Targeted Radiotherapy Boost Helps Pediatric Ependymoma Outcome

Kate Johnson

April 27, 2015

BARCELONA, Spain — Children with ependymoma and residual disease after initial surgery and radiotherapy can benefit from further surgery and an extra boost of radiotherapy, according to new research.

The findings, presented here at the European Society for Radiotherapy and Oncology (ESTRO) 3rd Forum, show that higher and more targeted radiotherapy doses can make a difference in this particularly challenging patient population.

"The subset of children with residual disease is at very high risk of local relapse/progression," said study investigator Lorenza Gandola, MD, head of the paediatric radiotherapy unit at the Fondazione IRCCS, Istituto Nazionale dei Tumori, in Milan.

"Aggressive local treatment, integrating second or further-look surgery, and an innovative radiation approach, such as a hypofractionated radiation boost, has the potential to ameliorate progression-free survival in these children by improving local control," she told Medscape Medical News.

Malignant ependymoma, the third most common brain tumor in children, is normally treated with a combination of surgery and radiotherapy, sometimes with the addition of chemotherapy.

A radiation dose of 59.4 Gy is currently recommended for pediatric cases worldwide. However, the subgroup of patients with measurable residue after surgery and radiotherapy has "historically had a worse prognosis compared with those completely resected," Dr Gandola explained.

Her team tested an "unconventional" strategy of targeting this residual tumor with a radiotherapy boost of 8 Gy delivered in two fractions and designed to spare surrounding healthy tissue from exposure.

Extra Radiotherapy Boost

The study involved 47 ependymoma patients (median age, 5 years) with macroscopic residual disease measurable on MRI after surgery who were eligible for the radiotherapy boost.

Of the tumors, 36 were in the posterior fossa and 11 were supratentorial. In addition, 22 were grade 3 and 25 were grade 2, she reported.

Before receiving the radiotherapy boost, 32 patients underwent additional surgical resection (four patients underwent three surgeries and one patient underwent five surgeries), she said.

This resulted in 11 complete resections and left 36 patients eligible for the boost.

For 13 of the eligible patients, the boost was deemed "unfeasible" — "mainly because of uncertainty in identifying the tumor volume after chemotherapy," said Dr Gandola. The fact that the boost was not delivered to these patients "represents the learning curve of the Italian pediatric radiation oncologists handling a new approach for these children," she noted. "We discovered that in a few cases, the boost was not delivered because of uncertainties on the part of the local radiation oncologist, so we have learned that we have to give more discussion to this kind of difficult situation."

Of the remaining 23 patients who received the boost (median age, 4.5 years), 16 were alive without progression after a median follow-up of 54 months. In this group of patients, the rate of progression-free survival is 70%, she said.

The other seven patients relapsed (four locally and three distally), which resulted in five deaths.

"There were no iatrogenic deaths or major toxicities among the boosted children. The hypofractionated boost was feasible, with acceptable and reversible toxicity," she said. She noted that four patients who received TomoTherapy developed radiation-related MRI changes, but these regressed within 8 months with steroid treatment.

Among the 47 patients with postsurgical residual disease, the subgroup of patients whose second surgery resulted in complete resection had the best 5-year event-free survival of 75%, which was not significantly different than the 5-year rate of 77% seen in patients whose disease was completely resected initially.

Patients with residual tumor after a second surgery had a lower rate of 5-year event-free survival (44%), but this improved in those who received the radiotherapy boost (56%), she said.

"An aggressive local treatment strategy, integrating multiple surgeries and radiotherapy boost, is required to improve outcomes in children with residual disease," she concluded.

The boost approach will now be investigated in an international clinical trial conducted by the Société Internationale d'Oncologie Pédiatrique (SIOP) Brain Tumor Committee, Dr Gandola reported.

"Most Promising Treatment"

Rolf Kortmann, MD, head of radiation therapy at the University of Leipzig in Germany and one of the investigators on the upcoming SIOP trial, said the local boost is currently "the most promising treatment in patients who cannot be completely resected."

"Residual disease is the major prognostic factor in the management of this tumor, and dose escalation with conventional techniques does not overcome this problem," he told Medscape Medical News. "This tumor also does not respond to chemotherapy, so any endeavors in that direction have been disappointing," he added. "A long time ago, we discussed whether it would be feasible to give a circumscribed boost, so these results are very important."

Dr Kortmann also noted that radiation oncologists' comfort, or lack thereof, with the feasibility of delivering the boost is an important consideration.

"It is new and if you are giving a high dose close to an organ at risk, you may not be used to doing that and may be reluctant. But this study was started 10 years ago, and now we are more familiar and are treating more precisely with the current technologies. We are launching our new trial soon, and everybody is already alert," he said.

"In cases like that of ependymoma, many patients are still not cured and subsequently die from their disease," said Philip Poortmans, MD, PhD, president of ESTRO. "Therefore, it is important to be able to recognize accurately children who are at high risk for recurrence, and to intensify their treatment."

He said the research demonstrates "a clear dose-effect relation" between tumor control and survival. The upcoming SIOP trial will clarify the benefit of "increasing the dose by a further 8 Gy, delivered with highly directed radiation therapy techniques that give a very localized dose to the target volume and a low dose to the surrounding normal tissue. We hope that this will bring about even better outcomes for these children."

Dr Gandola's work was supported by the Associazione Italiana per la Lotta al Neuroblastoma ONLUS, "Progetto pensiero." Dr Kortmann and Dr Poortmans have disclosed no relevant financial relationships.


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