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Purpose To determine whether the pattern of lung nodules in children with metastatic hepatoblastoma (HB) correlates with outcome. Methods Thirty-two patients with metastatic HB were enrolled on Children’s Oncology Group Protocol AHEP0731 and treated with vincristine and irinotecan (VI). Responders to VI received two additional cycles of VI intermixed with six cycles of cisplatin/fluorouracil/vincristine/doxorubicin (C5VD), and nonresponders received six cycles of C5VD alone. Patients were imaged after every two cycles and at the conclusion of therapy. All computed tomography scans and pathology reports were centrally reviewed, and information was collected regarding lung nodule number, size, laterality, timing of resolution, and pulmonary surgery. Results Among the 29 evaluable patients, only 31% met Response Evaluation Criteria in Solid Tumors (RECIST) for measurable metastatic disease. The presence of measurable disease by RECIST, the sum of nodule diameters greater than or equal to the cumulative cohort median size, bilateral disease, and ≥ 10 nodules were each associated with an increased risk for an event-free survival event ( P = .48, P = .08, P = .065, P = .03, respectively), with nodule number meeting statistical significance. Ten patients underwent pulmonary resection/metastasectomy at various time points, the benefit of which could not be determined because of small patient numbers. Conclusion Children with metastatic HB have a poor prognosis. Overall tumor burden may be an important prognostic factor for these patients. Lesions that fail to meet RECIST size criteria (ie, those < 10 mm) at diagnosis may contain viable tumor, whereas residual lesions at the end of therapy may constitute eradicated tumor/scar tissue. Patients may benefit from risk stratification on the basis of the burden of lung metastatic disease at diagnosis.

e22525 Background: Many childhood cancer survivors have been exposed to hepatotoxic agents. We assessed longitudinal hepatic injury, using alanine aminotransferase (ALT) elevation, and associated factors in a large cohort of long-term survivors. Methods: We evaluated SJLIFE participants ( > 10 years post-diagnosis, age ≥18 years) who had two or more determinations of ALT (T1 baseline, T2 last evaluation). Elevated ALT was defined as ALT > Upper Limit of Normal (ULN, 30 IU/mL for males and 19 IU/mL for females). Elastic net was used to perform model selection for elevated ALT at T2. Modified Poisson regression was used to identify risk factors for elevated ALT at T2. Results: Serial ALT assessments were available for 1941 survivors (49.6% female, 82.2% non-Hispanic white [NHW]). Their median age at diagnosis and T1 were 7.6 years (interquartile range [IQR] = 3.4-13.5) and 31.7 years (IQR = 26.1-38.1), respectively. Elapsed time from diagnosis to T1, and T1 to T2, were 23.3 years (IQR = 17.8-29.6) and 5.2 years (IQR = 4.4-5.7). ALT was normal at T1 and T2 in 45.7%, and persistently (25.9%) or newly (11.7%) abnormal in 37.6%. Compared to those with normal ALT at T1, those with elevated ALT at T2 were more likely to have NHW race/ethnicity, treatment with busulfan, increasing volume of the liver exposed to 10 Gray (Gy) or more (V10), body mass index (BMI) > 25 kg/m2, hepatitis C, metabolic syndrome, or treatment with atorvastatin, rosuvastatin or simvastatin at T2. History of hematopoietic stem cell transplantation (HSCT), but not busulfan, were additional risk factors included in the models for V15 and V20 (Table). Conclusions: Demographic, treatment, lifestyle, and non-oncologic interventions increase the risk for ALT elevation in survivors. These results may guide future treatment designs and lifestyle interventions. [Table: see text]

Rare pediatric tumors account for approximately 10% of all childhood cancers, which in themselves are a rare entity. The diverse histologies and clinical behaviors of rare pediatric tumors pose challenges to the investigation of their biologic and clinical features. National and international cooperative groups such as the Rare Tumor Committee of the Children's Oncology Group, Rare Tumors in Pediatric Age Project, and European Cooperative Study Group for Pediatric Rare Tumors have developed several initiatives to advance knowledge about rare pediatric cancers. However, these programs have been only partially effective, necessitating the development of alternative mechanisms to study these challenging diseases. In this article, we review the current national and international collaborative strategies to study rare pediatric cancers and alternative methods under exploration to enhance those efforts, such as independent registries and disease-specific, National Cancer Institute–sponsored clinics.

Purpose Treatment outcome for black patients with cancer has been significantly worse than for their white counterparts. We determined whether recent improved treatment had narrowed the gap in outcome between black and white pediatric patients. Patients and Methods In a parallel comparison, we analyzed survival by disease category between black and white patients with childhood cancer registered in one of the 17 cancer registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program or treated at St Jude Children's Research Hospital, which provides comprehensive treatment to all patients regardless of their ability to pay, from 1992 to 2000 and from 2001 to 2007. Results Analysis of the SEER data indicated that in both study periods, black patients had significantly poorer rates of survival than did white patients, with the exception of a few types of cancer. Despite significantly improved treatment outcomes for patients who were treated from 2001 to 2007, the racial difference in survival has actually widened for acute myeloid leukemia and neuroblastoma. By contrast, in the cohorts treated at St Jude Children's Research Hospital, there were no significant differences in survival between black and white patients in either study period, regardless of the cancer type. Importantly, the outcome of treatment for acute lymphoblastic leukemia, acute myeloid leukemia, and retinoblastoma has improved in parallel for both races during the most recent study period. Conclusion With equal access to comprehensive treatment, black and white children with cancer can achieve the same high cure rates.

Purpose When a child's cancer progresses beyond current treatment capability, the parents are likely to participate in noncurative treatment decision making. One factor that helps parents to make these decisions and remain satisfied with them afterward is deciding as they believe a good parent would decide. Because being a good parent to a child with incurable cancer has not been formally defined, we conducted a descriptive study to develop such a definition. Methods In face-to-face interviews, 62 parents who had made one of three decisions (enrollment on a phase I study, do not resuscitate status, or terminal care) for 58 patients responded to two open-ended questions about the definition of a good parent and about how clinicians could help them fulfill this role. For semantic content analysis of the interviews, a rater panel trained in this method independently coded all responses. Inter-rater reliability was excellent. Results Among the aspects of the definition qualitatively identified were making informed, unselfish decisions in the child's best interest, remaining at the child's side, showing the child that he is cherished, teaching the child to make good decisions, advocating for the child with the staff, and promoting the child's health. We also identified 15 clinician strategies that help parents be a part of making these decisions on behalf of a child with advanced cancer. Conclusion The definition and the strategies may be used to guide clinicians in helping parents fulfill the good parent role and take comfort afterward in having acted as a good parent.

Purpose Pediatric colorectal carcinoma (CRC) is rare, but the available data suggest that it is more likely than adult CRC to be advanced at presentation and to have a poor outcome. We sought to better characterize pediatric CRC. Patients and Methods We reviewed the clinical and pathologic features, prognostic factors, and outcome of CRC in 77 children and adolescents (ages 7 to 19 years) referred to St Jude Children's Research Hospital between 1964 and 2003. Results At presentation, 76 patients had one or more signs or symptoms of CRC (abdominal pain, altered bowel habits, weight loss, anemia). Tumors were evenly distributed between the right and left colon; 62% were mucinous adenocarcinoma. At presentation, 86% of patients had advanced-stage disease; more than half had distant metastases. Overall outcome was poor. Advanced stage and mucinous histology were significant predictors of adverse outcome. Stage-specific survival at 10 years was 67% ± 27% (stage 1), 38% ± 15% (stage 2), 28% ± 11% (stage III), and 7% ± 4% (stage 4). Although no patient had a diagnosis of polyposis syndrome before diagnosis of CRC, 17 (22%) had colon polyps and eight (including two who previously underwent pelvic radiotherapy) had multiple polyps. Conclusion Initial signs and symptoms of CRC are similar in pediatric and adult patients. The strikingly higher frequency of mucinous histology suggests that the biology of CRC differs in pediatric and adult patients and may contribute to poor outcomes. Children should be included in prospective clinical trials for CRC.

PurposeTo study the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity as well as irinotecan disposition in pediatric patients with solid tumors receiving low-dose, protracted irinotecan (15 to 75 mg/m2daily for 5 days for 2 consecutive weeks).Patients and MethodsSeventy-four patients on five institutional clinical trials received irinotecan (15 to 75 mg/m2) daily intravenously or orally for 5 days for 2 consecutive weeks. Genomic DNA was genotyped for UGT1A1*28, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the UGT1A1 promoter region. Patients were evaluated for gastrointestinal and hematologic toxicity, as well as baseline and maximal serum bilirubin levels. Toxicity and pharmacokinetic results were evaluated during courses 1 and 2 of irinotecan therapy.ResultsThe frequencies of 6/6, 6/7, and 7/7 genotypes were 27 (36.5%), 36 (48.6%), and 9 (12.2%) of 74 patients, respectively. Patients with 7/7 genotype had a statistically greater baseline total bilirubin than patients with 6/6 or 6/7 genotype (P = .005). UGT1A1*28 genotype was not associated with grade 3 and 4 neutropenia (P = .21 for course 1; P = .23 for course 2) or diarrhea (P = .176 for course 1; P = .87 for course 2). However, patients with the 7/7 genotype tended to have higher SN-38 area under the plasma time-concentration curve (AUC) values and lower SN-38G/SN-38 AUC ratios.ConclusionSevere toxicity was not increased in pediatric patients with the 7/7 genotype when treated with a low-dose protracted schedule of irinotecan. Therefore, UGT1A1 genotyping is not a useful prognostic indicator of severe toxicity for patients treated with this irinotecan dosage and schedule.

Purpose To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the histone deacetylase inhibitor, depsipeptide, in children with refractory or recurrent solid tumors. Patients and Methods Depsipeptide was administered as a 4-hour infusion weekly for 3 consecutive weeks every 28 days at dose levels of 10 mg/m2, 13 mg/m2, 17 mg/m2, and 22 mg/m2. Pharmacokinetics and histone acetylation studies were performed in the first course. The levels of H3 histone and acetyl-H3 histone were evaluated in peripheral blood mononuclear cells (PBMC) using immunofluorescence techniques. Results There were 24 patients, and 18 who were assessable were enrolled. DLTs included reversible, asymptomatic T-wave inversions, without any associated changes in troponin levels or evidence of ventricular dysfunction, in the inferior leads in two patients at 22 mg/m2 and in the lateral leads in one patient at 13 mg/m2 (n = 1), and transient asymptomatic sick sinus syndrome and hypocalcemia in one patient at 17 mg/m2. At the MTD (17 mg/m2), the median depsipeptide clearance was 6.8 L/h/m2 with an area under the plasma depsipeptide concentration-time curve from 0 to infinity of 2,414 ng/mL/h, similar to adults. Accumulation of acetylated H3 histones was seen in all patients in a dose independent manner, with maximal accumulation at a median of 4 hours, (range, 0 hours to 20 hours) after the end of the infusion. No objective tumor responses were observed. Conclusion Depsipeptide is well tolerated in children with recurrent or refractory solid tumors when administered weekly for 3 consecutive weeks every 28 days and inhibits histone deacetylase activity in PBMC in a dose-independent manner. The recommended phase II dose in children with solid tumors is 17 mg/m2.

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×h/mL; standard deviation [SD], 6.8 ng × h/mL v 10.4 ng × h/mL; SD, 4.3 ng × 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.

Purpose To estimate the response rate and toxicity associated with intravenous topotecan when it is administered on a protracted schedule according to a pharmacokinetically guided dosing approach to treat childhood high-risk neuroblastoma. Patients and Methods In this prospective phase II trial, topotecan was administered intravenously daily for 5 days for each of 2 consecutive weeks for two cycles. On the basis of topotecan systemic clearance, doses were individualized to attain a single-day topotecan lactone area under the plasma concentration-time curve (AUC) of 80 to 120 ng/mL · h. Patients subsequently received standard treatment. Results Both cycles were administered to 28 (93%) of the 30 enrolled patients (median age, 3.1 years). Target topotecan AUCs were achieved in 92 (72%) of the 127 measurements conducted after pharmacokinetically guided adjustment; the median dosage required to achieve target AUCs was 2.7 mg/m2 (range, 0.95 to 3.8 mg/m2). The response rate was 60% (95% CI, 41% to 77%); there were one complete and 17 partial responses. No patient experienced disease progression during initial topotecan therapy. Primary tumor volumes decreased (median decrease, −58.2%; range, −95.1% to −4.9%) in the 26 patients with available size data. Homovanillic acid levels in 16 (89%) of 18 patients and vanillylmandelic acid levels in 14 (78%) of 18 patients were lower (P = .002 and P = .018, respectively) after topotecan therapy. Reversible grade 4 myelosuppression occurred in all patients, but no deaths occurred as a result of infection or toxicity. Conclusion Topotecan is active against neuroblastoma when it is administered on a protracted schedule and targeted systemic exposure is achieved.

Purpose To determine the dose limiting toxicity (DLT), maximum-tolerated dose (MTD), and pharmacokinetic profile of tirapazamine (Sanofi Synthelabo Research, Malvern, PA) combined with cyclophosphamide in children with recurrent solid tumors. Patients and Methods Patients received a 2-hour infusion of tirapazamine, followed by 1,500 mg/m2 cyclophosphamide, and mesna once every 3 weeks. Dose escalation of tirapazamine began at 250 mg/m2 and was increased by 30% in subsequent cohorts. If DLT was hematologic, less-heavily pretreated patients were to be enrolled until their DLTs were encountered, and MTDs defined. Pharmacokinetic profiles were also characterized. Results Twenty-three patients were enrolled onto the study. Pharmacokinetic data were calculated for 22 patients. Prolonged neutropenia was the DLT at 420 mg/m2 in heavily pretreated patients. Grade 3, reversible ototoxicity was the DLT in less-heavily pretreated patients at 420 mg/m2. Two (one with neuroblastoma and one with rhabdomyosarcoma) had partial responses. One child with neuroblastoma had prolonged stable disease (10 cycles) at a dose of 250 mg/m2. This patient had disease detectable in the bone marrow only and all evidence of bone marrow involvement resolved for 17 cycles of therapy. Four other patients had stable disease. An apparent dose-proportional increase in tirapazamine maximal concentration and area under the curvelast was observed. Tirapazamine clearance, volume of distribution at steady-state, and terminal half-life did not appear to be dose-dependent. Conclusion The recommended dose of tirapazamine given with 1,500 mg/m2 of cyclophosphamide once every 3 weeks is 325 mg/m2. Neutropenia and ototoxicity were dose-limiting. Based on early evidence of antitumor activity, additional studies appear warranted.

PurposeWe conducted a phase I trial of the injectable formulation of topotecan given orally once daily for 5 days for 2 consecutive weeks (qd × 5 × 2) in pediatric patients with refractory solid tumors.Patients and MethodsCohorts of two to six patients received oral topotecan at 0.8, 1.1, 1.4, 1.8, and 2.3 mg/m2/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.ResultsDose-limiting toxicity occurred at 2.3 mg/m2/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/m2/d. Infrequent toxicities were mild nausea, vomiting, elevated liver ALT or AST, and rash. The maximum-tolerated dosage was 1.8 mg/m2/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.ConclusionOral topotecan (1.8 mg/m2/d) on a qd × 5 × 2 schedule is well tolerated and warrants additional testing in pediatric patients.

10561 Background: Assessment of late outcomes in neuroblastoma survivors has generally consisted of self-reported health events within retrospective cohorts. We aimed to characterize the health outcomes of a clinically-assessed cohort of long-term survivors of neuroblastoma diagnosed between 1963-2003. Methods: In a cohort of 239 ten-year survivors of neuroblastoma, of whom 137 (57%) underwent comprehensive clinical assessments, chronic conditions were graded using a modified version of the Common Terminology Criteria of Adverse Events, version 4.03. Comparisons were made using 272 clinically assessed community controls. Log-binomial regression was used to compare the prevalence of chronic conditions (grade 1-5) between survivors and controls and to calculate prevalence ratio (PR) and 95% confidence intervals (CI). Mean cumulative count (treating death as a competing risk) of chronic conditions by age was used to estimate cumulative burden with imputation of outcomes for non-clinically assessed survivors. Results: The median age at diagnosis was 0.9 (range: 0.0-14.4) and the median age at follow-up was 31.9 (range: 20.2-54.6) years for clinically assessed survivors. Median age of controls was 34.7 (range: 18.3-70.2). Treatment consisted of chemotherapy (75%), radiation (23%) and surgery (91%). Survivors were more likely than controls to have hearing loss (31.4% vs. 2.9%, PR = 10.7, 95% CI = 5.2-22.0), cardiomyopathy (8.8% vs. 0.7%, PR = 11.9, 95% CI = 2.7-52.5), hypothyroidism (10.9% vs. 5.2%, PR = 2.1, 95% CI = 1.1-4.3) or neurological disorders (56.9% vs. 32.4%, PR = 1.8, 95% CI = 1.4-2.2). At 35 years of age, the cumulative incidence of survivors experiencing at least one grade 3-5 condition was 67.3% (95% CI = 58.3-76.0%). By age 35 survivors experienced, on average, 8.5 (95% CI = 7.6-9.3) grade 1-5 and 2.4 (95% CI = 2.0-2.8) grade 3-5 conditions per 100 survivors, which was higher than the burden of grade 1-5 (3.3 [95%CI = 2.9-3.7]) and grade 3-5 (0.9 [95%CI = 0.7-1.0]) conditions identified among controls. Conclusions: Two-thirds of survivors are affected by severe or life-threatening health conditions. Continued follow-up, screening and intervention provide opportunities to optimize health.

10534 Background: We are conducting a Phase II trial of the anti-GD2 mAb hu14.18K322A given concomitantly with CT in newly diagnosed pts with HR NB. Our primary objective is to compare the response rate (RR; defined as ≥ PR) after two courses of CT with cyclophosphamide (CTX)/topotecan (TPT) and hu14.18K322A with GM-CSF and IL-2 to the RR reported by Park et al. (JCO 29:4351, 2011), using identical CT with GCSF only, in a two-stage group sequential design. Semiquantitative MIBG scoring (Curie; CS) has been shown to be a prognostic indicator of outcome in pts with HR NB (Yanik et al, J Nucl Med, 2013), particularly, those with CS > 2 at end of induction (EoI) CT have inferior outcomes. Here we update the RR and report the CS at EoI CT. Methods: Pts received induction CT (6 cycles) as described by Park et al, with the addition of hu14.18K332A (on d 2-5; 40mg/m2/d x 4d), daily sc GM-CSF and sc IL-2 (1 x 106 IU/m2/dose) qod x 6. 123I-MIBG scans and scoring (CS) were obtained on all pts at diagnosis, after second course of CT and at EoI. Results: 42 evaluable pts completed the first two courses of CT (24 male, median age 2.9 yrs (range 6 m -15.2 yrs), 36 INSS 4, 19 MYCNamplified); 40/42 evaluable pts had measurable reductions in primary tumor volume after two courses of CT (median 79%, average 69%, range +5 – 100%). Responses (≥ PR) after two courses were seen in 32/42 (76.2%; 95% CI 61.3 – 87.9%); No mAb dose-reductions were made but 20/43 (47%) pts had infusion times extended. The development of human anti-human antibody reactivity (HAHA) to hu14.18K322A in the first 22 pts is minimal. Of the 36 INSS 4 pts, 1 withdrew prior to EoI and 2 are too early. The median CS at diagnosis for the 33 stage 4 pts who have completed induction CT was 18 (range 1 – 28). At EoI the median CS was 0 (range 0 -23); 29/33 INSS 4 pts had EoI CS ≤ 2. Conclusions: The addition of hu14.18K322A to two courses of CTX/TPT significantly improves the RR compared to two courses of CTX/TPT alone (32/42 vs 12/30 as reported by Park et al,; P = 0.000004). The improved median CS of the stage 4 patients from 18 at diagnosis to 0 at EoI suggest the improvement in early RR may translate into improved EFS as well. Clinical trial information: NCT01857934.

10557 Background: This retrospective study sought to identify predictors of metastatic site failure (MSF) in patients with high-risk (HR) neuroblastoma (NB). Methods: Seventy-six patients with HR NB treated on prospective trials at from 1997 to 2014 were eligible for inclusion. All patients were treated with induction chemotherapy (chemo) with surgery followed by myeloablative chemo & stem cell rescue. Primary & metastatic site (MS) RT were applied according to institutional protocol. CT & I-123 MIBG scans were used to assess Curie scores at diagnosis, post-induction, post-transplant & failure. Overall (OS), & progression-free survival (PFS) were described using the Kaplan-Meier estimator. Cox proportional hazards frailty (cphfR) & CPH regression (CPHr) were used to identify covariates predictive of MSF & new site MSF. Results: Forty-two (55%) patients had documented MSFs. Consolidative MS RT was applied to 30 MSs in 10 patients. Original site MSF occurred in 146 of 383 (38%) & 18 of 30 (60%) non-irradiated & radiated MSs respectively. Original site MSF occurred in post-induction MIBG avid lesions in 68 of 81 (84%) & 12 of 14 (85%) non-irradiated & radiated MSs respectively. The median OS & PFS were 61 mo (95% CI 42.6-NR) & 24.1 mo (95% CI 16.5-38.7). Univariate cphfR identified an increased hazard for original MSF when MIBG avid following induction chemo (HR 4.9, 95%CI 1.1-20.9, p = 0.03) & transplant (HR 7.3 95%CI 1.8-30.2, p = 0.006) relative to lesions that cleared after induction. Notably, MS RT nor site location did not modify the hazard for MSF. Multivariate CPHr identified inability to undergo transplant (HR 32.4 95%CI 9.3-96.8, p < 0.001) &/or maintenance chemo (HR 5.2, 95%CI 1.7-16.2, p = 0.005) & the presence of lung metastases (HR 4.4 95%CI 1.7-11.1, p = 0.002) at diagnosis as predictors of new site MSF. The new MSF free survival at 3 years was 25% vs. 87% in patients with high-risk factors relative to those without the risk factors suggesting limited benefit of consolidative MS RT in this population. Conclusions: Metastatic lesions that remained MIBG avid following induction chemo & post-transplant had an increased hazard for MSF. Consolidative site RT likely has limited benefit in patients with HR features.

10567 Background: We assessed hepatic injury (HI) in a large cohort of childhood cancer survivors (CCS). Methods: We measured aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in 2751 SJLIFE CCS ( > 10 years (yrs) post-diagnosis, age ≥18 yrs), and graded using the Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Multivariable log binomial regression was used to estimate associations between demographic and clinical factors and grades 1–4 ALT and AST. Variables with a p < 0.1 were examined in multivariable models. Results: 1339 (48.7%) CCS were female. 2271 (82.6%) were non-Hispanic white (NHW). Median age at diagnosis - 7.4 yrs, median age at evaluation - 31.4 yrs, and median time from diagnosis to evaluation - 23.2 yrs. 177 (6.4%) had grades 1-4 AST (grade 1 = 164, grade 2 = 9, grade 3 = 4), and 421 (15.3%) had grades 1-4 ALT (grade 1 = 394, grade 2 = 18, grade 3 = 8). The multivariable results are shown in the table below. Conclusions: Male gender, obesity, hepatitis C virus infection, and treatment with busulfan are risk factors for increased AST and ALT. V10 is an additional risk factor for increased ALT. These results may guide future treatment designs and lifestyle interventions. [Table: see text]

PURPOSE: To determine the frequency of CNS involvement at diagnosis of non-Hodgkin’s lymphoma (NHL), to characterize its pattern of presentation, and to determine its prognostic significance. PATIENTS AND METHODS: We reviewed the records of 445 children (1975 through 1995) diagnosed with NHL (small noncleaved cell NHL/B-cell acute lymphoblastic leukemia [SNCC NHL/B-ALL], 201 patients; lymphoblastic, 113; large cell, 119; other, 12). Tumor burden was estimated by serum lactate dehydrogenase (LDH) measurement and reclassification of disease stage irrespective of CNS involvement (modified stage). RESULTS: Thirty-six of 445 children with newly diagnosed NHL had CNS involvement (lymphoma cells in the CSF [n = 23], cranial nerve palsy [n = 9], both features [n = 4]), representing 13%, 7%, and 1% of small noncleaved cell lymphoma, lymphoblastic lymphoma, and large-cell cases, respectively. By univariate analysis, CNS disease at diagnosis did not significantly impact event-free survival (P = .095), whereas stage and LDH did; however, children with CNS disease at diagnosis were at 2.0 times greater risk of death than those without CNS disease at diagnosis. In a multivariate analysis, CNS disease was not significantly associated with either overall or event-free survival, whereas both serum LDH and stage influenced both overall and event-free survival. Among cases of SNCC NHL/B-ALL, CNS disease was significantly associated with event-free and overall survival (univariate analysis); however, in multivariate analysis, only LDH had independent prognostic significance. Elevated serum LDH or higher modified stage were associated with a trend toward poorer overall survival among children with CNS disease. CONCLUSION: A greater tumor burden at diagnosis adversely influences the treatment outcome of children with NHL and CNS disease at diagnosis, suggesting a need for ongoing improvement in both systemic and CNS-directed therapy.

The identification of new therapies for high-risk (HR) hepatoblastoma is challenging. Children's Oncology Group study AHEP0731 included a HR stratum to explore the efficacy of novel agents. Herein, the authors report the response rate to the combination of vincristine (V) and irinotecan (I) and the outcome of patients with high-risk hepatoblastoma.Patients with newly diagnosed metastatic hepatoblastoma or those with a serum α-fetoprotein (AFP) level100 ng/mL were eligible. Patients received 2 cycles of V at a dose of 1.5 mg/mA total of 32 patients with a median age at diagnosis of 26 months (range, 11-159 months) were enrolled between September 2009 and February 2012. Fourteen of 30 evaluable patients were responders (RECIST and AFP in 6 patients, RECIST only in 3 patients, and AFP only in 5 patients). The median AFP decline after 2 cycles of VI for the entire group was 345,565 ng/mL (85% of the initial AFP). The 3-year event-free and overall survival rates were 49% (95% confidence interval, 30%-65%) and 62% (95% confidence interval, 42%-77%), respectively.The VI combination appears to have substantial activity against HR hepatoblastoma. The ultimate impact of this regimen in improving the outcomes of children with HR hepatoblastoma remains to be determined. Cancer 2017;123:2360-2367. © 2017 American Cancer Society.

10501Background: The chimeric anti-GD2 mAb dinutuximab improves EFS in HR NB when administered in the setting of minimal residual disease following intensive chemotherapy (CT) (Yu et al. NEJM 2010)...

10519Background: Angiogenesis is required for tumor growth and metastasis. Both VEGF and PDGFR are key regulators of tumor vasculature. In preclinical models, dual inhibition of VEGF and PDGFR sign...

PURPOSE Leukemic cell characteristics were analyzed in infants less than 1 year of age with acute lymphoblastic leukemia (ALL) to determine adverse prognostic factors that might explain the poor prognosis of this group. PATIENTS AND METHODS Treatment outcomes were analyzed according to the presenting clinical and laboratory features of 30 infants treated between May 1979 and April 1993. A stepwise multivariate regression model was used to identify the most important prognostic indicator with respect to event-free survival. RESULTS Infant ALL cases were characterized by high presenting leukocyte count (median, 87 x 10(9)/L), increased frequency of CNS leukemia (50%), and blast cells with a CD10- phenotype (67%), myeloid-associated antigen expression (48%), and 11q23/MLL rearrangement (68%). The 11q23/MLL involvement was correlated with age less than 6 months, CD10- phenotype, myeloid-associated antigen expression, and high leukocyte count. Although 11q23/MLL involvement, age less than 6 months, myeloid-associated antigen expression, and female sex were each significantly associated with an inferior treatment outcome, only rearranged 11q23/MLL emerged as an independent predictor of prognosis in multivariate analysis (P = .01). Infants with this genetic abnormality had a 4.7-fold (95% confidence interval, 1.3- to 17.0-fold) increased risk in adverse events compared to other infants. CONCLUSION The 11q23/MLL involvement of blast cells identifies a major subgroup of infant ALL cases that require an innovative treatment approach. Infants who lack this genetic abnormality have an intermediate prognosis and could be treated accordingly on risk-directed protocols.

PURPOSE To determine the dose-limiting toxicity and potential efficacy of topotecan in pediatric patients with refractory malignant solid tumors. PATIENTS AND METHODS In this phase I clinical trial, 27 patients received topotecan 0.75-1.9 mg/m2 by continuous intravenous infusion daily for 3 days. Fifty-three treatment courses were given to these patients. RESULTS Myelosuppression was the dose-limiting toxicity at levels of 1.3 to 1.9 mg/m2 for 3 days, requiring significant support with transfused packed RBCs and platelets. Myelosuppression was variable in severity at the 1.0-mg/m2 dosage level; thus, additional patients were treated with this dosage, followed by human recombinant granulocyte-colony stimulating factor (G-CSF). Other toxicities were not significant. One patient with neuroblastoma had a complete response that lasted for 8 months. Stable disease activity was recorded for other patients with neuroblastoma, rhabdomyosarcoma, and islet cell carcinoma. Pharmacokinetic studies showed that topotecan plasma concentrations ranged from 1.6 to 7.5 ng/mL during infusions of 1.0 mg/m2/d, and that there was a biphasic plasma distribution with a mean terminal half-life of 2.9 +2- 1.0 hours. CONCLUSION Topotecan is a promising anticancer agent that deserves phase II testing in pediatric solid tumors. We recommend that pediatric phase II topotecan trials use 1.0 mg/m2/d for 3 days as a constant intravenous infusion, followed by G-CSF for 14 days, and that these treatment courses be repeated every 21 days.

PURPOSE The tolerance of escalating targeted doses of carboplatin combined with ifosfamide (IFOS)/etoposide (VP-16) (ICE) was assessed in children with recurrent solid tumors. PATIENTS AND METHODS To reduce interpatient variability in carboplatin systemic exposure, 45 children were treated with doses individualized to a target area under the serum concentration versus time curve (AUC) based on renal function, using technetium 99-diethyl-enetriamine pentaacetic acid (99mTc-DTPA) clearance to estimate glomerular filtration rate (GFR). Cohorts of at least three patients received carboplatin at an initial target AUC of 2 mg/mL x min, with escalations of 1 mg/mL x min in subsequent cohorts. Courses consisted of carboplatin on day 1 followed by IFOS 2 g/m2 plus VP-16 100 mg/m2 on days 2 and 3. Patients received at least two courses, with a maximum of eight courses possible in the absence of progressive disease. When only moderate toxicity occurred after escalation to 5 mg/mL x min, a third dose of IFOS plus VP-16 was added. After three patients were treated at this level, carboplatin escalation proceeded. RESULTS Neutropenia and thrombocytopenia were the dominant toxicities in the 43 assessable patients. At the target AUC of 8 mg/mL x min, 13 of 20 cycles were associated with febrile neutropenia. For phase II trials, we recommend a carboplatin target AUC of 6 mg/mL x min with three doses of IFOS and VP-16 for patients with prior craniospinal irradiation or high-dose cisplatin (CDDP)/VP-16, or 7 mg/mL x min for patients without such histories. There were two complete responses (CRs), 13 partial responses (PRs), and 17 objective responses (ORs). CONCLUSION The ICE regimen shows promising activity in pediatric solid tumors. The clear relationship between hematologic toxicity and carboplatin systemic exposure supports the use of targeted dosing in further trials of ICE chemotherapy.

Twenty-five children with refractory solid tumors were given recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in escalated doses of 60 to 1,500 micrograms/m2 as 2-hour intravenous infusions, beginning 24 hours after myelosuppressive treatment with cisplatin and etoposide. Tolerance to rhGM-CSF was exceptional even at dose levels that exceeded the maximum-tolerated dosage (MTD) reported for adults. The agent produced dose-related increases in platelet and neutrophil counts, resulting in significantly shorter durations of severe neutropenia and thrombocytopenia (P less than .01 for each analysis). At the higher dosages (greater than or equal to 750 micrograms/m2), treatment with rhGM-CSF reduced the median number of days of antibiotic therapy for fever and neutropenia by approximately one half. We conclude that rhGM-CSF is well tolerated by leukopenic children in doses as high as 1,500 micrograms/m2. An MTD was not reached in this study. The ability of the growth factor to reduce severe neutropenia and thrombocytopenia suggests it will have an important role in the management of childhood solid tumors.

10041 Background: Despite a well-developed risk classification schema utilizing both clinical and biologic factors, the clinical outcome of neuroblastoma (NB) is remarkably heterogeneous. Replicative immortality in cancers is mediated by 2 known telomere maintenance mechanisms (TMMs): telomerase reactivation and alternative lengthening of telomere (ALT). We hypothesized that TMMs are essential for cancer development in high-risk NBs (HR-NBs) but not low-risk or stage 4S NBs that frequently undergo spontaneous regression. We investigated the prevalence of known molecular events involved in TMMs in NB risk categories. Methods: The analysis included 47 NBs from 27 patients with high-risk disease and poor outcomes and 19 patients with low- or intermediate-risk disease and good outcomes (LR-NBs). Presence of the ALT phenotype was determined by telomeric fluorescence in situ hybridization (FISH), and its association with ATRX alterations was evaluated by immunohistochemistry. Direct sequencing of the TERT promo...

9534 Background: Less than 40% of children with high-risk neuroblastoma achieve long-term survival, and at diagnosis, it is not possible to identify patients who will be cured. Microarray studies have proposed expression signatures associated with outcome within high-risk cohorts. However, integrating this technology as a clinical test has been difficult, in part due to the lack of available frozen tissue and high quality RNA. The nCounter overcomes this obstacle, using formalin-fixed paraffin embedded tissue (FFPE). Our objective is to test the correlation of a previously published “ultra high-risk” microarray gene signature developed in the MYCN nonamplified high-risk population (Asgharzadeh et al, J Natl Cancer Inst, 2006) with the gene expression signature obtained with the nCounter (NanoString Technologies) using RNA isolated from FFPE MYCN nonamplified high-risk neuroblastoma samples. Methods: FFPE tumor samples linked to clinical outcome data were obtained from 6 collaborative institutions. Tumor content of each sample was assessed morphologically. RNA was isolated using the RNeasy FFPE-kit. Customized probes corresponding to the candidate genes were designed by NanoString. Hybridization reactions were performed in duplicate using 100 ng of RNA. Positive and negative control probes and housekeeping probes were included in every reaction and were used to normalize data for differences in purification, hybridization, and capture efficiencies Results: Forty-two MYCN nonamplified high-risk neuroblastoma samples were analyzed by the nCounter. The cohort 5-year event-free survival and overall survival were 44.6 +/- 8.0% and 53.8 +/- 8.4% respectively. Highly degraded RNA (RIN ~ 1.5-2.8) was obtained. Unsupervised clustering and principle components analysis on normalized expression data showed differential expression of most of the genes with clustering of cases depending upon outcome (FDR = 0.05). Conclusions: Our results demonstrate that the nCounter can yield gene expression profiles that are similar to microarray gene signatures. Further investigation of the clinical utility the nCounter technology to prognosticate outcome in patients with high-risk neuroblastoma is warranted.

9500 Background: Angiogenesis is necessary for tumor growth, metastasis, and survival. Endothelial cells and pericytes, key cellular components of blood vessels, are primarily regulated by VEGF and...

9523 Background: Immunotherapy, including combination anti-GD2 mAb ch14.18 and cytokines, improves the outcome of patients with advanced neuroblastoma. Dose escalation of antibodies targeting GD2 a...

9545 Background: Carboplatin and cisplatin are highly active chemotherapeutic agents but have significant toxicities. Oxaliplatin is active in cisplatin-resistant cell lines with a different clinical toxicity profile (less renal, bone marrow, and ototoxicity). The combination of ifosfamide, carboplatin and etoposide is active in pediatric tumors but myelosuppression is dose-limiting. Substituting oxaliplatin in this regimen may allow further dose intensification or be useful in cisplatin-resistant tumors. This study evaluated the safety and estimated the maximum tolerated dose (MTD) of IOE in children with refractory solid tumors. Methods: Oxaliplatin was given intravenously (IV) on day 1 with IV ifosfamide and etoposide on days 1-3 of a 21-day course. Cohorts of 3-6 patients were enrolled at 2 dose levels (see table). A third level with filgrastim or pegfilgrastim (GCSF) support was also evaluated. Results: Twelve evaluable patients (median age 6 yrs, 8 M) received a total of 38 courses (median 2, rang...

2523 Background: Gefitinib is an orally active inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. Neuroblastoma, rhabdomyosarcoma, osteosarcoma, and high-grade gliomas are known to express EGFR. Thus, three phase I studies evaluating gefitinib pharmacokinetics were conducted in children with recurrent/refractory solid tumors (COG ADVL0016 and SJZD1839) or brain tumors (PBTC007). Because of wide inter-individual variability in gefitinib disposition, the present study was conducted to describe the population PK of gefitinib and to assess the relationship between gefitinib disposition and patient covariates. Methods: Subjects received daily oral gefitinib ranging from 100 to 500 mg/m2 as single agent therapy for 8 to 10 days prior to PK evaluation. Multiple plasma samples were collected per subject and analyzed using a validated LC MS/MS assay. The data consisted of 73 subjects and 600 samples. Data were analyzed using NONMEM v5 to obtain gefitinib apparent oral clearance (CL/F), appar...

10024 Background: The combination of a platinating agent with etoposide is effective in many pediatric solid tumors. In preclinical models, oxaliplatin is as potent as cisplatin or carboplatin. Cli...

3078 Background: Recent USFDA recommendations include a dosage adjustment for patients who are homozygous for the UGT1A1*28 allele (i.e., 7 TA repeats in the promoter) due to an increase in neutropenia when those patients receive IRN. However, this recommendation was based upon data from adults treated with high IRN dosage (e.g., 350 mg/m2). This study evaluates the relationship between UGT1A1 promoter genotype and phenotype (i.e., SN-38 glucuronidation and IRN toxicity) in patients treated with low-dose, protracted IRN. Methods: 31 children treated on 2 institutional protocols received low dosage (20 to 60 mg/m2) i.v. IRN daily for 5 days of 2 consecutive weeks. PK sampling and UGT1A1 genotyping were performed during cycle 1. Patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the UGT1A1 promoter region. All patients were evaluable for gastrointestinal and hematological toxicity, primarily grades 3 and 4 neutropenia and diarrhea. Results: The frequencies of 6/6, 6/7, and 7/7 genotypes were 9/31 (29%), 15/31 (48%), and 7/31 (23%), respectively. Patients with 7/7 genotype had a statistically greater baseline bilirubin than patients with 6/6 or 6/7 genotype (p No significant financial relationships to disclose.

8528 Background: Depsipeptide, a histone deacetylase inhibitor, has demonstrated potent antitumor activity against human tumor cell lines (including neuroblastomas) at IC50s < 10nM and in various x...

8521 Background: Gefitinib (Iressa), an oral Epidermal Growth Factor receptor (EGFR) inhibitor that has been well tolerated in adults, modulates intracellular drug effects through inhibition of efflux pumps (e.g., BCRP). In xenograft models of pediatric solid tumors it has additive/synergistic activity with IRN, which was independent of EGFR status. We are conducting a Phase I study of this combination in children with refractory solid tumors. Methods: Our objectives are to estimate the maximum tolerated dose and dose-limiting toxicities (DLT) of gefitinib administered daily × 21 days in combination with protracted intravenous IRN [day 1- 5, day 8 - 12]. Pharmacokinetic (PK) studies of IRN and metabolites were obtained with and without concurrent gefitinib. PK studies of gefitinib were obtained on days –1 and 8. Courses are repeated every 21 days in the absence of DLT or disease progression. Results: At present, 2 cohorts have been evaluated (age 3 –15 yrs, median 5 yrs). Cohort 1 (n = 5) received continu...

2011 Background: We are conducting a Phase I and pharmacokinetic (PK) study of gefitinib and IRN in children with refractory solid tumors with the objective to evaluate the effect of gefitinib on I...

2012 Background: Gefitinib (ZD1839, Iressa), an oral EGFR tyrosine kinase inhibitor, significantly increased the oral bioavailability of irinotecan in preclinical murine pharmacokinetic studies. Ba...

PURPOSE: In a preclinical model of neuroblastoma, administration of irinotecan daily 5 days per week for 2 consecutive weeks ([qd × 5] × 2) resulted in greater antitumor activity than did a single 5-day course with the same total dose. We evaluated this protracted schedule in children. PATIENTS AND METHODS: Twenty-three children with refractory solid tumors were enrolled onto a phase I study. Cohorts received irinotecan by 1-hour intravenous infusion at 20, 24, or 29 mg/m2 (qd × 5) × 2 every 21 days. RESULTS: The 23 children (median age, 14.1 years; median prior regimens, two) received 84 courses. Predominant diagnoses were neuroblastoma (n = 5), osteosarcoma (n = 5), and rhabdomyosarcoma (n = 4). The dose-limiting toxicity was grade 3/4 diarrhea and/or abdominal cramps in six of 12 patients treated at 24 mg/m2, despite aggressive use of loperamide. The maximum-tolerated dose (MTD) on this schedule was 20 mg/m2/d. Five patients had partial responses and 16 had disease stabilization. On day 1, the median systemic exposure to SN-38 (the active metabolite of irinotecan) at the MTD was 106 ng-h/mL (range, 41 to 421 ng-h/mL). CONCLUSION: This protracted schedule is well tolerated in children. The absence of significant myelosuppression and encouraging clinical responses suggest compellingly that irinotecan be further evaluated in children using the (qd × 5) × 2 schedule, beginning at a dose of 20 mg/m2. These results imply that data obtained from xenograft models can be effectively integrated into the design of clinical trials.