Radiation Necrosis in Pediatric Patients with Brain Tumors Treated with Proton Radiotherapy

Discussion

The prospective diagnosis of radiation necrosis in patients with brain tumor remains challenging and strongly reliant on clinical and radiologic data because biopsy of new imaging findings is uncommon, particularly in pediatric patients who may develop new lesions in critical structures such as the brain stem. Because a myriad of imaging appearances have been described with radiation necrosis, prospectively diagnosing radiation necrosis relies on a multitude of factors, including the imaging appearance and timing of necrosis and the larger clinical picture from the multidisciplinary care of these patients. In most cases, the confirmation of radiation necrosis is the result of the serial clinical and radiologic follow-up of these patients. The imaging pattern most frequently encountered among our patients treated with PBT was that of multifocal small areas of parenchymal enhancement not immediately adjacent to the resection cavity, which resolved at a median of 5.0 months. These findings are similar to those from a smaller series of patients treated with PBT by Sabin et al.¹⁰ The imaging pattern we identified may help radiologists avoid misdiagnosis of tumor progression or at least consider the diagnosis of radiation necrosis in pediatric patients with brain tumor with PBT.

Radiation necrosis has been more extensively evaluated in adults compared with children. The Quantitative Analyses of Normal Tissue Effects in the Clinic group reviewed 8 adult studies, including nearly 3700 patients, and estimated a 5% and 10% risk of symptomatic radiation necrosis in patients who received fractionated radiation with total doses of 72 and 90 Gy.¹⁶ In contrast, there are few reported large series of radiation necrosis in patients with pediatric brain tumors. In 1 study of 101 children treated with photon radiation therapy, 5% of patients developed radiation necrosis based on clinicoradiologic follow-up.² In another study of 49 patients with malignant brain tumors treated with photon radiation therapy, high-dose thiotepa, and autologous stem cell rescue, 37% of patients developed posttreatment abnormal brain imaging findings, which were defined broadly to include contrast-enhancing lesions, T2-weighted or FLAIR hyperintense lesions, hemorrhage, or subdural fluid, though the percentage of radiation necrosis was not reported.³ In our series, 31% of patients developed radiation necrosis based on imaging, indicating a trend toward a higher incidence of necrosis with PBT compared with the incidence reported for photon radiation therapy, which was similar to the high percentage in a series of 17 patients treated with PBT, of whom 47% developed an imaging diagnosis of radiation necrosis.¹⁰ Our results differed, however, from those of 2 separate series of pediatric patients treated with PBT for ependymoma and medulloblastoma/primitive neuroectodermal tumor, in which no cases of radiation necrosis were reported; however, neither series described the methodology for detection of radiation necrosis to determine the significance of this difference.^12,13

Potential reasons for the differences in the reported incidence of radiation necrosis between photon and proton radiation therapy include differences in the clinicoradiologic definition, exclusion of patients or certain tumors, and differences in medical or radiation therapy. We chose to exclude patients who did not have 6-month follow-up imaging because our median timing to development of necrosis occurred at 5 months. We chose to require radiation necrosis to demonstrate contrast enhancement rather than any new signal abnormality on imaging, which may decrease the percentage of radiation necrosis in our series. In studies that rely on a clinicoradiologic diagnosis of radiation necrosis, there is no strict timeframe in which radiation necrosis must resolve, remain stable, or begin to decrease. A time requirement is ultimately necessary, however, to establish a basis from which a clinicoradiologic diagnosis of radiation necrosis is determined. We used a relatively conservative requirement that the enhancement resolve or begin to decrease at 6 months, and this may lower the incidence of radiation necrosis in our patients. Last, studies relying on a clinicoradiologic diagnosis of radiation necrosis without histopathology cannot be directly compared with studies describing radiation necrosis on the basis of histopathology. In our study, we cannot definitively conclude that these areas of enhancement represent radiation necrosis on histopathology versus an alternate process that is exacerbated by the effects of chemotherapy.

Pseudoprogression is one such potential consideration for an alternate process occurring in these patients. The pathophysiology of pseudoprogression is poorly understood, and there is overlap in both terminology and appearance with radiation necrosis; however, tissue obtained from patients with pseudoprogression does not demonstrate the same findings seen in radiation necrosis.¹⁷ Pseudoprogression typically is defined as occurring within 3 months after completion of treatment but can range up to 6 months after therapy completion.^17,18 In addition to relatively late timing encountered in our patients, the areas of necrosis were not within areas of resected tumor and were not within adjacent structures in which tumor growth would characteristically occur, both of which are atypical for pseudoprogression. Therefore, the current definition, description, and understanding of pseudoprogression do not provide an adequate explanation of our findings. If one recognizes the potential effects of chemotherapy in conjunction with PBT and the lack of histologic proof in our patients, “treatment-related cerebral necrosis” may be a more preferable description of the findings among our patients and more indicative of potential multifactorial causes than radiation alone. Ultimately, the major point of emphasis is that PBT may result in a significant degree of necrosis and the effects of PBT may be potentiated by additional factors, particularly chemotherapy.

The potential for chemotherapeutic interactions with radiation therapy has been well-documented, albeit not well-understood. For example, as chemosensitizers, temozolomide and bevacizumab have been used concurrently with radiation therapy in high-grade gliomas, and carboplatin has been studied as a radiation sensitizer with medulloblastomas and other CNS tumors.^{19⇓⇓–22} In addition, chemotherapeutics such as anthracycline and doxorubicin are commonly avoided during radiation and can even remotely result in radiation recall with a later insult.²³ Finally, there are many chemotherapeutics that may have direct CNS toxicity such as methotrexate and ifosfamide, which could potentiate CNS radiation necrosis. With this in mind, the presence, timing, and dosage of single or multiple chemotherapeutic agents in conjunction with radiation may influence the incidence and severity of radiation necrosis. Although we are not able to implicate specific agents in our study, due to different treatment protocols for different tumors, we are able to show that the presence of multiple chemotherapeutic agents significantly increases the risk of radiation necrosis in our study. Fifty percent of the patients in this study received multiple chemotherapeutic agents and therefore compose a large percentage of our patients who received radiation. Furthermore, the risk factor of atypical teratoid rhabdoid tumor pathology may be related to intensive chemotherapy because all patients with atypical teratoid rhabdoid tumors received high-dose neoadjuvant chemotherapy with stem cell rescue before radiation therapy at our institution. These findings together underscore the importance of further study in understanding the interaction of chemotherapy and radiation therapy in the context of designing a brain tumor treatment plan.

Predicting the timing of radiation necrosis remains challenging, and a wide range from months to years has been reported. Understanding of the timing to development of necrosis, however, remains an important factor when imaging findings potentially representing radiation necrosis are encountered. In our series, radiation necrosis was seen at a median of 5.0 months (range, 3–11 months). This compares with radiation necrosis described at a median of 1.2 months (range, 0.5–8.0 months) and 8 months (range, 2–39 months) in 2 large series of patients with pediatric brain tumors treated with photon radiation therapy and a median time of 3.9 months in a smaller series of patients treated with PBT.^2,3 It remains uncertain which factors in patients with pediatric brain tumor account for the difference in time to development of radiation necrosis compared with adult patients, which is more typical at or greater than 12 months.^1,24 Based on the proposed pathogenesis of radiation necrosis, there may be differences in the vascular endothelium, progenitor cells, oligodendrocytes, microglia, local microenvironment, and inflammatory response in the developing brain compared with adults accounting for the differences in timing.^4⇓⇓–7 Last, differences in imaging-frequency practice patterns likely contribute to differences in the reported timing to the development of radiation necrosis, particularly because many patients may be asymptomatic. Therefore, the median time and range of the time to development of radiation necrosis encountered in our patients should be considered an approximation rather than an absolute time period.

The clinical significance of MR imaging changes suggestive of radiation necrosis is a common question for the health care provider and his or her patients. Among our series of patients with pediatric brain tumors treated with PBT who demonstrated radiation necrosis, 25% demonstrated severe symptoms (based on the CTCAE grading scale) with medical intervention indicated. On the basis of these findings, any patient who develops similar MR imaging findings suggestive of radiation necrosis should raise high suspicion by the clinician for the current or later development of clinical symptoms, though most subjects may remain symptom-free.

Because radiation therapy remains the mainstay for many CNS tumor types, it is common for patients to receive fairly standardized maximum doses, depending on the location of the tumor. Thus, because the given radiation doses were not sufficiently heterogeneous, we were not able to document dose dependence in necrosis. However, the target doses typically used for PBT are frequently based on prescribed doses determined for photon radiation therapy. Whether similar doses using protons is required to maintain equivalent cure rates or whether lower doses with equivalent volumes may be as effective with less toxicity is not well understood.