NEW YORK – Researchers from Seattle Children's found that young cancer patients with group 3 medulloblastoma, a biomarker-defined subgroup, saw improved outcomes with more intense therapy that included carboplatin and radiation therapy.
The randomized Phase III trial enrolled 294 patients with medulloblastoma and followed them over 10 years. Patients were randomized to two arms with and without carboplatin. In one arm patients received craniospinal radiotherapy, weekly vincristine, and maintenance chemotherapy, and in another arm, they received chemoradiotherapy with weekly carboplatin followed by maintenance chemo.
Researchers performed retrospective molecular analysis using Illumina's Infinium MethylationEpic BeadChip methylation array. They also conducted whole-exome sequencing on patient samples using Illumina's TruSeq DNA Exome kit.
Across the whole study population, the five-year event-free survival was 66.4 percent among patients receiving carboplatin, compared to 59.2 percent among patients in the control arm. Patients who received carboplatin had a five-year overall survival rate of 77.6 percent versus 68.8 percent for the control arm.
However, researchers saw the greatest improvement in outcomes among patients with group 3 medulloblastoma. In this molecular group, patients who received carboplatin had a five-year event-free survival of 73.2 percent and a five-year overall survival rate of 82.8 percent. In comparison, group 3 patients who did not receive carboplatin had a five-year event-free survival rate of 53.7 percent and a five-year overall survival rate of 63.7 percent.
"We observed 19 percent higher survival exclusively in group 3 medulloblastoma patients who were randomized to receive intensified chemoradiotherapy with concurrent carboplatin, and 25 percent higher survival for metastatic group 3 medulloblastoma patients," the authors wrote.
Carboplatin-treated patients' improved outcomes, however, came at the cost of increased toxic effects. Patients in the carboplatin treatment arm experienced more hematologic adverse effects during the induction phase and had a higher risk of thrombocytopenia and febrile neutropenia that continued into the first cycles of maintenance therapy.
Group 3 medulloblastoma is thought to be the deadliest form of the disease. It is defined by MYC amplification, large cell/anaplastic histology, diagnosis at a young age, or the presence of metastases at diagnosis. The three other medulloblastoma molecular subgroups include one group for patients with activated WNT pathways, another with activated SHH pathways, and group 4, which tend also to have poor outcomes, though not as bad as group 3.
In this study, molecular subgroup classification was available for 89 percent of the cohort, or 231 patients. The five-year overall survival rate for all patients with a molecular classification was 100 percent in the WNT pathway activated group; around 54 percent for those with the SHH pathway activated; 74 percent for group 3 patients; and 77 percent for group 4 patients.
However, researchers only observed outcomes improvement in group 3 patients with the addition of carboplatin. "It is therefore appropriate to avoid therapy intensification in groups of patients who would not be expected to benefit, specifically in those with WNT, SHH, and group 4 medulloblastoma," the authors wrote.
Researchers noted the importance of molecular diagnosis for medulloblastoma patients outside of the research setting. They also urged oncologists to run the full suite of tests to identify patients in molecular subgroups 3 and 4.
"Although immunohistochemistry panels and targeted sequencing may differentiate WNT and SHH subgroups, additional molecular profiling tests, such as NanoString or DNA methylation platforms, are needed to confidently distinguish group 3 from group 4 medulloblastoma," they wrote. "Although widely used as a research tool, there is a need to increase the clinically certified laboratories offering medulloblastoma subtyping."