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Background Diffuse intrinsic pontine glioma (DIPG) is a devastating cancer of childhood and adolescence. Methods The study included patients between 3 and 20 years with clinically and radiologically confirmed DIPG. Primary endpoint was 6-month progression-free survival (PFS) following administration of nimotuzumab in combination with external beam radiotherapy (RT). Nimotuzumab was administered intravenously at 150 mg/m 2 weekly for 12 weeks. Radiotherapy at total dose of 54 Gy was delivered between week 3 and week 9. Response was evaluated based on clinical features and MRI findings according to RECIST criteria at week 12. Thereafter, patients continued to receive nimotuzumab every alternate week until disease progression/unmanageable toxicity. Adverse events (AE) were evaluated according to Common Terminology Criteria for Adverse Events (CTC-AE) Version 3.0 (CTC-AE3). Results All 42 patients received at least one dose of nimotuzumab in outpatient settings. Two patients had partial response (4.8%), 27 had stable disease (64.3%), 10 had progressive disease (23.8%) and 3 patients (7.1%) could not be evaluated. The objective response rate (ORR) was 4.8%. Median PFS was 5.8 months and median overall survival (OS) was 9.4 months. Most common drug-related AEs were alopecia (14.3%), vomiting, headache and radiation skin injury (7.1% each). Therapy-related serious adverse events (SAEs) were intra-tumoral bleeding and acute respiratory failure, which were difficult to distinguish from effects of tumor progression. Conclusions Concomitant treatment with RT and nimotuzumab was feasible in an outpatient setting. The PFS and OS were comparable to results achieved with RT and intensive chemotherapy in hospitalized setting.

Radiotherapy of tumours proximal to normal CNS structures is limited by the sensitivity of the normal tissue. Prior to the development of prophylactic strategies or treatment protocols a detailed understanding of the mechanisms of radiation induced CNS toxicity is mandatory. Histological analysis of irradiated CNS specimens defines possible target structures prior to a delineation of cellular and molecular mechanisms. Several lesions can be distinguished: Demyelination, proliferative and degenerative glial reactions, endothelial cell loss and capillary occlusion. All changes are likely to result from complex alterations within several functional CNS compartments. Thus, a single mechanism responsible cannot be separated. At least four factors contribute to the development of CNS toxicity: (1) damage to vessel structures; (2) deletion of oligodendrocyte-2 astrocyte progenitors (O-2A) and mature oligodendrocytes; (3) deletion of neural stem cell populations in the hippocampus, cerebellum and cortex; (4) generalized alterations of cytokine expression. Several underlying cellular and molecular mechanisms involved in radiation induced CNS toxicity have been identified. The article reviews the currently available data on the cellular and molecular basis of radiation induced CNS side effects. © 2001 Cancer Research Campaign http://www.bjcancer.com

Supratentorial white matter is an important part of the brain and a major site of detrimental effects after whole brain radiotherapy (WBRT). It is not known if prevalence of metastases in white matter justifies standard inclusion of white matter in whole brain treatment. In this retrospective analysis we examined the frequency of metastasis in supratentorial deep cerebral white matter with cerebral magnetic resonance imaging (MRI). Deep white matter (DWM) was defined as white matter in corpus callosum with forceps anterior and posterior and centrum semiovale. Lesions extending from grey matter, gyrus or ventricles into white matter were not classified as DWM metastases. Brain MRI of 198 patients from two centres were analyzed. In total 1330 metastases were counted and only 4.6 % were located in DWM. Metastases in DWM were small (median diameter 6 mm). Only 1/41 patients (2 %) with a singular metastasis had a DWM metastasis, 2/35 patients (6 %) with 2 metastases had a DWM metastasis, 14/79 patients (18 %) with 3–9 metastases and 12/43 patients (28 %) with >9 metastases had a single or more DWM metastases (p = 0.003). There appeared to be tumor related differences with renal cell carcinoma showing significantly more DWM metastasis (6/17, 35 %), than NSCLC (11/85, 13 %, p = 0.024), breast cancer (1/20, 5 %, p = 0.019) or colorectal cancer (0/10, 0 %, p = 0.033). Overall, relevant preservation of DWM from metastases, especially in oligometastatic disease, was shown. This implies that DWM in patients with only few brain metastases is unnecessarily damaged by conventional WBRT.

Purpose We evaluated clinical outcomes in the subset of patients who underwent radiotherapy (RT) due to progressive pilocytic astrocytoma within the Multicenter Treatment Study for Children and Adolescents with a Low Grade Glioma HIT-LGG 1996. Patients and methods Eligibility criteria were fulfilled by 117 patients. Most tumors (65 %) were located in the supratentorial midline, followed by the posterior fossa (26.5 %) and the cerebral hemispheres (8.5 %). Median age at the start of RT was 9.2 years (range 0.7–17.4 years). In 75 cases, external fractionated radiotherapy (EFRT) was administered either as first-line nonsurgical treatment (n = 58) or after progression following primary chemotherapy (n = 17). The median normalized total dose was 54 Gy. Stereotactic brachytherapy (SBT) was used in 42 selected cases. Results During a median follow-up period of 8.4 years, 4 patients (3.4 %) died and 33 (27.4 %) experienced disease progression. The 10-year overall (OS) and progression-free survival (PFS) rates were 97 and 70 %, respectively. No impact of the RT technique applied (EFRT versus SBT) on progression was observed. The 5-year PFS was 76 ± 5 % after EFRT and 65 ± 8 % after SBT. Disease progression after EFRT was not influenced by gender, neurofibromatosis type 1 (NF1) status, tumor location (hemispheres versus supratentorial midline versus posterior fossa), age or prior chemotherapy. Normalized total EFRT doses of more than 50.4 Gy did not improve PFS rates. Conclusion EFRT plays an integral role in the treatment of pediatric pilocytic astrocytoma and is characterized by excellent tumor control. A reduction of the normalized total dose from 54 to 50.4 Gy appears to be feasible without jeopardizing tumor control. SBT is an effective treatment alternative.

The prognosis of high-grade glioma in children is poor. Interferon-gamma may increase the immune surveillance of glioma cells. Earlier clinical evidence had shown that low dose cyclophosphamide (CPM) increased immune response. After induction treatment with simultaneous radiation and chemotherapy, patients were treated with individually increasing interferon-gamma (IFN-gamma) doses starting from 25 microg/m2/d s.c. increasing up to a maximum of 175 microg/m2/d within 7 weeks. Cyclophosphamide was given at 300 mg/m2 i.v. every 21 days. Forty pediatric glioma patients were enrolled (median age: 8.5 year, male: n = 22). Tumor locations included cerebral cortex (n = 8), basal ganglia (n = 4), brainstem (n = 24), cerebellum (n = 3), spinal cord (n = 1). Histologies were GBM (n = 14), AA (n = 14), LGG (n = 2, diffuse intrinsic pontine glioma). There was grade IV toxicity for thrombocytopenia (10%) and leucopenia (2.5%), grade III toxicity for central nervous (2.5%) and hepatic (5%) side effects, no toxic death. The observation time of the six surviving patients was: 1.2, 1.9, 4.2, 4.4, 4.6 and 4.7 years respectively. The median overall survival (1 year) was not significantly different from a historical control group (0.8 years). The survival of pontine gliomas appeared even inferior when compared to the previous protocol (n.s.). Maintenance treatment with IFN-gamma and low dose CPM has no sufficient beneficial effect for the treatment of high-grade glioma.

Background: High-grade glioma (HGG) of the cerebellum accounts for only 5% of paediatric HGG. Since little is known about these tumours, the present study aimed at their further characterisation. Methods: Twenty-nine paediatric patients with centrally reviewed cerebellar HGG were identified from the HIT-GBM/HIT-HGG database. Clinical and epidemiological data were compared with those of 180 paediatric patients with cortical HGG. Results: Patients with cerebellar tumours were younger (median age of 7.6 vs 11.7 years, P =0.028), but both groups did not differ significantly with regard to gender, tumour predisposing syndromes, secondary HGG, primary metastasis, tumour grading, extent of tumour resection, chemotherapy regimen, or radiotherapy. Except for an increased incidence of anaplastic pilocytic astrocytoma (APA) in the cerebellar subset (20.7% vs 3.3%; P <0.001), histological entities were similarly distributed in both groups. As expected, tumour grading had a prognostic relevance on survival. Compared with cortical HGG, overall survival in the cerebellar location was significantly worse (median overall survival: 0.92±0.02 vs 2.03±0.32 years; P =0.0064), and tumour location in the cerebellum had an independent poor prognostic significance as shown by Cox-regression analysis ( P =0.019). Conclusion: High-grade glioma represents a group of tumours with an obviously site-specific heterogeneity associated with a worse survival in cerebellar location.

In children, treatment regimen for high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG) are generally not stratified according to disease stage. The hypothesis was that secondary disseminating disease (SDD) in children with HGG is related to an even worse outcome. Description of SDD pattern was performed. In total, 270 children with newly diagnosed HGG or DIPG were eligible for retrospective analysis of SDD. Medical and computer records of these patients were reviewed for demographic characteristics, sites of dissemination, prognostic variables. Forty-six (17%) of the 270 patients had developed SDD. The median time to SDD was 8.2 months. The median overall survival (OS) after dissemination was 3.2 months. The SDD was located parenchymal in the supratentorial (34.8%), infratentorial (6.5%), supratentorial and infratentorial (19.6%), spinal (10.9%), spinal and cerebral (6.5%) regions of the CNS, or leptomeningeal (21.7%). For HGG patients, the median OS was shorter among patients with SDD than among patients without SDD (1.02 vs 1.41 years, P =0.0495). In the group of patients with SDD, patients with cerebrospinal fluid dissemination had a worse outcome compared with patients with parenchymal metastases. Summarising, SDD is a negative prognostic factor for patients with HGG outside the pons. Treatment stratification should be considered.

Adult medulloblastoma is a rare tumor with few retrospective studies published so far. The role of adjuvant chemotherapy or chemotherapy at relapse is unclear. This study reports therapy and outcome in all adult (>or=16 years old) medulloblastoma (n=34) and supratentorial primitive neuroectodermal tumor (PNET) patients (n=2) treated in 2 neuro-oncological centers between 1976 and 2002. The median age was 24.5 years (range 16-76). After resection, 16 patients were treated with craniospinal radiotherapy alone, 20 patients also received adjuvant chemotherapy (8 vincristine, CCNU, cisplatin; 7 methotrexate alone or methotrexate/vincristine-based polychemotherapy; 5 other protocols). Median survival in the whole cohort was 126 months (2+ - 200+months). Five-year and 10-year survival rates were 79 % and 56%. Adjuvant chemotherapy was associated with a non-significant trend to prolonged survival (relative risk (RR) 1.89; p=0.068). The median progression-free survival (PFS) after primary therapy was 83 months. At relapse, 10 of 12 evaluable patients achieved a complete response upon second-line therapy. The median survival times from first (n=17) and second relapse (n=9) were 21 months (0-67+ months; 5/17 without second relapse) and 20 months (1-29 months). Cox regression analysis revealed the infiltration of the floor of the 4(th) ventricle at diagnosis as the only therapy-independent prognostic factor (RR 0.48; p=0.03). In conclusion, adjuvant chemotherapy may prolong survival in adult medulloblastoma patients. Moreover, second-line therapy may be beneficial for these patients. As in pediatric medulloblastoma patients, primary infiltration of the floor of the 4(th) ventricle indicates a poor prognosis.

Background High-grade (HGG) and diffuse intrinsic pontine gliomas (DIPG) with primary metastatic spread are extremely rare and have a dismal prognosis. Analogous to simultaneous radiochemotherapy in non-metastatic HGG and DIPG, concurrent craniospinal irradiation (CSI) and metronomic temozolomide (metroTMZ) may represent a reasonable therapeutic approach. However, the antitumor efficacy and toxicity of this treatment still have to be investigated. Patients and methods Between March 2007 and December 2012, six children with primary metastatic HGG (n = 4) or DIPG (n = 2) received CSI and concurrent metroTMZ based on individual treatment recommendations and, in some cases, within the HIT-HGG 2007 multicenter trial. Outcome and treatment-related toxicities were evaluated. Results All patients received irradiation to the entire craniospinal axis (35.2 Gy, n = 5; 36 Gy, n = 1:) and 5 received a local boost to macroscopic tumor deposits. Simultaneously, metroTMZ (75 mg/m 2 /day, n = 5; 60 mg/m 2 /day, n = 1) was administered. Additionally, 1 patient received nimotuzumab once per week. Within a median follow-up of 10.0 months (range 6.5–18.7 months), all patients experienced disease progression and 5 patients died. Median progression-free survival was 4.0 ± 0.8 months (range 2.4–10.7 months) and median overall survival was 7.6 ± 3.5 months (range 4.0–17.6 months). Acute myelosuppression most severely limited application of this aggressive treatment strategy. Severe hematotoxicities (≥ grade 3) occurred in all patients and metroTMZ had to be interrupted or discontinued in 4 out of 6 cases. Conclusion Concurrent CSI and metroTMZ might represent a feasible treatment approach for primary metastatic HGG and DIPG. On the basis of our experience, severe but manageable acute hematotoxicity has to be expected. An international effort is warranted to reassess the efficacy and toxicity of this approach within a prospective study.