Treatment Of Pediatric Brain Tumors Research Articles

Shared molecular targets in pediatric gliomas and ependymomas

Recent advances in multidisciplinary treatment approaches have improved the overall prognosis of pediatric brain tumors, but some patients remain refractory to treatment and do poorly. Several molecularly targeted therapies are under development for the treatment of brain tumors, and high-grade gliomas in adults are a particular area of study. To better understand if these new therapies can be used in pediatric populations, we examined the expression of the following seven marker genes involved in signaling pathways targeted by new therapies: β-catenin, suppressor of fused (SUFU), erythroblastic leukemia viral oncogene homolog (ERBB) 2, platelet-derived growth factor receptorα (PDGFRα), proliferating cell nuclear antigen (PCNA), secreted protein acid and rich in cysteine (SPARC), and granulocyte colony-stimulating factor receptor (G-CSFR). Samples from 27 patients with the primitive neuroectodermal tumor (PNET)/medulloblastomas (MBs) (n = 8), ependymomas (n = 5), or gliomas (n = 14) were assessed by quantitative real-time PCR. [Correction made here after initial online publication]. We assigned an EXP score to compare across samples and determined the levels of gene expression among tumor cell types. Gene expression varied among the different tumors, but, within a tumor type, clear expression patterns were seen. The expression of SUFU, ERBB2, and PCNA in metastatic MBs were greater than that seen in non-metastatic MBs. Most glioma cases highly expressed PDGFRα and G-CSFR. Additionally, the expression patterns of gliomas and ependymomas were similar (r = 0.77, P = 0.04), but PNET/MBs substantially differed from gliomas (r = -0.37, P = 0.41) or ependymomas (r = 0.23, P = 0.62). The development of new drugs targeting up-regulated pathways may be useful for the treatment of pediatric brain tumors. As new drugs are developed, gliomas and ependymomas may be treated with similar compounds.

Pediatric meningioma: current approaches and future direction

With improvement in leukemia therapy, central nervous system (CNS) tumors are the leading cause of cancer mortality in children and the most expensive of all human neoplasms to treat. Meningiomas are rare intracranial tumors in childhood and adolescence arising from arachnoid cell clonal outgrowth in the meninges. There have been no collaborative prospective therapeutic trials for pediatric meningioma because of its rarity, and the best evidence for management comes from retrospective case analyses and extrapolation from the treatment of adult meningioma. However this may not be ideal, because the underlying biology of adult and pediatric meningiomas seems to be different, as is the case for other CNS tumors. In addition, treatment of pediatric brain tumors requires consideration of long-term quality of life. This review reflects on what is currently known about pediatric meningiomas and opportunities for future directions.

Neurocognitive outcomes after proton radiation for pediatric brain tumors.

9508 Background: Radiation therapy is integral in treatment of pediatric brain tumors. However, conventional photon radiation is associated with long-term neurocognitive sequelae, including decreme...

DAMD to Do Better!

DAMD, a high-throughput platform for assessing DNA methylation changes, provides new insights into the development and treatment of pediatric brain tumors.

Magnetic Resonance Diffusion Tensor Imaging of the Optic Nerves to Guide Treatment of Pediatric Suprasellar Tumors

Background/Aims: As a preoperative planning tool, conventional magnetic resonance (MR) imaging may have limited value in differentiating tumors from white matter tracts. MR diffusion tensor imaging (MRDTI) has become a useful tool for evaluating white matter tracts in relation to surrounding structures and has been used in surgical planning for brain tumors involving white matter. We investigated the use of DTI of the optic nerves in surgical planning for pediatric suprasellar tumors. Methods: We present findings in 10 pediatric control patients and 2 cases of pediatric suprasellar tumors in which a routine 6-direction DTI of the brain was performed at 3 T. Postprocessing permitted the study of the diffusion tensor parameters, as well as the tractography, of the optic nerves. Results: The control patients demonstrated the optimization of the technique and permitted the quantitation of fractional anisotropy and apparent diffusion coefficient values. The tumor cases demonstrated the utility of optic nerve DTI to differentiate between optic nerves and suprasellar/chiasmatic brain tumors. Conclusions: A routine 6-direction DTI of the pediatric brain at 3 T permits a detailed DTI study of the optic nerves. Optic nerve tractography can be used to aid in the evaluation and treatment of pediatric brain tumors in the area of the optic chiasm.

Growth Hormone Therapy and the Risk of Tumor Recurrence after Brain Tumor Treatment in Children

To assess the effect of human growth hormone (hGH) therapy and other factors on tumor recurrence after treatment of pediatric brain tumors (BTs), we retrospectively analyzed data from 108 craniopharyngioma, medulloblastoma, and ependymoma patients. Risk factors were identified using multifactorial univariate regression analysis. Recurrences occurred in 41 and second malignant neoplasms in 4 patients. There were significant correlations for completeness of tumor removal and recurrence-free survival (RFS). 13/44 hGH-treated and 28/59 non-hGH-treated children relapsed. This difference was found only for medulloblastomas and accounted for by higher rates of incomplete tumor removal in non-hGH patients. Craniopharyngioma recurrence correlated only with RFS. Malignant BT recurrence correlated with completeness of tumor removal, chemotherapy, and RFS. 4 children developed SMNs, 3/4 after hGH therapy. Our regression model yielded accurate within-sample prediction of recurrence for 90% of the study population. We conclude that hGH therapy after treatment of pediatric BTs does not increase tumor recurrence risk.

Treatment of Early Childhood Medulloblastoma by Postoperative Chemotherapy Alone—A Critical Review

Despite comprehensive treatment with surgery, radiation, and chemotherapy, medulloblastoma remains the most common malignant brain tumor in children with a five-year disease free survival rate of only 40% in those less than 10 years of age. Although adjuvant regimens are an integral component in patient management, radiotherapy in very young children is limited by the susceptibility of the immature brain to radiation-induced cognitive deficits. Thus, the development of an effective adjuvant protocol employing chemotherapy alone is of substantial interest. Rutkowski and colleagues published the results of their trial investigating the treatment of medulloblastoma solely with postoperative chemotherapy (Rutkowski et al. Treatment of Early Childhood Medulloblastoma by Postoperative Chemotherapy Alone. N Engl J Med. 2005;352(10): 978–986). In this multi-institutional clinical trial, 43 patients with histologically confirmed medulloblastoma were treated after surgery with an intensive chemotherapy protocol, consisting of three cycles of intravenous cyclophosphamide, vincristine, methotrexate, carboplatin, and etoposide, as well as intraventricular methotrexate. Results were as follows: in children with complete resection, partial resection, and macroscopic metastases, the five-year progression-free and overall survival rates were 82% and 93%, 50% and 56%, and 33% and 38%, respectively. Furthermore, desmoplastic histology, metastatic disease, and age less than two years were found to be independent prognostic factors for tumor relapse and poor survival. Of note, there were no instances of unexpected toxicity, with only asymptomatic leukoencephalopathy occurring in the majority of patients. Although the mean IQ of patients in this cohort was significantly lower than that of healthy, matched controls, it was higher than that of patients receiving cerebral radiation. Based on these findings, the authors concluded that in young children without metastases, chemotherapy may be used alone as adjuvant treatment for medulloblastoma, especially after gross total resection or those with desmoplastic variants, which portends a more favorable prognosis. This article highlights the growing importance of chemotherapy in the treatment of pediatric brain tumors, and represents a substantial step forward in the management of medulloblastoma. In the past, postoperative radiotherapy was frequently used in this patient population. Although highly effective, the risk of permanent cognitive side effects severely limits its use in children younger than five years of age. In such cases, chemotherapy may be employed to delay neuraxis irradiation. This study, which is the largest conducted to date in children <3 years old, demonstrates that patients receiving intensive chemotherapy may not only achieve excellent outcomes, but may also avoid the need for radiotherapy all together. As expected, cognitive testing in this cohort demonstrated milder side effects from chemotherapy than radiotherapy. It is important to note, however, factors other than radiation therapy may impact on quality of life and neuropsychiatric development. Regardless, the authors’ findings have implications for the current management guidelines of pediatric CNS malignancies by supporting the notion that radiotherapy may be avoided in young children without compromising prognosis.

Treatment-related Myelodysplastic Syndrome After Temozolomide Use in a Child

Temozolomide is an effective alkylating agent that is increasingly used for the treatment of pediatric brain tumors. Secondary, or treatment-related, myelodysplasia is a life-threatening complication of alkylating chemotherapy and has been reported in children with brain tumors after treatments other than temozolomide. We describe for the first time a case of temozolomide-related myelodysplasia in a child.

Chemotherapy for Malignant Brain Tumors of Childhood

During the past 3 decades, chemotherapeutic agents for the treatment of pediatric brain tumors have been extensively evaluated in a myriad of schedules, doses, and combinations. Remarkable advances in outcome have been achieved for certain children, notably those with medulloblastoma, but with a high cost to quality of life. In addition, the success achieved for medulloblastoma is offset by lack of progress for high-grade glioma. Despite intensive investigation, no single chemotherapeutic regimen stands out for children with high-grade glioma, with most succumbing to their disease. Further treatment intensification using conventional nonspecific chemotherapy is more likely to result in additional toxicity without major advances in survival. Genome-wide analysis using microarray technology has contributed significantly to our understanding of tumor biology, shifting the focus onto novel agents that target molecular changes crucial for tumor proliferation or survival. These selective agents are likely to be less toxic to normal cells and more effective.

Treatment of pediatric brain tumors

Over the past decades considerable advances have been made in neurosurgery, radiotherapy and chemotherapy resulting in improved survival and cure rates for children with brain tumors. Here we review four of the most common subtypes of pediatric brain tumors, low-grade and high-grade astrocytomas, medulloblastomas and ependymomas, highlighting their molecular features regarding their tumor biology, and promising potential therapeutic targets that may hold promise for finding new "molecular targeted" drugs. Importantly, appropriate clinical trial design will play a critical role in the evaluation of new and novel treatment approaches for pediatric brain tumors.

Radiotherapy for pediatric brain tumors: when and how

Radiotherapy plays a central role in the treatment of pediatric brain tumors. Historically, surgical resection alone was the mainstay of treatment for pediatric CNS malignancies. During the past 75 years, radiotherapy has been incorporated into the upfront treatment of many pediatric brain tumors either as adjuvant therapy for resected tumors, definitive treatment for unresectable malignancies or as prophylactic therapy for occult microscopic disease. Many CNS malignancies, which were once universally fatal are now curable with multimodality approaches that integrate surgery, chemotherapy and radiotherapy. Unfortunately, the long-term CNS side effects of radiotherapy remain a major obstacle for survivors of childhood tumors. In this article we will discuss these issues in detail and summarize the ongoing efforts to reduce the risks of these toxicities.

Late Onset Psychosis in Survivors of Pediatric Central Nervous System Malignancies

Late Onset Psychosis in Survivors of Pediatric Central Nervous System Malignancies

Commentary: Lessons in Pediatric Neuropsycho-Oncology: What We've Learned Since Johnny Gunther

In his paper, ‘‘Lessons in Pediatric NeuropsychoOncology: What We’ve Learned Since Johnny Gunther’’, Ris (2007) successfully accomplishes a formidable task. He provides a biographical and literary anchor that allows for the succinct summary of the history of neurooncological treatment, current status and standard of care, recent innovations and advances in the treatment of pediatric brain tumors. He also presents important information on current directions in both the measurement of neurocognitive late effects, and importantly, work that is being done to reduce the neurocognitive complications associated with the treatment of many childhood brain tumors. This is a brief, concise but comprehensive presentation. I do not believe that I have ever read an article that covered so much scientific ground in such a brief presentation. In this sense, the review raises the benchmark for literature summaries. Ris’s (2007) introduction to the paper begins with a reminder of the tragedy of childhood brain tumors that was so aptly and poignantly presented in the 1949 book, Death Be Not Proud written by the father of an adolescent who died from a particularly malignant brain tumor, glioblastoma multiforme. I was immediately struck by this reference because the book was required reading in one of my junior high school English classes. I had completely forgotten about this memoir. It is a wonderful book, and I do not know if it is still required reading in grade school, but if the reader of this commentary is not familiar with the book, he/she should immediately purchase and read it. Since 1949, neuro-oncologists have made incredible advances in the treatment of childhood brain tumors, but brain tumors remain a malignancy that is associated with significant neurocognitive and psychosocial late effect complications. While treatment advances are improving long-term survival, the childhood brain tumors remain a disease process that present a daunting challenge for all medical professionals in the area of pediatric oncology. Advances in treatment have occurred with many childhood brain tumors, but as Dr Ris reminds us, glioblastoma multiforme continues to be associated with only a 4–16% incidence of long-term disease-free survival. The article begins in the time period of John Gunther Jr’s diagnosis, treatment, and death, and then proceeds to review advances in the treatment of both brain tumors and the leukemias throughout the 1970s, 1980s and 1990s and brings us up-to-date regarding the current standard of care, and also late effects research.

Advances in treatment of pediatric brain tumors

Advances in treatment of pediatric brain tumors

Advances in Treatment of Pediatric Brain Tumors

The long-term survival of children with brain tumor has improved considerably in the last three decades, owing to advances in neuroimaging, neurosurgical, and radiation therapy modalities, coupled with the application of conventional chemotherapy. MRI, MR spectroscopy and diffusion-weighted MRI have contributed to more accurate diagnosis, prognostication and better treatment planning. Neurosurgical treatment has been advanced by the use of functional MRI, and intraoperative image-guided stereotactic techniques and electrophysiologic monitoring. The use of 3-D conformal and intensity-modulated radiation therapy, stereotactic radiosurgery, and radiosensitizing agents has made radiation therapy safer and more effective. Conventional chemotherapy, administered either alone or combined with radiation therapy has improved survival and quality of life of children with brain tumors. These improved outcomes have also occurred, due, in part, to their treatment on collaborative national and international studies. Recent promising diagnostic and therapeutic strategies have resulted from advances in understanding molecular brain tumor biology. Important new approaches include the refinement of drug-delivery strategies, the evaluation of biologic markers to stratify patients for optimal treatment and to exploit these molecular differences using "targeted" therapeutic strategies. These approaches include blocking tumor cell drug resistance mechanisms, immunotherapy, inhibition of molecular signal transduction pathways important in tumorigenesis, anti-angiogenic therapy, and gene therapy. The thrust of such approaches for children with brain tumors is especially directed at reducing the toxicity of therapy and improving quality-of-life, as well as increasing disease-free survival.

Molecularly Targeted Therapy for Pediatric Brain Tumors

Treatment of pediatric brain tumors remains a challenge because of the toxicity associated with conventional treatment and the relative resistance of tumors at the time of recurrence. The traditional approach of administering cytotoxic agents at the maximum tolerated dose is being supplanted by the development of molecularly targeted agents aimed at critical cellular changes that are responsible for the growth and spread of cancer cells. These agents theoretically should be more specific for tumor cells and less toxic to normal cells. While the idea of targeted therapy has generated much excitement in the oncology community, the degree of benefit to patients with central nervous system (CNS) tumors remains unclear. Numerous challenges remain in the development of these agents, including identification of meaningful targets, delivery of agents in sufficient quantity at the target site, and determination of any biologic response to these agents. This article discusses the rationale behind several of these agents and their use in pediatric patients with brain tumors.

Response to chemotherapy of a radiation-induced glioblastoma multiforme

Radiation-induced glioblastoma multiforme (GBM) is particularly resistant to treatment and therapeutic options are limited. We report a patient with a radiation-induced GBM who had a complete response to carmustine and survived for 44 months. Case report of a 38-year-old man with a radiation-induced GBM that responded to carmustine. Our patient developed a left occipital GBM 35 years after a left cerebellar astrocytoma was treated with surgery and radiation therapy (4500 rad). The GBM was treated with subtotal resection followed by four cycles of carmustine; a complete response was achieved. He relapsed 34 months after diagnosis and with further surgery survived 44 months from his diagnosis of GBM. GBMs may be a late complication of radiation treatment for pediatric brain tumors. If further radiotherapy is not a therapeutic option, chemotherapy may result in prolonged survival.

Analysis of interleukin-13 receptor alpha2 expression in human pediatric brain tumors.

Compared with normal brain tissue cells, human malignant glioma cells express higher levels of interleukin-13 receptor (IL-13R). However, whether this receptor is expressed in situ has not been carefully examined. With IL-13R-targeted cytotoxin (IL13-PE38QQR, comprising IL-13 and a mutated form of Pseudomonas exotoxin [PE]) being tested in three Phase I/II clinical trials for the treatment of adult human glioma, and with pediatric studies being planned, the authors set out to analyze pediatric brain tumor tissue specimens for the expression of IL-13R. Using in situ hybridization and immunohistochemical staining, the authors examined 58 pediatric brain tumor specimens for expression of the predominant IL-13 binding and internalizing protein (IL-13Ralpha2) chain at the mRNA and protein levels. Overall, approximately 83% of pediatric brain tumor samples expressed IL-13Ralpha2. One hundred percent (11 of 11) high-grade astrocytoma, 79% (26 of 33) low-grade astrocytoma, 67% (4 of 6) medulloblastoma, and 67% (2 of 3) ependymoma samples were positive for IL-13Ralpha2. Among IL-13Ralpha2-positive samples, 88% (42 of 48 samples) had positive expression in > or = 50% of all tumor fields. The results obtained using both assays were consistent with each other. The current study established that pediatric brain tumor specimens expressed the IL-13Ralpha2 chain. Because the IL-13Ralpha2 chain is a major binding component of the IL-13R complex, these results suggest that the targeting of IL-13R may represent a useful approach for the treatment of pediatric brain tumors.

833 The Use of Intraoperative Magnetic Resonance Imaging for the Treatment of Pediatric Brain Tumors

833 The Use of Intraoperative Magnetic Resonance Imaging for the Treatment of Pediatric Brain Tumors

Growth Failure After Treatment of Pediatric Brain Tumors

Primary brain tumors are the most common solid tumors that occur in childhood. With improved management of these tumors, there are more survivors with long-term sequelae of radiation and chemotherapy including growth failure. The aim of this study was to assess growth prospectively in children with nonpituitary-related primary brain tumors. Forty-one children 3.1 to 13.8 years of age diagnosed consecutively between 1989 and 1992 with a primary nonpituitary-related brain tumor were studied. Of 34 prepubertal children, 14 (41%) were diagnosed as having growth hormone (GH) deficiency. All 14 children were treated with cranial irradiation. During the first year from completion of brain tumor therapy, the annual height velocity of those children confirmed subsequently as being GH-deficient was 3.06 +/- 1.19 cm compared with 5.29 +/- 2.21 cm for those who were not GH-deficient. During the second year, the annual height velocity was 3.29 +/- 1.14 cm per year for the GH-deficient group compared with 5.48 +/- 1.24 cm per year for the non-GH-deficient group. All children with GH deficiency received cranial irradiation and chemotherapy. Two of 34 children developed precocious puberty. Primary hypothyroidism was diagnosed in 6 of 41 children (12%). We conclude that GH deficiency and primary hypothyroidism are common after cranial irradiation and chemotherapy for nonpituitary-related brain tumors. Linear growth appears to reflect GH status accurately in children with brain tumors. Precise auxologic evaluation is simple and noninvasive and may reflect more accurately GH status than provocative GH testing. These findings reflect the need for prospective growth monitoring of children with nonpituitary-related brain tumors treated with cranial irradiation and chemotherapy. Early diagnosis of GH deficiency facilitates early initiation of GH therapy and optimization of final height.