Michael Stevens

Carboplatin pharmacokinetics in children: the development of a pediatric dosing formula. The United Kingdom Children's Cancer Study Group.

PURPOSE The aim of this study was to define the pharmacokinetics of carboplatin in children and use the data to develop a pediatric dose formula. It was anticipated that renal function would be a major determinant of carboplatin disposition and the relationship between carboplatin clearance and glomerular filtration rate (GFR) was examined in detail. PATIENTS AND METHODS Plasma carboplatin pharmacokinetics were measured as ultrafiltrable platinum in 22 patients (5 to 63 kg) following 200 to 1,000 mg/m2 of carboplatin. GFR was measured by the plasma clearance of chromium 51-edathamil (51Cr-EDTA). RESULTS Carboplatin pharmacokinetics in children were best described in most patients (16 of 22) by a two-compartment model. The dose-normalized area under the plasma carboplatin concentration versus time curve (AUC) ranged from 3.1 to 9.6 mg/mL.min/400 mg/m2 and there was only a weak linear relationship between carboplatin dose and AUC (R2 = .31). There was a significant relationship between absolute carboplatin and 51Cr-EDTA clearances (R2 = .56), but the relationship was weaker (R2 = .28) when both clearances were normalized for body surface area. Carboplatin plasma clearance was predicted by the equation: clearance = GFR (mL/min) + 0.36 x body weight (BW; kg), and a modified form of the adult carboplatin dose formula is proposed: dose (mg) = target AUC x (GFR [mL/min] + [0.36 x BW(kg)]). Two further equations were developed that use the 51Cr-EDTA half-life (t1/2) to calculate the GFR and these may reduce errors resulting from inaccurate measurement of the volume of distribution for 51Cr-EDTA. In patients treated with single-agent carboplatin or carboplatin plus vincristine, there was a significant sigmoidal relationship between AUC and thrombocytopenia (R2 = .56). CONCLUSION GFR-based carboplatin dosing in children should be feasible and will be evaluated prospectively.

Prospective Validation of Renal Function–Based Carboplatin Dosing in Children With Cancer: A United Kingdom Children’s Cancer Study Group Trial

PURPOSE Carboplatin dosing in adults with cancer is based on renal function. The purpose of the current study was to validate a previously developed pediatric carboplatin-dosing formula. PATIENTS AND METHODS Thirty-eight pediatric patients were randomized to receive a carboplatin dose calculated according to surface area or a renal function-based dosing formula. On the next course of therapy, the alternative dosing method was used for each patient. Carboplatin pharmacokinetics (based on free plasma platinum concentrations) were measured after both courses. RESULTS The mean observed areas under the carboplatin concentration-versus-time curve (AUCs) after renal function- and surface area-based dosing were 98% and 95% of the target AUCs, respectively. The variation in the observed AUC was significantly less after renal function-based dosing (F test, P =.02), such that 74% of courses had an observed AUC within +/- 20% of the target value, versus 49% for courses after dosing according to surface area. Only one of 22 courses at the center with the most experience with renal function-based dosing was associated with an AUC outside +/- 20% of the target value, versus nine of 22 courses after surface area-based dosing in the same center. There was a relationship (r(2) =.71) between carboplatin AUC and thrombocytopenia in 10 neuroblastoma patients treated with a combination of carboplatin, vincristine, etoposide, and cyclophosphamide. CONCLUSION Renal function-based carboplatin dosing in children results in more consistent drug exposure than surface area-based drug administration.

DNA ploidy and proliferative activity (S-phase) in childhood soft-tissue sarcomas: their value as prognostic indicators

The value of DNA ploidy as a prognostic indicator is well established in many cancers, but recent studies in childhood rhabdomyosarcoma (RMS) have been contradictory. In a retrospective study of 128 cases of soft-tissue sarcoma (STS) diagnosed since 1980, the prognostic value of clinical, histological and flow cytometric parameters was compared, using univariate and multivariate methods. Eighty-one RMSs, 18 extraosseous Ewings (EOE)/peripheral neuroectodermal tumours (PNETs) and 29 other non-RMS STSs were histologically and clinically reviewed. Five year actuarial survival was 63.4% for all STSs and 69.4% for RMSs. Paraffin-embedded tissue blocks were available for flow cytometry in 90 cases. Of the RMSs, 65.5% were aneuploid [DNA index (DI) > 1.1] compared with 23% of the EOE/PNETs and 31% of non-RMS STSs. Median S-phase was also significantly higher in RMSs (17.0%) than in other STSs (10.8%) (P = 0.0023). Univariate analysis in RMSs showed that stage, ploidy status, S-phase, site and tumour size all had a significant impact on survival. In multivariate analysis of 59 cases of RMS, one clinical and two flow cytometric parameters were independently associated with poor prognosis. These were stage (IV), nonhyperdiploidy (DI < 1.10 and > 1.8) and a high rate of proliferative activity (S-phase > 14.0%). These results confirm that ploidy and S-phase are important new prognostic indicators in rhabdomyosarcoma.

Ifosfamide nephrotoxicity in children: histopathological features in two cases.

We report on two children with rhabdomyosarcoma who received ifosfamide as part of their chemotherapy schedule. Both children subsequently developed severe ifosfamide-induced nephrotoxicity, necessitating electrolyte supplementation. We describe the histopathological findings of renal biopsies performed in these children after the onset of renal dysfunction and comment on the possible mechanisms involved in ifosfamide nephrotoxicity.

Spectrum of peritoneal mesothelioma in childhood: clinical and histopathologic features, including DNA cytometry.

Different types of peritoneal mesothelioma (PM) occur in children and adults. All these share certain histopathologic features but differ in other aspects, such as age of occurrence, site and sex predominance, etiology, and biologic behavior. The article describes four patients, two with cystic PM (one of whom had multiple recurrences) and two with malignant PM (one of whom had pleural metastases). These cases illustrate the variable behavior of this tumor in childhood and highlight the difficulties encountered in diagnosis and treatment. Three different groups of mesothelioma are recognized: a classic, asbestos-related, malignant mesothelioma of adults, typically occurring in the pleural cavity; a multicystic mesothelioma, predominantly affecting the pelvic peritoneum of young women and associated with a good prognosis; and mesotheliomas in children, which are not associated with asbestos exposure and have an unpredictable biologic behavior requiring individual treatment strategies. In the patients studied, DNA index measured by flow cytometry showed a difference between the cystic (aneuploid) and malignant (diploid) tumors. The proliferative rate (S phase) of the tumor was low in all four cases.

21-day schedule oral etoposide in children- a feasibility study

To determine the feasibility and toxicity of prolonged oral etoposide in children, 22 patients with relapsed or refractory disease were commenced on etoposide 50-100 mgs/m2 per day for 21 days. A second course was administered after full blood count recovery, followed by disease reassessment. In total, 72 courses were evaluable for toxicity, with 10% of completed courses complicated by febrile neutropenia. 15 patients were evaluable for response, with 1 partial response, 10 stable disease and 4 progressive disease. This schedule was well tolerated with acceptable toxicity when doses of less than 80 mg/m2/day were administered and warrants further evaluation.

The Assessment of Subclinical Ifosfamide-Induced Renal Tubular Toxicity Using Urinary Excretion of Retinol-Binding Protein

The excretion of retinol-binding protein in early morning urine samples, expressed as a ratio to urinary creatinine (RBPCR), was used as a measure of proximal renal tubular toxicity in children during or after treatment with ifosfamide-containing chemotherapy. The results showed a progressive increase in renal tubular leak after exposure to ifosfamide that persisted after treatment. The toxic effect appeared to be greatest in younger children and at least partly dose-dependent, although partially reversible after each course of chemotherapy. However, few patients had related symptoms and none experienced major metabolic difficulty. RBPCR appears to offer a sensitive and noninvasive way of monitoring sequential change in renal tubular function after exposure to ifosfamide. Further studies are required to define more clearly the effect of cumulative dose, age, and drug scheduling and to identify whether a level of renal tubular dysfunction, measured by RBPCR or a similar noninvasive technique, can identify a threshold beyond which further exposure to ifosfamide is likely to be significantly and permanently damaging.

RECURRENT HEMANGIOPERICTYOMA OF THE CHEST WALL: Report of a Case in a 5-Year-Old Boy

Hemangiopericytoma in infants and children is usually benign. A case of recurrent hemangiopericytoma of the mediastinum in a 5-year-old boy is reported. The tumor recurred twice because of incomplete excision in the first instance. Immunohistochemistry of this enigmatic tumor is reviewed and ultrastructural features are described. The importance of total initial excision of the tumor and a prolonged follow-up is highlighted.

Severe Thrombocytopenia in Sickle Cell Crisis

Thrombocytopenia is unusual in sickle cell disease. We present the case of a child with homozygous sickle cell disease who experienced life-threatening thrombocytopenia during a prolonged and disabling vasoocclusive episode. Irreversibly sickled cells were conspicuously absent from the peripheral blood at presentation and during the subsequent protracted illness. These observations illustrate the pathophysiology of the intravascular events during vasoocclusive crisis and provide indirect evidence for the consumption of both platelets and irreversibly sickled cells at sites of infarction.

Intracardiac thrombus and tricuspid valve obstruction: a complication of Hickman catheter use

The risk of catheter-related sepsis is well recognized in immunocompromised patients with an indwelling central venous line, but the hazard of thrombus involving the right atrium is less well known. We report the case of a child who died after intraartrial thrombus obstructed the tricuspid valve. The predisposing factors and available treatment strategies are discussed.