial irradiation from the treatment of childhood ALL may help preserve global cognitive abilities. However, treatment with chemotherapy alone is not without risks. The investigators highlight the need for continued research to develop new strategies for treating pediatric ALL to produce cures while minimizing cognitive late effects.
Neurocognitive Dysfunction and CNS Pathology in Adult Survivors of Childhood Hodgkin Lymphoma
Survivors of pediatric Hodgkin lymphoma are at increased risk of a spectrum of late effects, including cardiopulmonary complications and stroke. Because the treatment of Hodgkin lymphoma does not include CNS-directed therapy, survivors have not been systematically evaluated for neurocognitive function.;
Using the SJLIFE cohort, Kevin R. Krull, PhD (Epidemiology & Cancer Control, Psychology), and colleagues evaluated a series of long-term survivors of pediatric Hodgkin lymphoma. In the Journal of Clinical Oncology, Dr. Krull’s team reported results from their assessment of 62 adult survivors. Evaluations included neurocognitive testing, magnetic resonance imaging (MRI) of the brain, echocardiography, pulmonary function testing, and physical examination.
Compared with age-expected norms, Hodgkin lymphoma survivors exhibited poorer performance on neurocognitive testing, including sustained attention, short-term memory, long-term memory, working memory (i.e., the system of short-term storage and manipulation of information), naming speed (i.e., how quickly one can verbally identify objects in pictures), and cognitive fluency (i.e., the ability to perform simple or complex tasks efficiently).
MRI examinations revealed that 53% of the survivors had leukoencephalopathy, a condition that primarily affects the white matter of the brain, and 37% had evidence of cerebrovascular injury. Reduced cognitive fluency was associated with the presence of leukoencephalopathy. A striking finding was an association between the risk of leukoencephalopathy and the dose of thoracic radiation received.
This study provides the first evidence that Hodgkin lymphoma survivors are at risk for neurocognitive impairment, which is associated with radiologic indices suggestive of reduced brain integrity. Moreover, the results suggest that cardiopulmonary dysfunction, such as reduced blood flow or low oxygenation of the blood, plays a role in the etiology of the neurocognitive deficits in these survivors.
On the basis of these findings, Dr. Krull and colleagues were awarded a 5-year grant from the National Cancer Institute to evaluate neurocognitive outcomes among a large population of pediatric Hodgkin lymphoma survivors.
Treatment-Related Risk Factors Associated with Secondary Colorectal Cancer
Second malignant neoplasms are a serious long-term consequence of treatment for childhood cancer. They represent the second leading cause of death among survivors, surpassed only by relapse of the primary disease.
Using large cohorts like the Childhood Cancer Survivor Study, investigators have characterized the incidence and risk factors associated with second malignancies that arise during the first 3 to 4 decades after cancer therapy. However, as cure rates improve and the childhood cancer survivor population ages, new second malignancies are most likely to emerge. Therefore, identifying the treatment-related risk factors associated with particular neoplasms will allow us to identify high-risk groups who would benefit from early detection.
Colorectal carcinoma is one secondary malignant neoplasm that has not been fully investigated. The treatment-related risk factors associated with its development and the long-term risk of the disease arising in childhood cancer survivors are unknown. Kerri A. Nottage, MD (Hematology), and colleagues reported in the Journal of Clinical Oncology the occurrence of secondary colorectal carcinomas among long-term childhood cancer survivors.
From their investigation of more than 13,000 oncology patients treated at St. Jude, Dr. Nottage and her team identified 19 patients with adenocarcinoma of the colon or rectum, representing an 11-fold increase in the expected incidence. Secondary colorectal cancers were more likely to occur in an irradiated segment of the colon, and for each 10-Gy increase in radiation dose, the risk of colorectal carcinoma increased by 70%. The volume of colon tissue exposed to radiation was also associated with increased risk of secondary colorectal cancer.
In addition to the risk associated with radiation exposure, the investigators found that patients whose treatment regimen included alkylating agents (e.g., cyclophosphamide, ifosfamide, and busulfan) were at an approximately 9-fold higher risk of a secondary colorectal carcinoma.
These data provide strong support for initiating colorectal cancer screening earlier among childhood cancer survivors, especially for those who have received treatments that are associated with a high risk of the neoplasm.