Csilla Csáki

ADMINISTRATION OF ETHYOL (AMIFOSTINE) TO A CHILD WITH MEDULLOBLASTOMA TO AMELIORATE HEMATOLOGICAL TOXICITY OF HIGH DOSE CARBOPLATIN

The first report on the administration of the chemoprotective agent Ethyol (amifostine) in conjunction with high dose carboplatin to a patient in the pediatric/adolescent age group is presented. A 17 year old teenager with recurrent cerebellar medulloblastoma received a total of five courses of high dose carboplatin 2 x 600 mg/m2 (1200 mg/m2 total) in each cycle. A complete response has been observed following the third treatment cycle. However, cumulative grade IV hematological toxicity developed following each of the first four treatments. Therefore, the fifth treatment was administered in conjunction with amifostine, at a dose of 2 x 740 mg/m2. Time to complete hematological recovery (Hb > 100 g/l, granulocytes > 2.0 G/l, platelets > 100 G/l) was 52, 58, 72, 78 and 50 days, respectively, following treatments nos 1, 2,,3, 4 and 5. The duration of grade III-IV neutropenia (< 1.0 G/l) was 3, 7, 8, 10 and 5 days, respectively. The duration of grade II-IV thrombocytopenia (platelets < 75 G/l) was 10, 25, 35, 40 and 32 days, respectively. Grade IV thrombocytopenia (platelets < 25 G/l) lasted for 5, 10, 12, 18 and 3 days, respectively, after each consecutive treatment. The total number of platelet transfusions was 1, 2, 2, 3 and 1, with the transfusion of 6, 9, 11, 11 and 5 units of platelets. The administration of amifostine has not been accompanied by any serious side effect. A short decrease in body temperature and a transient drop of blood pressure have been observed. Although hematological toxicity of high dose carboplatin has not been eliminated by amifostine, we conclude that significant protection was achieved in this situation of progressive bone marrow exhaustion.

Human recombinant cranulocyte-macrophage colony-stimulating factor in pediatric oncology practice

This paper reports preliminary experiences with human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) in children with malignant diseases administered for three indications: (1) chemotherapy-induced neutropenia and sepsis, (2) prolonged neutropenia decreasing dose intensity, and (3) prevention of neutropenia after sublethal doses of chemotherapy. It was concluded that in the daily dose of 5 micrograms/kg subcutaneously, GM-CSF is capable of reducing the duration of chemotherapy-induced neutropenia and may be an effective tool in maintaining dose intensity and achieving dose escalation.

Pharmacokinetic studies on Elobromol in children with brain tumors

Systemic pharmacoklnetlcs of high dose (500 mg/m2), orally administered Elobromol (dibromodulcltol, DBD) were studied In 16 chemotherapeutlc courses administered to five patients. Cerebrosplnal fluid (CSF) DBD levels were also analyzed In two patients. Bromoepoxydulcitol (BED), dlanhydrodulcltol (DAD) are cytotoxlc, whereas bromoanhydrodulcKol (BAD) and anhydroepoxydulcltol (AED) are Inactive metabolites detectable during the blotransformatlon of DBD. The HPLC method, developed by our team, is suitable for the determination of both DBD and its main metabolites (DAD and BAD). Our publication Is the first In the literature to describe the pharmacokinetic properties of these three hexitol derivatives in pediatric patients. With the exception of one patient, concentration time curves were analyzed by the one-compartment model. From 30 mln following administration, DBD was detectable in all plasma samples for at least 12 h; its concentration, however, was usually undetectable by 24 h. Though highly variable In value, DAD concentrations were detectable during all but one of the therapeutic courses. The following peak concentrations were observed: DBD=3.46-30.63 µM, DAD== 1.70-6.17 µM and BAD=0-5.63 µM. The correlation of AUCBAD and AUCDBD values were exponential up to 200 µM h with no additional increase detectable above this limit: the distribution of AUCBAD and AUCDBD was described by a maximum curve. The possibility of enterohepatlc reclrculation could not be excluded for any of the compounds studied. Each of the three hexitol derivatives was detectable in CSF even if the concentration of the Individual metabolite remained undetectable In plasma. DBD CSF concentrations were almost constant in the period from 2.5 to 8 h following administration. Due to rising DAD concentrations, however, the value of the CSF/plasma concentration ratio was >1. The cumulation of the Inactive BAD metabolite In CSF was also significant.

EFFECT OF ETOPOSIDE ON THE PHARMACOKINETICS OF METHOTREXATE IN VIVO

The effect of etoposide on the pharmakoklnetics of methotrexate (MTX) was examined In vivo. High-dose (5 g/m2/24 h) MTX therapy was combined with two etoposide (100 mg/m2/ 1 h) infusions as a part of the medulloblastoma protocol developed In our department. Vepesld therapy was administered In two different schedules. The first group of patients received etoposide Immediately before and at the end (24 h) of MTX treatment. The second group was treated with etoposide at 24 and at 48 h after starting MTX infusion. In this latter group both treatment-related grade III and grade IV toxicity developed more frequently than in the first group (58.6 versus 29.2%, for grade 3 toxicity p=0.019, for grade 4 toxic signs p=0.040, respectively). We observed that after the second dose of etoposide given at 48 h (second group) both total and unbound serum MTX levels (determined by highperformance liquid chromatography) were elevated by 53- 109 and 26-65%, respectively, by the third hour after completion of Vepesid infusion. This effect was detectable for 6 h. All the liver and kidney functions of the patients were within the normal range. These results suggest the possibility of partial recirculation of extra/lntracellular MTX Into the blood after etoposide administration. Based on these results, the therapeutic protocol has been modified, and Vepesld Is given prior to and at the end (24 h) of high-dose MTX treatment. Under these conditions only a slight decrease of MTX elimination has been detected between 25 and 28 h. These results emphasize the role of possible scheduledependent interactions of cytostatlc drugs. [© 1998 Llppincott Williams & Wilkins.]

Diffuse plasmacytosis in a child with brainstem glioma following multiagent chemotherapy and intensive growth factor support

The use of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in order to abrogate chemotherapy-induced neutropenia has become a routine part of many cancer treatment regimes. However, there are still very few data available about possible complications related to repeated or prolonged use of these agents in patients with malignant solid tumors. The authors report a child with brainstem glioma who received repeated cycles of multiagent chemotherapy with G- or GM-CSF support. During this period of 10 months, no clinical side effects were observed that could have been attributed to growth factor administration. However, postmortem histological examination revealed the presence of diffuse plasmacytosis, a rare hematological disorder in childhood. Undifferentiated plasma cells of nonmonoclonal origin could be demonstrated infiltrating bone marrow, lungs, and lymph nodes of the patient. Based on previously published in vitro and in vivo evidence on the interleukin-6 (IL-6)-mediated stimulatory effect of G- and GM-CSF on myeloma cell proliferation, the authors suggest a possible link between extensive growth factor support and the development of plasmacytosis in this patient.