Showing papers by "Sue C. Kaste published in 2013"

Phase I Study of Vismodegib in Children with Recurrent or Refractory Medulloblastoma: A Pediatric Brain Tumor Consortium Study

Abstract: Purpose: To investigate the safety, dose-limiting toxicities, and pharmacokinetics of the smoothened inhibitor vismodegib in children with refractory or relapsed medulloblastoma. Experimental design: Initially, vismodegib was administered daily at 85 mg/m 2 and escalated to 170 mg/m 2 . The study was then revised to investigate a flat-dosing schedule of 150 mg for patients with small body surface area (BSA, 0.67–1.32 m 2 ) or 300 mg for those who were larger (BSA, 1.33–2.20 m 2 ). Pharmacokinetics were performed during the first course of therapy, and the right knees of all patients were imaged to monitor bone toxicity. Immunohistochemical analysis was done to identify patients with Sonic Hedgehog (SHH)-subtype medulloblastoma. Results: Thirteen eligible patients were enrolled in the initial study: 6 received 85 mg/m 2 vismodegib, and 7 received 170 mg/m 2 . Twenty eligible patients were enrolled in the flat-dosing part of the study: 10 at each dosage level. Three dose-limiting toxicities were observed, but no drug-related bone toxicity was documented. The median (range) vismodegib penetration in the cerebrospinal fluid (CSF) was 0.53 (0.26–0.78), when expressed as a ratio of the concentration of vismodegib in the CSF to that of the unbound drug in plasma. Antitumor activity was seen in 1 of 3 patients with SHH-subtype disease whose tumors were evaluable, and in none of the patients in the other subgroups. Conclusions: Vismodegib was well tolerated in children with recurrent or refractory medulloblastoma; only two dose-limiting toxicities were observed with flat dosing. The recommended phase II study dose is 150 or 300 mg, depending on the patient9s BSA. Clin Cancer Res; 19(22); 6305–12. ©2013 AACR .

Phase I Trial, Pharmacokinetics, and Pharmacodynamics of Vandetanib and Dasatinib in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma

Abstract: Purpose: Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG. Experimental Design: Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m 2 once daily) and dasatinib (65 and 85 mg/m 2 twice daily). Dose-limiting toxicities were evaluated during the first 6 weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42 ± 3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMC) was evaluated. Results: Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable with previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs. Conclusions: The MTD of vandetanib and dasatinib in combination was 65 mg/m 2 for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer. Clin Cancer Res; 19(11); 3050–8. ©2013 AACR .

Imaging in childhood cancer: A society for pediatric radiology and children's oncology group joint task force report

Abstract: Contemporary medical imaging is a cornerstone of care for children with cancer. As 5-year survival rates for children with cancer exceed 80%, imaging technologies have evolved in parallel to include a wide array of modalities. Here, we overview the risks and benefits associated with commonly used imaging modalities and survey the current landscape of medical imaging for children with cancer. We find evidence-based imaging guidelines to assist in protocol development and to guide decision-making for optimal patient care are often lacking. The substantial variation in protocol-based recommendations for imaging both during and following therapy may hinder optimal clinical research and clinical care for children with cancer.

A comparison of non-contrast and contrast-enhanced MRI in the initial stage of Legg-Calvé-Perthes disease.

Abstract: Background A prognostic indicator of outcome for Legg-Calve-Perthes disease (LCP) is needed to guide treatment decisions during the initial stage of the disease (stage 1), before deformity occurs. Radiographic prognosticators are applicable only after fragmentation (stage II).

Is routine pelvic surveillance imaging necessary in patients with Wilms tumor

Abstract: BACKGROUND: It is unclear whether routine pelvic imaging is needed in patients with Wilms tumor. Thus, the primary objective of the current study was to examine the role of routine pelvic computed tomography (CT) in a cohort of pediatric patients with Wilms tumor. METHODS: With institutional review board approval, the authors retrospectively identified 110 patients who had Wilms tumor diagnosed between January 1999 and December 2009 with surveillance imaging that continued through March 2011. The authors estimated overall survival (OS), event-free survival (EFS), and dosimetry from dose length product (DLP) conversion to the effective dose (ED) for every CT in a subgroup of 80 patients who had CT studies obtained using contemporary scanners (2002-2011). Metal-oxide-semiconductor field-effect transistor (MOSFET) dosimeters were placed within organs of anthropomorphic phantoms to directly calculate the truncal ED. EDDLP was correlated with EDMOSFET to calculate potential pelvic dose savings. RESULTS: Eighty patients underwent 605 CT examinations that contained DLP information, including 352 CT scans of the chest, abdomen, and pelvis; 123 CT scans of the chest and abdomen; 102 CT scans of the chest only; 18 CT scans of the abdomen and pelvis; 9 CT scans of the abdomen only; and 1 CT that was limited to the pelvis. The respective 5-year OS and EFS estimates were 92.8% ± 3% and 2.6% ± 4.3%. Sixteen of 110 patients (15%) developed a relapse a median of 11.3 months (range, 5.0 months to 7.3 years) after diagnosis, and 4 patients died of disease recurrence. Three patients developed pelvic relapses, all 3 of which were symptomatic. The estimated ED savings from sex-neutral CT surveillance performed at a 120-kilovolt peak without pelvic imaging was calculated as 30.5% for the average patient aged 1 year, 30.4% for the average patient aged 5 years, 39.4% for the average patient aged 10 years, and 44.9% for the average patient aged 15 years. CONCLUSIONS: Omitting pelvic CT from the routine, off-therapy follow-up of patients with Wilms tumor saved an average 30% to 45% of the ED without compromising disease detection. Cancer 2013. © 2012 American Cancer Society.

Bevacizumab-Associated Osteonecrosis of the Wrist and Knee in Three Pediatric Patients With Recurrent CNS Tumors

Abstract: Introduction Despite significant treatment advances and survival improvement in a variety of pediatric CNS tumors, there remains a large number of children who succumb to their disease. A variety of novel biologic and targeted therapies have been evaluated in an effort to improve survival. One class of therapeutics that is being widely explored is antiangiogenic agents. Angiogenesis is the development of new vasculature and is critically important for tumor growth, invasion, and metastases. Vascular endothelial growth factor (VEGF) and its isoforms play a role in tumor angiogenesis, are overexpressed in a variety of human cancers, and may be associated with tumor progression. Among the many antiangiogenic agents, bevacizumab (BVZ) has been widely studied in pediatric and adult patients since its development in 1997. BVZ is a humanized monoclonal immunoglobulin G1 antibody against all human VEGF isoforms and their proteolytic fragments. BVZ has been shown to decrease vascular permeability and increase cellular apoptosis in a variety of tumor xenografts, including CNS tumors. As with most new agents, the understanding of its adverse effect profile is evolving as new patterns of adverse events are reported. Numerous reports have documented osteonecrosis of the jaw associated with BVZ alone and/or in combination with other chemotherapies, steroids, and bisphosphonates. Maxillary osteonecrosis has previously been well described in association with the use of bisphosphonates and steroids. In the case of bisphosphonates, this phenomenon usually occurs after trauma. However, spontaneous osteonecrosis has developed in a subset of patients. It is hypothesized that bisphosphonates inhibit osteoclast function, thereby causing a defect in remodeling and wound healing of the jaw. There appears to be an increased risk of jaw osteonecrosis in adult patients treated with either single-agent BVZ or concomitantly with bisphosphonates. Although most case reports have described osteonecrosis of the jaw in adults, there are a few case reports that have described antiangiogenic-associated osteonecrosis in the appendicular skeleton (Table 1). We report osteonecrosis in the lunate bone of the wrist and the knee in three children with recurrent CNS tumors treated with BVZ in combination with irinotecan (CPT-11) on a phase II study that enrolled children with recurrent brain tumors. In this trial, patients received BVZ (10 mg/kg per day) and CPT-11 (125 to 250 mg/m per day) intravenously every 2 weeks (one course 4 weeks of treatment) until disease progression, unacceptable toxicity, or a maximum of 24 months of therapy. As a result of possible deleterious effects of epiphyseal growth resulting from VEGF inhibition, patients were required to have a baseline x-ray of the left knee and periodically thereafter during therapy and if they had symptoms of skeletal pain. To our knowledge, this is the first case series to describe BVZ-associated osteonecrosis in children.

The role of PET/CT in assessing pulmonary nodules in children with solid malignancies.

Abstract: OBJECTIVE. The purpose of this article is to assess the feasibility and utility of PET/CT in distinguishing benign from malignant pulmonary nodules in patients with solid childhood malignancies. SUBJECTS AND METHODS. This prospective study was conducted between March 2008 and August 2010. We enrolled 25 subjects 21 years old or younger with solid childhood malignancies and at least one pulmonary nodule measuring 0.5–3.0 cm. PET/CT was performed within 3 weeks of diagnostic chest CT. Three panels of three reviewers each reviewed diagnostic CT only (panel 1), PET/CT only (panel 2), or diagnostic CT and PET/CT concurrently (panel 3) and predicted each nodule's histologic diagnosis as benign, malignant, or indeterminate. Interreviewer agreement was assessed with the kappa statistic. Using nodule biopsy or clinical follow-up as reference standards, the sensitivity, specificity, and accuracy for each panel was assessed. Logistic regression was used to assess the nodule's maximum standardized uptake value (SUVma...

Magnetic resonance imaging is the preferred method to assess treatment-related skeletal changes in children with brain tumors.

Abstract: Purpose To evaluate the growing skeleton for potential altered skeletalgenesis associated with antiangiogenesis therapy. Patients and Methods Knee radiographs and magnetic resonance imaging (MRI) were prospectively obtained on patients enrolled on two consecutive clinical trials using vandetanib, a potent oral (VEGF receptor 2) VEGFR-2 inhibitor alone or combined with dasatinib, a multiple tyrosine kinase inhibitor, in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Results Fifty-nine patients (32 females) underwent 119 MRIs; 51 patients underwent 89 radiographs of the knees. The median age at enrollment was 6.2 years (range, 2.4–17.6 years). The dose of vandetanib ranged from 50 to 145 mg/m2/day. The median treatment duration was 205 days. Only two patients have not experienced disease progression after 18 and 60 months from diagnosis. MRI identified clinically significant premature physeal fusion in both knees of one patient, focal physeal thickening in one, osteonecrosis in eight patients (present at enrollment in one), and bony spicules crossing the physis in two patients (bilateral in one). MRI follow-up period averaged 5.3 months (range, 0–25.5 months; median, 3.5 months). Radiographs delineated normally fused physes in two patients but no cases of premature physeal fusion, osteonecrosis or bony spicules. Conclusions As MRI provided greater information than radiographs, and thus would be a more sensitive test to assess skeletalgenesis in pediatric patients. Pediatr Blood Cancer 2013;160:1552–1556. © 2013 Wiley Periodicals, Inc.

Interrupted development of dentition in children receiving bone marrow transplantation for acute lymphocytic Leukemia: a case series

Abstract: This case series depicts dental anomalies that may develop in children who have undergone bone marrow transplantation (BMT) for acute lymphoblastic leukemia (ALL). The most common finding in these patients was root stunting; other abnormalities included microdontia, hypodontia, taurodontia, caries, enamel pearls, and pulpal calcification. Recognition of these adverse effects of BMT on odontogenesis, as demonstrated on panoramic radiograph images, will allow healthcare providers to explain to parents and patients the possible dental outcomes associated with BMT and to optimize their dental health regimen.

The Evaluation of Factors Believed to Contribute to Obesity in Acute Lymphocytic Leukemia Survivors

Abstract: Background. Obesity rates for pediatric acute lymphocytic leukemia (ALL) survivors vary from 11% to 57%. Researching dietary behaviors may identify dietary risks leading to obesity and opportunities for intervention. Objective. To evaluate the relationship between caloric and macronutrient intake on the incidence of obesity in pediatric ALL. Design/setting/participants. Retrospectively reviewed data of 142 participants was examined. Participants were grouped into categories based on body mass index (BMI) for adults and Centers for Disease Control and Prevention growth charts for children. Twenty-four-hour food recall records were reviewed to assess dietary intake. Confounding factors and caloric/macronutrient intake were compared across obesity classes. Main outcome measurements. Macronutrient levels were compared between groups. Descriptive data examined. BMI at enrollment on BONEII, age at diagnosis, ethnicity, gender, corticosteroid use, cranial radiation therapy, and standard/high risk. ALL group. Results. Thirty-nine percent of participants were overweight/obese. ALL survivors who consumed a higher percentage of their calories from protein were more likely to be underweight/normal weight while participants who consumed more calories and total carbohydrates were more likely to be overweight/obese. There was no relationship with the other factors examined. Conclusion. Dietary interventions should be designed to ensure patients consume adequate amounts of protein while limiting portion sizes and carbohydrate-based snacks.

Late and Acute Effects of Pediatric Cancer Therapy on the Oral Cavity

Abstract: Pediatric cancer therapy has advanced to become curative for many types of cancer. The overall survival of patients treated for childhood cancer is now in the range of 90%. The May 2009 issue of the Journal of Clinical Oncology reported improved survival from about 30% in 1960 to 80% in 2004. An epidemiologic study (Mariotto et al. 2009) estimated that in the United States alone, there are more than 300,000 survivors of childhood cancer. However, this success has not come without a price. Pediatric cancer therapy is given during a time of growth, and late effects in the oral cavity can alter the growth and development of teeth and bones and affect overall health for the duration of a patient’s life. The severity of these clinical and anatomical complications depends on tumor diagnosis, therapy exposure (chemotherapy, radiation, hematopoietic stem cell transplantation or a combination of several therapies), patient age and developmental status at the time of therapy and the resulting toxicity. In this chapter we will discuss some of the most important oral complications in pediatric oncology, with a focus on late effects of cancer and its treatment. Early complications will also be briefly described. Although the emphasis of this book is neurologic malignancy, oral complications occur in association with such malignancies because of the type of cancer therapy used. The prevention and management of these complications will be discussed, as well as the need for collaboration between dental providers and the oncology team for the improvement of outcomes.