Topotecan clearance based on a single sample and a population pharmacokinetic model: Application to a pediatric high-risk neuroblastoma clinical trial.

BACKGROUND: Topotecan, an antitumor drug with systemic exposure (SE)-dependent activity against many pediatric tumors has wide interpatient pharmacokinetic variability, making it challenging to attain the desired topotecan SE. The study objectives were to update our topotecan population pharmacokinetic model, to evaluate the feasibility of determining individual topotecan clearance using a single blood sample, and to apply this approach to topotecan data from a neuroblastoma trial to explore exposure-response relationships. PROCEDURE: Our previous population pharmacokinetic and covariate model was updated using data from 13 clinical pediatric studies. A simulation-based Bayesian analysis was performed to determine if a single blood sample could be sufficient to estimate individual topotecan clearance. Following the Bayesian approach, single pharmacokinetic samples collected from a Children's Oncology Group Phase III clinical trial (ANBL0532; NCT0056767) were analyzed to estimate individual topotecan SE. Associations between topotecan SE and toxicity or early response were then evaluated. RESULTS: The updated population model included the impact of patient body surface area (BSA), age, and renal function on topotecan clearance. The Bayesian analysis with the updated model and single plasma samples showed that individual topotecan clearance values were estimated with good precision (mean absolute prediction error ≤16.2%) and low bias (mean prediction error ≤7.2%). Using the same approach, topotecan SE was derived in patients from ANBL0532. The exposure-response analysis showed an increased early response after concomitant cyclophosphamide and topotecan up to a topotecan SE of 45 h ng/mL. CONCLUSIONS: A simple single-sample approach during topotecan therapy could guide dosing for patients, resulting in more patients reaching target attainment.

Disrupted development and integrity of frontal white matter in patients treated for pediatric medulloblastoma.

BACKGROUND: Treatment of pediatric medulloblastoma is associated with known neurocognitive deficits that we hypothesize are caused by microstructural damage to frontal white matter (WM). METHODS: Longitudinal MRI examinations were collected from baseline (after surgery but before therapy) to 36 months in 146 patients and at 3 time points in 72 controls. Regional analyses of frontal WM volume and diffusion tensor imaging metrics were performed and verified with tract-based spatial statistics. Age-adjusted, linear mixed-effects models were used to compare patient and control images and to associate imaging changes with Woodcock-Johnson Tests of Cognitive Abilities. RESULTS: At baseline, WM volumes in patients were similar to those in controls; fractional anisotropy (FA) was lower bilaterally (P < 0.001) and was associated with decreased Processing Speed (P = 0.014) and Broad Attention (P = 0.025) performance at 36 months. During follow-up, WM volumes increased in controls but decreased in patients (P < 0.001) bilaterally. Smaller WM volumes in patients at 36 months were associated with concurrent decreased Working Memory (P = 0.026) performance. CONCLUSIONS: Lower FA in patients with pediatric medulloblastoma compared with age-similar controls indicated that patients suffer substantial acute microstructural damage to supratentorial frontal WM following surgery but before radiation therapy or chemotherapy. Additionally, this damage to the frontal WM was associated with decreased cognitive performance in executive function 36 months later. This early damage also likely contributed to posttherapeutic failure of age-appropriate WM development and to the known association between decreased WM volumes and decreased cognitive performance.

Pineoblastoma-The Experience at St. Jude Children's Research Hospital.

BACKGROUND: Pineoblastomas are rare, supratentorial, primitive neuroectodermal tumors. OBJECTIVE: To document outcomes with multimodal therapy and evaluate the impact that the degree of surgical resection has on outcome. METHODS: A departmental brain tumor database was queried to identify all patients with pathologically proven pineoblastoma who were treated from January 1997 to June 2015 at St. Jude Children's Research Hospital. For each patient, we recorded demographic, pathological, radiological, surgical, and clinical follow-up data. The effect of degree of surgical resection on survival outcomes was analyzed. RESULTS: Forty-one patients (21 male, 20 female) treated for pineoblastoma were identified. The median age at diagnosis was 5.5 years (range 0.4-28.1) and the median follow-up was 34.5 months. Nineteen patients experienced tumor relapse with a median progression-free survival of 11.3 months, and 18 ultimately succumbed to their disease. Patients who died or experienced treatment failure were younger (median, 2.69 vs 6.5 years, P = .026) and more likely to have metastatic disease at diagnosis (12 [63.2%] vs 5 [22.7%], P = .012). When analyzing only patients 5 years of age or older with focal disease at presentation, those who had a gross total resection or near-total resection-compared with subtotal resection or biopsy-had greater overall survival (75.18 vs 48.57 months), with no patients dying as a result of their cancer. CONCLUSION: Poor prognostic variables for children with pineoblastoma include young age, metastatic disease at presentation, and tumor relapse. For patients older than 5 years with focal disease, maximal tumor resection should be the goal.

Population Pharmacokinetics of Oral Topotecan in Infants and Very Young Children with Brain Tumors Demonstrates a Role of ABCG2 rs4148157 on the Absorption Rate Constant.

For infants and very young children with brain tumors, chemotherapy after surgical resection is the main treatment due to neurologic and neuroendocrine adverse effects from whole brain irradiation. Topotecan, an anticancer drug with antitumor activity against pediatric brain tumors, can be given intravenous or orally. However, high interpatient variability in oral drug bioavailability is common in children less than 3 years old. Therefore, this study aimed to determine the population pharmacokinetics of oral topotecan in infants and very young children, specifically evaluating the effects of age and ABCG2 and ABCB1 on the absorption rate constant (Ka), as well as other covariate effects on all pharmacokinetic parameters. A nonlinear mixed effects model was implemented in Monolix 4.3.2 (Lixoft, Orsay, France). A one-compartment model with first-order input and first-order elimination was found to adequately characterize topotecan lactone concentrations with population estimates as [mean (S.E.)]; Ka = 0.61 (0.11) h(-1), apparent volume of distribution (V/F) = 40.2 (7.0) l, and apparent clearance (CL/F) = 40.0 (2.9) l/h. After including the body surface area in the V/F and CL/F as a power model centered on the population median, the ABCG2 rs4148157 allele was found to play a significant role in the value of Ka Patients homozygous or heterozygous for G>A demonstrated a Ka value 2-fold higher than their GG counterparts, complemented with a 2-fold higher maximal concentration as well. These results demonstrate a possible role for the ABCG2 rs4148157 allele in the pharmacokinetics of oral topotecan in infants and very young children, and warrants further investigation.

Medulloblastoma-translating discoveries from the bench to the bedside.

Medulloblastoma is a form of brain cancer that mainly arises during infancy and childhood. Our understanding of this disease has transitioned rapidly; what was once thought of as a single disease entity is now known to be a compendium comprising at least four distinct subtypes of tumour (Wnt, sonic hedgehog [SHH], group 3, and group 4 medulloblastomas) that have characteristic molecular signatures, distinctive clinical features, and are associated with different outcomes. Importantly, medulloblastomas occurring in infants (aged up to 3 years) and adults have unique characteristics, which distinguish the disease from that seen in children aged >3 years. Accordingly, modern treatment approaches in medulloblastoma integrate the molecular and clinical features of the disease to enable provision of the most-effective therapies for each patient, and to reduce long-term sequelae. This Review discusses our current knowledge of medulloblastoma. In particular, we present the genetic and histological features, patient demographics, prognosis, and therapeutic options for each the four molecular tumour subtypes that comprise this disease entity. In addition, the unique features of medulloblastoma in infants and in adults, as compared with childhood and/or adolescent forms, are described.

Resection of infantile brain tumors after neoadjuvant chemotherapy: the St. Jude experience.

OBJECT: Brain tumors in infants are often large, high grade, and vascular, making complete resection difficult and placing children at risk for neurological complications and excessive blood loss. Neoadjuvant chemotherapy may reduce tumor vascularity and volume, which can facilitate resection. The authors evaluated how an ongoing institutional prospective chemotherapy trial would affect patients who did not have a gross-total resection (GTR) immediately and who therefore required further surgical intervention to achieve definitive tumor resection. METHODS: Thirteen infants (4 girls and 9 boys) who were enrolled in an institutional protocol in which they were treated with multiagent chemotherapy (methotrexate, vincristine, cisplatin, and cyclophosphamide with vinblastine for high-risk patients) subsequently underwent second-look surgery. The primary outcome was extent of resection achieved in postchemotherapy surgery. Secondary outcomes included intraoperative blood loss, radiographic response to the chemotherapy, complications during chemotherapy, and survival. RESULTS: Three infants underwent biopsy, 9 underwent subtotal resection, and 1 patient did not undergo surgery prior to chemotherapy. On subsequent second-look surgery, 11 of 13 patients had a GTR, 1 had a near-total resection, and 1 had a subtotal resection. In each case, a marked reduction in tumor vascularity was observed intraoperatively. The average blood loss was 19% of estimated blood volume, and 6 (46%) of 13 patients required a blood transfusion. Radiographically, chemotherapy induced a reduction in tumor volume in 9 (69%) of 13 patients. Emergency surgery was required in 2 patients during chemotherapy, 1 for intratumoral hemorrhage and 1 for worsening peritumoral edema. The average follow-up period for this cohort was 16.5 months, and at last follow-up, 4 patients (31%) had died, 1 patient had progressive metastatic spinal disease, and the rest had either no evidence of disease or stable disease. CONCLUSIONS: A GTR of pediatric brain tumors is one of the most important predictors of outcome. The application of the authors' neoadjuvant induction chemotherapy protocol in a variety of tumor types resulted in devascularization of all tumors and volume regression in the majority, and subsequently facilitated resection, with acceptable intraoperative blood loss. Intracranial complications may occur during chemotherapy, ranging from incidental and asymptomatic to life threatening, necessitating close monitoring of these children.

Challenging issues in pediatric oncology.

Improvements in protocol-driven clinical trials and supportive care for children and adolescents with cancer have reduced mortality rates by more than 50% over the past three decades. Overall, the 5-year survival rate for patients with pediatric cancer has increased to approximately 80%. Recognition of the biological heterogeneity within specific subtypes of cancer, the discovery of genetic lesions that drive malignant transformation and cancer progression, and improved understanding of the basis of drug resistance will undoubtedly catalyze further advances in risk-directed treatments and the development of targeted therapies, boosting the cure rates further. Emerging new treatments include novel formulations of existing chemotherapeutic agents, monoclonal antibodies against cancer-associated antigens, and molecular therapies that target genetic lesions and their associated signaling pathways. Recent findings that link pharmacogenomic variations with drug exposure, adverse effects, and efficacy should accelerate efforts to develop personalized therapy for individual patients. Finally, palliative care should be included as an essential part of cancer management to prevent and relieve the suffering and to improve the quality of life of patients and their families.

Tyrosine kinase inhibitor enhances the bioavailability of oral irinotecan in pediatric patients with refractory solid tumors.

PURPOSE: To assess the maximum-tolerated dosages (MTDs), and dose-limiting toxicities (DLTs) of the epidermal growth factor receptor inhibitor gefitinib and of intravenous (IV) irinotecan when administered together in children with refractory solid tumors. To assess the effect of gefitinib on the pharmacokinetics of IV irinotecan and on the bioavailability of a single oral dose of irinotecan. PATIENTS AND METHODS: IV irinotecan (15 or 20 mg/m(2)) was given daily for 5 days of 2 consecutive weeks. Oral gefitinib (150 or 112.5 mg/m(2)) was concomitantly given daily for 12 or 21 days. A single oral dose of irinotecan was given on day 9 of course 2 to allow pharmacokinetic analysis. RESULTS: The study enrolled 29 patients with recurrent solid tumors. The 21-day regimen of oral gefitinib with irinotecan was not tolerated. Diarrhea was the most common DLT. The MTD of the combination regimen was 15 mg/m(2)/d of IV irinotecan for 5 days of 2 consecutive weeks and 112.5 mg/m(2)/d of gefitinib given for 12 days. Gefitinib increased the bioavailability of oral irinotecan by four-fold over that observed in historical controls (median, 0.09 v 0.42; P < .000001), reducing the apparent clearance (an inverse measure of exposure) of irinotecan and SN-38 by 37% and 38%, respectively (P < .0001). A partial response was observed in a patient with refractory Ewing sarcoma. CONCLUSION: IV irinotecan given with 12 days of oral gefitinib is well tolerated in children. We observed one partial response. Gefitinib significantly enhances the bioavailability of oral irinotecan. This combination warrants further investigation, particularly with orally administered irinotecan.

Cefixime allows greater dose escalation of oral irinotecan: a phase I study in pediatric patients with refractory solid tumors.

PURPOSE: Irinotecan is active against a variety of malignancies; however, severe diarrhea limits its usefulness. In our phase I study, the intravenous formulation of irinotecan was administered orally daily for 5 days for 2 consecutive weeks (repeated every 21 days) to children with refractory solid tumors. Our objectives were to determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of oral irinotecan and to evaluate whether coadministration of cefixime (8 mg/kg/d beginning 5 days before irinotecan and continuing throughout the course) ameliorates irinotecan-induced diarrhea. PATIENTS AND METHODS: In separate cohorts, irinotecan doses were escalated from 15 to 45 mg/m2/d without cefixime and then from 45 to 60 and 75 mg/m2/d with cefixime. RESULTS: Without cefixime, diarrhea was dose limiting at irinotecan 45 mg/m2/d. Myelotoxicity was not significant at any dose. The MTD was 40 mg/m2/d without cefixime but 60 mg/m2/d with cefixime. Systemic exposure to SN-38 at the MTD was significantly higher with cefixime than without cefixime (mean SN-38 area under the curve: 19.5 ng x h/mL; standard deviation [SD], 6.8 ng x h/mL v 10.4 ng x h/mL; SD, 4.3 ng x h/mL, respectively; P = .030). CONCLUSION: Cefixime administered with oral irinotecan is well tolerated in children and allows greater dose escalation of irinotecan. Because diarrhea is a major adverse effect of both intravenous and oral irinotecan, further evaluation of the use of cefixime to ameliorate this adverse effect is warranted.

Phase I and pharmacokinetic study of topotecan administered orally once daily for 5 days for 2 consecutive weeks to pediatric patients with refractory solid tumors.

PURPOSE: We conducted a phase I trial of the injectable formulation of topotecan given orally once daily for 5 days for 2 consecutive weeks (qd x 5 x 2) in pediatric patients with refractory solid tumors. PATIENTS AND METHODS: Cohorts of two to six patients received oral topotecan at 0.8, 1.1, 1.4, 1.8, and 2.3 mg/m(2)/d every 28 days for a maximum of six courses. Twenty patients (median age, 10.6 years) received a total of 51 courses. Eight patients received topotecan capsules during course 2 only. RESULTS: Dose-limiting toxicity occurred at 2.3 mg/m(2)/d and consisted of prolonged grade 4 neutropenia (n = 2), grade 3 stomatitis as a result of radiation recall (n = 1), grade 3 hemorrhage (epistaxis) in the presence of grade 4 thrombocytopenia (n = 1), and grade 3 diarrhea in the presence of Clostridium difficile infection (n = 1). Dose-limiting, prolonged grade 4 neutropenia and thrombocytopenia occurred in one patient at 1.4 mg/m(2)/d. Infrequent toxicities were mild nausea, vomiting, elevated liver ALT or AST, and rash. The maximum-tolerated dosage was 1.8 mg/m(2)/d; the mean (+/- standard deviation) area under the plasma concentration-time curve for topotecan lactone at this dosage was 20.9 +/- 8.4 ng/mL. h. The population mean (+/- standard error) oral bioavailability of the injectable formulation was 0.27 +/- 0.03; that of capsules was 0.36 +/- 0.06 (P =.16). Disease stabilized in nine of 19 assessable patients for 1.5 to 6 months. CONCLUSION: Oral topotecan (1.8 mg/m(2)/d) on a qd x 5 x 2 schedule is well tolerated and warrants additional testing in pediatric patients.

Risk factors for traumatic and bloody lumbar puncture in children with acute lymphoblastic leukemia.

CONTEXT: Traumatic or bloody lumbar puncture (LP) reduces the diagnostic value of the procedure and may worsen the outcome of patients with acute lymphoblastic leukemia (ALL). Little is known about the risk factors for traumatic and bloody LP. OBJECTIVES: To determine the risk factors for traumatic and bloody LP. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of 956 consecutive patients with newly diagnosed childhood ALL who were treated at a pediatric cancer center between February 1984 and July 1998. INTERVENTIONS: All patients underwent a diagnostic LP followed by a median of 4 LPs to instill intrathecal chemotherapy. MAIN OUTCOME MEASURE: Traumatic LP was defined as an LP in which cerebrospinal fluid contained at least 10 red blood cells (RBCs) per microliter and bloody LP as one in which the cerebrospinal fluid contained at least 500 RBCs per microliter. RESULTS: Of the 5609 LPs evaluated, 1643 (29%) were traumatic and 581 (10%) were bloody. The estimated odds ratios (ORs) and 95% confidence intervals (CIs) for traumatic LP were 1.5 (95% CI, 1.2-1.8) for black vs white race, 2.3 (95% CI, 1.7-3.0) for age younger than 1 year vs 1 year or older, 1.4 (95% CI, 1.2-1.7) for early vs recent (dedicated procedure area and general anesthesia) treatment era, 1.5 (95% CI, 1.2-1.8) for platelet count of 100 x 10(3)/ microL or more vs less than 100 x 10(3 )/ microL, 10.8 (95% CI, 7.7-15.2) for short (1 day) vs longer (>15 days) interval since the previous LP, and 1.4 (95% CI, 1.1-1.8) for the least vs the most experienced practitioners. Analyses for bloody LP yielded similar results. CONCLUSIONS: The unmodifiable risk factors for traumatic and bloody LP include black race, age younger than 1 year, a traumatic or bloody previous LP performed within the past 2 weeks, and a previous LP performed when the platelet count was 50 x 10(3)/ microL or less. Modifiable risk factors include procedural factors reflected in treatment era, platelet count of 100 x 10(3)/ microL or less, an interval of 15 days or less between LPs, and a less experienced practitioner.