1. In this open-label, single-center, phase 2 study, pediatric patients that received proton radiotherapy for medulloblastoma had cumulative incidence of grade 3-4 ototoxicity of 12% at 3 years and 16% at 5 years. Ototoxicity was graded with the Pediatric Oncology Group ototoxicity scale (0-4).
2. Progression-free survival was 83% at 3 years.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Medulloblastoma is a pediatric primitive neuroectodermal tumor that arises in the cerebella and is the most common malignant pediatric brain tumor. Overall survival has much improved in recent decades with a combination of surgery, radiotherapy and chemotherapy interventions. Unfortunately, such interventions frequently lead to long-term sequelae. Efforts are underway to identify ways to reduce the radiation dose while preserving therapeutic responses. One such advance is proton radiotherapy, which allows for greater precision with radiation delivery. In this phase 2 clinical trial, patients aged 3-21 years with medulloblastoma received proton craniospinal irradiation and were followed for cumulative incidence of ototoxicity at 3 years as the primary outcome. Additional secondary outcomes such as neuroendocrine toxicity and neurocognitive toxicity were also analyzed. Overall, the study demonstrated survival outcomes with proton radiotherapy comparable to those with conventional radiotherapy. In addition, toxicity profile was deemed acceptable by the investigators – cumulative incidences of grade 3-4 ototoxicity was 12% at 3 years and 16% at 5 years. Possible limitations of the study include the relatively small sample size (n=59) and the open-label nature of the trial design.
The study was funded by US National Cancer Institute and Massachusetts General Hospital.
Relevant Reading: Late neurocognitive sequelae in survivors of brain tumours in childhood
In-Depth [phase 2 trial]: This non-randomized, open-label, phase 2 trial is a single-center study aimed at assessing the survival outcomes and long-term toxicity of proton radiotherapy treatment for medulloblastoma. 59 patients aged 3 to 21 years with medulloblastoma were enrolled and received proton craniospinal irradiation of 16-36 Gy radiobiological equivalents (GyRBE) delivered at 1.8 GyRBE per fraction, followed by a boost dose. The primary outcome was cumulative incidence of ototoxicity at 3 years, as graded with the Pediatric Oncology Group ototoxicity scale (0-4). Additional secondary outcomes such as neuroendocrine and neurocognitive toxicities were also assessed.
The cumulative incidence of ototoxicity at 3 years was 12% (95% CI 4-25) among 45 evaluable patients who had no grade 3-4 hearing loss at baseline. The incidence at 5 years was 16% (95% CI 6-29). In assessing neurocognitive outcomes, the median follow-up time was 5.2 years (IQR 2.6-6.4). Falls in processing speed was noted to be the most significant decrease, whereas perceptual reasoning and working memory were not significantly affected. In assessing neuroendocrine toxicities, incidence of any hormone deficiency was 63% (95% CI 48-75) at 7 years from the start of proton radiotherapy. The most common hormonal deficiency was growth hormone (55%, 95% CI 40-68). Endocrine deficits were not significantly associated with sex, age at treatment, craniospinal irradiation, or boost field.
Proton radiotherapy demonstrated 3-year progression free survival of 83% (95% CI 71-90) for all patients, 87% (95% CI 72-93) for standard risk patients, and 75% (95% CI 50-89) for immediate-high risk patients. Median time to progression was 30 months (IQR 16-53).
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