Summary: tumor- and treatment-related late morbidity

Among 240 five-year survivors in a St. Jude cohort of 361 children, the 15-year cumulative incidence was 18% for monocular blindness, 22% for hearing loss, 29% for growth hormone deficiency, 33% for thyroid hormone deficiency, 26% for ACTH deficiency, 53% for overweight or obesity, and 38% for at least one seizure; 34% of 182 survivors tested had an IQ below 85, compared with 16% in the normative sample. Among children with progressive hypothalamic/chiasmatic tumors, the cumulative incidence of monocular blindness was 57% at 15 years. In a Dutch nationwide cohort of 117 children treated for optic pathway glioma, 18.8% had binocular severe visual impairment or blindness after a median of 8.3 years. In the Childhood Cancer Survivor Study, survivors of astrocytoma and glial tumors showed radiotherapy dose-dependent impairment in attention, processing speed, and memory, and cranial radiotherapy of 50 Gy or more was associated with a 25-year cumulative incidence of CNS subsequent neoplasms of 7.1%, compared with 1.0% without radiotherapy. Chemotherapy is associated with myelosuppression, peripheral neuropathy, allergic reactions, and other toxicities; grade 3 to 4 peripheral nervous system toxicity occurred in 19% of children receiving carboplatin and vincristine in COG A9952.

Cumulative late effects among 5-year survivors: St. Jude cohort

“OS at 15 years was 86% (95% confidence interval [CI] 82%–90%), and PFS was 55% (95% CI 51%–58%). Among the 240 5-year survivors, the 5-, 10-, and 15-year cumulative incidence of adverse outcomes included blindness: 10%, 13%, and 18%, respectively; hearing loss: 8%, 14%, and 22%; obesity/overweight: 18%, 35%, and 53%; hyperinsulinism: 1%, 5%, and 24%; growth hormone deficiency: 13%, 27%, and 29%;thyroid hormone deficiency: 16%, 28%, and 33%; and adrenocorticotropic hormone (ACTH) deficiency: 12%, 22%, and 26%.” (opens the source at this quote in a new tab)
“Survivors of childhood LGG experience substantial long-term adverse effects that continue to increase well beyond the 5-year survival time point.” (opens the source at this quote in a new tab)

Visual impairment

“Lesions in the hypothalamic/chiasmatic region were responsible for most cases of vision loss (27 of 31, 87%), and among patients with progressive gliomas in this location the cumulative incidence of monocular legal blindness was 57% at 15 years from diagnosis.” (opens the source at this quote in a new tab)
“Additionally, the cumulative incidence of a measured visual field deficit was 31.5% (95% CI 22.7%–40.3%) at 15 years, with a cumulative incidence of over 47% in hypothalamic/chiasmatic lesions, regardless of the progression status.” (opens the source at this quote in a new tab)

“After a median follow‐up of 8.3 years (range: 0.1–23.8 years) after the start of treatment, severe VI or blindness (>1.0 LogMAR) was observed in both eyes in 18.8% of 117 patients and in 34.6% of 234 included eyes.” (opens the source at this quote in a new tab)
“Independent prognostic factors for severe VI or blindness included starting therapy under the age of 2 years and hypothalamic involvement of the OPG.” (opens the source at this quote in a new tab)

“At completion of chemotherapy, VA improved (32% of subjects), remained stable (40%), or declined (28%). Tumor location was the most consistent prognostic factor for poor VA outcome. There was poor correlation between radiographic and VA outcomes.” (opens the source at this quote in a new tab)

“Visual impairment affects up to 80% of patients with optic pathway or hypothalamic tumors” (opens the source at this quote in a new tab)

Endocrine dysfunction and hypothalamic obesity

“In Cox's multiple regression analysis, both location in the diencephalon and use of RT were statistically significant independent predictors of development of each of these outcomes (Table 4), while GTR was protective for development of GH deficiency (HR = 0.2, 95% CI 0.1–0.6).” (opens the source at this quote in a new tab)
“Consistent with a known risk for hypothalamic injury-mediated obesity, 75% of these patients are overweight or obese.” (opens the source at this quote in a new tab)

“While overall survival exceeds 90% at five years, most patients experience significant long-term morbidity including visual impairment, multiple endocrine deficiencies, and hypothalamic obesity.” (opens the source at this quote in a new tab)

Hearing loss

“The cumulative incidence of hearing loss was 8%, 14%, and 22% (95% CI at 15 years 13.2–30.3) at 5, 10, and 15 years, respectively, but a deficit severe enough to recommend a hearing aid was uncommon (6%) at 15 years.” (opens the source at this quote in a new tab)

Neurocognitive deficits

“Sixty-one patients (34%) had an IQ score <85, compared with 16% in the normative sample (z = 0.18, P < .001, z-test for testing 1 sample proportion).” (opens the source at this quote in a new tab)
“In the multiple regression model, younger age at diagnosis (P = .016), epilepsy (P = .048), and shunt placement (P = .029) were significantly predictive of lower IQ.” (opens the source at this quote in a new tab)

“Survivors diagnosed with astrocytoma and glial tumors were impaired in attention and/or processing speed and memory by a statistically significant extent, with a clear cranial RT dose–response pattern.” (opens the source at this quote in a new tab)

“Neurocognitive impairment, most commonly attention deficits reported in 34–55% of survivors” (opens the source at this quote in a new tab)

Seizures and epilepsy

“The cumulative incidence of at least 1 seizure was 38.0% (95% CI 29.5%–46.5%) (Table 2). Both seizure and epilepsy were associated only with tumor location above the tentorium cerebri, but not with extent of resection.” (opens the source at this quote in a new tab)

Late effects of radiotherapy: subsequent neoplasms, vasculopathy, and chronic conditions

“Patients who received cranial RT of 50 Gy or more (n = 813) had a cumulative incidence of a subsequent neoplasm within the CNS of 7.1% (95% CI = 4.5% to 9.6%) at 25 years from diagnosis compared with 1.0% (95% CI = 0% to 2.3%) for patients who had no RT. Survivors had higher risk than siblings of developing new endocrine, neurological, or sensory complications 5 or more years after diagnosis.” (opens the source at this quote in a new tab)
“There was a dose-dependent association between RT to the frontal and/or temporal lobes and lower rates of employment, and marriage.” (opens the source at this quote in a new tab)

“Although radiation therapy (RT) is an effective treatment modality for pLGG, it is associated with substantial risk of late effects, including neurocognitive deficits, endocrine abnormalities, secondary malignancy, and vascular complication; therefore, it is not recommended for the majority of children diagnosed with pLGG.” (opens the source at this quote in a new tab)

“Young children are more at risk for late effects of radiotherapy, including decrease in intellectual function, endocrine deficits, second neoplasms, hearing loss, and vasculopathy.” (opens the source at this quote in a new tab)

“however the hazard ratio of death due to non-glioma related causes of 2.4 (P-value = 0.0006) in patients treated with radiation suggests that radiation-induced mortality may have accounted for some of the deaths that were not directly due to glioma” (opens the source at this quote in a new tab)

Toxicity of first-line chemotherapy

“Chemotherapies have many associated toxicities, including risks for myelosuppression, peripheral neuropathy, allergic/anaphylactic reaction, constipation, sodium dysregulation, secondary malignancy, and renal and hepatic dysfunction.” (opens the source at this quote in a new tab)

“The incidence of peripheral nervous system grade 3 to 4 toxicity was 19% for CV and 19% for TPCV because of the vincristine in both regimens.” (opens the source at this quote in a new tab)

Chronic disease burden across functional domains

“Although there is high associated morbidity, tumor-related mortality is relatively rare. pLGG is now conceptualized as a chronic disease, underscoring the importance of functional outcomes and quality-of-life measures.” (opens the source at this quote in a new tab)

“The late adverse effects of the disease and treatment of it in combination with the damage to important functional structures puts a heavy burden on patients and can lead to loss of visual function and impairment of neurologic, endocrine, and cognitive functioning” (opens the source at this quote in a new tab)

“The diverse domains that can potentially be affected are described as follows: motor function, speech, eating and swallowing, sensory functions, seizures, neuropathy, organ function after systemic treatment, late effects due to cranial radiation (vascular changes and secondary tumors, endocrine and hypothalamic function, sleep and energy, neuro-cognition and education, psychosocial effects, and quality of life.” (opens the source at this quote in a new tab)

Visual acuity at long-term follow-up after first-line chemotherapy for optic pathway glioma

“With an average follow-up of 6.5 years, VA improved or remained stable in 59% and 61% of children with NF1 and sporadic OPGs, respectively.” (opens the source at this quote in a new tab)
“These findings raise the question as to whether chemotherapy is effective in preserving vision; it may well be that treatment after a certain point of visual deterioration cannot prevent further decline.” (opens the source at this quote in a new tab)

Residual morbidity and disability grade in survivors and their relation to quality of life

“Despite the improved management and survival of pediatric low-grade glioma, roughly 80% of all survivors experience some morbidity.” (opens the source at this quote in a new tab)
“Greater disability was weakly but significantly correlated with lower scores on the proxy-evaluated total quality of life (r=-0.32, p<0.05). Disability also correlated with lower scores on the friends subscale (r>-0.3, p<0.05) in both the self- and proxy reports.” (opens the source at this quote in a new tab)

Academic achievement and delayed emergence of cognitive impairment

“Since the majority of pediatric LGG patients are survivors with the lasting effects of brain injury, they frequently are in long-term need for healthcare resources” (opens the source at this quote in a new tab)
“Problems with academic achievement play a role in 60% of LGG survivors, and over years, developmental problems can continue, and even worsen. Cognitive impairments may appear years after diagnosis, even in children without initial severe deficits.” (opens the source at this quote in a new tab)

Neuropathy and renal toxicity attributable to first-line vincristine and carboplatin

“The first-line chemotherapeutic treatment for low-grade glioma patients is the combination of vincristine and carboplatin. Peripheral neuropathy due to vincristine occurs during 57% of LGG treatment” (opens the source at this quote in a new tab)
“Carboplatin can cause kidney damage resulting in hypomagnesemia, rarely indicating supplement and sometimes hypocalcemia and distal renal tubular acidosis” (opens the source at this quote in a new tab)

Frequency of neurologic impairment by domain in children with low-grade glioma

“Children with LGG may experience a diversity of neurologic impairments, including ataxia 40%, motor weakness 44%, seizures 16%, cranial nerve deficits 14%, eye movement disorders and/or visual impairment 46%, and hearing loss 16% and also cognitive dysfunction 36%” (opens the source at this quote in a new tab)

Endocrine and hypothalamic dysfunction at 30-year follow-up and what it requires of monitoring

“After a 30-year follow-up, patients encounter GH deficiency in 40%, central precocious puberty in 26%, gonadotropin deficiency in 20%, thyroid dysfunction in 13%, and ACTH deficiency in 13%.” (opens the source at this quote in a new tab)
“Additionally to endocrine dysfunction also hypothalamic damage can be present especially in LGG of the supratentorial midline. These patients have twofold increased risk of endocrine deficiencies” (opens the source at this quote in a new tab)
“A proper attention for diverse features of hypothalamic dysfunction is needed: hyperphagia, hypophagia, body mass index, behavioral problems, sleep-wake problems, and temperature instability due to autonomic dysregulation.” (opens the source at this quote in a new tab)

Seizures after resection and hearing loss after surgery or platinum chemotherapy

“Also after the resection of hemispheric pLGG, seizures can occur, not only directly after surgery (ranging from 15 to 70%), but also on the long term in approximately 30% of patients” (opens the source at this quote in a new tab)
“About 10% of children experiences hearing loss after surgery on an LGG in the cerebellum” (opens the source at this quote in a new tab)
“For this reason, carboplatin has been used most often in the treatment of pediatric LGG with lesser risk of hearing loss” (opens the source at this quote in a new tab)

Occupation, income, and education in adulthood after radiotherapy

“On the long term, younger age at diagnosis and treatment with radiotherapy in LGG patients resulted in sevenfold lower occupation scores, more sheltered work, lower income, and less education in adulthood” (opens the source at this quote in a new tab)
“This lower occupation score was also related to vision, hearing, and motor impairments.” (opens the source at this quote in a new tab)

Tovorafenib (DAY101)

Long-term morbidity