Newer approaches in the field of radiation therapy have raised the bar in the treatment of central nervous system (CNS) malignancies, with recognized advances that have aimed to increase the therapeutic index by improving conformality of the radiation dose to the planned target volume. Beyond these advances, the continued evolution of more effective systems for delivery of radiation to the CNS may offer further benefit not only to adults but also to pediatric patients, a cohort of the population that may be more sensitive to the long-term effects of radiation. This article describes several novel irradiation techniques under investigation that hold promise in the pediatric population. These include newer approaches to intensity-modulated radiation therapy; stereotactic radiosurgery and radiation therapy; particle therapy, most notably proton therapy, which may be of particular benefit in enabling young patients to avoid radiation-related adverse effects; and radioimmunotherapy strategies that spare healthy tissue from radiotoxicity by delivering therapy directly to tumor tissue. Although emerging strategies for the delivery of radiation therapy hold promise for improved outcomes in pediatric patients, there must be rigorous long-term evaluation of consequences associated with the various techniques employed, to weigh risks, benefits, and impact on quality of life.
This article is the second of a two-part series that examines concepts and approaches related to minimizing late treatment toxicities resulting from radiation therapy of pediatric central nervous system (CNS) tumors. Here, we discuss the specifics of refining current strategies for radiation delivery, as well as new and up-and-coming heavy particle techniques and radiotherapeutics.
Volumetric Modulated Arc Therapy (VMAT)
Modern radiation therapy involves the use of megavoltage photon energies to focus the dose on predetermined targets. Methods of radiation delivery include three-dimensional conformal radiation therapy (3D-CRT) using static fields, as well as newer methods of 3D-CRT intensity-modulated radiation therapy (IMRT), which uses computer-generated images to conform the shape of the radiation beam to the shape of the tumor as the beam exits the linear accelerator, in order to improve dose profiles and local tumor control. VMAT is a form of IMRT that involves rotation of the radiation gantry in an arc, with beam modulation. This modulated-arc approach provides multiple planes of treatment that enable normal tissue to be spared high doses of radiation but result in larger regions of low-dose scatter. The risks and benefits of conformal strategies vs irradiation techniques that generate a larger volume of low-dose scatter radiation continue to be debated.
Stereotactic radiation delivery involves either a single dose, as in stereotactic radiosurgery (SRS); or a few large doses per fraction, as applied in stereotactic radiation therapy (SRT). These methods have been used both for dose escalation and to achieve ablative biologic effects. The approach is highly conformal and has been used with great success to treat a variety of malignant and benign diseases in adults. SRS/SRT may have a similar clinical application in the management of pediatric patients. The technique was first used employing Gamma Knife radiosurgery, requiring a headframe attached to the skull bone. However, with developments in stereotactic radiation therapy such as IMRT SRS/SRT, radiation can be delivered via a frameless technique. This approach has been used in the adult population. In 2014, Nanda et al reported their experience using a frameless stereotactic technique in the re-irradiation of recurrent pediatric CNS lesions. They found the technique was feasible in their 5 young patients, avoided trauma to the cranium, and decreased the amount of time that patients spent under general anesthesia.
1. Nanda R, Dhabbaan A, Janss A, et al. The feasibility of frameless stereotactic radiosurgery in the management of pediatric central nervous system tumors. J Neurooncol. 2014; 117:329-35.
2. Bowers DC, Liu Y, Leisenring W, et al. Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2006;24:5277-82.
3. Ellenberg L, Liu Q, Gioia G, et al. Neurocognitive status in long-term survivors of childhood CNS malignancies: a report from the Childhood Cancer Survivor Study. Neuropsychology. 2009;23:705-17.
4. Roddy E, Mueller S. Late effects of treatment of pediatric central nervous system tumors. J Child Neurol. 2016;31:237-54.
5. Inskip PD, Sigurdson AJ, Veiga L, et al. Radiation-related new primary solid cancers in the Childhood Cancer Survivor Study: comparative radiation dose response and modification of treatment effects. Int J Radiat Oncol Biol Phys. 2016;94:800-7.
6. Freund D, Zhang R, Sanders M, Newhauser W. Predictive risk of radiation induced cerebral necrosis in pediatric brain cancer patients after VMAT versus proton therapy. Cancers (Basel). 2015;7:617-30.
7. Jermann M. Particle therapy statistics in 2014. Int J Part Ther. 2015;2:50-4.
8. MacDonald SM, Trofimov A, Safai S, et al. Proton radiotherapy for pediatric central nervous system germ cell tumors: early clinical outcomes. Int J Radiat Oncol Biol Phys. 2011;79:121-9.
9. Brodin NP, Munck af Rosenschold P, Blomstrand M, et al. Hippocampal sparing radiotherapy for pediatric medulloblastoma: impact of treatment margins and treatment technique. Neuro Oncol. 2014;16:594-602.
10. Combs SE, Kessel K, Habermehl D, et al. Proton and carbon ion radiotherapy for primary brain tumors and tumors of the skull base. Acta Oncol. 2013;52:1504-9.
11. Leroy R, Benahmed N, Hulstaert F, et al. Proton therapy in children: a systematic review of clinical effectiveness in 15 pediatric cancers. Int J Radiat Oncol Biol Phys. 2016;95:267-78.
12. Rieber JG, Kessel KA, Witt O, et al. Treatment tolerance of particle therapy in pediatric patients. Acta Oncol. 2015;54:1049-55.
13. Pulsifer MB, Sethi RV, Kuhlthau KA, et al. Early cognitive outcomes following proton radiation in pediatric patients with brain and central nervous system tumors. Int J Radiat Oncol Biol Phys. 2015;93:400-7.
14. Yock TI, Yeap BY, Ebb DH, et al. Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study. Lancet Oncol. 2016;17:287-98.
15. Indelicato DJ, Flampouri S, Rotondo RL, et al. Incidence and dosimetric parameters of pediatric brainstem toxicity following proton therapy. Acta Oncol. 2014;53:1298-304.
16. Kasper HB, Raeke L, Indelicato DJ, et al. The Pediatric Proton Consortium Registry: a multi-institutional collaboration in U.S. proton centers. Int J Part Ther. 2014;1:323-33.
17. Verma V, Mishra MV, Mehta MP. A systematic review of the cost and cost-effectiveness studies of proton radiotherapy. Cancer. 2016;122:1483-501.
18. He P, Kramer K, Smith-Jones P, et al. Two-compartment model of radioimmunotherapy delivered through cerebrospinal fluid. Eur J Nucl Med Mol Imaging. 2011;38:334-42.
19. Kramer K, Kushner BH, Modak S, et al. Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma. J Neurooncol. 2010;97:409-18.
20. Kramer K, Pandit-Taskar N, Zanzonico P, et al. Low incidence of radionecrosis in children treated with conventional radiation therapy and intrathecal radioimmunotherapy. J Neurooncol. 2015;123:245-9.
21. Vera DR, Eigner S, Henke KE, et al. Preparation and preclinical evaluation of 177Lu-nimotuzumab targeting epidermal growth factor receptor overexpressing tumors. Nucl Med Biol. 2012;39:3-13.
22. Luther N, Zhou Z, Zanzonico P, et al. The potential of theragnostic 124I-8H9 convection-enhanced delivery in diffuse intrinsic pontine glioma. Neuro Oncol. 2014;16:800-6.