Irradiation For Medulloblastoma Research Articles

RADT-07. CLINICAL RESULTS, ACUTE AND EARLY LATE TOXICITY AFTER PROTON RADIOTHERAPY FOR PEDIATRIC MEDULLOBLASTOMA, RETROSPECTIVE ANALYSIS

Abstract Craniospinal irradiation with boost to primary tumor site (and metastatic sites) is current radiotherapy standard for most patients diagnosed with medulloblastoma (MB). This treatment is effective, but survivors frequently develop long-term toxicity affecting the quality of life. Proton radiotherapy has the same efficacy compared to conventional photon-based techiques, but might achieve lower risk of toxicity. We retrospectivelly analyzed our cohort of patients irradiated for MB in our institution, using IMPT (intensity modulated proton therapy). Between May 2013 and December 2023 eighty patients (50 male, 30 female, median age at radiotherapy 8 years/range 3-17/) with primary or recurrent MB (not previously irradiated) were treated and included into analysis. 36 patients were treated for high-risk MB (mostly metastatic), 44 pts for SR disease. Neoadjuvant, concurrent and adjuvant systemic treatment was applied according to the protocol selected by the pediatric oncologist. All but one patients completed their treatment, acute toxicity including hematological was mild and lead to treatment interruption in seven cases. With a median of follow-up 39,6 months (range 3-119) 62 pts were in complete remission, 3 pts alive with disease, 14 died from disease progression and one died from complication (intracranial hemorrhage). We were able to identify two secondary malignancies potentially associated with IMPT (thyroid cancer, radiation induced high-grade glioma). Most common endocrinopathy observed in our patients was hypothyroidism and growth-hormon decifit. Due to lack of data, we were not able to analyze cognitive functions and quality of life. There was one case of severe brainstem necrosis with persistent neurological deficit, treated with corticosteroids and bevacizumab. Proton radiotherapy using IMPT for craniospinal irradiation in MB is feasible, treatment outcomes and toxicity are encouraging, although a longer follow-up is needed.

MDB-15. CLINICAL CHARACTERISTICS AND OUTCOME OF CHILDHOOD LI-FRAUMENI SYNDROME MEDULLOBLASTOMA PATIENTS

Abstract Patients with Li-Fraumeni syndrome (LFS) who develop medulloblastoma (MB) have a very poor prognosis. The development of novel therapeutic strategies is challenged by the lack of clinical data for this patient group. We here present clinical and molecular data on a retrospective cohort of pediatric patients with LFS-associated MB. This is an international, retrospective, multicenter cohort study. Patients with LFS-associated MB under 21 years and class 5 (pathogenic) or class 4 (likely pathogenic) constitutional TP53 variants were included. We evaluated TP53 mutation status (constitutional and somatic), DNA methylation subgroup, treatment modalities, event-free (EFS) and overall survival (OS), patterns of recurrence, as well as occurrence of secondary neoplasms. Forty-seven individuals with LFS-associated MB were included. MBs were classified mainly as Sonic Hedgehog (SHH) group (87%). TP53 variants were classified as class 5 (70%) and class 4 (30%). The majority (74%) of TP53 variants represented missense variants. The 2-year (y-) EFS and -OS were 33% and 53%, respectively. A significantly better outcome was seen in patients who received post-operative radiotherapy (RT) (2y-EFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-EFS: 24%, 2y-OS: 48%) compared with patients who received no RT (2y-EFS: n.a., 2y-OS: 25%). No significantly different outcomes were seen between patients treated either according to protocols including high-intensity chemotherapy or receiving only maintenance-type chemotherapy (2y-EFS: 42% and 31%, 2y-OS: 68% and 53%, respectively). Patients with LFS-associated MB have a dismal prognosis. Use of RT in LFS-associated MB significantly increased survival rates in the presented cohort, but choice of chemotherapy regimen did not influence their clinical outcome. To improve the outcome of patients with LFS-associated MB, prospective collection of clinical data and development of novel treatments are required.

RADT-30. RADIATION INDUCED MENINGIOMA IN BACKGROUND OF CHILDHOOD CRANIAL IRRADIATION: A CASE SERIES

Abstract BACKGROUND Cranial irradiation as part of prophylactic (PCI) or radical treatment for childhood malignancies can be associated with late consequences such as radiotherapy induced meningioma. METHODS We are reporting 5 such patients treated at our institute. RESULTS Case 1: 24y female received PCI for Acute Lymphoblastic Leukemia at the age of 2, and developed right frontal meningioma which was resected and pathology confirmed grade 2 atypical meningioma. It was treated with radiotherapy 60Gy/30fr and 2 year follow up scans remain stable. Case 2: 31y male received PCI as a child, and developed parieto-occipital meningioma which was excised multiple times. Pathology revealed Grade 2 atypical meningioma and was treated with radiotherapy 60Gy/30fr. Follow up scans 3.5 yrs later remain stable.Case3: 37y male received PCI at the age of 3, and developed multiple site meningiomas which were excised. Pathology showed likely Grade 2 meningioma. The sphenoid wing lesion progressed 2 years later, was re-excised and treated recently with radiotherapy 60Gy/30fr. Case 4: 52y female treated with radiotherapy for retinoblastoma at the age of 6-8 wks, developed left sphenoid wing meningioma which was resected and pathology revealed malignant meningioma. Radiotherapy 60Gy/30fr was recently completed.Case 5: 24y female treated with radiotherapy for medulloblastoma at the age of 5, developed meningiomas at multiple sites. Over the span of 10 years the frontal and clinoid lesions increased in size, and were treated with SRS/SRT recently. CONCLUSION All patients had background of cranial radiation and developed meningioma with latency period ranging 19 to 52 years. It is not possible to make an inference on gender, site of meningioma or craniaI dose correlation because of small number of cases and lack of data on dose. Further research is needed on how to prevent secondary malignancies in such patients and on standard of care for secondary meningiomas.

Beta-blockers disrupt mitochondrial bioenergetics and increase radiotherapy efficacy independently of beta-adrenergic receptors in medulloblastoma.

SummaryBackgroundMedulloblastoma is the most frequent brain malignancy of childhood. The current multimodal treatment comes at the expense of serious and often long-lasting side effects. Drug repurposing is a strategy to fast-track anti-cancer therapy with low toxicity. Here, we showed the ability of β-blockers to potentiate radiotherapy in medulloblastoma with bad prognosis.MethodsMedulloblastoma cell lines, patient-derived xenograft cells, 3D spheroids and an innovative cerebellar organotypic model were used to identify synergistic interactions between β-blockers and ionising radiations. Gene expression profiles of β-adrenergic receptors were analysed in medulloblastoma samples from 240 patients. Signaling pathways were explored by RT-qPCR, RNA interference, western blotting and RNA sequencing. Medulloblastoma cell bioenergetics were evaluated by measuring the oxygen consumption rate, the extracellular acidification rate and superoxide production.FindingsLow concentrations of β-blockers significantly potentiated clinically relevant radiation protocols. Although patient biopsies showed detectable expression of β-adrenergic receptors, the ability of the repurposed drugs to potentiate ionising radiations did not result from the inhibition of the canonical signaling pathway. We highlighted that the efficacy of the combinatorial treatment relied on a metabolic catastrophe that deprives medulloblastoma cells of their adaptive bioenergetics capacities. This led to an overproduction of superoxide radicals and ultimately to an increase in ionising radiations-mediated DNA damages.InterpretationThese data provide the evidence of the efficacy of β-blockers as potentiators of radiotherapy in medulloblastoma, which may help improve the treatment and quality of life of children with high-risk brain tumours.FundingThis study was funded by institutional grants and charities.

Pretreatment Normal WM Magnetization Transfer Ratio Predicts Risk of Radiation Necrosis in Patients with Medulloblastoma.

Radiation necrosis, for which abnormal WM enhancement is a hallmark, is an uncommon complication of craniospinal irradiation in children with medulloblastoma. The magnetization transfer ratio measures macromolecular content, dominated by myelin in the WM. We investigated whether the pretreatment supratentorial (nonsurgical) WM magnetization transfer ratio could predict patients at risk for radiation necrosis after radiation therapy for medulloblastoma. Ninety-five eligible patients with medulloblastoma (41% female; mean age, 11.0 [SD, 5.4] years) had baseline balanced steady-state free precession MR imaging before proton or photon radiation therapy. Associations among baseline supratentorial magnetization transfer ratio, radiation necrosis (spontaneously resolving/improving parenchymal enhancement within the radiation field)3, age, and the presence of visible brain metastases were explored by logistic regression and parametric/nonparametric techniques as appropriate. Twenty-three of 95 (24.2%) children (44% female; mean age, 10.7 [SD, 6.7] years) developed radiation necrosis after radiation therapy (19 infratentorial, 1 supratentorial, 3 both). The mean pretreatment supratentorial WM magnetization transfer ratio was significantly lower in these children (43.18 versus 43.50, P = .03). There was no association between the supratentorial WM magnetization transfer ratio and age, sex, risk/treatment stratum, or the presence of visible brain metastases. A lower baseline supratentorial WM magnetization transfer ratio may indicate underlying structural WM susceptibility to radiation necrosis and may identify children at risk for developing radiation necrosis after craniospinal irradiation for medulloblastoma.

Stroke-Like Migraine after Radiation Treatment Syndrome in Children with Cancer

AbstractStroke-like migraine attacks after radiation therapy (SMART) syndrome is a symptom complex of transient neurological deficits, headache, and abnormal cortical contrast enhancement on brain MRI. Pathophysiology is unclear, but exposure to cranial radiation (RT) is a sine qua non. We report five children with SMART syndrome treated with RT therapy for medulloblastoma (n = 3), atypical teratoid rhabdoid tumor (n = 1), and pleomorphic xanthoastrocytoma (n = 1). Median age at tumor diagnosis was 9.4 years (range 5.1–14.7). Median follow-up from cancer diagnosis was 3.1 years (range 1.4–12.9). All patients had 54 Gy focal RT treatment and medulloblastoma children had additional 36 Gy craniospinal irradiation. Median time from the end of RT to first transient neurological deficit was 1 year (range 0.7–12.1). The median follow-up since first SMART episode was 0.6 years (range 0.3–2.6). Presenting symptoms included the gradual development of unilateral weakness (n = 4), non-fluent dysphasia (n = 1), somnolence (n = 1), and headaches (n = 3). Neurological deficits resolved within 30 minutes to 10 days. Transient cortical enhancement on magnetic resonance imaging (MRI) was confirmed in two children and was absent in the other three. Two children had a single and three had multiple episodes over the next few months. Two children with protracted symptoms responded to 3 days treatment with high dose intravenous methylprednisolone. Symptoms ultimately resolved in all patients. SMART syndrome is a rare disorder characterized by slow evolution of neurological deficits with variable abnormal cortical contrast enhancement. The use of steroids may improve symptoms and speed resolution.

Radiotherapy in Medulloblastoma-Evolution of Treatment, Current Concepts and Future Perspectives.

Simple SummaryCraniospinal irradiation (CSI) is the backbone of medulloblastoma treatment and the first treatment to achieve a cure in many patients. Within the last decades, significant efforts have been made to enhance efficacy in combination with chemotherapy. With this approach, a majority of low- and standard-risk patients can be cured. In parallel, many clinical trials have dealt with CSI-dose reduction and reduction of boost volume in order to decrease long-term toxicity, particularly neurotoxicity. Within these trials, standardized quality assurance has helped to increase the accuracy of treatment and improve prognosis. More recently, advances of radiotherapy techniques such as proton treatment allowed for better sparing of healthy tissue in order to further diminish detrimental long-term effects. Major future challenges are the adaption of radiotherapy regimens to different molecularly defined disease groups alone or together with new targeted agents. Moreover, and even more importantly, innovative combinatorial treatments are needed in high- and very-high risk situations.Medulloblastoma is the most frequent malignant brain tumor in children. During the last decades, the therapeutic landscape has changed significantly with craniospinal irradiation as the backbone of treatment. Survival times have increased and treatments were stratified according to clinical and later molecular risk factors. In this review, current evidence regarding the efficacy and toxicity of radiotherapy in medulloblastoma is summarized and discussed mainly based on data of controlled trials. Current concepts and future perspectives based on current risk classification are outlined. With the introduction of CSI, medulloblastoma has become a curable disease. Due to combination with chemotherapy, survival rates have increased significantly, allowing for a reduction in radiation dose and a decrease of toxicity in low- and standard-risk patients. Furthermore, modern radiotherapy techniques are able to avoid side effects in a fragile patient population. However, high-risk patients remain with relevant mortality and many patients still suffer from treatment related toxicity. Treatment needs to be continually refined with regard to more efficacious combinatorial treatment in the future.

Radiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B

Long-term complications such as radiation-induced second malignancies occur in a subset of patients following radiation-therapy, particularly relevant in pediatric patients due to the long follow-up period in case of survival. Radiation-induced gliomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies such as acute lymphoblastic leukemia (ALL) and medulloblastoma (MB). We perform comprehensive (epi-) genetic and expression profiling of RIGs arising after cranial irradiation for MB (n = 23) and ALL (n = 9). Our study reveals a unifying molecular signature for the majority of RIGs, with recurrent PDGFRA amplification and loss of CDKN2A/B and an absence of somatic hotspot mutations in genes encoding histone 3 variants or IDH1/2, uncovering diagnostic markers and potentially actionable targets.

A novel PLK1 inhibitor onvansertib effectively sensitizes MYC-driven medulloblastoma to radiotherapy.

Group 3 medulloblastoma (MB) is often accompanied by MYC amplification. PLK1 is an oncogenic kinase that controls cell cycle and proliferation and has been preclinically validated as a cancer therapeutic target. Onvansertib (PCM-075) is a novel, orally available PLK1 inhibitor, which shows tumor growth inhibition in various types of cancer. We aim to explore the effect of onvansertib on MYC-driven medulloblastoma as a monotherapy or in combination with radiation. Crisper-Cas9 screen was used to discover essential genes for MB tumor growth. Microarray and immunohistochemistry on pediatric patient samples were performed to examine the expression of PLK1. The effect of onvansertib in vitro was measure by cell viability, colony-forming assays, extreme limiting dilution assay, and RNA-Seq. ALDH activity, cell-cycle distribution, and apoptosis were analyzed by flow cytometry. DNA damage was assessed by immunofluorescence staining. Medulloblastoma xenografts were generated to explore the monotherapy or radio-sensitizing effect. PLK1 is overexpressed in Group 3 MB. The IC50 concentrations of onvansertib in Group 3 MB cell lines were in a low nanomolar range. Onvansertib reduced colony formation, cell proliferation, stem cell renewal and induced G2/M arrest in vitro. Moreover, onvansertib in combination with radiation increased DNA damage and apoptosis compared with radiation treatment alone. The combination radiotherapy resulted in marked tumor regression in xenografts. These findings demonstrate the efficacy of a novel PLK1 inhibitor onvansertib in vitro and in xenografts of Group 3 MB, which suggests onvansertib is an effective strategy as monotherapy or in combination with radiotherapy in MB.

Observed-to-expected incidence ratios of second malignant neoplasms after radiation therapy for medulloblastoma: A Surveillance, Epidemiology, and End Results analysis.

The authors analyzed the incidence and types of second malignant neoplasms (SMNs) in patients treated for medulloblastoma. The authors compared the incidence of SMNs after radiotherapy (RT) for medulloblastoma in patients treated in 1973-2014 with the incidence in the general population with the multiple primary-standardized incidence ratio function of Surveillance, Epidemiology, and End Results 9. Observed-to-expected incidence (O/E) ratios and 95% confidence intervals (CIs) were reported for the entire cohort and by disease site according to age at diagnosis, treatment era, and receipt of chemotherapy. P values < .05 were considered statistically significant. Of the 1294 patients with medulloblastoma who received RT, 68 developed 75 SMNs. The O/E ratio for SMNs among all patients was 4.49 (95% CI, 3.53-5.62; P < .05). The site at highest risk was the central nervous system (CNS; O/E, 40.62; 95% CI, 25.46-61.51), which was followed by the endocrine system (O/E, 15.95; 95% CI, 9.12-25.91), bone (O/E, 14.45; 95% CI, 1.75-52.21), soft tissues (O/E, 9.01; 95% CI, 1.09-32.56), the digestive system (O/E, 5.03; 95% CI, 2.51-9.00), and the lymphatic/hematopoietic system (O/E, 3.37; 95% CI, 1.35-6.94). The O/E ratio was higher for patients given chemotherapy and RT (O/E, 5.52; 95% CI, 3.75-7.83) than for those given RT only (O/E, 3.96; 95% CI, 2.88-5.32). Patients with medulloblastoma are at elevated risk for SMNs in comparison with the general population. Variations in O/E for SMNs by organ systems were found for treatment modality, age at diagnosis, and time of diagnosis. The most common site, the CNS, was involved more often in younger patients and those given chemotherapy with RT.

AsiDNA Is a Radiosensitizer with no Added Toxicity in Medulloblastoma Pediatric Models.

Medulloblastoma is an important cause of mortality and morbidity in pediatric oncology. Here, we investigated whether the DNA repair inhibitor, AsiDNA, could help address a significant unmet clinical need in medulloblastoma care, by improving radiotherapy efficacy without increasing radiation-associated toxicity. To evaluate the brain permeability of AsiDNA upon systemic delivery, we intraperitoneally injected a fluorescence form of AsiDNA in models harboring brain tumors and in models still in development. Studies evaluated toxicity associated with combination of AsiDNA with radiation in the treatment of young developing animals at subacute levels, related to growth and development, and at chronic levels, related to brain organization and cognitive skills. Efficacy of the combination of AsiDNA with radiation was tested in two different preclinical xenografted models of high-risk medulloblastoma and in a panel of medulloblastoma cell lines from different molecular subgroups and TP53 status. Role of TP53 on the AsiDNA-mediated radiosensitization was analyzed by RNA-sequencing, DNA repair recruitment, and cell death assays. Capable of penetrating young brain tissues, AsiDNA showed no added toxicity to radiation. Combination of AsiDNA with radiotherapy improved the survival of animal models more efficiently than increasing radiation doses. Medulloblastoma radiosensitization by AsiDNA was not restricted to a specific molecular group or status of TP53. Molecular mechanisms of AsiDNA, previously observed in adult malignancies, were conserved in pediatric models and resembled dose increase when combined with irradiation. Our results suggest that AsiDNA is an attractive candidate to improve radiotherapy in medulloblastoma, with no indication of additional toxicity in developing brain tissues.

Craniospinal Irradiation in Medulloblastoma using High Energy Medical Linear Accelerator: an Innovative Approach to Planning Technique

Background: Craniospinal irradiation (CSI) of medulloblastoma poses technological challenges due to the involvement of large treatment volume. Commonly, the whole treatment length is covered with two different isocentric plans in which the junction is shifted after every five fractions to overcome the possibility of hot and cold spot.Objective: This study aims to evaluate dosimetrically and clinically the innovative planning technique for the CSI which doesn’t need re-planning and re-setup of patients after every five fractions.Material and Methods: Computed tomography was done for fifteen (ten children and five adults) patients diagnosed with medulloblastoma. Treatment planning for 36 Gray (Gy) in 20 fractions (#) at the rate of 1.8Gy/# was done on the treatment planning system. A single plan for children was created with two bilateral fields of 6 Mega Voltage (MV) energy for cranium and one posterior field of 6 MV for spinal cord (C1-S2). Two plans for adult patients were created, first plan was with two bilateral fields of 6 MV for cranium and two posterior oblique fields of 6 MV for cervical and the part of thoracic spinal cord (up to T8-T9). The second plan was with a single posterior field of 15 MV covering remaining thoracic (T8-T9 to T12), lumbar and sacrum (up to lower border of S2) spine. After careful evaluation of all the plans, treatment was delivered; acute toxicities were recorded.Results: 95% of prescribed dose was received by more than 95% of planning target volume in all the plans with the acceptable hot spot and good homogeneity index. All the patients reported common radiation induced acute toxicities (headache, vomiting, weakness) during radiotherapy.Conclusion: The new planning technique for CSI has acceptable dosimetric and acute clinical possibilities; therefore it can be used for CSI for improved homogeneous dose delivery.

Craniospinal Irradiation in Medulloblastoma using High Energy Medical Linear Accelerator: an Innovative Approach to Planning Technique

Craniospinal irradiation (CSI) of medulloblastoma poses technological challenges due to the involvement of large treatment volume. Commonly, the whole treatment length is covered with two different isocentric plans in which the junction is shifted after every five fractions to overcome the possibility of hot and cold spot. This study aims to evaluate dosimetrically and clinically the innovative planning technique for the CSI which doesn't need re-planning and re-setup of patients after every five fractions. Computed tomography was done for fifteen (ten children and five adults) patients diagnosed with medulloblastoma. Treatment planning for 36 Gray (Gy) in 20 fractions (#) at the rate of 1.8Gy/# was done on the treatment planning system. A single plan for children was created with two bilateral fields of 6 Mega Voltage (MV) energy for cranium and one posterior field of 6 MV for spinal cord (C1-S2). Two plans for adult patients were created, first plan was with two bilateral fields of 6 MV for cranium and two posterior oblique fields of 6 MV for cervical and the part of thoracic spinal cord (up to T8-T9). The second plan was with a single posterior field of 15 MV covering remaining thoracic (T8-T9 to T12), lumbar and sacrum (up to lower border of S2) spine. After careful evaluation of all the plans, treatment was delivered; acute toxicities were recorded. 95% of prescribed dose was received by more than 95% of planning target volume in all the plans with the acceptable hot spot and good homogeneity index. All the patients reported common radiation induced acute toxicities (headache, vomiting, weakness) during radiotherapy. The new planning technique for CSI has acceptable dosimetric and acute clinical possibilities; therefore it can be used for CSI for improved homogeneous dose delivery.

Silencing of E3 Ubiquitin Ligase RNF8 Enhances Ionizing Radiation Sensitivity of Medulloblastoma Cells by Promoting the Deubiquitination of PCNA.

DNA damage response induced by ionizing radiation (IR) is an important event involved in the sensitivity and efficiency of radiotherapy in human medulloblastoma. RNF8 is an E3 ubiquitin ligase and has key roles in the process of DNA damage and repair. Our study aimed to evaluate the effect of RNF8 in the DNA damage repair induced by IR exposure in medulloblastoma cells. We found that the levels of RNF8 were significantly upregulated by γ-ray irradiation in a dose-dependent manner in medulloblastoma cells and colocalized with γ-H2AX, a sensitive marker of DNA double-strand breaks induced by γ-ray radiation. RNF8 knockdown was observed to enhance the sensitivity of IR in medulloblastoma cells, as evaluated by reduced cell survival. The apoptosis and cell cycle arrest of medulloblastoma cells were dramatically increased by RNF8 suppression after IR treatment. Furthermore, RNF8 inhibition did not affect the protein levels of BRCA1, a crucial protein involved in IR-induced DNA damage repair, but significantly decreased the recruitment of BRCA1 and increased the level of γ-H2AX at DNA damage sites compared to the control. A significant increase in OTM was observed in medulloblastoma cells treated by RNF8 shRNA after exposure to IR, indicating the effect of RNF8 on DNA damage and repair. Additionally, PCNA, a major target for ubiquitin modification during DNA damage response, was found to be monoubiquitinated by E3 ligase RNF8 and might contribute to the low radiosensitivity in medulloblastoma cells. Altogether, our findings may provide RNF8 as a novel target for the improvement of radiotherapy in medulloblastoma.

Radiation-induced glioblastoma with rhabdoid characteristics following treatment for medulloblastoma: A case report and review of the literature.

Glioblastoma multiforme (GBM) is a high-grade glioma that may develop from several other central nervous system tumors after radiation therapy. We herein report a case of GBM occurring 8 years after radiation therapy for medulloblastoma. The secondary tumor was histologically distinctly different from the primary tumor. Previously reported cases indicate that GBM induced by radiation therapy is associated with a highly aggressive clinical course with a high risk of early recurrence and poor prognosis. In addition, histological examination revealed that the tumor cells exhibited characteristics of both GBM and rhabdoid tumor cells. The diverse pathological characteristics of GBM may reflect the potential effects of radiation therapy on the tumor.

P206] Gafchromic and alanine detectors for verification of field junctions in craniospinal proton irradiation

Purpose Radiotherapy is one of essential methods of treatment for medulloblastoma – a primitive neuroectodermal tumor growing in cerebellum. Proton craniospinal irradiations are recommended because of sparing of intermediate-to-low-dose to healthy tissues and reduction of side effects, including secondary cancers. Two laterally opposed cranial fields and several posterior spine fields are usually used for irradiation in medulloblastoma as well in conventional radiotherapy as in proton one. In this field configuration a potential dose inhomogeneity at the field junctions can appear. We have investigated the dose homogeneity in the junction areas using Gafchromic films and alanine detectors. Methods A clinical plan for an anthropomorphic phantom of a 5-year-old child have been prepared. There were two opposed lateral brain fields and 2 posterior spine fields. Therefore two field junctions were investigated. Then the phantom was equipped with alanine detectors and Gafchromic films at chosen positions mainly in junction areas and irradiated. Alanine doses were assessed using proton beam calibration (5–20 Gy). The calibration curve was designed upon developed protocol based on ISO/WD 15566.1 document. Alanine doses were then compared with doses in the treatment plan. Gafchromic films were analyzed using in-house developed AnalyseGafchromic software allowing to calculate dose based on triple channel calibration and apply corrections on scanner spatial inhomogeneity and scan-to-scan instability. Finally, the measured 2D dose distributions were compared with dose planes exported from TPS (Treatment Planning System) using gamma index analysis. Results The compatibility of alanine doses and TPS doses was at the level of 1%. For all the dose planes measured with Gafchromic passing rates of gamma index test (3%/3 mm) was higher than 95%. Conclusions Patients with medulloblastoma may benefit greatly from proton radiotherapy, however the main condition for a successful treatment is a careful and accurate field junctions, where all the uncertainties of beam model in TPS, CT calibration curve and Patient Positioning may affect the dose delivered to the patient. We have proved that Gafchromic films and alanine detectors can be successfully used for complex system check for ability to irradiate the target with sufficient accuracy.

Radiation-Induced Benign Meningioma after Radiotherapy for Medulloblastoma: Case report and brief review of the literature

Radiation-Induced Benign Meningioma after Radiotherapy for Medulloblastoma: Case report and brief review of the literature

Impact of acute hematological toxicity on treatment interruptions during cranio-spinal irradiation in medulloblastoma: a tertiary care institute experience.

To analyze treatment interruptions due to acute hematological toxicity in patients of medulloblastoma receiving cranio-spinal irradiation (CSI). Prospectively collected data from case records of 52 patients of medulloblastoma treated between 2011 and 2014 was evaluated. Blood counts were monitored twice a week during CSI. Spinal irradiation was interrupted for patients with ≥grade 2 hematological toxicity and resumed after recovery to grade 1 level (TLC >3000; platelet count >75,000). Treatment interruptions and hematological toxicity were analyzed. Median age was 11years. All patients received adjuvant CSI of 36Gy, followed by boost of 18Gy to posterior fossa, at 1.8Gy per fraction. Concurrent chemotherapy was not given. Adjuvant chemotherapy was given after CSI for high risk patients. Spinal fields were interrupted in 73.1% of patients. Cause of first interruption was leucopenia in 92.1%, thrombocytopenia in 2.6%, and both in 5.3%. Median number of fractions at first interruption was 8, with 25% of interruptions in first week. Median duration for hematological recovery after nadir was 5days for leucopenia and 3days for thrombocytopenia. Half of the patients had at least 2 interruptions, and 19% subsequently developed grade 3 toxicity. On multivariate analysis, significant correlation with duration of delay was observed for pre-treatment haemoglobin, number of fractions at first interruption, grade and duration of recovery of leucopenia. Acute hematological toxicity with CSI is frequently under-reported. Patients with low pre-treatment hemoglobin, early onset leucopenia, profound leucopenia and prolonged recovery times are at a higher risk of having protracted courses of irradiation. Frequent monitoring of blood counts and timely interruption of spinal fields of irradiation at grade 2 level of hematological toxicity minimizes the risk of grade 3 and grade 4 toxicity, while reducing the interruptions in irradiation of the gross tumour bed.

Papillary carcinoma thyroid as a second malignant neoplasm following radiotherapy for medulloblastoma in childhood: A rare case report

Second malignant neoplasm is a rare but dreaded late sequelae of the treated primary childhood malignancies. Surgical excision combined with radiochemotherapy represents the gold standard of therapy for medulloblastoma. The effectiveness of such a combined treatment has encouraged the use of radiotherapy even in young pediatric patients, in spite of the increased risk of a second radio-induced malignancy. Irradiation is the well-known risk factor for the development of benign and malignant thyroid tumors. Children are more exposed to this risk because their thyroid gland is more sensitive to the carcinogenic effect of ionizing radiation. We report the case of a 20-year-old male who initially presented at the age of 2 years with a medulloblastoma and was treated with surgery and radiotherapy. The patient again presented 18 years after radiotherapy with bilateral neck masses which proved to be lymphadenopathy secondary to papillary carcinoma of the thyroid. The patient also had multiple bilateral metastatic pulmonary nodules. Radio-induced thyroid tumors are well-recognized nosographic entities due to the particular sensitivity of this gland to ionizing radiations. However, only a few papers on radio-induced thyroid neoplasms after the central nervous system (CNS) irradiation have been published in the literature. We report an additional case of thyroid neoplasm following childhood CNS irradiation for the treatment of posterior fossa medulloblastoma and emphasize that clinicians should judiciously use the radiotherapy for treatment of childhood malignancies and also radiologists should be familiar with the long-term complications of antineoplastic therapies to facilitate early diagnosis and treatment.

Comparison of Endocrine Dysfunction and Dosimetry in Pediatric Patients Treated With Proton Versus Photon Radiation Therapy for Medulloblastoma

Comparison of Endocrine Dysfunction and Dosimetry in Pediatric Patients Treated With Proton Versus Photon Radiation Therapy for Medulloblastoma