A practice-changing study that used molecular testing to distinguish between subtypes of medulloblastoma has shown a significant improvement in survival for children with high-risk disease who underwent treatment intensification with carboplatin.
“Each of the four subgroups of medulloblastoma has a different prognosis, but for this particular subgroup, 20 fewer children out of every 100 would have survived prior to this study,” James Olson, MD, professor of medicine, French Hutchinson Cancer Research Center, University of Washington, Seattle, said in an interview.
“This is the reason for celebration – for now and forevermore, we can expect 20 more children with high-risk, group 3 medulloblastoma to survive,” he said.
“We recommend that all children with high-risk, group 3 medulloblastoma receive carboplatin and all children in the other subgroups do not, because we don’t want them to experience the toxicity without benefit,” Dr. Olson said.
The study was published online July 22, 2021, in JAMA Oncology.
Hematologic toxicity was more pronounced in the carboplatin arm in the induction phase of the protocol, and toxicity persisted into the first cycles of maintenance therapy. On the other hand, “there weren’t enough additional side effects to recommend children not get carboplatin if they would benefit from it,” Dr. Olson noted.
At least 75% of children with newly diagnosed medulloblastoma survive, although those with high-risk, group 3 disease have a substantially poorer prognosis than those with other molecular subtypes.
However, if a child with medulloblastoma experiences relapse, “the likelihood of survival is near zero, so it’s important to get it right the first time,” Dr. Olson said.
One of the patients who took part in this trial, Sammy Loch of Seattle, is now 27 years old and has been cancer free for 11 years.
She was diagnosed with medulloblastoma when in high school. At the time of her diagnosis, she was asked by her pediatric oncologist at Seattle Children’s Hospital about taking part in the study. After careful consideration, she agreed.
“Participating in research was my way to give back and pay it forward,” Ms. Loch said in a statement. “It’s really exciting to know more people will survive because of the research I was involved in,” she added. She continues to pay her debt forward, serving as a therapist for people with chronic health conditions and raising funds for pediatric cancer research.
Patients had high-risk features
The study involved 261 evaluable patients (median age, 8.6 years). All patients had high-risk features, including metastatic disease (72.4% of the group), diffuse anaplastic histologic characteristics (22.2%), and incomplete surgical resection (5.4%), defined as residual tumor greater than 1.5 cm2.
“All patients received 36 Gy craniospinal radiotherapy with boost to the posterior fossa of 55.8 Gy cumulative dose with conventional fractionation of 1.8 Gy/d,” Dr. Olson and colleagues explain. Patients also received six doses of vincristine 1.5 mg/m2 weekly during radiotherapy and were randomly assigned to receive carboplatin 35 mg/m2 for a total of 30 doses given daily prior to radiotherapy or placebo.
This regimen was followed by maintenance therapy, which consisted of six 28-day cycles of the combination of cisplatin 75 mg/m2 on day 1; cyclophosphamide 1,000 mg/m2 on days 2 and 3; and vincristine 1.5 mg/m2 on days 1 and 8.
Patients were originally assigned to receive an additional 12 cycles of isotretinoin or placebo, to be given during and after maintenance therapy. However, randomization to isotretinoin was discontinued early because of futility.
The study was initially powered to evaluate medulloblastoma as a single disease. However, as a result of biologic insights gained after the study was conceived, it was amended to include a molecular subgroup analysis to better distinguish patients who might truly benefit from intensified therapy, the authors explained.