The effectiveness and safety of proton beam radiation therapy in children and young adults with Central Nervous System (CNS) tumours: a systematic review.

BACKGROUND: Central nervous system (CNS) tumours account for around 25% of childhood neoplasms. With multi-modal therapy, 5-year survival is at around 75% in the UK. Conventional photon radiotherapy has made significant contributions to survival, but can be associated with long-term side effects. Proton beam radiotherapy (PBT) reduces the volume of irradiated tissue outside the tumour target volume which may potentially reduce toxicity. Our aim was to assess the effectiveness and safety of PBT and make recommendations for future research for this evolving treatment. METHODS: A systematic review assessing the effects of PBT for treating CNS tumours in children/young adults was undertaken using methods recommended by Cochrane and reported using PRISMA guidelines. Any study design was included where clinical and toxicity outcomes were reported. Searches were to May 2021, with a narrative synthesis employed. RESULTS: Thirty-one case series studies involving 1731 patients from 10 PBT centres were included. Eleven studies involved children with medulloblastoma / primitive neuroectodermal tumours (n = 712), five ependymoma (n = 398), four atypical teratoid/rhabdoid tumour (n = 72), six craniopharyngioma (n = 272), three low-grade gliomas (n = 233), one germ cell tumours (n = 22) and one pineoblastoma (n = 22). Clinical outcomes were the most frequently reported with overall survival values ranging from 100 to 28% depending on the tumour type. Endocrine outcomes were the most frequently reported toxicity outcomes with quality of life the least reported. CONCLUSIONS: This review highlights areas of uncertainty in this research area. A well-defined, well-funded research agenda is needed to best maximise the potential of PBT. SYSTEMATIC REVIEW REGISTRATION: PROSPERO-CRD42016036802.

DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies.

Molecular subclassification is rapidly informing the clinical management of medulloblastoma. However, the disease remains associated with poor outcomes and therapy-associated late effects, and the majority of patients are not characterized by a validated prognostic biomarker. Here, we investigated the potential of epigenetic DNA methylation for disease subclassification, particularly in formalin-fixed biopsies, and to identify biomarkers for improved therapeutic individualization. Tumor DNA methylation profiles were assessed, alongside molecular and clinical disease features, in 230 patients primarily from the SIOP-UKCCSG PNET3 clinical trial. We demonstrate by cross-validation in frozen training and formalin-fixed test sets that medulloblastoma comprises four robust DNA methylation subgroups (termed WNT, SHH, G3 and G4), highly related to their transcriptomic counterparts, and which display distinct molecular, clinical and pathological disease characteristics. WNT patients displayed an expected favorable prognosis, while outcomes for SHH, G3 and G4 were equivalent in our cohort. MXI1 and IL8 methylation were identified as novel independent high-risk biomarkers in cross-validated survival models of non-WNT patients, and were validated using non-array methods. Incorporation of MXI1 and IL8 into current survival models significantly improved the assignment of disease risk; 46 % of patients could be classified as 'favorable risk' (>90 % survival) compared to 13 % using current models, while the high-risk group was reduced from 30 to 16 %. DNA methylation profiling enables the robust subclassification of four disease subgroups in frozen and routinely collected/archival formalin-fixed biopsy material, and the incorporation of DNA methylation biomarkers can significantly improve disease-risk stratification. These findings have important implications for future risk-adapted clinical disease management.

MYC family amplification and clinical risk-factors interact to predict an extremely poor prognosis in childhood medulloblastoma.

The MYC oncogenes are the most commonly amplified loci in medulloblastoma, and have previously been proposed as biomarkers of adverse disease prognosis by us and others. Here, we report focussed and comprehensive investigations of MYCC, MYCN and MYCL in an extensive medulloblastoma cohort (n = 292), aimed to define more precisely their biological significance and optimal clinical application to direct improved disease risk-stratification and individualisation of therapy. MYCC and MYCN expression elevations were multifactorial, associated with high-risk (gene amplification, large-cell/anaplastic pathology (LCA)) and favourable-risk (WNT/SHH molecular subgroups) disease features. Highly variable cellular gene amplification patterns underlay overall MYC copy number elevations observed in tumour biopsies; we used these alternative measures together to define quantitative methodologies and thresholds for amplification detection in routinely collected tumour material. MYCC and MYCN amplification, but not gain, each had independent prognostic significance in non-infants (≥3.0-16.0 years), but MYCC conferred a greater hazard to survival than MYCN when considered across this treatment group. MYCN's weaker group-wide survival relationship may be explained by its pleiotropic behaviour between clinical disease-risk groups; MYCN predicted poor prognosis in clinical high-risk (metastatic (M+) or LCA), but not standard-risk, patients. Extending these findings, survival decreased in proportion to the total number of independently significant high-risk features present (LCA, M+ or MYCC/MYCN amplification). This cumulative-risk model defines a patient group characterised by ≥2 independent risk-factors and an extremely poor prognosis (<15% survival), which can be identified straightforwardly using the reported MYC amplification detection methodologies alongside clinical assessments, enabling targeting for novel/intensified therapies in future clinical studies.

Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups.

Medulloblastoma is heterogeneous, being characterized by molecular subgroups that demonstrate distinct gene expression profiles. Activation of the WNT or SHH signaling pathway characterizes two of these molecular subgroups, the former associated with low-risk disease and the latter potentially targeted by novel SHH pathway inhibitors. This manuscript reports the validation of a novel diagnostic immunohistochemical method to distinguish SHH, WNT, and non-SHH/WNT tumors and details their associations with clinical, pathological and cytogenetic variables. A cohort (n = 235) of medulloblastomas from patients aged 0.4-52 years was studied for expression of four immunohistochemical markers: GAB1, ß-catenin, filamin A, and YAP1. Immunoreactivity (IR) for GAB1 characterizes only SHH tumors and nuclear IR for ß-catenin only WNT tumors. IRs for filamin A and YAP1 identify SHH and WNT tumors. SHH, WNT, and non-SHH/WNT tumors contributed 31, 14, and 55% to the series. All desmoplastic/nodular (D/N) medulloblastomas were SHH tumors, while most WNT tumors (94%) had a classic phenotype. Monosomy 6 was strongly associated with WNT tumors, while PTCH1 loss occurred almost exclusively among SHH tumors. MYC or MYCN amplification and chromosome 17 imbalance occurred predominantly among non-SHH/WNT tumors. Among patients aged 3-16 years and entered onto the SIOP PNET3 trial, outcome was significantly better for children with WNT tumors, when compared to SHH or non-SHH/WNT tumors, which showed similar survival curves. However, high-risk factors (M+ disease, LC/A pathology, MYC amplification) significantly influenced survival in both SHH and non-SHH/WNT groups. We describe a robust method for detecting SHH, WNT, and non-SHH/WNT molecular subgroups in formalin-fixed medulloblastoma samples. In corroborating other studies that indicate the value of combining clinical, pathological, and molecular variables in therapeutic stratification schemes for medulloblastoma, we also provide the first outcome data based on a clinical trial cohort and novel data on how molecular subgroups are distributed across the range of disease.

The addition of high-dose tamoxifen to standard radiotherapy does not improve the survival of patients with diffuse intrinsic pontine glioma.

The study aimed to examine the tolerability of the combination of radiotherapy and tamoxifen and the effect on median and event free survival as well as collecting data on the use of steroids in this population. 31 patients with diffuse intrinsic pontine glioma, diagnosed on clinical and radiological criteria, were treated with high-dose oral tamoxifen (120 mg/m(2)/day) given concomitantly with standard dose radiotherapy (54 Gy in 1.8 Gy fractions over 6 weeks). Results Tamoxifen was well tolerated with no grade 3 or 4 CTC toxicity reported. At 1 year, the progression free and event free survival were 3.2% (95% CI: 0.2-14.1%), and at 6 months 19.4% (CI: 7.9% to 34.6%). The overall survival at 1 year was 16.1% (CI: 5.9-30.9%) with median survival 6.32 months. In this study, in which tamoxifen was used in conjunction with radiotherapy, progression free survival was shown to be less good when compared with historical data HR = 3.1 (CI: 1.7-5.7). There was no significant reduction in overall survival. The addition of high-dose tamoxifen, although well tolerated, confers no clinical benefit to patients treated with diffuse intrinsic pontine glioma treated with standard radiotherapy.

Outcomes of non-anaplastic stage III and 'inoperable' Wilms tumour treated in the UKW3 trial.

BACKGROUND AND PURPOSE: To describe the outcome of patients with stage III Wilms tumours (WT) treated in the UKW3 trial. MATERIAL AND METHODS: Patients with a pathologically confirmed stage III non-anaplastic WT at nephrectomy (Group A) or with an 'inoperable' tumour at diagnosis managed by biopsy and pre-operative chemotherapy (Actinomycin D-Vincristine-Doxorubicin) but stage I or II at subsequent nephrectomy (Group B) were included. RESULTS: The 4-year overall (OS)/event free survival (EFS) for Group A (n = 117) patients was 90%(95%CI:83-94)/81%(CI:73-87) and for Group B (n = 32) 94%(CI:77-98)/88%(CI:70-95). The 4-year OS/EFS of patients with pathological stage III WT according to whether they received flank/abdominal radiotherapy (95 patients) or not (37 patients, 22 from UKW3 pooled with 17 patients from UKW2) were 91%(CI:83-95)/82%(CI:73-89), and 84%(CI:67-92)/78%(CI:61-89), respectively. The 4-year OS/EFS for patients having one reason to be stage III versus two or three was 92%(CI:84-96)/83%(CI:73-90) and 85%(CI:70-93)/78%(CI:61-88), respectively. CONCLUSION: Our findings question the inclusion of biopsy or pre-operative chemotherapy as sole criterion for assigning a tumour stage III. Selected patients with pathological stage III WT can survive without radiotherapy. Whilst cautious interpretation is needed due to the post hoc nature of these analyses, further biological studies may better characterise those who could benefit from reduced therapy.

Nodule formation and desmoplasia in medulloblastomas-defining the nodular/desmoplastic variant and its biological behavior.

Among the variants of medulloblastoma in the current WHO classification of nervous system tumors, the desmoplastic variant, which has been reported to constitute 5%-25% of pediatric medulloblastomas, is defined by its nodular collections of neurocytic cells bounded by desmoplastic internodular zones. We have studied the frequency, morphological features and biological behavior of medulloblastomas in two contemporaneous SIOP/UKCCSG trial cohorts of children with medulloblastomas, CNS9102 (n = 315) and CNS9204 (n = 35), focusing on tumors with nodular and desmoplastic phenotypes. In children aged 3-16 years (CNS9102), the nodular/desmoplastic medulloblastoma represented 5% of all tumors, while in infants aged <3 years (CNS9204) this variant represented 57% of medulloblastomas. Using iFISH to detect molecular cytogenetic abnormalities in medulloblastomas with a nodular architecture, we demonstrated distinct genetic profiles in desmoplastic and non-desmoplastic (classic and anaplastic) tumors; in particular, abnormalities of chromosome 17 occurred in the latter, but not the former. Significantly different outcomes were demonstrated for classic, nodular/desmoplastic and large cell/anaplastic medulloblastomas in both cohorts. In conclusion, the nodular/desmoplastic medulloblastoma appears to have clinical, genetic and biological characteristics that set it apart from other variants of this tumor.

beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee.

PURPOSE: Identifying pathobiological correlates of clinical behavior or therapeutic response currently represents a key challenge for medulloblastoma research. Nuclear accumulation of the beta-catenin protein is associated with activation of the Wnt/Wg signaling pathway, and mutations affecting components of this pathway have been reported in approximately 15% of sporadic medulloblastomas. We tested the hypothesis that nuclear immunoreactivity for beta-catenin is a prognostic marker in medulloblastoma, and assessed the relationship between nuclear beta-catenin immunoreactivity and mutations of CTNNB1 and APC. PATIENTS AND METHODS: Medulloblastomas from children entered onto the International Society for Pediatric Oncology (SIOP)/United Kingdom Children's Cancer Study Group (UKCCSG) PNET3 trial (n = 109) were examined for beta-catenin immunoreactivity, and where tissue was available, evidence of CTNNB1 and APC mutations. The results were correlated with clinicopathologic variables, principally outcome. RESULTS: Children with medulloblastomas that showed a nucleopositive beta-catenin immunophenotype (27 of 109; 25%) had significantly better overall (OS) and event-free (EFS) survivals than children with tumors that showed either membranous/cytoplasmic beta-catenin immunoreactivity or no immunoreactivity (P = .0015 and P = .0026, respectively). For beta-catenin nucleopositive and nucleonegative medulloblastomas, 5-year OS was 92.3% (95% CI, 82% to 100%) versus 65.3% (95% CI, 54.8 to 75.7%), and 5-year EFS was 88.9% (95% CI, 77% to 100%) versus 59.5% (95% CI, 48.8 to 70.2%), respectively. Mutations in CTNNB1 were found exclusively among medulloblastomas that demonstrated nuclear beta-catenin immunoreactivity, but no evidence of APC mutation was found in these cases. All children with beta-catenin nucleopositive large cell/anaplastic medulloblastomas and beta-catenin nucleopositive medulloblastomas presenting with metastatic disease are alive at least 5 years postdiagnosis. CONCLUSION: Nuclear accumulation of beta-catenin appears to be a marker of favorable outcome in medulloblastoma, and should be investigated further in large group-wide trials.

Analysis of patients with supratentorial primitive neuro-ectodermal tumours entered into the SIOP/UKCCSG PNET 3 study.

The SIOP PNET 3 study was designed to determine whether 10 weeks of moderately intensive chemotherapy given after surgery and before radiotherapy (RT) would improve the outcome for patients with primitive neuroectodermal tumours (PNETs) compared with RT alone. Patients with a histological diagnosis of supratentorial PNET (StPNET) and no radiological evidence of metastatic disease were initially eligible for randomisation to either chemotherapy followed by craniospinal RT 35 Gy in 21 fractions with a boost of 20 Gy in 12 fractions to the primary site, or RT alone. In respect of the increasing recognition that StPNET were high-risk tumours, randomisation for this group closed in November 1999. This analysis includes both randomised and non-randomised patients with StPNET entered into the study database. Sixty-eight patients aged 2.9-16.6 years (median 6.5 years) were included in the analysis (chemotherapy+RT: 44, RT alone: 24). Fifty-four patients (79%) had a non-pineal and 14 (21%) a pineal site. At a median follow-up of 7.4 years, for all patients overall survival (OS) at 3 and 5 years was 54.4% and 48.3%, respectively. Event-free survival (EFS) at 3 and 5 years was 50.0% and 47.0%, respectively. There was no statistically significant difference in OS or EFS according to treatment received. OS (P=0.05) and EFS (P=0.03) were significantly better for patients with pineal primary sites. EFS for pineal tumours were 92.9% at 3 years and 71.4% at 5 years and for non-pineal primaries 40.7% at 3 years and 40.7% at 5 years. This study confirmed the relatively good survival for non-metastatic pineal PNETs but poor survival of non-pineal StPNETs. There was no evidence that pre-radiation chemotherapy improved outlook. Future treatment programs should be directed at the particular natural history of these tumours, to further define prognostic factors and to explore further biological characteristics.

Current developments in radiotherapy for paediatric brain tumours.

This review summarises current developments in radiation oncology and how they impact on the management of children with brain tumours. Improved understanding of radiobiology has led to attempts to improve the therapeutic ratio with hyperfractionated radiotherapy. Recent advances in planning and delivery of radiotherapy, including three-dimensional conformal radiotherapy, intensity modulated radiotherapy, and proton therapy allow a more precise localisation of the maximum dose region with maximum sparing of normal brain. Increasingly interactions between drugs and radiotherapy are exploited, but it is important to evaluate toxicity of combined modality therapy. The introduction of models to predict the impact of radiotherapy dose-volume parameters on long-term neuropsychological function will hopefully lead to further benefit with respect to sparing of normal tissue morbidity.

The effectiveness and safety of proton beam radiation therapy in children with malignant central nervous system (CNS) tumours: protocol for a systematic review.

BACKGROUND: The aim of this study is to use a systematic review framework to identify and synthesise the evidence on the use of proton beam therapy (PBT) for the treatment of children with CNS tumours and where possible compare this to the use of photon radiotherapy (RT). METHODS: Standard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Twelve electronic databases have been searched, and further citation, hand searching and reference checking will be employed. Studies assessing the effects of PBT used either alone or as part of a multimodality treatment regimen in children with CNS tumours will be included. Relevant economic evaluations will also be identified. The outcomes are survival (overall, progression-free, event-free, disease-free), local and regional control rates, short- and long-term adverse events, functional status measures and quality of survival. Two reviewers will independently screen and select studies for inclusion in the review. All interventional study designs will be eligible for inclusion in the review. However, initial scoping searches indicate the evidence base is likely to be limited to case series studies, with no studies of a higher quality being identified. Quality assessment will be undertaken using pre-specified criteria and tailored to study design if applicable. Studies will be combined using a narrative synthesis, with differences in results between studies highlighted and discussed in relation to the patient population, intervention and study quality. Where appropriate, if no studies of a comparative design are identified, outcomes will be compared against a range of estimates from the literature for similar populations and treatment regimens from the best available evidence from studies that include the use of advanced conventional photon therapy. DISCUSSION: The evidence base for the use of PBT in children with CNS tumours is likely to be relatively sparse, highly heterogeneous and potentially of a low quality with small sample sizes. Furthermore, selection and publication biases may limit the internal and external validity of studies. However, any tentative results from the review on potential treatment effects can be used to plan better quality research studies that are of a design appropriate for outcome comparison with conventional therapy. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015029583.

Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study.

PURPOSE: To determine whether preradiotherapy (RT) chemotherapy would improve outcome for Chang stage M0-1 medulloblastoma when compared with RT alone. Chemotherapy comprised vincristine 1.5 mg/m2 weekly for 10 weeks and four cycles of etoposide 100 mg/m2 daily for 3 days, and carboplatin 500 mg/m2 daily for 2 days alternating with cyclophosphamide 1.5 g/m2. PATIENTS AND METHODS: Patients aged 3 to 16 years inclusive were randomly assigned to receive 35 Gy craniospinal RT with a 20 Gy posterior fossa boost, or chemotherapy followed by RT. RESULTS: Of 217 patients randomly assigned to treatment, 179 were eligible for analysis (chemotherapy + RT, 90 patients; RT alone, 89 patients). Median age was 7.67 years, and median follow-up was 5.40 years. Overall survival (OS) at 3 and 5 years was 79.5% and 70.7%, respectively. Event-free survival (EFS) at 3 and 5 years was 71.6% and 67.0%, respectively. EFS was significantly better for chemotherapy and RT (P =.0366), with EFS of 78.5% at 3 years and 74.2% at 5 years compared with 64.8% at 3 years and 59.8% at 5 years for RT alone. There was no statistically significant difference in 3-year and 5-year OS between the two arms (P =.0928). Multivariate analysis identified use of chemotherapy (P =.0248) and time to complete RT (P =.0100) as having significant effect on EFS. CONCLUSION: This is the first large multicenter randomized study to demonstrate improved EFS for chemotherapy compared with RT alone. It is anticipated that this regimen could reduce ototoxicity and nephrotoxicity compared with cisplatin-containing schedules. The importance of avoiding interruptions to RT has been confirmed.

Outcome for patients with metastatic (M2-3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy.

The aim of this study was to determine the outcome for patients with Chang stage M2-3 medulloblastoma (MB) treated with surgery and pre-radiotherapy (RT) chemotherapy (CT). Between 1992 and 2000, 68 patients aged 2.8-16.4 years (median 7.8 years) with M2-3 MB were treated with CT comprising vincristine, etoposide, carboplatin and cyclophosphamide. For 61 patients, CT was followed by craniospinal RT 35 Gy/21 fractions with a posterior fossa (PF) boost, 20 Gy/12 fractions. Twenty-four (35%) irradiated patients received a metastatic boost (mean dose to metastases 47.4 Gy, range 40.0-55.1 Gy). With 7.2-years of median follow-up, overall survival (OS) rates at 3 and 5 years were 50.0% (95% Confidence Interval (CI): 38.1-61.9%) and 43.9% (95% CI: 32.0-55.7%), respectively, event-free survival (EFS) rates at 3 and 5 years were 39.7% (95% CI: 28.1-51.3%) and 34.7% (95% CI: 23.2-46.2%), respectively. Univariate analysis did not demonstrate an impact of age, gender, M stage, extent of resection, RT duration or metastatic boost. For patients commencing RT within 110 days of surgery, EFS was significantly (P=0.04) worse than for those who commenced RT later than this. Response to pre-RT CT was assessable from institutional reports for 44 (65%) patients, and 17 (39%) had a complete response (CR), 15 (34%) a partial response (PR), 4 (9%) stable disease (SD) and 8 (18%) progression. Although CT improved outcome for M0-1 patients in the primitive neuroectodermal tumour (PNET-3) randomised study, and resulted in a high response rate in this study, there has been no apparent improvement in outcome for M2-3 patients when compared with earlier multi-institutional series. Newer approaches such as more intensive CT and RT need to be explored.

Radiotherapy for benign disease; assessing the risk of radiation-induced cancer following exposure to intermediate dose radiation.

Most radiotherapy (RT) involves the use of high doses (>50 Gy) to treat malignant disease. However, low to intermediate doses (approximately 3-50 Gy) can provide effective control of a number of benign conditions, ranging from inflammatory/proliferative disorders (e.g. Dupuytren's disease, heterotopic ossification, keloid scarring, pigmented villonodular synovitis) to benign tumours (e.g. glomus tumours or juvenile nasopharyngeal angiofibromas). Current use in UK RT departments is very variable. This review identifies those benign diseases for which RT provides good control of symptoms with, for the most part, minimal side effects. However, exposure to radiation has the potential to cause a radiation-induced cancer (RIC) many years after treatment. The evidence for the magnitude of this risk comes from many disparate sources and is constrained by the small number of long-term studies in relevant clinical cohorts. This review considers the types of evidence available, i.e. theoretical models, phantom studies, epidemiological studies, long-term follow-up of cancer patients and those treated for benign disease, although many of the latter data pertain to treatments that are no longer used. Informative studies are summarized and considered in relation to the potential for development of a RIC in a range of key tissues (skin, brain etc.). Overall, the evidence suggests that the risks of cancer following RT for benign disease for currently advised protocols are small, especially in older patients. However, the balance of risk vs benefit needs to be considered in younger adults and especially if RT is being considered in adolescents or children.

Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas.

Histopathologic assessment of 273 non-desmoplastic medulloblastomas (MBs) from children aged 3 to 16 years and entered into the SIOP/UKCCSG (International Society of Pediatric Oncology/United Kingdom Children's Cancer Study Group) PNET3 trial revealed that 47 (17%) fulfilled criteria for the recently proposed anaplastic variant. In addition, an anaplastic phenotype was focally present in all 5 (2%) large cell MBs from this series. Children with large cell MBs had the worst outcome, but there was also a significant difference between the event-free and overall survivals of children with classic MBs and those with anaplastic MBs. While objective morphometric analysis confirmed that subjective evaluation of nuclear size and variability contributed to the separation of MBs into classic, anaplastic, and large cell variants, these cytologic measures were not themselves prognostic indicators. However, anaplastic and classic MBs also possessed significantly different mitotic counts/indices, and these measures of proliferation were related to survival. Significant prognostic indicators in a multivariate survival analysis were histologic variant, metastases at presentation, and subtotal surgical excision of tumor. Our study supports the concept of an anaplastic variant among MBs, demonstrating that it has clinical utility.

Impact of radiotherapy parameters on outcome in the International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 study of preradiotherapy chemotherapy for M0-M1 medulloblastoma.

PURPOSE: To analyze the impact of radiotherapy (RT) parameters on outcome in a randomized study of pre-RT chemotherapy for M0-M1 medulloblastoma. METHODS AND MATERIALS: Patients were randomized to RT alone or RT preceded by chemotherapy with vincristine, etoposide, carboplatin, and cyclophosphamide. RT consisted of craniospinal RT, 35 Gy in 21 fractions, followed by a posterior fossa (PF) boost of 20 Gy in 12 fractions. The accuracy of cribriform fossa, skull base, and PF field placement was assessed. RESULTS: Between 1992 and 2000, 217 patients were randomized, of whom 179 were eligible for analysis. At a median follow-up of 5.4 years, the 3- and 5-year overall survival rate was 79.5% and 70.7%, respectively. The 3- and 5-year event-free survival (EFS) rate was 71.6% and 67.0%, respectively. EFS was significantly better for the chemotherapy plus RT group (3-year EFS rate 78.5% vs. 64.8%, p = 0.0366). Overall survival and EFS were significantly better for patients completing RT within 50 days compared with those taking >50 days to complete RT (3-year overall survival rate 84.1% vs. 70.9%, p = 0.0356, 3-year EFS rate 78.5% vs. 53.7%, p = 0.0092). Multivariate analysis identified the use of chemotherapy (p = 0.0248) and RT duration (p = 0.0100) as predictive of better EFS. Planning films were reviewed for 131 (74.4%) of 176 patients. Sixty-five (49.6%) had no targeting deviations and 58 (44.3%) had one or more deviations. PF recurrence occurred in 11 (34.4%) of 32 with a PF targeting deviation compared with 13 (16.3%) of 80 without (p = 0.043). No statistically significant impact of other targeting deviations on recurrence risk or EFS were found. CONCLUSION: The results of this study have confirmed the importance of the duration of RT for medulloblastoma. Also, attention to detail when planning RT is important, as illustrated in the case of PF field placement.

Quantitative assessment of inter-clinician variability of target volume delineation for medulloblastoma: quality assurance for the SIOP PNET 4 trial protocol.

BACKGROUND AND PURPOSE: To assess inter-clinician variability amongst specialist paediatric radiation oncologists in delineating clinical target volumes for treating medulloblastoma as a quality assurance exercise prior to the introduction of the SIOP PNET 4 trial protocol of conformal radiotherapy to the posterior fossa and tumour bed. PATIENTS AND METHODS: Participants from 17 UK centres attended an educational meeting and then completed a clinical planning exercise to outline: (1) the whole posterior fossa and (2) the tumour bed. Quantitative analysis of the volumes, lengths, spatial positioning and axial planes for each individual was carried out and variation between individuals analysed. RESULTS: Outlining of the posterior fossa was reasonably consistent, although most variation was seen in defining the superior border of the tentorium. A major difference was the decision whether or not to include the post-surgical meningocoele in the clinical target volume (CTV). The CTV for the tumour bed was under treated by all participants due to lack of inclusion of pre-operative tumour extent. CONCLUSIONS: This exercise demonstrated several ambiguities in the draft protocol and highlighted particular areas of inter-clinician variation. Consequently the protocol was revised and improved to take account of these findings. We recommend that planning exercises, in conjunction with education and training, should be implemented before the start of any new radiotherapy trial. In the future, the use of image transfer will allow prospective peer review of target volumes before treatment commences. These measures are essential to ensure that alterations in clinical practice are achieved in a uniform way.

Multifactorial uptake of Tc-99m methylene diphosphonate in chronic renal failure.

Soft-tissue calcifications are a frequent complication in patients with chronic renal failure. Numerous underlying factors are thought to favor their formation. A case is presented of a patient who was in end-stage renal failure, secondary to glomerulonephritis. A renal transplant had not been successful. She was on long-term dialysis and had suffered aluminum toxicity (positive desferrioxamine test). She complained of proximal myopathy and bone pain.