Group 3 is one of at least four medulloblastoma molecular subgroups that may help improve diagnostic accuracy as part of an "integrated diagnosis," according to Dr. Sarah Leary of Seattle Children's and colleagues. The 2016 World Health Organization Classification of Tumors of the Central Nervous System defined an "integrated diagnosis" as including WNT (WNT signaling pathway activated), SHH (SHH signaling pathway activated) with or without TP53 mutation, and non-WNT/non-SHH (provisionally designated group 3 and group 4) medulloblastoma.
"This study confirms that children with medulloblastoma need an integrated molecular diagnosis, going beyond the microscope to characterize and group tumors according to changes in the DNA," Dr. Leary told Reuters Health by email.
"It is not too surprising to see a benefit to added therapy, but what was surprising was how clearly the study showed the importance of tumor biology, even though the study began before we had the tools we use today to make a more personalized integrated molecular diagnosis," she said. "This allows us to better select who is likely to benefit, and just as important, who is not likely to benefit and should not need to receive extra therapy."
"Treatment with carboplatin during radiation is a new standard for children with group 3 high-risk medulloblastoma," she concluded.
The multicenter trail, published in JAMA Oncology, included 261 evaluable patients with newly diagnosed high-risk medulloblastoma from 2007-2018. Participants' median age was 8.6 years and 70% were male. At enrollment, they were stratified by clinical high-risk criteria: 72% had metastatic disease; 22%, diffuse anaplasia; and 5% had greater than 1.5-cm2 residual disease.
Participants were randomized to 36-Gy craniospinal radiation therapy and weekly vincristine with or without daily carboplatin followed by six cycles of maintenance chemotherapy with cisplatin, cyclophosphamide, and vincristine with or without 12 cycles of isotretinoin during and following maintenance.
The primary clinical end point was event-free survival and the primary biology end point was molecular subgroup classification by DNA methylation array.
For all participants, the five-year event-free survival was 62.9% and overall survival was 73.4%.
Isotretinoin randomization was closed early due to futility.
With carboplatin, five-year event-free survival was 66.4% versus 59.2% without; however, the effect was observed only in group 3 subgroup patients: 73.2% with carboplatin versus 53.7% without.
Five-year overall survival differed by molecular subgroup: WNT pathway activated, 100%; SHH pathway activated, 53.6%; group 3, 73.7%; and group 4, 76.9%.
The authors conclude, "These findings further support the value of an integrated clinical and molecular risk stratification for medulloblastoma."
Dr. Sadhana Jackson of the US National Cancer Institute, coauthor of a related editorial, commented in an email to Reuters Health, "While more molecular data may assist with risk stratification, it leaves many clinicians and investigators questioning how to apply all this data to their patients."
"The lack of ready access to testing that differentiates group 3 from group 4 challenges the applicability of these findings," she noted. "It is also worth noting that despite the pediatric neuro-oncology community's sincere desire to decrease toxicity of medulloblastoma therapy by de-escalating treatment accordingly, only a trial that increased therapy intensity has been proven to be successful to date."
"The current study provides us with glimmers of hope for the survival of children with high-risk group 3 medulloblastoma and that the treatment paradigm for all high-risk patients can be improved through incorporation of detailed molecular analyses," she said. "It also provides us with a window into the behavior of high-risk group 3 medulloblastoma, with a nod to future treatment options for more treatment responsive/favorable high-risk patients."
SOURCE: https://bit.ly/3i6Bexv and https://bit.ly/3ycbHsk JAMA Oncology, online June 22, 2021.
By Marilynn Larkin
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