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 School of Medicine, Seattle, Washington, told Medscape Medical News.
"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," Olson said.
The study was published online July 22 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," 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," Olson notes.
One of the patients who took part in this trial, Sammy Loch, in Seattle, Washington, 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," 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 >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," 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 1000 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 explain.
The World Health Organization categorizes tumors of the central nervous system (CNS) into four groups. The authors followed this system of categorization for their patients with medulloblastoma. The four groups are as follows:
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)
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, vs 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 emphasize.
"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," OIson observed. "Genetic analysis is essential," he added.
In an earlier study, 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, write Allison Martin, MD, Albert Einstein College of Medicine, New York City, and Sadhana Jackson, MD, National Institutes of Health, Bethesda, Maryland, 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 point 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. (Olson counters 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 note 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. Olson has disclosed no relevant financial relationships. Martin reports that she previously owed shares in Celgene, which she has subsequently sold.
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