Adult Childhood Cancer Survivors at Risk for Cognitive Impairment With Age

Adult survivors of childhood cancer have a higher risk of developing cognitive impairment later in adulthood, according to study findings published in JAMA Network Open.

Researchers in North America conducted a cohort study of 2,375 adults (54.6% women) from the Childhood Cancer Survivor Study who had been diagnosed with cancer between January 1, 1970 and December 31, 1986. The control group comprised 232 siblings of these adult survivors.

Childhood cancer diagnoses consisted primarily of 1,316 cases of acute lymphoblastic leukemia (ALL), 571 cases of Hodgkin lymphoma (HL), and 488 cases of central nervous system (CNS) tumors. Treatments consisted of cranial radiation therapy (CRT) and various chemotherapies including different administrations of methotrexate, anthracycline, and alkylator chemotherapy.

The researchers performed a longitudinal assessment of new-onset neurocognitive impairment from January 2021 to May 2022. They obtained baseline measurements at 23.4 years after initial childhood cancer diagnosis and follow-up measurements at 35 years after childhood cancer diagnosis.

The researchers analyzed neurocognitive impairment using the validated, 32-item Childhood Cancer Survivor Study Neurocognitive Questionnaire (CCSS-NCQ). This questionnaire assesses memory, organization, emotional regulation, and processing speed.

Compared with their siblings who were cancer-free, adult childhood cancer survivors in all diagnosis and treatment groups demonstrated new-onset memory impairment. Around 14% of ALL survivors treated with chemotherapy only and 25.8% of ALL survivors treated with CRT demonstrated increased rates of memory impairment on the CCSS-NCQ. Individuals with ALL who were treated with CRT also showed increased risk for problems with emotional regulation and task efficiency.

Approximately 34.7% of individuals with CNS tumors and 16.6% of individuals with HL demonstrated new-onset memory impairment compared with only 7.8% of siblings in the cancer-free control group. Those with childhood CNS tumors also demonstrated increased risk for developing impairments in processing, organization, and emotional regulation.

Cancer treatments most associated with memory impairment in adult survivors of childhood cancer included:

• intrathecal, intravenous, and oral methotrexate (RR, 1.57; 95% CI, 1.01-2.46)
• craniospinal irradiation (RR, 1.97; 95% CI, 1.33-2.90) in CNS tumor survivors
• focal radiation (RR, 1.60; 95% CI, 1.09-2.33) in CNS tumor survivors
• intrathecal, intravenous, and intramuscular methotrexate (RR, 2.31; 95% CI, 1.10-4.83) in ALL survivors treated with chemotherapy only
• cumulative alkylator doses greater than or equal to 8000 mg/m² (RR, 2.80; 95% CI, 1.28-6.12) in ALL survivors treated with chemotherapy only
• radiation exposure to the temporal lobe greater than 50 Gy (RR, 2.05; 95% CI, 1.47-2.86)

The cancer treatment most associated with impaired emotional regulation involved anthracyclines (RR, 2.61; 95% CI, 1.01-6.81) to treat HL survivors. Cytarabine (RR, 2.55; 95% CI, 1.22-5.35) and lomustine (RR, 2.99; 95% CI, 1.05-8.56) impaired organization among HL survivors. Various combinations of anthracycline and alkylator chemotherapy impaired task efficiency in ALL survivors.

Women showed higher risk of developing new-onset memory impairment, compared with men (ALL treated with CRT relative risk [RR], 1.48; 95% CI, 1.14-1.92; ALL treated with chemotherapy only RR, 2.18; 95% CI, 1.22-3.91; HL RR, 2.45; 95% CI, 1.52-3.69).

In addition to gender, smoking, decreased physical activity levels, and low educational status increased risk for memory impairment following childhood cancer treatment.

“The findings of this cohort study emphasize that childhood cancer survivors may be at perennial risk of cognitive decline throughout their lives,” the researchers noted. “Practitioners should consider neurocognitive surveillance for all survivors despite the lack of neurocognitive impairments at time of completion of therapy.”

“Serial evaluations of neurocognitive function in every survivor, including those who did not receive CNS-directed therapies, and adherence to survivorship late-effects screening recommendations will be critical to maintaining cognitive function in aging cancer survivors,” they added.

Study limitations ranged from the potential use of outdated therapies to treat childhood cancers in some individuals in this study’s cohort that may no longer represent current treatments to the small sibling cohort may not fully represent the population without cancer. The outcome measure tool also may not have captured all possible neurocognitive impairments in childhood cancer survivors.