Long-term toxicities of chemoradiotherapy in children with standard-risk medulloblastoma

Background. Medulloblastoma (MB) is one of the most common malignant brain tumors in children. In the standard-risk group, 5-year overall survival reaches 75–85 %, however, high treatment efficacy is accompanied by a considerable risk of late toxic effects that substantially impact patients’ quality of life. The most prevalent complications include cognitive and endocrine disorders, sensorineural hearing loss, and scoliosis. Long-term follow-up of survivors remains non-standardized.

The aim of this study was to comprehensively assess the spectrum and frequency of late effects after chemoradiotherapy in children with standard-risk MB and to identify factors influencing their development.

Materials and methods. A retrospective analysis was performed in 144 patients with standard-risk MB treated at the Dmitry Rogachev National Medical Research Center between 2013 and 2023. All patients received craniospinal irradiation at a dose of 23.4–24.0 Gy or 35.2–36.0 Gy with a posterior fossa boost to 54–55 Gy, followed by maintenance chemotherapy (lomustine, cisplatin, vincristine). To assess late effects (endocrine dysfunction, sensorineural hearing loss, scoliosis, chronic nutritional deficiency, polyneuropathy), detailed clinical and laboratory data were available for 55 patients, neurocognitive outcomes were analyzed in 30, and oncologic follow-up for secondary tumors in all 144. The cumulative incidence of complications was estimated using competing-risks methodology, subgroup comparisons were performed with Gray’s test, with p < 0.05 considered statistically significant.

Results. The median age at the start of radiotherapy was 8.2 years, median follow-up 3.2 years. The most frequent late effects were cognitive (96.7 %) and endocrine disorders (89.1 %). Less frequent complications included scoliosis (50.9 %), sensorineural hearing loss (47.3 %), nutritional deficiency (32.7 %), and polyneuropathy (25.5 %), secondary neoplasms occurred in 4.2 % of patients. The most common cognitive impairments involved reduced psychomotor speed, attention, memory, emotional stability, and learning ability. Following therapy, a statistically significant increase was observed in the frequency of memory impairment (p = 0.01) and learning difficulties (p = 0.027). Growth hormone deficiency was detected in 70.1 % of patients (median time to onset – 1.7 years), the diagnosis was confirmed in 43 %, and growth hormones replacement therapy was initiated in only one-third. Hypothyroidism was diagnosed in 69.1 %, secondary adrenal insufficiency in 21.8 %, and gonadal dysfunction in 16.4 %. Growth hormone deficiency and hypothyroidism developed significantly earlier in patients who received craniospinal irradiation 35.2 Gy, although their long-term cumulative incidence was similar to those treated with 23.4 Gy. The 6-year cumulative incidence of secondary neoplasms was 4.7 %; most were high-grade diffuse gliomas (n = 3) with a median survival not exceeding one year.

Conclusions. Chemoradiotherapy for standard-risk MB is associated with a wide spectrum of late toxicities, predominantly cognitive and endocrine, most of which can be effectively managed when detected in a timely manner. Unwarranted de-escalation of therapy without reliable prognostic justification is unacceptable due to the high risk of fatal relapse. Systematic long-term monitoring of late effects, application of modern toxicity-reduction approaches, and comprehensive rehabilitation programs are essential components of optimal survivorship care for patients with MB.

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