A phase I study in paediatric patients to evaluate the safety and pharmacokinetics of SPI-77, a liposome encapsulated formulation of cisplatin.

Pre-clinical studies indicate that cisplatin encapsulated in STEALTH((R))liposomes (SPI-77) retains anti-tumour activity, but has a much reduced toxicity, compared to native cisplatin. A phase I study was conducted to determine the toxicity and pharmacokinetics of SPI-77 administered to children with advanced cancer not amenable to other treatment. Paediatric patients were treated at doses ranging from 40 to 320 mg m(-2)by intravenous infusion every 4 weeks. Blood samples taken during, and up to 3 weeks after, administration and plasma and ultrafiltrate were prepared immediately. Urine was collected, when possible, for 3 days after administration. SPI-77 administration was well tolerated with the major toxicity being an infusion reaction which responded to modification of the initial infusion rate of SPI-77. Limited haematological toxicity and no nephrotoxicity were observed. No responses to treatment were seen during the course of this phase I study. Measurement of total plasma platinum showed that cisplatin was retained in the circulation with a half life of up to 134 h, with maximum plasma concentrations approximately 100-fold higher than those reported following comparable doses of cisplatin. Comparison of plasma and whole blood indicated that cisplatin was retained in the liposomes and there was no free platinum measurable in the ultrafiltrate. Urine recovery was less than 4% of the dose administered over 72 h. Results from this phase I study indicate that high doses of liposomal cisplatin can safely be given to patients, but further studies are required to address the issue of reformulation of liposomally bound cisplatin.

Cyclophosphamide metabolism in children following a 1-h and a 24-h infusion.

PURPOSE: The pharmacokinetics and metabolism of cyclophosphamide (CPA) when given as a 1-h and a 24-h infusion to children were compared. METHODS: Thirteen children with a variety of different malignancies received an identical dose of cyclophosphamide as a 1- and 24-h infusion. In each case the concentration of CPA and its principal metabolites were measured by a thin-layer-chromatography-photographic-densitometry technique. RESULTS: Cyclophosphamide clearance was greater during the 24-h infusion, following time-dependent increases in the metabolism of the drug (autoinduction) (median 5.1 vs 3.1 l/h/m2: P = 0.037). Autoinduction was seen in five children (38%), producing a median end of infusion concentration of 49% (range 28-89%) of the maximum and was not accompanied by an increase in the production of the principal inactive metabolites carboxyphosphamide and dechloroethylcyclophosphamide. CONCLUSIONS: These results suggest potential benefits of prolonging the infusion of CPA in clinical practice.

Low grade astrocytomas in the West of Scotland 1987-96: treatment, outcome, and cognitive functioning.

BACKGROUND: Low grade astrocytomas are among the most common central nervous system tumours in children. AIMS: To identify risk factors for the development of persistent intellectual handicap. METHODS: The notes of 30 children with histologically proven low grade astrocytoma who presented during the period 1987-96 were reviewed. Thirteen of these children who were diagnosed with intracranial tumours between 1992 and 1996 underwent cognitive assessment one year after the completion of treatment. RESULTS: Low grade astrocytomas were found in the cerebellum (59%), thalamus (17%), cerebral hemispheres (10%), and the cervical spinal cord (9%). Where possible all patients were treated with gross total resection of the tumour. Symptomatic children with tumours judged to be inoperable underwent biopsy followed by radiotherapy (13%). Three patients developed progressive disease following surgery and underwent repeat surgery and radiotherapy. Survival at a median follow up of 75 months (range 30-131) is 97%. At one year after the completion of treatment persisting cognitive impairment was common. The strongest predictor of IQ scores was the duration of symptoms of increased intracranial pressure preoperatively. CONCLUSIONS: Although the overall survival rate of children with low grade astrocytoma is excellent, significant long term disability occurs. Early diagnosis is essential to reduce postoperative cognitive morbidity.

Consolidation therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of cytosine arabinoside, epipodophyllotoxins and cyclophosphamide.

The intensification of post-remission induction therapy has been shown to improve the relapse-free survival for childhood acute lymphoblastic leukaemia (ALL), and is now a standard component of the treatment of childhood acute lymphoblastic leukaemia. For cytosine arabinoside (ara-C), methotrexate, vincristine and corticosteroids, in-vitro studies indicate that the extracellular drug concentration and exposure time are important determinants of cytotoxicity for human leukaemia cell lines. For L-asparaginase, epipodopyllotoxins and cyclophosphamide, there have been few studies of the relationship between cellular pharmacology and cytotoxicity in relation to ALL. The clinical and cellular pharmacology of methotrexate and cytosine arabinoside have been studied in relation to childhood ALL in vivo. For these drugs, there is evidence to suggest that maintenance of plasma concentrations that are biochemically optimal is necessary to maximize anti-leukaemic effects. For cytosine arabinoside in particular, optimal extracellular fluid concentrations are not likely to be achieved or maintained by bolus or short-duration i.v. infusions. A potentially important example of this may be served by the success of antimetabolite-based intrathecal chemotherapy for CNS-directed treatment of childhood ALL. Intrathecal administration of both methotrexate and cytosine arabinoside results in prolonged leukaemic cell exposure to cytotoxic concentrations of the drug. For vincristine, anthracyclines and asparaginase, the actual dose intensity received by children during consolidation therapy may be important, and there is considerable interpatient variation in the pharmacokinetics of cyclophosphamide and teniposide in the therapy of childhood cancers. The importance of this relationship to childhood ALL is not known. The pharmacological and cellular pharmacological studies performed at St Jude Children's Research Hospital (Memphis, TN, USA) have allowed investigation of the relationships between the clinical and cellular pharmacology of methotrexate and prognosis, and have supported the individualization of consolidation therapy with this drug. Cytosine arabinoside has been less well studied in relation to childhood ALL, although evidence exists to suggest that the administration of conventional-dose bolus or infusion schedules may not be optimal in terms of the antileukaemic efficacy of this antimetabolite. For L-asparaginase, ongoing studies may allow the relationship between dose and schedule of administration to be related to pharmacodynamic measures such as asparagine depletion and prognosis. Therefore, through knowledge of clinical and cellular pharmacological properties, it may be possible to optimize the consolidation phase of therapy for childhood ALL, without disrupting the fundamental principles by which the overall treatment is administered. This may be particularly important for children with disease that has inherent or acquired resistance to therapy.

Hepatic cirrhosis and portal hypertension in neuroblastoma.

Hepatic portal hypertension is an unusual complication of cancer therapy. The authors report 2 children under the age of 18 months with disseminated neuroblastoma who developed cavernous transformation of the portal vein during chemotherapy. While the older child remains well, the second patient succumbed from overwhelming variceal hemorrhage as a result of this condition. Full recovery of hepatic function is not invariable following the regression of extensive liver infiltration by neuroblastoma and consideration should be given to follow-up Doppler ultrasound imaging of the hepatic portal system in affected infants.

Metabolism and pharmacokinetics of oxazaphosphorines.

The 2 most commonly used oxazaphosphorines are cyclophosphamide and ifosfamide, although other bifunctional mustard analogues continue to be investigated. The pharmacology of these agents is determined by their metabolism, since the parent drug is relatively inactive. For cyclophosphamide, elimination of the parent compound is by activation to the 4-hydroxy metabolite, although other minor pathways of inactivation also play a role. Ifosfamide is inactivated to a greater degree by dechloroethylation reactions. More robust assay methods for the 4-hydroxy metabolites may reveal more about the clinical pharmacology of these drugs, but at present the best pharmacodynamic data indicate an inverse relationship between plasma concentration of parent drug and either toxicity or antitumour effect. The metabolism of cyclophosphamide is of particular relevance in the application of high dose chemotherapy. The activation pathway of metabolism is saturable, such that at higher doses (greater than 2 to 4 g/m2) a greater proportion of the drug is eliminated as inactive metabolites. However, both cyclophosphamide and ifosfamide also act to induce their own metabolism. Since most high dose regimens require a continuous infusion or divided doses over several days, saturation of metabolism may be compensated for, in part, by auto-induction. Although a quantitative distinction may be made between the cytochrome P450 isoforms responsible for the activating 4-hydroxylation reaction and those which mediate the dechloroethylation reactions, selective induction of the activation pathway, or inhibition of the inactivating pathway, has not been demonstrated clinically. Mathematical models to describe and predict the relative contributions of saturation and autoinduction to the net activation of cyclophosphamide have been developed. However, these require careful validation and may not be applicable outside the exact regimen in which they were derived. A further complication is the chiral nature of these 2 drugs, with some suggestion that one enantiomer may have a favourable profile of metabolism over the other. That the oxazaphosphorines continue to be the subject of intensive investigation over 30 years after their introduction into clinical practice is partly because of their antitumour activity. Further advances in analytical and molecular pharmacological techniques may further optimise their use and allow rational design of more selective analogues.

Cyclophosphamide metabolism in children with Fanconi's anaemia.

Although patients with Fanconi's anaemia (FA) exhibit a heightened sensitivity to DNA cross-linking agents, modified doses of CY continue to be used in their conditioning prior to BMT. We measured the pharmacokinetics and metabolism of CY in six children with FA using an established high performance thin layer chromatography technique. CY doses ranged between 5 and 20 mg/kg (median 10 mg/kg). The median CY clearance was 0.6 l/h/m2 (range 0.4-1.1 l/h/m2), t1/2 was 8.1 h (range 6.7-9.5 h) and volume of distribution was 0.19 l/kg (range 0.16-0.34 l/kg), respectively. These results contrast with those previously reported from a comparable group of non-FA children in whom the median CY clearance was 3.2 l/h/m2 (range 2-5 l/h/m2) (P = 0.035), t1/2 was 2.4 h (range 2-3.8 h) (P = 0.035) and volume of distribution 0.5 l/kg (range 0.26-0.95 l/kg) (NS). Unlike the control group in whom the presence of inactive metabolites of CY was common, metabolites could not be found in any FA patient. The enhanced sensitivity of children with FA to CY may in part result from altered drug metabolism.

The effect of fluconazole on cyclophosphamide metabolism in children.

Fluconazole is increasingly used in children receiving chemotherapy. Many of these patients are being treated with cyclophosphamide, which must undergo hepatic metabolism to produce active alkylating species. As a consequence of the cytochrome P-450 inhibitory properties of fluconazole, a potential interaction exists between these two agents that could influence the therapeutic effect of cyclophosphamide. To investigate this interaction, a retrospective case series of patients was chosen from a population of children with a previously established profile of cyclophosphamide metabolism. Twenty-two children who were not receiving other therapy known to influence drug metabolism were selected and analyzed in terms of fluconazole treatment; of these, nine were receiving fluconazole and thirteen were identified as controls. Study design was not randomized. The plasma clearance of cyclophosphamide was lower in patients receiving fluconazole [mean(SD) 2.4(0.71) versus 4.2(1.2) l/h/m2, p =.001]. In vitro studies were performed to characterize the interaction between fluconazole and cyclophosphamide in six human liver microsomes. The concentration of fluconazole required to reduce the production of 4-hydroxycyclophosphamide to 50% of control values (IC50) varied between 9 and 80 microM (median 38 microM). Further studies of the effect of fluconazole on 4-hydroxycyclophosphamide production in vivo are warranted to determine whether this interaction reduces the therapeutic effect of cyclophosphamide in clinical practice.

Small-bowel volvulus during treatment for renal tumors.

Intestinal obstruction as a result of postnephrectomy adhesions occurs in up to 7% of children treated for Wilms' tumor. The authors report two children who developed small-bowel volvulus during the treatment of their renal tumor. Both underwent urgent resection of their ischemic bowel with primary anastamosis and are long-term survivors. The risk of this complication may be increased in young children with bulky tumors who receive abdominal radiotherapy.

Outcome and toxicity of an Ifosfamide-based soft tissue sarcoma treatment protocol in children. The importance of local therapy.

Background. Although the survival of children with soft tissue sarcoma (STS) has improved considerably, the outcome of patients with metastatic disease, and those with primary tumours of the extremities or parameningeal sites remains disappointing. We describe the clinical outcome of an ifosfamide-based regimen with local therapy directed only to children who failed to achieve a complete response to initial chemotherapy.Patients and Methods. Twenty-one children with STS (16 rhabdomyosarcoma) who presented with unresectable tumours were treated with five courses of ifosfamide (9 g/m(2)) and etoposide (600 mgm(2)). Patients who did not achieve a complete response then received local therapy. Chemotherapy with ifosfamide combined with etoposide, vincristine (1.5 mg/m(2) and doxorubicin (60 mg/m(2)) or vincristine and actinomycin D (1.5 mg/m(2)) was continued for one year.Results and Discussion. Objective responses to five courses of ifosfamide and etoposide were seen in all patients. Disease free survival (DFS) at a median follow up of 59 months was 57% (95% CI 29-75%). The DFS of children who received local therapy was 89% compared with 33% in those who received chemotherapy alone (p=0.027). Locoregional recurrences did not occur in children who received radiotherapy to the site of the primary tumour. Ifosfamide-based chemotherapy does not reduce the incidence of loco-regional recurrence in children who do not receive local therapy.

High-dose cyclophosphamide for poor-prognosis and recurrent pediatric brain tumors: a dose-escalation study.

PURPOSE: To determine the maximum-tolerated dose (MTD) of cyclophosphamide (CTX) when administered over 2 consecutive days followed by hematopoetic stem-cell rescue given as two sequential courses to children with glioblastoma multiforme, poor-prognosis pontine gliomas, and other recurrent CNS tumors. PATIENTS AND METHODS: Two identical doses of CTX were administered 24 hours apart to 14 children and followed by hematopoetic stem-cell rescue. This treatment was repeated immediately following hematologic recovery. The starting dose of CTX was 2.5 g/m2/d with increments of 0.5 g/m2/d. CTX pharmacokinetics and metabolism were measured during 22 courses of treatment. Toxicity and tumor response were recorded. RESULTS: There were two toxic deaths at the dose level of 4 g/m2/d. These were not clearly related to cardiac toxicity and may have been due to generalized capillary leak syndrome. Thus, the MTD of CTX was 3.5 g/m2/ d. There were six complete responses (CRs) (46%; (95% confidence interval [CI], 19% to 73%) and four partial responses (PRs) (31%; 95% CI, 6% to 56%), and one patient achieved stable disease. All children with intracranial primitive neuroectodermal tumors (PNETs) improved following CTX. The median duration of tumor response was 6 months (range, 4 to 29) and only one patient remains disease-free following CTX alone. Overall survival is 21% (95% CI, 13% to 29%) at a median follow-up time of 27 months (range, 12 to 34). CONCLUSION: The MTD of CTX when followed by hematopoetic stem-cell rescue is 3.5 g/m2 administered on each of 2 consecutive days. This treatment was tolerable in children with poor-prognosis brain tumors and produced complete responses in children with recurrent PNETs.

Recurrent pneumomediastinum and pneumothorax in Langerhans cell histiocytosis.

Pneumothorax is an unusual complication of pulmonary Langerhans cell histiocytosis. We report three children who developed recurrent intrathoracic air leaks. In one case, bilateral pneumothoraces may have been precipated by intermittent positive pressure ventilation during general anaesthesia. Chemical pleurodesis was unsuccessful in preventing recurrence of pneumothoraces in two children. The use of extracorporeal membrane oxygenation as an alternative to intermittent positive pressure ventilation in children with respiratory failure from Langerhans cell histiocytosis is discussed.

Cyclophosphamide and ifosfamide metabolites in the cerebrospinal fluid of children.

Although both cyclophosphamide (CP) and ifosfamide (IF) are used in the treatment of central nervous system tumors, little is known about the concentration of either drug or their metabolites in the cerebrospinal fluid (CSF) of children. The concentrations of the parent oxazaphosphorine and its principal metabolites were measured simultaneously in the plasma and CSF of 25 children. Twenty-one patients received CP for the treatment of either acute lymphoblastic leukemia, non-Hodgkin's lymphoma, or medulloblastoma, and 4 children received IF for the treatment of rhabdomyosarcoma. A high degree of interpatient variation was seen in terms of the CSF concentration of CP and the CSF:plasma ratio. The CSF:plasma ratio was greater for IF than for CP (P < 0.001). In contrast to IF, where the majority of metabolites was measured in the CSF, no child receiving CP had detectable metabolites. Children receiving dexamethasone had lower concentrations of CP in the CSF (P = 0.04). The CSF:plasma ratio for isophosphoramide mustard was greater than that for either parent drug or any other metabolite. These results demonstrate that IF enters the CSF to a greater extent than CP in children. The ability of both IF and CP and their metabolites to cross the blood-brain barrier may be reduced by dexamethasone.

Cyclophosphamide pharmacokinetics in children.

1. Cyclophosphamide pharmacokinetics were measured in 38 children with cancer. 2. A high degree of inter-patient variation was seen in all pharmacokinetic parameters. Cyclophosphamide half-life varied between 1.1 and 16.8 h, clearance varied between 1.2 and 10.61 h-1 m-2 and volume of distribution varied between 0.26 and 1.48 1 kg-1. 3. The half-life of cyclophosphamide was prolonged at high dose levels (P = 0.008). 4. Children who had received prior treatment with dexamethasone showed a mean increase in clearance of 2.51 h-1 m-2 (P = 0.001) presumably as a result of CYP450 enzyme induction. 5. Treatment with allopurinol or chlorpromazine was associated with a significant increase in cyclophosphamide half-life (P < 0.001 in both cases). 6. Dose and concurrent treatment may influence cyclophosphamide metabolism in vivo and thus potentially alter the drugs therapeutic effect.

Intrasubject variation in children of ifosfamide pharmacokinetics and metabolism during repeated administration.

The aim of this study was to investigate intrasubject variability in ifosfamide (IFO) pharmacokinetics and metabolism which may influence clinical effect, since the pharmacology of this drug is dependent on metabolism. A group of 11 patients (ages 1-16 years) were studied on at least two occasions. IFO, 9 gm-2 was administered as a continuous infusion over 72 h. Plasma and urine samples were collected and concentrations of IFO and its metabolites were determined. Comparisons were made between courses in the same subject, allowing for differences in age and prior IFO treatment. There was a wide variation in drug (twofold) and metabolite (up to tenfold) AUCs between courses in the same patient. Although some patients did show an increase in clearance between courses (up to threefold), there was no significant consistent change in overall pharmacokinetics among the different courses studied in the same patient. There was a significant decrease (up to 63%) in the AUC of the inactive metabolite 3-dechloroethylifosfamide (3-DCI) in later courses compared with the first course studied (P = 0.032, paired t-test). This was matched by an increase in the AUC of the total dechloroethylated metabolites with course (P = 0.015, paired t-test). None of the other metabolites measured showed any consistent change in plasma or urine levels between courses. Overall, the AUC of parent drug correlated with age (r2 = 0.86, P = 0.011), and postinfusion half-life correlated with plasma bilirubin (r2 = 0.89, P = 0.007). This study demonstrated large and seemingly unpredictable intrasubject variability in IFO pharmacokinetics and metabolism during repeated administrations. Investigations relating the clinical effects of IFO to pharmacokinetics and metabolism must take this variation into account.

Solid alveolar rhabdomyosarcoma with a t(2;13).

We report a child with a progressive "solid alveolar rhabdomyosarcoma" in whom analysis of tumor cells revealed a t(2;13) translocation characteristic of the classical alveolar subtype. Both subtypes of alveolar rhabdomyosarcoma are associated with a poor response to treatment and the occurrence of this translocation in both is suggestive of a common biologic origin.

Cyclophosphamide metabolism in children.

The alkylating agent cyclophosphamide is a prodrug which is metabolized in vivo to produce both therapeutic and toxic effects. Cyclophosphamide metabolism was investigated in 36 children with various malignancies. Concentrations of cyclophosphamide and its principal metabolites were measured in plasma and urine using a quantitative high-performance TLC method. The results indicated a high degree of inter-patient variation in metabolism. In contrast to previous adult studies on urinary metabolites, plasma carboxyphosphamide concentrations did not support the existence of polymorphic metabolism. Plasma concentrations of dechlorethylcyclophosphamide and carboxyphosphamide were correlated in individual patients, suggesting that the activity of both aldehyde dehydrogenase and cytochrome P450 enzyme(s) determine carboxyphosphamide production in vivo. The presence of ketocyclophosphamide in plasma was strongly associated with dexamethasone pretreatment and was also accompanied by a high clearance of the parent drug. Interpatient differences in metabolism reflect individual levels of enzyme expression and may contribute to variation in clinical effect.