Population pharmacokinetics of trabectedin in adolescent patients with cancer.

PURPOSE: To characterize the trabectedin population pharmacokinetics in children and adolescent patients with cancer and compare it with the trabectedin pharmacokinetics in adults. METHODS: Plasma concentrations from ten adolescent and three children with cancer (age range 4.0-17.0 years) treated with trabectedin at doses ranging from 1.1 to 1.7 mg/m2, administered as a 24-h continuous intravenous infusion every 3 weeks, were available for the analysis. An external model evaluation was performed to verify whether a previously developed adult population pharmacokinetic model was predictive of the pediatric plasma concentrations of trabectedin. The maximum a posteriori estimation of the individual pharmacokinetic parameters for pediatric patients was conducted, after successful completion of the external evaluation step. The relationships between pharmacokinetic parameters and body size were evaluated. RESULTS: External evaluation methods showed no major differences between the adult population and children and adolescent patients of this study. The mean ± standard deviation (SD) of the individual estimated clearance and central volume of distribution in these children/adolescent patients was 36.4 ± 16.1 L/h and 13.2 ± 6.54 L, respectively. These values were similar to the typical values reported for adult patients-37.6 L/h and 13.9 L (for females) and 16.1 L (for males). The median area under the plasma concentration versus time curve (AUC) in children/adolescent patients was 55.1 µg h/L, while in the adult population the median AUC was 61.3 µg h/L, both administered a 1.5 mg/m2 dose regimen with mean (range) BSA for adults = 1.86 (0.90-2.80) vs children/adolescent patients = 1.49 (0.66-2.54). CONCLUSIONS: The adult population pharmacokinetic model adequately described the trabectedin plasma concentrations and its variability in the pediatric population of patients involved in this assessment that mostly comprised adolescents. The trabectedin systemic exposure achieved in this population was comparable (within 12%) to the exposure obtained in adult population when the same dose, expressed in mg/m2, was administered.

Thyroid-stimulating hormone suppression for protection against hypothyroidism due to craniospinal irradiation for childhood medulloblastoma/primitive neuroectodermal tumor.

PURPOSE: Hypothyroidism is one of the earliest endocrine effects of craniospinal irradiation (CSI). The effects of radiation also depend on circulating thyroid-stimulating hormone (TSH), which acts as an indicator of thyrocyte function and is the most sensitive marker of thyroid damage. Hence, our study was launched in 1998 to evaluate the protective effect of TSH suppression during CSI for medulloblastoma/primitive neuroectodermal tumor. PATIENTS AND METHODS: From Jan 1998 to Feb 2001, a total of 37 euthyroid children scheduled for CSI for medulloblastoma/primitive neuroectodermal tumor underwent thyroid ultrasound and free triiodothyronine (FT3), free thyroxine (FT4), and TSH evaluation at the beginning and end of CSI. From 14 days before and up to the end of CSI, patients were administered l-thyroxine at suppressive doses; every 3 days, TSH suppression was checked to ensure a value <0.3 mum/ml. During follow-up, blood tests and ultrasound were repeated after 1 year; primary hypothyroidism was considered an increased TSH level greater than normal range. CSI was done using a hyperfractionated accelerated technique with total doses ranging from 20.8-39 Gy; models were used to evaluate doses received by the thyroid bed. RESULTS: Of 37 patients, 25 were alive a median 7 years after CSI. They were well matched for all clinical features, except that eight children underwent adequate TSH suppression during CSI, whereas 17 did not. Hypothyroidism-free survival rates were 70% for the "adequately TSH-suppressed" group and 20% for the "inadequately TSH-suppressed" group (p = 0.02). CONCLUSIONS: Thyroid-stimulating hormone suppression with l-thyroxine had a protective effect on thyroid function at long-term follow-up. This is the first demonstration that transient endocrine suppression of thyroid activity may protect against radiation-induced functional damage.

Phase I trial of intrathecal spartaject busulfan in children with neoplastic meningitis: a Pediatric Brain Tumor Consortium Study (PBTC-004).

PURPOSE: A phase I trial of intrathecal Spartaject Busulfan (SuperGen, Inc., San Ramon, CA) was conducted in children with neoplastic meningitis following recurrent primary brain tumors to describe toxicities, estimate the maximum tolerated dose (MTD), and document evidence of responses to this agent. EXPERIMENTAL DESIGN: The continuous reassessment method was used to assign cohorts of patients to doses of intrathecal Spartaject Busulfan via an Ommaya reservoir and/or lumbar puncture twice weekly for 2 weeks followed by an assessment of toxicity and response. Patients with stable disease or an objective response continued to receive intrathecal Spartaject Busulfan plus systemic chemotherapy at regular intervals. Cerebrospinal fluid and blood were obtained for pharmacokinetic studies in patients with Ommaya reservoirs after the first dose of intrathecal Spartaject Busulfan. Seven evaluable patients were assigned to the starting dose of 5 mg, two patients to 7.5 mg, three patients to 10 mg, seven patients to 13 mg, and four patients to 17 mg. RESULTS: Between September 2000 and May 2003, 28 patients were enrolled in this study. Twenty-three patients (median age, 8.8 years; range, 2.5-19.5 years) were evaluable for estimating the MTD, and dose-limiting toxicities were observed in three and included grade 3 vomiting (n = 1 at 5 mg), grade 3 headache (n = 1 at 17 mg), and grade 3 arachnoiditis (n = 1 at 17 mg). Pharmacokinetic data showed that post-infusion concentrations of busulfan ranged from 50 to 150 microg/mL and declined to <1 microg/mL within 5 hours. CONCLUSIONS: Intrathecal Spartaject Busulfan was well tolerated in children with neoplastic meningitis from brain tumors, and the recommended dose for future phase II studies is 13 mg.

Ewing family tumors: potential prognostic value of reverse-transcriptase polymerase chain reaction detection of minimal residual disease in peripheral blood samples.

In more than 95% of patients, the Ewing family of tumors (ET) has chimeric transcripts caused by fusion of the EWS gene to either FLI1 or ERG. The presence of specific EWS-FLI1 or EWS-ERG transcripts in peripheral blood (PB) samples of patients being treated for ET was prospectively evaluated, and these data were correlated to their clinical status. The authors studied 113 PB samples from 28 patients with ET. Treatment included chemotherapy, radiotherapy, and surgical excision of tumor after induction therapy. PB samples were taken prospectively at least 2 weeks after resection of tumor. Nested reverse-transcriptase polymerase chain reaction (RT-PCR) followed by Southern blot was performed in all samples. Resected tumors were reviewed for the degree of response to chemotherapy and volume. Seventy-seven PB samples from 28 patients had EWS-FLI1/ERG transcripts. In 11 patients, PB samples became negative with treatment, and, in 5 of them, the samples remained negative throughout the study. Samples taken during progression were always positive and, in 4 patients, became positive before progression was clinically evident. All patients with transcripts other than EWS-FLI1 type 1 (n = 3) died from tumor progression. This is a sensitive assay to monitor circulating tumor cells in Ewing tumors. The preliminary data suggest that progression is preceded by positive samples and may be related to specific transcript types.

Primitive neuroectodermal tumor of the retroperitoneal cavity.

We report a case of primitive neuroectodermal tumor (PNET) arising from the retroperitoneal cavity. Because of infiltration, the tumor was excised en bloc with the left kidney. Despite postoperative adjuvant chemotherapy and local radiation therapy, the tumor recurred and the patient died of the disease 3 months postoperatively. Serum levels of neuron-specific enolase (NSE) correlated with those of lactate dehydrogenase (LDH), and it is suggested that monitoring NSE and LDH is useful in evaluating tumor recurrence. The clinical course and the treatment of this aggressive tumor are reviewed.

Carboplatin in childhood medulloblastoma/PNET: feasibility of an in vivo sensitivity test in an "up-front" study.

Sixteen patients with high risk MB/PNET at diagnosis were included in a pilot study employing carboplatin (CBDCA) as a single drug prior to conventional therapy. The main goal of the study was to identify in a short-term trial a significant response that would predict further response to CBDCA in the single patient. Exploration of CBDCA activity was focused on response after the first course as compared to the response following the second course. A course consisted of CBDCA 600 mg/m2 on days 1 and 2 administered in a 1 h infusion to be repeated 3-4 weeks later. After two cycles we observed 1 CR and 9 PR, that is a 62% response rate. The first course resulted in 5 PR, 5 MR, 5 SD, and 1 PD; after the subsequent course in all responding patients, response persisted or improved whereas in no patient with SD any improvement was observed. The correlation of response to the first course with response to the second course was statistically significant (P = 0.0009). The main toxicity of the single course was hematologic and consisted of rapidly reversible grade 3-4 neutropenia and thrombocytopenia in 94% of patients. Pharmacokinetic studies showed a very limited interpatient variability of both Cmax 57.6 +/- 9.9 micrograms/ml) and AUC (15.3 +/- 1.5 mg/ml.min) of free CBDCA, which eliminates an important variable in the evaluation of response. In conclusion, this "in vivo test" appears effective, reasonably safe, and reproducible in identifying patients likely to benefit from CBCDA: after a period of time as short as 3-4 weeks following the first course, multidrug chemotherapy including CBDCA may be employed in the responding patients, whereas an alternative regimen would be indicated in the non-responding patients.

Busulphan is active against neuroblastoma and medulloblastoma xenografts in athymic mice at clinically achievable plasma drug concentrations.

High-dose busulphan-containing chemotherapy regimens have shown high response rates in children with relapsed or refractory neuroblastoma, Ewing's sarcoma and medulloblastoma. However, the anti-tumour activity of busulfan as a single agent remains to be defined, and this was evaluated in athymic mice bearing advanced stage subcutaneous paediatric solid tumour xenografts. Because busulphan is highly insoluble in water, the use of several vehicles for enteral and parenteral administration was first investigated in terms of pharmacokinetics and toxicity. The highest bioavailability was obtained with busulphan in DMSO administered i.p. When busulphan was suspended in carboxymethylcellulose and given orally or i.p., the bioavailability was poor. Then, in the therapeutic experiments, busulphan in DMSO was administered i.p. on days 0 and 4. At the maximum tolerated total dose (50 mg kg(-1)), busulphan induced a significant tumour growth delay, ranging from 12 to 34 days in the three neuroblastomas evaluated and in one out of three medulloblastomas. At a dose level above the maximum tolerated dose, busulphan induced complete and partial tumour regressions. Busulphan was inactive in a peripheral primitive neuroectodermal tumour (PNET) xenograft. When busulphan pharmacokinetics in mice and humans were considered, the estimated systemic exposure at the therapeutically active dose in mice (113 microg h ml(-1)) was close to the mean total systemic exposure in children receiving high-dose busulphan (102.4 microg h ml(-1)). In conclusion, busulphan displayed a significant anti-tumour activity in neuroblastoma and medulloblastoma xenografts at plasma drug concentrations which can be achieved clinically in children receiving high-dose busulphan-containing regimens.

Dose escalation with repeated intrathecal injections of 131I-labelled MAbs for the treatment of central nervous system malignancies.

We have previously demonstrated a 33% response rate in patients with primitive neurectodermal tumours after the direct injection of 131I-monoclonal antibodies (MAbs) into the cerebrospinal fluid (CSF). Dose-limiting toxicity is myelosuppression due to the passage of the radioimmunoconjugate from the CSF to the blood compartment. This occurs at doses of 2220 MBq of 131I-MAb and above, although this is not seen in all patients studied and appears to be related to the degree of prior therapy received. Rather than attempting to improve the efficacy of this approach to the treatment of disseminated disease within the CSF compartment by dose escalation and haemopoietic rescue, we have explored the possibility of repeatedly administering the radioimmunoconjugate. Eight patients were recruited to the study, two of whom received two and six of whom received three injections of 131I-MAb. After repeated administration of 131I-MAb pharmacokinetic data revealed that, with one exception, the radioimmunoconjugate cleared from the CSF compartment with similar kinetics, while its residence time in the blood decreased with each injection. This was due to the development of an anti-mouse Ig response in the blood. Clearance of 131I-MAb from the ventricular CSF appears to be independent of the presence of an anti-mouse Ig response in this compartment. The differential clearance of the radioimmunoconjugate from the ventricular CSF and from the blood results in a marked increase in the therapeutic index that can be achieved. Up to 5920 MBq of 131I-MAb was administered as the third injection of radioimmunoconjugate and combined doses of up to 12,500 MBq were given without either haematological or neurological toxicity. These data illustrate that dose escalation and thus an increase in the dose rate delivered to tumour cells within the CSF is possible if ways are found to reduce the residence time of the radioimmunoconjugate in the blood compartment. Suggestions as to how this can best be achieved are reviewed in detail.

Absence of germline and somatic p53 alterations in children with sporadic brain tumors.

Cancers of the central nervous system are the most common solid tumors of childhood. Although somatic alterations of the p53 tumor suppressor gene have been implicated in brain tumorigenesis, the role of germline p53 mutations in the development of childhood brain tumors has not been well defined. As a component of an ongoing extensive study of the epidemiology of childhood brain tumors, we prospectively examined the germline and tumor p53 gene status in 85 children without a family history of cancer who were diagnosed with a sporadic malignant central nervous system tumor. Using PCR/single-strand conformational polymorphism analysis and direct DNA sequencing, 85 children were screened for the presence of constitutional p53 sequence alterations in exons 2 and 4 through 11. No mutations were identified. Commonly reported sequence polymorphisms were observed at codon 72, as well as in 2 other previously described nucleotide residues. Forty-four brain tumor samples were available for analysis and of these 40 were paired with peripheral blood. Once again, no p53 mutations were found. Of the 5 germline samples with the 2 common polymorphisms, only one had a paired tumor sample for comparison and the tumor contained the same alteration as the germline. Of note, one tumor, a PNET of the cerebellum (medulloblastoma), showed loss of heterozygosity at codon 72. We can conclude that the frequency of germline and somatic p53 mutations in sporadic childhood brain tumors is very low, probably less than 1%, and there is no need to screen these patients routinely for their germline p53 status. However, the potential significance of LOH at codon 72 remains to be elucidated.

Phase I study of irinotecan in pediatric patients with malignant solid tumors.

PURPOSE: To determine the dose-limiting toxicity, maximum tolerated dose, and potential efficacy of irinotecan in children with refractory malignant solid tumors. PATIENTS AND METHODS: In the present phase I clinical trial, 28 patients received irinotecan 50 to 200 mg/m2 per day by intravenous 2-hour infusion over the course of 3 days, repeated once after an interval of 25 days. Fifty-one treatment courses were administered to these patients. RESULTS: Dose-limiting toxicities were observed at the dose of 200 mg/m2 per day for 3 days. Diarrhea and hematopoietic toxicities were the dose-limiting factors, and the former required support with intravenous fluid administration. The occurrence of vomiting was variable. Decreases in clinical tumor marker levels were observed in the majority of patients who received two cycles of irinotecan 80 mg/m2 per day to 200 mg/m2 per day over the course of 3 days, and partial response was attained in four patients who received irinotecan in two cycles of 140 mg/m2 per day to 200 mg/m2 per day over the course of 3 days. Pharmacokinetic studies showed that the plasma concentration of irinotecan and its active metabolite SN-38 ranged from 93 to 2,820 ng/mL and 5.2 to 34.8 ng/mL, respectively, during 3-day infusions of irinotecan 200 mg/m2 per day. The mean clearance of irinotecan was 14.54 L/h per m2 (range 8.45-20.83 L/h per m2). CONCLUSION: The maximum tolerated dose was determined to be a dose of irinotecan between 160 mg/m2 per day and 180 mg/m2 per day administered over the course of 3 consecutive days on an inpatient basis, repeated once after 25 days off, and our results indicate that irinotecan is a promising anticancer agent that is worthy of phase II trials in pediatric solid tumors.