Intensive Therapy Boosts Survival of High-Risk Brain Tumors in Kids

MEMPHIS, Tenn., Sept. 7 -- For children with high-risk medulloblastoma, an aggressive approach can boost five-year survival to about 70% from the current 55%, researchers here reported.

By adapting craniospinal radiotherapy doses to the tumor risk profile and delivering a shorter regimen of dose-intensive chemotherapy, Amar Gajjar, M.D. of St, Jude's Children's Research Hospital here, and colleagues, found they could significantly improve both overall and event-free five-year survival.

The children responded with both high-risk and standard-risk medulloblastoma, Dr. Gajjar and colleagues reported in an early online release from The Lancet Oncology.

"Not only can we now cure about 70% of children with high-risk medulloblastoma, we can also cure more than 80% of those with standard-risk disease with a shorter, and therefore more convenient, chemotherapy approach," Dr. Gajjar said.

Conventional treatment for medulloblastoma consists of surgical resection, followed by postoperative radiotherapy and one year of chemotherapy. For children ages three-years and older with standard-risk disease, defined as no evidence of metastasis and residual disease of 1.5 cm² or less, the combination has produced cure rates of about 70%, the authors noted.

"By contrast, survival has remained poor for children ages three years or older who have high-risk medulloblastoma (i.e., residual disease >1.5 cm² or metastatic disease), and fewer than 55% of children with high-risk disease survive for longer than 5 years," they wrote.

To see whether they could improve those odds, the investigators tried a therapeutic strategy whereby the intensity of radiotherapy would be adapted to the individual child's degree of risk.

They treated 134 children with medulloblastoma under the protocol, which called for surgical resection of tumors and assessment of patients for risk.

Patients were determined to have average risk if they were classified as being at average-risk (86 patients), if their residual tumors were no more than 1.5 cm² in diameter, and they had no evidence of metastatic disease.

The children were considered to be at high risk (48 patients) if their residual tumors were greater than 1.5 cm² in diameter or if they had metastatic disease localized to the neuraxis.

All patients underwent risk-adapted craniospinal radiotherapy in doses of 23.4 Gray for average-risk disease, and 36.0 to 39.6 Gy for high-risk disease. All patients then underwent four cycles of Cytoxan (cyclophosphamide)-based, dose-intensive chemotherapy.

The patients were evaluated regularly for disease status and treatment side-effects. The primary endpoint was five-year event-free survival, with overall survival and event-free survival secondary endpoints.

In all, 119 (89%) of the 134 children completed the planned protocol. Among patients in the average-risk group, overall five-year survival was 85% (95% confidence interval, 75%-94%). Among those at high risk, survival was comparable to that of average-risk patients treated with standard protocols: 70% (95% CI, 54%-84%).

Five-year event-free survival was 83% (95% CI, 73%-93%) for average-risk patients, and 70% (55%-85%) for high-risk patients.

In addition, tumor histology for 116 patients was available for central review, which revealed a significant correlation between histological subtype and five-year event-free survival (P=0.04).

The investigators found that in children with medulloblastomas with classic histology, five-year survival was 84% (95% CI, 74%-95%), compared with 77% (95% CI, 49%-100%) for those with desmoplastic tumors, and 57% (95% CI. 33%-80%) for those with large-cell anaplastic tumors.

The chemotherapy regimen was generally well-tolerated, and there were no treatment-related deaths, the authors noted. Unexpected grade 3 or grade 4 toxicities include cardiac dysrhythmias or congestive heart failure in three patients, hyperbilirubinemia in two, elevated creatinine concentration in one, stomatitis in nine, and increased serum glutamic oxaloacetic transaminase or serum glutamic pyruvic transaminase in eight patients.

There were no secondary malignancies in patients treated during the trial, although one patient, who was included in the analysis, developed acute lymphoblastic leukemia three months after completing the protocol.

The investigators attributed their excellent results to the early use of high-dose radiotherapy and to the use of a short, dose-intensive, alkylator-based chemotherapeutic regimen. Craniospinal radiotherapy was also essential to the improved survival they saw in patients with metastatic disease, they noted.

"Our research focused on understanding the biology of medulloblastoma," Dr. Gajjar said. "We now need to develop a biological system of staging that works in conjunction with the current clinical staging system to further refine treatment for this disease.".

Until such a system is developed, however, "investigators should consider adopting a similar therapeutic strategy to ours for their high-risk patients," he said. "This approach should be feasible in most pediatric oncology units at academic medical centers, but meticulous staging and careful attention to detail during radiotherapy planning and treatment are essential to obtaining similar outcomes."