Study results
The World Health Organization categorizes tumors of the central nervous system into four groups. The authors followed this system of categorization for their patients with medulloblastoma. The four groups are WNT, in which WNT signaling pathway is activated; SHH, in which the SHH signaling pathway is activated; with or without TP53 mutation (provisionally designated group 3); and non-WNT/non-SHH (provisionally designed group 4)
The primary endpoint of the trial was event-free survival (EFS). In the patient population overall, there was no significant difference regarding this endpoint among those who received carboplatin and those who did not (EFS at 5 years, 66.4% vs. 59.2%).
However, there was a significant improvement among the patients in subgroup 3. Among those patients, EFS at 5 years was 73.2% with carboplatin versus 53.7% without (P = .047).
Similarly, in the overall group, there was no significant improvement in overall survival (OS) at 5 years from the addition of carboplatin (77.6% vs. 68.8% without carboplatin). However, the OS at 5 years varied widely between the different subtypes. There was again a significant improvement in OS at 5 years among the patients in subgroup 3 (82% with carboplation vs 63.7% without).
The beneficial effects from the addition of carboplatin on both endpoints were seen exclusively in patients in group 3, the authors emphasized.
“The WNT group does really well with less therapy, so if we treated all children the same, we would likely be overtreating WNT children and undertreating group 3 children,” Dr. Olson observed. “Genetic analysis is essential.”
In an earlier study, Dr. Olson and colleagues found that 70% of children with primitive neuroectodermal tumor of the CNS and pineoblastoma had been misdiagnosed even by outstanding children’s oncology centers because clinicians were relying on microscopic diagnosis.
“With molecular diagnosis, we were able to learn that many of these children had completely different diseases that require complexly different treatments, so doing diagnosis by molecular classification is absolutely essential,” he reemphasized.
“Glimmers of hope”
This study provides clinicians with “glimmers of hope” that children with high-risk, group 3 medulloblastoma will experience improvements in survival, wrote Allison Martin, MD, Albert Einstein College of Medicine, New York, and Sadhana Jackson, MD, National Institutes of Health, Bethesda, M.d., in an accompanying editorial.
The editorialists hope that “the treatment paradigm for all patients with high-risk disease can be improved through incorporation of detailed molecular analyses.”
However, they pointed out that DNA methylation and other advanced testing methods used to distinguish subgroups 3 and 4 in this study are not widely available, even at most Children’s Oncology Group member institutions. (Dr. Olson countered that, even if these sophisticated tests are not available at all pediatric oncology centers, tests will be performed if clinicians send tissue to the few sites that are equipped to conduct them.)
The editorialists also noted that therapy intensification with carboplatin is associated with an increased risk for adverse effects – “underscoring the importance of correctly identifying patients who could benefit from this intervention and avoid unnecessary toxic effects.”
The study was funded by the National Cancer Institute. Dr. Olson has disclosed no relevant financial relationships. Dr. Martin reported that she previously owed shares in Celgene, which she has subsequently sold.
A version of this article first appeared on Medscape.com.