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Summary: Focus on new drug development over the last few years has yielded new agents that differ from unspecific classical chemotherapeutics and ionizing radiation, while still targeting the cancer cell itself. Antiangiogenesis is a totally distinct approach targeting the tumor''s blood vessels. This concept has now found its eligibility for the treatment of several adult solid tumors: the human antivascular endothelial growth factor (VEGF) antibody bevacizumab, as well as the VEGF receptor tyrosine kinase inhibitors, sunitinib and sorafinib, have recently been licensed by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of colorectal, renal, and lung cancer. Other antiangiogenic drugs are under preclinical and early clinical evaluation. However, what do we know of the use of these drugs in pediatric solid tumors, such as sarcomas and embryonal and neuronal tumors? For some time now, neuroblastoma has been shown to be dependent on angiogenesis. However, the first preclinical data on antiangiogenic drugs in neuroblastoma have not been published until recently, and clinical trials with antiangiogenic agents in neuroblastoma treatment protocols are scarce. This review adresses current knowledge on the important role and mechanisms of angiogenesis in neuroblastoma and summarizes available preclinical and clinical results of antiangiogenic agents used to treat neuroblastoma. Our review clearly demonstrates that clinical trials are urgently needed to bring forward promising antiangiogenesis concepts in neuroblastoma therapy. [Copyright &y& Elsevier]

Paediatric medicines are often prescribed off label because appropriate clinical and pharmacological studies have not been conducted in children. A European directive is being written to promote the development of paediatric medicines through incentives to pharmaceutical companies, as is already the case in the US.Method. – In order to evaluate the status of anticancer drugs, we analyzed the paediatric information available in the Vidal® 2000 dictionary for cytotoxic chemotherapy.Results. – Among the 76 products, 48 were currently used to treat children with cancer. An indication for paediatric use was described in only 29% of them. Paediatric use was mentioned in the posology chapter in 56% of cases, and in the warning or contra-indication chapter in 17% of cases. Ten products (21%) were devoid of paediatric information.Discussion. – The paucity of this official paediatric information contrasts with the number of clinical and pharmacological studies that have been conducted and published by paediatric oncology societies and groups. Indeed, almost 80% of children with cancer are treated using prospective therapeutic research protocols. In conclusion, anticancer medicines have been evaluated in children, but official paediatric information is poor. This situation can be significantly improved with the literature currently available. On the other hand, prospective clinical studies are needed to better define the optimal dose in children under one year of age, to evaluate long-term sequelae in cured patients and to provide appropriate galenic forms for oral chemotherapy.Conclusion. – Incentives are urgently needed to facilitate access to therapeutic innovations in oncology and their development in children with cancer. [Copyright &y& Elsevier]

Focus on new drug development over the last few years has yielded new agents that differ from unspecific classical chemotherapeutics and ionizing radiation, while still targeting the cancer cell itself. Antiangiogenesis is a totally distinct approach targeting the tumor's blood vessels. This concept has now found its eligibility for the treatment of several adult solid tumors: the human antivascular endothelial growth factor (VEGF) antibody bevacizumab, as well as the VEGF receptor tyrosine kinase inhibitors, sunitinib and sorafinib, have recently been licensed by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of colorectal, renal, and lung cancer. Other antiangiogenic drugs are under preclinical and early clinical evaluation. However, what do we know of the use of these drugs in pediatric solid tumors, such as sarcomas and embryonal and neuronal tumors? For some time now, neuroblastoma has been shown to be dependent on angiogenesis. However, the first preclinical data on antiangiogenic drugs in neuroblastoma have not been published until recently, and clinical trials with antiangiogenic agents in neuroblastoma treatment protocols are scarce. This review adresses current knowledge on the important role and mechanisms of angiogenesis in neuroblastoma and summarizes available preclinical and clinical results of antiangiogenic agents used to treat neuroblastoma. Our review clearly demonstrates that clinical trials are urgently needed to bring forward promising antiangiogenesis concepts in neuroblastoma therapy.

The French Cancer Plan 2003-2007 has made translational research central to its research programme, to ensure the care-research continuum and the quickest application possible for the most recent discoveries, for the patients' benefit. This is a new field of research, still little-known or ill-understood. A working group, composed of physicians and researchers from academic research and industrial research, sought to define translational research in cancerology and define the issues at stake in it. Translational research needs to develop in close connection with the patients in order to enable a bi-directional flow of knowledge from cognitive research toward medical applications and from observations made on patients toward cognitive research. Placed under the aegis of the French National Cancer Institute and Leem Research, the group has put forth a strategy for implementing translational research in cancerology in France to make it attractive, competitive and efficient and to foster the development of public-private partnerships.

Cancer gene therapy has offered many hopes but its first use in humans revealed some pitfalls and at least three main problems: lack of efficacy and specificity of current vectors to deliver therapeutic genes, poor diffusion of the therapeutic effects inside the tumor (absence of bystander effect), poor distribution of the vectors injected inside the tissue. To address some of these issues, several teams have developed tumor selective replicating adenoviruses, some of them being already in the clinic. First results are promising but complementary studies are needed to define if these agents will take place in the therapeutic armentorium against cancer., (Copyright John Libbey Eurotext 2003.)

Childhood and adolescent cancers are rare diseases. Despite the progress in treatment (more than two-thirds of all cases are cured), cancer remains the leading cause of death by disease in children older than 1 year. Access to new drugs that are more efficacious or better tolerated is therefore an important public health priority. The objective of our round table was thus to take inventory of the situation and to propose recommendations aimed at facilitating coordinated, rational and more rapid access to new treatments. The active participation of paediatric oncologists, parents, pharmaceutical companies and regulatory authorities proved not only necessary but very constructive. Pharmaceutical companies have developed very few new anticancer agents for children during the past 10 years. The round table identified current trends that appear propitious: the mobilisation of parents and patients' associations; European initiatives to encourage companies to assess drugs in children; regulatory initiatives to guide drug development; and the existence of structured clinical research networks in paediatric oncology, including for the development of early treatment. The round table recommends the following measures to improve access to new treatments for children and adolescents with cancer: 1. Conduct preclinical paediatric evaluation of all anticancer agents that begin the development process for adults (research and validation of treatment targets; pharmacological evaluation in relevant experimental models) to help choose the agents to study in children. 2. Initiate paediatric clinical development before the first application for authorization for adults is filed, when sufficient safety and tolerability data are available, that is, after the phase I trials in adults and optimally during the phase II trials. 3. Optimise paediatric clinical evaluation by defining development plans early and by reducing the duration of studies (enlargement of the early treatment research network to ensure adequate recruitment; new evaluation methods; better extrapolation of pharmacological data from adults to children for dose-finding). 4. Improve information to and participation of parents and patients in clinical research for new treatments. The prerequisite for the success of this project became rapidly clear to all the round-table participants: cooperation and partnership between specialists and other scientists from academia, parent associations, pharmaceutical companies and regulatory authorities. Only with such cooperation can progress in treatment occur and new hopes for recovery be fulfilled.

Unlabelled: Methotrexate elimination may be delayed by different drugs. Such a delay may produce severe toxic complications., Case Reports: We report two cases of adolescents treated for malignant diseases who presented a delayed methotrexate elimination even though they received ciprofloxacin. The first patient had already received several courses of methotrexate without toxicity before this episode. The second patient tolerated methotrexate when ciprofloxacin was not associated to the treatment., Conclusion: High-dose methotrexate-ciprofloxacin association should be avoided.

The significant progress made in pediatric oncology during recent years has been due to a major breakthrough in the field of molecular biology and the introduction of new therapeutic strategies that take into account both the quality and the duration of life. Molecular biology has already been instrumental in more fully categorizing the 'small round-cell tumor' group, and in reclassifying the 'Ewing family' tumors. It also provides a valuable tool for the prognostic evaluation of neuroblastomas through the analysis of the N-myc oncogene. In addition, it has permitted the identification of the Li-Fraumeni syndrome of predisposition to cancer in the child, thereby raising the problematical ethical issue of communicating relevant information to subjects at risk. Two examples illustrate innovative strategic concepts: 1) Burkitt's lymphoma, or an example of the successful de-intensification of treatment; and 2) brain tumors in young children, regarding which the desire to improve the quality of life has led to innovative attempts to replace radiotherapy by chemotherapy. Considerable progress has been made in the field of neuropsychology, thereby permitting an improved assessment of disorders and a better management of rehabilitation programs. New anti-cancer agents and also chemo- and radiotherapy that spare healthy tissue are also being developed. Gene therapy and molecular biology will play a major role in future therapeutic strategies; and are now at the preclinical trial stage. This significant overall progress leads to a reconsideration of the organizational approach toward treatment of the pediatric patient population suffering from cancer, and a critical assessment of disease management, which should take into account not only the technical aspects of the disease but also familial and social considerations.

In chemosensitive tumors, cancer chemotherapy is active as drug combinations. During the development of new anticancer drugs, preclinical experimental models may help to design drug combinations. Indeed, in vitro models are able to define drug interactions in terms of synergism, additivity or antagonism, while in vivo models can evaluate therapeutic synergism along with toxicity in a clinical setting. The methodology for in vitro and in vivo evaluation of anticancer drug combinations is described. The limits are discussed. In conclusion, preclinical models contribute to the clinical development of drug combinations which are nevertheless designed on the basis of clinical therapeutic principles.

Discovered during the sixties, anthracycline antibiotics are today widely used anti-cancer drugs. Their potentially fatal cardiac toxicity, which is related in part to the total cumulative dose, has been described since 1967. The aim of this paper is to describe their biological and clinical toxic effects on the heart, especially of children, and to propose prevention guidelines. The mechanisms of cardiac toxicity, with their destructive consequences on functional myocytes reserve, are shortly recalled. Acute, sub-acute and chronic clinical aspects of anthracycline's cardiomyopathy are the subject of a literature review. In Pediatric Oncology, the prolonged survival usually observed allows delayed congestive heart failure to occur by myocardial reserve insufficiency, as hemodynamic needs are quickly increasing, especially at the end of the somatic growth. Furthermore, the frequency of cardiac abnormalities is increasing with time after therapy, reaching about half of the explored patients after 15 years. The main known methods to prevent such a toxicity are reviewed. The parcimonious use of anthracyclines is already seen in children. Every method to decrease the maximal plasma concentration of the drug (weekly schedule or prolonged infusion) has to be considered. The active cardioprotectant agent such as ICRF-187, is in clinical development. Detection, prevention, and therapy of cardiac abnormalities, which are likely to precede delayed heart failure, still remains a difficult problem in these more and more numerous children to be cured of cancer.

Background: Juvenile granulosa cell tumors (JGCT) of the ovary are rare in children. The over-all outcome after surgery is relatively good, but the indication and type of complementary treatment for severe forms are still unclear., Population: A retrospective survey of the majority of patients with JGCT of the ovary admitted between 1965 and 1990 to 11 French oncologic pediatric centers was carried out. Medical records including surgical and histological data, were analyzed and each tumor was retrospectively classified by the same pathologist according to the Wollner classification., Results: There were 40 patients aged 7 months to 22 years (mean: 6 years); 28 were less than 10 year old at diagnosis. Three had enchondromatosis (Ollier's disease). At diagnosis, all patients presented with an abdominal tumor, 23 had developed manifestations of precocious pseudopuberty, 2 had signs of virilization after a normal puberty and 2 had secondary amenorrhea. Surgery was always the primary treatment: unilateral ovariectomy in 35 cases, bilateral in 4 and biopsy alone in 1 case. There were 21 stage I, 1 stage II, 16 stage III and 2 stage IV cases. 13 patients received combined chemotherapy and 2 abdominal radiotherapy. 34 patients were alive and disease-free 10 months to 26 years after surgery and 6 died. All 23 patients with precocious pseudopuberty had a favorable outcome., Conclusions: This study confirms earlier reports. Unilateral ovariectomy is the first-choice therapy. There is no evidence that tumors complicated by rupture and hemoperitoneum require chemotherapy. Combined chemotherapy does not appear to improve the prognosis for the rare malignant forms. The factors of good prognosis are age less than 10 years and the presence of precocious pseudopuberty.

Thirty-two children were treated for metastatic Ewing sarcoma by high-dose chemotherapy followed by autologous bone marrow transplantation. Fourteen patients entered phase II studies of high-dose alkylating agents. The response rate observed was 61%. High-dose chemotherapy was used as consolidation in complete remission of 18 patients. Disease free survival appears to be better than that observed under conventional altered chemotherapy. However, with only 4/18 long term survivors, these results remain unsatisfactory, taking into account the recent encouraging results of semi-continuous conventional chemotherapy.

In terms of pharmacology, drug delivery is an important obstacle in the development of brain tumor chemotherapy. The blood-brain barrier limits the drug penetration in normal brain tissue around the tumor and at distant potential metastatic sites. In the tumor, the altered blood-brain barrier, ie blood-tumor barrier, decreases the drug entry in malignant cells. The knowledge of the blood-brain barrier physiology and the definition of the laws that govern the drug delivery to the central nervous system allow the development of new strategies to increase drug delivery to the tumor. In pediatric oncology, the more appropriate methods are the use of anticancer agents that easily cross the blood-brain barrier and the development of high-dose systemic chemotherapy regimens with or without bone marrow rescue.

We prospectively evaluated after randomization in 60 consecutive recipients of bone marrow transplantation the efficiency of a short administration of vancomycin (10 mg/kg I.V. q 6 H, day -5 to +1). Thirty-three patients were randomized as controls and 27 were designed to receive vancomycin. Both groups were similar in terms of age, diagnosis, status, allogeneic or autologous graft, in vitro marrow treatment or not. Eighteen patients (30%) experienced bacteremias: 15/18 bacteremias were due to Gram positive organisms, including 11 streptococci. These infections occurred with a similar frequency in both groups, the relatively low incidence of bacteremias in this study needs further evaluation in new patients to insure the prophylactic effects of a course of vancomycin in bone marrow transplant recipients.

This presentation reports on patients with 13 B - acute lymphoblastic leukemia (ALL), treated with intensive chemotherapy. To date 5 patients are alive, in complete remission (greater than 24 months), 4 of them had CNS disease at diagnosis; 7 patients relapsed, 2 to 4 months after complete remission, 6 of them having CNS relapse, isolated or with bone marrow involvement. The improvement in prognosis of B-ALL results from intensive chemotherapy, but the prognosis remains poor because of early relapses, especially CNS relapses (survival rate is less than 50%). The authors propose new therapeutic approaches.