The use of carboplatin but not isotretinoin in children with high-risk medulloblastoma led to an increase in event-free survival at 5 years.
Medulloblastoma is the second most common, malignant brain tumour in children. It develops in between 250 and 400 children each year and more than 70% of cases occur in those younger than 10 years of age. It is a highly invasive cancer that arises in the cerebellum and disseminates throughout the central nervous system. Survival depends to a large extent on whether or not the disease has spread. For example, among children without disseminated disease, the event-free survival at 5 years has been shown to be around 80%. However, the cancer can return and the 3-year survival rate for relapsed cancer is low at around 18%. Medulloblastomas are categorised into different groups, with group 3 being more aggressive and therefore high-risk, with a 5-year survival of approximately 20%–30%. The use of carboplatin as a radiosensitiser has been found to be a promising strategy in patients with high-risk medulloblastoma and isotretinoin has been shown to induce apoptosis of medulloblastoma cells. There is also data showing that the addition of isotretinoin to carboplatin, enhances tumour sensitivity in squamous cell carcinoma xenografts.
With some evidence suggesting that the combination of isotretinoin and carboplatin may be of greater value in the treatment of medulloblastoma, a team from the Cancer and Blood Disorders Centre, Seattle, US, decided to undertake a randomised trial to examine the impact on survival of combination therapy in children with high-risk (group 3) medulloblastoma. Included patients were randomised to chemotherapy with 36-GY craniospinal radiation therapy and weekly vincristine with or without daily carboplatin, followed by 6 cycles of maintenance chemotherapy with or without 12 cycles of isotretinoin. The primary outcome of the trial was event-free survival.
There were 261 children with a mean age of 8.6 years (70% male), 72% of whom at metastatic disease included in the analysis and the median follow-up time was 6.7 years. For all participants, the 5-year overall survival was 73.4% (95% CI 66.7–80.1%). The overall 5-year event-free survival with carboplatin was 66.4% (95% CI 56.4%–76.4%) vs 59.2% (95% CI 48.8%–69.6%) without carboplatin. However, in the subgroup of patients with group 3 medulloblastoma, the 5-year event-free survival for patients given carboplatin was even higher, 73.2% vs 53.7% without carboplatin. In addition, the overall survival with carboplatin was 82.8% vs 63.7% without the drug. The isotretinoin arm was closed early due to an interim analysis finding that addition of the drug was unlikely to have a positive effect on event-free survival, i.e., 68.6% with isotretinoin vs 67.8% without.
The authors concluded that the use of carboplatin and radiotherapy should be recommended for paediatric patients with high risk medulloblastoma although use of isotretinoin added little value.
Leary SES et al. Efficacy of Carboplatin and Isotretinoin in Children with High-risk Medulloblastoma. A Randomised Clinical Trial from the Children’s Oncology Group. JAMA Oncol 2021