Reducing the radiation therapy dose currently used to treat high-risk neuroblastoma in children is possible, according to the promising results from our recent prospective trial, meaning reduced toxicities for many of these young patients.
Our study, published in the International Journal of Radiation Oncology, provides the first evidence that a dose reduction of three gray (Gy) — from 21 Gy to 18 Gy — can prevent local failure in pediatric neuroblastoma.
The study included 25 pediatric patients (median age 4.3 years) with high-risk neuroblastoma enrolled in the pilot trial at Memorial Sloan Kettering Cancer Center between September 2014 and April 2017. (1) Patients received a radiation dose of 18 Gy rather than the commonly used 21 Gy, which is associated with excellent local control rates (over 90 percent) after gross total resection of primary tumors (2), (3), (4) but also late toxicities, including diabetes mellitus, growth abnormalities, and an increased risk of developing secondary cancers decades later. (5), (6), (7)
No patients experienced local failures within the radiation field after a median follow-up period of 3.5 years after treatment. Three patients experienced marginal failure in locations that fell outside the radiation therapy field. Progression-free and overall survival rates at three years were 55 percent and 91 percent respectively for patients in their first complete remission, and 43 percent and 76 percent for patients not in metastatic complete remission. Acute toxicities were negligible, and late toxicities were minimal during this early follow-up period. (1)
Given these promising results, our next step is to evaluate a further dose reduction to 15 Gy on our protocol to assess whether it will provide similarly excellent local control and survival rates. As this is a pilot study, our findings will need to be validated in a larger, multi-institutional trial before being accepted as the standard of care.
A Novel Dose-Reduction Protocol
Neuroblastoma is a rare cancer of the sympathetic nervous system that forms solid tumors in the adrenal glands, abdomen, neck, chest, or pelvis, and can spread to the bones and bone marrow. About 700 children are diagnosed with neuroblastoma every year in the United States. It is the cancer most often found in infants.
Aggressive multimodality treatment — including dose-intensive induction chemotherapy, surgical resection, local radiation therapy, immunotherapy, and differentiation therapy — has improved survival rates for patients with high-risk neuroblastoma but can result in major acute and long-term toxicities. (8), (9)
For the treatment of pediatric tumors, it is imperative to find the minimal dose necessary to achieve excellent oncologic outcomes and, at the same time, minimize late morbidities in long-term survivors. To date, dose-reduced radiation therapy has not been tested in neuroblastoma, unlike prospective trials conducted for other pediatric tumors, including Wilms’ tumor, Hodgkin lymphoma, medulloblastoma, and rhabdomyosarcoma. (1)
To address this gap, we developed a prospective dose-reduction protocol for high-risk neuroblastoma and assessed local control and patterns of failure, survival outcomes, and toxicities. A dose reduction of 3 Gy is small in size but highly promising for sparing late effects. The fields used for high-risk neuroblastoma are usually extensive, and the steepest part of the dose-response curve for growth impairment is from 15 to 21 Gy.
Patients eligible to enroll in our study were under the age of 18 years with high-risk neuroblastoma and had undergone induction chemotherapy and gross total resection. High-risk neuroblastoma was defined as stage IV disease diagnosed under the age of 18 months or MYCN-amplified stage III or IV diagnosed at any age. All patients received anti-GD2 immunotherapy with either murine-3F8 (n=20) or humanized 3F8 (n=5), and for 24 of 25 patients, at least one cycle was administered before radiation therapy. (1) Note that this timing contrasts with practice elsewhere, including the Children’s Oncology Group protocol ANBL0032, in which patients receive immunotherapy after completing radiation therapy. (10)
The radiation therapy comprised 18 Gy in 12 fractions given twice daily on weekdays. Patients received either intensity-modulated radiation therapy with photons or proton therapy. To assess local control and progression-free survival, patients underwent an I-meta-iodobenzylguanidine scan and CT or MRI scans of the primary site, plus bone marrow evaluations, at least every three months for two years. (1)
The median age of patients at the time of enrolment in the study was 4.3 years (range: 1.6 to 9.4 years). Twenty-three of 25 patients (92 percent) had stage IV high-risk neuroblastoma, and eight (32 percent) had MYCN-amplified disease. After induction therapy, 11 patients (44 percent) were in complete remission according to international criteria. (11) Three patients (12 percent) received proton therapy, and the rest received intensity-modulated photon therapy. Most patients (80 percent) received radiation therapy in between the first two cycles of antibody therapy. Twelve patients also received a bivalent anti-neuroblastoma vaccine after completion of the antibody therapy. (1)
Overall, 18 Gy successfully controlled disease where it was delivered. After a median time of 3.5 years (range: 1.8 to 4.2 years) from the initiation of radiation therapy, there were no local failures among the 25 patients. Three patients had marginal failures, defined as soft tissue failure near but completely outside the radiation therapy field in locations that received 0 Gy, as confirmed by dosimetric review at 1.1, 1.1, and 2.4 years postradiation therapy. To address marginal failures in the future, generous margins should be employed to cover all at-risk nodal regions. (1)
The respective progression-free and overall survival rates at three years were 54.5 percent and 90.9 percent for patients in their first complete remission, and 42.9 percent and 76.2 percent for patients not in metastatic complete remission. (1) These progression-free and overall survival rates were similar to a large cohort of high-risk neuroblastoma patients treated with 21 Gy after gross total resection at MSK. (12)
Advancing Pediatric Neurologic Cancer
MSK has the world’s largest neuroblastoma program, with about 125 new visits per year. We are committed to pioneering innovative treatments that prolong survival while minimizing long-term side effects.
Study co-author and MSK physician-scientist Nai-Kong Cheung, who heads the MSK Neuroblastoma Program, conceived and developed the immunotherapy drug naxitamab (also called humanized 3F8) for patients with high-risk neuroblastoma. The drug works by attaching to a marker called GD2 on neuroblastoma cells that survive chemotherapy or radiation so that the patient’s immune cells can recognize and destroy the cancer cells. The drug received Breakthrough Therapy Designation from the US Food and Drug Administration in September 2018 for the treatment of patients with high-risk neuroblastoma.
Our trial to test dose-reduction radiation therapy in pediatric patients with neuroblastoma (NCT02245997) is open and recruiting, with a target primary completion date of September 2020. We are also conducting 16 other clinical trials in neuroblastoma to test innovative treatment approaches and explore the correlation between molecular markers and clinical outcomes.
The study was supported by grant P30 CA 008748 from the National Institutes of Health.
Dr. Cheung is the inventor and owner of issued patents licensed by MSK to Ymabs Therapeutics, Biotec Pharmacon, and Abpro. MSK licensed Hu3F8 and 8H9 to Y-mabs Therapeutics. Both MSK and Dr. Cheung have a financial interest in Y-mabs Therapeutics. Dr. Cheung is an advisory board member for Abpro and Eureka Therapeutics. Shakeel Modak and Dr. Wolden report personal fees from Y-mabs Therapeutics.