Methylation subgroup analyses identified children with medulloblastoma who had improved PFS without radiation, intraventricular chemotherapy or high-dose chemotherapy, study data showed.
Thus, although a risk-adapted approach did not improve EFS overall among children with medulloblastoma, molecularly driven risk-adapted approaches may be an important avenue for future study.
“This study has important ramifications for treatment of young children with medulloblastoma, a group whose long-term survival rates are stalled at about 50% and PFS remains even lower,” Giles Robinson, MD, assistant member of the department of oncology at St. Jude Children’s Research Hospital, said in a press release. “Combination therapy with radiation and chemotherapy has increased survival rates of older children and adolescents, but radiation toxicity has limited its use in younger patients, particularly those [younger than] 3 years old. Now we have identified a subtype of medulloblastoma that accounts for about 25% of infant medulloblastoma and that can be treated successfully with reduced-intensity chemotherapy.”
The researchers performed a multicenter phase 2 trial of 81 children aged 5 years or younger between Nov. 27, 2007, and April 19, 2017. All patients had histologically confirmed medulloblastoma and were treated at six centers in Australia and the U.S.
Patients began therapy within 31 days following definitive surgery, had Lansky performance scores of at least 30 and had not received any prior chemotherapy or radiation.
Robinson and colleagues used clinical and histological criteria to stratify children into low-risk (n = 23), intermediate-risk (n = 32) and high-risk (n = 26) groups.
All children received induction chemotherapy with methotrexate, vincristine, cisplatin and cyclophosphamide; children in the high-risk group received an additional five doses of vinblastine.
Low-risk patients received two four-week cycles of cyclophosphamide (1,500 mg/m2 on day 1), etoposide (100 mg/m² on days 1 and 2) and carboplatin (area under the curve 5 mg/mL per min on day 2). Patients considered intermediate risk underwent focal radiation therapy (54 Gy with a clinical target volume of 5 mm over 6 weeks), and those who were high-risk received chemotherapy with targeted IV topotecan (area under the curve 120-160 ng-h/mL days 1 to 5) and IV cyclophosphamide (600 mg/m² days 1 to 5).
All patients underwent maintenance chemotherapy with cyclophosphamide, topotecan and erlotinib (Tarceva, Genentech).
EFS and patterns of methylation profiling associated with PFS served as the co-primary endpoints.
The researchers stopped accrual to the low-risk group on Dec. 1, 2015, because 1-year EFS was considered below the threshold for the stopping rule.
Five-year EFS in the whole cohort was 31.3% (95% CI, 19.3-43.3) after a median follow-up of 5.5 years.
Five-year EFS was 55.3% in the low-risk cohort, compared with 24.6% in the intermediate-risk cohort (HR = 2.5; 95% CI, 1.19-5.27) and 16.7% in the high-risk cohort (HR = 3.55; 95% CI, 1.66-7.59).
When Robinson and colleagues divided patients into methylation subgroups, 5-year PFS was 51.1% (95% CI, 34.6–67.6) in the sonic hedgehog (SHH) subgroup (n = 42), compared with 8.3% (95% CI, 0-24) in the group 3 subgroup (n = 24) and 13.3% (95% CI, 0-37.6) in the group 4 subgroup (n = 10).
Robinson and colleagues identified two methylation subtypes in the SHH subgroup, which they named iSHH-I (n = 21) and iSHH-II (n = 21). Five-year PFS was 27.8% (95% CI, 9-46.6) for the iSHH-I subtype compared with 75.4% (95% CI, 55-95.8) for iSHH-II.
“The 75% 5-year PFS of patients with iSHH-II in this trial signifies that these patients do not require craniospinal radiotherapy, myeloablative chemotherapy or any intraventricular therapy,” the researchers wrote. “Unfortunately, the same cannot be said for the iSHH-I population, whose 5-year PFS was 28%.”
Grade 3 to 4 febrile neutropenia (n = 48; 59%), neutropenia (n = 21; 26%), infection with neutropenia (n = 20; 25%), leucopenia (n = 15; 19%), vomiting (n = 15; 19%) and anorexia (n = 13; 16%) were the most common adverse events.
“[Although] we’ve understood for some time that medulloblastoma is not a single disease, the results of this molecular analysis are a humbling reminder of differences within medulloblastoma subgroups that influence treatment response,” Robinson said. “That is important to keep in mind as the next generation of molecularly driven therapies are designed.”
Future studies should be international, collaborative trials that incorporate larger numbers of patients to evaluate the need to give different treatment to patients with iSHH-I or iSHH-II populations, Alvaro Lassaletta, MD, of the department of pediatric hematology and oncology at Hospital Infantil Universitario Niño Jesús in Madrid, wrote in an accompanying editorial.
“Indeed, the study by Robinson and colleagues along with other studies exploring medulloblastoma biology provide an important framework and support the idea that risk stratification by molecular subclassification could be a robust alternative to stratification by clinical risk factors,” Lassaletta wrote. “Molecular subclassification is also likely to lead to personalized treatments and, most importantly when treating young patients, decrease the long-term toxicity associated with cancer treatments.” – by Andy Polhamus
Disclosures: Robinson reports no relevant financial disclosures. Please see the study for a list of all other authors’ relevant financial disclosures. Lassaletta reports no relevant financial disclosures.