Radiation therapy continues to be a key component in the management of pediatric malignancies. Increasing the likelihood of cure while minimizing late treatment toxicity in these young patients remains the primary goal. Within the realm of central nervous system neoplasms, efforts to further improve the efficacy of radiation therapy continue, while balancing risks of damage to uninvolved tissue. Radiation therapy can result in second malignancies, as well as cerebrovascular, neurotoxic, neurocognitive, endocrine, psychosocial, and quality-of-life effects. In this article we describe these acute and late effects and their implications, and we highlight strategies that have emerged to reduce both the volume of tissue that is irradiated and the radiation dose delivered. The feasibility, efficacy, and risks of these newer approaches to radiation therapy continue to be evaluated and monitored; robust outcome data are needed.
Strategies to Reduce the Toxicity of Radiation Therapy
The significant morbidity experienced by some pediatric cancer survivors raises the question of how the therapeutic index can be altered to maximize outcomes. As imaging modalities, conformity of radiation techniques, chemotherapy options, and surgical techniques improve, strategies to delay or forgo radiation, as well as reduce radiation dose or treatment volumes, have become increasingly sought after and feasible (Table).
Timing of radiation
Epidemiologic studies of the effects of radiation on the pediatric brain have demonstrated a relationship between timing, dose, and volume of radiation therapy. The possibility of avoiding the need for radiation completely, or delaying its use in young children, has been an active area of research in the pediatric population. Multiple studies are evaluating the sequencing of radiation in the treatment paradigm, since alternative modalities may have improved efficacy when given before, after, or concurrently with radiation (see Table).
Younger age at time of treatment is a consistent risk factor for late sequelae of radiation toxicity, with one of the most notable age-response relationships evident in studies of neurocognitive effects.[8,25,26] For this reason, radiation oncologists have hesitated to use radiation in young children and infants. Response-based radiation has been employed in multiple protocols (see Table) in an attempt to control disease with surgery and/or chemotherapy first, or avoid radiation altogether until patients reach a specified age. An important key to these strategies is the ability to determine the age at which patients are most susceptible to radiation-induced toxicity. Therefore, continued study of the mechanisms underlying radiation damage is imperative in this population.
In order to reduce radiation-related toxicity, the Head Start III trial attempted to defer radiation in young children with ependymoma using dose-intense chemotherapy and autologous hematopoietic stem cell rescue. This proved to be an effective strategy in patients with supratentorial ependymomas, but was ineffective in patients with infratentorial disease. There is, however, prospective evidence that radiation is safe and effective in very young patients, and that improved oncologic outcomes in ependymoma counterbalance toxicity, thus making radiation therapy necessary to achieving the goal of cure.[28,29] In the era of precision medicine, and with the adoption of molecular classifications of disease, personalized treatment based on biology, age, and disease response may become a feasible and appropriate future approach.[30-32] However, if delaying or avoiding irradiation in an individual patient would not result in superior outcomes, then other methods to reduce toxicity while maintaining the role of radiation need to be pursued.
Reduction in radiation dose
Radiation dose has also been correlated with risk of toxicity for certain late effects in pediatric malignancies. Analysis of the CCSS cohort suggests that the risk of stroke increases by 5% per Gy of radiation delivered (with an overall rate of first stroke reported as 625 per 100,000 person-years), and excess relative risk for a second CNS malignancy is 0.69 per Gy of radiation exposure. For this reason, efforts are ongoing to minimize the total dose delivered to pediatric patients; dose de-escalation may be a valid method to reduce late morbidity, particularly in patients whose cancers carry an excellent prognosis.
In most cases, dose de-escalation is made possible via synergy with other treatment modalities to maintain the desired clinical outcomes. The evolution of therapeutic approaches for management of medulloblastoma demonstrates this paradigm. In recent decades, the administration of chemotherapy enabled successful reduction of the dose of craniospinal irradiation (CSI) required to treat standard-risk medulloblastoma—from 36 Gy to 23.4 Gy, followed by a posterior fossa boost. However, trials of radiation dose de-escalation in the absence of chemotherapy showed inferior survival outcomes.[36,37] With this change in dose to the spinal axis, multiple groups have demonstrated improved neurocognitive outcomes in the 23.4-Gy CSI cohort. These findings precipitated further reduction of the CSI dose to 18 Gy in young patients; however, recent data suggest that reducing the radiation dose to this level is associated with inferior event-free survival and overall survival outcomes.
Since advances in surgical and systemic therapy can reduce the burden of disease, response-based dose de-escalation of radiation therapy is being investigated to provide individualized treatment options. As an example, retrospective and early-phase trials including patients with intracranial germ cell tumors report equivalent outcomes with response-based radiation therapy, and these results have provided the basis for several ongoing phase III trials (see Table).
Reduction in treatment volumes
Increasing the conformity of treatment in order to reduce the volume of normal tissue exposed to radiation is an additional way to reduce late toxicity. There are two relevant components: the conformity of the high-dose region to the treatment target; and the overall volume of tissue irradiated, even to a low dose.
Radiation volumes are outlined based on the visible tumor seen on imaging and during physical examination (gross tumor volume; the area encompassing subclinical disease, based on known patterns of spread (clinical target volume [CTV]); and a margin of error for treatment uncertainties (planning target volume) (Figure). Minimizing these volumes, or increasing the accuracy of dose delivery, can have a substantial impact on the total amount of tissue treated—just as the difference in the total volume of a sphere can increase dramatically when the radius is increased even as little as a few millimeters.
- Radiation is one of the most effective therapies to date for many pediatric malignancies, but exposure of the developing brain to radiation can be associated with cerebrovascular events, secondary malignancy, endocrine effects, and psychosocial/quality-of-life disturbances.
- Numerous clinical trials now underway are investigating reduced-dose, reduced-field, response-adapted, risk-adapted, or delayed radiation therapy to better understand which approaches will have the most meaningful impact with the least possible toxicity.
- Accurate imaging is the cornerstone of tumor identification, target volume delineation, and radiation treatment planning; modalities most commonly used in the pediatric population include CT, MRI, and functional imaging.
Accurate imaging is the cornerstone of tumor identification, target volume delineation, and radiation treatment planning. Modalities that are most commonly used in the pediatric population include CT, MRI, and functional imaging. In recent years the wise philosophy of modifying imaging techniques in order to reduce unnecessary toxicity from diagnostics has taken hold. The use of CT in the pediatric population is somewhat discouraged, since CT delivers ionizing radiation and has inferior soft-tissue resolution compared with MRI. There is, however, ongoing research in the pediatric population to develop novel CT imaging methods that minimize the radiation dose delivered to these young patients.
The use of MRI has become more ubiquitous in the imaging of primary CNS diseases, due to its benefits of reduced toxicity (since it provides nonionizing radiation) and superior multifaceted soft-tissue resolution compared with CT. The gross tumor volume can be optimized with modern MRI-based imaging techniques, resulting in excellent gross tumor delineation. Novel MRI sequences, such as diffusion- and perfusion-weighted imaging, are currently under investigation for use in differentiating tumor grade in situ, predicting pathways of microscopic spread, and monitoring treatment response.[41,42] Knowledge of patterns of spread in situ for individual patients will allow radiation oncologists to more accurately conform CTV to true subclinical disease and avoid toxicity to uninvolved areas. In addition to these imaging advances, as we learn more about the mechanisms underlying late radiation treatment toxicity, therapy may be conformed away from uninvolved critical structures, such as the temporal lobes.
Additional data can be gleaned from metabolic characterization of disease in situ. Fluorodeoxyglucose–positron emission tomography scanning has been applied in the pediatric population to aid in surgical resection, radiation treatment planning, and diagnosis of recurrent or residual disease. Novel radiotracers, such as [11C]-methionine, [11C]-thymidine, [18F]-L-dihydroxyphenylalanine, and [18F]-fluorothymidine, characterize additional tumor metabolic pathways and may be useful as biomarkers for future radiation and surgical treatment planning.[44,45]
Newer surgical techniques and chemotherapeutic options may permit further cytoreduction of gross and subclinical disease, and may minimize the area requiring radiation. Modeling of the radiation dose to critical organs has shown a theoretical decrease in the risk of late toxicity when smaller treatment volumes are used. In a prospective cohort of ependymoma, disease control was maintained when CTV volumes were decreased to 1 cm. The authors of this study highlight the benefits of neoadjuvant chemotherapy, as well as maximum safe resection, even if achieving this requires a second surgery. However, it appears that for certain pathologies, reduced margins do not increase marginal relapse rates.[28,29,46] The late HRQOL and toxicity data from these reports will be of great interest as these cohorts mature.
Although not within the scope of this article, it is important to make note of novel systemic therapies under investigation for CNS diseases—including immunotherapies and targeted agents—which may further alter the therapeutic index. These novel modalities may offer new opportunities to delay or forgo radiation therapy, and may present unique interactions when combined with radiation. Ultimately, the benefits of reduced radiation will need to be weighed against the potential risks of poorer survival outcomes, and long-term follow-up will be essential.
Diligent postradiation follow-up of pediatric patients is necessary for documentation, treatment, and ultimately prevention of late sequelae. Ongoing studies examining the efficacy of novel radiation therapy techniques will enable superior risk-benefit discussions. Improving the therapeutic index and maximizing outcomes for pediatric cancer patients is a rapidly evolving area of research, and will continue to be a multidisciplinary endeavor. The ongoing research into molecular classification of CNS tumors will result in new risk stratification of these diseases. Given the diverse natural history of these subgroups, it will be important to revisit options for individual patients in terms of surgery, systemic therapy, and radiation techniques and agents. Notably, while alternative treatment modalities may be useful in reducing radiation toxicity, their long-term consequences must be studied with the same rigor that is applied to evaluation of radiation therapy, in order to more clearly understand the true risk-benefit effects.
Acknowledgment: This research was supported in part by the intramural research program at the National Institutes of Health, National Cancer Institute, Radiation Oncology Branch, funded by grant ZID BC 010990.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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