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PURPOSE: To evaluate the efficacy and safety of irinotecan in paediatric recurrent or refractory neuroblastoma. PATIENTS AND METHODS: Thirty seven patients aged between 6 months and < or = 20 years, with relapsed or refractory neuroblastoma, received irinotecan at 600 mg/m(2) administered as a 60-min infusion, every 3 weeks. Tumour response was evaluated by conventional radiological and mIBG scans every two cycles. RESULTS: No objective response was observed during the study. Stable disease was observed in 13% of evaluable patients. Median times to progression and survival were 1.4 months (range, 1.2-1.5 months) and 8.8 months (range, 6.7-11.3 months), respectively. One forty two cycles were administered, with a median of two cycles per patient (range, 1-17 cycles). The most common grade 3-4 toxicities were neutropenia (65% of patients), anaemia (43%), thrombocytopenia (38%), vomiting (14%), abdominal pain or cramping (8%), and nausea (5%). CONCLUSION: Irinotecan administered intravenously as a single agent every 3 weeks induced no objective response in relapsed or refractory neuroblastoma. [ABSTRACT FROM AUTHOR]

Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, ‘DaunoXome’, as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m−2 for Group A and 100 mg m−2 for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events.British Journal of Cancer (2006) 95, 571–580. doi:10.1038/sj.bjc.6603288 www.bjcancer.com Published online 1 August 2006 [ABSTRACT FROM AUTHOR]

Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age approximately 13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m(-2)/150 mg m(-2) day(-1), 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1-7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin-temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m(-2) cisplatin and 150 mg m(-2) x 5 temozolomide in heavily treated, and 200 mg m(-2) x 5 temozolomide in less-heavily pretreated children. [ABSTRACT FROM AUTHOR]

CPT-11 (irinotecan) is a DNA-topoisomerase I inhibitor with preclinical activity against neuroblastoma (NB) xenografts. The aim was to establish in vivo an NB xenograft resistant to CPT-11 in order to study the resistance mechanisms acquired in a therapeutic setting. IGR-NB8 is an immature NB xenograft with MYCN amplification and 1p deletion, which is sensitive to CPT-11. Athymic mice bearing advanced-stage subcutaneous tumours were treated with CPT-11 (27 mg kg(-1) day(-1) x 5) every 21 days (1 cycle) for a maximum of four cycles. After tumour regrowth, a new in vivo passage was performed and the CPT-11 treatment was repeated. After the third passage, a resistant xenograft was obtained (IGRNB8-R). The tumour growth delay (TGD) was reduced from 115 at passage 1 to 40 at passage 4 and no complete or partial regression was observed. After further exposure to the drug, up to 28 passages, the resistant xenograft was definitively established with a TGD from 17 at passage 28. Resistant tumours reverted to sensitive tumours after 15 passages without treatment. IGR-NB8-R remained sensitive to cyclophosphamide and cisplatin and cross-resistance was observed with the topoisomerase I inhibitor topotecan. No quantitative or qualitative topoisomerase I modifications were observed. The level of expression of multidrug resistance 1 (MDR1), MDR-associated protein 1 (MRP1) and, breast cancer resistance protein, three members of the ATP-binding cassette transporter family was not modified over passages. Our results suggest a novel resistance mechanism, probably not involving the mechanisms usually observed in vitro. [ABSTRACT FROM AUTHOR]

This report describes a single-centre study with temozolomide (TMZ) (200 mg m(-2) day(-1) x 5 per cycle of 28 days) in children with (recurrent) high-grade glioma. Magnetic resonance imaging was performed every two cycles. In all, 20 patients were treated between 1998 and 2001 after the UKCCSG/SFOP TMZ phase II trial. All patients had measurable disease. Totally, 15 patients had a relapse after surgery+/-radiotherapy+/-chemotherapy. Overall, five patients received TMZ after surgery or biopsy, awaiting radiotherapy. There were one clinically malignant grade II glioma, 11 grade III and eight grade IV gliomas. Seven tumours had oligodendroglial features. Mean age at start of TMZ was 12.0 years (range 3-20.5 years). In total, eight patients had >8 cycles (range 3-30). One VGPR (currently in CR after surgery), three PRs (with a PFS of 4, 4 and 11 months, respectively) and one MR (PFS 14 months) were observed. Three out of five responses occurred after >4 courses. The overall response rate was 20%. Median progression-free survival (PFS) was 2.0 months (range 3 weeks-34+ months). PFS rate was 20% after 6 months. Median overall survival (OS) was 10 months. Nine patients showed a clinical improvement. Three patients vomitted shortly after TMZ administration, eight patients (13 cycles) experienced grade III/IV thrombocytopenia, occurring predominantly during the fourth week of the first two cycles. Five patients experienced neutropenia, and three patients febrile neutropenia. TMZ is a well-tolerated ambulatory treatment for children with malignant glial tumours. This drug warrants further study in these highly chemoresistant tumours and should be studied either as upfront therapy or in combination therapy. [ABSTRACT FROM AUTHOR]

We analysed the clinical features and outcome of young patients with non-Ewing's flat bone sarcoma treated during the era of contemporary chemotherapy. The characteristics and outcome of 25 patients (15 males and 10 females) with primary or radiation-related flat bone sarcoma treated in the Pediatrics Department at the Institut Gustave Roussy from 1981 to 1999 were reviewed. In all, 20 patients had osteosarcoma, four chondrosarcoma and one malignant fibrous histiocytoma. The age at diagnosis ranged from 2 to 23 years (median, 15 years). Nine tumours were located in the craniofacial bones, 11 in the pelvis and five in flat bones at other sites. Four patients had metastatic disease at diagnosis. Radiation-associated flat bone osteosarcoma was diagnosed in 10 out of 25 cases. The projected overall survival and event-free survival (EFS) rates at 5 years were 45.1 and 34.3% for all the 25 patients. The EFS rate of patients with second bone sarcoma was similar to that of patients with de novo flat bone sarcoma (P=0.1). The aim of treatment was curative for 24 patients, 23 of whom were treated with intensive chemotherapy regimens and 19 with surgery. Significant adverse prognostic factors on survival included incomplete surgical resection (P=0.001) and use of regimens without pre- and postoperative chemotherapy (P=0.007). Nine of the 25 patients were treated with pre- and postoperative chemotherapy and complete surgical resection. Among them, eight are alive with no disease. Radical surgical resection is the overriding prognostic factor for flat bone sarcomas in young patients. Nevertheless, our results suggest a more favourable outcome since the advent of intensive chemotherapy.British Journal of Cancer (2004) 90, 613-619. doi:10.1038/sj.bjc.6601564 www.bjcancer.com [ABSTRACT FROM AUTHOR]

In addition to its primary role as growth factor, human growth hormone (hGH) can also participate in cell survival, as already documented by its protective effect on human monocytes or human promyelocytic leukaemia U937 cells exposed to a Fas-mediated cell death signal. However, despite similarities in the molecular events following Fas and TNF-alpha receptor engagement, we report that U937 cells, genetically engineered to constitutively produce hGH, were made more sensitive to TNF-alpha-induced apoptosis than parental cells. This was due to overproduction of the antioxidant glutathione, which decreased the nuclear factor (NF)-kappaB activity known to control the expression of survival genes. These findings were confirmed in vivo, in nude mice bearing U937 tumours coinjected with recombinant hGH and the NF-kappaB -inducing anticancer drug daunorubicin, to avoid the in vivo toxicity of TNF-alpha. This study therefore highlights one of the various properties of hGH that may have potential clinical implications. [ABSTRACT FROM AUTHOR]

In spite of aggressive surgery, irradiation and/or chemotherapy, treatment of malignant gliomas remains a major challenge in adults and children due to high treatment failure. We have demonstrated significant cell lysis and antitumour activity of the E1B-55 kDa-gene-deleted adenovirus ONYX-015 (dl1520, CI-1042; ONYX Pharmaceuticals) in subcutaneous human malignant glioma xenografts deriving from primary tumours. Here, we show the combined efficacy of this oncolytic therapy with radiation therapy. Total body irradiation (5 Gy) of athymic nude mice prior to intratumoral injections of ONYX-015 1 x 10(8) PFU daily for 5 consecutive days yielded additive tumour growth delays in the p53 mutant xenograft IGRG88. Radiation therapy was potentiated in the p53 functional tumour IGRG121 with a 'subtherapeutic' dose of 1 x 10(7) PFU daily for 5 consecutive days, inducing significant tumour growth delay, 90% tumour regression and 50% tumour-free survivors 4 months after treatment. These potentiating effects were not due to increased adenoviral infectivity or replication. Furthermore, cell lysis and induction of apoptosis, the major mechanisms for adenoviral antitumour activity, did not play a major role in the combined treatment strategy. Interestingly, the oncolytic adenovirus seemed to accelerate radiation-induced tumour fibrosis. Potentiating antitumour activity suggests the development of this combined treatment for these highly malignant tumours. [ABSTRACT FROM AUTHOR]

The maximum tolerated dose of paclitaxel administered by 24-hour continuous infusion in children is known. Short infusion might offer equivalent antitumour efficacy and reduced haematological toxicity, without increasing the allergic risk. Our aims were to determine the maximum tolerated dose and the pharmacokinetics of paclitaxel in children when administered in 3-h infusion every 3 weeks. Patients older than 6 months, younger than 20 years with refractory malignant solid tumours were eligible when they satisfied standard haematological, renal, hepatic and cardiologic inclusion criteria with life expectancy exceeding 8 weeks. Paclitaxel was administered as a 3-hour infusion after premedication (dexamethasone, dexchlorpheniramine). Pharmacokinetic analysis and solvent assays (ethanol, cremophor) were performed during the first course. 20 courses were studied in 17 patients; 4 dosage levels were investigated (240 to 420 mg/m[sup2]). No dose-limiting haematological toxicity was observed. Severe acute neurological and allergic toxicity was encountered. One treatment-related death occurred just after the infusion at the highest dosage. Delayed peripheral neurotoxicity and moderate allergic reactions were also encountered. Pharmacokinetic analysis showed dose-dependent clearance of paclitaxel and elevated blood ethanol and Cremophor EL levels. Although no limiting haematological toxicity was reached, we do not recommend this paclitaxel schedule in children because of its acute neurological toxicity. [ABSTRACT FROM AUTHOR]

In vivo transfer of wild-type (wt) p53 gene via a recombinant adenovirus has been proposed to induce apoptosis and increase radiosensitivity in several human carcinoma models. In the context of combining p53 gene transfer and irradiation, we investigated the consequences of adenoviral-mediated wtp53 gene transfer on the cell cycle and radiosensitivity of a human head and neck squamous cell carcinoma line (SCC97) with a p53 mutated phenotype. We showed that ectopic expression of wtp53 in SCC97 cells resulted in a prolonged G1 arrest, associated with an increased expression of the cyclin-dependent kinase inhibitor WAF1/p21 target gene. A transient arrest in G2 but not in G1 was observed after irradiation. This G2 arrest was permanent when exponentially growing cells were transduced by Ad5CMV-p53 (RPR/INGN201) immediately after irradiation with 5 or 10 Gy. Moreover, levels of cyclins A2 and B1, which are known to regulate the G2/M transition, dramatically decreased as cells arrived in G2, whereas maximal levels of expression were observed in the absence of wtp53. In conclusion, adenoviral mediated transfer of wtp53 in irradiated SCC97 cells, which are mutated for p53, appeared to increase WAF1/p21 expression and decrease levels of the mitotic cyclins A2 and B1. These observations suggest that the G2 arrest resulted from a p53-dependent premature inactivation of the mitosis promoting factor. [ABSTRACT FROM AUTHOR]

High-dose busulphan-containing chemotherapy regimens have shown high response rates in children with relapsed or refractory neuroblastoma, Ewing’s sarcoma and medulloblastoma. However, the anti-tumour activity of busulfan as a single agent remains to be defined, and this was evaluated in athymic mice bearing advanced stage subcutaneous paediatric solid tumour xenografts. Because busulphan is highly insoluble in water, the use of several vehicles for enteral and parenteral administration was first investigated in terms of pharmacokinetics and toxicity. The highest bioavailability was obtained with busulphan in DMSO administered i.p. When busulphan was suspended in carboxymethylcellulose and given orally or i.p., the bioavailability was poor. Then, in the therapeutic experiments, busulphan in DMSO was administered i.p. on days 0 and 4. At the maximum tolerated total dose (50 mg kg–1), busulphan induced a significant tumour growth delay, ranging from 12 to 34 days in the three neuroblastomas evaluated and in one out of three medulloblastomas. At a dose level above the maximum tolerated dose, busulphan induced complete and partial tumour regressions. Busulphan was inactive in a peripheral primitive neuroectodermal tumour (PNET) xenograft. When busulphan pharmacokinetics in mice and humans were considered, the estimated systemic exposure at the therapeutically active dose in mice (113 μg h ml–1) was close to the mean total systemic exposure in children receiving high-dose busulphan (102.4 μg h ml–1). In conclusion, busulphan displayed a significant anti-tumour activity in neuroblastoma and medulloblastoma xenografts at plasma drug concentrations which can be achieved clinically in children receiving high-dose busulphan-containing regimens. 1999 Cancer Research Campaign [ABSTRACT FROM AUTHOR]

A series of 23 children with primitive neuroectodermal tumours (PNET) were analysed with comparative genomic hybridization (CGH). Multiple chromosomal imbalances have been detected in 20 patients. The most frequently involved chromosome was chromosome 17, with a gain of 17q (11 cases) and loss of 17p (eight cases). Further recurrent copy number changes were detected. Extra copies of chromosome 7 were present in nine patients and gains of 1q were detected in six patients. A moderate genomic amplification was detected in one patient, involving two sites on 3p and the whole 12p. Losses were more frequent, and especially involved the chromosomes 11 (nine cases), 10q (eight cases), 8 (six cases), X (six patients) and 3 (five cases), and part of chromosome 9 (five cases). These recurrent chromosomal changes may highlight locations of novel genes with an important role in the development and/or progression of PNET. [ABSTRACT FROM AUTHOR]