The recent treatment protocols used in the management of children with brain tumors have greatly improved the survival rate in these patients. The authors present a review of the endocrine dysfunctions associated with the different types of treatment. Cranial irradiation is the first cause of endocrine disorders, growth failure being the main risk. A simplified protocol for endocrine evaluation and treatment of the disorders is suggested.

Serotonin (5-Hydroxytryptamine) seems to play a dominant role in triggering vomiting induced by cytotoxic agents through the stimulation of 5-HT3 receptors. They have been observed in the GI tract as well as in the brain (area postrema). Ondansetron is a specific antagonist of 5-HT3 serotonin receptors. Its anti-emetic activity is very powerful in the ferret. The availability of an injectable or oral form of this product allows the overall treatment of acute and delayed emesis and its administration is in accordance with different schedules: single IV injection or a continuous 24 hour infusion or repeated IV injection followed by oral treatment. The pharmacokinetics of the drug are as follows: absorption begins about 30 minutes after the administration per os, its biodisponibility is about 60%, its clearance: 20 ml/minute and its elimination half life about 3 hours. Different double blind studies, carried out in parallel groups or in cross over, demonstrated the superiority of ondansetron over metoclopramide in the control of nausea and vomiting, whether or not the chemotherapy contained cisplatin; a more recent study shows also that ondansetron was superior to alizapride and methylprednisolone in combination. Side effects of ondansetron do not include extrapyramidal symptoms but only headaches and constipation. The use of ondansetron improves the well-being of patients receiving chemotherapy and increases protocol compliance.

The photodynamic therapy of cancer (PDT) by porphyrins is now at a turning point with the advent of phase III clinical trials. The transport of photofrin II and its delivery to tumor cells and vasculature is believed to be a determinant of tumor necrosis by suppressing the oxygen supply. However, this treatment must be improved by increasing the selectivity of the photosensitizer uptake by tumors and also by using photosensitizers absorbing in the 700-800 nm range where tissues have the highest transmittance. In addition, these new photosensitizers (chlorines, phthalocyanines...) should be rapidly excreted to avoid the only secondary effect of the PDT: the long-lasting photosensitivity of the patient skin. Finally, the combination of PDT with other therapies or its chemopotentiation by "bioreductive" drugs which interfere with the metabolism of hypoxic cells resulting from the PDT are potential means for improving the effectiveness of this new modality for cancer treatment.

Germinal cells are particularly sensitive to cancer chemotherapy in males. This toxicity is difficult to evaluate. It is the most frequently observed in young patients treated for curable cancers, by alkylants, specially if the treatment is intense and long. Depending on the patient and his age, on the cancer and its treatment, recovery of a normal spermatogenesis may be observed in a minority of cases and sometimes lately. This hazard must be told to the patient who is invited to preserve his sperm which is not always of enough good quality. There is no proved means to protect gonadal function. Therefore modifications of chemotherapy are desirable to decrease its toxicity.

Children with metabolic or toxic diseases affecting the brain stem were examined by MRI in an attempt to obtain images of brain stem systematization fibres and to determine their origin. A toxic cause may be envisaged in hazy, ill-systematized lesions, and a metabolic cause in well-systematized lesions.

In experimental models chemotherapeutic agents enhance spontaneous metastases. Vascular toxicity and myelotoxicity may account for this phenomenon. However, drugs may act directly on tumor cells. Clonogenic resistant cells are involved in the metastatic process facilitation. Fundamental biological mechanisms are evoked to explain these observations. Mutagenicity and its consequences on gene expression or regulation are another hypothesis. Clinical investigations are necessary to confirm the results obtained from animal models.

Concentrations of estrogen receptors, progesterone receptors, unconjugated estrogens (estradiol and estrone) and sulfate-conjugated estrogens (estradiol sulfate and estrone sulfate) were determined in patients treated with Decapeptyl and in controls. After prolonged Decapeptyl therapy, a highly significant fall in progesterone receptors was evidenced; estrogen receptors were found to be decreased in the myoma as compared with the secretory phase in controls and in the myometrium as compared with the proliferative phase in controls. Tissue levels of estrone sulfate and estradiol sulfate decreased very substantially. In conclusion, Decapeptyl emerges as a very promising agent for the treatment of uterine myomas.

A prospective study of mandibular alveolar bone resorption has been achieved on 49 patients with upper aerodigestive tract tumor and treated by radiation therapy and/or a chemotherapy, on 30 patients who were not treated. All these patients were subjected to dental extractions followed by X rays in coronal and sagittal view, during at least one year, at the rate of one X ray every three months. The comparative study enabled to show a quite similar resorption for the two population, a slightly more important resorption on incisor and canine regions, and a stopping of the resorption about five months later according to dental extractions. Radiation therapy and chemotherapy (therapeutic doses) may not have significant influence on alveolar bone resorption after dental extractions.

Treatments given for childhood malignancies can alter gonadal function by several mechanisms: (1) cranial irradiation may cause either gonadotrophin deficiency or premature puberty. (2) Irradiation of the testes can induce germinal epithelium dysfunction even if the dose delivered is very low; Leydig cell failure occurs beyond 5-6 Gy and ovarian insufficiency beyond 6-7 Gy. (3) Chemotherapy is considerably more toxic for the germinal epithelium of the testes than for the ovaries; alkylating agents are especially toxic. Analysis of the consequences of preparation for bone marrow transplantation by chemotherapy or total body irradiation will be required when longer follow-up are available.

THP-adriamycin (pirarubicin) is a new anthracycline-analogue. In France, the drug is achieving the phase II studies and the step of phase III studies is going on. As this point of its development, it is already possible to conclude that the drug probably shares the same efficacy as adriamycine, especially in breast cancer, but exhibits a better tolerance in term of alopecia and cardiac toxicity, as predicted by preclinical studies. Its pharmacological properties make the drug an original compound, exciting for investigations in the field of loco-regional therapy.

Navelbine (NVB) (5'-noranhydrovinblastine) is a new semi-synthetic vincaalkaloid (VA) exhibiting a high affinity for tubulin and considerable anticancer activity in patients. A better hematologic tolerance and a weak neurotoxicity have been reported for this drug as compared to other VA. Moreover, NVB presents a relatively high bioavailability and a good digestive tolerance, thus offering original perspectives for the treatment of ambulatory cancer patients. A clinical pharmacokinetic study of NVB was carried out on 12 patients after oral administration of the drug. The pharmacokinetic parameters were similar to those of intravenous administration and also showed a high interindividual variability. Studies on the in vitro metabolism of NVB using hepatic microsomal fractions from 22 different donors demonstrated the formation of 3 metabolites. The biotransformation rate quantitatively varies from one human liver specimen to another, a fact which could be, in part, at the origin of the interindividual variability of the therapeutic response.

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.