Robot-guided convection-enhanced delivery of carboplatin for advanced brainstem glioma.

BACKGROUND: Patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis with median survival reported as 9 months. The failure of systemic chemotherapy to improve prognosis may be due to inadequate penetration of the blood-brain barrier (BBB). Convection-enhanced delivery (CED) has the potential to improve outcomes by facilitating bypass of the BBB. We describe the first use of carboplatin for the treatment of advanced DIPG using a robot-guided catheter implantation technique. METHODS: A 5-year-old boy presented with a pontine mass lesion. The tumor continued to progress despite radiotherapy. Using an in-house modification to neuroinspire stereotactic planning software (Renishaw Plc., Gloucestershire, UK), the tumor volume was calculated as 43.6 ml. A transfrontal trajectory for catheter implantation was planned facilitating the in-house manufacture of a recessed-step catheter. The catheter was implanted using a neuromate robot (Renishaw Plc., Gloucestershire, UK). The initial infusion of carboplatin (0.09 mg/ml) was commenced with real-time T2-weighted MRI, facilitating estimation of the volume of infusate distribution. Infusions were repeated on a total of 5 days. RESULTS: The catheter implantation and infusions were well tolerated. A total volume of 49.8 ml was delivered over 5 days. T2-weighted MRI on completion of the final infusion demonstrated signal change through a total volume of 35.1 ml, representing 95 % of the targeted tumor volume. Follow-up at 4 weeks revealed clinical signs of improvement and increased T2 signal change throughout the volume of distribution. However, there was tumor progression in the regions outside the volume of distribution. CONCLUSIONS: This case demonstrates the feasibility of accurately and safely delivering small-diameter catheters to the brainstem using a robot-guided implantation procedure, and real-time MRI tracking of infusate distribution.

The experience of mothers caring for a child with a brain tumour.

BACKGROUND: Brain tumours are the second most common form of childhood cancer, accounting for over 20% of all cases in European children. Understanding the impact of diagnosis and treatment of a brain tumour on the family is an essential pre-requisite to identifying ways to provide effective support. AIM: (1) To explore the impact of having a child with a brain tumour on the main caregiver in the family; (2) to describe mothers' experiences of coping with their child's illness, including personal barriers and strengths; and (3) to identify causes of stress and sources of support to inform improvements in care delivery. METHOD: Participants were drawn from a group of caregivers enrolled in a longitudinal study of outcome following diagnosis of a childhood brain tumour. Six caregivers took part, two from each of the high-, medium- and low-impact groups based on their Impact on Families Scale scores. Semi-structured interviews were used, with questions covering: (1) impact of the diagnosis on main caregiver and family; (2) personal barriers and strengths; and (3) causes of stress and sources of support. Interviews were transcribed verbatim and coded manually into five themes, which comprised 19 subthemes. FINDINGS: Coping methods and provision of help and support were major preoccupations for main caregivers from all impact groups. Caregivers in the high-impact group reported less conflict. High- and medium-impact group caregivers had experienced less 'hindrance and heartache', than those with low impact scores, suggesting that the stress associated with diagnosis and treatment of the tumour may have increased cohesion and acceptance within these families. CONCLUSION: Families of children diagnosed with a brain tumour experience considerable negative impact and may perceive themselves as struggling to cope. Provision of help and support, within and outside the extended family, including from health, education and other services, is perceived as helpful.

Treatment of CNS malignant rhabdoid tumors.

BACKGROUND: Central Nervous System (CNS) rhabdoid tumours are a highly malignant group of neoplasms usually occurring in children under 2 years of age with characteristic histopathologic findings but unclear histiogenesis and almost uniformly fatal outcome. There is still no proven curative therapy available. PROCEDURE: The clinical course and the successful outcome of therapy in two children with primary CNS rhabdoid tumour are described in this context. Both children had subtotal excision of the primary tumour and received chemotherapy based on the SIOP Malignant Mesenchymal Tumour (MMT-95) protocol with addition of triple intrathecal chemotherapy. Following this, one of the patients received high dose therapy (busulphan and thiotepa), whereas the other had craniospinal radiotherapy with a boost to the primary site. RESULTS: The treatment was reasonably well tolerated and both patients are alive with no evidence of disease 52 months and 65 months after the primary diagnosis. Their favourable outcomes are compared with those of 49 others reported in the literature. CONCLUSIONS: Intensified therapy (with autologous bone marrow transplantation and intrathecal chemotherapy) may improve the prognosis of patients with malignant rhabdoid tumour.

Remission induction therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of vincristine, corticosteroids, L-asparaginase and anthracyclines.

Remission induction therapy with vincristine, a corticosteroid, L-asparaginase and an anthracycline has been the mainstay of the initial phase of treatment for childhood acute lymphoblastic leukaemia (ALL) for the past 25 years. The speed and depth of the early response to remission induction therapy has become an important determinant of the intensity of subsequent therapy in many protocols worldwide. Moreover, the detection of significant levels of minimal residual disease at the end of remission induction may have an important bearing on subsequent outcome. Although these clinical observations may reflect, in part, the inherent sensitivity of lymphoblasts to remission induction therapy, the pharmacology of these agents in relation to childhood ALL may also play an important part in early response to therapy. In-vitro studies of human leukaemia cell lines indicate that both the extracellular fluid concentration and duration of exposure to vincristine and anthracyclines are important determinants of cytotoxicity. For L-asparaginase and corticosteroids, the cellular and molecular pharmacological determinants of chemosensitivity have been partially characterized, but further work is needed in this area. The clinical pharmacology of vincristine and L-asparaginase have been well characterized in relation to childhood ALL, and considerable interpatient pharmacokinetic variability exists for these drugs. For corticosteroids and anthracyclines, pharmacology studies are needed in order to fully characterize and understand the factors influencing interpatient pharmacokinetic variability for these agents in relation to childhood ALL. Whereas the relationship between the clinical pharmacology, and potentially important pharmacodynamic effects such as asparagine depletion, has been well characterized for therapy with L-asparaginase, similar studies have yet to be performed for the other drugs that form the mainstay of remission induction therapy for childhood ALL. Therefore, further studies are required to investigate the relative importance of the clinical and cellular pharmacology of vincristine, corticosteroids, L-asparaginase and anthracyclines in the speed and depth of response to remission induction therapy for childhood ALL. Where these have been studied, interindividual differences in the clinical and cellular pharmacology of anticancer agents have been shown to be important determinants of the long-term disease-free survival for children with ALL.

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.

Growth hormone hypersecretion in a girl with neurofibromatosis type 1 and an optic nerve glioma: resolution following chemotherapy.

Growth hormone hypersecretion is extremely rare in childhood. We report a girl with neurofibromatosis type 1, an extensive optic nerve glioma and growth hormone hypersecretion. She was treated with chemotherapy to prevent further extension of her sight-threatening tumour. Three years after chemotherapy her growth hormone hypersecretion has resolved although she has gone on to develop precocious puberty.

The role of pharmacokinetic and pharmacodynamic studies in the planning of protocols for the treatment of childhood cancer.

The chemosensitive nature of many childhood cancers means that chemotherapy has a greater role in therapy than in adult practice. However, the present methods, schedules of administration and combinations have often been derived form historical precedent rather than from pharmacological knowledge. For many drugs, paediatric phase I and II studies have never been performed and reliance on adult studies will be inadequate as children may show differences in drug disposition or susceptibility to toxicity. In this review, we examine pharmacokinetic and pharmacodynamic studies as they relate to the treatment of a 'model' childhood cancer in the UK: acute lymphoblastic leukaemia (ALL). Each of the drugs used is examined in the light of pharmacological evidence. For the drugs L-asparaginase, methotrexate, cytarabine and the thiopurines, this evidence suggests that the current use of these drugs is not optimal and that significant improvements in cure for ALL might be achieved by pharmacologically guiding their use. We highlight an important recent study demonstrating a 10% increase in long-term survival in childhood ALL by the use of pharmacologically guided dosing compared to standard (by body surface area) dosing. Since significant improvements in survival may depend upon such effective use, we suggest that pharmacological studies become an integral part of phase II and phase III trials of treatments for childhood cancer.

Central nervous system metastasis in Wilms' tumor: a review of three consecutive United Kingdom trials.

BACKGROUND: Central nervous system (CNS) metastasis is an uncommon event in pediatric oncology, and typically occurs at the end stage of the disease. Previous reports suggest that brain metastases in patients with Wilms' tumor might behave differently. METHODS: This study reviews the data from three consecutive United Kingdom Children's Cancer Study Group trials (UKW 1, 2, and 3) focusing on this entity. RESULTS: Seven children of 1249 (0.6%) entered into Wilms' tumor studies developed CNS metastases between 2-27 months after initial diagnosis. At last follow-up 3 patients still were alive and 4 had died; the mean follow-up from recurrence in the surviving patients was 63 months. Radiotherapy and chemotherapy were administered to all surviving patients. Those patients who died had tumors with particularly aggressive features or extensive disease. CONCLUSIONS: CNS metastasis of Wilms' tumor is not in itself a terminal event. With regard to other sites of recurrence, salvage therapy can be expected to be effective in patients without other adverse prognostic features.

Chemotherapy for spinal cord astrocytoma: can natural history be modified?

Standard treatment of spinal cord astrocytomas is based upon surgery, followed by radiotherapy when resection is incomplete or when histology is of high grade. Owing to the major consequences of radiotherapy on the spine in childhood, alternative therapies must be explored. The potential role of chemotherapy in the management of spinal cord astrocytoma remains to be defined. Two patients are described. The first was a 19-month-old child with an anaplastic astrocytoma of the cervical spinal cord that progressed rapidly after initial partial resection. Chemotherapy was begun according to the UKCCSG Baby Brain Protocol, with marked clinical improvement. Reassessment by MRI at 4 months showed improvement, and at the end of treatment no evaluable disease remained. The second was a 4-year-old child with a recurrent low-grade astrocytoma. Chemotherapy according to the SIOP Protocol for Low Grade Gliomas was administered for 3 months, after which marked tumour regression was seen, with neurological recovery. These patients demonstrate the potential value and low morbidity of chemotherapy in spinal cord astrocytoma. The management of this rare tumour is discussed.

A study of the feasibility and accuracy of pharmacokinetically guided etoposide dosing in children.

Pharmacokinetically guided dosing was performed in nine paediatric patients receiving etoposide. Doses on day 2 of a 2- or 3-day schedule were adapted on the basis of the day-1 area under the plasma etoposide concentration vs time curve (AUC). The day-1 AUC was estimated using a limited sampling model and the day-2 target AUC defined by the etoposide dose-AUC relationship observed in 33 children. Target AUC values (4.6-8.2 mg ml(-1) x min) were achieved with a high degree of precision and with little bias (mean error 11% and root mean squared error 15% respectively). Pharmacokinetic parameters were similar to those reported previously in children, although interpatient pharmacokinetic variability was less than that observed previously: plasma clearance, 23 (18-26) ml min(-1) m(-2); volume of distribution at steady state (Vdss), 6.0 (3.9-8.9) l m(-2); t(1/2) 254 (127-550) min (median and range). This study has demonstrated that pharmacokinetically guided dosing with etoposide is feasible. However, pharmacokinetically guided dosing is likely to be of most benefit in patients with abnormalities of renal or hepatic function, or in children with prior exposure to cisplatin.

Etoposide for the treatment of paediatric tumours: what is the best way to give it?

Etoposide is one of the most important drugs available for the treatment of paediatric malignancies. Although there is evidence of schedule dependency for etoposide therapy in adults with small-cell lung cancer, the relevance of this observation to childhood cancers is uncertain. Prolonged parenteral or oral etoposide therapy has not yet shown a clear-cut advantage over intermittent treatment, and there are still no data to show that the administration of etoposide as a short intravenous (i.v.) daily infusion for 5 days does not represent acceptable therapy for primary disease. The pharmacokinetic variability seen with etoposide argues strongly for the use of pharmacologically guided dosing, and the introduction of etoposide phosphate will simplify both parenteral etoposide administration and the future evaluation of alternative etoposide schedules. Although the impact of molecular and cellular pharmacological investigations on the clinical use of etoposide has yet to be felt, the tools to perform these studies are now available and prospective trials can be designed. Such studies, performed in the setting of a pharmacologically guided trial to ensure control over pharmacokinetic variability, should identify the best way of treating children with etoposide.

Pharmacokinetically guided dosing of carboplatin and etoposide during peritoneal dialysis and haemodialysis.

Two patients with relapsed Wilms' tumour and renal failure requiring dialysis were given carboplatin and etoposide by pharmacokinetically guided dosing. The target area under the drug plasma concentration vs time curve (AUC) was 6 mg ml-1 min for carboplatin and 18 and 21 mg ml-1 min for etoposide. On course 1 measured AUCs of carboplatin and etoposide were 6 and 20 mg ml-1 min for patient 1 and 6 and 21 mg ml-1 min for patient 2 respectively. Peritoneal dialysis did not remove carboplatin or etoposide from the plasma, however carboplatin but not etoposide was cleared by haemodialysis. Therapy with carboplatin and etoposide is possible in children and adults with renal failure who require dialysis, but in this situation pharmacokinetic monitoring is essential.

Exposure and schedule dependency of etoposide in neuroblastoma and leukaemia cells in vitro.

Using an in vitro clonogenic assay system, we examined the relationship between concentration, duration and schedule of exposure to etoposide and cytotoxicity in three cell lines. Two cell lines (SK-N-SH and IMR32) were derived from human neuroblastomas, and one (L1210) was the original murine leukaemia cell line used to define schedule dependency of etoposide in vivo. Cytotoxicity was found to be determined by the product of concentration and duration of exposure over a 120-fold range of durations and a 100-fold range of concentrations. No difference in cytotoxicity was seen following equivalent exposure either continuously or in two separate intervals. In one cell line, exposure to etoposide when at confluence led to a highly resistant subpopulation comprising 10-15% of the entire cell number. This did not seem to be associated with any difference in the rate of etoposide efflux from cells preloaded with 3H-etoposide. We conclude that etoposide does not show schedule dependency in vitro, but cytotoxicity is related to total exposure to etoposide. The schedule dependency seen in vivo may possibly arise from host pharmacokinetic factors.

Concentration-dependent effects of 9-cis retinoic acid on neuroblastoma differentiation and proliferation in vitro.

The observation that neuroblastoma cells differentiate in response to retinoic acid (RA) in vitro has led to clinical trials using either 13-cis or all-trans RA. Since 9-cis RA may also have important biological functions, we have compared the potential of RA isomers to induce differentiation and inhibit cell proliferation of SH SY 5Y neuroblastoma cells. 9-cis RA at high concentrations is better at inducing morphological differentiation than either all-trans or 13-cis RA and as effective at inhibiting proliferation. Hence, 9-cis RA or stable analogues may have important therapeutic potential in the treatment of neuroblastoma.

Etoposide pharmacokinetics in children: the development and prospective validation of a dosing equation.

Pharmacokinetic studies of etoposide administered at 100-200 mg/m2 to 33 children are described. Twenty-seven studies were performed in children aged < 10 years. Repeat studies were performed in 11 patients. Median pharmacokinetic parameters were as follows: plasma clearance, 26 ml/min/m2; volume of distribution, 4.9 liters/m2; area under the etoposide plasma concentration-time curve (AUC), 3.9 mg/ml x min per 100 mg/m2. Interindividual variability in pharmacokinetic parameters was large (coefficient of variation (CV) = 30, 28, and 27%, respectively) in comparison with intraindividual variability (CV = 12, 14, and 12%, respectively). Variability in AUC was much greater in those patients treated with 150-200 mg/m2 etoposide than with 100 mg/m2 (CV, 35 versus 13%) and was related to variability in renal function and prior exposure to cisplatin. Data from the first 20 studies were used to develop pharmacokinetic monitoring equations which were validated in a further 13 patients. The most accurate equation relies upon the elimination constant of 51Cr-EDTA and a single blood specimen taken at the end of the etoposide infusion. [formula: see text] where K = 51Cr-EDTA elimination rate constant. This equation showed no significant bias, and the predictive error was small with respect to AUC calculated according to a two-compartment model. Predictive error did not increase with increasing AUC, whereas a marked increase in predictive error was seen for dosing according to body surface area. Dosing according to body surface area alone led to marked over- or underexposure to etoposide in 8 patients. Pharmacokinetic monitoring using the equation described would have identified these patients and permitted dose modification. This approach provides an accurate means of monitoring etoposide AUC for administration times of 1-4 h without the need for detailed pharmacokinetic sampling. It will allow a significant reduction in the variability of exposure seen with surface area-based dosing.

Prohibitive toxicity of a dose-intense regime for metastatic neuroblastoma containing ifosfamide, doxorubicin and cisplatin.

Three patients with stage 4 neuroblastoma were treated with a schedule comprising alternating modules of myelosuppressive (ifosfamide, etoposide, doxorubicin) and less myelosuppressive (vincristine, cisplatin) drugs given every 10 days regardless of the neutrophil count. A partial response was seen in two patients, and a very good partial response, in one patient. Extensive blood-component support was required. Non-haemopoietic toxicity was severe and led to treatment delays in two patients. Ifosfamide-related encephalopathy was seen in one patient and nephrotoxicity, in two patients. Mucositis was severe in two patients, may have contributed to the high rate of sepsis observed, and precluded the use of doxorubicin in one patient. As ifosfamide and doxorubicin were felt to be responsible for much of the toxicity, a subsequent schedule did not include these agents.