Phase II study of irinotecan in combination with temozolomide (TEMIRI) in children with recurrent or refractory medulloblastoma: a joint ITCC and SIOPE brain tumor study.

BACKGROUND: This multicenter phase II study investigated temozolomide + irinotecan (TEMIRI) treatment in children with relapsed or refractory medulloblastoma. METHODS: Patients received temozolomide 100-125 mg/m(2)/day (days 1-5) and irinotecan 10 mg/m(2)/day (days 1-5 and 8-12) every 3 weeks. The primary endpoint was tumor response within the first 4 cycles confirmed ≥4 weeks and assessed by an external response review committee (ERRC). In a 2-stage Optimum Simon design, ≥6 responses in the first 15 evaluable patients were required within the first 4 cycles for continued enrollment; a total of 19 responses from the first 46 evaluable patients was considered successful. RESULTS: Sixty-six patients were treated. Seven responses were recorded during stage 1 and 15 in the first 46 ERRC evaluated patients (2 complete responses and 13 partial responses). The objective response rate during the first 4 cycles was 32.6% (95% confidence interval [CI], 19.5%-48.0%). Median duration of response was 27.0 weeks (7.7-44.1 wk). In 63 patients evaluated by local investigators, the objective response rate was 33.3% (95% CI, 22.0%-46.3%), and 68.3% (95% CI, 55.3%-79.4%) experienced clinical benefit. Median survival was 16.7 months (95% CI, 13.3-19.8). The most common grade 3 treatment-related nonhematologic adverse event was diarrhea (7.6%). Grade 3/4 treatment-related hematologic adverse events included neutropenia (16.7%), thrombocytopenia (12.1%), anemia (9.1%), and lymphopenia (9%). CONCLUSIONS: The planned study primary endpoint was not met. However, its tolerability makes TEMIRI a suitable candidate chemotherapy backbone for molecularly targeted agents in future trials in this setting.

Benefits and limitations of errorless learning after surviving pediatric brain tumors: a case study.

Survivors of childhood brain tumors often acquire complex cognitive difficulties including impairments in attention, processing speed, and different aspects of memory function. These impairments can affect their learning in the real world and in the classroom. However, the efficacy of memory rehabilitation techniques post treatment has not yet been assessed in these patients. We present the case of a 15-year-old boy, C.J., who acquired a profound episodic memory impairment due to a metastatic germ cell tumor and subsequent treatment. The focus of this study was the application of an errorless learning technique to a verbal learning task. We were interested to test whether C.J. would benefit from errorless learning as compared to errorful learning. Results of an experiment and a follow-up study indicated that C.J.'s learning was more efficient under errorless conditions, although access to the information from long-term memory remained cue dependent. Implications for learning with or without the support of episodic memory are discussed, and future directions for memory rehabilitation of brain tumor survivors are outlined.

A phase I and pharmacokinetic study of plitidepsin in children with advanced solid tumours: an Innovative Therapies for Children with Cancer (ITCC) study.

AIMS: To determine the maximum tolerated dose, the recommended dose (RD) for phase II studies, dose-limiting toxicities and pharmacokinetics (PK) for plitidepsin administered as a 3-h intravenous infusion every 2weeks (one cycle) to children with refractory or relapsed solid tumours. METHODS: Consecutive cohorts of patients were treated according to a standard '3+3' design with escalating doses of plitidepsin at 4, 5 and 6mg/m(2). Additional 15 patients were recruited at the RD to further evaluate safety and pharmacokinetic associations with respect to age, dose level and toxicity. RESULTS: Thirty-eight of 41 patients registered received plitidepsin. Dose-limiting toxicities during the first three treatment cycles related to myalgia, elevated creatine phosphokinase, transaminase increase and nausea/vomiting. The RD for plitidepsin is 5mg/m(2). PK analyses revealed high inter-patient variability in plasma, but a similar clearance of plitidepsin in children and adolescents. One partial response confirmed at 4weeks in a patient with neuroblastoma and one unconfirmed partial response in a pancreatoblastoma were observed; four other patients with neuroblastoma, medulloblastoma, glioblastoma and rhabdoid tumour had disease stabilisations lasting ⩾3months. CONCLUSION: Plitidepsin administered to children as a 3-h infusion every 2weeks is received with manageable toxicity for children with cancer, and the RD is 5mg/m(2). Pharmacokinetic parameters in children and adolescents are comparable to adults. Future phase II studies of plitidepsin are warranted, and our results suggest that plitidepsin could be appropriately developed in combination with other antitumour where myelosuppression is dose-limiting.

Preoperative vincristine for an inoperable choroid plexus papilloma: a case discussion and review of the literature.

The authors report the case of a 14-month-old boy with a large right intraventricular choroid plexus papilloma (CPP) for which the first attempt at resection resulted in life-threatening intraoperative hemorrhage. The tumor was unsuitable for embolization, and neoadjuvant ifosfamide, carboplatin, etoposide (ICE) chemotherapy had no effect on tumor size. However, chemotherapy with vincristine, although not impacting on CT perfusion parameters, resulted in a significant decrease in tumor size, enabling complete resection with manageable blood loss. The mechanism underlying the effect of vincristine in this case is uncertain, but it is a treatment strategy that warrants further evaluation for the treatment of CPPs that are not amenable to embolization.

SenseCam as a rehabilitation tool in a child with anterograde amnesia.

We present the case of a 13-year-old boy, CJ, with profound episodic memory difficulties following the diagnosis of a metastatic intracranial germ cell tumour and subsequent treatment with radiotherapy and chemotherapy. At the core of this study is the first application of SenseCam to a child with severe memory impairment. CJ was taken for a walk while he was wearing SenseCam. This included visiting four different locations. We manipulated the number of locations he could review on SenseCam "films" and then tested recognition memory (forced choice) for both reviewed and non-reviewed locations. We also collected his justifications for the choices he made. Our results indicate that repeated viewings of SenseCam images support the formation of personal semantic memories. Overall our results suggest that the use of SenseCam in memory rehabilitation extends beyond supporting episodic memory and recollection, and supports the feasibility of its use with children who have marked memory difficulties.

Are reported increases in incidence of primary CNS tumours real? An analysis of longitudinal trends in England, 1979-2003.

Reported increases in the incidence of CNS tumours in the developed world in the 1970s to 1990s have been a cause for concern and debate. It still remains to be adequately answered whether these increases are true or an artefact of changes in diagnostic and registration practices. Using high-quality national cancer registration data, we have analysed incidence trends for each major histological subgroup of CNS tumour (2000 World Health Organisation (WHO) classification) registered in those aged 0-84 years for the whole of England during the period 1979 through 2003. 134,509 primary CNS tumours of malignant, benign and uncertain behaviour located in the brain, meninges, spinal cord, cranial nerves, other parts of the central nervous system and in the pituitary and pineal glands were registered. In summary, we present the single largest nationwide study on the longitudinal incidence trends of CNS tumours. The increase in incidence observed in the 1970s and 1980s was mainly in the young and the elderly and has now plateaued and may even be decreasing. There is however variation in trends by histology. The incidence of some histological sub-groups has continued to increase until the most recent period of analysis. Much of the initial increase can be attributed to the emergence of much more widely available neuroimaging, while the most recent incidence changes for specific sub-groups of CNS tumours appear to be due to greater diagnostic specificity leading to a shift in registered categories. However, the trends for high-grade astrocytomas and other gliomas need further observation and investigation.

Nutritional problems in children treated for medulloblastoma: implications for enteral nutrition support.

BACKGROUND: The aim of this study was to identify the nature and severity of nutritional problems associated with the current treatment of medulloblastoma and to identify any risk factors for nutritional morbidity during treatment. PROCEDURE: A multicentre retrospective audit of medical and dietetic notes of 41 children treated for medulloblastoma in three UK paediatric oncology centres was undertaken. Data on nutritional status, nutritional support, mutism, swallowing and common toxicity criteria (CTC) scores for vomiting, constipation and mobility were collected at defined points in treatment from diagnosis until 12 months post-treatment. RESULTS: Significant problems including weight loss, vomiting and constipation were highlighted early on in treatment. The majority of patients were well nourished at diagnosis with a mean percentage weight: height of 99.8%, however nutritional status started to decline early in treatment during radiotherapy, coinciding with 49% of patients having grade 1 or above CTC score for vomiting and constipation. The decline in nutritional status continued, peaking by course 2 of chemotherapy with a mean weight loss of 8.2% since diagnosis. Proactive supplementary feeding early in treatment by one of the three centres demonstrated a superior nutritional outcome when compared statistically to the two centres that fed only as a response to nutritional decline. CONCLUSION: The study highlighted significant morbidity associated with the current treatment of medulloblastoma. Findings suggest the need to consider earlier proactive nutritional intervention to prevent nutritional decline during treatment. These early nutritional problems may be related to toxicities of radiotherapy and concomitant vincristine.

Age-incidence patterns of primary CNS tumors in children, adolescents, and adults in England.

Around 25% of all tumors in those 0-14 years of age and 9% in those 15-24 years of age involve the CNS. They are the most common cause of cancer-related deaths in both age groups. In adults 25-84 years of age, the proportion of CNS tumors is 2%; 5-year overall survival is 10%-15%; and survivors have considerable morbidity. Comprehensive up-to-date population-based incidence data on these tumors are lacking. We present incidence rates for primary CNS tumors based on data derived from the high-quality national cancer registration system in England. A total of 54,336 CNS tumors of malignant, benign, and uncertain behavior were registered across the whole of England from 1995 through 2003. The age-standardized rates for all ages (0-84 years) was 9.21 per 100,000 person-years. This is higher than previously reported for England because it includes nonmalignant CNS tumors and hence gives a more accurate picture of burden of disease. The age-standardized rates for those 0-14 years of age, 15-24 years of age, and 25-84 years of age were 3.56, 3.26, and 14.57 per 100,000 person-years, respectively. In this article, we describe the changing patterns in the epidemiology of primary CNS tumors in these three age groups with respect to sex, tumor behavior, and histology using the current WHO classification. This information will provide a reference for future studies nationally and internationally and make comparisons relevant and meaningful.

Chronic hypoxia promotes hypoxia-inducible factor-1alpha-dependent resistance to etoposide and vincristine in neuroblastoma cells.

Hypoxia is widespread in solid tumors as a consequence of poorly structured tumor-derived neovasculature. Direct measurement of low oxygen levels in a range of adult tumor types has correlated tumor hypoxia with advanced stage, poor response to chemotherapy and radiotherapy, and poor prognosis. Little is known about the importance of hypoxia in pediatric tumors; therefore, we evaluated the effects of hypoxia on the response of the neuroblastoma cell lines SH-EP1 and SH-SY5Y to the clinically relevant drugs, vincristine, etoposide, and cisplatin. Short periods of hypoxia (1% O2) of up to 16 hours had no effect on drug-induced apoptosis or clonogenic survival. Prolonged hypoxia of 1 to 7 days leads to reduction in vincristine- and etoposide-induced apoptosis in SH-SY5Y and SH-EP1 cells, and this was reflected in increased clonogenic survival under these conditions. Neither short-term nor prolonged hypoxia had any effect on the clonogenic response to cisplatin in SH-SY5Y cells. Hypoxia-inducible factor-1 (HIF-1) alpha was stabilized in these cell lines within 2 hours of hypoxia but was no longer detectable beyond 48 hours of hypoxia. Up-regulation of carbonic anhydrase IX showed HIF-1alpha to be transcriptionally active. Down-regulation of HIF-1alpha by short hairpin RNA interference and the small-molecule 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole reduced hypoxia-induced drug resistance. These results suggest that prolonged hypoxia leads to resistance to clinically relevant drugs in neuroblastoma and that therapies aimed at inhibiting HIF-1alpha function may be useful in overcoming drug resistance in this tumor.