Benefit of increased resection extent varies by molecular subgroup in medulloblastoma

The degree to which extent of resection served as a prognostic marker for patients with medulloblastoma may heavily depend on molecular subgroup affiliation, according to the results of an integrated clinical and molecular analysis.

Prior research has suggested a link between incomplete medulloblastoma resection and high-risk disease, leading to use of second-look surgeries and intensified chemoradiotherapy, according to study background.

“Medulloblastoma is no longer considered a single entity, but rather consists of four distinct molecular subgroups (WNT, SHH, group 3 and group 4) with distinct demographics, clinical features including prognosis, transcriptomes, and genetics,” Eric M. Thompson, MD, pediatric neurosurgeon and spine surgeon at Duke Children’s Hospital & Health Center, and colleagues wrote. “All previous studies of the prognostic importance of extent of resection for medulloblastoma have been done without knowledge of subgroup affiliation.”

Thompson and colleagues sought to account for the effect of molecular subgroups on the prognostic value of extent of resection in patients with medulloblastoma.

They used data from the Medulloblastoma Advanced Genomics International Consortium to retrospectively identify 787 patients (WNT tumors, n = 86; SHH tumors, n = 242; group 3 tumors, n = 163; group 4 tumors, n = 296) with a histological diagnosis of medulloblastoma and complete resection and survival data. Patients were treated between April 1997 and February 2013.

The researchers classified subgroups by gene expression profiling of frozen or formalin-fixed paraffin-embedded tissue. They used postoperative imaging to classify extent of resection as gross total resection (no residual tumor), near-total resection (< 1.5 cm² tumor remaining) or subtotal resection ( 1.5 cm² tumor remaining).

The effect of extent of resection by molecular subgroup, as well as other clinical variables, on PFS and OS served as the primary endpoint.

Multivariate OS and PFS analyses adjusted for molecular subgroup, age (< 3 years vs. 3 years), metastatic status, geographic location (North America or Australia vs. the rest of the world), chemotherapy receipt and craniospinal irradiation receipt.

Gross total resection improved PFS compared with subtotal resection (HR = 1.45; 95% CI, 1.07-1.96); however, this did not extend to OS (HR = 1.23; 95% CI, 0.87-1.72).

Further, gross total resection did not confer a PFS or OS benefit over near-total resection (PFS, HR = 1.05; 95% CI, 0.71-1.53; OS, HR = 1.14; 95% CI, 0.75-1.72).

Greater extent of resection did not translate to a significant survival benefit for patients with WNT, SHH or group 3 tumors (gross total resection vs. subtotal resection, HR = 1.03; 95% CI, 0.67-1.58). However, patients with group 4 tumors did experience PFS improvements with gross total resection compared with subtotal resection (HR = 1.97; 95% CI, 1.22-3.17). This benefit appeared even greater among patients with metastatic disease (HR = 2.22; 95% CI, 1-4.93).

However, gross total resection did not prolong OS in this subgroup compared with subtotal resection (HR = 1.67; 95% CI, 0.93-2.99).

The researchers acknowledged the lack of central radiographic review as a study limitation.

“These data question the clinical benefit of second-look surgery for small residual WNT, SHH or group 3 medulloblastomas because of the possible morbidity of surgery and the delay in the commencement of radiation,” Thompson and colleagues wrote. “Both previous studies and our results question the statistical significance and clinical magnitude of effect for the use of residual disease as a criterion to classify patients as high risk and precipitate high-dose craniospinal radiotherapy. Our data suggest an urgent need to revisit residual disease as a risk stratification criterion, especially since more informative and robust molecular markers have been described and validated.”

The researchers’ findings could decrease the treatment burden through a reduction in surgical morbidity for some patients; however, there are a few caveats to consider regarding the study’s conclusions, Darren Hargrave, MBChB, MD, MRCP, FRCPCH, pediatric neuro-oncologist at Great Ormond Street Hospital in London, wrote in an accompanying editorial.

“The possibility of a treatment effect in high-risk patients who are receiving more intensive strategies cannot be excluded because such regimens might overcome the negative effect of residual disease, which could in turn be more relevant for some molecular subgroups than for others,” Hargrave wrote. “The possible benefits of a less aggressive surgical approach leading to a reduction in the frequency or severity of posterior fossa syndrome with cerebellar mutism cannot be concluded because the link between extent of resection and this disorder is not clear in the scientific literature and is probably complex and multifactorial.” – by Cameron Kelsall

Disclosure: Thompson reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Hargrove reports no relevant financial disclosures.