Late-developing toxicities

Late effects associated with CNS-directed therapies include subsequent neoplasms, neuroendocrine disturbances, leukoencephalopathy, and neurocognitive impairments.

Subsequent neoplasms are observed primarily in survivors who received cranial radiation therapy. Meningiomas are the most commonly observed second neoplasm and are most often of low malignant potential. However, high-grade lesions can also occur. In a SJCRH retrospective study of more than 1,290 patients with ALL who had never relapsed, the 30-year cumulative incidence of a subsequent neoplasm occurring in the CNS was 3%. Excluding meningiomas, the 30-year cumulative incidence was 1.17%.[32] Nearly all of these CNS subsequent neoplasms occurred in previously irradiated patients. In a Pediatric Normal Tissue Effects in the Clinic (PENTEC) report on subsequent malignancies, patients who received radiation therapy to the brain had a pooled excess relative ratio per Gy of 0.44 for subsequent meningiomas. Patients treated with 12 Gy of radiation therapy have a substantially lower potential for developing meningiomas than those treated with 24 Gy.[33]

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Neurocognitive impairments, which can range in severity and functional consequences, have been documented in long-term ALL survivors treated both with and without radiation therapy. In general, patients treated without cranial radiation therapy have less severe neurocognitive sequelae than irradiated patients, and the deficits that do develop represent relatively modest declines in a limited number of domains of neuropsychological functioning.[34-37] For patients who receive cranial radiation therapy, the frequency and severity of toxicities appear dose-related. Patients treated with 18 Gy of cranial radiation therapy appear to be at lower risk of severe impairments compared with those treated with doses of 24 Gy or higher. Younger age at diagnosis and female sex have been reported in many studies to be associated with a higher risk of neurocognitive late effects.[38]

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Several studies have also evaluated the impact of other components of treatment on the development of late neurocognitive impairments. A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple intrathecal chemotherapy showed no clinically meaningful difference.[24][Level of evidence C1] Controversy exists about whether patients who receive dexamethasone have a higher risk of neurocognitive disturbances.[39] In a SJCRH study of nonirradiated long-term survivors, treatment with dexamethasone was associated with increased risk of impairments in attention and executive function.[40] Conversely, long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment did not demonstrate any meaningful differences in cognitive functioning based on corticosteroid randomization.[41] In the COG AALL0232 study, patients with high-risk ALL were randomly assigned to receive either prednisone or dexamethasone during induction therapy.[42] Neurocognitive testing was done 8 to 24 months after treatment. Mean scores for all attention and executive functioning measures were in the average range, and there was no difference in scores between the patients who received prednisone and the patients who received dexamethasone. In the same study, patients were randomly assigned to receive either high-dose methotrexate or escalating methotrexate. There were no differences in attention or executive functioning scores between the two treatment groups.[42]

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Investigators have also examined whether exposure to anesthetic agents affects neurocognition in children who undergo treatment for ALL. One study included 144 patients with high-risk B-ALL (aged 6–12 years at diagnosis), and only 2% of these patients received cranial radiation. Higher cumulative exposure to propofol (frequently used as sedation for lumbar punctures during treatment) was associated with impairment in reaction time/processing speed in neurocognitive testing performed 1 year after the completion of ALL therapy.[43] Another study from SJCRH included 212 survivors of childhood ALL (all at least 5 years from initial diagnosis). Greater exposure to propofol and fluranes and longer cumulative anesthesia duration were associated with increased risks of general neurocognitive impairment and dysfunction on tests of processing speed and attention.[44] The long-term implication of these findings awaits longer follow-up.

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Evidence (neurocognitive late effects of cranial radiation):

A SJCRH study of 567 adult long-term survivors of childhood ALL underwent neurocognitive testing (mean time from diagnosis, 26 years).[40]

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A SJCRH study of 567 adult long-term survivors of childhood ALL underwent neurocognitive testing (mean time from diagnosis, 26 years).[40]

Patients treated with 24 Gy of cranial radiation therapy showed the highest rates of impairment. Up to one-third of these patients demonstrated impairments (defined as test scores 2 or more standard deviations below age-adjusted national norms) in attention, memory, processing speed, and executive function.

A SJCRH study of 567 adult long-term survivors of childhood ALL underwent neurocognitive testing (mean time from diagnosis, 26 years).[40]

Significantly fewer patients who had received 18 Gy of cranial radiation therapy demonstrated severe impairments compared with those who had received 24 Gy. In general, there was no significant difference in rates of impairment between nonirradiated survivors and those who received 18 Gy of cranial radiation therapy. However, the 18-Gy group was at increased risk of academic problems.

A SJCRH study of 567 adult long-term survivors of childhood ALL underwent neurocognitive testing (mean time from diagnosis, 26 years).[40]

In addition to being dose-related, the neurocognitive impact of cranial radiation therapy was also dependent on age at diagnosis, with higher frequency of impairments in patients diagnosed at a younger age.

A study compared memory impairment in patients who received 18 Gy of cranial radiation therapy (n = 127) versus 24 Gy of cranial radiation therapy (n = 138).[45]

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A study compared memory impairment in patients who received 18 Gy of cranial radiation therapy (n = 127) versus 24 Gy of cranial radiation therapy (n = 138).[45]

Long-term survivors who received 24 Gy of cranial radiation therapy demonstrated significant impairments in immediate and delayed memory, compared with survivors who received 18 Gy.

In a randomized trial comparing irradiated (at a dose of 18 Gy) and nonirradiated standard-risk ALL patients, the following was observed: [34][Level of evidence A3]

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In a randomized trial comparing irradiated (at a dose of 18 Gy) and nonirradiated standard-risk ALL patients, the following was observed: [34][Level of evidence A3]

Cognitive function for both groups (assessed at a median of 6 years postdiagnosis) was in the average range, with only subtle differences noted between the groups in cognitive skills.

In a randomized trial, hyperfractionated radiation therapy (at a dose of 18 Gy) did not decrease neurological late effects when compared with conventionally fractionated radiation therapy. Cognitive function for both groups was not significantly impaired.[46]

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Evidence (neurocognitive late effects in nonirradiated patients):

In the SJCRH long-term follow-up study of 567 adult long-term survivors, some nonirradiated patients also demonstrated neurocognitive impairments.[40]

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In the SJCRH long-term follow-up study of 567 adult long-term survivors, some nonirradiated patients also demonstrated neurocognitive impairments.[40]

The age-adjusted mean test scores for nonirradiated patients were very similar to that of expected national norms. However, approximately 15% of the nonirradiated survivors participating in this study demonstrated impairments in some domains, including attention, memory, processing speed, and executive function.

In the SJCRH long-term follow-up study of 567 adult long-term survivors, some nonirradiated patients also demonstrated neurocognitive impairments.[40]

Despite the impairments noted on neurocognitive testing, overall, the educational attainment and employment status of the tested ALL survivors were similar to age- and sex-adjusted expected proportions using census data for the U.S. population.

In a second study from SJCRH, patients enrolled on Total Study XV (which omitted cranial radiation therapy in all patients) underwent comprehensive neuropsychological assessments at induction, end of maintenance, and 2 years after completion of therapy.[47]

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In a second study from SJCRH, patients enrolled on Total Study XV (which omitted cranial radiation therapy in all patients) underwent comprehensive neuropsychological assessments at induction, end of maintenance, and 2 years after completion of therapy.[47]

Neurocognitive function was largely age appropriate 2 years after completing therapy, without evidence of excess impairment on measures of intellectual functioning, academic abilities, learning, and memory. Problems with sustained attention were observed at an increased frequency in this population compared with normative expectations.

In a second study from SJCRH, patients enrolled on Total Study XV (which omitted cranial radiation therapy in all patients) underwent comprehensive neuropsychological assessments at induction, end of maintenance, and 2 years after completion of therapy.[47]

High-risk patients who received more intensive CNS-directed chemotherapy (including high-dose methotrexate and more doses of intrathecal chemotherapy) were at greater risk of difficulties in attention, processing speed, and academics.

In a subsequent study from the SJCRH, 400 patients in the Total XVI study (enrolled between 2007 and 2017) underwent neurocognitive testing after the completion of therapy (approximately 3 years from diagnosis). None of the patients received cranial radiation, but the number of doses of triple intrathecal therapy (ITT) chemotherapy varied by risk group and CNS status. Patients with low-risk ALL were prescribed 13 to 21 doses, while patients with standard- and high-risk ALL were prescribed 16 to 27 doses.[48]

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In a subsequent study from the SJCRH, 400 patients in the Total XVI study (enrolled between 2007 and 2017) underwent neurocognitive testing after the completion of therapy (approximately 3 years from diagnosis). None of the patients received cranial radiation, but the number of doses of triple intrathecal therapy (ITT) chemotherapy varied by risk group and CNS status. Patients with low-risk ALL were prescribed 13 to 21 doses, while patients with standard- and high-risk ALL were prescribed 16 to 27 doses.[48]

Compared with age-normative expectations, the entire patient cohort exhibited neurocognitive impairments in multiple domains, including attention, working memory, executive function, fine motor skills, and adaptive skills.

In a subsequent study from the SJCRH, 400 patients in the Total XVI study (enrolled between 2007 and 2017) underwent neurocognitive testing after the completion of therapy (approximately 3 years from diagnosis). None of the patients received cranial radiation, but the number of doses of triple intrathecal therapy (ITT) chemotherapy varied by risk group and CNS status. Patients with low-risk ALL were prescribed 13 to 21 doses, while patients with standard- and high-risk ALL were prescribed 16 to 27 doses.[48]

For patients with low-risk ALL, there was no correlation between the number of ITT doses (<20 vs. >21) and neurocognitive measures.

In a subsequent study from the SJCRH, 400 patients in the Total XVI study (enrolled between 2007 and 2017) underwent neurocognitive testing after the completion of therapy (approximately 3 years from diagnosis). None of the patients received cranial radiation, but the number of doses of triple intrathecal therapy (ITT) chemotherapy varied by risk group and CNS status. Patients with low-risk ALL were prescribed 13 to 21 doses, while patients with standard- and high-risk ALL were prescribed 16 to 27 doses.[48]

For patients with standard- and high-risk ALL, those who received the highest number of ITT doses (>27) had an increased risk of impairment than those who received fewer doses, especially in working memory, attention, and fine motor skills.

In a subsequent study from the SJCRH, 400 patients in the Total XVI study (enrolled between 2007 and 2017) underwent neurocognitive testing after the completion of therapy (approximately 3 years from diagnosis). None of the patients received cranial radiation, but the number of doses of triple intrathecal therapy (ITT) chemotherapy varied by risk group and CNS status. Patients with low-risk ALL were prescribed 13 to 21 doses, while patients with standard- and high-risk ALL were prescribed 16 to 27 doses.[48]

Patients with public or no insurance had worse neurocognitive outcomes than those with private insurance.

In a subsequent study from the SJCRH, 400 patients in the Total XVI study (enrolled between 2007 and 2017) underwent neurocognitive testing after the completion of therapy (approximately 3 years from diagnosis). None of the patients received cranial radiation, but the number of doses of triple intrathecal therapy (ITT) chemotherapy varied by risk group and CNS status. Patients with low-risk ALL were prescribed 13 to 21 doses, while patients with standard- and high-risk ALL were prescribed 16 to 27 doses.[48]

Among patients with standard- and high-risk ALL, boys had a higher risk of neurocognitive impairments than girls, as did patients who were younger at diagnosis.

In a subsequent study from the SJCRH, 400 patients in the Total XVI study (enrolled between 2007 and 2017) underwent neurocognitive testing after the completion of therapy (approximately 3 years from diagnosis). None of the patients received cranial radiation, but the number of doses of triple intrathecal therapy (ITT) chemotherapy varied by risk group and CNS status. Patients with low-risk ALL were prescribed 13 to 21 doses, while patients with standard- and high-risk ALL were prescribed 16 to 27 doses.[48]

The clinical manifestations of the neurocognitive impairments (if any) found by end-of-treatment neurocognitive testing, and their trajectories over time, were not evaluated in this study.

In the COG AALL06N1 (NCT00437060) trial, patients with high-risk B-ALL who had been enrolled in the AALL0232 trial received a neurocognitive evaluation. These patients had been randomly assigned to receive either high-dose methotrexate with leucovorin rescue or escalating-dose IV methotrexate with pegasparaginase during the interim maintenance phase of therapy in the AALL0232 trial. A neurocognitive evaluation, which included an assessment of intellectual function (estimated intelligence quotient [IQ]), working memory, and processing speed, was conducted after the completion of therapy.[49]

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In the COG AALL06N1 (NCT00437060) trial, patients with high-risk B-ALL who had been enrolled in the AALL0232 trial received a neurocognitive evaluation. These patients had been randomly assigned to receive either high-dose methotrexate with leucovorin rescue or escalating-dose IV methotrexate with pegasparaginase during the interim maintenance phase of therapy in the AALL0232 trial. A neurocognitive evaluation, which included an assessment of intellectual function (estimated intelligence quotient [IQ]), working memory, and processing speed, was conducted after the completion of therapy.[49]

The method of methotrexate delivery was unrelated to differences in neurocognitive outcomes after controlling for ethnicity, race, age, gender, insurance status, and time off treatment.

In the COG AALL06N1 (NCT00437060) trial, patients with high-risk B-ALL who had been enrolled in the AALL0232 trial received a neurocognitive evaluation. These patients had been randomly assigned to receive either high-dose methotrexate with leucovorin rescue or escalating-dose IV methotrexate with pegasparaginase during the interim maintenance phase of therapy in the AALL0232 trial. A neurocognitive evaluation, which included an assessment of intellectual function (estimated intelligence quotient [IQ]), working memory, and processing speed, was conducted after the completion of therapy.[49]

Survivors younger than 10 years at diagnosis had a statistically significantly lower estimated IQ and processing speed scores than older patients.

In the COG AALL06N1 (NCT00437060) trial, patients with high-risk B-ALL who had been enrolled in the AALL0232 trial received a neurocognitive evaluation. These patients had been randomly assigned to receive either high-dose methotrexate with leucovorin rescue or escalating-dose IV methotrexate with pegasparaginase during the interim maintenance phase of therapy in the AALL0232 trial. A neurocognitive evaluation, which included an assessment of intellectual function (estimated intelligence quotient [IQ]), working memory, and processing speed, was conducted after the completion of therapy.[49]

Additionally, patients with public health insurance had significantly lower estimated IQ scores than participants with U.S. private or military insurance.

Late-developing toxicities

Studies cited in this source section

Publication references