Abstract
BACKGROUND
Recently published data demonstrated proton therapy (PRT) significantly reduced cognitive decline relative to photons for pediatric medulloblastoma. These findings imply that ...reductions in dose to critical CNS structures during the boost phase may account for better outcomes over time. Here, we examine differences in dosimetric data for medulloblastoma patients treated on ACNS0331 with photon (Intensity Modulated Radiation Therapy, 3D-Conformal Radiation Therapy) vs PRT to identify potential structures responsible for cognitive benefit.
METHODS
COG ACNS0331 was a randomized trial examining the impact of reduced craniospinal irradiation (CSI) dose (standard vs low dose, in patients aged 3–7) and volume (whole posterior fossa vs involved field) in pediatric medulloblastoma patients. We identified 136 patients (IMRT=95, 3DCRT=28, Proton=13) enrolled on ACNS0331 with complete radiation and imaging data and re-contoured 10 critical brain structures to calculate dose.
RESULTS
Proton therapy significantly reduced the dose to critical structures. For example, temporal lobe mean dose and V30 were 30Gy/38% (PRT), 40Gy/89% (IMRT), 41Gy/84% (3DCRT)), hippocampi mean dose were 51 Gy (IMRT), 52 Gy (3DCRT), and 44Gy (PRT) and cochlear mean dose were 43 Gy (IMRT), 49 Gy (3DCRT), and 31Gy (PRT). Dose to several other critical structures were also significantly reduced including the whole brain, supratentorium, cerebellum, and pituitary.
CONCLUSIONS
Proton therapy greatly reduces dose to critical CNS structures when compared to IMRT or 3DCRT. Further studies are needed to correlate dose reductions in these structures with improved cognitive outcomes.
Abstract
BACKGROUND
Spine stereotactic radiosurgery (SSRS) is a non-invasive technique that delivers ablative radiotherapy for optimal control of bony disease. While SSRS is known to provide ...excellent local control (LC) and minimal toxicity in adults, the role of SSRS in pediatrics is less clear.
PURPOSE
To evaluate SSRS in pediatric patients with spinal metastases.
METHODS
A retrospective review of patients (<18 yrs) treated with SSRS at MDACC was performed after IRB approval. Descriptive statistics were utilized for analysis.
RESULTS
From 2011–2019, 12 metastatic osseous sites (3 cervical, 4 thoracic, 5 lumbar-sacral) in 9 patients were treated. Median follow-up was 9 months (range 2–41). Six males (67%) and 3 females (33%) all KPS ≥70, received radiation to ≤3 contiguous vertebral bodies. Median age was 16 yrs (range 8–18). No patients required sedation. Histologies included 7 osteosarcomas, one rhabdomyosarcoma and one Ewing’s sarcoma. Metastatic epidural spinal cord compression scores ranged from 0 (6), 1b (3) and 3 (3). No sites had surgery prior to SSRS and one site received prior conventional radiation. SSRS doses included 24 Gy in 1 fraction (7), 24–27 Gy in 3 fractions (4) and 50 Gy in 5 fractions (1). Six-month LC was 83% with one local failure following 27 Gy. OS at 6 and 12 mo were 55% and 23%. There was no grade ≥3 acute toxicity, no radiation myelopathy or vertebral compression fractures.
CONCLUSION
In this initial report, SSRS represents a promising modality that is well tolerated and provides excellent LC. However, further follow-up is warranted in the pediatric setting.
Abstract
Pediatric high-grade gliomas (pHGG) are malignant brain tumors with a high mortality rate. Radiotherapy (RT) is one of the cornerstones of current pHGG treatment, while the efficacy of ...chemotherapeutics remains inferior. The use of chemotherapeutics that specifically sensitize tumor cells to irradiation are poorly understood, but may help to increase the effect of RT in pHGG treatment. Since recent studies revealed pHGG to be epigenetically dysregulated, we tested 148 epigenetic drugs on eight primary pHGG models in the presence and absence of RT, to assess their radiosensitizing potential. Based on synergy scores, we found 22 compounds that resulted in enhanced cytotoxicity in the presence of RT. The effect of these compounds on pHGG was further investigated by tracking spheroid growth microscopically for 30 days, identifying four molecules that stopped spheroid-expansion solely in combination with RT (p=<0.001, multilevel regression). Parallel cell-viability assays reported identical results. Furthermore, tumor migration in 3D matrigel growth assays, using non-toxic doses of the four identified compounds, revealed that two compounds (the selective HDAC-inhibitors; chidamide and entinostat) stop the infiltrative growth characteristics of pHGG cells, exclusively in combination with RT. RNA-Seq data showed that entinostat and chidamide inhibit DNA-repair pathways like the Fanconi anemia cascade and homologous recombination. Since we anticipate that entinostat- or chidamide-induced radiosensitization can be enhanced by blocking kinase-driven escape mechanisms, we are currently conducting a kinome-wide CRISPR/Cas9 knockout screen in three primary pHGG models to develop combinational therapies. These results highlight entinostat and chidamide as potential radiosensitizers in pHGG treatment.
Abstract
BACKGROUND
Proton beam therapy (PBT) provides dosimetric benefits in sparing normal tissue when treating pediatric patients with brain tumors. We report the preliminary clinical outcomes of ...surgery and adjuvant PBT for patients under 3 years old diagnosed as intracranial ependymoma at our institute.
METHODS
This is a retrospective review of the medical records for 3 children with ependymoma in the fourth ventricle, diagnosed between March 2013 and September 2019. PBT was performed after tumor resection in all the patients.
RESULTS
Gross total resection was achieved in 2 males and 1 female patients with fourth ventricle WHO grade II to III ependymoma at 15, 18, and 37 months old. All the patients received adjuvant PBT (54.0 GyE/30 fractions) to the postoperative tumor bed under general anesthesia or sedation. PBT was acutely well tolerated, with mostly mild alopecia and skin reactions at the irradiated sites. At a median follow-up of 54 months (4–59 months) after irradiation, all the patients are alive without recurrence. No serious late adverse events were observed in any of the patients.
CONCLUSION
The number of patients in this study remains small for drawing any definite conclusion, however our preliminary results are still encouraging. Further studies of a large number of pediatric patients with long term follow-up are needed to more fully assess tumor control and late adverse events.
Abstract
BACKGROUND
Pediatric brainstem gliomas rarely occur and are a heterogeneous group of diseases, which increases the difficulty of treatment strategy. Here, we present a case of pediatric ...pontine glioma treated with Gamma Knife surgery (GKS) after open biopsy. CASE DESCRIPTION: An 11-year-old boy presented with diplopia due to the left MLF syndrome. MRI showed a well-circumscribed, protruding tumor with partial gadolinium enhancement in the dorsal pons. An open biopsy was performed via the suprafacial triangle following midline suboccipital approach. Histological examinations revealed high cellularity and mild atypia. Immunohistochemistry demonstrated positive stain for GFAP and Olig2 antibodies, and negative for p53 protein. The Ki67-labeling index was 6.8%. Pyrosequence analysis indicated IDH1/2 wild type (wt), BRAF V600 wt, H3F3A K27 wt, FGFR1 wt, and TERT wt. The final diagnosis was pediatric diffuse astrocytoma, WHO grade II, pons. GKS was performed one month after the biopsy. After transient worsening of the symptom, it disappeared gradually. The tumor is stable for three years with mild shrinkage of the size. DISCUSSION: Gross total resection (GTR) of pediatric low-grade, brainstem gliomas may result in a good prognosis. However, unlike pilocytic astrocytoma, diffuse astrocytoma is not easy to perform GTR without any complications. There are some reports regarding GKS for brainstem gliomas, which prove an increase in progression free survival rate. No marked tumor regression is achieved in our case, but tumor growth is well-controlled so far.
CONCLUSION
GKS after biopsy can be a useful treatment option for pediatric low-grade brainstem gliomas.
Abstract
Treatment for medulloblastoma involves craniospinal irradiation which is associated with devastating late effects. Clinical trials that simply reduce radiotherapy dosage have resulted in ...inferior survival rates, whereas new chemo/radiotherapy combinations that improve survival have been identified using preclinical models. However, the potential late effects of novel treatments are currently understudied and the assessment of radiation-induced late effects in mice remains challenging. Here, we aimed to measure the effect of multifractionated radiotherapy on the juvenile mouse brain as a baseline measure for future studies. NOD/Rag1-/- mice received either 8Gy whole-brain radiotherapy (WBRT) using an X-RAD SmART preclinical platform, 18Gy fractionated WBRT (9x2Gy doses), single, or multiple sham treatments beginning at postnatal day (P)16. Mice were aged to adulthood (>P63), then high resolution anatomical brain scans were obtained on a Bruker 9.4T MRI to measure the effects of WBRT on whole brain and specific regional area volumes. A single 8Gy dose (n=10) markedly reduced brain volume by 8.5% compared to single-sham controls (n=11, p<0.0001), whereas fractionated 18Gy treatment (n=7) did not cause significant differences in brain volume compared to multi-sham controls (n=4, p>0.99). Current analyses are focused on measuring treatment effects on specific areas of the brain, as well as other anatomical differences using a range of MRI techniques. These results will serve as a valuable tool to measure potential treatment-associated effects caused by novel chemo/radiotherapy combinations on the developing brain. This will enable future studies to assess the potential safety of novel treatment to inform clinical decision making.
Abstract
We report a case of radiation-induced glioma in the pons after radiation therapy for germ cell tumor. A 17-year-old man was diagnosed as HCG and AFP secreting germ cell tumor at the age of ...9. The tumor was located in the suprasellar region, which filled up most part of the third ventricle. Five courses of chemotherapy with cisplatin, etoposide, and cyclophosphamide, and whole ventricle plus local radiation therapy (total 51.2 Gy / 32Fr) were performed. After the treatment, most part of the tumor was regressed, and only small enhanced lesion remained. Six years after the treatment, he started to be ataxic, and worsened. An MRI revealed an enhanced lesion in the pons. Lesion biopsy was performed via the right cerebellar peduncle. Histopathological diagnosis confirmed the lesion was high grade glioma. He underwent extended local radiation therapy (50.4 Gy / 28 Fr) and administered temozolomide. Later, bevacizumab was added, and 3 months after treatment started, the size of the tumor was reduced and his symptoms were improving. There is no established treatment for radiation induced glioma. However, additional radiation therapy, temozolomide and bevacizumab appears to be useful to reduce tumor size and resolve the symptoms, even if it is transient.
Abstract
BACKGROUND
If new lesions are observed during follow-up of the malignant tumor after treatment, it is difficult to distinguish whether the tumor is a recurrent lesion, secondary cancer, or ...radiation necrosis of the brain. We have encountered a patient with symptomatic radiation necrosis of the cerebellum 16 years after treatment of medulloblastoma. CASE PRESENTATION: A 24-year-old man who had received a tumor resection and chemoradiotherapy for cerebellar medulloblastoma at the age of 8 presented with dizziness. For the past 16 years, there was no recurrence of the tumor. He subsequently underwent MRI scan, and T1-Gd image showed enhanced lesion in the right cerebellar peduncle. Cerebrospinal fluid cytology analysis was negative for tumor. We suspected tumor reccurence or secondary cancer, and performed lesion biopsy. The result of the pathological examination was radiation necrosis of the cerebellum. DISCUSSION: The interval of radiation necrosis of the brain and radiotherapy can vary from months to more than 10 years. So, whenever a new lesion is identified, radiation brain necrosis must be envisioned. According to guidelines in Japan, there is no absolute examination for discriminating tumor recurrence from radiation brain necrosis and diagnosis by biopsy may be required.
CONCLUSION
We experienced a case of symptomatic radiation necrosis of the cerebellum 16 years after treatment. In patients showing new lesion after long periods of time, the possibility of radiation necrosis to be considered.
Abstract
INTRODUCTION
We present our experience of a novel approach using intensity modulated proton therapy(IMPT) for cranio-spinal irradiation(CSI) leading to reduced acute esophageal toxicity and ...reduced treatment interruptions. MATERIAL AND
METHODS
Seven children younger than 12 years old treated consecutively with CSI using IMPT were included in this study. Three among 7 children received concurrent chemotherapy(CCT). Entire vertebral body(VB) was part of target volume in all patients. The IMPT plan was generated using 3 fields with single field optimisation technique. Last 5 patients were treated using dose gradient(DG) (98-93%) deliberately created in anterior most 3-5mm of VB. Initial 2 patients were treated with intention of covering entire VB with 98% isodose. Monte Carlo algorithm was used for dose calculations and optimisation, and robustness assessed for 3mm setup and 3.5% range uncertainty.
RESULTS
The CSI dose ranged from 21.6GyE to 35GyE. In patients without DG, maximum and mean dose to esophagus(36.67GyE vs. 25.45GyE, 31.53GyE vs. 20.41GyE), midline mucosa(28.95GyE vs. 25.31GyE, 21.8GyE vs. 14.61GyE) and bowel bag(32.9GyE vs. 24.27GyE, 3.59GyE vs. 3.21GyE) were higher compared to patients with DG. Both patients where DG was not created, developed grade 2 esophageal toxicities requiring supportive care and treatment interruptions(4 and 2days). All 5 patients with DG did not develop significant esophageal toxicity and had no interruptions.
CONCLUSION
Creating a dose gradient over anterior VB using IMPT reduces dose to esophagus and midline mucosa leading to lower acute esophageal toxicity which potentially avoids treatment interruptions during CSI.
Abstract
BACKGROUND
The use of highly conformal proton therapy in adolescents and young adults (AYAs) for management of brain/skull-base tumours is becoming increasingly common. This study aims to ...assess the long-term clinical outcomes, prognostic factors and employment status of AYAs (15–39 years) treated with pencil-beam-scanning proton-therapy (PT).
METHODS
Between 1997–2018, 176 AYAs were treated with PT at the Paul Scherrer Institute. Median age was 30 years (range, 15–39) and the male/female ratio was 0.8.
RESULTS
After a median follow-up of 66 months (range, 12–236), 24 (13.6%) local failures and 1 (0.6%) distant failure were observed between 6 and 152 months after PT. The most common histologies treated were chordomas/chondrosarcomas (61.4%), followed by meningiomas (14.2%) and gliomas (15.3%). The 6-year local-control (LC), distant-progression-free survival and overall-survival (OS) rate was 83.2%, 97.4% and 90.2% respectively. On univariate analysis, age ≥24 years was a negative prognostic factor for LC. Recurrent disease, infratentorial tumours and low-grade-glioma histology were poor prognostic factors for both LC and OS. The 6-year ≥G3 PT-related late toxicity-free survival was 88.5%. The moderate-high grade late toxicity crude rates were 37.8% G2, 12.2% G3, 0.6% G4 and 0.6% G5. No secondary malignancies were observed. The unemployment rate was 7.3% at PT, rising to 25.3% at survivorship. High-grade(≥G3) toxicity rate in the unemployed vs employed group was 21% vs 8.5%.
CONCLUSION
PT is an effective treatment for AYAs with brain/skull-base tumours with good tumour control and acceptable long-term toxicity. Despite having satisfactory clinical outcomes, around 1 in 4 AYAs surviving brain/skull base tumours are unemployed.
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