Postsurgery Radiation Increases Survival in Pediatric Patients With Ependymoma
Thomas E. Merchant, DO, PhD, St. Jude Children’s Research Hospital, Memphis, Tennessee, spoke with Oncology Learning Network about the clinical significance of a phase 2 Children’s Oncology Group (COG) clinical trial he led on the use of immediate postoperative radiation in children aged <3 years with ependymoma.
Findings from the COG study demonstrated that postoperative radiation improves outcomes in this population, including among patients who historically have had poor prognoses (J Clin Oncol. 2019 Feb 27. Epub ahead of print).
Thomas E. Merchant, DO, PhD, consults with a patient with ependymoma at St. Jude.
Photo credit: St. Jude Children’s Research Hospital.
What is the current standard of care for pediatric patients with intracranial ependymoma?
The current standard of care for children aged ≥12 months is surgery and radiation therapy. Questions occasionally arise about the treatment of the rare case of a child under the age of 12 months, where efforts to delay radiation therapy might be considered.
What existing data led you to evaluate event-free and overall survival outcomes in children with ependymoma treated with surgery, radiation, and chemotherapy?
In the mid-1990s the outcomes for children with ependymoma were poor. Young children were treated with regimens designed to delay or avoid irradiation. Chemotherapy was given after surgery. Tumor progression was common and salvage therapy unsuccessful. Regardless of age, macroscopic residual disease was often present after surgery which limited the effectiveness of adjuvant therapy.
The promise of conformal radiation therapy using photons and more aggressive surgery was introduced in the late 1990s in the RT1 protocol activated at St. Jude Children’s Research Hospital. The RT1 protocol pioneered the use of conformal radiation in young children with brain tumors including ependymoma. For the first time, radiation therapy was given immediately following surgery to children under the age of 3 years with intracranial ependymoma. Coupled with more aggressive surgery, including second surgery when children were referred for radiation therapy after incomplete resection, the event-free and overall survival soared.
The results of the RT1 protocol were presented to investigators in the COG and a study (ACNS0121) was designed to implement conformal radiation therapy in the pediatric cooperative group and to encourage specialized care for ependymoma including the goal of gross-total resection.
Please briefly describe your study and its findings. Were any of the outcomes particularly surprising?
At first, the most surprising outcome was the level of acceptance of conformal radiation therapy for young children. The use of chemotherapy to delay or avoid irradiation had been the hallmark of clinical trial designs for your children with brain tumors for decades.
The study opened in 2003 and completed its accrual goals in 4 years. The rapid rate of accrual exceeded expectations and 111 of the 378 enrolled patients were under the age of 3 years.
Furthermore, 115 member institutions of the COG participated, and all were able to adhere to the rigorous guidelines and quality standards.
The study was designed to administer immediate post-operative irradiation for patients enrolled after near-total or gross-total resection. The event-free and overall survival for this group mirrored the outcomes achieved on the St. Jude RT1 protocol reflecting the ability of the investigators in the COG to perform high-quality surgery and administer conformal radiation therapy.
The large number of patients—the largest series reported to date—allowed for additional analysis that showed patients with anaplastic ependymoma (grade 3) fared worse than those with differentiated or classic ependymoma (grade 2), an important study question at the time.
It was a surprise that the agreement between tumor grade reported by the local institutions and the central reviewers was excellent and the difference in tumor grade significant. More importantly, the outcomes showed that children under the age of 3 years had outcomes equivalent to those aged >3 years at the time of enrollment. Even more compelling, when the outcomes (event-free and overall survival) were compared with those of the last, large-scale brain tumor protocol that included young children with ependymoma and a radiotherapy-avoidance strategy, there was a 3-fold improvement in event-free survival and 2-fold improvement in overall survival!
The outcomes that were most surprising to the study team were the lack of difference in the posterior fossa (PF)A and PFB subgroupings for infratentorial ependymoma and the lack of significance of RELA fusion status in supratentorial ependymoma. These findings sent a strong message to investigators who study outcomes based on molecular profiling: we need to understand the treatment associated with tissue resources and the contribution of radiation therapy, and its sequence in the therapeutic regimen, to the end points of event-free and overall survival! The study found that gain of chromosome 1q was a marker for local and distant (metastatic) tumor progression after surgery and radiation therapy for infratentorial ependymoma. This finding that will be used in the design of future trials.
The study had two additional treatment arms. One arm included observation after surgery for supratentorial grade 2 ependymoma after complete resection. The small number of patients and poor event-free survival for this group suggested that post-operative observation for this unique group should not be considered standard and further investigation is required. Another arm of the study enrolled patients after subtotal resection.
These patients received a brief course of chemotherapy (2 months) and were recommended to have additional surgery. About half the patient underwent second surgery and many were able to achieve gross-total resection to improve their outcomes.
What are the real-world applications of these findings in clinical practice? How can they affect the treatment landscape for these patients?
In the early to mid-1990s, conformal radiation therapy was developed for the treatment of prostate cancer, lung cancer, and other tumors in adults. The development took place at several major centers in the US and was partly funded by the US National Cancer Institute. The principles of conformal radiation therapy were adopted for the treatment of localized brain tumors in 1996 at St. Jude Children’s Research Hospital along with the nomenclature used to target for 3-dimensional radiation therapy as outlined earlier by the International Commission on Radiation Units and Measurements in 1993.
When radiation oncologists showed neurosurgeons and pediatric oncologists that non-involved brain could be spared, conformal radiation therapy was recognized as a means to improve outcomes for difficult to treat tumors in young children include those with ependymoma.
The introduction and acceptance of radiation therapy for young children with ependymoma at St. Jude and later in the pediatric cooperative groups, including those in the United States and Europe, has allowed investigators to focus on the importance of surgery (extent of resection and limiting morbidity) and the testing of systemic or new agents to further improve outcomes.
While we are pleased that the 5-year event-free survival rates approach or exceed 70% depending on the extent of resection and underlying molecular characteristics of the tumor, there is still much room for improvement.
Do you and your co-investigators intend to expand upon this research?
Current trials in the United States and Europe sponsored respectively by the COG (ACNS0831) and International Society for Pediatric Oncology were designed to expand upon this research and take advantage of the information gained from ACNS0121.
In both studies patients are randomized to observation or chemotherapy after radical surgery and radiation therapy. Both studies include observation arms for select patients and chemotherapy and second surgery prior to irradiation in patients initially treated with subtotal resection.
The excellent outcomes after radical surgery and radiation therapy provide a new disease control benchmark against which to test the ability of systemic therapy to further improve outcomes.