Hollie A. Jackson

Iodine-131—Metaiodobenzylguanidine Double Infusion With Autologous Stem-Cell Rescue for Neuroblastoma: A New Approaches to Neuroblastoma Therapy Phase I Study

PURPOSE Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) provides targeted radiotherapy with more than 30% response rate in refractory neuroblastoma, but activity infused is limited by radiation safety and hematologic toxicity. The goal was to determine the maximum-tolerated dose of (131)I-MIBG in two consecutive infusions at a 2-week interval, supported by autologous stem-cell rescue (ASCR) 2 weeks after the second dose. PATIENTS AND METHODS The (131)I-MIBG dose was escalated using a 3 + 3 phase I trial design, with levels calculated by cumulative red marrow radiation index (RMI) from both infusions. Using dosimetry, the second infusion was adjusted to achieve the target RMI, except at level 4, where the second infusion was capped at 21 mCi/kg. RESULTS Twenty-one patients were enrolled onto the study at levels 1 to 4, with 18 patients assessable for toxicity and 20 patients assessable for response. Cumulative (131)I-MIBG given to achieve the target RMI ranged from 22 to 50 mCi/kg, with cumulative RMI of 3.2 to 8.92 Gy. No patient had a dose-limiting toxicity. Reversible grade 3 nonhematologic toxicity occurred in six patients at level 4, establishing the recommended cumulative dose as 36 mCi/kg. The median time to absolute neutrophil count more than 500/microL after ASCR was 13 days (4 to 27 days) and to platelet independence was 17 days (6 to 47 days). Responses included two partial responses, eight mixed responses, three stable disease, and seven progressive disease. Responses by semiquantitative MIBG score occurred in eight patients, soft tissue responses occurred in five of 11 patients, but bone marrow responses occurred in only two of 13 patients. CONCLUSION The lack of toxicity with this approach allowed dramatic dose intensification of (131)I-MIBG, with minimal toxicity and promising activity.

Phase I Trial of Oral Irinotecan and Temozolomide for Children With Relapsed High-Risk Neuroblastoma: A New Approach to Neuroblastoma Therapy Consortium Study

PURPOSE Irinotecan and temozolomide have single-agent activity and schedule-dependent synergy against neuroblastoma. Because protracted administration of intravenous irinotecan is costly and inconvenient, we sought to determine the maximum-tolerated dose (MTD) of oral irinotecan combined with temozolomide in children with recurrent/resistant high-risk neuroblastoma. PATIENTS AND METHODS Patients received oral temozolomide on days 1 through 5 combined with oral irinotecan on days 1 through 5 and 8 through 12 in 3-week courses. Daily oral cefixime was used to reduce irinotecan-associated diarrhea. RESULTS Fourteen assessable patients received 75 courses. Because neutropenia and thrombocytopenia were initially dose-limiting, temozolomide was reduced from 100 to 75 mg/m(2)/d for subsequent patients. Irinotecan was then escalated from 30 to 60 mg/m2/d. First-course grade 3 diarrhea was dose-limiting in one of six patients treated at the irinotecan MTD of 60 mg/m2/d. Other toxicities were mild and reversible. The median SN-38 lactone area under the plasma concentration versus time curve at this dose was 72 ng . hr/mL. One patient with bulky soft tissue disease had a complete response through six courses. Six additional patients received a median of seven courses (range, three to 22 courses) before progression. CONCLUSION This all-oral regimen was feasible and well tolerated in heavily pretreated children with resistant neuroblastoma, and seven (50%) of 14 assessable patients had response or disease stabilization for three or more courses in this phase I trial. SN-38 lactone exposures were similar to those reported with protracted intravenous irinotecan. The dosages recommended for further study in this patient population are temozolomide 75 mg/m2/d plus irinotecan 60 mg/m2/d when given with cefixime.

Comparison of Iodine-123 Metaiodobenzylguanidine (MIBG) Scan and [18F]Fluorodeoxyglucose Positron Emission Tomography to Evaluate Response After Iodine-131 MIBG Therapy for Relapsed Neuroblastoma

PURPOSE Children with relapsed neuroblastoma have poor survival. It is crucial to have a reliable method for evaluating functional response to new therapies. In this study, we compared two functional imaging modalities for neuroblastoma: metaiodobenzylguanidine (MIBG) scan for uptake by the norepinephrine transporter and [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) uptake for glucose metabolic activity. PATIENTS AND METHODS Patients enrolled onto a phase I study of sequential infusion of iodine-131 ((131)I) MIBG (NANT-2000-01) were eligible for inclusion if they had concomitant FDG-PET and MIBG scans. (131)I-MIBG therapy was administered on days 0 and 14. For each patient, we compared all lesions identified on concomitant FDG-PET and MIBG scans and gave scans a semiquantitative score. RESULTS The overall concordance of positive lesions on concomitant MIBG and FDG-PET scans was 39.6% when examining the 139 unique anatomic lesions. MIBG imaging was significantly more sensitive than FDG-PET overall and for the detection of bone lesions (P < .001). There was a trend for increased sensitivity of FDG-PET for detection of soft tissue lesions. Both modalities showed similar improvement in number of lesions identified from day 0 to day 56 scan and in semiquantitative scores that correlated with overall response. FDG-PET scans became completely negative more often than MIBG scans after treatment. CONCLUSION MIBG scan is significantly more sensitive for individual lesion detection in relapsed neuroblastoma than FDG-PET, though FDG-PET can sometimes play a complementary role, particularly in soft tissue lesions. Complete response by FDG-PET metabolic evaluation did not always correlate with complete response by MIBG uptake.

Phase II Study of Oral Capsular 4-Hydroxyphenylretinamide (4-HPR/Fenretinide) in Pediatric Patients with Refractory or Recurrent Neuroblastoma: A Report from the Children's Oncology Group

Purpose: To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma. Experimental Design: Patients received 7 days of fenretinide: 2,475 mg/m2/d divided TID (<18 years) or 1,800 mg/m2/d divided BID (≥18 years) every 21 days for a maximum of 30 courses. Patients with stable or responding disease after course 30 could request additional compassionate courses. Best response by course 8 was evaluated in stratum 1 (measurable disease on CT/MRI ± bone marrow and/or MIBG avid sites) and stratum 2 (bone marrow and/or MIBG avid sites only). Results: Sixty-two eligible patients, median age 5 years (range 0.6–19.9), were treated in stratum 1 (n = 38) and stratum 2 (n = 24). One partial response (PR) was seen in stratum 2 (n = 24 evaluable). No responses were seen in stratum 1 (n = 35 evaluable). Prolonged stable disease (SD) was seen in 7 patients in stratum 1 and 6 patients in stratum 2 for 4 to 45+ (median 15) courses. Median time to progression was 40 days (range 17–506) for stratum 1 and 48 days (range 17–892) for stratum 2. Mean 4-HPR steady-state trough plasma concentrations were 7.25 μmol/L (coefficient of variation 40–56%) at day 7 course 1. Toxicities were mild and reversible. Conclusions: Although neither stratum met protocol criteria for efficacy, 1 PR + 13 prolonged SD occurred in 14/59 (24%) of evaluable patients. Low bioavailability may have limited fenretinide activity. Novel fenretinide formulations with improved bioavailability are currently in pediatric phase I studies. Clin Cancer Res; 17(21); 6858–66. ©2011 AACR.

Phase I trial of fenretinide delivered orally in a novel organized lipid complex in patients with relapsed/refractory neuroblastoma: a report from the New Approaches to Neuroblastoma Therapy (NANT) consortium.

A phase I study was conducted to determine the maximum‐tolerated dose, dose‐limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4‐HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma.

Dose Escalation Study of No-Carrier-Added 131I-Metaiodobenzylguanidine for Relapsed or Refractory Neuroblastoma: New Approaches to Neuroblastoma Therapy Consortium Trial

131I-metaiodobenzylguanidine (MIBG) is specifically taken up in neuroblastoma, with a response rate of 20%–37% in relapsed disease. Nonradioactive carrier MIBG molecules inhibit uptake of 131I-MIBG, theoretically resulting in less tumor radiation and increased risk of cardiovascular toxicity. Our aim was to establish the maximum tolerated dose of no-carrier-added (NCA) 131I-MIBG, with secondary aims of assessing tumor and organ dosimetry and overall response. Methods: Eligible patients were 1–30 y old with resistant neuroblastoma, 131I-MIBG uptake, and cryopreserved hematopoietic stem cells. A diagnostic dose of NCA 131I-MIBG was followed by 3 dosimetry scans to assess radiation dose to critical organs and soft-tissue tumors. The treatment dose of NCA 131I-MIBG (specific activity, 165 MBq/μg) was adjusted as necessary on the basis of critical organ tolerance limits. Autologous hematopoietic stem cells were infused 14 d after therapy to abrogate prolonged myelosuppression. Response and toxicity were evaluated on day 60. The NCA 131I-MIBG was escalated from 444 to 777 MBq/kg (12–21 mCi/kg) using a 3 + 3 design. Dose-limiting toxicity (DLT) was failure to reconstitute neutrophils to greater than 500/μL within 28 d or platelets to greater than 20,000/μL within 56 d, or grade 3 or 4 nonhematologic toxicity by Common Terminology Criteria for Adverse Events (version 3.0) except for predefined exclusions. Results: Three patients each were evaluable at 444, 555, and 666 MBq/kg without DLT. The dose of 777 MBq/kg dose was not feasible because of organ dosimetry limits; however, 3 assigned patients were evaluable for a received dose of 666 MBq/kg, providing a total of 6 patients evaluable for toxicity at 666 MBq/kg without DLT. Mean whole-body radiation was 0.23 mGy/MBq, and mean organ doses were 0.92, 0.82, and 1.2 mGy/MBq of MIBG for the liver, lung, and kidney, respectively. Eight patients had 13 soft-tissue lesions with tumor-absorbed doses of 26–378 Gy. Four of 15 patients had a complete (n = 1) or partial (n = 3) response, 1 had a mixed response, 4 had stable disease, and 6 had progressive disease. Conclusion: NCA 131I-MIBG with autologous peripheral blood stem cell transplantation is feasible at 666 MBq/kg without significant nonhematologic toxicity and with promising activity.

A phase I study of zoledronic acid and low‐dose cyclophosphamide in recurrent/refractory neuroblastoma: A new approaches to neuroblastoma therapy (NANT) study

Zoledronic acid, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone is a common metastatic site of advanced neuroblastoma. We previously reported efficacy of zoledronic acid in a murine model of neuroblastoma bone invasion prompting this Phase I trial of zoledronic acid with cyclophosphamide in children with neuroblastoma and bone metastases. The primary objective was to determine recommended dosing of zoledronic acid for future trials.

PET imaging in pediatric neuroradiology: current and future applications

Molecular imaging with positron emitting tomography (PET) is widely accepted as an essential part of the diagnosis and evaluation of neoplastic and non-neoplastic disease processes. PET has expanded its role from the research domain into clinical application for oncology, cardiology and neuropsychiatry. More recently, PET is being used as a clinical molecular imaging tool in pediatric neuroimaging. PET is considered an accurate and noninvasive method to study brain activity and to understand pediatric neurological disease processes. In this review, specific examples of the clinical use of PET are given with respect to pediatric neuroimaging. The current use of co-registration of PET with MR imaging is exemplified in regard to pediatric epilepsy. The current use of PET/CT in the evaluation of head and neck lymphoma and pediatric brain tumors is also reviewed. Emerging technologies including PET/MRI and neuroreceptor imaging are discussed.

131I-Metaiodobenzylguanidine with Intensive Chemotherapy and Autologous Stem Cell Transplantation for High-Risk Neuroblastoma. A New Approaches to Neuroblastoma Therapy (NANT) Phase II Study

(131)I-Metaiodobenzylguanidine ((131)I-MIBG) has been used as a single agent or in combination with chemotherapy for the treatment of high-risk neuroblastoma. The activity and toxicity of (131)I-MIBG when combined with carboplatin, etoposide, and melphalan (CEM) and autologous stem cell transplantation (SCT) are now investigated in a phase II multicenter study. Fifty patients with MIBG-avid disease were enrolled into 2 cohorts, stratified by response to induction therapy. The primary study endpoint was response of patients with refractory (n = 27) or progressive disease (n = 15). A second cohort of patients (n = 8) with a partial response (PR) to induction therapy was included to obtain preliminary response data. (131)I-MIBG was administered on day -21 to all patients, with CEM given days -7 to -4, and SCT given on day 0. (131)I-MIBG dosing was determined by pre-therapy glomerular filtration rate (GFR), with 8 mCi/kg given if GFR was 60 to 99 mL/minute/1.73 m(2) (n = 13) and 12 mCi/kg if GFR ≥ 100 mL/minute/1.73 m(2) (n = 37). External beam radiotherapy was delivered to the primary and metastatic sites, beginning approximately 6 weeks after SCT. Responses (complete response + PR) were seen in 4 of 41 (10%) evaluable patients with primary refractory or progressive disease. At 3 years after SCT, the event-free survival (EFS) was 20% ± 7%, with overall survival (OS) 62% ± 8% for this cohort of patients. Responses were noted in 3 of 8 (38%) of patients with a PR to induction, with 3-year EFS 38% ± 17% and OS 75% ± 15%. No statistically significant difference was found comparing EFS or OS based upon pre-therapy GFR or disease cohort. Six of 50 patients had nonhematologic dose-limiting toxicity (DLT); 1 of 13 in the low GFR and 5 of 37 in the normal GFR cohorts. Hepatic sinusoidal obstructive syndrome (SOS) was seen in 6 patients (12%), with 5 events defined as dose-limiting SOS. The median times to neutrophil and platelet engraftment were 10 and 15 days, respectively. Patients received a median 163 cGy (61 to 846 cGy) with (131)I-MIBG administration, with 2 of 3 patients receiving >500 cGy experiencing DLT. The addition of (131)I-MIBG to a myeloablative CEM regimen is tolerable and active therapy for patients with high-risk neuroblastoma.

Complementary Roles of Sonography and Magnetic Resonance Imaging in the Assessment of Fetal Urinary Tract Anomalies

Objective. The purpose of our study was to determine whether fetal magnetic resonance imaging (MRI) provides additional information that might affect the obstetric management of pregnancies complicated by sonographically diagnosed fetal urinary tract anomalies. Methods. Fetal MRI and sonography were used to study 39 women with suspected fetal urinary tract anomalies in the second and third trimesters of pregnancy. Results. In 24 of 39 cases (61%), fetal MRI confirmed the sonographic diagnosis. In 14 cases (36%), fetal MRI modified the initial sonographic diagnosis and counseling but did not change obstetric management. In 1 case (3%), the addition of fetal MRI resulted in a substantial change in the management of the pregnancy. Conclusions. During the second and third trimesters of pregnancy, fetal MRI showed fetal urinary tract anomalies in excellent anatomic detail. Fetal MRI is a useful complementary tool in the assessment of sonographically diagnosed fetal urinary tract anomalies. In a small percentage of cases, it can have a substantial impact on obstetric management.